NEPHSAP - Renal Pathology Cases

Volume 10 • Number 4 • July 2011
NephSAP
®
Nephrology Self-Assessment Program
Renal Pathology
Guest Co-Editors:
Glen S. Markowitz, MD,
M. Barry Stokes, MD,
Neeraja Kambham, MD,
Leal C. Herlitz, MD, and
Vivette D. D’Agati, MD
■ Editor-in-Chief: Stanley Goldfarb, MD
■ Deputy Editor: Raymond R. Townsend, MD
NephSAP
®
EDITOR-IN-CHIEF
Stanley Goldfarb, MD
University of Pennsylvania Medical School
Preface
Philadelphia, PA NephSAP® is one of the three major publications of the American Society of Nephrology
(ASN). Its primary goals are self-assessment, education, and the provision of Continuing
DEPUTY EDITOR Medical Education (CME) credits and Maintenance of Certification (MOC) credits for
Raymond R. Townsend, MD individuals certified by the American Board of Internal Medicine. Members of the ASN
University of Pennsylvania Medical School
Philadelphia, PA
automatically receive NephSAP with their monthly issue of The Journal of the American
Society of Nephrology (JASN).
MANAGING EDITOR
EDUCATION: Medical and Nephrologic information continually accrues at a rapid pace.
Gisela Deuter, BSN, MSA
Washington, DC
Bombarded from all sides with demands on their time, busy practitioners, academicians, and
trainees at all levels are increasingly challenged to review and understand all this new material.
ASSOCIATE EDITORS Each bimonthly issue of NephSAP is dedicated to a specific theme, i.e., to a specific area
Rajiv Agarwal, MD of clinical nephrology, hypertension, dialysis, and transplantation, and consists of an Editorial,
Indiana University School of Medicine a Syllabus, a Commentary on the Syllabus, and self-assessment questions. Over the course of
Indianapolis, IN
24 months, all clinically relevant and key elements of nephrology will be reviewed and updated.
David J. Cohen, MD
The authors of each issue digest, assimilate, and interpret key publications from the previous
Columbia University
New York, NY issues of other years and integrate this new material with the body of existing information.
Michael J. Choi, MD SELF-ASSESSMENT: Twenty-five single-best-answer questions will follow the 50 to 75 pages
Johns Hopkins University School of Medicine
Baltimore, MD
of Syllabus text. The examination is available online with immediate feedback. Those answer-
Michael Emmett, MD ing ⬎75% correctly will receive CME credit, and receive the answers to all the questions along
Baylor University with brief discussions and an updated bibliography. To help answer the questions, readers may
Dallas, TX go to the ASN web site, where relevant material from UpToDate in nephrology will be posted.
Linda F. Fried, MD, MPH Thus, members will find a new area reviewed every 2 months, and they will be able to test their
University of Pittsburgh understanding with our quiz. This format will help readers stay abreast of developing areas of
Pittsburgh, PA
clinical nephrology, hypertension, dialysis, and transplantation, and the review and update will
Richard J. Glassock, MD
Professor Emeritus, The David Geffen School
support those taking certification and recertification examinations.
of Medicine at the University of California CONTINUING MEDICAL EDUCATION: Most state and local medical agencies as well as
Los Angeles, CA
hospitals are demanding documentation of requisite CME credits for licensure and for staff
Kathleen D. Liu, MD
University of California San Francisco appointments. A maximum of 48 credits annually can be obtained by successfully completing
San Francisco, CA the NephSAP examination. In addition, individuals certified by the American Board of Internal
Kevin J. Martin, MBBCh Medicine may obtain credits towards Maintenance of Certification (MOC) by successfully
St. Louis University School of Medicine completing the self-assessment portion of NephSAP.
St. Louis, MO
Rajnish Mehrotra, MD BOARD CERTIFICATION AND INSERVICE EXAMINATION PREPARATION: Each issue
Harbor UCLA Research and Education Institute will also contain 5 questions and answers examining core topics in the particular discipline
Torrance, CA reviewed in the Syllabus. These questions are designed to provide trainees with challenging
Patrick T. Murray, MD questions to test their knowledge of key areas of nephrology.
University College Dublin
Dublin, Ireland ⬁ This paper meets the requirements of ANSI/NISO Z39.48-1921 (Permanence of Paper),
Patrick H. Nachman, MD effective with July 2002, Vol. 1, No. 1.
University of North Carolina
Chapel Hill, NC GUEST CO-EDITORS
Aldo J. Peixoto, MD
Yale University Vivette D. D’Agati, MD Glen S. Markowitz, MD
West Haven, CT Columbia University Medical Center Columbia University Medical Center
New York, NY New York, NY
Richard H. Sterns, MD
University of Rochester School of Medicine Leal C. Herlitz, MD M. Barry Stokes, MD
and Dentistry Columbia University Medical Center Columbia University Medical Center
Rochester, NY New York, NY New York, NY
John P. Vella, MD
Neeraja Kambham, MD
Maine Medical Center
Portland, ME Stanford University School of Medicine
Stanford, CA
FOUNDING EDITORS
Richard J. Glassock, MD, MACP
Editor-in-Chief Emeritus NephSAP®
Robert G. Narins, MD, MACP ©2011 by The American Society of Nephrology
NephSAP
®
Volume 10, Number 4, July 2011
Renal Pathology
Editorial 271
Problem-based learning- A new approach for NephSAP—
Ronald J. Falk, MD
Syllabus 272
Learning Objectives—
Glen S. Markowitz, MD, M. Barry Stokes, MD,
Neeraja Kambham, MD, Leal C. Herlitz, MD, and
Vivette D. D’Agati, MD
Section 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .273
Section 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .279
Section 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .285
Section 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .291
Section 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .297
Section 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .305
Section 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .311
Section 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .317
Section 9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .323
Section 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .329
Section 11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .335
Section 12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .341
Section 13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .347
Section 14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .353
Section 15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .359
Section 16 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .367
NephSAP
®
Section 17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .373
Section 18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .379
Section 19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .385
Section 20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .393
Section 21 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .401
Section 22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .407
CME Self-Assessment Questions . . . . . . . . . . . . . . . . . . . . . 415

Questions Linked to UpToDate in Green
Reverse Table of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . 422

NephSAP
®
Upcoming Issues
Chronic Kidney Disease and Progression—
Linda F. Fried, MD, and Michael J. Choi, MD . . . . . . .September 2011
Transplantation—
John P. Vella, MD, and David J. Cohen, MD . . . . . . . .November 2011
Pediatric Nephrology—
Howard Trachtman, MD, and Debbie Gipson, MD . . . . . .January 2012
Hypertension—
Raymond R. Townsend, MD, and Aldo J. Piexoto, MD . . . .March 2012
Glomerular, Vascular, and Tubulointerstital Diseases—

Richard J. Glassock, MD, and Patrick Nachman, MD . . . . . .May 2012
Diabetic Nephropathy—
Kumar Sharma, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . .July 2012
Renal Bone Disease, Disorders of Divalent Ions, and

Nephrolithiasis—
Stanley Goldfarb, MD and Kevin Martin, MBBCh . . . . .September 2012
End-Stage Disease and Dialysis—

Rajnish Mehrotra, MD and Rajiv Agarwal, MD . . . . .November 2012
NephSAP
®
The Editorial Board of NephSAP extends its sincere appreciation to the following reviewers. Their efforts and insights have helped to
improve the quality of this postgraduate education offering.
NephSAP Review Panel
Nihal Y. Abosaif, MBBCh Rajiv Dhamija, MD Pranay Kathuria, MD, FASN
St. James University Hospital Walk in Medical Care University of Oklahoma College of Medicine
Leeds, United Kingdom Artesia, CA Tulsa, OK
Georgi Abraham, MBBS Susan R. DiGiovanni, MD Quresh T. Khairullah, MD, FASN
Pondicherry Institute of Medical Sciences Virginia Commonwealth University St. Clair Specialty Physicians
Madras Medical Mission Richmond, VA Detroit, MI
Chennai, India
Francis Dumler, MD Apurv Khanna, MD
Pablo H. Abrego, MD, FASN William Beaumont Hospital SUNY Upstate Medical University
Marshfield Clinic Royal Oak, MI Syracuse, NY
Wausau, WI
Mahmoud T. El-Khatib, MD, PhD, FASN Ramesh Khanna, MD
Anil K. Agarwal, MD, FASN University of Cincinnati Medical Center University of Missouri at Columbia
Ohio State University Medical Center Cincinnati, OH School of Medicine
Columbus, OH Columbia, MO
Lynda A. Frassetto, MD, FASN
Mustafa Ahmad, MD University of California at San Francisco Edgar V. Lerma, MD, FASN
King Fahad Medical City San Francisco, CA University of Illinois at Chicago
Riyadh, Saudi Arabia College of Medicine
Duvuru Geetha, MD
Chicago, IL
Jafar Al-Said, MD, FASN Johns Hopkins University
Bahrain Specialist Hospital Baltimore, MD Meyer D. Lifschitz, MD
Manama, Bahrain Shaare Zedek Medical Center
Carl S. Goldstein, MD
Jerusalem, Israel
Dante Amato-Martinez, MD, PhD Robert Wood Johnson Medical School
Universidad Nacional Autónoma de México New Brunswick, NJ Philippe S. Madhoun, MD
Tlalnepantla, Mexico Chu Charleroi
Nabil G. Guirguis, MD
Charleroi, Belgium
Anis U. Ansari, MD Kidney Dialysis and Transplant Group
Medical Associates Bridgeport, WV Jolanta Malyszko, MD, PhD, FASN
Clinton, IA Medical University
Pawan K. Gupta, MD
Bialystok, Poland
Akhtar Ashfaq, MD, FASN Altoona Regional Health System
North Shore University Hospital Altoona, PA Naveed N. Masani, MD
Great Neck, NY Winthrop University Hospital
Carsten Hafer, MD
Mineola, NY
Azra Bihorac, MD, FASN University of Hannover
University of Florida Hannover, Germany Hanna W. Mawad, MD, FASN
Gainesville, FL University of Kentucky Medical Center
Richard N. Hellman, MD
Lexington, KY
Mona B. Brake, MD Indiana University School of Medicine
Robert J. Dole VA Medical Center Indianapolis, IN Pascal Meier, MD, FASN
Wichita, KS Centre Hospitalier Universitaire Vaudois
Ekambaram M. Ilamathi, MD, FASN
Lausanne, Switzerland
Mauro Braun, MD Suffolk Nephrology Consultants
Cleveland Clinic Florida Stony Brook, NY Beckie Michael, DO, FASN
Weston, FL Marlton Nephrology and Hypertension
Viswanathan S. Iyer, MD, FASN
Marlton, NJ
Chokchai Chareandee, MD, FASN AKD-HTN LLC
Regions Hospital Harrisburg, PA Shahriar Moossavi, MD, PhD
Saint Paul, MN Wake Forest University Baptist
Bernard G. Jaar, MD
Medical Center
W. James Chon, MD, FASN Johns Hopkins Medical Institutions and
Winston-Salem, NC
University of Chicago Medical Center Nephrology Center of Maryland
Chicago, IL Baltimore, MD Scott R. Mullaney, MD
University of California at San Diego
Devasmita Choudhury, MD Avanelle V. Jack, MD
San Diego, CA
University of Texas Southwestern Louisiana State University Health
Medical School Sciences Center Quaid J. Nadri, MD, FASN
Dallas, TX New Orleans, LA King Faisal Specialist Hospital and
Research Center
Bulent Cuhaci, MD, FASN Sharon L. Karp, MD
Riiyadh, Saudi Arabia
Drexel University College of Medicine Indiana University School of Medicine
Philadelphia, PA Indianapolis, IN
Suzanne M. Norby, MD, FASN Karthik M. Ranganna, MD Robert J. Shay, MD, FASN
Mayo Clinic Drexel University College of Medicine East Georgia Kidney and
Rochester, MN Philadelphia, PA Hypertension Group
Augusta, GA
Michal Nowicki, MD Pawan K. Rao, MD, FASN
Medical University of Łódź St. Joseph’s Hospital Health Center Bhupinder Singh, MD, FASN
Łódź, Poland Syracuse, NY Southwest Kidney Institute
Tempe, AZ
Macaulay A. Onuigbo, MD, FASN Joel C. Reynolds, MD, FASN
Mayo Clinic Brooke Army Medical Center Rolf A.K. Stahl, MD
Eau Claire, WI San Antonio, TX University of Hamburg
Hamburg, Germany
Than N. Oo, MD Robert M.A. Richardson, MD
Nephrology Center University of Toronto Harold M. Szerlip, MD, FASN
Kalamazoo, MI Toronto, ON, Canada Medical College of Georgia
Augusta, GA
Kevin P. O’Reilly, MD Bijan Roshan, MD
Columbus Nephrology, Inc. Joslin Diabetes Center Bekir Tanriover, MD
Columbus, OH Harvard Medical School Dialysis Nephrology Associates
Boston, MA Dallas, TX
Malvinder S. Parmar, MB, MS, FASN
Northern Ontario School of Medicine Abinash C. Roy, MD Tushar J. Vachharajani, MD, FASN
Timmins, ON, Canada University of Utah School of Medicine Wake Forest University
Saint George, UT School of Medicine
Pairach Pintavorn, MD, FASN
Winston-Salem, NC
East Georgia Kidney and Hypertension Mario F Rubin, MD
Augusta, GA Massachusetts General Hospital Allen W. Vander, MD, FASN
Boston, MA Kidney Center of South Louisiana
Paul H. Pronovost, MD, FASN
Thibodaux, LA
Yale University School of Medicine Ehab R. Saad, MD, FASN
Waterbury, CA Medical College of Wisconsin Luigi Vernaglione, MD
Milwaukee, WI M. Giannuzzi Hospital
Mohammad A. Quasem, MD, FASN
Manduria, Italy
State University of New York Mohammad G. Saklayen, MD
Binghamton, NY Wright State University Medical School Shefali Vyas, MD
Dayton, OH Saint Barnabas Medical Center
Wajeh Y. Qunibi, MD
Livingston, NJ
University of Texas Health Sciences Center Ramesh Saxena, MD, PhD
San Antonio, TX University of Texas Southwestern Alexander Woywodt, MD, FASN
Medical Center Lancashire Teaching Hospitals NHS
Venkat Ramanathan, MD, FASN
Dallas, TX Foundation Trust
Baylor College of Medicine
Preston, United Kingdom
Houston, TX Gaurang M. Shah, MD
Long Beach VA Healthcare System
Long Beach, CA
NephSAP
®
Program Mission and Objectives

The mission of the Nephrology Self-Assessment Program (NephSAP) is to regularly provide a vehicle that will be useful for clinical
nephrologists who seek to renew and refresh their clinical knowledge and diagnostic and therapeutic skills. This Journal consists of a
series of challenging, clinically oriented questions based on case vignettes, a detailed Syllabus that reviews recent publications,
and an Editorial on an important and evolving topic. Taken together, these parts should assist individual clinicians under-
taking a rigorous self-assessment of their strengths and weaknesses in the broad domain of nephrology.
Accreditation and Credit Designation

The American Society of Nephrology is accredited by the Accreditation Council for Continuing Medical Education to provide con-
tinuing medical education for physicians.
The ASN designates this journal-based activity for a maximum of 12AMAPRA&ategory Credits™. Physicians should claim
only the credit commensurate with the extent of their participation in the activity.
Continuing Medical Education (CME) Information

CME Credit: 12.0 AMA PRA Category 1 Credits™
Date of Original Release: July 2011
Examination Available Online: on or before Monday, July 18, 2011
Audio Files Available: There are no audio files for this issue.
CME Credit Eligible Through: June 30, 2012
Answers: Correct answers with explanations will be posted on the ASN website in July 2012 when the issue is archived.
UpToDate Links Active: July and August 2011
Core Nephrology question links active: No core questions for this issue
Target Audience: Nephrology Board and recertification candidates, practicing nephrologists, and internists.
Method of Participation:
● Read the syllabus that is supplemented by original articles in the reference lists, and complete the online self-assessment
examination.
● Examinations are available online only after the first week of the publication month. There is no fee. Each participant is
allowed two attempts to pass the examination (⬎75% correct) for CME credit.
● Upon completion, review your score and incorrect answers.
● Your CME certificate can be printed immediately after completion.
● Answers and explanations are provided with a passing score and/or after the second attempt.
● CME Credit will be posted to your transcript within 48 hours after checking the attestation box.
Instructions to access the Online Examination and Evaluation:
● Go to the ASN website: www.asn-online.org.
● Click the CME tab at the top of the homepage.
● Click the ASN CME Center button on the left side of the page.
● Click on to the ASN CME Center icon.
● Login to the ASN website.
● Select Claim Credits for the NephSAP topic-activity you would like to complete.
● Complete the NephSAP examination.
● Complete the evaluation.
● Enter the number of CME credits commensurate with your participation in the activity.
● Check the box attesting that you have completed this activity.
● You can print your CME certificate immediately.
● CME credit will be posted to your transcript within 48 hours.
● View or print your full transcript anytime at “My CME Center.”
NephSAP
®
Instructions to Obtain American Board of Internal Medicine (ABIM) Maintenance of Certification

(MOC) Points:
Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria:
● Be certified by ABIM in internal medicine and/or nephrology and must be enrolled in the ABIM–MOC program
via the ABIM website (www.abim.org).
● Take the self-assessment examination within the timeframe specified in this issue of NephSAP.
● Designate the issue for MOC points by clicking on the MOC link on the CME certificate page after passing the examination.
You will be leaving the ASN site and transferring the information directly to the ABIM in real-time.
● Provide your ABIM Certificate ID number and your date of birth.
● You will receive a confirmation message from the ABIM indicating the receipt of your information.
MOC points will be applied to only those ABIM candidates who have enrolled in the program. It is your responsibility to complete
the ABIM MOC enrollment process.
Instructions to access the ASN website, NephSAP, and the UpToDate link
Compatible Browser: The ASN website (asn-online.org) has been formatted for cross-browser functionality, and should
display correctly in all modern web browsers. We recommend that you use Internet Explorer.
Monitor Settings: The ASN website was designed to be viewed in a 1024 ⫻ 768 or higher resolution.
Technical Support: If you are having difficulty viewing any of the pages, please refer to the ASN technical support page
for possible solutions. If you continue having problems, contact Hal Nesbitt at [email protected].
UpToDate provides an additional source of information that should help you answer up to 5 selected NephSAP
questions from each issue. The link is free and will remain active for the first 60 days after publication for each
issue.
● On the ASN home page, double click on the NephSAP link (NephSAP cover) on the bottom side of the page.
● On the NephSAP page, click on the UpToDate button on the left hand side to access the current links.
NephSAP
®
Disclosure Information
The ASN is responsible for identifying and resolving all conflicts of interest prior to presenting any educational activity to learners to ensure that
ASN CME activities promote quality and safety, are effective in improving medical practice, are based on valid contents, and are independent of the
control from commercial interests and free of commercial bias. All faculty are instructed to provide balanced, scientifically rigorous and evidence-
based presentations. In accordance with the disclosure policies of the Accreditation Council for Continuing Medical Education (ACCME) as well as
guidelines of the Food and Drug Administration (FDA), individuals who are in a position to control the content of an educational activity are re-
quired to disclose relationships with a commercial interest if (a) the relation is financial and occurred within the past 12 months; and (b) the individ-
ual had the opportunity to affect the content of continuing medical education with regard to that commercial interest. For this purpose, ASN consider
the relationships of the person involved in the CME activity to include financial relationships of a spouse or partner. Peer reviewers are asked to
abstain from reviewing topics if they have a conflict of interest. Disclosure information is made available to learners prior to the start of any ASN
educational activity.
Agarwal, Rajiv—Research funding: Abbott; Consultant/scientific advisor: Rockwell Medical, Watson Pharma; Honoraria: Abbott, Astra-Zeneca, Merck
Cohen, David J.—Research funding: Life Cycle Pharma, Novartis, Roche, Wyeth; Honoraria: Bristol-Myers-Squibb, Novartis, Roche
Emmett, Michael—Honoraria: Braintree Laboratories Fresenuis; Editorial board membership: American Journal of Cardiology, Clinical
Nephrology
Fried, Linda F.—Research funding: Merck, Reata; Honoraria: Pfizer
Fuchs, Elissa (Medical Editor)—none
Glassock, Richard J.—Consultant: Bio-Marin (inactive), Eli Lilly (active), FibroGen (inactive), Genentech (active), Lighthouse Learning (active),
Novartis (active), QuestCor (active), Wyeth (inactive); Ownership interests: LaJolla Pharmaceutical, Reata Inc.; Honoraria: American Society of
Nephrology, various medical schools for lectures and/or visiting professor; Membership board of directors/scientific advisor: American Renal
Associates, Los Angeles Biomedical Institute, University Kidney Research Associates (UKRO), Wyeth; Editorial board: UpToDate, American
Journal of Nephrology; Royalties: Oxford University Press; Paid expert testimony: Various legal firms regarding product liability
Goldfarb, Stanley—Consultant: Marval Scientific; Honoraria: GE Healthcare, Fresenius; Editorial board: Clinical Nephrology.
Liu, Kathleen D.—Ownership interest: Amgen; Honoraria: University of Virginia; Editorial board: Advances in Chronic Kidney Disease;
Other relationship: two biomarker studies, Abbott, CMIC.
Martin, Kevin J.—Consultant: Abbott, Cytochroma, Kai, Shire; Honoraria: Abbott, Genzyme, Kai, Shire; Scientific advisor: Abbott,
Cytochroma, Kai
Mehrotra, Rajnish—Research funding: Amgen, Baxter, Shire; Consultant: Novartis; Honoraria: AMAG, Baxter, Healthcare Shire
Murray, Patrick T.—Employment: spouse, Merck, Sharpe, & Dohme (Europe); Consultant: FAST Diagnostics (USA); Research funding:
Abbott, Alere, Argutus Medical; Honoraria: Sanofi Aventis; Editorial board: Clinical Journal of the American Society of Nephrology.
Nachman, Patrick H.—Honoraria: QuestCor; Multicenter clinical trial participation: Otsuka
Peixoto, Aldo J.—Consultant: Abbott, Sanofi-Aventis; Research funding: Pulsemetric; Honoraria: Boehringer-Ingelheim, Merck, Novartis,
Takeda; Scientific advisor/membership: Associate Editor–Blood Pressure Monitoring; Editorial Board: American Journal of Nephrology,
Brazilian Journal of Nephrology
Sterns, Richard H.—Honoraria: Astellas, Otsuka, Merck
Townsend, Raymond R.—Consultant: Daiichi-Sankyo, GlaxoSmithKline, Merck, Nicox, Novartis, Roche; Research funding: Novartis;
Honoraria: American Society of Hypertension, National Kidney Foundation
Vella, John P.—none
Editorial author:
Falk, Ronald J.—none
Guest Co-editors:
D’Agati, Vivette D.—none
Herlitz, Leal C.—none
Kambham, Neeraja—none
Markowitz, Glen S.—Consultant: Salix Pharmaceutical; Honoraria: Genzyme
Stokes, M. Barry—none
Commercial Support
There is no commercial support for this issue.
Nephrology Self-Assessment Program - Vol 10, No 4, July 2011
Editorial
Problem-based learning- A new approach for NephSAP
Ronald J. Falk, MD
Department of Medicine, Division of Nephrology, University of North Carolina, Chapel Hill,
Chapel Hill, North Carolina
Optimally, problem-based learning simulates au- the accumulated evidence. The questions mimic Ameri-
thentic cases found in the practice of clinical medicine. can Board of Internal Medicine questions found on initial
This approach to learning promotes analytical and eval- or recertification exams.
uative thinking while emphasizing new information es- In reality, kidney biopsy conferences that use prob-
sential for understanding complex concepts. In nephrol- lem-based learning as their base are, in fact, examples of
ogy, it has been nephropathologists who have, by the “team-based learning.” Ideally, cases are not just de-
very nature of their craft, promoted and refined problem- scribed by the clinician and displayed by the pathologist
based learning. Many of us who became passionate about but also ignite lively discourse between experienced
glomerular diseases were introduced to the subject during physicians from multiple disciplines, each pushing the
engaging kidney biopsy conferences. There, the clinician other to hone in on specific clinical or pathologic detail,
presented a complex clinical scenario and the nephro- pathogenic considerations, and analysis of how best to
pathologist would reveal the captivating, dynamic im- manage the patient. In medical schools, problem-based
ages of glomerular, vascular, or tubulointerstitial com- learning has evolved into team-based learning to better
partments ravaged by a disease process. Typically, the emulate collaborative patient management. Groups of
nephropathologist artfully unfolded the diagnosis using students optimize learning when each member explores
images of light, immunofluorescence, and electron mi- different aspects of the presenting problem. The group
croscopy only after inviting a trainee to describe the must reach consensus on specific patient management
pathology, provide a differential diagnosis, and suggest a decisions and then articulate the justification of their
diagnosis. The case provided a springboard for the as- decision to the other students. Team-based learning is a
sembled cognoscenti to wax eloquent on the nature of the practical and highly effective learning strategy that max-
disease process, its natural history, and potential therapy. imizes active learning in the context of authentic clinical
The treating clinician was energized by these events and challenges. It also accommodates the best of didactic
gained a better understanding of a particular patient’s instruction where critical information is gained; expert
disease and optimal therapy. Kidney biopsy conferences insights or “pearls” are shared, collectively providing
remain wonderful examples of problem-based learning opportunities for learners to exercise critical thinking and
where clinical and pathologic correlations are illumi- evidence-based, decision-making skills to solve intrigu-
nated, new understandings of disease considered, and ing and complex clinical scenarios.
patient care improved. All of these NephSAP cases will be available on the
In this issue of NephSAP, Dr. Markowitz and col- American Society of Nephrology website and download-
leagues have recreated a virtual kidney biopsy confer- able for group discussion or team-based learning. One
ence. Using a problem-based learning approach, 22 cases can readily imagine these cases as the basis of a virtual
are presented spanning the spectrum of glomerular dis- kidney biopsy conference and an excellent resource
ease with varying degrees of diagnostic difficulty. A for nephrology trainees and for those in practice who
clinical vignette is followed by artfully displayed pa- wish to “revisit” their understanding of glomerular
thology. The critical question is asked: “What is the disease or plan to take recertifying exams. This edition
diagnosis?” The rationale for the consensus answer is of NephSAP provides an alternative approach to learn-
considered and then a succinct, well-referenced, state-of- ing that differs from that which NephSAP readers have
the-art discussion ensues. The learner can readily appre- come to expect. Periodic change is refreshing, and one
ciate the clinicopathological correlates and frame the can imagine this format will be used in other spheres
question as to how best to manage the patient based on of nephrology.
271
Syllabus
Learning Objectives
Glen S. Markowitz, MD*, M. Barry Stokes, MD*, Neeraja Kambham, MD†,
Leal C. Herlitz, MD*, and Vivette D. D’Agati, MD*
*Department of Pathology & Cell Biology, Columbia University Medical Center and the
New York Presbyterian Hospital, New York, New York; and †Department of Pathology,
Stanford University School of Medicine, Stanford, California
1. To recognize the light microscopic, immunofluo- pathologic findings and pathogenesis, briefly touched
rescence, and ultrastructural findings in the most on clinical presentation, and avoided the topic of
common forms of glomerular disease. treatment. At the end of the last section on page 422,
2. To discuss recent advances in the pathogenesis of we provide a reverse table of contents that will
glomerular, tubulointerstitial, and vascular dis- allow the reader to look up specific diseases of
eases. interest.
3. To examine the most common secondary etiolo- The first four authors of this issue of NephSAP
gies of the major patterns of glomerular disease. share the great fortune of having been trained and/or
4. To formulate a differential diagnosis based on
mentored by our senior author, Vivette D’Agati. So
integration of clinical and pathologic findings in
much emphasis is placed on the founders of the field
medical renal disease.
of renal pathology, and yet not enough is placed on the
This issue of NephSAP is the first to cover the
individuals who have brought us into the modern era.
topic of renal pathology. In putting this together, we
There is no better example than Vivette, who has been
were given the freedom to create a unique format.
Each of the 22 sections in this issue begins with a instrumental in refining the pathologic classification of
clinical history and a set of renal biopsy images; the numerous medical renal diseases, in defining new
reader is then asked to determine the diagnosis. The disease entities, and in continuously providing insights
following page provides the reasoning behind the di- into disease pathogenesis. We wish to dedicate this
agnosis, followed by a discussion of the disease entity. issue to Dr. D’Agati, an unusual decision considering
We chose this format because it has been our experi- that she is the senior author. As in the many other
ence that renal pathology is learned best by clinical- projects we have undertaken jointly, Vivette selflessly
pathologic correlation. In an effort not to overlap with poured her energy into this project and brought it to a
the outstanding NephSAP on “Glomerular, Vascular, significantly higher level. She has been and continues
and Tubulointerstitial Diseases” written by Patrick to be a role model, knowing no limits when it comes
Nachman and Richard Glassock, we focused on renal to the pursuit of excellence.
272
Section 1: CASE PRESENTATION 100 mmHg, 2⫹ pitting edema of the lower extremities, and a
weight of 273 lb. The patient had a creatinine level of 0.82
A 54-year-old African-American woman presents with full mg/dl and bland urine sediment. All serologies were negative
nephrotic syndrome including 24-hour urine protein of 5.8 g, or normal including anti-nuclear antibody, anti-DNA antibody,
serum albumin of 2.2 g/dl, edema, and a recent 25-lb weight hepatitis B surface antigen (HbsAg), hepatitis C antibody,
gain. Past medical history was significant for hypertension for anti-neutrophil cytoplasmic antibody (ANCA), rheumatoid
20 years, arthritis of the knees for which she had been treated factor, C3, and C4. There was no evidence of a monoclonal
with nonsteroidal anti-inflammatory drugs (NSAIDs), and serum or urine spike. Initial treatment consisted of discontin-
morbid obesity. Her medications included meloxicam, hydro- uation of meloxicam and the addition of an angiotensin recep-
chlorothiazide, lisinopril, lovastatin, and propoxyphene with tor blocker. Two months later, the patient’s nephrotic param-
acetaminophen. Physical examination revealed a BP of 140/ eters remained unchanged. Renal biopsy was performed.
Figure 1. Figure 2.
Figure 4.
Figure 3. IgG
What is the BEST diagnosis?

A. FSGS
B. Membranoproliferative glomerulonephritis
C. Minimal change disease
D. Membranous nephropathy (MN)
E. Fibrillary glomerulonephritis
273
274 Nephrology Self-Assessment Program - Vol 10, No 4, July 2011
Answer HbsAg, and hepatitis C virus antibody studies. Workup for

The renal biopsy findings are diagnostic of mem- malignancy is also warranted, with the extent of test-
branous nephropathy (MN). Figure 1 shows a glomerulus ing in part guided by the patient’s age and whether
of normal size and cellularity. The major abnormality by there is a history of tobacco use (3).
light microscopy is mild thickening of the glomerular
basement membranes (GBMs). Jones methenamine silver Pathology
stain demonstrates characteristic projections (“spikes”) of
Light Microscopy. In MN, glomeruli range from
basement membrane material perpendicular to the
normal in size to enlarged and appear normocellular
GBM (Figure 2). Immunofluorescence reveals 3⫹
with patent capillary lumina (Figure 1). The most
intensity granular global capillary wall positivity for
distinctive light microscopic finding is GBM thicken-
IgG (Figure 3). Similar staining was seen for ␬ and ␭
ing, which is due to the presence of spike formation
light chains. There was 1⫹ granular staining for C3 between the subepithelial immune deposits (Figure 2).
with negative C1q (data not shown). No immune The GBM spikes project toward the urinary space,
deposits were identified in the mesangium, tubular are the classic diagnostic light microscopic feature
basement membranes, or vessel walls. Global subepi- of MN, and are best seen with Jones methenamine
thelial electron-dense deposits and intervening spikes silver and periodic acid–Schiff stains. Trichrome
of basement membrane material are identified by elec- stain may be helpful in demonstrating red-staining
tron microscopy (Figure 4). The podocyte foot pro- (fuchsinophilic) immune deposits between the blue-
cesses are extensively effaced. On the basis of the staining GBM spikes. Glomerular intracapillary fi-
pathologic findings, negative serologies, and the ab- brin thrombi may occasionally be encountered; be-
sence of remission after NSAID withdrawal, a diag- cause their presence suggests a hypercoagulable state,
nosis of primary MN was favored. the possibility of renal vein thrombosis should be
excluded. Crescents are rarely seen and when identi-
Membranous Nephropathy fied should prompt testing for anti-GBM antibodies
MN is commonly regarded as the most common and ANCA (4,5) as well as systemic lupus erythema-
cause of nephrotic syndrome in Caucasian adults. MN tosus. Proximal tubules usually contain lipid and pro-
is defined by the presence of subepithelial immune tein resorption droplets and may exhibit significant
deposits leading to a spectrum of glomerular capillary degenerative changes, particularly in the setting of
wall alterations, most typically the formation of inter- severe and unrelenting proteinuria. Over time, chronic
vening “GBM spikes.” MN can be divided into pri- tubulointerstitial scarring may ensue, and the degree of
mary and secondary forms. Primary MN is regarded as tubular atrophy and interstitial fibrosis is often consid-
the prototypic glomerular disease mediated by in situ ered a prognostic marker in patients with MN. Inter-
immune complex formation. A pattern of MN can also stitial foam cells also may develop, particularly in
occur secondary to autoimmune disease, neoplasia, patients with longstanding heavy proteinuria.
infection, and exposure to certain therapeutic agents.
Immunofluorescence. The subepithelial deposits
Clinical Characteristics of MN stain dominantly for IgG (Figure 3), with lower
The defining clinical feature of MN is protein- intensity for C3 and similar intensity for ␬ and ␭.
uria, and the majority of patients have full nephrotic Lesser intensity positivity for IgM, IgA, or C1q may
syndrome (1,2). At the time of presentation, most occur in a minority of cases.
patients have normal renal function, and approxi- Electron Microscopy. Subepithelial electron-dense
mately half have microhematuria. MN is most com- deposits are the characteristic ultrastructural finding.
mon in Caucasian individuals and adults, is rare in The evolution of the deposits and corresponding GBM
infants and young children, and exhibits a male:female alterations pass through four stages, as originally de-
ratio of approximately 2:1. In contrast to primary MN, fined by Ehrenreich and Churg (6). Stage 1 MN is
secondary forms of MN are most commonly encoun- defined by small and sparse subepithelial deposits.
tered in young children and in individuals who are These may indent the GBM, but there are no spikes. At
older than 60 years. Serologic evaluation of all pa- the light microscopic level, glomeruli in stage 1 MN
tients with MN should include anti-nuclear antibody, appear unremarkable or show only subtle abnormali-
Nephrology Self-Assessment Program - Vol 10, No 4, July 2011 275
ties. Slight vacuolization of the GBM may be demon- or stage 3, and multiple stages can coexist in a single
strable with silver stain, and minute trichrome-red biopsy or even a single glomerulus.
deposits may be visible on high power. The GBM is
usually normal in thickness, although it may appear Clinical-Pathologic Correlation
rigid with associated podocyte swelling. Stage 2 MN Multiple pathologic findings have been reported
is the most frequently encountered in biopsy practice to predict reduced renal survival in MN, including the
and is characterized by global subepithelial deposits degree of tubular atrophy and interstitial fibrosis, the
separated by intervening projections of the GBM, development of segmental glomerulosclerosis (7,8),
referred to as “GBM spikes.” In stage 3, the subepi- the intensity of complement deposition by immuno-
thelial deposits and GBM spikes become covered and fluorescence (9,10), and the presence of deposits in
enclosed by overlying neomembrane formation, pro- multiple stages (“heterogeneous deposits”) (11). Al-
ducing chain-like thickenings (Figure 5). By stage 4, though these pathologic findings may be associated
the deposits have been incorporated into an irregularly with a worse prognosis, they do not appear to predict
thickened GBM. In stage 4 and, to a lesser extent, clinical outcomes independent of baseline clinical
stage 3, deposits become more electron lucent as variables (10).
they undergo resorption. In some cases of stage 4
MN, deposits are no longer visible, making it diffi- Secondary Forms of MN
Secondary forms of MN, which represent ap-
cult to establish a definitive diagnosis of MN.
proximately 25% of cases (12), fall into four main
Importantly, the Ehrenreich & Churg staging of
categories. First and foremost, MN may occur second-
MN provides a useful framework to understand the
ary to autoimmune/collagen vascular diseases, most
process of subepithelial deposit formation and incor-
notably systemic lupus erythematosus (i.e., “membra-
poration into the GBM, but its clinical relevance is
nous lupus nephritis”) but also rheumatoid arthritis,
limited because there is no good correlation with the
Sjögren syndrome, mixed connective tissue disease,
degree of proteinuria, renal function, or prognosis. sarcoidosis, Grave disease, and Hashimoto thyroiditis.
Furthermore, “progression” from one stage to another Second, MN may be associated with malignancy, most
(e.g., stage 2 to stage 3) can be associated with commonly carcinomas of the lung, prostate, breast,
improvement or worsening of proteinuria. In clinical and gastrointestinal tract (3,13,14). A recent study
practice, more than 80% of cases of MN are in stage 2 from France found that 10% of adult patients with MN
had evidence of malignancy, which was often occult at
the time of renal biopsy. Malignancy was more com-
mon in patients with MN who were older than 60 years
and had a history of significant tobacco use, suggest-
ing an increased need for screening in this population
(3,12). Multiple therapeutic agents have been impli-
cated in the development of MN, including gold,
penicillamine, multiple NSAIDs, COX-2 inhibitors,
and captopril. Infectious causes of MN include hepa-
titis B, hepatitis C, syphilis, and multiple parasites.
Primary MN typically reveals isolated subepithe-
lial immune deposits that stain predominantly for IgG.
Any deviations from this pathologic picture should
suggest a possible secondary form of disease. For
Figure 5. A case of stage 3 MN exhibits complex thickening instance, mesangial or endocapillary proliferation, de-
of the glomerular capillary walls by subepithelial and in- posits at other sites (e.g., mesangial, subendothelial,
tramembranous deposits ranging from electron dense to tubular basement membranes, vessel walls), the im-
electron lucent. Most of the deposits are separated by spikes
and incorporated into the GBM by an overlying new layer
munofluorescence finding of a “full house” of staining
of basement membrane material. The foot processes are for immunoglobulins (IgG, IgM, and IgA) and com-
diffusely effaced. Magnification, ⫻2500. plement (C3 and C1q), and the ultrastructural finding
of endothelial tubuloreticular inclusions favor a sec- Gp330/megalin antibodies generated against tubular
ondary form of MN, in particular membranous lupus brush border antigen cross-react with Gp330 ex-
nephritis (12) (Figure 6). An exception to this rule is pressed on the soles of podocyte foot processes. In this
neoplasia-associated MN, which is usually indistin- model, immune complexes formed in situ are capped
guishable morphologically from primary MN. and shed off the podocyte’s clathrin-coated pits into
Multiple reports have attempted to use staining the subepithelial region, producing MN. Subsequent
for the subclasses of IgG as a means of differentiating studies on the passive HN model have demonstrated
primary from secondary MN (15–17). In primary MN, that proteinuria is complement dependent (20,21) and
IgG4 predominates, but IgG1 is also commonly pres- involves formation of the C5b-C9 membrane attack
ent and is thought to play a role in complement complex which inserts into the podocyte cell mem-
activation. In membranous lupus nephritis, all sub- brane, inciting podocytes to synthesize proteases, ox-
classes of IgG1 (i.e., IgG1 through IgG4) are com- idants, TGF-␤, and extracellular matrix (22,23). Al-
monly seen with staining for IgG4 typically least though Gp330 is not expressed by human podocytes,
intense. In MN related to malignancy, positivity for the HN model has been critically important to eluci-
IgG1, IgG2, IgG4, and rarely IgG3 is found. Given the date the role of in situ immune complex formation in
significant overlap in findings, we have not found the pathogenesis of MN.
staining for IgG subclasses to be particularly helpful as An advance in the search for a human Heymann
a diagnostic tool, although it is extensively used in the antigen occurred in 2002, when Debiec et al. (24)
research context. identified a newborn male with severe nephrotic syn-
drome caused by MN associated with antibodies
Etiology and Pathogenesis against neutral endopeptidase (NEP), a protein ex-
Heymann nephritis (HN) is the classic animal
pressed on both the proximal tubular brush border and
model of MN, which is produced by immunizing rats
podocytes. The patient’s mother was NEP deficient
with fractionated renal cortex enriched in proximal
and had developed antibodies against NEP during a
tubular brush borders (Fx1A). Passive transfer of im-
previous pregnancy that ended in miscarriage. Trans-
mune serum to naive rats produces a passive model of
placental transfer of anti-NEP antibodies led to MN in
HN. The critical immunogenic component of Fx1A is
the immediate postnatal period. On the basis of this
Gp330/megalin (18,19), known as the “Heymann an-
family, NEP became the first human podocyte antigen
tigen.” Gp330/megalin is expressed on rat proximal
shown to act as a “Heymann antigen” (24). Additional
tubular brush border and podocyte foot processes,
families with antenatal MN resulting from transpla-
where it functions as an LDL receptor. The anti-
cental transfer of anti-NEP antibodies have been iden-
tified (25).
A tremendous breakthrough in our understanding
of the pathogenesis of primary MN occurred in 2009,
when Beck and colleagues (26,27) identified antibod-
ies against a conformation-dependent epitope of the
M-type phospholipase A2 receptor (PLA2R) in 75% of
patients with primary (idiopathic) MN. PLA2R is a
mannose-containing transmembrane receptor glyco-
protein expressed on podocytes and at lower levels on
type II pneumocytes and leukocytes (28). Patients with
idiopathic MN have circulating, predominantly IgG4
antibodies against PLA2R but no evidence of circulat-
Figure 6. In this case of MN, the global subepithelial ing immune complexes, supporting the concept of in
deposits are accompanied by prominent mesangial and sub- situ immune complex formation (26). Antibodies
endothelial deposits, as well as focal endothelial tubulore- eluted from the deposits of primary MN have speci-
ticular inclusions (not shown). The patient was found to
have evidence of systemic lupus erythematosus, and the
ficity for PLA2R (26). The presence of anti-PLA2R
final diagnosis was membranous lupus nephritis. Magnifi- antibodies in the serum of the majority of patients with
cation, ⫻6000. primary MN and their absence in secondary forms
identify PLA2R as the major target antigen in primary cance of focal segmental glomerulosclerosis. Am J Kidney Dis 41:
38 – 48, 2003
MN. Anti-PLA2R antibody serum levels seem to be 9. Wehrmann M, Bohle A, Bogenschutz O, Eissele R, Freislederer A,
specific for primary MN and to correlate with disease Ohlschlegel C, Schumm G, Batz C, Gartner HV: Long-term progno-
activity (26,27). Treatment-induced remissions are as- sis of chronic idiopathic membranous glomerulonephritis. Clin Neph-
rol 31: 67–76, 1989
sociated with reduction in the levels of circulating 10. Troyanov S, Roasio L, Pandes M, Herzenberg AM, Cattran DC:
anti-PLA2R autoantibody (26). Recurrence of primary Renal pathology in idiopathic membranous nephropathy: A new
MN in the allograft has been associated with reappear- perspective. Kidney Int 69: 1641–1648, 2006
11. Yoshimoto K, Yokoyama H, Wada T, Furuichi K, Sakai N, Iwata Y,
ance of anti-PLA2R antibodies (29). More recently, Goshima S, Kida H: Pathologic findings of initial biopsies reflect the
Stanescu et al. have demonstrated that MN is linked to outcomes of membranous nephropathy. Kidney Int 65: 148 –153,
the HLA-DQA1 allele on chromosome 6p21, a finding 2004
12. Glassock RJ: Secondary membranous glomerulonephritis. Nephrol
which supports a central role for autoimmunity in the Dial Transplant [Suppl 1]: 64 –71, 1992
pathogenesis of MN (30). 13. Burstein DM, Korbet SM, Schwartz MM: Membranous glomerulo-
The pathogenesis of most forms of secondary nephritis and malignancy. Am J Kidney Dis 22: 5–10, 1993
14. Eagen JW, Lewis EJ: Glomerulopathies of neoplasia. Kidney Int 11:
MN is likely to involve immune responses to nonglo- 297–303, 1977
merular antigens (e.g., infectious pathogens, tumors, 15. Doi T, Mayumi M, Kanatsu K, Suehiro F, Hamashima Y: Distribu-
nuclear autoantigens). The target antigen could be- tion of IgG subclass in membranous nephropathy. Clin Exp Immunol
58: 57– 62, 1984
come “planted” on the subepithelial aspect of the 16. Kuroki A, Shibata T, Honda H, Totsuka D, Kobayashi K, Sugisaki T:
GBM favored by its small size and cationic charge, Glomerular and serum IgG subclasses in diffuse proliferative lupus
followed by in situ binding of a circulating antibody. It nephritis, membranous lupus nephritis, and idiopathic membranous
nephropathy. Intern Med 41: 936 –942, 2002
is also possible that some patients have circulating 17. Ohtani H, Wakui H, Komatsuda A, Okuyama S, Masai R, Maki N,
preformed immune complexes that have the potential Kigawa A, Sawada K, Imai H: Distribution of IgG subclass deposits
to dissociate and reform in the subepithelial space in malignancy-associated membranous nephropathy. Nephrol Dial
Transplant 19: 574 –579, 2004
because of their low avidity and cationic charge. The 18. Heymann W, Hackel DB, Harwood S, Wilson SG, Hunter JL:
responsible antigens are probably diverse depending Production of nephrotic syndrome in rats by Freund’s adjuvants
on the condition and include nucleosomal antigens in and rat kidney suspensions. Proc Soc Exp Biol Med 100: 660 –
664, 1959
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B–associated MN (31). nephritis is a membrane glycoprotein of the renal proximal tubule
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20. Baker PJ, Ochi RF, Schulze M, Johnson RJ, Campbell C, Couser
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Section 2: CASE PRESENTATION albumin was 1.7 g/dl, and urinalysis showed 4⫹ protein
and 5 to 10 erythrocytes per high-power field with no
A 58-year-old African American man presents with an cellular casts. A 24-hour urine collection contained
85-lb weight gain over the past month as a result of 12.4 g of protein. Serologic evaluation revealed negative
progressive anasarca. Past medical history is significant or normal anti-nuclear antibody, anti-DNA antibody, C3,
for 12 years of hypertension and diet-controlled diabetes. C4, hepatitis B surface antigen, hepatitis C antibody, and
Baseline serum creatinine 1 year prior was 1.1 mg/dl. At HIV serology. No monoclonal serum or urine spikes were
the time of biopsy, serum creatinine was 6.3 mg/dl, serum detected by serum and urine protein electrophoresis.
Figure 1. Figure 2.
Figure 3. Figure 4.

A. Collapsing focal segmental glomerulosclerosis (FSGS)
B. Pauci-immune necrotizing and crescentic glomerulonephritis
C. Hypertensive nephrosclerosis with ischemic glomerulosclerosis
D. Diabetic nephropathy
E. FSGS, tip lesion variant
279
Answer the glomerular tuft accompanied by overlying glomer-

The renal biopsy findings are diagnostic of col- ular epithelial cell hypertrophy and hyperplasia (3).
lapsing FSGS (Answer A). Figure 1 shows global The term “glomerular collapse” was first introduced
“collapse” of the glomerular tuft characterized by by Weiss et al. in 1986 (4) to describe an unusual
severe wrinkling and retraction of the glomerular base- clinicopathologic complex of severe nephrotic syn-
ment membranes (GBMs), resulting in loss of patency drome, rapidly progressive renal failure, and glomer-
of glomerular capillary lumina (JMS, 400⫻). Figure 2 ular collapse occurring in six African American pa-
highlights the remaining glomerular tuft in blue and tients. Differentiation of the collapsing and cellular
illustrates the absence of increased mesangial matrix variants has been a source of controversy (5). The
or hyaline insudation (Masson Trichrome, 400⫻). Columbia classification defines the cellular variant as
Bowman’s space is filled with swollen glomerular one with expansile (rather than implosive) lesions
epithelial cells containing numerous intracytoplasmic owing to endocapillary hypercellularity such as foam
protein resorption droplets (bright red). The epithelial cells and infiltrating leukocytes, although visceral ep-
cells form a “pseudocrescent” that can be differenti- ithelial hyperplasia is also commonly encountered.
ated from a true inflammatory crescent by the absence The collapsing variant is distinguished clinically by its
of spindled cells, pericellular matrix, intervening fibrin, presentation with severe nephrotic syndrome, aggres-
or rupture of the underlying GBMs. Figure 3 shows sive course, and poor prognosis. Collapsing FSGS can
diffuse tubular degenerative changes with simplifica- be primary (idiopathic) or secondary to a variety of
tion of the lining epithelium as well as several tubular causes, notably viral infections such as HIV and cer-
microcysts filled with proteinaceous casts (H&E, tain drug toxicities. Most series of primary collapsing
200⫻). Immunofluorescence microscopy revealed glomerulopathy have described a strong African
global glomerular tuft staining for IgM (1⫹) and C3 American racial predominance, implicating genetic
(2⫹) in areas of collapsing sclerosis. Visceral and risk factors.
tubular epithelial cells contained protein resorption
droplets staining for albumin. Figure 4 shows wrin- Clinical Characteristics
kling and collapse of the GBMs accompanied by Primary collapsing FSGS can occur at any age
hyperplasia of overlying podocytes, which contain but is more common in young adults with mean age of
rounded electron-dense intracytoplasmic protein resorp- 30 to 41 years in three large series containing a total of
tion droplets (3,000⫻). Podocyte foot process efface- 103 patients (6 – 8). In these three series from Chicago,
ment is diffuse. No immune-type electron-dense deposits Chapel Hill, and New York City, there was African
or endothelial tubuloreticular inclusions are seen. American racial predominance of 86, 81, and 61%,
which was significantly higher than in classic FSGS
Collapsing FSGS NOS. Male patients predominate in most series. The
The term FSGS is applied to a heterogeneous typical clinical presentation is severe nephrotic syn-
group of glomerular lesions mediated by podocyte drome (with mean urine protein levels of 14.3, 13.2,
injury and resulting in podocyte depletion and progres- and 10.2 g, respectively) and renal insufficiency (with
sive segmental and global glomerulosclerosis. Differ- mean serum creatinine levels of 3.8, 3.5, and 4.2
entiating primary (or idiopathic) forms of FSGS from mg/dl, respectively) (6 – 8). Median renal survival is
secondary forms that have established etiologic asso- substantially worse than in other forms of FSGS,
ciations is critical to guiding therapeutic management. ranging from 13 to 15 months (6 – 8). In a comparative
Identifying the histologic subtype of FSGS adds im- study of the histologic variants, the collapsing subtype
portant pathogenetic and prognostic information (1,2). had the lowest percentage of complete and partial
The collapsing variant is one of five recognized his- remissions (13 versus 39% for FSGS NOS) and the
tologic subtypes of FSGS (including FSGS not other- highest percentage of ESRD (65 versus 35% for FSGS
wise specified [NOS], perihilar variant, cellular vari- NOS) (1). There is general agreement that the collaps-
ant, tip variant, and collapsing variant) (3). ing variant has the lowest remission rate and worst
Collapsing FSGS, also called “collapsing glo- long-term prognosis (2,9).
merulopathy,” is defined by the presence of at least The incidence of idiopathic collapsing FSGS
one glomerulus with segmental or global collapse of appears to have increased in the past few decades
(6,10). At Columbia University Medical Center, no cases C1. The protein resorption droplets within podocyte
of collapsing FSGS were found before 1979, but the and tubular epithelial cytoplasm often stain with anti-
incidence of primary (idiopathic) collapsing FSGS pro- sera to IgG, IgA, and albumin. True immune complex
gressively increased through the 1980s and by the mid- deposition within the glomerular tuft is absent, how-
1990s represented 24% of cases of primary FSGS (10). ever.
Serologic evaluation of patients with collapsing Electron Microscopy. By electron microscopy, the
FSGS, particularly in those of African and Hispanic collapsed segments display wrinkling and retraction of
descent, should include HIV testing because HIV- the GBMs, causing luminal narrowing or obliteration.
associated nephropathy is a common secondary cause Overlying the collapsed tuft, the podocytes exhibit
of collapsing FSGS. Drug nephrotoxicity, most nota- complete foot process effacement with foci of detach-
bly with pamidronate (11) and IFN therapy (12), can ment from the GBM and intervening accumulation of
cause collapsing FSGS, as discussed in the section on loose extracellular matrix. The pseudocrescents con-
Secondary Forms of Collapsing FSGS. tain plump glomerular epithelial cells that often appear
confluent with the parietal epithelial layer, obliterating
Pathology the urinary space. These large epithelial cells typi-
Light Microscopy. Light microscopic features of cally contain abundant intracytoplasmic electron-
collapsing FSGS are distinctive. Although glomerular dense rounded, membrane-bound inclusions repre-
collapse may be segmental in distribution, more typi- senting protein resorption droplets. Glomeruli
cally the entire glomerular globe is affected, producing without collapse usually have extensive podocyte
a picture of global collapsing sclerosis. Collapsing foot process effacement involving ⬎50% of the
lesions are characterized by occlusion of capillary glomerular capillary surface area. Endothelial cells
lumina as a result of implosive wrinkling and retrac- should be examined for the presence of tubuloreticular
tion of the GBMs, best seen with the Jones methena- inclusions, which are commonly seen in the setting of
mine silver or periodic acid–Schiff stains. Accompa- HIV infection and IFN therapy but not in primary
nying the tuft collapse are dramatic proliferation and collapsing FSGS. Endothelial tubuloreticular inclu-
hypertrophy of overlying visceral epithelial cells, sions, which are considered “interferon footprints,”
which typically contain large intracytoplasmic protein consist of 24 nm interanastamosing tubular structures
resorption droplets. Whereas other subtypes of FSGS located within the dilated endoplasmic reticulum of
often show expansion of extracellular matrix, intracap- the endothelial cell cytoplasm (Figure 5).
illary foam cells, hyalinosis, and segmental adhesions
to Bowman’s capsule, these features are typically
absent, at least in the early stages of collapsing FSGS.
In the late stages, the collapsed tuft retracts into a solid
sphere crowned by a monolayer of hypertrophied vis-
ceral epithelial cells. Tubulointerstitial abnormalities
are also prominent and may appear out of proportion
to the degree of glomerulosclerosis. Tubular degener-
ative and regenerative changes include loss of brush
border, shedding of cytoplasmic fragments into tubu-
lar lumina, tubular epithelial hypertrophy, and en-
larged vesicular nuclei with prominent nucleoli. The
formation of tubular microcysts containing loose pro-
teinaceous casts is a distinctive feature of collapsing
FSGS. Figure 5. In the setting of collapsing FSGS, the finding of
endothelial tubuloreticular inclusions (TRI), which are in-
Immunofluorescence. Within collapsing segments,
teranastamosing tubular structures within the dilated endo-
immunofluorescence typically shows staining of the plasmic reticulum of endothelial cells, raises the possibility
glomerular tuft with IgM, C3, and, less commonly, of HIV infection. Magnification, ⫻20,000.
Secondary Forms of Collapsing FSGS (11). Proteinuria and renal insufficiency typically im-
Collapsing FSGS is associated with a variety of prove after drug withdrawal but do not reach baseline
systemic conditions. The most common and best un- levels. Patients treated with IFN-␣ (for hepatitis C
derstood association is HIV infection, producing HIV- virus infection), IFN-␤ (for multiple sclerosis), or
associated nephropathy (HIVAN). HIV-1 directly in- IFN-␥ (for idiopathic pulmonary fibrosis or chronic
fects renal epithelial cells (including podocytes, granulomatous disease) may develop collapsing FSGS
parietal epithelial cells, and tubular epithelial cells), with severe nephrotic syndrome that improves after
where it is capable of active replication and quasispecies drug discontinuation (12).
evolution (13,14). Once the virus infects renal epithe- Acute vaso-occlusive injury in the setting of
lium, it causes dysregulation of host genes to produce cholesterol embolization (23) and severe renovascular
nephropathy. Genetic engineering in the mouse has iden- disease (24) have also been reported to cause severe
tified several specific HIV-1 genes as particularly impor- proteinuria and collapsing glomerulopathy. In renal
tant in HIVAN pathogenesis. Podocyte-specific ex- allografts, collapsing FSGS has been described in a
pression of vpr and nef acts synergistically to produce variety of settings (25), most notably prominent mi-
nephropathy in double transgenic mice (15). Vpr plays crovascular disease, suggesting a role for ischemic
a role in intranuclear transport of the HIV-1 preinte- injury (26). Finally, rare familial forms of collapsing
gration complex and causes G2 cell-cycle arrest. Tu- FSGS have been described (27), including a new
bular epithelial cells transfected with vpr develop association with action myoclonus renal failure syn-
cell-cycle arrest and inability to undergo cytokinesis, drome caused by autosomal recessive mutations in
resulting in increased chromosomal copy number and lysosomal membrane protein SCARB2/LIMP-2 (28).
enlarged nuclei, accounting for the typical tubular cell
enlargement and “reactivity” seen histologically in Etiology and Pathogenesis
human and murine HIVAN (16). Nef, a major HIV-1 Podocyte injury is a central pathogenetic mech-
virulence factor, contains a proline-rich motif that anism in all types of FSGS. The unique morphology of
interacts with the SH3 domain of Src family kinases, collapsing FSGS with implosion of the glomerular tuft
activating signal transduction events that cause disrup- and proliferation of overlying epithelial cells supports
tion of the actin cytoskeleton, podocyte dedifferentia- a severe and rapid podocyte injury. Podocytes are
tion, and proliferation (17,18). The strong African highly differentiated cells with a unique cytoarchitec-
American racial predominance of HIV-associated ne- ture required for structural support of the glomerular
phropathy supports the importance of genetic suscep- capillaries, synthesis of the GBM, and regulation of
tibility (see Etiology and Pathogenesis section). The glomerular permselectivity. Differentiated podocytes
use of antiretroviral therapy in HIV-1–infected pa- are postmitotic cells, and podocyte development is
tients has reduced the incidence and attenuated the characterized by the expression of maturity markers
course of HIVAN (15). such as Wilms’ tumor 1, podocalyxin, and synaptopo-
Other viral infections that have been associated din. In collapsing FSGS, both idiopathic and HIV-
with collapsing FSGS include cytomegalovirus (19), associated podocytes become dedifferentiated and
parvovirus B19 (20), and simian virus 40 (21). Rare dysregulated, losing expression of these maturity
cases have also been described in association with markers and acquiring markers of proliferation, such
tuberculosis, Epstein-Barr virus infection, and eryth- as Ki-67 (29). In contrast, mature podocyte markers
rophagocytosis syndrome (22). In some of these are retained in membranous nephropathy and minimal
forms, there is a potential for podocyte infection by the change disease, despite severe proteinuria and foot
inciting virus (20,21), whereas in others, podocyte process effacement.
injury probably results from indirect cytokine effects The podocyte dedifferentiation in collapsing
or innate immunity (20). FSGS has made it difficult to identify the origin of the
Drug nephrotoxicity is another secondary cause proliferating glomerular epithelial cells within the
of collapsing FSGS. Treatment with high-dosage pseudocrescents. Using lineage-specific markers for
pamidronate has been associated with the development parietal epithelial cells, such as cytokeratins, there is
of collapsing FSGS in patients being treated for hy- increasing evidence that parietal epithelial cells con-
percalcemia of malignancy and osteolytic metastases tribute to the cellular proliferation seen in collapsing
FSGS of various causes (30 –32). The recent identifi- drome, progressive irreversible renal failure, and glomerular “col-
lapse”: A new clinicopathologic entity? Am J Kidney Dis 7: 20 –28,
cation of a stem cell reservoir in Bowman’s capsule 1986
that can repopulate podocytes supports the concept 5. Schwartz MM, Lewis EJ: Focal segmental glomerular sclerosis: The
that both immature podocytes and cells of parietal cellular lesion. Kidney Int 28: 968 –974, 1985
6. Haas M, Spargo BH, Coventry S: Increasing incidence of focal-
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ies performed on glomeruli microdissected from hu- 7. Detwiler RK, Falk RJ, Hogan SL, Jennette JC: Collapsing glomeru-
lopathy: A clinically and pathologically distinct variant of focal
man renal biopsies with primary collapsing FSGS segmental glomerulosclerosis. Kidney Int 45: 1416 –1424, 1994
have confirmed reduced expression of podocyte ma- 8. Valeri A, Barisoni L, Appel GB, Seigle R, D’Agati V: Idiopathic
turity markers and slit diaphragm proteins, supporting collapsing focal segmental glomerulosclerosis: A clinicopathologic
study. Kidney Int 50: 1734 –1746, 1996
the concept of the dysregulated podocyte phenotype. 9. Laurinavicius A, Hurwitz S, Rennke HG: Collapsing glomerulopathy
They have also identified overrepresentation of pari- in HIV and non-HIV patients: A clinicopathological and follow-up
etal markers and genes involved in biologic processes study. Kidney Int 56: 2203–2213, 1999
10. Barisoni L, Valeri A, Radhakrishnan J, Nash M, Appel G, D’Agati V:
of development and differentiation, consistent with Focal segmental glomerulosclerosis: A 20-year epidemiologic study
expansion of the parietal cell compartment and recruit- [Abstract]. J Am Soc Nephrol 5: 347, 1994
ment of progenitor cells (35). 11. Markowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath
S, Kuhn JA, Dratch AD, D’Agati VD: Collapsing focal segmental
The genetic basis for the strong African Ameri-
glomerulosclerosis following treatment with high-dose pamidronate.
can racial predisposition to FSGS has been linked to J Am Soc Nephrol 12: 1164 –1172, 2001
allelic variants in a region of chromosome 22 includ- 12. Markowitz GS, Nasr SH, Stokes MB, D’Agati VD: Treatment with
IFN-alpha, -beta, or -gamma is associated with collapsing focal
ing MYH9 encoding myosin heavy chain 9 and
segmental glomerulosclerosis. Clin J Am Soc Nephrol 5: 607– 615,
APOL1 encoding apolipoprotein L-1 (36,37), which 2010
are in close linkage disequilibrium. Two specific se- 13. Bruggeman LA, Ross MD, Tanji N, Cara A, Dikman S, Gordon RE,
Burns GC, D’Agati VD, Winston JA, Klotman ME, Klotman PE:
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Renal epithelium is a previously unrecognized site of HIV-1 infec-
with the development of FSGS. APOL1, a constituent tion. J Am Soc Nephrol 11: 2079 –2087, 2000
of HDL particles in the blood, confers resistance to 14. Marras D, Bruggeman LA, Gao F, Tanji N, Mansukhani MM, Cara
A, Ross MD, Gusella GL, Benson G, D’Agati VD, Hahn BH,
trypanosomal infection through its ability to lyse
Klotman ME, Klotman PE: Replication and compartmentalization of
Trypanosoma brucei brucei, the parasite that causes HIV-1 in kidney epithelium of patients with HIV-associated nephrop-
sleeping sickness. Subspecies of Trypanosoma athy. Nat Med 8: 522–526, 2002
evolved in Africa that were resistant to lysis, in turn 15. Zuo Y, Matsusaka T, Zhong J, Ma J, Ma LJ, Hanna Z, Jolicoeur P,
Fogo AB, Ichikawa I: HIV-1 genes vpr and nef synergistically
favoring evolutionary mutations in human APOL1 that damage podocytes, leading to glomerulosclerosis. J Am Soc Nephrol
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Husain M, Najfeld V, Planelles V, D’Agati VD, Klotman ME,
come at the cost of increased risk for FSGS, although Klotman PE: HIV-1 Vpr inhibits cytokinesis in human proximal
the mechanistic basis for the renal effects remains tubule cells. Kidney Int 74: 1049 –1058, 2008
unknown (37) Thus, analogous to the emergence of 17. Lu TC, He JC, Wang ZH, Feng X, Fukumi-Tominaga T, Chen N, Xu
J, Iyengar R, Klotman PE: HIV-1 Nef disrupts the podocyte actin
sickle cell trait to resist malaria, the genetic resistance cytoskeleton by interacting with diaphanous interacting protein.
to the infectious pathogen is a dominant trait (present J Biol Chem 283: 8173– 8182, 2008
in heterozygotes), whereas the host disease is reces- 18. He JC, Husain M, Sunamoto M, D’Agati VD, Klotman ME, Iyengar
R, Klotman PE: Nef stimulates proliferation of glomerular podocytes
sive (present in homozygotes). through activation of Src-dependent Stat3 and MAPK1,2 pathways.
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syndrome. Kidney Int 69: 1892–1898, 2006 and pamidronate-associated collapsing focal segmental glomerulo-
23. Greenberg A, Bastacky SI, Iqbal A, Borochovitz D, Johnson JP: sclerosis are parietal epithelial cells. Kidney Int 70: 338 –344, 2006
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Section 3: CASE PRESENTATION count of 7200, platelets of 340,000, and normal serum electrolytes
(Na, K, Cl, CO2, and Ca). Urinalysis revealed 3⫹ protein and
A 74-year-old Caucasian woman presents with nephrotic syn- microhematuria without red blood cell casts. Serologies included
drome and microhematuria. Past medical history includes long- negative anti-nuclear antibody, anti-neutrophil cytoplasmic anti-
standing hypothyroidism, depression, and a 3-year history of body, hepatitis B surface antigen, hepatitis C virus antibody, HIV,
hypertension. The patient’s medications include levothyroxine, rheumatoid factor, and cryoglobulins. Serum complements (C3
metoprolol, irbesartan/hydrochlorothiazide, sertraline, montelu- and C4) were within the normal range. Serum protein electropho-
kast, and fexofenadine. Physical examination reveals a BP of resis revealed reduced albumin 3.0 (normal 3.6 to 4.7 g/dl) and
138/80 mmHg and 2⫹ lower extremity edema. The patient denies reduced gamma globulins 0.4 (normal 0.6 to 1.6 g/dl). Both serum
history of diabetes, fever, rash, arthralgias, or gross hematuria. protein electrophoresis and urine protein electrophoresis with
Laboratory studies include serum creatinine level of 1.3 mg/dl, immunofixation were negative for monoclonal protein. Kidney
blood urea nitrogen of 43 mg/dl, 24-hour urine protein of 5.12 g, size by ultrasound was 10.4 and 10.3 cm. A renal biopsy was
serum albumin of 3.3 g/dl, hematocrit of 31.4%, white blood cell performed.
Figure 1. Figure 2.
Figure 4.
Figure 3. IgG.
Figure 5. Figure 6.
285
What is the BEST diagnosis? Proliferative Glomerulonephritis with Monoclonal

A. Primary membranoproliferative glomerulonephritis IgG Deposits
type 1 Among dysproteinemia-related renal diseases,
B. Acute postinfectious glomerulonephritis those manifesting monoclonal glomerular deposits of
C. Light- and heavy-chain deposition disease (LHCDD) IgG are relatively uncommon. Renal diseases caused
by monoclonal IgG deposition include LHCDD (1),
D. Proliferative glomerulonephritis with monoclonal IgG
deposits type 1 cryoglobulinemic glomerulonephritis (2), im-
munotactoid glomerulonephritis (3), light- and heavy-
E. Immunotactoid glomerulonephritis
chain amyloidosis (4), and, rarely, fibrillary glomeru-
lonephritis (3).
Answer In 2004, 10 patients with a novel form of glo-
The combined light microscopic, immunoflu- merular injury related to monoclonal IgG deposition
orescence, and electron microscopic findings are that could not be assigned to any of the previously
diagnostic of proliferative glomerulonephritis with recognized diagnostic categories were reported as
monoclonal IgG deposits. A representative glomer- “proliferative glomerulonephritis with monoclonal
ulus is enlarged and hypercellular with accentuated IgG deposits” (PGNMID) (5). By immunofluores-
lobularity. The glomerular capillary lumina are cence, the glomerular deposits were monoclonal,
globally narrowed by mesangial and endocapillary staining for a single light-chain isotype and a single ␥
proliferation including infiltrating monocytes and heavy-chain subclass. Light microscopy disclosed an
neutrophils. (Figure 1). Some of the expanded mes- endocapillary proliferative or membranoproliferative
angial areas display nodular mesangial sclerosis, glomerulonephritis, and electron microscopy revealed
and many glomerular basement membranes (GBMs) granular electron-dense deposits, mimicking ordinary
appear duplicated with mesangial interposition, pro- immune-complex glomerulonephritis. A monoclonal
ducing a membranoproliferative pattern. (Figure 2). serum or urine protein was identified in 50% of pa-
On immunofluorescence staining for IgG (Figure 3), tients, although none had evidence of multiple my-
there is global granular to semilinear staining of eloma or B cell lymphoproliferative disorder (5). The
glomerular capillary walls, as well as granular de- same authors subsequently enlarged their experience
posits in the mesangium. A similar pattern of stain- to 37 cases with longer follow-up (6). Forty additional
ing was present for C3 and C1q, with negativity for patients with PGNMID have been reported by other
IgM and IgA (data not shown). Strong global gran- groups (7–16).
ular to semilinear staining for ␬ outlines the glo-
merular capillary walls, with fewer deposits in the Clinical Features
mesangium (Figure 4, left). There is no staining for PGNMID is an increasingly recognized disorder
IgG or ␬ light chain in the distribution of Bowman’s primarily seen in Caucasian adults. Although the glomer-
capsule or tubular basement membranes. By con- ular immune deposits have the characteristics of mono-
trast, the stain for ␭ light chain (Figure 4, right) is clonal IgG deposits, the relationship of this condition to
completely negative. Because of the seemingly underlying or future hematologic disorder remains un-
monoclonal deposition of IgG␬ by routine immuno- certain. In the largest reported series, 81% of patients
fluorescence, staining for the IgG isotypes (1 were Caucasian and 62% were female (6). The disease
through 4) was performed. There is positivity for was most often diagnosed in late middle age (mean 54
IgG3 in the distribution of the IgG␬ deposits, with years) but with wide age range (20 to 81 years) (6). All
negative staining for IgG1, IgG2, and IgG4 (Figure patients presented with proteinuria (mean 24 hour urine
5). By electron microscopy (Figure 6), glomerular protein of 5.7 g), 68% had renal insufficiency (mean
capillary lumina are narrowed by circumferential serum creatinine level 2.8 g), and 77% had hematuria.
mesangial interposition and duplication of GBMs in Full nephrotic syndrome was present in nearly half of
association with granular mesangial and subendo- cases. Serum cryoglobulin titers were negative in all
thelial deposits. Although some of the deposits patients. Serum complements were depressed in 27% of
exhibit a variegated texture, no deposits with orga- patients, including four with reduced C3 and C4, three
nized substructure are identified. with isolated depression of C4, and three with isolated
depression of C3. In 30% of patients, there was a mono- and one IgG3␭) exhibiting the same heavy- and light-
clonal serum protein with the same heavy- and light- chain isotypes as had been detected in their native
chain isotype as was detected in the glomerular deposits, kidney biopsies. No patient had evidence of a serum
although only one patient had preexisting myeloma. One M-spike before or after transplantation. Recurrence
patient had primary renal amyloidosis (AL ␭ type) diag- was treated with a combination of high-dosage pred-
nosed at the same time as PGNMID on renal biopsy, nisone and rituximab in three patients and prednisone
despite a negative bone marrow for myeloma. Although and cyclophosphamide in one. After a mean posttrans-
several patients had a history of carcinoma, one had plantation follow-up of 43 months, all four patients
underlying HIV infection and one had autoimmune he- had a reduction in proteinuria and histologic activity of
molytic anemia, no consistent clinical profile that iden- the glomerulonephritis. Three patients also had im-
tifies patients at risk for developing PGNMID has proved serum creatinine, with the exception of the
emerged. single patient with intercurrent rejection.
Eighteen (56%) patients received immunomodula-
tory therapy, with or without concurrent renin-angioten- Pathology
sin system blockade (6). These 18 patients included nine Diagnostic criteria for PGNMID (6) include renal
of the 11 patients who had a positive M-spike. Treatment biopsy findings of glomerulonephritis with the following:
was not standardized and consisted of prednisone alone (1) glomerular immune deposits staining positive for ␥
in six patients, prednisone and an alkylating agent (cy- heavy chain (IgG), with negativity for ␣ (IgA) and ␮
clophosphamide or chlorambucil) in three patients, tha- (IgM) heavy chains, indicating restriction to a single (␥)
lidomide in one, bortezomib in one, mycophenolate Ig class; (2) positive staining for a single ␥ (IgG) subclass
mofetil in three, and rituximab in four. On follow-up of (IgG1, IgG2, IgG3, or IgG4); (3) positive staining for a
a mean of 30.3 months (range 1 to 114), available for 32 single light-chain isotype (␬ or ␭), indicating monoclo-
patients, 37.5% had complete or partial recovery, 37.5% nality; (4) predominantly granular electron-dense depos-
had persistent renal dysfunction, and 21.9% progressed its in mesangial, subendothelial, and/or subepithelial lo-
to ESRD (6). On univariate analysis, correlates of ESRD cations by electron microscopy, resembling immune
were higher creatinine at biopsy, percentage glomerulo- complex glomerulonephritis; and (5) no clinical or labo-
sclerosis and degree of interstitial fibrosis, but not treat- ratory evidence of cryoglobulinemia.
ment or the presence of M-spike. On multivariate anal-
Light Microscopy. The most common histologic
ysis, a higher percentage of glomerulosclerosis emerged
pattern is membranoproliferative glomerulonephritis, fol-
as the only independent predictor of ESRD (6).
This retrospective, uncontrolled study was un- lowed by endocapillary proliferative glomerulonephritis
able to show a statistical benefit of treatment, perhaps (6,12). Irregular segmental membranous features are fre-
because of the small sample size and the tendency to quent in this setting. There are also rare examples of
treat patients with more severe pathologic features. Of predominantly mesangial proliferative (6,15) or membra-
interest, only one patient lacking M-spike at presenta- nous glomerulonephritis (6,9,16). The membranoprolif-
tion subsequently developed M-spike. In addition, no erative variant is characterized by mesangial expansion
patient with M-spike at presentation subsequently de- by increased cells and matrix as well as mesangial cell
veloped hematologic malignancy such as myeloma or interposition and duplication of GBMs. Infiltrating mac-
B cell lymphoproliferative disorder (6). Longer fol- rophages and neutrophils may be seen. Crescents may
low-ups on a larger number of patients are needed to occur in up to one third of cases but usually involve a
determine the risk for developing a hematologic ma- minority of glomeruli. Most cases are associated with
lignancy and the optimal therapeutic regimen. some degree of interstitial inflammation, fibrosis, and
PGNMID may recur in the allograft (13,17). A tubular atrophy ranging from mild to severe.
recent report described four patients with recurrent Immunofluorescence. The IgG deposits are located
PGNMID documented by allograft biopsy at a mean of exclusively in the glomeruli and usually involve both
3.8 months after transplantation. Recurrence was her- the mesangium and the peripheral glomerular capillary
alded by the development of proteinuria, hematuria, walls. The deposits are commonly granular but occa-
and allograft dysfunction. In all cases, there was glo- sionally exhibit a semilinear or smudgy texture. All
merular deposition of monoclonal IgG3 (three IgG3␬ cases show light-chain restriction, with sole staining
for ␬ in approximately three quarters of cases and sole membranoproliferative or diffuse proliferative glomeru-
staining for ␭ in the remaining one quarter. There may lonephritis pattern, typically with prominent infiltrating
be some nonspecific focal staining for IgM in areas of monocytes and large subendothelial and intracapillary
glomerulosclerosis, but no specific staining for IgM or immune deposits forming “immune thrombi” (2). Ul-
IgA is observed. The majority of cases exhibit depo- trastructurally, the deposits commonly show an annu-
sition of C3 (97%) and C1q (64%) in the distribution lar-tubular or fibrillar substructure. Serum cryoglobu-
of the IgG deposits. PGNMID should be confirmed by lin testing demonstrates a type 1 cryoglobulin
staining for the IgG subtypes (1 through 4) when the composed of monoclonal IgG, usually of ␬ isotype.
routine immunofluorescence panel shows light-chain The glomerular deposits in immunotactoid glomerulo-
restriction. By definition, the IgG deposits should stain nephritis are composed of microtubular structures with
for a single IgG isotype, indicating that they are a diameter of 30 to 50 nm often arranged in parallel
monotypic. In the largest series, the 32 cases studied stacks, whereas in fibrillary glomerulonephritis they
included nine IgG1, two IgG2, and 21 IgG3 (6). There are composed of Congo red–negative, randomly ori-
were no examples of monoclonal IgG4. Interestingly, ented fibrils measuring 16 to 24 nm in diameter (3).
IgG1 and IgG2 deposits were more commonly ob- Light- and heavy-chain amyloidosis is extremely rare,
served in patients with a demonstrable M-spike, and, like light-chain amyloidosis, exhibits deposits of
whereas only two of the 21 patients with IgG3 had a Congo red–positive haphazardly oriented fibrils 8 to
positive M-spike. Thus, IgG3 was the most common 14 nm in diameter (4).
subtype in patients lacking an M-spike, suggesting that
it may have particular pathogenetic significance in this Pathogenesis
subgroup. The cause of PGNMID seems to involve the
Electron Microscopy. Non-organized granular exclusively glomerular deposition of a monoclonal
electron-dense deposits are confined to the glomerular IgG molecule. Most cases have deposition of mono-
compartment, without involvement of Bowman’s cap- clonal IgG3␬. Fewer have been reported with mono-
sule, tubular basement membranes, interstitium, or clonal IgG3␭, IgG1␬, IgG1␭, or IgG2␭. By immuno-
vessel walls. Most cases have a combination of mes- staining, the deposited IgG molecule contains all three
angial and subendothelial electron-dense deposits in a constant domains (CH1, CH2, and CH3), suggesting
diffuse and global distribution. Subepithelial deposits the deposition of a complete (nondeleted) Ig molecule
occur in approximately one half of cases and are more (5). Only sequencing of the pathogenic IgG would
irregularly distributed, in a predominantly segmental determine whether there are unique mutations or sub-
pattern. The few cases with global subepithelial de- stitutions that predispose to glomerular deposition by
posits are those with predominantly membranous fea- promoting self-aggregability, enhancing charge inter-
tures by light microscopy. In some cases, the deposits actions with glomerular constituents, or increasing
have a variegated texture, with areas of greater or hydrophobicity. Because the CH2 domain is present, it
lesser electron density. However, organized fibrils and is not surprising that activation of complement is
microtubules are not typically observed. commonly observed as glomerular co-deposits of C1q
and C3, which may lead to hypocomplementemia.
Differential Diagnosis The four IgG subtypes differ in their quantity and
Other glomerular diseases with monoclonal IgG chemical properties. IgG3 comprises only 8% of total
deposits can be distinguished from PGNMID on the circulating IgG, but it has properties that could make it
basis of their combined pathologic and clinical fea- intrinsically “nephritogenic” (18 –20). For example, it is
tures. Randall-type LHCDD is characterized by nod- the most positively charged subclass (pI 8.2 to 9.0),
ular glomerulosclerosis by light microscopy; diffuse which could promote binding to negative charge sites in
linear staining of glomerular and tubular basement the glomerular capillary wall. It has the largest molecular
membranes for a single heavy chain and a single light weight (170,000 Da), which makes it likely to become
chain by immunofluorescence; and nonfibrillar, punc- concentrated in the glomerular capillaries during filtra-
tate electron-dense deposits in the GBMs and tubular tion. IgG3 also has the capacity to self-aggregate via
basement membranes by electron microscopy (1). Fc–Fc interactions, which might favor formation of in-
Type 1 cryoglobulinemic glomerulonephritis exhibits a traglomerular electron-dense aggregates. Interestingly,
IgG3 also is the most common isotype in murine and Appel GB, Aucouturier P, D’Agati VD: Proliferative glomerulone-
phritis with monoclonal IgG deposits: A distinct entity mimicking
human lupus nephritis, cryoglobulinemia, and IgG my- immune-complex glomerulonephritis. Kidney Int 65: 85–96, 2004
eloma hyperviscosity syndrome (19,20). 6. Nasr SH, Satoskar A, Markowitz GS, Valeri AM, Appel GB, Stokes
The ability of some monoclonal IgG to self-aggre- MB, Nadasdy T, D’Agati VD: Proliferative glomerulonephritis with
monoclonal IgG deposits. J Am Soc Nephrol 20: 2055–2064, 2009
gate in vitro suggests that the glomerular IgG deposits 7. Evans DJ, Macanovic M, Dunn MJ, Pusey CD: Membranous glo-
may not be complexed to antigen (16). However, because merulonephritis associated with follicular B-cell lymphoma and sub-
only 30% of patients have a corresponding M-spike and epithelial deposition of IgG1-kappa paraprotein. Nephron Clin Pract
93: c112— c118, 2003
evidence of myeloma is rare, it remains unclear whether 8. Lee JG, Moon KC, Lee JE, Kim P, Lee JG, Kim JH, Lee KY: A case
the monoclonal IgG in some patients could deposit in the of proliferative glomerulonephritis with monoclonal IgG deposits.
course of an antigen-driven immune response, perhaps as Korean J Nephrol 23: 987–991, 2004
9. Komatsuda A, Masai R, Ohtani H, Togashi M, Maki N, Sawada K,
part of an antigen-antibody complex formed by specific Wakui H: Monoclonal immunoglobulin deposition disease associated
B cell clones. Challenge by foreign antigen typically with membranous features. Nephrol Dial Transplant 23: 3888 –3894,
elicits a polyclonal immune response. Hypothetically, in 2008
10. Bridoux F, Zanetta G, Mougenot B, Goujon JM, Vanhille P, Bauwens
the course of an immunologic response to exogenous or M, Chevet D, Ronco P, Preud’homme JL, Touchard G: Glomeru-
endogenous antigens, one or more clones of B cells could lopathy with non-organized and non-Randall type monoclonal immu-
proliferate and produce monoclonal IgG molecules (par- noglobulin deposits: A rare entity [Abstract]. J Am Soc Nephrol 12:
94A, 2001
ticularly IgG3) with the ability to self-aggregate and
11. Geldenhuys L, Jones B: Glomerulonephritis with monoclonal immu-
rapidly deposit in glomeruli through entrapment and/or noglobulin deposits [Abstract]. J Am Soc Nephrol 19: 671A, 2008
interaction with negative charge sites in the glomerular 12. Masai R, Wakui H, Komatsuda A, Togashi M, Maki N, Ohtani H,
Oyama Y, Sawada K: Characteristics of proliferative glomerulo-
capillary walls. The small quantity of this monoclonal
nephritis with monoclonal IgG deposits associated with mem-
IgG may elude detection by serum protein electrophore- branoproliferative features. Clin Nephrol 72: 46 –54, 2009
sis with immunofixation because of its avidity for the 13. Albawardi A, Sataskar A, Brodsky S, Nadasdy GM, Nadasdy T:
Proliferative glomerulonephritis with monoclonal IgG deposits recurs
glomeruli and rapid aggregability favored by the mole-
or may develop de novo in renal allografts. [Abstract]. Mod Pathol
cule’s intrinsic physical properties and the high intraglo- 23: 337A, 2010
merular concentrations reached during glomerular siev- 14. Alpers CE, Tu WH, Hopper J Jr, Biava CG: Single light chain
subclass (kappa chain) immunoglobulin deposition in glomerulone-
ing. The possibility of an oligoclonal IgG response with
phritis. Hum Pathol 16: 294 –304, 1985
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excluded on the basis of the renal biopsy findings be- responsive nephrotic syndrome in a patient with proliferative glomer-
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cause monoclonality can be proved only by immunoblot-
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Section 4: CASE PRESENTATION RBC casts. Laboratory evaluation shows serum creatinine
level of 1.4 mg/dl, 24-hour urine protein of 7.2 g/d, serum
A 27-year-old African-American woman presents with albumin of 2.4 g/dl, decreased serum complements (C3 62
nephrotic syndrome during the first trimester of her first [normal 80 to 180]; C4 ⬍6 [normal 10 to 45]), positive
pregnancy. She has a past history of hepatitis C virus (HCV) rheumatoid factor (RF), and positive type 2 mixed cryo-
infection (presumed to be from tattoos) and poorly con- globulin (IgM-␬/IgG). All other serologic tests are negative
trolled hypertension of unknown duration. Physical exami- or normal, including anti-nuclear antibody, anti-DNA anti-
nation reveals BP of 160/100 and 2⫹ lower extremity body, antistreptolysin-O, anti-neutrophil cytoplasmic anti-
edema. Urinalysis shows 4⫹ protein and 15 red blood cells body, anti– glomerular basement membrane (anti-GBM) an-
(RBCs) per high-power field, with dysmorphic RBCs but no tibody, and hepatitis B surface antigen.
Figure 1. Figure 2.
Figure 3. Figure 4. IgM

A. Acute postinfectious glomerulonephritis (GN)
B. Thrombotic microangiopathy
C. Fibrillary GN
D. Diffuse lupus nephritis
Figure 5. E. HCV-associated cryoglobulinemic GN
291
Answer HCV infection is cryoglobulinemic GN with features

Figure 1 shows a glomerulus with global oblit- of MPGN (5).
eration of capillary lumina by large periodic acid–
Schiff (PAS)-positive deposits forming “hyaline Clinical Characteristics
thrombi.” There is mesangial hypercellularity with HCV-associated MPGN typically presents
segmental peripheral mesangial interposition and du-
with nephrotic or subnephrotic proteinuria and mi-
plication of GBMs, producing a membranoprolifera-
crohematuria, with variable renal insufficiency and
tive pattern. In addition, the glomerular capillar-
hypertension (6). Some patients present with a
ies contain focal infiltrating monocytes/macrophages.
mixed picture of nephrotic and nephritic syndrome.
Figure 2 contains another representative glomerulus
Most patients have a long history (many years to
stained with Masson’s trichrome. The intracapillary
decades) of HCV infection before the development
hyaline thrombi stain orange-red (fuchsinophilic),
of HCV-associated MPGN; thus, this condition
consistent with immune material. Figure 3 illustrates
overwhelmingly affects adults. Many have cirrhosis
silver-negative intraluminal and subendothelial depos-
its as well as segmental duplication of GBMs, forming and active viral replication (i.e., positive serum
double contours. Figure 4 shows intense staining of HCV RNA by polymerase chain reaction). How-
the capillary walls and intracapillary hyaline thrombi ever, glomerular disease may occur in the absence
for IgM. Similar staining was seen for ␬ light chain, of liver disease, and HCV infection may be first
with weaker positivity for IgG and ␭ light chain (data recognized around the time of renal biopsy. Mixed
not shown). In addition, there were glomerular depos- cryoglobulinemia, usually with monoclonal IgM-␬
its of C3 and C1q in a predominantly peripheral RF activity, is detected in 50 to 70% of cases, and
capillary wall distribution. Figure 5 shows subendo- extrarenal manifestations of cryoglobulinemia, in-
thelial electron-dense deposits with an organized an- cluding palpable purpura, arthralgias, and neuropa-
nular-microtubular substructure (diameter 30 nm). The thy, occur in a minority of patients (1,7). Of note, a
subendothelial deposits were globally distributed negative cryoglobulin test does not rule out the
throughout the glomerular capillaries and also formed diagnosis because cryoglobulins precipitate if the
larger intracapillary aggregates, corresponding to the test sample cools below 37°C during transit from
immune “thrombi” seen by light microscopy. These the bedside to laboratory, leading to a false-negative
biopsy findings are consistent with HCV-associated result. In other patients, cryoglobulinemia may be
cryoglobulinemic GN. transient and difficult to detect. Useful surrogate
markers for mixed cryoglobulinemia include a pos-
itive latex fixation test for RF and the presence of
HCV-Related GN
HCV infects an estimated 2 to 3% of the world monoclonal IgM-␬ bands on serum protein electro-
population and is a leading cause of chronic liver phoresis with immunofixation. Hypocomplementia
disease, including cirrhosis and hepatocellular carci- is usually present with a reduced C4 more common
noma. Chronic HCV infection also gives rise to extra- than reduced C3 and frequent reduction in CH50.
hepatic disease, including GN, and many of these Liver transaminases may be elevated in patients
manifestations are related to tissue deposition of type with chronic liver disease.
2 mixed cryoglobulins composed of monoclonal Clinically detectable renal disease develops in
IgM-␬ and polyclonal IgG. The most common patterns approximately 25% of patients with HCV-associ-
of HCV-related glomerular disease are membranopro- ated mixed cryoglobulinemia (8). However, a pro-
liferative GN (MPGN), with or without cryoglobuline- tocol biopsy study showed a high frequency (83%)
mia, and membranous glomerulopathy (MGN) (1). of subclinical immune complex GN in HCV-
HCV infection has also been associated with fibrillary infected patients undergoing liver transplantation
GN and immunotactoid glomerulopathy (FGN/ITG) (9). Co-infection with HIV is not uncommon in
(2), FSGS (3), and other diseases, including IgA ne- those who have a history of intravenous drug use,
phropathy and postinfectious GN (4). However, the and HIV-related kidney disease may coexist with
most common glomerular disease associated with HCV-associated GN (10,11).
Pathology HIV-associated nephropathy, may display only mild

Light Microscopy. Most cases of HCV-associated mesangial hypercellularity and sparse mesangial de-
GN display a membranoproliferative pattern, with posits (11). Other patterns of glomerular disease
duplication of GBMs, cellular interposition, and that have been reported in small numbers of HCV-
subendothelial immune deposits. Cases with cryo- infected patients include FGN/ITG (2), IgA ne-
globulin deposition often display a diffuse endocap- phropathy (4), thrombotic microangiopathy (14),
illary proliferative and exudative pattern with nu- and FSGS (3). In cases of FGN or ITG, light micros-
merous intracapillary mononuclear leukocytes/ copy shows either an MPGN or MGN pattern, immuno-
macrophages and focal large intracapillary “hyaline fluorescence is positive for IgG and C3, and ultrastruc-
thrombi” that represent cryoglobulin precipitates. tural evaluation reveals randomly oriented fibrillar or
Immune deposits may also be seen in the subendo- microtubular deposits, respectively. The pathologic find-
thelial and mesangial regions. Immune deposits are ings in HCV-associated FSGS and IgA nephropathy are
acellular, “glassy,” eosinophilic, and PAS positive indistinguishable from primary and other secondary
and appear bright red or orange with trichrome forms of these diseases. Moreover, cases of HCV-
stain. On high magnification, immune material may associated FSGS frequently have other risk factors (e.g.,
be seen in phagolysosomes of intracapillary macro- heroin exposure, African American race, and IFN ther-
phages. Cases of MPGN without cryoglobulin de- apy) (15), raising the possibility of chance occurrence
posits typically show less leukocyte infiltration and rather than a direct causative role for HCV.
more obvious duplication of GBMs (“tram- Immunofluorescence Microscopy. Cases of MPGN,
tracking”) with cellular interposition. Cases of with or without cryoglobulinemia, show diffuse, finely
HCV-associated MGN show subepithelial immune granular, or pseudolinear peripheral capillary wall and
deposits and variable GBM spikes, often with mes- mesangial staining for IgM, IgG, and C3. In cases of
angial hypercellularity and mesangial immune de- cryoglobulinemic GN, staining for IgM is usually
posits. Not uncommonly, biopsies show segmental strongest, and ␬ staining is stronger than ␭ light chain,
features of both MPGN and MGN, and, if pro- reflecting the presence of monoclonal IgM-␬ in most
nounced, these changes resemble MPGN type 3 mixed cryoglobulins. Weak IgA and C1q staining has
(Burkholder type). Podocytes are often swollen and also been described. Prominent IgG and IgM staining
may display cytoplasmic protein droplets, reflecting is seen within cryoglobulin thrombi, but C3 is usually
the presence of heavy proteinuria. Crescents are not as intense as in the capillary wall deposits. In
uncommon and usually affect a minority of glom- non-cryoglobulinemic MPGN, IgG staining and C3
eruli, although there are rare reports of involvement staining may predominate and have a semilinear or
of ⬎50% of glomeruli (12,13). garland pattern, outlining the peripheral capillary
Tubular epithelium may show degenerative loops. Arterial staining for IgM, IgG, and C3 and
and regenerative changes, including loss of apical
fibrinogen may be seen in the distribution of arterial
brush border, nuclear enlargement, and prominent
cryoglobulin deposits, with or without associated vas-
nucleoli. Patchy interstitial mononuclear inflamma-
culitis. Fibrinogen may be seen in vessel walls if there
tory cell infiltrates are common. Tubular atrophy
is vasculitis. In cases of MGN, there is diffuse global
and interstitial fibrosis are generally mild and may
granular capillary wall staining for IgG (usually with
reflect underlying arterionephrosclerosis as a result
C3) in a subepithelial distribution, with variable mes-
of longstanding hypertension. Arterial vessels gen-
angial staining.
erally show medial hyperplasia and intimal fibrosis,
consistent with age. Cryoglobulin precipitates may Electron Microscopy. Discrete electron-dense de-
be seen in interstitial capillaries and within the posits are seen in subendothelial and mesangial areas
lumen and wall of small or medium-sized arterial and occasionally form large intracapillary aggregates.
vessels, often accompanied by endarteritis. Rarely, Not infrequently, segmental subepithelial deposits are
this may lead to cortical necrosis (7). also seen; cases with numerous subepithelial deposits
Cases of HCV-GN with coexisting glomerular resemble MPGN type 3 (Burkholder subtype). Depos-
diseases, such as diabetic glomerulosclerosis or its may also be seen within membrane-bound phagoly-
sosomes of intracapillary macrophages. Of note, de- Etiology and Pathogenesis

posits are occasionally sparse and difficult to identify, The development of HCV-associated GN fol-
particularly in cases with exuberant infiltrating lows an immunologic response to viral infection. Why
monocytes/macrophages, suggesting aggressive most patients are infected for more than a decade
phagocytosis. Non-cryoglobulin deposits have a before they develop cryoglobulinemia is unknown.
uniform/amorphous electron-dense appearance, Both cryoglobulins type II (polyclonal IgG/monoclo-
whereas cryoglobulin deposits often display an orga- nal IgM-␬) and type III (mixed polyclonal IgG and
nized substructure consisting of short, curved, thick- IgM) may occur in HCV-infected patients and give
walled tubular structures that appear annular on cross- rise to GN. The cryoprecipitates typically contain
section and measure approximately 30 to 35 nm in anti-HCV IgG with specificity for HCV RNA, in
diameter. Small, spoke-like peripheral projections may particular the viral nucleocapsid-core.
be seen on the outer aspect of the annular structures HCV infects B lymphocytes and may stimulate
(16). Importantly, the organized substructure may be cryoglobulin production and promote inflammation by
only focally present and must be specifically sought engaging Toll-like receptors and via binding of HCV
under high-power examination. Other types of orga- envelope protein E2 to a cellular receptor, CD81,
nized structure, including “finger-prints” and crystal- present on the surface of hepatocytes and B cells (23).
line arrays, have also been reported in cryoglobulin The IgM RF is thought to be produced by HCV-
deposits. Endothelial tubuloreticular inclusions are of- infected B cells. There is evidence that the IgM anti-
ten present and may reflect HCV infection or previous bodies within the mixed cryoglobulins have specificity
exposure to IFN therapy. for the portion of the E2 envelope protein that binds to
CD81 (24).
Most HCV-related GN is mediated by glomeru-
Clinical-Pathologic Correlation
lar deposition of cryoglobulin, with subsequent com-
HCV-GN may have a relapsing course, with
plement activation and inflammation. Because cryo-
exacerbations linked to episodic fluctuations in se-
globulins are large molecules, they are likely to
rum cryoglobulin levels. Approximately 50% of
become concentrated in the glomerular capillary lu-
cases progress to end-stage kidney disease (7), and
mina in the course of glomerular filtration, promoting
recurrence in the renal allograft has been described concentration-dependent (rather than temperature-de-
(17). The management of HCV-associated GN is pendent) precipitation in the glomerular capillary bed.
complicated by a paucity of strong evidence-based Why only some HCV-infected patients develop cryo-
recommendations (18). This topic was discussed globulinemia and glomerular disease remains obscure.
recently in NephSAP (19) and in a comprehensive This may reflect inherent nephritogenic characteristics
review article (20). In cases with moderate protein- of particular cryoglobulin molecules, such as affinity
uria and/or slow decline in kidney function, first- for fibronectin (25) and/or immunogenetic differences
line therapy consists of antiviral therapy (Peg-IFN, in individual patients that govern immune responses
with or without Ribavirin) with the goal of clearing and clearance of cryoglobulins (26). The recent gen-
HCV RNA from the circulation (20). This approach eration of the transgenic thymic stromal lymphopoi-
has shown benefit in reducing proteinuria in cases etin mouse, which develops mixed cryoglobulinemia
of HCV-associated MPGN, MGN, and FGN and MPGN, is providing new pathogenetic insights
(6,21,22), although there is a high rate of clinical into the underlying immunologic and molecular mech-
relapse after therapy is discontinued. For cases with anisms of glomerular injury (27).
more severe glomerular disease (i.e., nephrotic range
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14. Baid S, Pascual M, Williams WW Jr, Tolkoff-Rubin N, Johnson SM, ulonephritis. Nephrol Dial Transplant 24: 2745–2751, 2009
Collins B, Chung RT, Delmonico FL, Cosimi AB, Colvin RB: Renal 27. Kowalewska J, Muhlfeld AS, Hudkins KL, Yeh MM, Farr AG,
thrombotic microangiopathy associated with anticardiolipin antibod- Ravetch JV, Alpers CE: Thymic stromal lymphopoietin transgenic
ies in hepatitis C-positive renal allograft recipients. J Am Soc Nephrol mice develop cryoglobulinemia and hepatitis with similarities to
10: 146 –153, 1999 human hepatitis C liver disease. Am J Pathol 170: 981–989, 2007
Section 5: CASE PRESENTATION serum albumin level of 3.6 g/dl. Urinalysis contains 300
mg/dl protein, and microscopic examination of the uri-
A 57-year-old Caucasian man is discovered to have nary sediment reveals 8 red blood cells (RBCs) per
microscopic hematuria, subnephrotic proteinuria, and re- high-power field and no casts. Serum IgA level is ele-
nal insufficiency. Past medical history is significant for vated, but all other serologies are negative or normal,
hypertension for 3 years. There is no history of diabetes including serum complement levels (C3 and C4), anti-
and no family history of renal disease. Physical exami- nuclear antibody, hepatitis B surface antigen, hepatitis C
nation reveals no edema and BP of 120/92 mmHg on antibody, anti-neutrophil cytoplasmic antibody (ANCA),
antihypertensive medications. The patient denies any and anti– glomerular basement membrane (anti-GBM)
history of recent infection, rash, arthralgias, or abdominal antibody. No monoclonal spike is detected by serum
pain. Laboratory evaluation includes serum creatinine protein electrophoresis. The kidneys measure 11.7 and
level of 1.7 mg/dl, 24-hour urine protein of 1.0 g, and 12.2 cm in length by ultrasound.
Figure 1. Figure 2. IgA
Figure 3.

A. Lupus nephritis class II
B. IgA nephropathy (IgAN)
C. Henoch-Schönlein purpura (HSP) nephritis
D. Resolving postinfectious glomerulonephritis
E. Minimal change disease with diffuse mesangial hypercellularity
297
Answer rare in individuals of African descent. The biopsy

Light microscopy revealed diffuse and global prevalence of IgAN ranges from ⬍10% in North
mesangial hypercellularity, defined as more than three America to 20 to 30% in Western Europe and
cells per mesangial region, affecting all 15 glomeruli Australia (8) and 40% in Japan (1). All ages are
in the biopsy (Figure 1). No glomeruli with endocap- affected, but most cases are diagnosed during the
illary proliferation, necrotizing features, crescents, or second and third decades of life. There is a male
segmental sclerosis were identified. Tubular atrophy predominance in Caucasians, equal gender distribu-
and interstitial fibrosis affected approximately 10% of tion in Asians, and female predominance in African
the cortex. Immunofluorescence microscopy showed Americans (9).
dominant 3⫹ diffuse and global mesangial staining for IgAN has diverse renal clinical presentations, but
IgA (Figure 2), with trace mesangial positivity for IgG most patients have hematuria (10). Gross hematuria
and IgM, 1 to 2⫹ C3, negative C1q, 2⫹ ␬ light chain, (which may be recurrent) is more common in children,
and 3⫹ ␭ light chain. The staining is centered in the whereas persistent microscopic hematuria is more com-
axial regions of the glomerulus, consistent with the mon in adults. Gross hematuria is often associated with
mesangium, with sparing of the glomerular capillary concurrent upper respiratory tract infection (i.e., synphar-
walls. Electron microscopy shows electron-dense deposits yngitic hematuria) or gastroenteritis. Proteinuria is gen-
within the mesangial matrix with pooling in the paramesan- erally mild (⬍1 g/d) or absent in children and is more
gial region (Figure 3). RBCs are present in the urinary common, but usually subnephrotic, in adults. Less
space. In this patient with negative serologies and absence of common presentations include nephrotic syndrome,
systemic disease, the dominant staining for IgA is diagnostic rapidly progressive glomerulonephritis, mixed ne-
of IgA nephropathy (IgAN). phrotic/nephritic syndrome, and chronic renal failure.
Some patients who have IgAN and present with ne-
IgA Nephropathy phrotic syndrome have coexistent minimal change
IgAN is the most common primary glomerular disease or membranous nephropathy (see Pathology
disease worldwide (1). IgAN is defined by the section). A subset of patients with IgAN and rapidly
findings of dominant or co-dominant glomerular progressive kidney failure and diffuse crescentic glo-
staining for IgA (compared with other immunoglob- merulonephritis have overlapping ANCA disease (ei-
ulins) on pathologic examination, in the absence of ther IgG or IgA ANCA with specificity for myeloper-
systemic lupus erythematosus. Although secondary oxidase) (11).
forms of IgAN may be encountered in a variety of Approximately 25% of patients with IgAN
systemic diseases (including chronic liver disease, have hypertension at initial presentation. Renal in-
ankylosing spondylitis, rheumatoid arthritis, Reiter sufficiency is usually absent in children, but some
syndrome, celiac disease, ulcerative colitis, and der- patients with gross hematuria have reversible acute
matitis herpetiformis, among others) (2), most cases renal failure as a result of acute tubular injury
of IgAN are primary. Primary IgAN has a variable associated with numerous RBC casts. In older pa-
clinical course, with slow progression to ESRD tients, particularly those with proteinuria and hyper-
occurring in approximately 30% of patients within tension, serum creatinine is often mildly elevated.
20 years (3). Clinical features associated with worse Serum complement C3 and C4 levels are typically
outcomes in IgAN include elevated serum creati- normal. Serum IgA and IgA-fibronectin levels may
nine, degree of proteinuria, systemic hypertension, be elevated, but these tests have no diagnostic or
and failure to achieve proteinuria ⬍1 g/d after prognostic significance.
therapy (3–5). In addition, the recently published
Oxford Classification of IgAN has identified patho-
Pathology
logic features that are prognostically significant, Light Microscopy. The pathologic spectrum of
independent of clinical characteristics (6,7). IgAN is broad and includes minimal or no glomerular
alterations by light microscopy, focal or diffuse mes-
Clinical Characteristics angial hypercellularity, endocapillary and extracapil-
IgAN affects all ethnic groups but seems to be lary proliferation, and segmental or global glomerulo-
most common in Asians and Native Americans and sclerosis. Mesangial hypercellularity (defined as ⬎3
Figure 4. A glomerulus displays endocapillary proliferation

and leukocyte infiltration occluding many capillary lumina.
Magnification, ⫻400 (PAS). Figure 6. A glomerulus contains a nearly circumferential
cellular crescent. The underlying tuft displays mesangial
cells per mesangial area) is usually present. Endocap- and endocapillary proliferation with infiltrating leukocytes.
Magnification, ⫻400 (PAS).
illary hypercellularity is variable (Figure 4) and is
typically focal and segmental, whereas other cases
Crescents and segmental fibrinoid necrosis are vari-
may have global endocapillary proliferation with in-
ably present (Figure 6) and occasionally affect ⬎50%
filtrating leukocytes. Some cases show membranopro-
of glomeruli (consistent with “crescentic IgA nephrop-
liferative features, with segmental or global peripheral
athy”). Segmental sclerosis and hyalinosis lesions are
mesangial interposition and duplication of GBMs. Im-
not uncommon (Figure 7) and may show residual
mune deposits may be seen in the mesangium and
underlying endocapillary hypercellularity or fibrous
subendothelial region; these deposits appear eosino-
crescent formation, consistent with scarring of seg-
philic with hematoxylin and eosin stain and fuchsino-
mental proliferative lesions. Globally sclerotic
philic (red or orange) with trichrome stain (Figure 5).
glomeruli are common in older patients and may be
related to age, hypertension, or progression of
Figure 7. A glomerulus contains a segmental scar (segmen-

Figure 5. A glomerulus contains many subendothelial and tal sclerosis) associated with an overlying small segmental
mesangial deposits that stain orange-red with trichrome fibrocellular crescent. Mesangial hypercellularity involves
stain. Magnification, ⫻600 (trichrome). the adjacent tuft. Magnification, ⫻400 (PAS).
IgAN. The degree of tubular atrophy and interstitial biopsies. There is typically staining for complement
fibrosis ranges from mild to severe (Figures 8 and 9) C3, without C1q, consistent with complement acti-
and is usually commensurate with the degree of glomeru- vation via the alternative and/or lectin pathways.
losclerosis. Proximal tubules may contain RBC casts and Staining for ␭ light chain is usually stronger than ␬,
show degenerative and regenerative features. Arteriosclero- reflecting the normal predominance of the ␭ isotype
sis and arteriolosclerosis are more common in older patients in circulating IgA molecules. Peripheral capillary
and those with a history of hypertension. Features of acute wall staining for IgA is seen in cases with endocap-
thrombotic microangiopathy (i.e., intravascular thrombi) illary proliferative or membranoproliferative fea-
may be seen in cases of advanced chronic IgAN with severe tures. Rare cases of coexistent IgAN and membra-
hypertension (12). Arteritis is not a feature of IgAN and, if nous nephropathy have been described and can be
present, suggests the differential diagnoses of HSP nephritis identified by their diffuse granular capillary wall
or coexistent ANCA vasculitis. staining for IgG and mesangial staining for IgA
Immunofluorescence. Dominant or co-dominant (13).
mesangial staining for IgA is the hallmark of IgAN. Electron Microscopy. Electron-dense deposits are
Weaker staining for IgG and IgM is seen in some seen at sites corresponding to the immunofluorescence
staining. Mesangial deposits are the most typical find-
ing and tend to aggregate beneath the GBM reflection
over the mesangium, a location referred to as “parame-
sangial” (Figure 3). Peripheral capillary wall deposits
are less common and usually subendothelial, associ-
ated with endocapillary proliferation. Occasional seg-
mental intramembranous or subepithelial deposits may
also occur. Some cases have localized textural changes
in the GBM such as segmental thinning and basket-
weave lamellation. These findings may reflect remod-
eling of basement membranes following resorption of
capillary wall deposits and are a likely source of
glomerular hematuria. Diffuse thinning of GBMs
should suggest coexistent thin basement membrane
Figure 8. This case of IgAN has well-preserved tubules with nephropathy. Podocyte foot process effacement is gen-
no significant interstitial fibrosis. Magnification, ⫻200 erally mild and focal in mesangial IgAN but more
(trichrome). diffuse in endocapillary proliferative forms with wide-
spread peripheral capillary wall deposits. Rare cases of
IgAN show diffuse foot process effacement and ex-
clusively mesangial deposits; if this is accompanied by
a clinical history of abrupt onset of nephrotic syn-
drome, a diagnosis of minimal change disease with
IgA deposits is warranted.
The differential diagnosis of IgAN includes other
conditions in which dominant IgA glomerular deposits
may occur. HSP nephritis is considered to be a sys-
temic form of IgAN manifesting purpuric rash (typi-
cally of the lower extremities), arthralgias, abdominal
pain/hematochezia, and glomerulonephritis. Not all
patients with HSP exhibit the full clinical syndrome.
Figure 9. In this example of IgAN, interstitial fibrosis and
HSP can occur at any age but is most prevalent in
tubular atrophy occupy approximately 60% of the cortex. young children and is usually transient. In some pa-
Magnification, ⫻200 (trichrome). tients with HSP, the multisystem disease resolves but
active IgAN persists for years. Deposits of IgA are related with renal outcomes, neither has been uni-
detectable in the glomeruli and in vasculitic lesions in versally adopted (7). Moreover, pathologic class did
the skin and gut. Other diagnostic considerations in- not predict renal outcomes independent of clinical
clude lupus nephritis, IgA-dominant acute postinfec- presenting features (e.g., hypertension, proteinuria)
tious glomerulonephritis (14,15), and HIV-related im- (21) or show superiority to a semiquantitative as-
mune complex glomerulonephritis (16). In addition, sessment of the degree of tubular atrophy and inter-
IgA cryoglobulinemia and IgA monoclonal gammopa- stitial fibrosis (22). The Oxford Classification of
thy may give rise to glomerular disease with IgA- IgAN was designed to identify pathologic features
dominant deposits. Clinical-pathologic correlation is that show high interobserver reproducibility and
necessary to distinguish these conditions from IgAN. predict adverse clinical outcome (rate of decline of
estimated GFR) independent of clinical variables at
Clinical-Pathologic Correlation time of biopsy or during follow-up (6,7). Therefore,
Most patients who have IgAN and present with it is best considered a prognostic grading system
hematuria, mild proteinuria, and preserved kidney rather than a comprehensive classification. Impor-
function have biopsy findings of mesangial hyper- tantly, because patients with HSP, proteinuria ⬍0.5
cellularity, focal proliferation, and/or focal glomer- g/d, estimated GFR ⬍30 ml/min, or ESRD in ⬍12
ulosclerosis. Heavier proteinuria and renal insuffi- months from onset were excluded, the Oxford co-
ciency are associated with more diffuse hort does not represent the complete spectrum of
endocapillary proliferation and subendothelial cap- IgAN. Among the study group of 265 IgA biopsies,
illary wall IgA deposits, as well as more sclerosing one third from children who were younger than 18
glomerular lesions. Diffuse crescentic disease years, four pathologic variables that fulfilled the
(⬎50% crescents) is associated with rapidly pro- aforementioned criteria were identified: Mesangial
gressive renal failure and acute nephritic syndrome. hypercellularity, Endothelial hypercellularity, Seg-
Some cases of IgAN with gross hematuria and acute mental glomerulosclerosis, and Tubular atrophy-
renal failure show relatively mild glomerular dis- interstitial fibrosis. These pathologic lesions consti-
ease but severe acute tubular injury as a result of tute the Oxford-MEST score (Table 1) (6,7).
numerous RBC casts. In this context, the acute The M (mesangial) score is calculated as fol-
kidney injury usually resolves as the hematuria lows: Each glomerulus is graded as 0 (⬍4 mesangial
subsides. IgAN presenting with chronic renal failure cells/mesangial area), 1 (4 to 5 mesangial cells/
generally shows diffuse glomerulosclerosis and ad- mesangial area), 2 (6 to 7 mesangial cells/mesangial
vanced tubular atrophy and interstitial fibrosis. area), or 3 (ⱖ8 mesangial cells/mesangial area). An
Cases with severe/accelerated hypertension may de- average score ⱕ0.5 is assigned M0, and a score of
velop arteriolar changes of thrombotic microangi- ⬎0.5 is assigned M1. In practice, if ⬎50% glomer-
opathy. uli have ⬎3 cells in a mesangial area, then the score
Numerous studies have identified associations is M1 (6). E1 is defined by increased number of
between clinical features and outcomes in IgAN. Of cells within glomerular capillary lumina causing
these, the most significant are elevated serum creati- narrowing of the lumina. S1 is defined by subtotal
nine (or low GFR), degree of proteinuria, persistence capillary obliteration by sclerosis or a synechial
of proteinuria despite therapy, and elevated mean attachment to Bowman’s capsule. Tubular atrophy
arterial BP. Most— but not all (17)—studies indicate and interstitial fibrosis are graded on the basis of the
worse outcomes in male patients. area of cortex involved: T0, 0 to 25%; T1, 26 to
Overall, childhood IgAN seems to have a more 50%; or T2, ⬎50%. Each of these pathologic fea-
benign course than the adult disease, and proliferative tures (M ⬎0.5, E1, S1, T1, and T2) are indepen-
lesions seem to have better outcomes in children dently predictive of clinical outcome in both chil-
compared with adults (18). dren (23) and adults with IgAN. Compared with
Oxford Classification/MEST Score. Several adults, children had more severe mesangial prolif-
pathologic classifications of IgAN have been pro- eration, more endocapillary proliferation, less
posed, including those of Lee et al. (19) and Haas chronic tubulointerstitial disease, and less arterio-
(20). Although these two classification systems cor- sclerosis (23). Adoption of this schema should stan-
Table 1. Oxford-MEST classification of IgAN(7)

Pathologic Lesion Score
Mesangial hypercellularity
0 ⫽ ⬍4 mesangial cells/mesangial area M0, ⱕ0.5
1 ⫽ 4–5 mesangial cells/mesangial area M1, ⬎0.5a
2 ⫽ 6–7 mesangial cells/mesangial area
3 ⫽ ⱖ8 mesangial cells/mesangial area (M ⫽ mean score)
Endocapillary proliferation E0, absent
increased no. of cells within glomerular capillary lumina causing luminal E1, present
narrowing (in at least 1 glomerulus)
Segmental glomerulosclerosis or presence of an adhesion (in at least 1 S0, absent
glomerulus) S1, present
Tubular atrophy/interstitial fibrosis T0, 0–25% of cortical area
T1, 26–50% of cortical area
T2, 51–100% of cortical area
a
More than 50% of glomeruli with at least 4 cells/mesangial area ⫽ M1.
dardize the reporting of pathologic features in IgAN polymorphisms of atherosclerosis-associated genes

and facilitate better design of therapeutic studies. (glycoprotein Ia and intercellular adhesion molecule
However, the Oxford-MEST score requires valida- 1) in progression of IgAN (28). Some patients with
tion in other patient populations, particularly those IgAN have heightened mucosal sensitivity to infec-
with more severe disease (including crescents), who tious pathogens or certain food antigens, such as
were not well represented in the original study gluten and ovalbumin, which may be important in
cohort (24). the onset of disease (29). Thus, it is likely that both
The biopsy presented in the index case had genetic susceptibility and environmental factors
diffuse mesangial proliferation only, consistent with contribute to disease expression.
a MEST score of M1, E0, S0, T0. The pathogenesis of primary IgAN is thought to
involve abnormalities of IgA structure that predispose
Etiology and Pathogenesis
Whether primary IgAN is a single disease to mesangial deposition and autoimmune responses to
entity or a clinicopathologic syndrome resulting the aberrant IgA molecules. Importantly, IgAN is
from diverse etiologies and pathogenetic mecha- associated with undergalactosylation of the hinge re-
nisms is uncertain. A role for genetic factors is gion of polymeric IgA1 molecules present in the
suggested by the different prevalence of IgAN in circulation and in the mesangial deposits. Defective
different ethnic groups and the occasional familial IgA galactosylation may be genetically determined or
cases. Linkage analysis studies in families with due to an acquired functional defect in the activity of
IgAN have identified multiple loci and risk alleles, the main galactosyl transferase enzymes (30). Abnor-
indicating that IgAN is likely a polygenic disease mal IgA1 galactosylation has been linked to reduction
(or multiple diseases). These include a major dis- in ␤1,3,galactosyltransferase activity and increase in
ease locus (IGAN1) on chromosome 6q22-23 in N-acetylgalactosamine-specific ␣2,6-sialyltransferase
Caucasian families, with a dominant mode of trans- activity (31). In support of this mechanism, a model of
mission and incomplete penetrance (25). Variants of IgAN has been produced in ␤1,4,galactosyltransferase
genes encoding IL5RA and TNFRSF6B, a decoy 1– deficient mice (32). T cell cytokine polarity may
receptor for a TNF family ligand, have been asso- also play a role in determining patterns of IgA galac-
ciated with sporadic IgAN (26). Most recently, a tosylation (33).
genome-wide analysis of familial and sporadic Circulating undergalactosylated IgA1 has been
cases of IgAN in white European patients identified shown to trigger an autoimmune response, with for-
a strong association with the HLA locus on chro- mation of anti-glycan IgG and IgA antibody-contain-
mosome 6p but not with other loci (27). A study of ing immune complexes (34,35). This may occur
Japanese patients identified a potential role for through an autoimmune response to the abnormal IgA
molecules or via molecular mimicry between the un- 11. Bollee G, Noel LH, Suarez F, Royal V, Gilardin L, de Serre NP,
El-Ghoul B, Lesavre P, Alyanakian MA, Fakhouri F: Pauci-immune
dergalactosylated IgA1 and microbial antigens. The crescentic glomerulonephritis associated with ANCA of IgA class.
defect in galactosylation also may promote self-aggre- Am J Kidney Dis 53: 1063–1067, 2009
gation of IgA1 molecules. The abnormal IgA1 mole- 12. Chang A, Kowalewska J, Smith KD, Nicosia RF, Alpers CE: A
clinicopathologic study of thrombotic microangiopathy in the setting
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Tomino Y, Mestecky J, Novak J: IgA1-secreting cell lines from bodies with restricted heterogeneity. J Clin Invest 119: 1668 –1677,
patients with IgA nephropathy produce aberrantly glycosylated IgA1. 2009
J Clin Invest 118: 629 – 639, 2008 36. El Karoui K, Hill GS, Karras A, Moulonguet L, Caudwell V,
32. Nishie T, Miyaishi O, Azuma H, Kameyama A, Naruse C, Hashimoto Loupy A, Bruneval P, Jacquot C, Nochy D: Focal segmental
N, Yokoyama H, Narimatsu H, Wada T, Asano M: Development of glomerulosclerosis plays a major role in the progression of IgA
immunoglobulin A nephropathy-like disease in beta-1,4-galactosyl- nephropathy. II. Light microscopic and clinical studies. Kidney Int
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Section 6: CASE PRESENTATION cutaneous manifestations. His medications include Atripla

(efavirenz, tenofovir, and emtricitabine), lisinopril, hydro-
A 60-year-old Caucasian man presents with a 6-week chlorothiazide, pravastatin, ezetimibe, and an insulin pump.
history of fatigue, weight loss, anorexia, and dysgeusia and The patient has a hematocrit of 26.2%, albumin of 4.3 g/dl,
is found to have nonoliguric acute kidney injury with a CD4 count of 397 cells/ml, HIV viral load of 48 copies/ml,
creatinine level of 5.2 mg/dl, increased from a baseline of and a urine protein-to-creatinine ratio of 2.51 g. Urinalysis
1.3 mg/dl 3 months earlier. The patient’s past medical reveals 2⫹ proteinuria and a bland urine sediment. The
history is notable for HIV infection, diabetes, hypertension, kidneys are normal in size by ultrasound. The patient’s
and hyperlipidemia. Physical examination reveals a BP of creatinine fails to improve with hydration, and a renal
160/80 mmHg, a weight of 147 lb, and no edema or biopsy is performed.
Figure 1. Figure 2.
Figure 3. Figure 4.

A. Toxic acute tubular necrosis (ATN) related to treatment
with tenofovir
B. HIV-associated nephropathy
C. Acute interstitial nephritis
D. Ischemic ATN
Figure 5. Kappa light chain E. Myeloma cast nephropathy (MCN)
305
Answer tion, radiocontrast, infection, or nonsteroidal anti-

The renal biopsy findings are diagnostic of my- inflammatory drug use (3–5).
eloma cast nephropathy (MCN). Figure 1 shows dif- The degree of proteinuria is variable in patients
fuse acute tubular injury associated with many brightly with MCN. Because MCN is a tubulointerstitial lesion
eosinophilic tubular casts. A distinctive feature of with intact glomerular filtration barrier, only subne-
MCN is that the casts stain minimally or not at all with phrotic albuminuria is typically seen. Conversely, the
the periodic acid–Schiff (PAS) (Figure 2). At higher quantity of light chain proteinuria may exceed ne-
magnification, the tubular casts are frequently sur- phrotic range (i.e., ⬎3 g/day); therefore, patients with
rounded by intraluminal multinucleated giant cells MM and MCN may have minimal proteinuria by
(Figure 3) and appear fractured with sharp edges dipstick urinalysis (which detects only albumin) but a
(Figure 4). Immunofluorescence staining of the casts disproportionately high level of proteinuria by 24-hour
is strongly positive for ␬ light chain (Figure 5) with urine protein quantification. A serum or urine mono-
negativity for ␭ light chain and all other immune clonal spike (M-spike) is found by electrophoresis in
reactants. 75 and 73% of patients with MM, respectively (6).
After receipt of the renal biopsy results, the When more sensitive immunoelectrophoresis is used,
patient was found to have free ␬ light chains in the a serum or urine M-spike is detected in 90 and 80% of
urine but no evidence of a monoclonal serum spike. patients, respectively (6). These values apply to a
Bone marrow biopsy revealed 25% plasmacytosis with patient population with MM; the corresponding per-
␬ light chain restriction. The patient was given a centages for patients with MCN are undoubtedly
diagnosis of multiple myeloma (MM), and chemother- higher.
apy was initiated. Ten months later, he has a creatinine The incidence of MCN is difficult to determine
of 1.7 mg/dl. because many patients with MM and AKI are not
subjected to renal biopsy. Three autopsy studies on
Myeloma Cast Nephropathy patients with MM identified MCN as the most com-
Light chain cast nephropathy (LCCN) is the most mon pattern of dysproteinemia-associated renal dis-
common histologic finding in patients with multiple ease, seen in 30% (7), 32% (8), and 48% (9) of
myeloma (MM), plasma cell dyscrasia, or dysproteine- postmortem examinations. By contrast, a renal bi-
mia (1). Because the overwhelming majority of pa- opsy– based series of patients with monoclonal gam-
tients with LCCN have evidence of MM, this condi- mopathy from Vanderbilt University found MCN to be
tion is more commonly referred to as myeloma cast less frequent than cryoglobulinemic glomerulonephri-
nephropathy (MCN) or simply “myeloma kidney.” tis or monoclonal Ig deposition disease (10). In our
Histologic findings in MCN are confined to the tu- experience at Columbia University, primary amyloid-
bules and interstitium and include widespread tubular osis is the only dysproteinemia-associated renal dis-
injury associated with distinctive, atypical tubular ease seen more commonly on renal biopsy than MCN.
casts that are composed of monoclonal light chains.
Pathology
Clinical Characteristics Light Microscopy. The predominant light micro-
The majority of patients with MCN present with scopic findings in MCN are widespread proximal and
acute kidney injury (AKI) and evidence of dyspro- distal tubular degenerative changes accompanied by
teinemia. When this occurs in the setting of known distinctive, atypical distal tubular casts (1). The tubu-
MM, a renal biopsy may not be performed. In contrast, lar degenerative changes resemble findings in ATN
a presentation of AKI with biopsy findings of MCN and include luminal ectasia, cytoplasmic simplifica-
may be the initial manifestation of dysproteinemia, in tion, irregular luminal contours, loss of brush border,
which case approximately 90% of patients will meet prominent tubular epithelial nucleoli, and apoptotic
criteria for MM (2). Less commonly, MCN may figures. The myeloma casts lie mainly in distal tubules
present with more indolent, subacute to chronic and collecting tubules, stain brightly with hematoxylin
renal insufficiency. In patients with an acute pre- and eosin (H&E), appear pale or nonreactive with PAS
sentation of MCN, a precipitating event or exposure stain, and exhibit polychromasia (mixed red and blue
is often identified, such as hypercalcemia, dehydra- staining) with trichrome stain. The casts often have a
hard appearance with sharp edges and lines of fracture. Pathogenesis

In some cases, the casts form striking rhomboidal, Critical early steps in our understanding of the
trapezoidal, or other geometric crystals. Some of the pathophysiology of dysproteinemia-associated renal
casts appear lamellated, probably reflecting admixture disorders such as MCN came from studies in which
with Tamm-Horsfall protein (THP). Intratubular animals were administered Bence Jones proteins. In
monocytes, neutrophils, or multinucleated giant cells 1976, Koss et al. (12) administered a single intraperi-
often adhere to the periphery of the casts. In some toneal dose of monoclonal light chain to C3H mice
instances, the casts seem to be fully engulfed within and created an animal model of MCN. A subsequent
the cytoplasm of the multinucleated giant cells. Rare experiment showed that only certain Bence Jones
cases have unusual Congophilic casts composed of proteins could produce this effect (13). A landmark
amyloid fibrils (11). study in 1991 demonstrated that when mice receive
Interstitial inflammation and edema commonly intraperitoneal injections of monoclonal light chains
accompany the cast formation. The interstitial infil- from patients with MCN, light chain deposition dis-
trate is typically composed of lymphocytes, mono- ease, or primary amyloidosis, the identical pattern of
cytes, neutrophils, and plasma cells and may be asso- renal injury develops (14). These studies suggested
ciated with lymphocytic or neutrophilic tubulitis. In that it is the particular amino acid sequence of a
some cases, the interstitial inflammation may be so monoclonal light chain that determines its biochemical
prominent as to lead to a mistaken diagnosis of acute properties and whether it has the potential to precipi-
interstitial nephritis. In other cases, there may be a tate in the renal tubules as MCN or produce an
paucity of abnormal casts but disproportionately se- alternative pattern of dysproteinemia-associated renal
vere interstitial edema and acute tubular injury, lead- disease.
ing to an incorrect diagnosis of ATN. Glomerular and THP is a glycoprotein expressed on the apical
vascular changes are not seen secondary to MCN, and, surface of the medullary thick ascending limb and is a
when present, an alternative cause should be sought. critical component of the distal tubular casts of MCN.
However, in older individuals, underlying biopsy fea- In healthy individuals, small amounts of THP are shed
tures of arterionephrosclerosis of aging are not uncom- into the urine, making THP a major protein constituent
mon. of normal urine. Among patients with dysproteinemia,
monoclonal light chains vary in their binding affinity
Immunofluorescence and Electron Microscopy. Im- for THP. A strong binding affinity for THP correlates
munofluorescence plays a critical role in establishing with a greater potential to develop MCN, and this
the diagnosis of MCN. In the vast majority of cases, binding is enhanced by furosemide, calcium, and acid-
the myeloma casts stain dominantly for a single ity (15,16). Specific reciprocal binding sites between
light chain (either ␬ or ␭), with little or no staining monoclonal light chains and THP have been identi-
for the reciprocal light chain. Rarely, the casts stain fied, and competition studies using peptides derived
with similar intensity for both ␬ and ␭; when this from these sequences are able to block light chain–
occurs, the diagnosis of MCN is more difficult and THP interactions, thereby inhibiting cast formation in
requires integration with the characteristic light mi- vitro (17,18).
croscopic changes as well as an appropriate clinical In addition to distal tubular casts, MCN is char-
history. Immunofluorescence is also helpful in di- acterized by widespread and significant proximal tu-
agnosing coexistent disease processes. For instance, bular injury, indicating that the proximal nephron is
light chain deposition disease is found in a signifi- also targeted. Light chains are very low molecular
cant subgroup of patients with MCN, producing weight proteins that are freely filtered by the glomer-
linear positivity of renal basement membranes for ulus. The proximal tubules are normal sites of cellular
the same pathogenic light chain isotype (2). By uptake and catabolism of filtered light chains. Studies
electron microscopy, the casts of MCN have a on cultured human kidney proximal tubular epithelial
unique, highly electron-dense ultrastructural ap- cells have shown that light chains exhibit a dosage-
pearance with angulated/geometric configurations, dependent toxicity characterized by DNA damage,
adherent monocytes and giant cells, and associated actin-cytoskeletal injury, increased apoptosis, and
acute tubular injury. eventual necrosis, and these events are accompanied
by morphologic changes reminiscent of ATN (19,20).

Bence Jones proteins also are able to induce increased
expression of profibrotic molecules and decreased
expression of E-cadherin, consistent with epithelial-
mesenchymal transformation (21). These observations
suggest that light chain–induced direct proximal tubu-
lar injury plays an important role in the pathogenesis
of MCN. It is likely that many of the precipitants of
MCN (e.g., dehydration, radiocontrast, nonsteroidal
anti-inflammatory drug exposure) act by promoting
proximal tubular injury, in turn resulting in higher
light chain delivery to the distal tubule, where the
critical concentrations required for light chain precip-
itation are reached.
Figure 6. In this example of LCFS, the proximal tubular
epithelia appear swollen and contain intracellular crystalline
Light Chain Fanconi Syndrome inclusions. Magnification, ⫻600 (trichrome).
Light chain proximal tubulopathy, more com-
monly referred to as light chain Fanconi syndrome
(LCFS), is a rare pattern of renal disease that must be
considered in the differential diagnosis of MCN
(22,23). Similar to MCN, LCFS is characterized by
tubular injury and crystalline deposits of monoclonal
light chains. In contrast to MCN, the crystals of LCFS
are intracellular rather than intratubular and are con-
fined to proximal rather than distal tubules. Correlat-
ing with the location of intracellular crystal accumu-
lation, the majority of patients with LCFS have
proximal tubular dysfunction, which manifests as par-
tial or complete Fanconi syndrome. Additional clinical
manifestations include slowly progressive renal dys-
function, subnephrotic proteinuria, and osteomalacia Figure 7. In a case of LCFS, immunofluorescence per-
resulting from chronic phosphaturia. formed on paraffin sections after pronase digestion reveals
The pathologic hallmark of LCFS is crystalline abundant intracellular crystals staining for ␬ light chain
within the tubular epithelial cytoplasm. Staining for all
inclusions within proximal tubular epithelial cells, other immune reactants was negative. Magnification, ⫻600.
usually associated with histologic evidence of acute
tubular injury. The intracellular crystals may be diffi- shaped electron-dense crystals confined to the cyto-
cult to identify by light microscopy and are often best plasm of the proximal tubules and often exhibiting a
visualized with trichrome stain (Figure 6). The crystals regular periodicity on high power examination
may appear rounded or needle-shaped by light micros- (Figures 8 and 9). Some of the crystals are membrane
copy and typically fail to stain with PAS. Because the bound, suggesting that they formed within endosomes
light chains are highly crystallized and inaccessible to or phagolysosomes (Figure 9).
antibody, immunofluorescence on frozen tissue yields Similar to other forms of dysproteinemia-associ-
inconsistent results. In our experience, repeat immu- ated renal disease, the development of LCFS depends
nofluorescence on formalin-fixed, paraffin-embedded on the specific amino acid sequences and resulting
tissue sections after antigen retrieval by enzymatic biologic properties of the monoclonal light chains. The
digestion with pronase (or other protease) may be monoclonal light chains seen in patients with LCFS
needed to confirm the monoclonal light chain compo- are mainly ␬ type, are typically derived from the VK1
sition of the crystals (24) (Figure 7). Ultrastructural subgroup (23), and are resistant to cathepsin B, a
evaluation typically reveals rhomboidal or needle- major proteolytic enzyme in the proximal tubule that
MM at the time of diagnosis or subsequently. How-

ever, most have a clinical picture of “smoldering MM”
with slowly progressive hematologic disease, accom-
panied by relatively indolent renal dysfunction
(22,23). Long-term prognosis is largely determined by
the ability to treat the underlying oncologic disorder.
References
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2006
Section 7: CASE PRESENTATION disease. Physical examination reveals a BP of 140/80

mmHg, height of 6 ft, weight of 201 lb, and no edema.
A 20-year-old Caucasian man presents with nephrotic Laboratory evaluation discloses a serum creatinine of 1.5
range proteinuria and renal insufficiency. Past medical his- mg/dl, 24-hour urine protein of 9.0 g, albumin of 3.2 g/dl,
tory is notable for proteinuria and hematuria since age 5, and bland urine sediment. Serum complements are in the
mild hearing loss, and a 4-year history of hypertension for normal range. Serologic workup is negative for anti-nuclear
which he was being treated with irbesartan. The patient antibody, hepatitis B surface antigen, hepatitis C antibody,
admits to using protein and creatine supplements to improve and HIV. The kidneys measure 14.6 and 14.5 cm by
athletic performance. Family history is negative for renal ultrasound. A renal biopsy is performed.
Figure 1. Figure 2.
Figure 4.
Figure 3.

A. FSGS
B. Hereditary nephritis (HN; Alport syndrome)
C. Minimal change disease
D. Fibrillary glomerulonephritis
E. Membranous nephropathy
311
Answer earliest manifestation of disease and persists through-

The renal biopsy findings are diagnostic of he- out childhood into adolescence. Occasional episodes
reditary nephritis (HN/Alport syndrome) (answer B). of gross hematuria may occur. With disease progres-
As shown in Figure 1, several glomeruli in the biopsy sion, subnephrotic or nephrotic range proteinuria de-
contained discrete lesions of segmental sclerosis (seen velops and is accompanied by declining renal func-
at 2 o’clock) with consolidation of the glomerular tuft tion. Most males with X-linked disease develop
by extracellular matrix and small adhesions to Bow- ESRD, often by age 30. There is increasing recogni-
man’s capsule. Some of the glomerular basement tion that many female carriers of X-linked mutations
membranes (GBMs) are irregularly thickened with also develop progressive renal disease. Extrarenal
focal duplications. Podocytes appear swollen (Figure manifestations of HN include sensorineural hearing
1, periodic acid–Schiff ⫻400). Other glomeruli in the loss and anterior lenticonus (of the eye), owing to the
biopsy (not shown) were unremarkable. Patchy inter- presence of diseased collagen IV networks in the
stitial fibrosis was accompanied by small clusters of Organ of Corti and lens capsule. Genetic testing for
interstitial foam cells (lipid-laden macrophages; Fig- HN has recently become available and involves se-
ure 2, Masson trichrome ⫻400). The 10 glomeruli quencing of the ␣3, ␣4, and ␣5 chains of type IV
sampled for immunofluorescence were negative for collagen in an effort to identify disease-causing muta-
immunoglobulins, complement components, and fi- tions, including splice site, truncating, and missense
brin/fibrinogen. Electron microscopy revealed diffuse mutations, as well as large and small deletions (4). The
thickening and lamellation of the GBMs (Figure 3, development of genetic testing was an arduous process
⫻8000; Figure 4, ⫻15,000). The lamellations replace because of the large size of the type IV collagen genes
and obscure the lamina densa, producing a “basket- and the tremendous heterogeneity of mutations in HN.
weave” appearance. Between the lamellated basement
membrane material are electron lucent zones. No im- Pathology
mune-type electron-dense deposits are identified. The
Light Microscopy. The light microscopic findings in
podocytes display extensive foot process effacement.
HN are nonspecific and depend on the severity of
disease at the time of biopsy. Early in the disease, the
Hereditary Nephritis glomeruli may be normocellular or show mild mesan-
HN is a genetic disorder caused by structural
gial hypercellularity. High-power examination of sil-
defects in type IV collagen, which is an integral
ver or periodic acid–Schiff stained slides may reveal
component of the GBM. HN was first described in
irregular GBM thickening and duplications at the light
1927 by Alport as a progressive familial nephropathy
microscopic level, corresponding to the foci of lamel-
that disproportionately affected males and was associ-
lation seen ultrastructurally. Disease progression is
ated with hearing loss. Since this classic description,
marked by the development of secondary focal seg-
HN is also commonly referred to as Alport syndrome
mental and global glomerulosclerosis accompanied by
(1). The incidence of HN is estimated to be approxi-
increasing tubulointerstitial scarring. Aggregates of
mately 1 in 50,000 live births but because of the
interstitial foam cells, which are lipid-laden macro-
familial nature of the disease, regional differences in
phages, typically accumulate between the tubules. In-
disease frequency are common (2). HN is most com-
terstitial foam cells are a common nonspecific finding
monly transmitted in an X-linked manner (80 to 85%
in diverse glomerular diseases with severe unremitting
of cases) but shows autosomal recessive inheritance in
proteinuria but for unknown reasons tend to be more
approximately 15% of cases and autosomal dominant
abundant in HN than in other conditions with compa-
inheritance in rare cases. Our understanding of the patho-
rable levels of proteinuria.
genesis of HN has grown tremendously in the past two
decades as a result of increased understanding of the Immunofluorescence. Standard immunofluorescence
genetics and molecular structure of type IV collagen. is generally negative in HN. Occasional cases of HN
have Ig and complement staining within the GBM and
Clinical Characteristics mesangium mimicking immune complex–mediated
The natural history of HN is well described (3). glomerulonephritis; however, the immune positivity is
Classically, persistent microscopic hematuria is the thought to be the result of nonspecific trapping of
immune reactants in the lamellated basement mem- tions to form hexamers: ␣1.␣1.␣2(IV)–␣1.␣1.␣2(IV),
branes (5). Immunofluorescent antibodies against the ␣3.␣4.␣5(IV)–␣ 3. ␣ 4. ␣ 5(IV), and ␣ 1. ␣ 1. ␣ 2(IV)–
␣1, ␣3, and ␣5 chains of collagen IV are commercially ␣5.␣5.␣6(IV). The ␣1.␣1.␣2(IV)–␣1.␣1.␣2(IV) net-
available (Wieslab, Lund, Sweden) and may help to work is expressed in all renal basement membranes
confirm the diagnosis of HN and provide prognostic including the GBM, tubular basement membranes
information (see Etiology and Pathogenesis section). (TBMs), and Bowman’s capsule. No known mutations
Electron Microscopy. Electron microscopy is re- in the ␣2 chain have been described, whereas rare
quired to establish a pathologic diagnosis of HN. patients with COL4A1 mutations and HANAC syn-
Classically, GBMs show prominent thickening and drome (Hereditary Angiopathy, Nephropathy, Aneu-
lamellation resulting in a “basket-weave” appearance, rysms, and muscle Cramps) have been reported (7).
and the podocytes overlying the abnormal basement The ␣3.␣4.␣5(IV)–␣3.␣4.␣5(IV) network is the main
membranes display variable foot process effacement. form of type IV collagen in the mature GBM and is
The lamellations form in the plane of the lamina densa also present in distal TBMs. The ␣1.␣1.␣2(IV)–
and typically enclose electron lucent zones. Minute ␣5.␣5.␣6(IV) hexamer is restricted to Bowman’s cap-
electron-dense granulations may collect between some sule and collecting duct TBMs.
of the lamellations. Early in the disease course in All known mutations that cause HN are found in
young males or at any point in adult females, the major COL4A3, COL4A4, or COL4A5. The majority of
ultrastructural finding may be GBM thinning (typi- cases of HN are X-linked and have mutations in
cally ⬍225 nm). Careful search under the electron COL4A5. In contrast, autosomal inheritance of HN is
microscope may reveal only rare foci of subtle textural associated with mutations in the ␣3 and/or ␣4 chain.
changes, such as early lamination, reticulation, and The ␣3.␣4.␣5(IV)–␣3.␣4.␣5(IV) network is the
scalloping, making differentiation from thin basement major collagen IV network in the mature GBM. In
membrane nephropathy difficult (if not impossible) on glomerular development, ␣1.␣1.␣2(IV)–␣1.␣1.␣2(IV)
morphologic grounds. In the setting of a strong family predominates in the immature GBM and must undergo
history of HN and ultrastructural findings of GBM a developmental switch with replacement by
thinning without well-developed lamellations, we of- ␣3.␣4.␣5(IV)–␣3.␣4.␣5(IV) as the GBM matures. In
ten use the term “hereditary nephritis with thin base- patients with HN, there is a failure of this normal
ment membrane phenotype” to indicate that it is not maturation process, leading to persistence of the im-
possible to differentiate with certainty between thin mature ␣1.␣1.␣2(IV)–␣1.␣1.␣2(IV) network in the
basement membrane nephropathy and early HN. GBM. As a result, the GBM of patients with HN
contains predominantly ␣1.␣1.␣2(IV)–␣1.␣1.␣2(IV)
Etiology and Pathogenesis rather than ␣3.␣4.␣5(IV)–␣3.␣4.␣5(IV). This is
Recent advances in our understanding of the clearly an oversimplification because intact or dis-
structure of type IV collagen coupled with the avail- rupted staining for the ␣3 and ␣5 chains of type IV
ability of genetic testing have led to dramatic progress collagen can be demonstrated by immunofluorescence
in unraveling the pathogenesis of HN, as reviewed by in a significant percentage of adult patients with HN.
Hudson et al. (6). The type IV collagen gene family It is likely that the size, type, and location of the
consists of six distinct ␣ chains (␣1 through ␣6), mutations within the COL4A3, COL4A4, and
each encoded by a separate gene. Genes for COL4A5 genes determine the relative contribution of
COL4A1 and COL4A2 are on chromosome 13, the ␣3.␣4.␣5(IV)–␣3.␣4.␣5(IV) and ␣1.␣1.␣2(IV)–
COL4A3 and COL4A4 are on chromosome 2, and ␣1.␣1.␣2(IV) to the GBM in individual patients
COL4A5 and COL4A6 are on the X chromosome. with HN.
These six ␣ chains assemble into triple helical protom- Our improved understanding of collagen IV dis-
ers that in turn form hexamers that are found in tribution in the kidney is useful in the renal biopsy
basement membranes. Despite the large number of diagnosis of HN (8). Antibodies directed against the
hypothetical combinations, only three triple helical ␣1, ␣3, and ␣5 chains of collagen IV have been
protomers are known to occur: ␣ 1. ␣ 1. ␣ 2(IV), commercially available for more than a decade (Wi-
␣3.␣4.␣5(IV), and ␣5.␣5.␣6(IV). Furthermore, these eslab). A normal staining pattern shows ␣1 in all
protomers are known to pair up in only three combina- basement membranes of the kidney; ␣3 in the GBM
Table 1. Usual expression patterns of ␣ subunits of type IV collagen

Parameter ␣1 in Kidney ␣3 in Kidney ␣5 in Kidney ␣5 in Skin
Normal and thin basement membrane All renal BMs GBM, D-TBM GBM, D-TBM, BC EBM
nephropathy
X-linked hereditary nephritis (male) All renal BMs Negative Negative Negative
X-linked hereditary nephritis (female) All renal BMs Mosaica Mosaica Mosaica
Autosomal recessive hereditary nephritis All renal BMs Negative D-TBM, BC EBM
BM, basement membrane; D-TBM, distal tubular BM; BC, Bowman’s capsule; EBM, epidermal BM.
a
Mosaic pattern: Normal distribution with intermittent, segmental areas with loss of positivity.
and distal TBMs; and ␣5 in the GBM, distal and (Figure 5). In contrast, there was complete absence of
collecting tubular TBMs, and Bowman’s capsule. In ␣3 and ␣5 from glomerular and distal TBMs and
males with X-linked HN, ␣5 staining may be reduced complete absence of ␣5 from Bowman’s capsule
or lost in the GBM, distal TBMs, and Bowman’s (Figure 6). Female carriers of X-linked mutations
capsule. Staining for ␣3 is similarly altered because in typically show discontinuous staining (“skip areas”)
the absence of intact ␣5, the ␣3.␣4.␣5 protomer does for ␣3 and ␣5 in GBMs rather than complete loss. This
not assemble normally and fails to become incorpo- can be explained by random inactivation of the mu-
rated into basement membranes (9). In homozygous tated X chromosome in individual podocytes during
mutations of autosomally encoded COL4A3 or development, causing females to be mosaics.
COL4A4, decreased staining for ␣3 and ␣5 in the Immunofluorescence studies on skin biopsy speci-
GBM and TBMs is seen, but ␣5 staining within mens may also provide useful information in X-linked HN
Bowman’s capsule is preserved because the ␣5.␣5.␣6 because the ␣1.␣1.␣2(IV)–␣5.␣5.␣6(IV) network is nor-
protomer is not affected (Table 1) (10). mally expressed in the epidermal basement membrane.
Although immunostaining for the ␣1, ␣3, and ␣5 Complete loss of ␣5 may be seen in males with
chains of collagen IV is useful, this approach has COL4A5 mutations. Because females are a mosaic for
limitations. A significant minority of patients with HN the mutation, the loss of immunoreactivity for
exhibit normal staining for the subtypes of collagen COL4A5 is typically segmental or discontinuous (Ta-
IV; although the precise percentage is unclear, it has ble 1). Again, whereas the loss of staining in the
been suggested to be in the range of 20% (11) and in epidermal basement membrane seems to be specific
our experience is closer to 50%. The presence or for the diagnosis of X-linked HN, a normal staining
absence of staining for ␣3 and ␣5 likely depends on pattern is seen in approximately 30% of patients as
the severity of the mutation. Patients with large dele- well as in all patients with autosomal forms of HN
tions or frame shift or truncating mutations are likely
to have loss of staining. By contrast, patients with
smaller mutations (e.g., missense mutations leading to
single amino acid substitutions) may exhibit an essen-
tially normal staining pattern, making it impossible to
exclude the diagnosis of HN on the basis of immuno-
fluorescence alone. We previously stained for ␣3 and
␣5 type IV collagen in 16 cases of biopsy-proven HN
and found that the mean age at the time of biopsy was
16.3 years in patients with loss of staining (and there-
fore likely larger mutations), as compared with 36.6
years in patients with intact staining (and likely
smaller mutations; P ⫽ 0.03) (12).
Staining for the subtypes of type IV collagen was
performed in the case of the 20-year-old man pre- Figure 5. Immunofluorescence staining for ␣1 chain of type
sented herein. It revealed positivity for the ␣1 subunit IV collagen is positive in all renal basement membranes.
in all renal basement membranes, including the GBM Magnification, ⫻400.
and higher rates of hearing loss and ocular disease (4).

Rate of progression to ESRD and hearing loss was also
shown to be mutation dependent in a large European
study of more than 400 males with COL4A5 muta-
tions. Large deletions, nonsense mutations, and muta-
tions associated with a change in the reading frame
were associated with 90% probability of ESRD by age
30 years, whereas missense or splice-site mutations
showed only 50 and 70% risk, respectively. Hearing
loss before age 30 was seen in 60% of patients with
missense mutations but in 90% of patients with all
other types of mutations (14).
Phenotype– genotype correlation in female carri-
ers has also been examined. As would be expected,
female heterozygotes have less severe renal disease
than males with only 12% reaching ESRD by age 40
(compared with 90% of males). Notably, the risk for
progression to ESRD increases significantly with age:
There is a 30 to 40% rate of ESRD in female carriers
who are older than 60 years (15). Interestingly, no
statistically significant association between genotype
and phenotype was observed in females. This is likely
due to the process of random X-chromosome inacti-
vation (lyonization), which can skew expression of
both the mutant and normal alleles.
References
1. Alport AC: Hereditary familial congenital haemorrhagic nephritis.
Figure 6. In contrast, staining for the ␣3 (A) and ␣5 (B) Br Med J 1: 504 –506, 1927
chains of type IV collagen is lost in glomerular and distal 2. Levy M, Feingold J: Estimating prevalence in single-gene kidney
TBMs. Magnification, ⫻400. diseases progressing to renal failure. Kidney Int 58: 925–943, 2000
3. Kashtan CE: Familial hematurias: What we know and what we
don’t. Pediatr Nephrol 20: 1027–1035, 2005
(13). Patients with autosomal forms retain staining for 4. Bekheirnia MR, Reed B, Gregory MC, McFann K, Shamshirsaz
COL4A5 because neither COL4A3 nor COL4A4 is AA, Masoumi A, Schrier RW: Genotype-phenotype correlation in
expressed in normal epidermal basement membrane. X-linked Alport syndrome. J Am Soc Nephrol 21: 876 – 883, 2010
5. Nasr SH, Markowitz GS, Goldstein CS, Fildes RD, D’Agati VD:
Clinical-Pathologic Correlations. Genetic testing Hereditary nephritis mimicking immune complex-mediated glomer-
ulonephritis. Hum Pathol 37: 547–554, 2006
has only recently become commercially available for
6. Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG: Al-
the diagnosis of HN and is being used increasingly in port’s syndrome, Goodpasture’s syndrome and type IV collagen.
routine practice. Establishing genotype–phenotype N Engl J Med 348: 2543–2556, 2003
7. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C,
correlations would significantly increase the prognos- Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon
tic value of such testing. Bekheirnia et al. (4) exam- M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco
ined males with X-linked HN and showed a relation- P: COL4A1 mutations and hereditary angiopathy, nephropathy,
aneurysms, and muscle cramps. N Engl J Med 357: 2687–2695,
ship among mutation type, location within the gene, 2007
and severity of disease. Average age of onset of ESRD 8. Haas M: Alport syndrome and thin glomerular basement membrane
was 37 years in patients with missense mutations, 28 nephropathy: A practical approach to diagnosis. Arch Pathol Lab
Med 133: 224 –232, 2009
years for patients with splice-site mutations, and 25 9. Naito I, Kawai S, Nomura S, Sado Y, Osawa G: Relationship
years for those with truncating mutations (P ⬍ between COL4A5 gene mutation and distribution of type IV colla-
0.0001). The position of the mutation in the gene was gen in male X-linked Alport syndrome. Kidney Int 50: 304 –311,
1996
also prognostic with mutations at the 5⬘ end of 10. Gubler MC, Knebelmann B, Beziau A, Broyer M, Pirson Y, Had-
COL4A5 being associated with earlier onset of ESRD doum F, Kleppel MM, Antignac C: Autosomal recessive Alport
syndrome: Immunohistochemical study of type IV collagen chain roder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C,
distribution. Kidney Int 47: 1142–1147, 1995 Smeets H, Gubler MC: X-linked Alport syndrome: Natural history in
11. Kashtan CE, Segal Y: Genetic disorders of glomerular basement 195 families and genotype-phenotype correlations in males. J Am Soc
membranes. Nephron Clin Pract 118: c9 – c18, 2011 Nephrol 11: 649 – 657, 2000
12. Markowitz GS, Gelber C, D’Agati VD: An 18-year-old male with 15. Jais JP, Knebelmann B, Giatras I, de Marchi M, Rizzoni G,
hematuria, renal insufficiency, and defective synthesis of type IV Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y,
collagen. Kidney Int 69: 2278 –2282, 2006 Dahan K, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz
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skin biopsies of Alport patients. Kidney Int 72: 512–516, 2007 Natural history and genotype–phenotype correlations in girls and
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Section 8: CASE PRESENTATION the abdomen, was normal. Recent urinalysis revealed no
proteinuria and 3⫹ heme; urinary microscopy showed 10 to
A 36-year-old Caucasian man without previous medical 20 red blood cells (RBCs) per high-power field, without
history was found to have microscopic hematuria with RBC casts. The patient has a stable serum creatinine level of
normal renal function during hospitalization for a motor 0.8 mg/dl. There is no history of hypertension or diabetes or
vehicle accident 4 years earlier. Since that time, he has had family history of renal disease. Serologic studies including
persistent microhematuria documented on routine urinaly- anti-nuclear antibody, anti-neutrophil cytoplasmic antibody,
ses, without episodes of gross hematuria or flank pain. A and antistreptolysin-O are negative, and serum complement
recent lower urinary tract workup for hematuria, including levels C3 and C4 are normal. A renal biopsy is performed for
urine culture, cystoscopy and computed tomography scan of investigation of persistent asymptomatic microhematuria.
Figure 1. Figure 2.
Figure 3. Figure 4.

A. Alport syndrome
B. IgA nephropathy (IgAN)
C. Thin basement membrane nephropathy (TBMN)
D. Normal renal biopsy
Figure 5. E. Unsampled FSGS
317
Answer life. Although unusual in children, mild proteinuria

The renal biopsy findings are diagnostic of thin can be detected in adults and is usually attributable to
basement membrane nephropathy (TBMN) (answer C). coexistent disease such as arterionephrosclerosis of
All 18 glomeruli sampled by light microscopy are normal hypertension or aging, obesity-related glomerulopa-
in size and cellularity with patent capillaries. By light thy, or IgAN. The presence of nephrotic syndrome or
microscopy, the glomerular basement membranes nephrotic range proteinuria should raise suspicion of a
(GBMs) appear delicate with normal texture and contour superimposed podocytopathy such as FSGS (4) or
(Figure 1, periodic acid–Schiff ⫻500). No immune-type minimal change disease (5).
fuchsinophilic deposits are detected with the trichrome TBMN is caused by a mutation in either the
stain. The tubulointerstitial compartment is well pre- COL4A3 or COL4A4 gene. The major differential
served, without evidence of tubular atrophy or interstitial diagnosis is hereditary nephritis/Alport syndrome, an-
foam cells (Figure 2, Jones methenamine silver ⫻200). other inherited disorder of collagen IV. This is espe-
The full immunofluorescence microscopy panel for im- cially problematic because both young boys and fe-
munoglobulins, light chains, and complement compo- male heterozygotes with X-linked Alport syndrome
nents was negative. Ultrastructural evaluation reveals often display thinning of GBMs as their only ultra-
diffuse thinning of the GBMs, which range from 165 to structural abnormality. TBMN differs from Alport
210 nm in thickness (mean 180 nm; Figure 3, ⫻ syndrome in its lack of progression to renal failure, the
3000). The mesangial areas are unremarkable absence of multisystem disease (e.g., sensorineural
(Figure 4, ⫻5000). There is no evidence of thickening hearing loss or ocular lenticonus), and its autosomal
or lamellation of the lamina densa, and no immune- dominant transmission without gender differences.
type electron-dense deposits are identified (Figure 5, ⫻
20,000). The podocyte foot processes appear overall Pathology
well preserved, with mild segmental effacement (Fig-
Light Microscopy. No significant histologic abnor-
ure 3). Special stains for the ␣1, ␣3, and ␣5 subunits
malities are observed in TBMN. The GBM thinning is
of collagen IV performed on frozen tissue showed a not obvious on light microscopy, although some cases
normal pattern of staining (not shown). may exhibit extremely delicate GBMs by silver or
periodic acid–Schiff stain. Mild mesangial hypercel-
Thin Basement Membrane Nephropathy lularity has been reported in a minority of cases (6).
TBMN is defined by diffuse attenuation of the With the exception of intratubular RBCs and rare RBC
GBMs, which is visible only at the ultrastructural casts, the tubulointerstitial and vascular compartments
level. Cases may be familial or sporadic and usually are unremarkable. Whereas the pediatric kidney biop-
present as isolated hematuria with preserved renal sies display unremarkable histology, focal global glo-
function. Given the absence of progressive renal fail- merulosclerosis, variable tubular atrophy, interstitial
ure and the frequent familial aggregation, it is often fibrosis, and arteriosclerosis are not uncommon in
referred to as “benign familial hematuria.” TBMN is older adults. These changes are usually a consequence
the most common inherited glomerular disease, affect- of aging or coexistent hypertension. Interstitial foam
ing ⬎1% of the population (1). cell aggregates are not a feature TBMN and should
suggest hereditary nephritis/Alport syndrome.
Clinical Characteristics
The classic presentation of TBMN is asymptom- Immunofluorescence. Direct immunofluorescence
atic microscopic hematuria. Often detected in child- staining for immunoglobulins and complements is
hood, the hematuria is typically described as persistent negative in TBMN. Weak segmental mesangial C3 or
(i.e., documented on two occasions at least 2 years IgM staining in the absence of corresponding electron-
apart) (1). Some patients may have intermittent micro- dense deposits is considered nonspecific. Stronger
hematuria that is not detected until adulthood, but staining for immune reactants may occur if the patient
episodes of macroscopic hematuria (after infection or has a superimposed immune complex–mediated dis-
strenuous exercise) are much less common (2,3). The ease (6).
urinary RBCs are dysmorphic, and RBC casts may be Electron Microscopy. Ultrastructural examination
observed. Renal function is well preserved throughout is required for the diagnosis of TBMN. There is
generally diffuse and global GBM thinning in the A diagnosis of TBMN requires accurate tech-
absence of other ultrastructural abnormalities. The niques for GBM measurement. The GBM is a trilam-
normal range of GBM thickness varies among indi- inar structure composed of a central lamina densa, an
viduals and can be influenced by the patient’s age and inner lamina rara interna, and an outer lamina rara
gender and by the particular fixation methods and externa. To include the laminae rarae, the GBM thick-
embedding compounds used for electron microscopy ness is measured from the outer edge of the endothelial
(7,8). Thus, it is important for each renal pathology cell plasma membrane to the outer edge of the cell
laboratory to establish its own thresholds for “thin” membrane of the podocyte foot processes. The GBMs
GBM on the basis of a value for GBM thickness that are measured only in the peripheral capillaries, avoid-
is ⬎2 standard deviations below the normal mean ing areas of GBM folds and the reflection over the
(6,7). At Columbia University, the mean normal GBM mesangium. One technique of GBM thickness mea-
thickness is 350 ⫾ 50 nm for male adults and 300 ⫾ surement includes the orthogonal intercept/mean har-
40 nm for female adults (6,8). GBM thickness pro- monic thickness method (11). The electron micros-
gressively increases from birth to 9 to 11 years and copy prints are overlaid with a grid of perpendicularly
then plateaus. Detailed analyses of pediatric biopsies oriented lines of known dimension, and the GBM
have established the estimated normal ranges of GBM width is recorded in “classes.” The intersections be-
thickness in children (9,10). tween the grid lines and the endothelial cell plasma
According to World Health Organization guide- membranes are analyzed, and a mean harmonic thick-
lines for diagnosis of TBMN, the GBM thinning ness is calculated using a set of equations, all of which
should be diffuse with mean GBM thickness ⬍250 nm can be time-consuming. Alternately, a simple mea-
in adults and ⬍180 nm in children aged 2 to 11 years surement of GBM thickness can be made using a
magnification graticule or metric ruler applied to an
(6). However, several investigators prefer a thresh-
electron microscopic print after correction for the
old of 225 nm in adults, especially women. It should
magnification of the photographic negative and the
also be emphasized that thinning should affect
enlargement factor from negative to print (6). In this
⬎50% of the total glomerular capillary area. Alter-
era of digital cameras, GBM measurements are most
nating zones of thinning and thickening of the GBM
easily and rapidly performed using the appropriate
with lamellation of the lamina densa should prompt
software. It is extremely important that multiple rep-
a diagnosis of hereditary nephritis/Alport syndrome.
resentative GBM measurements be taken over multi-
ple capillaries of several glomeruli to calculate an
accurate mean value.
Because a diagnosis of TBMN requires electron
microscopic examination, inadequate biopsies that
lack glomeruli in the tissue allocated for electron
microscopy pose a diagnostic challenge. Salvage elec-
tron microscopy on deparaffinized, formalin-fixed tis-
sue, which is usually performed in this situation, is
helpful to diagnose many glomerular diseases but is
distinctly unreliable as a means of diagnosing TBMN.
This is because the reprocessing technique itself
causes tissue dehydration and artifactual thinning of
Figure 6. In a case of minimal change disease superimposed the GBM. Although it may be possible to exclude
on TBMN, there is diffuse effacement of foot processes TBMN, it is not possible to diagnose TBMN accu-
with condensation of the actin cytoskeleton. The underlying
GBM is uniformly thinned (180 to 200 nm). The patient, an rately in deparaffinized, reprocessed tissue (8).
82-year old woman with longstanding history of microhe- Immunofluorescence for Collagen IV Subtypes. Re-
maturia, presented with abrupt onset of nephrotic syndrome
(lower extremity edema, proteinuria of 8.0 g/day, and serum
nal biopsy staining with commercially available anti-
albumin of 2.1 g/dl), which responded to steroid therapy. sera to the ␣1, ␣3, and ␣5 subunits of collagen IV is
Magnification, ⫻10,000, electron micrograph. helpful to support a diagnosis of TBMN and rule out
Alport syndrome. TBMN retains a normal pattern of may also cause TBMN in some kindreds, none have
immunoreactivity for all subunits (␣1 through ␣6) of yet been identified (17).
type IV collagen. The normal staining pattern for ␣3 is Recent genotypic studies suggest the existence of
diffuse linear positivity along the GBMs and distal a rare severe form of TBMN that does not represent
TBMs. The normal ␣5 staining pattern is similar to ␣3, misdiagnosed Alport syndrome. These patients have
with the exception that Bowman’s capsule, and col- diffuse thinning of the GBM with lesions of FSGS and
lecting duct TBMs are also positive. Because the clinically manifest with greater proteinuria, renal im-
GBMs are thin, the GBM staining for ␣3 and ␣5 pairment, and progression to end-stage kidney disease.
subunits in TBMN may appear weaker and more Molecular analyses have identified founder mutations
delicate than that of normal controls. Importantly, in in COL4A3 and COL4A4 genes in these families
TBMN no segmental or complete loss of staining for (4,18). It has been hypothesized that particular poly-
the ␣3 and ␣5 subunits typical of Alport syndrome is morphisms or unidentified modifier genes may under-
observed (6,7). It is important to recognize that stain- lie this more severe phenotype (19). For example,
ing for the ␣ subunits of collagen IV is not an absolute some investigators have identified mutations in
means to distinguish between TBMN and Alport syn- NPHS2 (encoding podocin) in unrelated patients with
drome because at least 20% (and in our experience TBMN and greater proteinuria (17,20), whereas others
closer to 50%) of patients with Alport syndrome retain have been unable to confirm NPHS2 mutations in
normal staining patterns (12,13) For more difficult pedigrees with TBMN and FSGS (21).
cases, genetic testing for mutations in COL4A3, Association with other Glomerular Diseases. GBM
COL4A4, and COL4A5 is commercially available. thinning may occur as a localized process in many
glomerular diseases, particularly when there is glo-
Pathogenesis merular capillary wall distension, rupture, and/or re-
Although TBMN is an inherited disorder with modeling. Unlike TBMN, these conditions exhibit
autosomal dominant transmission, a positive family short segments of thinning on a background of other,
history of hematuria can be elicited from only two obvious glomerular pathology. In addition, TBMN
thirds of patients. Seemingly sporadic cases may be with diffuse GBM thinning may coexist with another
due to undetected (subclinical) disease in other family glomerular disease as a dual glomerulopathy (5,6).
members, nonpenetrance of hematuria in affected fam- Approximately 30% of patients with IgAN have thin
ily members, or de novo mutations. Considerable ge- basement membranes, a frequency higher than in the
netic overlap exists between TBMN and Alport syn- general population, suggesting a possible pathogenetic
drome, and identification of type IV collagen gene link or selection bias for biopsy. In support of this
mutations in Alport syndrome has helped elucidate the hypothesis, patients with IgAN and TBMN often have
familial hematuria and do not manifest the usual ab-
pathogenesis of TBMN (12,14,15). It is now estab-
normalities of IgA glycosylation (5). Other reported
lished that TBMN is caused by heterozygous muta-
associations with TBMN are likely to occur by chance,
tions in the COL4A3 or COL4A4 gene located on
such as minimal change disease (Figure 6) and mem-
chromosome 2 (12,16). Mutations include missense or
branous nephropathy (6). In these cases, TBMN is
splice-site deletions or frame shifts. TBMN likely
usually an incidental finding and does not influence
represents a carrier state for autosomal recessive Al-
the overall prognosis of the superimposed glomerular
port syndrome, a disorder arising from similar ho-
disease.
mozygous or compound heterozygous COL4A3/
COL4A4 mutations (17). Too few mutations have
References
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ness and its application to the diagnosis of thin-membrane nephrop- J: The R229Q mutation in NPHS2 may predispose to proteinuria in
athy. Arch Pathol Lab Med 116: 43– 49, 1992 thin-basement-membrane nephropathy. Pediatr Nephrol 23: 2201–
12. Tryggvason K, Patrakka J: Thin basement membrane nephropathy. 2207, 2008
J Am Soc Nephrol 17: 813– 822, 2006 21. Deltas C: Thin basement membrane nephropathy: Is there genetic
13. Kashtan CE, Segal Y: Genetic disorders of glomerular basement predisposition to more severe disease? Pediatr Nephrol 24: 877– 879,
membranes. Nephron Clin Pract 118: c9 – c18, 2011 2009
Section 9: CASE PRESENTATION and 4⫹ protein, and urine sediment is active with too
numerous to count erythrocytes and occasional leukocytes.
A 10-year-old Caucasian girl presents with edema. Other Urine protein excretion is 6.5 g/day, and serum albumin is
than occasional upper respiratory tract infections, the pa- 1.7 g/dl. Serologic evaluation shows negative anti-nuclear
tient has no significant past medical history. There is no antibody, anti-DNA, hepatitis B surface antigen, hepatitis C
family history of renal disease. On examination, she is antibody, anti-neutrophil cytoplasmic antibody, and anti–
found to have new-onset hypertension (BP 137/76 mmHg; glomerular basement membrane (anti-GBM) antibodies.
⬎99th percentile for systolic BP), height of 146 cm, weight She has an elevated antistreptolysin-O titer, and both C3 and
of 45.7 kg, and 2⫹ lower extremity edema. She denies any C4 are depressed. The kidneys measure 11.6 and 12.1 cm by
episodes of gross hematuria. Urinalysis reveals 3⫹ blood ultrasound.
Figure 1. Figure 2.
Figure 3. C3 Figure 4. IgG
Figure 5. Figure 6.
323
What is the BEST diagnosis? in children, whereas adults frequently have an identi-
A. Acute postinfectious glomerulonephritis (APIGN) fiable underlying condition. MPGN also is classically
B. Membranoproliferative glomerulonephritis (MPGN) divided into three types on the basis of the combined
type 1 findings of light microscopy, immunofluorescence,
C. Dense deposit disease and electron microscopy. MPGN type 1 is the focus of
D. MPGN type 3, Strife and Anders subtype this section. MPGN type 2 is preferentially called
E. MPGN type 3, Burkholder subtype dense deposit disease because of its distinctive patho-
genesis and frequent lack of membranoproliferative
Answer features. MPGN type 3 is divided into the Burkholder
The renal biopsy findings show a membranopro- subtype and the Strife and Anders subtype and is
liferative glomerulonephritis (MPGN) type 1 pattern discussed briefly in the Differential Diagnosis section.
of injury (answer B). Given the young age of the Many of these morphologic variants of MPGN were
patient, the absence of systemic disease, the low serum described in the 1970s, before there was an under-
C3 and C4, and the otherwise negative serologic standing of pathogenesis, associations with hepatitis C
workup, this most likely represents idiopathic MPGN infection, and inherited or acquired disorders of alter-
type 1. Figure 1 (hematoxylin and eosin, ⫻400) shows native pathway complement activation. Concepts
an enlarged hypercellular glomerulus with accentuated about the validity of these historical subtypes are
lobularity. Figure 2 (Jones methenamine silver, ⫻600) evolving as new pathogenetic insights emerge.
highlights the presence of mesangial and subendothe-
lial immune deposits, which have a glassy pink ap- Clinical Characteristics
pearance. Glomerular capillaries are narrowed by mes- MPGN type 1 is reported to account for approx-
angial expansion and proliferation and contain imately 6% of nephrotic syndrome in children accord-
scattered intraluminal leukocytes. GBMs show seg- ing to the International Study of Kidney Disease in
mental duplications with mesangial interposition. Fig- Children (ISKDC) (1). Among adults, the relative
ures 3 (immunofluorescence for C3) and 4 (immuno- frequency of MPGN varies significantly depending on
fluorescence for IgG) show the immunofluorescence geographic location. In the United States and many
results including diffuse granular mesangial and seg- other industrialized nations, the relative frequency of
mental to global semilinear peripheral capillary wall MPGN type 1 is declining, accounting for ⬍5% of
staining for C3 (3⫹ intensity) and IgG (1⫹). Electron cases of nephrotic syndrome in adults, whereas in
microscopy (Figures 5 and 6) reveals numerous elec- parts of Africa and South America, MPGN is the most
tron-dense deposits in the mesangium, accompanied commonly encountered primary glomerular disease
by mesangial cell proliferation that severely narrows (2). Clinical symptoms may be predominantly ne-
the glomerular capillary lumina. Prominent subendo- phrotic, nephritic, or both. Approximately half of pa-
thelial deposits are present. At higher magnification, a tients report a respiratory tract infection before onset
large subendothelial deposit is seen, and a thin layer of of symptoms. Proteinuria is almost universally present
neomembrane has formed between the endothelium with more than half of patients presenting with ne-
and the deposit to produce a GBM double contour phrotic syndrome. Persistent microscopic hematuria is
(Figure 6). Occasional small subepithelial deposits are found in most patients. Approximately 10 to 20% of
also present. patients with MPGN type 1 present with an acute
nephritic syndrome, and some of these develop recur-
Membranoproliferative Glomerulonephritis rent episodes of gross hematuria. Although not all
MPGN is a morphologic pattern of glomerular patients have depressed serum C3 (and in some cases
injury characterized by cellular proliferation and thick- depressed C4) levels at presentation, the majority will
ening of glomerular capillary walls as a result of develop hypocomplementemia at some point in their
immune complex deposition, peripheral mesangial cell course. Renal insufficiency is seen in approximately
interposition, and duplication of GBMs. MPGN is 25% of patients at the time of diagnosis but is more
divided into primary (idiopathic) and secondary forms common in adults than in children. Hypertension is
of disease, which most often relate to infection or seen in approximately one-third of patients at onset
systemic conditions. Primary MPGN is more common and is usually mild (3).
Pathology cated (or double contoured) appearance of the glomer-

Light Microscopy. Light microscopic features of ular capillary wall. This new layer of membrane is
MPGN type 1 include diffuse and global glomerular often thinner and more irregular or incomplete than the
mesangial and endocapillary hypercellularity, causing original GBM. The deposits in idiopathic MPGN type
accentuation of the glomerular lobularity. Although 1 usually have a granular, nonorganized texture. The
the severity of proliferation can vary from mild to degree of deposit formation is highly variable, and
severe, the proliferation tends to be relatively uniform occasional scattered subepithelial electron-dense de-
across glomeruli in an individual biopsy. The mesan- posits may be seen. Podocyte foot process effacement
gium is expanded as a result of increased matrix, is usually extensive.
mesangial cell proliferation, and mesangial immune
deposits that typically have a glassy eosinophilic ap- Clinical-Pathologic Correlation
pearance. Glomerular capillary walls are thickened as The clinical course of idiopathic MPGN type 1 is
a result of the presence of subendothelial immune quite variable. Long-term prognosis was reported by
deposits and variable degrees of GBM duplication and Cameron et al. (4) in a study of 46 adults and 23
mesangial interposition (peripheral outgrowth of mes- children with MPGN type 1. During a follow-up
angial cells between the duplicated layers of GBM). period ranging from 2 to 21 years, 8% showed com-
GBM duplications (or double contours) are best ap- plete remission, 30% continued to have proteinuria but
preciated with a Jones methenamine silver or periodic maintained normal GFR, and 61% developed renal
acid–Schiff stain. In some cases, leukocytes (neutro- insufficiency, including 38% that reached ESRD.
phils and/or monocytes-macrophages) infiltrate glo- Yanagihara et al. (5) reported the outcome in 19
merular capillaries, adding to the hypercellularity. Japanese school children who were asymptomatic but
Crescent formation is seen in approximately 10% of received a diagnosis as a result of routine urinary
cases. screening. All of the patients received corticosteroid
treatment, and follow-up ranged from 10 to 24 years.
Immunofluorescence. Immunofluorescence typi- Among the 19 patients, 79% went into complete re-
cally shows global mesangial and peripheral capillary mission, 21% had persistent proteinuria, and none
wall immune deposits that stain dominantly for C3 and progressed to ESRD. Factors that have been proposed
also typically contain IgG and/or IgM. Weaker stain- to influence disease outcome include hypertension,
ing for IgA and C1q may be seen. The presence of impaired renal function, and anemia at the time of
both C1q and C3 supports complement activation by diagnosis. The presence of ⬎20% crescents, extensive
the classical pathway, whereas the presence of C3 may glomerulosclerosis, or prominent tubulointerstitial
indicate only alternative pathway activation. Deposits scarring are histologic predictors of poor outcome (3).
in the peripheral capillaries often have a semilinear (as
opposed to granular) appearance as a result of their Secondary Forms of MPGN Type 1
subendothelial location and the smooth outer contour As mentioned previously, a type 1 MPGN pat-
imposed by the overlying GBM. The regular periph- tern of injury can be seen secondary to a variety of
eral capillary wall distribution of the subendothelial systemic processes. Immune complex deposition in a
deposits often produces a lobular pattern of staining. mesangial and subendothelial distribution associated
Electron Microscopy. Electron microscopy shows with GBM duplication can be seen in autoimmune
variable expansion of the mesangium by cells and disorders such as systemic lupus erythematosus,
matrix, as well as mesangial electron-dense deposits. Sjögren syndrome, and rheumatoid arthritis. Chronic
Mesangial cells and mononuclear leukocytes may ex- infections are another common cause and include viral
tend into peripheral capillaries associated with double hepatitis (both B and C) with or without type II
contours of the GBM. Subendothelial electron-dense cryoglobulinemia, chronic bacterial infections in the
deposits typically predominate and may be enclosed setting of endocarditis, shunt nephritis or visceral
by a newly formed layer of basement membrane sep- abscess, and parasitic infections. Causative agents are
arating the immune deposits from the endothelium diverse and include a variety of bacteria (e.g., Strep-
(Figure 6). It is this internal layer of neomembrane tococcus, Meningococcus, Staphylococcus, Pneumo-
parallel to the original GBM that produces the dupli- coccus, leptospirosis, leprosy, syphilis), parasites (e.g.,
schistosomiasis, toxoplasmosis, malaria), and other with segmental GBM duplication. Immunofluores-
unusual organisms (e.g., mycoplasma, borreliosis, cence staining is typically dominant for C3 and often
leishmaniasis) (6). Cryoglobulinemic glomerulone- accompanied by IgG in both MPGN and APIGN. By
phritis of any cause classically displays membranopro- electron microscopy, type 1 MPGN should show more
liferative histology. Particularly in the adult popula- extensive subendothelial deposits and extensive redu-
tion, careful serologic workup and clinical correlation plication of GBMs with mesangial interposition,
are needed to exclude secondary causes of MPGN type whereas APIGN should display evidence of subepi-
1 before a diagnosis of idiopathic (primary) MPGN is thelial “hump” formation. Notably, occasional subep-
made. ithelial deposits may also be seen in type 1 MPGN.
Once MPGN is diagnosed, proper classification
Differential Diagnosis of the MPGN pattern is needed. MPGN type 1 is
When a membranoproliferative pattern of glo- typically dominated by subendothelial and mesangial
merular injury is identified by light microscopy, there deposits with GBM duplication and mesangial inter-
are many diagnostic considerations other than MPGN. position. MPGN type 3 has two subtypes, one de-
A subacute or chronic thrombotic microangiopathy scribed by Strife et al. (8) and Anders et al. (9) and
often displays a membranoproliferative appearance. It another defined by Burkholder et al. (10). The Burk-
can be distinguished by immunofluorescence positiv- holder subtype resembles MPGN type 1 but shows
ity for fibrin (often with nonspecific positivity for more pronounced subepithelial deposits, akin to a
IgM) and by the ultrastructural findings of electron- membranous pattern superimposed on a type 1 MPGN
lucent, flocculent material between the duplicated lay- (Figure 7). Like MPGN type 1, the Burkholder sub-
ers of GBM. Multiple immune complex–mediated type typically has deposits of Ig and complement, is
diseases may have a membranoproliferative appear- often associated with chronic infection, and likely has
ance by light microscopy including IgA nephropathy, a similar pathogenesis. In some cases, there is a
lupus nephritis, and fibrillary glomerulonephritis, al- continuum of findings between type 1 and type 3 in
though these entities can be distinguished from MPGN different glomeruli, supporting their similar pathogen-
type 1 on the basis of clinical history, serologies, the esis. The Strife and Anders subtype features more
composition of the deposits by immunofluorescence, complex intramembranous deposits that seem to ex-
and the ultrastructural appearance of the deposits. tend from the subendothelial to subepithelial aspects
Importantly, many forms of dysproteinemia-associ- of the GBM, causing irregular GBM thickening with
ated glomerular disease exhibit a membranoprolifera- disruption and fraying of the lamina densa (Figure 8).
tive appearance, including type 1 cryoglobulinemic It often has dominant or exclusive staining for C3 and
glomerulonephritis, immunotactoid glomerulopathy, may exhibit areas by electron microscopy that overlap
monoclonal Ig deposition disease, and “proliferative with features of dense deposit disease. Testing for
glomerulonephritis with monoclonal Ig deposits” (7). complement regulatory factors (factor H, factor I, and
In each of these conditions, the monoclonal nature of
the paraprotein deposits is often established by immu-
nofluorescence, which typically shows restricted pos-
itivity for a single light chain isotype and/or a single
heavy chain class. Furthermore, the deposits in type 1
cryoglobulinemic glomerulonephritis often have a dis-
tinctive substructure, whereas immunotactoid glo-
merulopathy is characterized by hollow microtubular
deposits with a diameter of 30 to 50 nm.
It may be particularly difficult to distinguish
MPGN from APIGN because both can present with a
mixed nephritic/nephrotic syndrome, history of pre-
Figure 7. MPGN type 3 of Burkholder. Note the presence of
ceding infection, and hypocomplementemia. On bi- prominent subendothelial and subepithelial deposits along
opsy, histologic features may overlap significantly, with segmental duplication of the glomerular basement
including mesangial and endocapillary proliferation membrane. Magnification, ⫻6000.
small, low-affinity, and cationic immune complexes

can penetrate beyond the lamina densa to lodge in the
subepithelial region. Following immune complex de-
position in the mesangium and glomerular capillary
walls, complement activation, predominantly via the
classical pathway, ensues. Complement activation
leads to the production of anaphylatoxin C3a, opsonin
C3b, and chemoattractants such as C5a that recruit
macrophages, neutrophils, and platelets to mediate
glomerular endothelial and mesangial injury via re-
lease of oxidants and proteases (3). Mesangial cells
Figure 8. MPGN type 3 of Strife and Anders. The electron- respond to the released cytokines and growth factors
dense deposits appear to be predominantly intramembra- (e.g., PDGF, TGF-␤) by proliferation, migration into
nous extending the full thickness of the GBM from the
subendothelial to the subepithelial aspect with focal disrup- the peripheral capillary walls, and matrix synthesis,
tion of the lamina densa. Magnification, ⫻6000. producing the characteristic membranoproliferative
pattern of injury.
Rare cases of MPGN type 1 contain exclusively
membrane co-factor protein) is needed to determine
C3 deposits, without identifiable immunoglobulin, and
the relationship of this variant to the disorders of
have been termed “glomerulonephritis C3” or “C3
alternative pathway complement regulation that medi-
glomerulopathy.” A range of mesangial proliferative
ate dense deposit disease. Dense deposit disease, pre-
to membranoproliferative patterns has been described
viously referred to as MPGN type 2, is characterized
(12). Associations with C3 nephritic factor (an auto-
by transformation of the lamina densa by ribbon-like
antibody to the C3bBb convertase) and genetic defects
electron-dense deposits that result from glomerular C3
in complement regulatory factors such as factor H,
deposition.
factor I, and membrane co-factor protein have been
Etiology and Pathogenesis identified in some of these cases, suggesting overlap-
MPGN type 1 (and presumably type 3) are ping features with dense deposit disease (13). Ex-
thought to begin with an antigenic stimulus that results panded testing for deficiencies in regulators of the
in the formation of immune complexes. The identity of alternative complement pathway is needed to better
this stimulus in primary MPGN type 1 is unknown, but define the pathogenesis of C3 glomerulopathy and its
the finding that many patients with primary MPGN relationship to other forms of MPGN.
have onset of disease or develop flares after an infec-
tion and have circulating immune complexes and hy-
References
pocomplementemia favors an immune complex–me- 1. International Study of Kidney Disease in Children: Nephrotic syn-
diated pathogenesis. Autoimmune disease and chronic drome in children: Prediction of histopathology from clinical and
laboratory characteristics at time of diagnosis. Kidney Int 13: 159 –
infection are known to result in immune complex 165, 1978
formation, and this is presumed to be the mechanism 2. Johnson RJ, Hurtado A, Merszei J, Rodriguez-Iturbe B, Feng L:
by which they cause secondary forms of MPGN type Hypothesis: Dysregulation of immunologic balance resulting from
hygiene and socioeconomic factors may influence the epidemiology
1. Mice repeatedly injected with exogenous preformed and cause of glomerulonephritis worldwide. Am J Kidney Dis 42:
immune complexes develop a membranoproliferative 575–581, 2003
pattern of glomerulonephritis. Varying the charge and 3. Zhou XJ, Silva FG: Membranoproliferative glomerulonephritis. In:
Heptinstall’s Pathology of the Kidney, 6th Ed., edited by Jennette
size of the immune complexes influences the location JC, Olson JL, Schwawrtz MM, Silva FG, Philadelphia, Lippincott
of immune complex deposition in the glomerulus (i.e., Williams & Wilkins, 2007, pp 253–319
mesangial, subendothelial, or subepithelial) (11). Per- 4. Cameron JT, Turner DR, Heaton J, Williams DG, Ogg CS, Chantler
C, Haycock GB, Hicke J: Idiopathic mesangiocapillary glomerulo-
sistent antigenemia, impaired clearance, and the size nephritis: Comparison of types 1 and 2 in children and adults and
and charge characteristics of the immune complexes long-term prognosis. Am J Med 74: 175–192, 1983
may favor deposition in particular glomerular sites. 5. Yanagihara T, Hayakawa M, Yoshida J, Tsuchiya M, Morita T,
Murakami M, Fukunaga Y: Long-term follow-up of diffuse mem-
Intermediate-sized complexes tend to be retained in branoproliferative glomerulonephritis type 1. Pediatr Nephrol 20:
the mesangial and subendothelial regions, whereas 585–590, 2005
6. Rennke HG: Secondary membranoproliferative glomerulonephritis. and proliferative glomerulonephritis: A correlative light, immu-
Kidney Int 47: 643– 656, 1995 nofluorescence and electron microscopic study. Lab Invest 23:
7. Nasr SH, Satoskar A, Markowitz GS, Valeri AM, Appel GB, 459 – 479, 1970
Stokes MB, Nadasdy T, D’Agati VD: Proliferative glomerulone- 11. Gallo GR, Caulin-Glaser T, Lamm ME: Charge of circulating im-
phritis with monoclonal IgG deposits. J Am Soc Nephrol 20: mune complexes as a factor in glomerular basement membrane
1986 –1996, 2009 localization in mice. J Clin Invest 67: 305–313, 1981
8. Strife CF, McEnery PT, McAdams AJ, West CD: Membranoprolif- 12. Servais A, Fremeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J,
erative glomerulonephritis with disruption of the glomerular base- Knebelmann B, Grunfeld JP, Lasavre P, Noel LH, Fakhouri F:
ment membrane. Clin Nephrol 7: 65–72, 1977 Primary glomerulonephritis with isolated C3 deposits: A new entity
9. Anders D, Agricola B, Sippel M, Thoenes W: Basement mem- which shares common genetic risk factors with heaemolyticuraemic
brane changes in membranoproliferative glomerulonephritis: syndrome. J Med Genet 44: 193–199, 2007
Characterization of a third type by silver impregnation of ultra 13. Boyer O, Noel LH, Balzamo E, Guest G, Biebuyck N, Charbit M,
thin sections. Virchows Arch A Patholol Anat Histol 376: 1–19, Salomon R, Fremeaux-Bacchi V, Niaudet P: Complement factor H
1977 deficiency and posttransplantation glomerulonephritis with isolated
10. Burkholder PM, Marchand A, Krueger RP: Mixed membranous C3 deposits. Am J Kidney Dis 51: 671– 677, 2008
Section 10: CASE PRESENTATION edema. Laboratory workup shows a serum creatinine level of
0.5 mg/dl, 24-hour urine protein of 6.2 g, albumin of 1.5 g/dl,
A 12-year-old Caucasian boy presents with a 1-month his- and urinalysis with 4⫹ albumin, too numerous to count red
tory of periorbital edema and several episodes of gross hema- blood cells, and scattered red blood cell casts. Serologic
turia over the last 3 weeks. The patient’s past medical history workup shows negative anti-nuclear antibody and anti-DNA
is remarkable for an episode of streptococcal pharyngitis 2 antibody, negative hepatitis B surface antigen and hepatitis C
months earlier. There is no family history of renal disease. antibody, elevated antistreptolysin-O titer, a moderately de-
Physical examination reveals a BP of 115/70 mmHg and creased C3 complement level, and a normal C4.
Figure 1. Figure 2.
Figure 3. Figure 4. C3
Figure 5. Figure 6.
329
What is the BEST diagnosis? Clinical Characteristics

A. Membranoproliferative glomerulonephritis (MPGN) DDD is most commonly diagnosed in children
type 1 between 5 and 15 years of age but may also have its
B. Acute postinfectious glomerulonephritis (APIGN) first clinical onset in adulthood. There is a Caucasian
C. MPGN type 3, Strife and Anders subtype racial predominance, and roughly equal numbers of
D. Dense deposit disease (DDD; also known as MPGN
males and females are affected. The appearance of
type 2) renal symptoms may be preceded by an infection,
E. Monoclonal Ig deposition disease particularly in children. Proteinuria, often in the ne-
phrotic range, and microscopic hematuria are typical
presenting features (1). A minority of patients may
Answer report episodes of gross hematuria. A presentation
The renal biopsy findings are diagnostic of dense with renal insufficiency is more common in adults
deposit disease (DDD; answer D). Light microscopic
than in children. A depression of serum C3, with
examination reveals diffuse ribbon like thickenings of
normal C4 and low CH50, is seen almost universally
the glomerular basement membranes (GBMs), which
in pediatric patients; however, only approximately half
appear glassy and eosinophilic with the hematoxylin
of adult patients show hypocomplementemia at the
and eosin (H&E) stain (Figure 1, ⫻600), periodic
time of diagnosis. By the second decade of life, many
acid–Schiff (PAS)-positive (Figure 2, ⫻400), and
patients with DDD develop extrarenal manifestations,
gray-purple with trichrome stain (Figure 3, ⫻400).
most commonly drusen owing to the formation of
The H&E stain also highlights global endocapillary
similar dense deposits within Bruch’s membrane of
hypercellularity, including scattered infiltrating neu-
the retina. Clinically significant visual problems occur
trophils. Although a few small segmental double con-
in approximately 10% of patients with DDD, but there
tours of the GBMs can be seen with PAS stain,
is no correlation between the severity of ocular disease
well-developed membranoproliferative features are
and renal disease. DDD can also be associated with
lacking. Also highlighted by PAS is the presence of a
acquired partial lipodystrophy primarily affecting the
segmental cellular crescent. Immunofluorescence
face and upper body, which is thought to be the result
shows strong staining for C3 only in a linear glomer-
of dysregulated alternative complement pathway acti-
ular capillary wall distribution with scattered large
vation in adipose tissue. The typical clinical course is
granular deposits in the mesangium (Figure 4, ⫻400).
that of progressive deterioration of renal function with
Focal linear staining is also seen in Bowman’s capsule
approximately half of patients with DDD progressing
and the surrounding tubular basement membranes.
to ESRD within 10 years of diagnosis (2).
Electron microscopy (Figure 5, ⫻3000; and 6, ⫻4000)
shows the classic markedly electron-dense deposits
permeating the lamina densa of the GBM, with seg- Pathology
ments of prominent thickening alternating with thinner Light Microscopy. A variety of patterns of glomer-
uninvolved segments, producing a “sausage-string” ular proliferation occur in DDD including membranopro-
appearance. liferative, mesangial proliferative, endocapillary prolifer-
ative, exudative (neutrophil rich), and crescentic forms.
The membranoproliferative and mesangial patterns are
Dense Deposit Disease
DDD is a rare glomerular disease most com- the most common (1,3). Regardless of the pattern, the
monly diagnosed in adolescents and children with an most consistent histologic finding is ribbon-like thicken-
incidence of one in 23 million population. DDD is ings of the GBMs by deposits that appear glassy and
defined at the ultrastructural level by highly electron- eosinophilic with the H&E stain, PAS-positive, red or
dense ribbon-like deposits that thicken and transform gray with the trichrome stain, and brownish with silver
the lamina densa of the GBM and also form rounded stain. Similar deposits may thicken Bowman’s capsule
aggregates in the mesangium. The underlying mecha- and tubular basement membranes.
nism is a systemic dysregulation of the alternative Immunofluorescence. DDD shows a distinctive
complement pathway resulting in persistent comple- staining pattern with intense isolated C3 positivity,
ment activation and glomerular deposition of C3. without significant staining for immunoglobulins or
C1q. In more chronic cases, nonspecific positivity for Clinical-Pathologic Correlation

IgM may occur. GBM staining is typically linear or In children, initial laboratory characteristics do
semilinear. A peculiar feature is the formation of two not appear to predict prognosis; however, several bi-
separate thin linear bands of positivity along the inner opsy characteristics have been associated with poor
and outer edges of the affected GBMs with no staining outcome. These include prominent lobulation of glom-
of the center, producing the false impression of a eruli, severe mesangial hypercellularity and sclerosis,
double contour (Figure 7). The mesangium often con- glomerular capillary occlusion by cellular prolifera-
tains round granules or ring-shaped deposits of C3 tion, and prominent involvement of the mesangium by
(Figure 7). Many cases also display patchy interrupted dense deposits (4). In a clinicopathologic study of 14
linear staining of Bowman’s capsule and tubular base- children and 18 adults with DDD, the only indepen-
ment membranes for C3. dent predictors of poor outcome were older age and
Electron Microscopy. A definitive diagnosis of elevation of the serum creatinine at diagnosis (1).
DDD requires ultrastructural demonstration of the dis-
tinctive intramembranous “dense deposits” corre- Differential Diagnosis
sponding to the immunoreactivity for C3. The deposits Because of the nonspecific clinical presentation,
are typically highly electron dense and cause a ribbon- the broad differential diagnosis includes essentially
like thickening of the lamina densa of the GBM. The any cause of glomerulonephritis, particularly those
deposits may show segmental interruptions, alternat- associated with hypocomplementemia, including lu-
ing with normal segments of GBM, producing a “sau- pus nephritis, APIGN, and MPGN types I and III. On
sage-string” appearance. Some of the dense deposits biopsy, DDD is most likely to be confused with
appear to extend from the lamina densa into the APIGN because both may show exudative and endo-
subendothelial zone. Rounded nodular deposits are capillary proliferative features, subepithelial humps,
often present in the mesangium, corresponding to the and dominant or isolated immunofluorescence staining
“ring forms” seen by immunofluorescence. Large sub- for C3. In addition, both conditions may present with
epithelial hump-shaped deposits resembling those of the nephritic syndrome after an upper respiratory tract
APIGN are present in a substantial minority of cases infection. Whereas APIGN in children typically re-
(1). Deposits in Bowman’s capsule and the tubular solves within approximately 6 weeks, accompanied by
basement membranes are common, whereas involve- normalization of serum C3, the glomerulonephritis
ment of interstitial capillaries and arterioles is rare. and reduced C3 persist in DDD.
DDD may show prominent membranoprolifera-
tive features, overlapping histologically with MPGN
types I and III. However, because not all cases of DDD
have a membranoproliferative phenotype, the term
DDD is now preferred over MPGN type II. MPGN
types I and III lack the ultrastructural finding of
markedly electron-dense transformation of the lamina
densa and typically stain for immunoglobulins in ad-
dition to C3 and C1q. Because some biopsies show
prominent subendothelial deposits typical of MPGN
type 1 that stain only for C3, the terms “C3 glomeru-
lonephritis” and “C3 glomerulopathy” have recently
been introduced. C3 glomerulopathy encompasses all
types of glomerulonephritis characterized by isolated
C3 deposition (including DDD, other variants of
Figure 7. Immunofluorescence staining for C3 shows nar- MPGN, and mesangial proliferative C3 glomerulone-
row parallel linear bands of positivity along the inner and phritis but excluding APIGN). It was proposed to
outer contours of the GBM, producing the illusion of a
double contour (bottom right). The mesangium contains
highlight the common feature of complement dysregu-
rounded granular deposits, or “ring forms,” another com- lation and emphasize the importance of screening for
mon feature of DDD. Magnification, ⫻400. abnormalities in the complement pathway whenever
glomerulonephritis with isolated C3 deposits is en- opment of DDD, yet other patients with DDD have
countered (5). reduced function of these factors as a result of allelic
Monoclonal Ig deposition disease (MIDD) must variants or the formation of autoantibodies (9). Mice
also be considered in the differential diagnosis of adult deficient in factor H have uncontrolled C3 activation and
DDD. Both MIDD and DDD have markedly electron- develop a membranoproliferative glomerulonephritis re-
dense band-like deposits involving the lamina densa, sembling DDD (10).
mesangium, and other basement membranes of the kid- Another mechanism by which the alternative
ney. MIDD is readily distinguishable from DDD by the pathway can become dysregulated is through the for-
demonstration of monoclonal light and/or heavy chains mation of a C3 nephritic factor (C3NeF). C3NeF is an
on immunofluorescence. Interestingly, monoclonal gam- autoantibody that binds to and stabilizes C3 conver-
mopathy of undetermined significance (MGUS) is not tase, protecting it from factor H– or factor I– mediated
an infrequent comorbidity in adult patients with DDD decay. Whereas a C3NeF is detectable in most chil-
and was reported in four of 18 adults in one series (1). dren with DDD using the hemolytic test or the C3NeF
Another report found MGUS in 71% of patients who IgG solid phase assay, up to half of patients with
had a diagnosis of DDD and were older than 49 years MPGN types I or III also have detectable C3NeF
(6). The link between plasma cell dyscrasias and the activity, making this a nonspecific marker (11).
development of DDD may be more than coincidental. How excessive alternative complement pathway
One report suggests that some abnormal monoclonal activation causes the formation of dense deposits in
immunoglobulins have the ability to bind complement tissues is unclear. A recent study used laser capture
regulatory proteins, such as factor H, resulting in microdissection and mass spectrometry to analyze the
dysregulation of the alternative complement pathway composition of the glomerular deposits in DDD and
and the development of DDD (7). Another reported found various components of the alternative and ter-
case demonstrated the ability of a monoclonal ␭ light minal complement pathways, including C3, C5, C6,
chain isolated from a patient with MGUS and C3 C7, C8, and C9 (12). Notably, the deposits also con-
glomerulonephritis to initiate activation of the fluid tain certain terminal complement complex regulators,
phase of the alternative pathway (8). Despite the such as clusterin and vitronectin, that function primar-
presence of MGUS, these older adults have a renal ily in the fluid phase. These findings suggest that the
biopsy picture of DDD with glomerular deposits of C3 terminal complement components are activated in the
only (without co-deposits of monoclonal light or fluid phase and form deposits in glomeruli, possibly
heavy chain) (6). favored by glomerular ultrafiltration.
Etiology and Pathogenesis References

1. Nasr SH, Valeri AM, Appel GB, Sherwinter J, Stokes MB, Said SM,
Dysregulation of the alternative complement path-
Markowitz GS, D’Agati VD: Dense deposit disease: Clinicopatho-
way drives the development of DDD. The alternative logic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol
complement pathway is unique because of its constitu- 4: 22–32, 2009
2. Appel GB, Cook T, Hageman G, Jennette JC, Kashgarian M,
tive low-level activation through spontaneous hydrolysis
Kirschfink M, Lambris JD, Lannning L, Lutz HU, Meri S, Rose NR,
of a reactive thiolester on C3, leading to the formation of Salant DJ, Sethi S, Smith RJ, Smoyer W, Tully HF, Tully SP, Walker
C3bBb as C3 convertase. Unregulated activation of C3 P, Welsh M, Wurzner R, Zipfel PF: Membranoproliferative glomer-
ulonephritis type II (dense deposit disease): An update. J Am Soc
convertase causes unbridled amplification of the alterna- Nephrol 16: 1392–1404, 2005
tive pathway, ultimately progressing to formation of the 3. Walker PD, Ferrario F, Joh K, Bonsib SM: Dense deposit disease is
membrane attack complex. Under normal circumstances, not a membranoproliferative glomerulonephritis. Mod Pathol 20:
605– 616, 2007
regulators both in the fluid phase and on cell surfaces 4. Southwest Pediatric Nephrology Study Group: Dense deposit disease
prevent inappropriate amplification of the alternative in children: Prognostic value of clinical and pathologic indicators.
pathway. Factor H and factor I both are important regu- Am J Kidney Dis 6: 161–169, 1985
5. Fakhouri F, Fremeaux-Bacchi V, Noel LH, Cook HT, Pickering MC: C3
lators in the fluid phase and directly promote decay of glomerulopathy: A new classification. Nat Rev Nephrol 6: 494–499, 2010
active C3 convertase. Absent or reduced activity of these 6. Sethi S, Sukov WR, Zhang Y, Fervenza FC, Lager DJ, Miller DV,
proteins is one potential source of alternative pathway Cornell LD, Krishnan SG, Smith RJ: Dense deposit disease associ-
ated with monoclonal gammopathy of undetermined significance.
dysregulation in DDD. Inherited mutations in factor H or Am J Kidney Dis 56: 977–982, 2010
I can cause deficiencies in these proteins and the devel- 7. Jokiranta TS, Solomon A, Pangburn MK, Zipfel PF, Meri S: Nephri-
togenic lambda light chain dimer: A unique human miniautoantibody 10. Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport
against complement factor H. J Immunol 163: 5490 –5496, 1999 MJ, Botto M: Uncontrolled C3 activation causes membranoprolifera-
8. Meri S, Koistinen V, Miettinen A, Tornroth T, Seppala IJ: Activation tive glomerulonephritis in mice deficient in complement factor H.
of the alternative pathway of complement by monoclonal lambda Nat Genet 31: 424 – 428, 2002
light chains in membranoproliferative glomerulonephritis. J Exp Med 11. Schwertz R, Rother U, Anders D, Gretz N, Scharer K, Kirschfink M:
175: 939 –950, 1992 Complement analysis in children with idiopathic membranoprolifera-
9. Abrera-Abeleda MA, Nishimura C, Smith JL, Sethi S, McRae JL, tive glomerulonephritis: A long-term follow-up. Pediatr Allergy
Murphy BF, Silvestri G, Skerka C, Jozsi M, Zipfel PF, Hageman GS, Immunol 12: 166 –172, 2001
Smith RJ: Variations in the complement regulatory genes factor H 12. Sethi S, Gamez JD, Vrana JA, Theis JD, Bergen HR, Zipfel PF,
(CFH) and factor H related 5 (CFHR5) are associated with mem- Dogan A, Smith RJH: Glomeruli of dense deposit disease contain
branoproliferative glomerulonephritis type II (dense deposit disease). components of the alternative and terminal complement pathway.
J Med Genet 43: 582–589, 2006 Kidney Int 75: 952–960, 2009
Section 11: CASE PRESENTATION kocyturia, but no cellular casts. Serologies include positive anti-
nuclear antibody of 1:40 (speckled pattern), negative anti-DNA
A 49-year-old Caucasian man presents with right upper antibody and anti-Smith antibodies, and reduced serum C3 (⬍10)
quadrant pain and is found to have acute renal failure and and C4 (⬍5) complement levels. Other serologies are negative or
hematuria. He has a history of deep vein thrombosis 12 normal, including hepatitis B surface antigen, hepatitis C anti-
years earlier, aortic valve thrombosis several years earlier, body, HIV, and anti-neutrophil cytoplasmic antibody. Complete
and positive anticardiolipin antibody. He has had hyperten- blood count reveals a hematocrit of 28%, white blood cell count of
sion for ⬍1 year and no diabetes. Physical examination 9000, and platelet count of 56,000. Schistocytes were identified on
reveals livedo reticularis on the lower extremities, no peripheral blood smear. The kidneys measure 12.0 cm and 12.8
edema, and a BP of 158/78 mmHg. Laboratory tests show cm in length by ultrasound. Three days after admission, he
serum creatinine level of 6.0 mg/dl (increased from a baseline develops signs of encephalopathy, and brain computed tomogra-
value of 1.0 mg/dl 3 months earlier) and a serum albumin of 2.3 phy scan reveals multiple microinfarcts. A renal biopsy is
g/dl. Urinalysis reveals 1⫹ protein, microhematuria and leu- performed.
Figure 1. Figure 2.
Figure 3. Fibrin
Figure 4.
A. Diffuse crescentic glomerulonephritis, pauci-immune type
B. Waldenstrom macroglobulinemia
C. Thrombotic thrombocytopenic purpura
D. Catastrophic antiphospholipid antibody (APA) syndrome
E. Hemolytic-uremic syndrome (HUS)
335
Answer patient’s plasma is diluted 1:1 with normal plasma, a

The glomerular capillary lumina are filled with prolonged dilute Russell’s viper venom time or kaolin
erythrocytes and fibrin thrombi (arrowheads), produc- clotting time) or by a specific enzyme-linked immu-
ing a picture of glomerular “paralysis” (Figure 1, noassay using a phospholipid matrix or a platform of
Jones methenamine silver, ⫻400). The glomerular ␤2GP-1. Although APA cause prolongation of clotting
endothelium of many capillaries appears denuded. No times in vitro, they have procoagulant properties in
crescents, rupture of glomerular basement membranes vivo.
(GBMs), or glomerular fibrinoid necrosis is seen. The APA syndrome may be primary (without associ-
arterioles show luminal obliteration by fibrin thrombi, ated systemic disease) or secondary to systemic lupus
associated with endothelial cell swelling and denuda- erythematosus (SLE) or a related connective tissue
tion (Figure 2, hematoxylin and eosin, ⫻600). In disease. Approximately 40% of patients with SLE
addition, some medial myocytes are replaced by fibrin, have APA (3), and 25 to 40% of these patients will
consistent with arteriolar fibrinoid necrosis; however, show signs of APA syndrome, which commonly in-
there is no inflammation of the vessel walls. Immuno- cludes kidney disease (4 – 6). The term “microangio-
fluorescence staining for fibrin/fibrinogen highlights pathic APA syndrome” has been proposed for patients
glomerular intracapillary fibrin thrombi filling the cap- with APA, small vessel thrombosis, and signs of
illary lumina as well as more delicate semilinear pos- microangiopathic hemolytic anemia (i.e., TMA) (7). A
itivity outlining the peripheral glomerular capillary small subset (⬍1%) of patients meet criteria for cata-
walls (Figure 3, ⫻400). Similar intraluminal staining strophic APA syndrome, which is defined by acute
for fibrin was found in the intima and lumina of involvement of three or more organs within a 1-week
arteries and arterioles (data not shown). With the period, small-vessel thrombosis in at least one organ
exception of nonspecific staining for IgM and C3 in a system, and a circulating APA (8 –10).
few areas of thrombosis, no regular deposits of Ig or
complement were detected in the glomeruli. By elec- Clinical Characteristics
tron microscopy, focal electron-dense fibrin tactoids APA syndrome has diverse clinical manifesta-
are seen within glomerular capillary lumina, associ- tions, reflecting the spectrum of organ involvement,
ated with endothelial cell swelling (Figure 4, ⫻5000). the size of vessels affected, and the presence of un-
These findings of acute thrombotic microangiopathy derlying disease. Common manifestations include
(TMA) with multisystem involvement and history of deep vein thrombosis, thrombotic stroke leading to
anticardiolipin antibody are consistent with cata- specific neurologic deficits or multi-infarct dementia,
strophic antiphospholipid antibody (APA) syndrome and recurrent fetal loss. Other frequent manifestations
(answer D). include nephropathy, livedo reticularis, nonthrombotic
endocarditis, pulmonary hypertension, myocardial in-
Catastrophic APA Syndrome farction, hepatic venous thrombosis causing Budd-
APA syndrome is a multisystem disorder char- Chiari syndrome, and adrenal infarction. The throm-
acterized by arterial, venous, and/or microvascular botic process may be associated with the development
thrombosis in the setting of a persistent circulating of anemia and thrombocytopenia. Clinically signifi-
APA (1). Thromboses generally involve medium- cant kidney disease affects 3 to 9% of patients with
sized or large arteries and veins but may also affect “classical” primary APA syndrome (11,12) and 71 to
small vessels including arterioles, venules, and capil- 78% of those with catastrophic APA syndrome (8,13).
laries, giving rise to TMA (2). APA are autoantibodies The renal manifestations of APA syndrome usu-
with specificity for a family of naturally occurring ally include hypertension, chronic renal insufficiency,
phospholipids including cardiolipin, phosphatidylcho- subnephrotic proteinuria, and microscopic hematuria
line, phosphatidylserine, and phospholipids of the clot- (14). Nephrotic syndrome is unusual. APA syndrome
ting cascade such as prothrombin and/or for the typically affects young or middle-aged adults, with
plasma co-factor ␤2 glycoprotein-1 (␤2GP-1) to men more commonly affected by primary APA syn-
which they bind. APA are detected by a positive lupus drome (14) and women by lupus-related disease (6). In
anticoagulant (LA) test (e.g., a prolonged partial patients with lupus, APA-associated nephropathy is
thromboplastin time that does not correct when the more commonly associated with extrarenal arterial
wall). Of note, acute TMA is seen in only one third of

patients who have primary APA syndrome and un-
dergo renal biopsy, whereas chronic vessel changes,
which are likely the sequelae of thrombosis, are more
common (14). Chronic arterial changes include re-
canalized thrombi, fibrous intimal hyperplasia, and
concentric onion-skin fibrous and fibrocellular occlu-
sions (14). Organized thrombi may form spherical
structures that resemble glomeruli (“glomeruloid bod-
ies”). A common finding is a band of cortical atrophy
involving the superficial cortex (14). More generalized
tubular atrophy and interstitial fibrosis may occur in
the distribution of the chronic vascular occlusions.
Other glomerular features of TMA include me-
Figure 5. An interlobular artery shows mucoid intimal
edema. Magnification, ⫻400 (hematoxylin and eosin). sangiolysis (loosening of the mesangial matrix, with
reduced staining intensity for periodic acid–Schiff and
silver stains) and duplication of GBMs, resembling
than venous thromboses and more commonly with LA
membranoproliferative glomerulonephritis (Figure 6).
than ACL antibodies (6). Patients who have lupus with
Unraveling of the GBM’s attachment to the mesan-
APA nephropathy have an increased incidence of
gium as a result of mesangiolysis may cause the
hypertension, higher serum creatinine levels, and
glomerular capillaries to balloon, producing microan-
greater interstitial fibrosis, which often portend worse
eurysms. Sclerotic glomeruli may have a fibrillar or
renal outcomes (6). Catastrophic APA syndrome pres-
reticulated quality with silver stain that differs from
ents with acute or rapidly progressive renal failure,
the more compact, solid staining seen in sclerotic
accelerated hypertension, and microangiopathic hemo-
glomeruli as a result of aging and/or hypertension.
lytic anemia and is more common in females (72% in
As many as one third of biopsies performed in
one study) (14). The renal clinical presentation of
patients with primary APA syndrome may show un-
catastrophic APA syndrome may be indistinguishable
derlying glomerular lesions other than TMA (12,15).
from that of HUS. Other renal manifestations of APA
These findings include lupus-like membranous or pro-
syndrome include renal cortical necrosis or infarction,
renal artery thrombosis or stenosis (which may be
associated with severe hypertension), and renal vein
thrombosis.
Pathology
Light Microscopy. The renal pathologic findings in
APA-associated nephropathy encompass the spectrum
of renal changes seen in other causes of TMA (14).
Acute TMA is characterized by the presence of fibrin
thrombi (with entrapped red blood cells and platelets)
within glomeruli (Figure 1), arterioles (Figure 2), and
interlobular arteries. Arterial vessels may show mu-
coid intimal edema and hyperplasia (Figure 5). In
severe disease (e.g., in catastrophic APA syndrome),
there may be fibrinoid necrosis of arterial myocytes, Figure 6. A glomerulus shows duplication of GBMs, mim-
interstitial hemorrhage, and frank cortical necrosis. icking membranoproliferative glomerulonephritis, in a case
of chronic APA nephropathy. There is also ischemic wrin-
Although leukocytes may be marginated in the lumen kling of GBMs and dissolution of the mesangial matrix,
of thrombosed vessels, there is typically no evidence consistent with mesangiolysis. Magnification, ⫻600 (Jones
of vasculitis (transmural inflammation of the vessel methenamine silver).
liferative glomerulonephritis, mesangial C3 glomeru- of coagulation and loose matrix material. Mesangioly-
lonephritis, minimal change disease, and FSGS. sis has a similar electron-lucent appearance owing to
Whether these findings represent coincidental unre- dissolution of the mesangial matrix. The subendothe-
lated renal disease or incipient lupus nephritis or are lial fluffy material may be incorporated into the glo-
directly related to APA is often unclear at the time of merular capillary wall by an underlying thin layer of
biopsy. Some of these patients will subsequently de- newly formed basement membrane, leading to a dou-
velop SLE, and it has been suggested that membra- ble-contoured glomerular capillary wall. Partial or
nous glomerulonephritis, in particular, may be a man- circumferential mesangial interposition often occurs in
ifestation of primary APA syndrome (2). Lupus these areas, producing a membranoproliferative pat-
nephritis is commonly found in patients with lupus- tern (Figure 7). Fibrin tactoids may be seen in areas
related APA nephropathy (6). Any class of lupus with fresh thrombosis (Figure 4). The glomerular en-
nephritis may be seen, but proliferative forms (classes dothelium is often swollen with loss of fenestrations
III and IV) tend to predominate, with the exception of and lifting off the GBM. Cases with coexistent lupus
class V (membranous) lupus nephritis in patients who nephritis have endothelial tubuloreticular inclusions
present with nephrotic syndrome. and electron-dense deposits at the sites of immune
Immunofluorescence. Glomerular and arteriolar complex deposition detected by immunofluorescence.
thrombi stain for fibrin/fibrinogen (Figure 3). Weaker,
nonspecific staining for IgM and C3 (and in some Differential Diagnosis
cases C1q) may be present in areas of thrombosis and The differential diagnosis of renal TMA is broad
in sclerosing glomeruli. Immune deposits that stain for and requires careful clinical correlation to reach a
IgG (with possible co-deposits of IgA, IgM, C3, and more specific diagnosis. A major cause of renal TMA
C1q) are a feature of coexistent lupus nephritis but are is HUS caused by infections by shigatoxin-producing
not seen in primary APA nephropathy. Escherichia coli (mostly of the O157:H7 serotype),
neuraminidase-producing Streptococcus pneumoniae,
Electron Microscopy. A characteristic ultrastruc-
or HIV. There is increasing recognition that some
tural finding in all forms of TMA, including that
patients with HUS have inherited deficiencies in reg-
related to APA syndrome, is the presence of ill-
ulators of the alternative complement pathway such as
defined, flocculent electron-lucent material (some-
factor H, membrane co-factor protein, factor I, or
times termed “fluff”) in the subendothelial space be-
complement C3 (16). Other individuals with HUS may
tween endothelial cells and the GBM (Figure 7). This
develop inhibitory autoantibodies to complement reg-
fluffy material is thought to contain degraded products
ulatory proteins, particularly to factor H (17). Throm-
botic thrombocytopenic purpura typically manifests
with skin and neurologic involvement and may be due to
genetic deficiency of von Willebrand factor cleaving pro-
tease (ADAMTS13) or inhibitory autoantibodies. Other
major causes of renal TMA include acute scleroderma
renal crisis, malignant hypertension, eclampsia of
pregnancy, drug toxicity, radiation toxicity, and neo-
plasia. Drugs that can cause TMA include a host of
chemotherapeutic agents (e.g., gemcitabine, mitomy-
cin C, tamoxifen, bleomycin, cisplatin, cytosine arabi-
noside, daunorubicin, antivascular endothelial growth
factor agents) (18,19), as well as antiplatelet agents
(ticlopidine and clopidogrel), quinine, calcineurin inhib-
itors, and oral contraceptives. Some patients with rheu-
matoid arthritis receiving anti–TNF-␣ agents have been
Figure 7. Electron micrograph showing subendothelial elec-
tron-lucent “fluff” (arrow) and duplication of basement
reported to develop APA and renal TMA (20,21). Al-
membranes (arrowheads), producing a membranoprolifera- though pathogenesis is diverse, these various forms of
tive pattern. Magnification, ⫻6000. TMA share injury to endothelial cells as a common
inciting event. Thus, the renal pathology of these condi- References

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Section 12: CASE PRESENTATION examination reveals a BP of 130/64 mmHg, weight of 118 lb,
and no edema or cutaneous manifestations. Urinalysis reveals
An 86-year-old Caucasian woman presents with acute 2⫹ protein, four to 10 red blood cells per high-power field, and
kidney injury (AKI) and a creatinine level of 2.22 mg/dl. numerous white blood cells. She has a normal serum free light
Past medical history is significant for chronic kidney chain ratio, no evidence of a monoclonal serum spike, no
disease with a baseline creatinine of 1.3 mg/dl 10 months eosinophilia, a negative urine culture, serum albumin of 3.9
earlier, osteoporosis, and recent 10-lb weight loss. The g/dl, serum calcium of 10.2 mg/dl, hematocrit of 32.9%, and a
patient recently underwent urogynecologic evaluation for urine protein-creatinine ratio of 1.8. Negative serologies in-
frequent nocturia and urge incontinence. She was found clude anti-nuclear antibody, anti– glomerular basement mem-
to have sterile pyuria, a second-degree cystocele, and an brane antibody, anti-neutrophil cytoplasmic antibody, hepa-
elevated post-void residual volume. She was treated with titis B surface antigen, and hepatitis C virus antibody.
a pessary, leading to mild improvement in her symptoms. Serum C3 and C4 are normal. Her kidneys measure 9.0
Her medications are limited to multivitamins and vitamin and 9.1 cm in length by ultrasound, without evidence of
D, although she has previously been treated for osteopo- obstruction. Three weeks later, the patient’s creatinine
rosis with monthly risedronate. There is no history of level remains elevated at 2.2 mg/dl. Renal biopsy is
nonsteroidal anti-inflammatory drug (NSAID) use. Physical performed.
Figure 1. Figure 2.
Figure 3. Figure 4.
A. Lymphoma of the kidney

B. Acute interstitial nephritis (AIN)
C. Acute tubular necrosis
D. Pauci-immune necrotizing and crescentic glomerulonephritis
E. Myeloma cast nephropathy
341
Answer to 30% of cases (4 –7). Much of these data come from

The renal biopsy findings are diagnostic of acute older series; in our more contemporary experience,
interstitial nephritis (AIN) (answer B). The predomi- infectious causes of AIN, including bacteria, myco-
nant finding at low magnification is diffuse interstitial bacteria, fungi, and viruses, compose no more than 5%
inflammation, as seen in Figure 1 (hematoxylin and of biopsied cases. Systemic, presumed autoimmune
eosin [H&E], ⫻200). At the lower left aspect of the processes are also a significant cause of AIN and
field, a glomerulus appears histologically unremark- include Sjögren syndrome, systemic lupus erythema-
able. Figure 2 demonstrates that at higher magnifica- tosus (“lupus interstitial nephritis”), Wegener granu-
tion, the interstitial infiltrate is composed of a mixture lomatosis, sarcoidosis, tubulointerstitial nephritis with
of lymphocytes, monocytes, and plasma cells (H&E, uveitis (TINU) syndrome, idiopathic hypocomple-
⫻400). The hallmark of AIN is the extension of mentemic interstitial nephritis (8), and the newly de-
interstitial inflammatory cells across tubular basement scribed entity of IgG4 immune complex tubulointer-
membranes (TBMs) to infiltrate the tubular epithe- stitial nephritis (9 –11). Importantly, a significant
lium, a finding referred to as tubulitis. Tubulitis is best percentage of cases of AIN, perhaps as many as 10%,
seen with periodic acid–Schiff stain, which highlights remain idiopathic.
TBMs (Figure 3, ⫻600). Interstitial eosinophils, IgG4 immune complex tubulointerstitial nephri-
which are present in Figure 4, are most frequently seen tis represents the renal component of a systemic auto-
in drug-induced AIN (H&E, ⫻600). On the basis of immune inflammatory process known as “IgG4-re-
the clinical history and pathologic findings, no defin- lated sclerosing disease.” It most commonly affects
itive etiology of AIN could be established for this older male adults and is characterized by significantly
patient. elevated serum IgG and IgG4 levels (11). This sys-
temic process most frequently involves the pancreas,
Acute Interstitial Nephritis hepatobiliary tract, salivary glands, and lymph nodes
AIN is a common cause of AKI that results from (11). Renal involvement occurs in a minority of cases,
a wide variety of conditions. AIN can be definitely is often associated with hypocomplementemia, and
diagnosed only by renal biopsy, where findings in- can manifest as diffuse parenchymal involvement or a
clude interstitial inflammation, tubulitis, and acute mass lesion (9,10). The histopathology can be distin-
tubular injury. Over weeks to months, chronic injury guished from other forms of AIN by the presence of
may ensue, including tubular atrophy and interstitial abundant TBMs and interstitial deposits of IgG and
fibrosis. Even in the chronic phase, residual interstitial complement, a swirling pattern of fibrosis, and the
mononuclear cell inflammation and tubulitis are typi- presence of abundant IgG4-producing plasma cells,
cally still seen. typically exceeding 40 IgG4⫹ plasma cells per high-
In the initial report of AIN in 1898, Councilman power field. Sjögren syndrome must be excluded be-
(1) described inflammation of the renal interstitium in fore the diagnosis of IgG4 immune complex tubulo-
children with diphtheria and scarlet fever and pro- interstitial nephritis can be definitely established.
posed that it represented a reactive, cytokine-mediated
response to infection. In the modern era, AIN is the Clinical characteristics
predominant diagnosis in approximately 2 to 6% of The only consistent clinical feature of AIN is
native renal biopsies (2– 4), and this number increases renal dysfunction, which can vary from insidious to
to 6 to 10% when only biopsies from patients who abrupt in onset and is typically not accompanied by
present with AKI are considered. oliguria. In most cases, urinalysis reveals leukocyturia,
The most common etiology of AIN is drug- which is usually associated with low-grade proteinuria
induced disease, which comprises approximately 70% and, in a minority of cases, microscopic hematuria. At
of cases (range 31 to 92%) (2–7). Among patients with the time of presentation, the majority of patients with
drug-induced AIN, the most common causative agents AIN do not require renal replacement therapy. Drug-
are antibiotics and NSAIDs, which together account induced AIN most commonly presents 1 to 3 weeks
for more than half of cases in many reports (2,3,5,6). after exposure to a therapeutic agent but may occur
Multiple large series suggest that infection is the earlier after repeat exposure or may be seen much
second most common cause of AIN, accounting for 10 later, as is often the case with NSAIDs.
Multiple clinical and laboratory findings may Detailed clinical history, physical examination,
provide clues to the pathogenesis of AIN in individual and serologic evaluation may provide important clues
patients. The initial report of drug-induced AIN by as to the etiology of non– drug-induced forms of AIN.
Baldwin et al. (12) described seven patients who For instance, uveitis and AIN are seen in patients with
developed AIN after treatment with penicillin or meth- Sjögren syndrome, sarcoidosis, or TINU syndrome;
icillin and noted the presence of systemic signs of a pulmonary disease suggests the possibility of sarcoid-
hypersensitivity reaction including fever, rash, and osis; signs of systemic vasculitis may implicate We-
eosinophilia. Subsequent experience has shown that gener granulomatosis; and pancreatitis raises the pos-
this “classic triad” of symptoms of drug-induced AIN sibility of IgG4 immune complex tubulointerstitial
is seen much more commonly after treatment with nephritis (9). Infectious causes of AIN should be
␤-lactam antibiotics than with other classes of drugs carefully excluded in immunosuppressed and trans-
and that, overall, the full triad is seen in ⬍10% of plant patients.
patients (3,13). Eosinophiluria, when present, is also Many patients with AIN present only with unex-
regarded as a relatively specific sign of drug-induced plained renal insufficiency, and the biopsy findings of
AIN. AIN come as a surprise to the nephrologist. The
Given the high prevalence of drug-induced AIN, possibility of AIN should be considered for all patients
the most common inciting therapeutic agents deserve with unexplained renal insufficiency, in particular in
special consideration. The form of AIN induced by the setting of leukocyturia and subnephrotic protein-
NSAIDs has distinctive features including the typical uria.
absence of signs of a hypersensitivity reaction, a long
duration of treatment (typically ⬎6 months) before the Pathology
development of AIN, and the usual absence of inter- Light microscopy. The diagnosis of AIN can be
stitial eosinophils (14). The 5-aminosalicylates, an- established only by light microscopy, where the pre-
other class of anti-inflammatory drugs that are mainly dominant findings are interstitial inflammation with
used to treat inflammatory bowel disease, are also extension of the infiltrate across TBMs, producing
commonly associated with AIN including 42 pub- “tubulitis” (Figures 1 through 3). All areas of the
lished cases (15) and an incidence that has been cortex may be involved, sometimes with particularly
estimated to be greater than 1 in 500 patients (15–17). intense inflammation in the outer medulla. In most
Similar to NSAIDs, the AIN that follows use of forms of interstitial nephritis, lymphocytes are the
5-aminosalicylates is associated with a longer duration predominant component of the interstitial infiltrate,
of therapy and the usual absence of eosinophils. The although monocytes, plasma cells, eosinophils, and
most rapidly rising cause of drug-induced AIN and, in neutrophils also may be seen. The relative composi-
some countries, the most common etiology overall is tion of the interstitial infiltrate may provide clues to
proton pump inhibitors (PPIs) used to treated gastritis the cause of AIN. For instance, the presence of prom-
and gastroesophageal reflux disease. PPI-induced AIN inent interstitial eosinophils strongly favors a drug-
appears to represent a class effect because it can induced cause, although the absence of eosinophils
follow the use of most, if not all, available PPIs. The does not argue against this possibility. Plasma cells are
AIN that follows the use of PPIs presents at a mean of particularly prominent with renal parenchyma infec-
3 months following exposure, is commonly associated tion by BK polyoma virus (BK nephropathy) and IgG4
with eosinophilic inflammation, and may exhibit signs immune complex tubulointerstitial nephritis with au-
of a systemic hypersensitivity reaction (18 –20). There toimmune pancreatitis. Prominent neutrophils, in par-
are at least 64 reports of biopsy-proven AIN related to ticular when accompanied by neutrophilic tubulitis,
PPIs (18). AIN has been attributed to multiple classes neutrophil casts, or microabscesses, suggest renal pa-
of antibiotics other than the ␤-lactams, including ri- renchymal infection, typically of bacterial origin (i.e.,
fampin, sulfonamides, and the fluoroquinolones, acute pyelonephritis) (Figure 5).
among many others. Importantly, drug-induced AIN The interstitial inflammation and tubulitis of
represents an idiosyncratic, non-dose-dependent reac- AIN are commonly accompanied by findings of acute
tion that can potentially follow the use of any thera- tubular injury, including luminal ectasia, cytoplasmic
peutic agent. simplification and vacuolization, irregular luminal
of renal biopsy in one large series (23). In that series,

the most frequent causes of GIN were drug-induced
and sarcoidosis, representing 44.7 and 28.9% of the 38
cases, respectively. The majority of drug-induced
cases of GIN were attributed to NSAIDs and antibi-
otics. Another series included 18 cases of GIN in
which 5 cases were attributed to sarcoidosis, 2 to
TINU, 2 were drug-induced, and 9 were idiopathic
(24). In our experience, NSAIDs are a very uncommon
cause of GIN. In contrast, anticonvulsants such as
dilantin are an important diagnostic consideration in
patients with GIN (25). Less common causes of GIN
include Wegener granulomatosis; infections from my-
cobacterium tuberculosis, fungi, Escherichia coli, and
Figure 5. The finding of abundant interstitial and intratu-
bular neutrophils is the hallmark of infectious forms of other Gram-negative organisms; and idiopathic forms
interstitial nephritis (i.e., acute pyelonephritis). Magnifica- of disease (26). When granulomas with large epithe-
tion, ⫻600 (H&E). lioid histiocytes occur in the setting of acute bacterial
pyelonephritis, they may produce a picture of mega-
contours, prominent nucleoli, and apoptotic figures, as locytic interstitial nephritis or xanthogranulomatous
well as interstitial edema. In the absence of resolution, pyelonephritis. The distinguishing feature of GIN is
tubular atrophy and interstitial fibrosis may develop, the presence of interstitial aggregates of epithelioid
and, when extensive, these chronic features portend a histiocytes that form granulomas and are commonly
poor prognosis. Glomeruli are spared in the acute accompanied by multinucleated giant cells (Figure 6).
phase, but they may become retracted with thickening The size and number of granulomas seen at biopsy can
of Bowman’s capsule in areas of interstitial fibrosis. vary widely, ranging from a few to many with areas of
confluence. In sarcoidosis, the granulomas are typi-
Immunofluorescence and electron microscopy. Im- cally discrete and noncaseating, and the giant cells
munofluorescence is unrevealing in the majority of may contain distinctive Schaumann bodies (laminated
cases of drug-induced or infectious forms of AIN, with calcific concretions) or asteroid bodies (stellate inclu-
the exception of rare reports of TBM deposits in sions). Histologic findings in GIN are otherwise sim-
methicillin-associated AIN (21) and in the setting of ilar to AIN and include interstitial inflammation, tu-
BK nephropathy (22). In contrast, TBM immune de- bulitis, and subsequent tubulointerstitial scarring. For
posits are common in patients with a systemic, pre-
sumed autoimmune cause of AIN, including Sjögren
syndrome, systemic lupus erythematosus, idiopathic
hypocomplementemic interstitial nephritis, IgG4 im-
mune complex tubulointerstitial nephritis, and rarely
TINU syndrome. Regardless of cause, the immunoflu-
orescence finding of immune complex TBM deposits
usually corresponds with the ultrastructural finding of
electron-dense deposits in TBMs. Electron micros-
copy may also reveal extensive foot process efface-
ment in patients who develop both AIN and minimal
change disease after treatment with NSAIDs.
Granulomatous interstitial nephritis. In the con-
text of AIN, the finding of granulomatous interstitial
nephritis (GIN) merits special consideration. Clini- Figure 6. In this example of GIN secondary to sarcoidosis,
cally, GIN has a similar clinical presentation to AIN a large aggregate of multinucleated giant cells forms an
but a significantly lower incidence, representing 0.5% interstitial granuloma. Magnification, ⫻400 (H&E).
any GIN, fungal and mycobacterial infections should report from the UK MDC Glomerulonephritis Register and a review
of the literature. Nephrol Dial Transplant 13[Suppl 7]: 12–16, 1998
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by urine cultures. nephritis: Clinical features and response to corticosteroid therapy.
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5. Buysen JG, Houtlhoff HJ, Krediet RT, Arisz L: Acute interstitial
to infection in infectious forms of AIN. The interstitial nephritis: A clinical and morphological study in 27 patients. Nephrol
infiltrates in systemic, presumed autoimmune forms of Dial Transplant 5: 94 –99, 1990
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Renal biopsy in patients with unexplained renal impairment and
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8. Kambham N, Markowitz GS, Tanji N, Mansukhani MM, Orazi A,
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388 –399, 2001
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1. Councilman WT: Acute interstitial nephritis. J Exp Med 3: 393– 420, basement membrane immune deposits in association with BK polyo-
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nephritis: A clinicopathologic study of 46 cases from a single insti- 27. Levinson RD, Park MS, Rikkers SM, Reed EF, Smith JR, Martin TM,
tution. Int J Surg Pathol 14: 57– 63, 2006 Rosenbaum JT, Foster CS, Sherman MD, Holland GN: Strong
24. Joss N, Morris S, Young B, Geddes C: Granulomatous interstitial associations between specific HLA-DQ and HLA-DR alleles and the
nephritis. Clin J Am Soc Nephrol 2: 222–230, 2007 tubulointerstitial nephritis and uveitis syndrome. Invest Ophthalmol
25. Ram R, Swarnalatha G, Prasad N, Prayaga A, Dakshina Murthy KV: Vis Sci 44: 653– 657, 2003
Granulomatous interstitial nephritis following prolonged use of phe- 28. D’Agati VD, Theise ND, Pirani CL, Knowles DM, Appel GB:
nytoin. Saudi J Kidney Dis Transpl 20: 131–133, 2009 Interstitial nephritis related to nonsteroidal anti-inflammatory agents
26. Mignon F, Mery JP, Mougenot B, Ronco P, Roland J, Morel-Maroger and ␤-lactam antibiotics: A comparative study of the interstitial
L: Granulomatous interstitial nephritis. Adv Nephrol Necker Hosp 13: infiltrates using monoclonal antibodies. Mod Pathol 2: 390 –396,
219 –245, 1984 1989
Section 13: CASE PRESENTATION earlier. Physical examination reveals a BP of 187/92 mmHg,
3⫹ pitting lower extremity edema, and no hepatosplenomeg-
An 87-year-old Caucasian woman presents with abrupt aly or cutaneous manifestations. Laboratory evaluation reveals
onset of lower extremity edema and is found to have nephrotic a 24-hour urine protein of 18.0 g, serum albumin 1.7 g/dl,
syndrome and acute kidney injury (AKI) with a creatinine level hematocrit 34%, normal C3 and C4 complement levels, and no
of 2.84 mg/dl. Past medical history is significant for hyperten- evidence of a monoclonal serum or urine spike. Urinalysis
sion, depression, anemia, osteoarthritis, peptic ulcer disease, reveals 4⫹ protein with 8 to 10 red blood cells per high-power
and bladder incontinence. Her medications include furo- field, 30 to 50 white blood cells per high-power field, and no
semide, metoprolol, duloxetine, mirtazapine, alprazolam, hy- cellular casts. Urine cultures are positive for Escherichia coli.
droxycodone, pantoprazole, risedronate, aspirin, and polysac- The following serologies are negative: Anti-nuclear antibody,
charide-iron complex. There is no history of diabetes or recent hepatitis C antibody, hepatitis B surface antigen, anti-neutro-
nonsteroidal anti-inflammatory drug (NSAID) use, and the phil cytoplasmic antibody, and anti– glomerular basement
patient’s baseline serum creatinine was 0.6 mg/dl 3 months membrane (anti-GBM) antibody.
Figure 1. Figure 2.
Figure 4.
Figure 3.

A. Minimal change disease (MCD)
B. Amyloidosis
C. Membranous nephropathy
D. FSGS, glomerular tip lesion variant
Figure 5. E. Acute tubular necrosis
347
Answer significant glomerular abnormalities by light micros-

The renal biopsy findings are diagnostic of min- copy or evidence of immune deposits by immunoflu-
imal change disease (MCD) (answer A). Light micros- orescence microscopy. Thus, the term “nil disease”
copy reveals a representative glomerulus with normo- was aptly applied in the past. The earlier designation
cellular tuft, patent capillary lumina, and GBMs of “lipoid nephrosis” originated from the observation of
normal thickness (Figure 1, Jones methenamine, lipid resorption droplets in the tubules by light micros-
⫻400). No glomeruli with segmental sclerosis were copy with corresponding oval fat bodies on urinalysis.
identified. The proximal tubules are separated by mild Other alternate names for MCD include minimal
interstitial edema and exhibit diffuse degenerative change nephrotic syndrome and minimal lesion.
changes characterized by luminal ectasia, epithelial sim-
plification, irregular luminal contours, loss of brush Clinical Presentation
border, and enlarged nuclei with prominent nucleoli MCD characteristically presents with abrupt on-
(Figure 2, hematoxylin and eosin [H&E], ⫻400). set of edema and full NS. Milder degrees of subne-
These findings of acute tubular injury are seen in the phrotic proteinuria without edema have been reported
majority of patients with MCD who present with AKI. rarely in patients with histologic features of MCD and
A blood vessel displays moderate to severe arterio- a clinical response to steroid therapy, suggesting the
sclerosis (Figure 3, H&E, ⫻400). On ultrastructural occasional presentation with subclinical disease (3).
evaluation, the podocytes exhibit nearly complete foot The proteinuria is highly selective, consisting largely
process effacement (involving over 95% of the glo- of albumin. Hypertension and microhematuria may be
merular capillary surface area) with focal microvillous seen in a small subset of patients. The serologic
transformation of their cytoplasm (Figures 4 and 5, studies including serum complement levels are nor-
⫻6000 and ⫻8000, respectively). No electron-dense mal. Acute renal failure can be a presenting feature in
deposits are identified. After receipt of the renal bi- adults with severe hypoalbuminemia and preexisting
opsy results, the patient was started on oral predni- arterionephrosclerosis of aging and/or hypertension.
sone. Three weeks later, her creatinine had declined to These patients usually manifest features of acute tu-
1.1 mg/dl and her edema was substantially improved. bular necrosis and variable interstitial edema on bi-
opsy, as seen in this case. Other causes of acute renal
Minimal Change Disease failure in MCD include coexistent drug-induced inter-
Although MCD can occur at any age, the age stitial nephritis, particularly secondary to NSAID use.
distribution is bimodal with peak incidences in In children, MCD has a M:F ratio of 2:1, but there is
young children and older adults. MCD accounts for no gender predominance in adults. Among adults pre-
34 to 76% of nephrotic syndrome (NS) in children senting with NS, Caucasians have a higher incidence
(1). The frequency of MCD as a cause of NS of MCD than African Americans.
progressively decreases in older children and young
adults. On the basis of the high probability of MCD Pathology
as a cause of NS, young children with NS do not Light Microscopy. By definition, no significant glo-
undergo a renal biopsy unless they are steroid re- merular alterations are identified histologically in
sistant. Conversely, because ⬍25% of adults with MCD. The GBMs are normal in thickness and contour.
NS have MCD, renal biopsy is essential to establish The glomerular cellularity is typically normal. In bi-
a diagnosis before the initiation of therapy (2). A opsies with prominent mesangial proliferation, the
biopsy diagnosis of MCD in elderly patients can variant “diffuse mesangial hypercellularity” (DMH)
often be complicated by the increased prevalence of should be considered. Occasional globally sclerotic
other preexisting pathologies such as age-related glomeruli may be observed, and their frequency in-
arterionephrosclerosis, hypertensive nephrosclero- creases in older patients. However, the presence of
sis, or early diabetic nephropathy. In one series, even a single glomerulus with segmental sclerosis is
MCD was the most common cause of NS in patients sufficient to diagnose FSGS. Tubular atrophy and
who were older than 80 years (2). interstitial fibrosis attributable to coexistent arterion-
MCD is characterized by severe foot process ephrosclerosis of hypertension or aging may be ob-
effacement by electron microscopy in the absence of served in adults but should raise suspicion for under-
sampled FSGS in a child. This is a particularly its can be seen in IgM nephropathy, C1q nephropathy,
important consideration in a kidney biopsy with sub- or coexistent IgA nephropathy.
optimal sampling of deep juxtamedullary glomeruli, Diffuse Mesangial Hypercellularity. DMH is a
where the first lesions of FSGS typically develop. variant of MCD that is predominantly seen in young
Prominent protein and lipid resorption droplets are children and is associated with higher rates of initial
often observed in the tubules of MCD. Usually no steroid resistance and a higher incidence of microhe-
significant interstitial inflammation is seen. The pres- maturia than the usual form of MCD (Figure 6).
ence of significant interstitial inflammation and tubu- However, the remission rates of both groups are sim-
litis, sometimes associated with eosinophils, should ilar after 52 weeks of follow-up, and long-term out-
raise the suspicion of NSAID-induced MCD and acute comes are comparable (6). The renal biopsy findings
interstitial nephritis. Varying severity of arterio- and are akin to MCD except for the presence of diffuse
arteriolosclerosis may be observed in older patients. mesangial hypercellularity defined as more than four
Acute tubular injury characterized by simplified mesangial cells per area of mesangium and affecting
tubular epithelium, sloughed epithelial cells, and loss ⬎80% of the glomeruli sampled (6), although the
of proximal tubular brush borders typically occurs in exact criteria vary in different studies (7). A recent
adults with MCD and the syndrome of “MCD with pediatric study suggested that DMH (defined as more
acute renal failure.” This combination of findings is than three cells per mesangial area) in the presence of
thought to be mediated by hemodynamic factors with NS predicts multiple relapses but preservation of nor-
intravascular volume depletion in the setting of pro- mal renal function (8). Immunofluorescence is usually
found hypoalbuminemia and edema, in turn causing negative but may occasionally demonstrate mesangial
renal hypoperfusion and ischemic tubular injury. IgM and C3 only. Ultrastructural features include diffuse
Older adults with history of hypertension and vascular podocyte injury similar to MCD. Small paramesangial
narrowing as a result of arteriosclerosis are most deposits may be present in some cases, corresponding to
susceptible to this complication (4,5). the IgM and C3 staining.
Immunofluorescence. Immunofluorescence staining Relationship with FSGS. One of the challenges in
for immunoglobulins and complements is usually neg- pediatric NS is to determine whether biopsy findings
ative. Tubular protein resorption droplets may be high- of apparent MCD in fact represent undersampled
lighted by staining for albumin. High-intensity mes- FSGS. This sampling error may explain a diagnosis of
angial IgM or C1q staining should suggest IgM FSGS rendered on a repeat biopsy in a patient with a
nephropathy and C1q nephropathy, respectively, both previous biopsy diagnosis of MCD. It has also been
of which may be considered variants of MCD in this argued that MCD and FSGS represent a continuum of
setting. The presence of significant mesangial IgA
deposits (at least 1⫹ intensity) in an otherwise classic
case of MCD suggests a dual diagnosis of MCD with
coexistent mesangial IgA nephropathy.
Electron Microscopy. The ultrastructural abnor-
malities are limited to extensive podocyte foot process
effacement, usually involving ⬎75% of the total cap-
illary surface area examined. A sheet of podocyte
cytoplasm overlies normal GBMs, often with conden-
sations of actin cytoskeleton parallel to the GBM.
Villous projections of the podocyte cytoplasm into the
urinary space are often described as “microvillous
transformation” of the podocyte cell bodies. These
podocyte changes may be milder in partially treated
MCD but become extensive in the setting of a relapse. Figure 6. Diffuse mesangial hypercellularity is a variant of
No immune-type electron-dense deposits are identified MCD characterized by four or more mesangial cells per
in MCD. Significant mesangial electron-dense depos- mesangial area. Magnification, ⫻400 (H&E).
podocyte disease (podocytopathy) depending on the cytes can respond to external stimuli by activating
severity and reversibility of the podocyte injury and enzymatic pathways that dysregulate the actin cyto-
that some cases of MCD may evolve into FSGS over skeleton and filtration slit diaphragm.
time. In the majority of patients, however, the different Abnormalities in the proportion of T cell subsets
clinical course and pathologic findings at the outset have been documented in the serum of patients with
suggest that MCD and FSGS are two distinct entities. MCD. In general, patients with MCD have predomi-
Several studies have attempted to apply immu- nance of (T helper 2) Th2 cytokine response that has
nohistochemical methods to improve the accuracy of a role in antibody production and allergic reactions.
biopsy diagnosis of MCD and FSGS, but these tests Th2 cytokines are produced by lymphocytes and mast
are not used in clinical practice. A few investigators cells. MCD has also been linked to atopy and elevated
have reported reduced or redistributed GBM nephrin serum IgE levels (16). Levamisole, an immunostimu-
staining, but other studies could not confirm these lant and antihelminth drug used to reduce the relapse
findings (9). ␣-Dystroglycan, a podocyte protein im- rate of MCD is known to augment the Th1 response
portant in adhesion to GBM, may be reduced in MCD, and thus reset the Th1/Th2 balance (11). Although
but additional confirmatory studies are needed to es- most of the data focus on T cell abnormalities in
tablish the clinical utility of this immunostain (10). MCD, B cell responses may also play a role. Hypo-
gammaglobulinemia is seen in MCD with particularly
Pathogenesis suppressed levels of IgG1 and IgG2 and class-switch-
The pathogenesis of MCD is poorly understood. ing of B cells to increase production of IgG4 and IgE
It is thought to be mediated by targeted podocyte (17,18). It remains uncertain to what extent some of
injury, possibly through the presence of a circulating these immunologic abnormalities are cause or conse-
“permeability factor” with the ability to alter podocyte quence of the NS (19).
structure and glomerular permselectivity. There is sub- Hypotheses on pathogenesis include the presence
stantial evidence that patients with MCD have dys- of a circulating soluble factor and/or lack of an inhib-
regulated immunity, especially involving T lympho- itory molecule causing reorganization of the podo-
cytes. Treatment response to immunosuppressive cyte’s actin cytoskeleton, leading to reversible foot
agents such as corticosteroids and occurrence of MCD process effacement and proteinuria (20). Circumstan-
in association with viral infections (e.g., measles), tial evidence for such a theory includes the disappear-
Hodgkin’s lymphoma, thymoma, and T cell lympho- ance of NS when a kidney with MCD is transplanted
mas support such T cell theories. In the absence of into a patient without NS and reversal of recurrent
glomerular inflammation, the injury is likely cytokine MCD-associated NS in the allograft by plasmaphere-
mediated. Podocytes express receptors for interleukins sis. A circulating “permeability factor” was initially
(IL-4, -10, and -13) and chemokines (CCR and described in patients with FSGS (21) but has not been
CXCR), as well as Toll-like receptors (11), and in fully characterized. T cell hybridomas derived from T
vitro studies have demonstrated that particular cyto- cells of patients with MCD produce a glomerular
kines have direct effects on podocyte signaling, cyto- permeability factor, presumably a lymphokine, that
skeletal organization, motility and maintenance of the induces proteinuria in rats (22). Recent studies have
filtration barrier. Overexpression of IL-13 can induce shown that hemopexin, a heme-scavenging molecule,
MCD like nephropathy in rats (12). The induction of may be linked to MCD. Activated hemopexin func-
CD80 (B7–1) expression by podocytes after lipopoly- tions as a serine protease causing remodeling of podo-
saccharide exposure in mice causes reversible protein- cytes and alters the glomerular filtration barrier. It
uria and foot process effacement resembling human causes reorganization of the podocyte’s actin-based
MCD (13). CD80 also has been identified in the urine cytoskeleton and requires the slit diaphragm protein
of patients with MCD but not FSGS, suggesting it may nephrin for this function. Hemopexin is abundantly
be a useful biomarker (14). Podocyte expression of present in plasma and is an acute-phase reactant but is
CD80 has been shown to induce cathepsin L–mediated also synthesized by mesangial cells. It has been pro-
cleavage of large GTPase dynamin and synaptopodin, posed that lack of a putative inhibitory/protective fac-
leading to disruption of the actin cytoskeleton and foot tor in MCD may expose podocytes to the effects of
process effacement (15). These data suggest that podo- activated hemopexin (23).
Recent advances in the pathogenesis of FSGS are reported associations with Epstein-Barr virus and
have highlighted the significance of mutations in HIV infection. Allergic reactions associated with bee
podocyte and slit diaphragm genes. However, to date, stings, pollen exposure, and envenomations can pre-
no homozygous or compound heterozygous mutations cede the development of MCD. These secondary as-
of podocyte genes have been observed in MCD. Some sociations suggest that diverse precipitants may result
patients with MCD have heterozygous allelic varia- in common pathogenic pathways to podocyte injury
tions with amino acid substitutions in nephrin and and the development of MCD.
podocin genes, but their clinical significance is unclear
because there is no correlation between these genetic References
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Section 14: CASE PRESENTATION 132/88 mmHg and 3⫹ lower extremity edema. Laboratory
values include serum creatinine level of 0.5 mg/dl, 24-hour
A 21-year-old Caucasian woman presents with new onset urine protein of 10.7 g, and serum albumin of 1.7 g/dl.
of lower extremity edema of approximately 3 to 4 weeks’ Urinalysis shows 4⫹ protein with no heme by dipstick and
duration. She had been diagnosed with mild hypertension an inactive urinary sediment. All serologies are negative or
and anemia (hematocrit 28%) 6 months earlier. She is taking normal, including anti-nuclear antibody, hepatitis B surface
no prescription medications and denies using over-the- antigen, hepatitis C antibody, and anti-neutrophil cytoplas-
counter medications. Physical examination reveals BP of mic antibody. A renal biopsy is performed.
Figure 1. Figure 2.
Figure 4.
Figure 3. IgM

A. Focal segmental necrotizing and crescentic glomerulonephritis
B. Focal segmental glomerulosclerosis (FSGS), collapsing variant (collapsing glomerulopathy)
C. Minimal change disease (MCD)
D. FSGS, tip variant
E. Membranous glomerulopathy
353
Answer
Figure 1 (Jones methenamine silver, ⫻400)
shows a glomerulus with a segmental lesion (arrow) at
the tubular pole, adjacent to the origin of the proximal
tubule. The capillary lumina are filled with endocap-
illary cells that have a foamy cytoplasm, consistent
with a segmental “cellular lesion.” There is swelling of
the overlying podocytes, which are confluent with prox-
imal tubular epithelial cells (arrowhead). The adjacent
glomerular capillaries are unremarkable. Figure 2 (peri-
odic acid–Schiff, ⫻400) shows a different glomerulus
from the same biopsy with a small segmental cellular
lesion that contains endocapillary foam cells, involves Figure 5. A glomerulus shows segmental sclerosis of the
the peripheral tuft, and forms a small adhesion to usual type, with obliteration of glomerular capillary lumina
Bowman’s capsule (arrow). This lesion does not ex- by extracellular matrix and hyaline, loss of overlying podo-
tend to the tubular pole in this section or in adjacent cytes, and broad adhesion to Bowman’s capsule. The scle-
rotic segments demonstrate no relationship to either the
levels. The other glomeruli in the biopsy showed no tubular pole or the vascular pole in the plane of section.
abnormalities by light microscopy. There was no ev- These findings are consistent with FSGS, NOS. Magnifica-
idence of tubular atrophy, interstitial fibrosis, or arte- tion, ⫻400 (periodic acid–Schiff).
riosclerosis. Immunofluorescence microscopy (Figure 3,
⫻400) shows segmental tuft positivity for IgM, con-
sistent with nonspecific trapping, probably in the dis-
tribution of a segmental lesion. Electron microscopy
(Figure 4, ⫻8000) shows diffuse foot process efface-
ment and no immune-type electron-dense deposits.
The biopsy findings support a diagnosis of the tip
variant of focal segmental glomerulosclerosis (FSGS),
also referred to as “glomerular tip lesion” (GTL;
answer D).
Glomerular Tip Lesion

The GTL is a distinctive pathologic lesion that
occurs in patients with heavy proteinuria or nephrotic Figure 6. A glomerulus shows segmental sclerosis and
syndrome. As first described by Howie and Beamer in hyalinosis involving the glomerular hilum. The vascular
pole and juxtaglomerular apparatus (seen at bottom) iden-
1984 (1), GTL consists of a small segmental lesion in tify the location of the lesion as perihilar. These findings are
the glomerular tuft adjacent to the origin of the prox- consistent with FSGS, perihilar variant. Magnification,
imal tubule (i.e., the tubular pole), with intracapillary ⫻400 (periodic acid–Schiff).
foam cells and/or hyaline, hyperplasia and vacuoliza-
tion of overlying podocytes, tuft adhesion to Bow- Since that initial report on GTL, there has been
man’s capsule, and confluence of podocytes with increasing recognition by a number of investigators
proximal tubular epithelial cells (1). According to this that tip lesions can occur in renal biopsies that also
original description, the remaining glomeruli show no contain other non-tip segmental lesions, including
pathologic alteration except for diffuse foot process sclerosing and cellular types. Therefore, the Columbia
effacement on electron microscopy, resembling the Classification of FSGS (2) proposed a less restrictive
findings in minimal change disease (MCD). Immuno- definition that incorporates tip lesions within the spec-
fluorescence microscopy may show segmental IgM trum of FSGS. This working proposal identifies five
and C3 staining, consistent with nonspecific trapping histologic subtypes of FSGS defined by light micro-
within the segmental lesions, but no immune-type scopic features: FSGS not otherwise specified (NOS;
deposits are seen. Figure 5), perihilar variant (Figure 6), cellular variant,
tip variant, and collapsing variant. In this schema, the prevalence in a series of 111 biopsies with segmental
tip variant of FSGS is defined by the presence of at lesions in Birmingham, United Kingdom, performed
least one tip lesion (as described above), in the ab- between 1980 and 1989 and a 66% prevalence in a
sence of collapsing lesions or perihilar sclerosis (2). later series (1985 through 2003), in a study population
Thus, the tip variant may contain other glomeruli with whose origin was not stated (10). Interestingly, the tip
segmental lesions of sclerosis that are located in the variant seems to be less common in African Ameri-
peripheral tuft or whose relationship to the vascular cans (13 to 15% of cases) (3–5), despite the higher
and tubular poles is indeterminate. Although mesan- overall frequency of FSGS in this population. How-
gial hypercellularity may be present (2), no mesangial ever, in one study, the majority (55%) of patients with
hypercellularity was reported in the largest series of tip tip lesion were African American (6). The reported
variant (3). frequency of the tip variant in children is low (2%
[11], 6% [12], and 0% [4]), possibly because renal
Clinical Characteristics biopsy is rarely performed in children with steroid-
FSGS, tip variant, typically presents with recent responsive nephrotic syndrome (4,11,12). Indeed, both
onset or short duration of full nephrotic syndrome/ of the pediatric series with cases of the tip variant of
heavy proteinuria. Among North Americans, the tip FSGS were performed in children who had steroid-
variant predominantly affects middle-aged or older resistant nephrotic syndrome and/or an atypical pre-
Caucasians and is rare in children and non-Caucasians sentation (11,12) and who might be expected to have
(3–5). Compared with FSGS NOS, the tip variant a longer duration of symptoms before biopsy and an
shows higher initial proteinuria and shorter duration of innately more aggressive course compared with those
symptoms before biopsy, akin to MCD (3). Both tip who underwent biopsy before starting therapy. Of
variant and collapsing variant show more frequent and note, GTL was identified retrospectively in 10% of
more severe nephrotic syndrome compared with other children who initially received a diagnosis of MCD
FSGS variants; however, tip variant has the best initial (13) and in five of eight autopsies of children dying
and final renal function and the highest rate of com- with nephrosis before 1950 (14). Thus, the tip variant
plete remission and renal survival at 5 years (5). Tip of FSGS may be underrecognized in children with
variant has the least severe chronic tubulointerstitial nephrotic syndrome because of biopsy selection bias.
injury, the least severe arteriosclerosis, and the lowest
frequency of hypertension (5). Although renal func-
Pathology
tion is usually normal at presentation, some patients
develop acute renal failure that resolves with remis- Light Microscopy. GTL is a focal finding, with
sion of nephrotic syndrome, suggesting a role for lesions identified in 12% (3) to 24% (6) of glomeruli
hemodynamic factors associated with severe hy- in adult series. In a review of autopsies of children
poalbuminemia and edema, similar to adult MCD with dying with nephrosis, Haas and Yousefzadeh (14)
acute kidney injury (3). As seen in MCD, some pa- identified GTL in five of eight cases, with 0.3 to 4.4%
tients with FSGS tip variant who achieve full remis- of total glomeruli involved. Although the early de-
sions following steroid therapy subsequently develop scriptions suggested that GTL involved all glomeruli
one or more relapses of nephrotic syndrome. (1,9), in the latest series from Howie et al. (10), only
The incidence of FSGS tip variant is unknown, two of 15 cases had tip lesions in ⬎50% glomeruli,
but the biopsy prevalence among US patients with and none showed 100% glomerular involvement.
FSGS ranges from 13% (6) to 17% (5). In a study of These findings emphasize the need to examine care-
225 patients with primary FSGS that excluded FSGS fully multiple biopsy levels for evidence of tip lesions
perihilar variant, the prevalences of the other variants and underscore the possibility of sampling error in
were tip variant, 26.6%; cellular variant, 9.7%; col- small biopsy specimens. Tip lesions are typically “cel-
lapsing variant, 24.8%; and NOS variant, 38.6% (7). lular” in appearance, with endocapillary foam cell
Deegens et al. (8) reported a 37% prevalence of tip accumulation and swelling and hyperplasia of overly-
variant in a predominantly Caucasian Dutch popula- ing visceral epithelial cells. Less frequently (19% of
tion with FSGS. Howie et al. (9), using the original, FSGS tip variant in one study [3]), the tip lesions have
more restrictive definition of GTL, reported a 9% a “sclerosing” appearance, with accumulation of hya-
line and acellular matrix material. Both cellular and Clinical Pathologic Correlation
sclerosing tip lesions may coexist in the same biopsy, Some cases of FSGS, tip variant progress to
but all are localized to the peripheral (tubular) pole ESRD, and tip variant may recur in the renal allograft
and demonstrate a relationship to the origin of the (10). Factors that predict poor renal outcome include
proximal tubule. The latter includes synechial attach- absence of remission of proteinuria (6) and greater
ment of the glomerular tuft to Bowman’s capsule, number of non-tip segmental lesions in the initial
prolapse or herniation of the glomerular tuft into the biopsy (3,10). Some studies have shown higher remis-
proximal tubule, and/or confluence of hyperplastic sion rates and less ESRD in FSGS, tip variant, com-
podocytes with proximal tubular cells. The Columbia pared with FSGS NOS (3,5), but others did not show
Classification requires that tip lesions involve ⬍25% any relationship between FSGS variant and outcome
of the glomerular tuft to differentiate lesions that (6,11,12). Some of these differences between studies
may be due to the different histologic criteria used for
originate at the tubular pole from larger lesions that
subclassification of FSGS. In a comparative series of
may have begun elsewhere in the glomerular globe but
patients with FSGS variants at Columbia University
reach the tubular pole only as they evolve.
(7), the percentage of complete and partial remis-
In the Columbia Classification of FSGS, tip vari-
sions was greatest for tip variant (76%), lowest for
ant, may show other segmental lesions in the same
collapsing variant (13%), and intermediate for cel-
biopsy as long as they are not collapsing or perihilar. lular variant (44%), compared with 39% for FSGS
In the only study of tip variant FSGS in which a NOS. There was an inverse relationship between
detailed pathologic analysis of all glomeruli was pro- remission status and development of ESRD across
vided, only 26% of cases showed “pure” tip lesions, subtypes. Thus, the incidence of ESRD was lowest
whereas other (non-tip) segmental lesions were seen in for tip variant (6%), highest for collapsing variant
74% of cases (3). However, no perihilar lesions were (65%), and intermediate for cellular variant (28%)
identified. Most of the non-tip lesions identified were compared with 35% for FSGS NOS. The values for
cellular and were located in the peripheral tuft or had tip variant approach the values for adult MCD,
in indeterminate relationship to the tubular pole and indicating that it has the best outcome of all FSGS
glomerular hilum. Conceivably, some of these lesions subtypes (7). For individual patients with nephrotic
represent tip lesions where the defining relationship to syndrome, remission response (to steroids and/or
the proximal tubule was not seen. Focal global glo- other therapies) remains the best predictor of out-
merulosclerosis may occur, but this is generally mild come in tip and other variants of FSGS (6).
and commensurate with the patient’s age. FSGS tip
variant typically shows no more than mild tubular Etiology and Pathogenesis
atrophy, interstitial fibrosis, and arteriosclerosis. A FSGS, tip variant, can be considered within the
subset shows acute tubular injury, and some display spectrum of primary podocytopathies. The etiology
patchy interstitial edema and mononuclear interstitial and pathogenesis of tip lesion are unknown. Like
inflammatory cell infiltrates. This acute tubular injury MCD and primary FSGS, it is thought to be the result
and interstitial edema are most often identified in of a yet unidentified circulating factor(s) that targets
biopsies from patients presenting with severe ne- the podocyte, leading to foot process effacement and
phrotic syndrome and acute renal failure. loss of filtration barrier (see pathogenesis section for
Case 13). It is likely that podocytes whose attachment
Immunofluorescence and Electron Microscopy. Non- to the glomerular basement membrane has been weak-
specific segmental staining for IgM and C3 is common ened by foot process effacement are more susceptible
in the distribution of the segmental lesions (Figure 3). to mechanical strain at the tubular pole, where there is
Electron microscopy typically shows diffuse foot pro- a convergence of protein-rich ultrafiltrate emanating
cess effacement involving patent capillaries (mean from all portions of the glomerular globe. Because of
93.5%; range 50 to 100%; Figure 4) (3). The podo- its contiguity to the tubular orifice, the tip region is
cytes may exhibit microvillous transformation of their particularly vulnerable to shear stress and turbulence,
cytoplasm. No immune-type electron-dense deposits which could pull the podocyte cell bodies toward the
are identified. tubular lumen, leading to podocyte detachment (15).
In addition, localized trauma from tuft prolapse into response to therapy of the histologic variants. J Am Soc Nephrol 15:
2169 –2177, 2004
the tubular pole may promote podocyte detachment 7. Stokes MB, Valeri AM, Markowitz GS, D’Agati VD: Cellular focal
and formation of adhesions at this site. In support of segmental glomerulosclerosis: Clinical and pathologic features. Kid-
this hypothesis, tip lesions also have been reported to ney Int 70: 1783–1792, 2006
8. Deegens JK, Steenbergen EJ, Borm GF, Wetzels JF: Pathological
occur in other proteinuric human glomerulopathies variants of focal segmental glomerulosclerosis in an adult Dutch
(e.g., membranous glomerulopathy, IgA nephropathy, population: Epidemiology and outcome. Nephrol Dial Transplant 23:
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9. Howie AJ, Lee SJ, Green NJ, Newbold KM, Kizaki T, Koram A,
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In conclusion, the tip variant of FSGS is a dis- of segmental sclerosing glomerular lesions in adults. Nephrol Dial
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tinctive pathologic finding that falls within the spec-
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12. Paik KH, Lee BH, Cho HY, Kang HG, Ha IS, Cheong HI, Jin DK,
In other individuals, tip lesion may be an early man- Moon KC, Choi Y: Primary focal segmental glomerular sclerosis in
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14. Haas M, Yousefzadeh N: Glomerular tip lesion in minimal change
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1. Howie AJ, Brewer DB: The glomerular tip lesion: A previously 1168 –1175, 2002
undescribed type of segmental glomerular abnormality. J Pathol 142: 15. Friedrich C, Endlich N, Kriz W, Endlich K: Podocytes are sensitive
205–220, 1984 to fluid shear stress in vitro. Am J Physiol Renal Physiol 291:
2. D’Agati VD, Fogo AB, Bruijn JA, Jennette JC: Pathologic classifi- F856 –F865, 2006
cation of focal segmental glomerulosclerosis: A working proposal. 16. Howie AJ: Changes at the glomerular tip: A feature of membranous
Am J Kidney Dis 43: 368 –382, 2004 nephropathy and other disorders associated with proteinuria. J Pathol
3. Stokes MB, Markowitz GS, Lin J, Valeri AM, D’Agati VD: Glomer- 150: 13–20, 1986
ular tip lesion: A distinct entity within the minimal change disease/ 17. El Karoui K, Hill GS, Karras A, Moulonguet L, Caudwell V,
focal segmental glomerulosclerosis spectrum. Kidney Int 65: 1690 – Loupy A, Bruneval P, Jacquot C, Nochy D: Focal segmental
1702, 2004 glomerulosclerosis plays a major role in the progression of IgA
4. Silverstein DM, Craver R: Presenting features and short-term outcome nephropathy: II. Light microscopic and clinical studies. Kidney Int
according to pathologic variant in childhood primary focal segmental 79: 643– 654, 2011
glomerulosclerosis. Clin J Am Soc Nephrol 2: 700 –707, 2007 18. Najafian B, Kim Y, Crosson JT, Mauer M: Atubular glomeruli and
5. Thomas DB, Franceschini N, Hogan SL, Ten Holder S, Jennette CE, glomerulotubular junction abnormalities in diabetic nephropathy.
Falk RJ, Jennette JC: Clinical and pathologic characteristics of focal J Am Soc Nephrol 14: 908 –917, 2003
segmental glomerulosclerosis pathologic variants. Kidney Int 69: 19. Howie AJ, Kizaki T, Beaman M, Morland CM, Birtwistle RJ, Adu D,
920 –926, 2006 Michael J, Williams AJ, Walls J, Matsuyama M, et al.: Different
6. Chun MJ, Korbet SM, Schwartz MM, Lewis EJ: Focal segmental types of segmental sclerosing glomerular lesions in six experimental
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Section 15: CASE PRESENTATION IU/ml, depressed C3 and C4 complement levels, a positive
IgG anti-cardiolipin antibody, and a negative lupus antico-
A 27-year-old Caucasian woman with a 10-year history agulant. Examination of the urine sediment discloses four to
of systemic lupus erythematosus (SLE) but no previous 10 red blood cells per high-power field, no significant white
history of renal disease presents with new onset of hema- blood cells, and no cellular casts. Previous manifestations of
turia and proteinuria. Laboratory evaluation reveals a serum SLE included pericarditis, alopecia, a malar rash, and ar-
creatinine level of 0.5 mg/dl, 24-hour urine protein of 2.9 g, thralgias. Physical examination reveals a BP of 122/76, an
serum albumin of 2.8 g/dl, white blood cell count of 2.4 ⫻ erythematous facial rash, and no edema. Medications in-
109/L, hematocrit of 36.8%, and platelet count of 127 ⫻ clude methylprednisolone 6 mg/day and plaquenil 200 mg/
109/L. Serologic evaluation reveals an anti-nuclear antibody day. The kidneys measure 12.1 and 11.5 cm in length by
(ANA) titer of ⬎1:1280, an anti-DNA antibody of ⬎500 ultrasound. Renal biopsy is performed.
Figure 1. Figure 2.
Figure 3. Figure 4.
Figure 5. IgG Figure 6.

359
What is the BEST diagnosis? Lupus nephritis (LN) refers to the spectrum of
A. Lupus nephritis (LN) class V immune complex (IC)-mediated renal disease seen in
B. LN class IV-S patients with SLE (1,2). The classification of LN has
gone through multiple revisions since the original
C. LN class IV-S and V
1974 World Health Organization Classification (3).
D. LN class IV-G
The most recent version, referred to as the Interna-
E. LN class IV-G and V tional Society of Nephrology/Renal Pathology Society
(ISN/RPS) 2003 Classification of Lupus Nephritis
Answer (4,5) (Table 1), has gained widespread acceptance and
In Figures 1 and 2, the glomeruli exhibit segmen-
is the approach used in this discussion.
tal endocapillary proliferation with infiltrating neutro-
Renal biopsy plays an important role in the diag-
phils and foci of karyorrhexis. The endocapillary pro-
nosis and treatment of patients with LN. Early in the
liferation has a distinctly segmental distribution,
disease process, biopsy may help to establish the diag-
involving ⬍50% of the glomerular tuft (hematoxylin,
nosis of SLE or the diagnosis of LN in a patient with
⫻400 for both). In Figure 3, the segmental endocap-
known SLE. An initial biopsy is useful to guide therapy.
illary proliferation is accompanied by a segmental
Repeat biopsies at 6-month intervals or longer are often
cellular crescent (Jones methenamine silver [JMS],
performed to assess the response to therapy and guide
⫻400). In contrast to the previous images, the glom-
subsequent treatment. In this section, the findings in LN
erulus in Figure 4 lacks endocapillary proliferation but
classes I through VI are reviewed, followed by a section
exhibits glomerular basement membrane (GBM)
on the clinical manifestations of the various classes. A
thickening with spike formation (JMS, ⫻600). Immu-
briefer discussion focuses on other lupus-related renal
nofluorescence reveals granular global mesangial and
disorders that fall outside the spectrum of LN.
granular to semilinear, segmental to global peripheral
capillary wall positivity for IgG (Figure 5, ⫻400). Pathology
There was similar staining for IgM, IgA, C3, and C1q Mesangial LN. Mesangial LN, which is the mildest
(not shown). Electron microscopy reveals global sub- form of LN, is defined by IC-mediated disease limited
epithelial and segmental subendothelial electron-dense to the mesangium. Mesangial LN is divided into LN
deposits (⫻6000). In the setting of SLE, the findings classes I and II. In class I, also referred to as “minimal
of segmental endocapillary proliferation involving the
majority of glomeruli are diagnostic of LN class IV-S. Table 1. Summary of ISN/RPS (2003) Classification of
The membranous changes, which are best seen on Lupus Nephritis
ultrastructural evaluation, merit an additional diagno-
sis of LN class V. Thus, the final diagnosis is LN class Class I Minimal mesangial LN
Class II Mesangial proliferative LN
IV-S and V (answer C).
Class III Focal LN (⬍50% of glomeruli)
III (A): active
Lupus Nephritis III (A/C): active and chronic
SLE is an autoimmune disease that involves III (C): chronic
multiple organ systems, most notably the kidney. Re- Class IV Diffuse LN (ⱖ50% of glomeruli)
nal disease can be seen at any time in the course of Diffuse segmental LN (IV-S)
SLE, is most frequently encountered during the first IV-S (A): active
year, and is associated with significant morbidity and IV-S (A/C): active and chronic
mortality. The percentage of patients who have SLE IV-S (C): chronic
Diffuse global LN (IV-G)
and develop renal disease is uncertain because many
IV-G (A): active
patients do not undergo renal biopsy and renal in- IV-G (A/C): active and chronic
volvement can be clinically silent. It has been esti- IV-G (C): chronic
mated that ⬎50% of patients with SLE will develop Class V Membranous LN
renal manifestations, which may include hematuria, Class VI Advanced sclerosing LN (ⱖ90% globally
proteinuria, full nephrotic syndrome, and/or renal in- sclerosed glomeruli without residual
sufficiency, at some point in their course. activity)
common finding is endocapillary proliferation, which

manifests as endothelial swelling and hypercellularity,
typically accompanied by infiltrating leukocytes.
There is usually a background of mesangial prolifer-
ation. Additional “active” lesions of endocapillary
involvement include GBM duplication with mesangial
interposition (i.e.,“membranoproliferative features”),
foci of fibrinoid necrosis or karyorrhexis, extracapil-
lary proliferation (i.e., cellular crescents), and suben-
dothelial deposits that are visible at the light micro-
scopic level. Of note, the subendothelial deposits in
LN often appear large, forming “wire loops” or intra-
capillary immune aggregates, which are referred to as
“hyaline thrombi” (Figure 9).
Figure 7. Mesangial proliferative LN (class II) is characterized
Endocapillary involvement in LN is classified as
by global mesangial proliferation, without endocapillary in- “focal lupus nephritis” (LN class III) or “diffuse lupus
volvement. In this example, more than three cells are present in nephritis” (LN class IV), on the basis of whether it is
most mesangial areas. Magnification, ⫻400 (H&E). present in ⬍50 or ⱖ50% of glomeruli, respectively
(Figures 1 through 3 and 8). Both LN classes III and
mesangial lupus nephritis,” mesangial immune depos- IV likely represent related forms that share a similar
its are seen by immunofluorescence and electron mi- pathogenesis but differ in the extent of glomerular
croscopy but are not accompanied by mesangial pro- involvement. Both are subclassified on the basis of
liferation at the light microscopic level. In contrast, whether the endocapillary involvement is active (A),
class II LN (“mesangial proliferative lupus nephritis”) chronic (C), or both active and chronic (A/C). Chronic
has mesangial immune deposits with mesangial pro- endocapillary lesions include segmentally or globally
liferation (Figure 7). sclerotic glomeruli that are the sequelae of previously
LN with endocapillary involvement. Endocapil- active endocapillary lesions. Clues that help to identify
lary involvement in LN can affect any percentage of postinflammatory glomerular scarring include residual
glomeruli in a biopsy, varies from segmental to global endocapillary hypercellularity or the presence of subcap-
in individual glomeruli (Figures 1 through 3 and 8), sular fibrosis with disruptions of Bowman’s capsule
and can have active or chronic features. The most typical of old fibrous crescents. In some cases, it may be
Figure 8. In contrast to LN IV-S, LN IV-G has diffuse and Figure 9. A characteristic feature of LN IV is large suben-
global endocapillary proliferation involving ⬎50% and usu- dothelial immune deposits forming “wire loops” and intra-
ally closer to 100% of the glomerular tuft. Magnification, capillary immune aggregates known as “hyaline thrombi.”
⫻400 (H&E). Magnification, ⫻400 (JMS).
difficult to determine whether a sclerotic glomerulus is these observations, all patients with LN and with
the result of LN or ischemic obsolescence. necrosis and crescent formation out of proportion to
Diffuse LN (LN IV) is further subdivided on the the degree of immune deposition should undergo
basis of whether the endocapillary lesions are predom- ANCA testing, preferably by ELISA because ANA
inantly segmental (S) or global (G) in distribution. The can mimic a perinuclear ANCA pattern by indirect
rationale for this distinction is based on the findings of immunofluorescence, and only ELISA can determine
the Lupus Nephritis Collaborative Study Group (6). In the ANCA specificity. Future studies are needed to
this prospective study, patients who met current crite- address the frequency and significance of ANCA pos-
ria for LN IV-S had a lower remission rate and poorer itivity in patients with LN, particular those with a
renal survival than patients with LN IV-G (6). Patients “pauci-immune” lesion.
with LN IV-S had a greater degree of fibrinoid necro- Renal biopsy reports from patients with LN
sis and less extensive immune deposition, leading the classes III and IV should include an assessment of
authors to propose the possibility of a distinct patho- disease activity and chronicity. The most widely ac-
genesis analogous to pauci-immune glomerulonephri- cepted and reproducible system is the activity and
tis (6). chronicity indices formulated by Austin et al. (17).
Subsequent studies using the ISN/RPS classifi- This system is particularly useful when comparing
cation of LN have failed to establish a difference in repeat biopsies. In general, the chronicity index is
prognosis between LN class IV-S and class IV-G considered to be more predictive of clinical outcome
(7–11). These studies did identify differences in pre- than the activity index (11,18).
senting clinical and pathologic features, however, with Membranous LN. Membranous LN, also referred to
LN class IV-G having a greater degree of proteinuria as LN class V, is characterized by segmental to global
and renal insufficiency and more abundant IC deposi- subepithelial electron-dense deposits. These membra-
tion, whereas LN class IV-S has more fibrinoid necro- nous changes are commonly accompanied by mesangial
sis (7,9). Among five studies that compared outcomes proliferation and deposits. Of note, endocapillary prolif-
in LN class IV-G versus LN class IV-S, one showed a eration should not be seen in LN class V; if present, then
better outcome in LN IV-G (10), one showed a better an additional diagnosis of LN class III or IV is warranted
outcome in LN IV-S (8), and three showed similar depending on the distribution of the endocapillary le-
outcomes between the two groups (7,9,11). Of note, sions. Because scattered subepithelial deposits can also
two of the studies documented transformations be- be found in patients with LN class III and class IV, an
tween LN class IV-S and class IV-G on repeat biopsies additional diagnosis of LN class V requires that subepi-
(7,9), supporting the concept of a similar pathogenesis. thelial deposits involve ⱖ50% of the glomerular tuft of
One possible explanation for why patients with ⱖ50% of glomeruli (4,5).
LN class IV-S exhibit more prominent necrosis and
less abundant immune deposition than patients with Advanced sclerosing LN. Advanced sclerosing
LN class IV-G is the role of anti-neutrophil cytoplas- LN, also referred to as LN class VI, is narrowly
mic antibodies (ANCA) (6,7,9). ANCA seropositivity defined as the presence of ⬎90% of glomeruli with
is seen in approximately 20% of patients with SLE by global sclerosis and no evidence of residual endocap-
indirect immunofluorescence (12) and 10% by ELISA illary proliferation in the remaining glomeruli (4,5). In
(13). Multiple reports have described renal biopsies our experience, ⬍1% of biopsies from patients with
from patients with SLE in which there was significant SLE fall into this category.
necrosis and crescent formation with only rare or Immunofluorescence. All cases of active LN and
absent subendothelial deposits (14 –16). This “pauci- even those with chronic lesions have identifiable im-
immune” picture led to testing for and discovery of mune deposits by immunofluorescence. The standard
ANCA seropositivity, most commonly anti-myeloper- immunofluorescence panel used by renal pathology
oxidase ANCA (14,16). Not surprising, the clinical laboratories includes antisera to three Ig classes—IgG,
presentation of patients with “necrotizing and crescen- IgM, and IgA—and two complement components—C3
tic LN with ANCA seropositivity” is typically one of and C1q. Positivity for all five immune reactants is
rapidly progressive glomerulonephritis, warranting ag- found in the majority of biopsies of LN, a finding
gressive immunosuppressive therapy (16). In light of referred to as “full house” staining. IgG is dominant or
co-dominant in virtually all cases of LN with more

variable positivity for IgM and IgA. Most cases have
positivity for both C3 and C1q, often with particularly
intense C1q. Importantly, deposits can also form at
other sites in any renal compartment, including Bow-
man’s capsule, tubular basement membranes (TBMs),
the interstitium, and blood vessels. These extra-glo-
merular deposits are most commonly seen in active
LN, particularly class IV. Immunofluorescence may
also reveal staining of tubular nuclei for IgG, a finding
referred to as “tissue ANA.”
Electron microscopy. Because of the limited avail- Figure 10. A large endothelial tubuloreticular inclusion is
identified in this electron micrograph, which is an enlarge-
ability of electron microscopy in many parts of the
ment of the right edge of Figure 6. Subepithelial and
world, the ISN/RPS classification of LN is based on subendothelial deposits are also present, and the subepithe-
findings by light microscopy and immunofluorescence lial deposits exhibit a focally organized substructure.
only. Nonetheless, electron microscopy is very helpful
to confirm a diagnosis of LN and often provides more in the normal range), and many have nephrotic-range
detailed information about the location of the immune proteinuria or nephrotic syndrome. Pure LN class V
deposits. In some cases, it uncovers unexpected findings, has the highest incidence of nephrotic syndrome, usu-
such as a component of membranous LN class V that ally with normal renal function. Not surprising, virtu-
went unrecognized in a patient with obvious class IV. ally all patients with LN VI have severe renal failure,
Mesangial electron-dense deposits are seen in all often with residual proteinuria and microhematuria.
classes of LN but are the predominant ultrastructural We recently reviewed our experience with LN at
finding in LN classes I and II. In addition to mesangial Columbia University over a 3-year period from 2008
deposits, subendothelial deposits are a hallmark of LN to 2010. Among a total of 640 LN biopsies, the
classes III and IV, whereas subepithelial deposits define majority (53.1%) were LN class IV, including 26.4%
LN class V. Electron microscopy may also reveal elec- with isolated LN class IV and 26.7% with mixed LN
tron-dense deposits outside the glomerular tuft in Bow- classes IV and V. LN class III was seen in 23.7% of
man’s capsule, TBMs, the interstitium, and blood ves- biopsies, including 10.6% with pure LN class III and
sels. A minority of cases exhibit deposits with a 13.1% with mixed LN classes III and V. Pure LN class
fingerprint or microtubular substructure. Tubuloreticular V was present in 15% of biopsies, whereas mesangial
inclusions (TRIs), also known as IFN footprints, are a LN (i.e., classes I and II) was present in 7.8% of
hallmark of LN that is found in the cytoplasm of endo- biopsies. Only two (0.3%) biopsies were classified as
thelial cells (Figure 10). TRIs are not specific for LN, LN class VI.
however, and can also be seen in patients with HIV and Lupus podocytopathy. There have been multiple
other viral infections as well as patients treated with IFN. case reports and three series of patients with SLE,
Clinical characteristics. The clinical manifesta- nephrotic syndrome, and renal biopsy findings of min-
tions of LN vary widely depending on the class, imal change disease (MCD) or FSGS (19 –21). To-
activity, and severity. Not surprising, the mesangial gether, these series describe 26 patients, including 15
patterns of LN (classes I and II) have the mildest with apparent MCD and 11 with FSGS. In the two
clinical manifestations, typically limited to microhe- series in which more detailed data are provided, seven
maturia and subnephrotic proteinuria, often ⬍1 g/day. of the 11 patients with MCD and one of the seven with
Most patients with LN class III have hematuria and FSGS also exhibited mesangial deposits, consistent
proteinuria, and a significant minority have nephrotic with underlying mesangial LN class I or II (19,20). A
syndrome and/or renal insufficiency. In LN class IV, diagnosis of lupus podocytopathy in a patient with
which is the most frequent class encountered in clin- SLE and nephrotic syndrome is based on the finding of
ical practice, ⬎50% of patients have hematuria and a severe diffuse foot process effacement in the absence
reduction in GFR (although serum creatinine may be of peripheral capillary wall immune deposits. The
higher incidence of podocytopathy in SLE than in the in LN, comprise 50% of the chronicity index score (17),
general population and the rapid remission of ne- and have a negative impact on clinical outcome (24).
phrotic syndrome after steroid therapy in all 11 pa-
tients with MCD and three of seven with FSGS sup- Pathogenesis
port the concept of a “lupus podocytopathy” (20,21). LN is a chronic IC-mediated disorder with com-
Lupus podocytopathy is seen most common early in plex pathogenesis. The predominance of SLE in fe-
the course of SLE or after a disease flare. A role for T males and the ability to attenuate the disease in murine
cell dysregulation, heightened cytokine milieu, or in models by hormonal manipulation underscore the im-
some cases nonsteroidal anti-inflammatory use has portance of hormonal factors. A role for genetic fac-
been proposed. Importantly, this entity should be rec- tors is supported by the increased incidence of SLE in
ognized as a highly steroid-responsive lesion (19 –21). first-degree relatives of patients with SLE, in monozy-
gotic than dizygotic twins, and in certain racial groups,
Vascular and tubulointerstitial lesions of SLE. A
such as African-Americans and Asians (25). In addi-
complex spectrum of vascular lesions is seen in pa-
tion, there are associations with certain HLA haplo-
tients with SLE. One of the most important is throm-
types (e.g., DR2, DR3, B8) (26) and inherited com-
botic microangiopathy, which is usually associated
plement deficiencies (e.g., C2 and C4).
with anti-phospholipid antibodies. This topic is cov-
LN is characterized by a broad range of autoan-
ered in Case 11 of this issue of NephSAP.
tibodies, the most pathogenic of which are anti-DNA
Vessel wall immune deposits are the most fre-
antibodies. The deposition of ICs in the glomeruli of
quent vascular lesion in LN and can occur in any class.
patients with LN is thought to involve three major
These deposits are detected by immunofluorescence
mechanisms, none of which are mutually exclusive:
and electron microscopy but do not elicit an inflam- (1) Autoantibodies against circulating antigens that
matory response and usually do not compromise the have become “planted” within the glomerulus, leading
vessel lumen. Thus, they are usually clinically silent. to in situ IC formation; (2) autoantibodies cross-react-
A minority of cases of LN, in particular active class ing with normal glomerular constituents, leading to in
IV, develop massive vascular immune deposits ad- situ IC formation; and (3) passive glomerular deposi-
mixed with fibrin that narrow the vessel lumen and are tion of preformed circulating IC. Many factors influ-
accompanied by endothelial and myocyte degenera- ence glomerular IC deposition, including the class and
tion. Because there is no inflammatory reaction, this subclass of Ig, the electric charge of the Ig, autoanti-
lesion has been termed “lupus vasculopathy” rather body specificity and cross-reactivity with glomerular
than vasculitis (22). It is usually associated with severe constituents, binding of autoantigens to glomerular
renal failure and hypertension. In contrast, the rare constituents through charge interactions, and clearance
entity of true inflammatory vasculitis in SLE, which of immune deposits through FcR interactions.
may be systemic, exhibits transmural, often necrotiz- Nucleosomes, which consist of DNA bound to
ing vessel wall inflammation without significant im- histones, are thought to play an important role in the
mune deposit formation, resembling microscopic development of LN. Patients with SLE have impaired
polyangiitis. Of note, thrombotic microangiopathy, lu- clearance of apoptotic cells, which frequently harbor
pus vasculopathy, and lupus vasculitis are associated nucleosomes on their surface (27). Because of their
with an increased risk for progression to ESRD (23). positive charge, nucleosomes have affinity for the nega-
TBM and interstitial deposits are common in LN, tively charged glomerular capillary wall, where they may
in particular LN class IV (24). The deposits are not become planted followed by in situ IC formation. There
usually visible by light microscopy, although there is is also evidence that anti-DNA antibodies exhibit a broad
often associated interstitial inflammation. Rarely, range of cross-reactivities to normal glomerular constit-
abundant tubulointerstitial immune deposits and se- uents such as mesangial cells, ␣-actinin-4, heparan sul-
vere interstitial inflammation occur in the absence of fate proteoglycans, laminin, and type IV collagen (28).
significant glomerular lesions. This unusual picture has Chromatin fragments generated may stimulate the innate
been referred to as “lupus interstitial nephritis.” In gen- immune system via Toll-like receptors, which are ex-
eral, tubular atrophy and interstitial fibrosis are prognos- pressed on infiltrating leukocytes and indigenous glomer-
tically important markers of chronic irreversible scarring ular cells (29).
The accumulation of immune deposits within Ueki K, Nojima Y: Revised classification of lupus nephritis is valuable in
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Section 16: CASE PRESENTATION manifestations. The patient has a 24-hour urine protein of
2.6 g, albumin of 2.7 g/dl, hematocrit of 27%, and an
A 37-year-old Caucasian woman presents with hema- active urine sediment with many red blood cells (RBCs)
turia, proteinuria, new-onset hypertension, a 12-lb weight but no RBC casts. Serologic evaluation reveals depressed
gain over 1 week, and oliguric acute kidney injury with a C3 and CH50 complement levels, normal C4, negative
serum creatinine level of 2.0 mg/dl. Past medical history anti-nuclear antibody and anti-neutrophil cytoplasmic an-
is notable for anxiety, depression, joint pains, iron defi- tibody, and no evidence of cryoglobulinemia. The kid-
ciency anemia related to menorrhagia, and tobacco use. neys measure 13.6 and 14.0 cm in length by ultrasound,
Her only medication is escitalopram (Lexapro). Physical without evidence of obstruction. One week later her
examination reveals a BP of 154/94 mmHg, height of creatinine remains elevated at 1.5 mg/dl, and renal biopsy
5⬘6⬙, weight of 197 lb, mild edema, and no cutaneous is performed.
Figure 1. Figure 2.
Figure 4.
Figure 3. C3

A. Seronegative lupus nephritis
B. Membranoproliferative glomerulonephritis type 1
C. Dense deposit disease
D. Cryoglobulinemic glomerulonephritis
E. Acute postinfectious glomerulonephritis (APIGN)
367
Answer tract (typically pharyngitis) or of the skin (impetigo).

The renal biopsy findings are diagnostic of acute The latency period from infection to glomerulonephri-
postinfectious glomerulonephritis (APIGN) (answer tis in most forms of APIGN is typically in the range of
E). Light microscopy reveals diffuse mesangial and 10 to 14 days, although in some cases the causative
endocapillary proliferation with abundant intracapil- infection may not have been clinically apparent. The
lary neutrophils (Figure 1, hematoxylin and eosin, most common sites of infection are the upper and
⫻400). At higher magnification, the many infiltrating lower respiratory tracts and skin. Other potential
neutrophils are better seen (Figure 2, Jones methena- causes include osteomyelitis, endocarditis, urinary
mine silver, ⫻600). Immunofluorescence staining for tract infections, and deep-seated abscesses. Laboratory
C3 reveals a “starry sky” pattern of mesangial and studies are often helpful in diagnosing APIGN. Impor-
capillary wall positivity (Figure 3, ⫻400). Electron tantly, serum complement levels are depressed in ap-
microscopy reveals subepithelial hump-shaped depos- proximately 70% of patients (2), with depression of
its, which are a classic feature of APIGN (Figure 4, the C3 complement level more constant and more
⫻8000). After the biopsy, the patient received only profound than changes in C4. Testing for anti–strep-
supportive treatment. Three months later, she had a tolysin-O and anti-DNAase B antibodies is useful to
creatinine of 0.9 mg/dl, and urinalysis revealed rare document a recent group A streptococcal infection.
RBCs and no significant proteinuria. APIGN is usually a self-limited process. In the
majority of patients, serum creatinine begins to decline
Acute Postinfectious Glomerulonephritis within 1 to 2 weeks, serum complements normalize by
APIGN is a clinical-pathologic entity that occurs 6 weeks, and hematuria resolves by 6 months. Com-
after an acute, typically self-limited infection. APIGN plete resolution is seen in the majority of children. In
is mainly seen in response to bacterial infections, most contrast, poorer outcomes are seen in adults, including
commonly of streptococcal or staphylococcal origin. a recent large North American series in which 56.1%
Importantly, classic post-streptococcal APIGN typi- of adults with biopsy-proven APIGN experienced
cally follows an infection and thus should be distin- complete recovery, 26.8% developed chronic kidney
guished from infectious forms of glomerular disease disease, and 17.1% progressed to ESRD (2). Out-
that occur in the setting of ongoing, persistent infec- comes are even worse in elderly patients who are older
tion, most commonly of viral origin, for instance than 65 years, in whom 22% achieved complete re-
hepatitis B virus–associated membranous nephropa- covery, 44% developed persistent renal disease, and
thy, hepatitis C–virus associated cryoglobulinemic 33% progressed to ESRD (1).
glomerulonephritis, or HIV-associated nephropathy. In developed countries, the incidence of APIGN
Conversely, some forms of ongoing bacterial infection has significantly declined in recent years, and there
also can produce APIGN, particularly in the setting of has been a shift toward Staphylococcus and a variety
endocarditis, abscess, pneumonia, cellulitis, or in- of Gram-negative bacteria as causative agents, partic-
fected intravascular catheters or shunts. In these situ- ularly in older adults. In these more developed regions,
ations, the onset of nephritis can be considered peri- APIGN is seen most commonly in patients at risk for
infectious rather than postinfectious. This scenario is infection, including the elderly and individuals with a
more common in older adults than in children and history of diabetes, alcohol abuse, malignancy, or
young adults (1). intravenous drug use (1– 4).
In underdeveloped countries with lower socio-
Clinical, Demographic, and Etiologic economic status, acute post-streptococcal glomerulo-
Considerations nephritis (APSGN) continues to be the most common
The most common clinical presentation of cause of APIGN. In these regions, the incidence of
APIGN is acute nephritic syndrome characterized by APSGN has been estimated at 24.3 and 2.0 cases per
microscopic or gross hematuria, acute kidney injury, 100,000 person-years in children and adults, respec-
proteinuria, new-onset or worsening hypertension, and tively, as compared with an incidence of 6.0 and 0.3
edema. APIGN is considerably more commonly in cases per 100,000 person-years in children and adults
children than adults, in whom it most frequently fol- in more developed countries (5). These estimates are
lows streptococcal infection of the upper respiratory in line with another study projecting 9.5 to 28.5 per
100,000 in industrialized nations (6). In additional to ent large global capillary wall deposits with scant or
sporadic cases, there have been multiple reports of absent mesangial deposits. As the name suggests, the
epidemic outbreaks of APIGN in areas of lower so- “mesangial pattern” of APIGN is characterized by a
cioeconomic status with crowded living conditions predominance of mesangial deposits and likely repre-
and poor hygiene (6). sents a stage in the resolution of the starry sky pattern.
This interpretation is supported by the observation that
Pathology the starry sky pattern is typically seen in the initial 2
weeks, whereas the mesangial pattern occurs later (8).
Light Microscopy. At the light microscopic level,
With respect to the composition of the deposits, stain-
APIGN most commonly manifests as a diffuse endo-
ing is typically positive for C3 and IgG. Staining for
capillary proliferative glomerulonephritis (DPGN;
C3 is usually of equal or greater intensity than IgG;
Figure 1). This pattern of glomerulonephritis, which is
this dominant or co-dominant staining for C3 is a
seen in ⬎70% of cases (1,2,4,7), is characterized by
highly characteristic feature of APIGN that is seen in
global mesangial and endocapillary proliferation with
most cases, including all 82 cases recently evaluated at
infiltrating leukocytes. The DPGN often has an exu-
our center (2). As expected for a polyclonal immune
dative appearance, a term denoting the distinctive
response, cases with positive staining for IgG usually
presence of numerous intraglomerular neutrophils
have a similar intensity of staining for ␬ and ␭ light
(Figures 1 and 2). In severe cases, the proliferative
changes may be accompanied by cellular crescents. chains. Low-intensity staining for IgM, IgA, and/or
Trichrome stain may demonstrate large subepithelial C1q is seen in fewer than half of cases. Staining for C3
fuchsinophilic deposits, which correspond to the typically persists longer than that for IgG. This ex-
hump-shaped deposits seen ultrastructurally. Over plains why isolated C3 positivity is frequently encoun-
time, the proliferative changes in APIGN begin to tered in the mesangial pattern, which is thought to
regress toward a mesangial pattern of glomerulone- represent a resolving phase (8).
phritis. Thus, the light microscopic finding of purely Electron Microscopy. The most specific and dis-
mesangial proliferation is seen more often in biopsies tinctive pathologic finding in APIGN is subepithelial
performed at a longer interval after infection and hump-shaped electron-dense deposits (Figure 4).
frequently represents an intermediate stage in the res- These hump-shaped deposits are often large and typ-
olution of APIGN. APIGN may also manifest as a ically appear confluent with the garland pattern of
focal endocapillary proliferative glomerulonephritis, a immunofluorescence, somewhat less prominent with
term that is defined by endocapillary proliferation in the starry sky pattern, and infrequent to absent with the
⬍50% of glomeruli. Membranoproliferative features mesangial pattern. Importantly, the subepithelial de-
(i.e., glomerular basement membrane [GBM] duplica- posits are frequently accompanied by less conspicuous
tion with mesangial interposition), large intracapillary mesangial and subendothelial deposits and do not
deposits, and fibrinoid necrosis are not typically seen elicit the spike formation seen in membranous ne-
in classic post-streptococcal APIGN. Tubulointersti- phropathy.
tial changes frequently accompany APIGN, including
acute tubular injury, RBC casts, interstitial edema, and
inflammation. If the glomerulonephritis fails to re- Clinical and Pathologic Criteria to Diagnose
solve, then chronic changes of segmental and global APIGN
glomerular scarring, fibrous crescents, tubular atro- In contrast to most forms of DPGN, which are
phy, and interstitial fibrosis may develop. treated with immunomodulatory therapy, the most
common approach to APIGN is antibiotic therapy and
Immunofluorescence. Three patterns of immuno- supportive measures. While it is critical to distinguish
fluorescence positivity have been described in patients APIGN from other forms of glomerulonephritis for
with APIGN (8). The “starry sky pattern,” which is therapeutic purposes, a definitive diagnosis may be
most frequently encountered, is characterized by difficult in some cases lacking the full constellation of
finely granular deposits distributed in peripheral cap- clinical and pathologic findings. Our diagnostic ap-
illary walls and the mesangium (Figure 3). In contrast, proach is to require at least three of the following five
the “garland pattern” is characterized by more conflu- clinical and pathologic findings to establish a diag-
its in which IgA is the sole or dominant Ig, accompa-

nied by similar intensity of staining for C3, is com-
monly seen in patients with diabetes and DGS and
most frequently follows skin and lower extremity
wound infections (10 –12). The most common infec-
tious agents have been Staphylococcus aureus and
Staphylococcus epidermidis, and outcomes are gener-
ally poor (10,11). This entity can be distinguished
from primary IgA nephropathy by the history of recent
staphylococcal infection and the presence of hypoco-
mplementemia, exudative features, and subepithelial
hump-shaped deposits.
Shunt nephritis is a distinctive clinical-patho-
logic variant of APIGN resulting from infection of a
Figure 5. In this example of APIGN superimposed on
nodular diabetic glomerulosclerosis, there is global en- ventriculo-atrial shunt used to treat hydrocephalus
docapillary proliferation with prominent intracapillary (13,14). Infection is typically occult, is associated with
neutrophils. Background changes of mesangial expansion low-virulence organisms including Staphylococcus
with nodule formation indicate underlying nodular dia- epidermidis or Propionibacterium acnes, and is often
betic glomerulosclerosis. Magnification, ⫻400 (periodic
acid–Schiff).
detected years after shunt placement (15). Unlike other
forms of APIGN, renal biopsy most commonly reveals
a membranoproliferative pattern of glomerulonephritis
nosis of APIGN: A history of recent infection (seen associated with mesangial and subendothelial deposits
in 84% of cases in our experience [1]), hypocomple- (Figure 6). By immunofluorescence, the deposits stain
mentemia (present in 74% of cases), the light mi- most frequently for C3 and IgM, and subepithelial
croscopic finding of a DPGN with exudative fea- hump-shaped deposits are not encountered. Successful
tures (72%), C3 dominant or co-dominant staining treatment requires shunt removal in addition to anti-
by immunofluorescence (100%), and the ultrastruc- biotics.
tural finding of hump-shaped subepithelial deposits A pauci-immune necrotizing and crescentic vari-
(90%) (2). ant of APIGN has also been described and is most
frequently encountered in the setting of infectious
Clinical-Pathologic Variants of APIGN endocarditis (16,17). Many patients have positive
APIGN is the most common pattern of glomer-
ulonephritis seen in patients with diabetes and under-
lying diabetic glomerulosclerosis (DGS) (9). Patho-
logic evaluation typically reveals well-established
findings of nodular DGS and APIGN, including a
DPGN with exudative features and C3 dominant or
co-dominant staining by immunofluorescence (Figure
5). In contrast to the more usual form of APIGN in
patients without diabetes, subepithelial hump-shaped
deposits are less frequent, whereas mesangial and
subendothelial deposits are often more prominent (2).
Two distinctive features of APIGN superimposed on
DGS include associations with staphylococcal rather
than streptococcal infection and poorer clinical out-
comes, with the majority progressing to ESRD (2).
Figure 6. A membranoproliferative pattern of APIGN with
Multiple reports have described an “IgA-domi- global GBM duplication and mesangial interposition can be
nant acute post-staphylococcal glomerulonephritis” seen in the setting of ventriculoperitoneal shunt nephritis.
(10 –12). This entity, which is characterized by depos- Magnification, ⫻400 (periodic acid–Schiff).
rheumatoid factor, and some have anti-neutrophil cy- are consistent with a more complex scenario in which
toplasmic antibody seropositivity. bacterial antigens, both circulating and planted at the
subepithelial and subendothelial aspects of the GBM,
Pathogenesis directly activate both the alternative complement path-
A brief overview of the complement system way (19) and the MBL pathway (20).
provides a framework for understanding the pathogen- The putative pathogenic antigen in most cases of
esis of APIGN. The complement system is a major APSGN is streptococcal pyrogenic exotoxin B (SPEB)
component of the innate, nonadaptive immune re- and its zymogen precursor (21–23). Circulating anti-
sponse and is mediated by a series of sequential bodies to SPEB can be identified in the overwhelming
enzymatic reactions that also greatly enhance, or majority of patients infected by nephritogenic group A
“complement,” the adaptive (or humoral) immune re- streptococci, including all 53 patients tested in one
sponse (18). Activation of the complement system study (21), and antibody levels correlate better with
leads to the formation of C3b from C3, which binds to infection than the more commonly available serum
the target of the immune response (i.e., bacteria) and markers such as anti–streptolysin-O or anti-DNAse B
promotes phagocytosis. The generation of chemotactin (24). SPEB has been localized to the glomerular de-
C5a recruits inflammatory cells to sites of inflamma- posits in APSGN and, more specifically, to the sub-
tion. The generation of C5b-9 can destroy target cells epithelial humps, where it co-localizes with C3 (21).
via formation of the membrane attack complex. The ability of SPEB to reach the subepithelial aspect
There are three distinct pathways of complement of the GBM is favored by its highly cationic charge,
activation (18). The classical pathway is activated by which would facilitate binding to anionic sites in the
the formation of antigen–antibody immune com- glomerular capillary wall. However, it is probably the
plexes, particularly those containing IgG of the IgG1 activation of complement on the subendothelial and
and IgG3 subtypes. In the classical pathway, the for- mesangial deposits, which are in contact with the
mation of C4b2b serves as C3 convertase. The man- circulation, that drives the influx of inflammatory cells
nose-binding lectin (MBL) pathway is activated inde- essential for the initiation of glomerulonephritis.
pendent of antibody by the binding of circulating An animal model of APSGN has been produced
lectins to polysaccharide residues on the surface of in mice by the passive transfer of anti-SPEB antibod-
bacteria, which in turn activates MBL-associated series, leading to acute glomerulonephritis, acute renal
ine proteases that activate complement components C2 failure, and proteinuria (25). A subsequent study by
and C4, leading to formation of C4b2b as C3 conver- the same group showed that anti-SPEB antibodies in
tase. The alternative complement pathway functions APSGN cross-react with human endothelial cells via
independent of antibodies, lectins, and the C4b2b C3 molecular mimicry and exhibit properties of autoanti-
convertase. It is continuously active at low levels as a bodies (26). Importantly, SPEB does not play a central
result of spontaneous ongoing C3 hydrolysis, binding role in all forms of APSGN, as evidenced by the fact
to factor B, and cleavage by factor D, leading to the that anti-SPEB antibodies were not detectable in a
formation of C3bBb as C3 convertase. C3bBb activa- recent Brazilian outbreak of APSGN associated with
tion is well controlled on human cells but is signifi- Streptococcus zooepidemicus (27). Thus, additional
cantly amplified on foreign cells, such that bacteria are nephritogenic antigens remain to be identified.
potent stimulators of the alternative pathway.
Multiple lines of evidence suggest that APIGN is References
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Section 17: CASE PRESENTATION significant only for chronic back pain. There is no history of
hypertension, diabetes, obesity, or tobacco use. The patient
A 62-year-old Caucasian man presents with a 2-week his- takes no prescription medications or nonsteroidal anti-inflam-
tory of low-grade fever, myalgias, cough, and decreased oral matory agents on an ongoing basis. Physical examination
intake, more recently accompanied by oliguria and a single reveals a BP of 146/79 mmHg and no edema or cutaneous
episode of gross hematuria. The patient was seen 5 days earlier manifestations. Chest x-ray is unremarkable. Urinalysis reveals
and given a course of ciprofloxacin, without symptomatic 2⫹ protein with too numerous to count red blood cells (RBCs)
improvement. Laboratory evaluation reveals acute kidney in- and rare white blood cells. Serologic results include a negative
jury with a creatinine level of 8.6 mg/dl, albumin 2.5 g/dl, anti-nuclear antibody and normal C3 and C4 complement
cholesterol 113 mg/dl, hematocrit 31%, white blood cell count levels. Additional serologies are pending at the time of renal
11,000, and platelet count 452,000. Past medical history is biopsy.
Figure 1. Figure 2.
Figure 4. Fibrin
Figure 3. IgG

A. Pauci-immune necrotizing and crescentic glomerulone-
phritis
B. Membranous nephropathy
C. Anti– glomerular basement membrane (anti-GBM) ne-
phritis
D. Henoch-Schönlein purpura nephritis
Figure 5. E. Lupus nephritis
373
Answer Clinical Presentation

The renal biopsy findings are diagnostic of anti- Anti-GBM nephritis is a rare disease, with epi-
GBM nephritis (answer C). Light microscopy reveals a demiologic studies suggesting an incidence of less
necrotizing and crescentic glomerulonephritis. Figure 1 than one case per million population per year (2).
(Jones methenamine silver [JMS], ⫻400) displays seg- More frequently seen in Caucasians, it has a bimodal
mental fibrinoid necrosis, GBM rupture, fibrin extrava- age and gender distribution with peak incidences in
sation into the urinary space, and an overlying segmental young men in their second and third decades of life
cellular crescent. In Figure 2 (JMS, ⫻400), similar and in older women in their sixth and seventh decades
changes are seen, although the crescent is circumferential of life. More than half of patients present with rapidly
with broad destruction of Bowman’s capsule and there is progressive glomerulonephritis and pulmonary hemor-
prominent periglomerular inflammation. Immunofluo- rhage, whereas one third present with isolated glomer-
rescence staining for IgG reveals intense linear positiv- ulonephritis. Older women are more likely to present
ity along the GBMs, one of which seems disrupted, with isolated renal involvement, whereas younger men
consistent with a site of rupture (Figure 3, ⫻400). are more likely to present with pulmonary-renal syn-
There is strong staining for fibrin/fibrinogen in the drome. Constitutional symptoms of malaise and weak-
distribution of a circumferential cellular crescent (Fig- ness are common, probably related in part to anemia
ure 4, ⫻400). Ultrastructural evaluation of an unin- and renal inflammation. Urine microscopy often re-
volved glomerulus shows no electron-dense deposits veals RBC casts, and proteinuria is typically subne-
and mild foot process effacement (Figure 5, ⫻10,000). phrotic. Rapidly progressive renal failure is the most
After receipt of the biopsy results, the patient was frequent presentation, but mild renal impairment and
found to have a high-titer anti-GBM antibody with isolated hematuria may occur in those with relatively
negative anti-neutrophil cytoplasmic antibody (ANCA) few glomeruli affected. Rarely, the renal function can
serology. be entirely normal in the face of severe hemoptysis
(3), but renal biopsy in this setting reveals linear GBM
staining for IgG.
Anti-GBM Nephritis Circulating anti-GBM antibodies are detectable
Anti-GBM nephritis is an autoimmune disorder by ELISA. Most testing is by solid-phase immunoas-
characterized by circulating antibodies directed say containing human or animal GBM or recombinant
against the GBM, specifically the noncollagenous antigen as substrate. In practice, the results of renal
(NC1) domain of type IV collagen. A pathologic biopsy are often obtained before serologic confirma-
diagnosis of anti-GBM nephritis requires the demon- tion. Rarely, biopsy-documented anti-GBM nephritis
stration by immunofluorescence of diffuse linear lo- can occur in the absence of detectable circulating
calization of IgG along the GBMs in the setting of anti-GBM antibodies by ELISA. In such cases, it is
crescentic glomerulonephritis. Both clinically and possible that the circulating antibody with specificity
pathologically, it is considered the most severe form of for collagen IV determinants is not detected by the
crescentic glomerulonephritis (1). The term “Good- substrate used for ELISA, or the pathogenic antibody
pasture syndrome” is applied to cases of pulmonary- has specificity for other GBM components such as
renal involvement, as originally described in 1919 by entactin (4,5). The sensitivity of ELISA may also be a
Ernest Goodpasture. The index case was an 18 year- factor because some circulating anti-GBM antibodies
old man who developed pulmonary hemorrhage and are detectable only by the more sensitive biosensor
acute renal failure after a flu-like illness. Some pa- analysis (6). Nonetheless, the serum level of anti-
tients present with combined pulmonary manifesta- GBM antibodies using standard techniques tends to
tions of lung hemorrhage and renal manifestations of correlate well with disease activity. Combined sero-
rapidly progressive glomerulonephritis, whereas in positivity for anti-GBM antibody and ANCA occurs in
others, involvement of one organ system precedes the a subset of patients, particularly older women.
other by a period of days or weeks. Some patients have
isolated anti-GBM nephritis without ever developing Pathology
pulmonary manifestations. By contrast, isolated pul- Light Microscopy. Almost all cases of anti-GBM
monary involvement is uncommon. nephritis have biopsy evidence of crescents, but cres-
centic glomerulonephritis (defined as ⬎50% of glom- scale of 0 to 4). Low-level linear staining for IgG, by
eruli containing crescents) is the most characteristic contrast, may be a nonspecific finding, especially in
and frequent histologic feature, affecting ⬎80% of older patients, allografts, and autopsy specimens. The
patients at the time of biopsy (7). Crescents tend to be clinical context must also be taken into account be-
of similar age and range from segmental to circumfer- cause patients with diabetes, obesity, or history of
ential. Isolated segmental fibrinoid necrosis of the cigarette smoking may have thickened GBMs with
glomerular tuft without crescents may be observed in low-intensity linear staining for IgG (usually not
biopsies performed early in the disease course (1). The ⬎1⫹) in the absence of crescentic glomerulonephri-
ruptured GBM is readily identified with periodic acid– tis. In equivocal cases, correlation with anti-GBM
Schiff or JMS stains, and the extravasated fibrin serology is needed. In the presence of pulmonary
within the urinary space and crescent stains bright disease, similar linear alveolar basement membrane
orange-red (fuchsinophilic) with trichrome stain. Mild staining for IgG can be demonstrated on lung biopsy,
glomerular neutrophil infiltration is often seen adja- but the immunofluorescence staining is more easily
cent to foci of glomerular necrosis. Glomerular tufts interpretable on a kidney biopsy. Distal tubular base-
unaffected by necrosis or crescents tend to be normal ment membranes occasionally have linear IgG staining
by light microscopy, with no evidence of mesangial or as well because they carry the same collagen IV
endocapillary proliferation. The cellular crescents of- isotypes as GBM, and this may account in part for the
ten have extensive destruction of Bowman’s capsule, associated severe tubulointerstitial inflammation. C3
merging with the adjacent interstitium. Periglomerular staining is typically more granular to semilinear and
inflammation and rare multinucleated giant cells are discontinuous. Rare patients have isolated linear GBM
likely a response to severe glomerular injury and may staining for IgA, rather than IgG, and the circulating
be identified in the absence of associated ANCA IgA anti-GBM antibodies have been shown to target
seropositivity. Severe tubulointerstitial inflammation, novel GBM antigenic determinants (8 –10).
interstitial edema, and acute tubular injury are fre- Electron Microscopy. In the acute phase, cellular
quently present, as are RBC casts. Vasculitis is not a crescents are associated with ruptures of the GBM,
feature of anti-GBM nephritis unless the patient has intracapillary fibrin, and extravasation of fibrin into
concurrent ANCA. The chronic phase of anti-GBM the urinary space. Fibrin is often intermingled with the
nephritis, as seen in late biopsies or more subacute cells of the crescent. There may be widening of the
presentation, often exhibits older fibrocellular/fibrous subendothelial zone by lucent material and glomerular
crescents and variable tubular atrophy and interstitial capillary infiltration by neutrophils or mononuclear
fibrosis. Even in the setting of extensive segmental leukocytes. Importantly, no granular immune-type
and global glomerulosclerosis with subcapsular fibro- electron-dense deposits are identified. This absence of
sis and no residual activity, identification of GBM and deposits is probably due to the uniform distribution of
Bowman’s capsule ruptures with periodic acid–Schiff the anti-GBM antibody, which does not aggregate to
or JMS stains should signal a previous necrotizing and form definable electron densities. Neutrophils and
crescentic glomerulonephritis as the initial process. RBCs gain entry into Bowman’s space through the
Immunofluorescence. In the context of a crescentic broad gaps in the GBM. Glomeruli with more chronic
glomerulonephritis, the finding of intense linear stain- features have progressive obliteration of the tuft by
ing of the GBM for IgG is diagnostic of anti-GBM extracellular matrix, leading to segmental and global
nephritis. The linear IgG staining may appear inter- glomerulosclerosis in association with fibrocellular or
rupted as a result of broad ruptures of the GBMs. In fibrous crescents. The ultrastructural findings are sim-
glomeruli with exuberant crescents and extensive de- ilar to those seen in ANCA-associated glomerulone-
struction of the tuft, it may be difficult to identify phritis, despite the different immunofluorescence find-
linear staining because no residual glomerular capil- ings.
laries are represented in the plane of section. Foci of Concurrent Disease. Up to one third of patients
necrosis and cellular crescents are usually highlighted with anti-GBM nephritis have concurrent circulating
with antisera to fibrin/fibrinogen. Most cases of anti- ANCA, usually with specificity for myeloperoxidase.
GBM nephritis have intense IgG staining (ⱖ2⫹ on a They can be detected either before or after the appear-
ance of anti-GBM antibodies. Some of these patients culating autoantibody is a mainstay of therapy, and
have arteritis or medullary capillaritis on renal biopsy, immunosuppressive therapy with corticosteroids and
and there may be other manifestations of systemic cyclophosphamide is aimed at reduction in inflamma-
vasculitis. Previous studies suggested that patients tion and antibody synthesis. T cells and macrophages
with concurrent anti-GBM nephritis and ANCA have may also play an important role in antigen recognition,
less severe disease and better renal and patient survival cell-mediated immunity, and exacerbation of inflam-
(even though patients tend to be older) compared with mation (1,18). Activated neutrophils and monocytes
patients with pure anti-GBM nephritis (11,12). Con- recruited by antibody binding and complement fixa-
versely, a more recent series demonstrated that such tion are thought to cause GBM perforations by release
“dual-positive” patients have a renal prognosis that is of reactive oxygen species and lytic proteases. The
similar to patients with isolated anti-GBM nephritis extravasation of fibrin and other growth factors into
(13). Relapse rates, however, are higher in the dual- Bowman’s space elicits the final pathway of crescent
positive group, similar to patients with isolated ANCA formation and destruction of the glomerulus.
disease. Given the therapeutic and long-term implica- The factors that trigger the autoimmune re-
tions of concurrent disease, it is recommended that all sponse include genetic predisposition and exposure
patients with anti-GBM nephritis be tested for ANCA. to environmental factors. There is a strong associa-
There are infrequent reports of concurrent anti- tion with major histocompatibility antigens DR (es-
GBM nephritis and membranous nephropathy (MGN). Ac- pecially DR2, carried by 85% of patients with anti-
curate diagnosis in such cases requires examination of GBM nephritis) and DQ (19). Environmental
immunofluorescence on high magnification to identify exposure to hydrocarbons before the onset of clin-
a layer of finely granular capillary wall staining for ical disease has been documented in several cases.
IgG above the linear GBM positivity for IgG. Ultra- Cigarette smoking and respiratory viral infections
structural identification of subepithelial membranous also seem to trigger autoimmunity and precipitate
deposits is needed for confirmation of coexistent dis- pulmonary manifestations.
ease. In these cases, MGN may precede or follow The target antigen for circulating anti-GBM an-
anti-GBM nephritis, or the two may develop simulta- tibodies is the NC1 domain of type IV collagen net-
neously. Although the concurrence of these two enti- works within the GBM. The same collagen networks
ties may be purely coincidental, experimental data are found within the basement membranes of pulmo-
based on animal models suggest a possible pathoge- nary alveolar capillaries. The elegant work of Ped-
netic link, possibly through epitope spreading (14). chenko et al. (20) elucidated the molecular architec-
The immunologic injury that is caused by anti-GBM ture of the “Goodpasture antigen.” The disease is now
disease or MGN may increase autoantigen synthesis understood to be an autoimmune “conformeropathy”
and exposure of potentially immunogenic GBM in which autoantibodies form to a conformational
epitopes that promote the development of a dual au- alteration in the ␣-3 and ␣-5 subunits of the NC1
toimmune glomerulopathy (15,16). It is unknown domain of collagen IV (20). Patients with Goodpasture
whether the specificity of the antibodies deposited in syndrome and anti-GBM nephritis form antibodies to
the subepithelial region is to phospholipase A2 recep- distinct epitopes encompassing the region EA and EB
tor, as seen in primary MGN, or to another antigenic of the ␣-3 NC1 monomer and region EA of the ␣-5
determinant. NC1 monomer. Interestingly, antibodies do not bind to
the native cross-linked ␣345NC1 hexamer, indicating
Pathogenesis that the target antigens must undergo a conformational
Anti-GBM nephritis (and Goodpasture syn- change to become autoantigens and to elicit an auto-
drome) is caused by development of autoimmunity to immune response (20,21).
a component of GBM. The pathogenic role of anti- Normally, the ␣-3, -4, and -5 chains of type IV
GBM antibodies was first demonstrated by Lerner et collagen assemble to form triple helical protomers,
al. in 1967 (17). There is a correlation between the which in turn dimerize by association through their
antibody titers and severity of disease, and persistently C-terminal NC1 domains to form interface hexamers
high levels are associated with immediate recurrence (22). The cross-linked hexamer is reinforced by sul-
in kidney transplants. Plasmapharesis to remove cir- filimine bonds and needs to be dissociated for autoan-
tibody binding to occur. A triggering event may alter 7. Johnson JP, Moore J Jr, Austin HA 3rd, Balow JE, Antonovych TT,
Wilson CB: Therapy of anti-glomerular basement membrane anti-
the quartenary structure of the ␣345NC1 hexamer, body disease: Analysis of prognostic significance of clinical, patho-
exposing neo-epitopes and eliciting autoantibody pro- logic and treatment factors. Medicine (Baltimore) 64: 219 –227, 1985
duction and binding. Putative triggers include enzy- 8. Ho J, Gibson IW, Zacharias J, Fervenza F, Colon S, Borza DB:
Antigenic heterogeneity of IgA anti-GBM disease: New renal targets
matic and nonenzymatic posttranslational modifica- of IgA autoantibodies. Am J Kidney Dis 52: 761–765, 2008
tions (e.g., oxidation, nitrosylation, glycation), rise in 9. Border WA, Baehler RW, Bhathena D, Glassock RJ: IgA antibase-
body temperature, and proteolytic cleavage (20). It has ment membrane nephritis with pulmonary hemorrhage. Ann Intern
Med 91: 21–25, 1979
been proposed that environmental exposure to infec-
10. Shaer AJ, Stewart LR, Cheek DE, Hurray D, Self SE: IgA antiglo-
tious agents, cigarette smoke, or organic solvents may merular basement membrane nephritis associated with Crohn’s dis-
inhibit the enzymes that catalyze the sulfilimine bond ease: A case report and review of glomerulonephritis in inflammatory
bowel disease. Am J Kidney Dis 41: 1097–1109, 2003
formation and promote hexamer dissociation (20,21).
11. Clyne S, Frederick C, Arndt F, Lewis J, Fogo AB: Concurrent and
Approximately 5 to 15% of patients with ESRD discrete clinicopathological presentations of Wegener granulomatosis
from Alport syndrome develop anti-GBM nephritis and anti-glomerular basement membrane disease. Am J Kidney Dis
after transplantation. Because of a heritable mutation 54: 1116 –1120, 2009
12. Bosch X, Mirapeix E, Font J, Borrellas X, Rodriguez R, Lopez-Soto
in ␣-5 collagen IV, these patients lack normal ␣345 A, Ingelmo M, Revert L: Prognostic implication of anti-neutrophil
hexamers in their native GBM and develop an immune cytoplasmic autoantibodies with myeloperoxidase specificity in anti-
response to normally expressed GBM antigens pre- glomerular basement membrane disease. Clin Nephrol 36: 107–113,
1991
sented in the renal allograft. Although the clinical and 13. Rutgers A, Slot M, van Paassen P, van Breda Vriesman P, Heeringa
pathologic features are similar to those of native anti- P, Tervaert JW: Coexistence of anti-glomerular basement membrane
GBM nephritis, the alloantibodies generated in post- antibodies and myeloperoxidase-ANCAs in crescentic glomerulone-
phritis. Am J Kidney Dis 46: 253–262, 2005
transplantation nephritis bind to the EA region of ␣-5 14. Fukatsu A, Brentjens JR, Killen PD, Kleinman HK, Martin GR,
NC1 of the intact hexamer, not to ␣-3 NC1. Unlike the Andres GA: Studies on the formation of glomerular immune deposits
situation in native anti-GBM nephritis, autoantibody in brown Norway rats injected with mercuric chloride. Clin Immunol
Immunopathol 45: 35– 47, 1987
binding is lessened upon dissociation of the hexamer, 15. Nasr SH, Ilamathi ME, Markowitz GS, D’Agati VD: A dual pattern
suggesting that the antibody binds to a surface epitope. of immunofluorescence positivity. Am J Kidney Dis 42: 419 – 426,
Thus, posttransplantation anti-GBM nephritis can oc- 2003
16. Troxell ML, Saxena AB, Kambham N: Concurrent anti-glomerular
cur in the absence of triggering events for hexamer basement membrane disease and membranous glomerulonephritis: A
dissociation (20). case report and literature review. Clin Nephrol 66: 120 –127, 2006
17. Lerner RA, Glassock RJ, Dixon FJ: The role of anti-glomerular
References basement membrane antibody in the pathogenesis of human glomer-
1. Jennette JC: Rapidly progressive crescentic glomerulonephritis. Kid- ulonephritis. J Exp Med 126: 989 –1004, 1967
ney Int 63: 1164 –1177, 2003 18. Bolton WK, Innes DJ Jr, Sturgill BC, Kaiser DL: T-cells and
2. Bolton WK: Goodpasture’s syndrome. Kidney Int 50: 1753–1766, macrophages in rapidly progressive glomerulonephritis: Clinicopath-
1996 ologic correlations. Kidney Int 32: 869 – 876, 1987
3. Cui Z, Zhao MH, Singh AK, Wang HY: Antiglomerular basement 19. Huey B, McCormick K, Capper J, Ratliff C, Colombe BW, Garovoy
membrane disease with normal renal function. Kidney Int 72: 1403– MR, Wilson CB: Associations of HLA-DR and HLA-DQ types with
1408, 2007 anti-GBM nephritis by sequence-specific oligonucleotide probe hy-
4. Saxena R, Bygren P, Cederholm B, Wieslander J: Circulating anti- bridization. Kidney Int 44: 307–312, 1993
entactin antibodies in patients with glomerulonephritis. Kidney Int 20. Pedchenko V, Bondar O, Fogo AB, Vanacore R, Voziyan P, Kitching
39: 996 –1004, 1991 AR, Wieslander J, Kashtan C, Borza DB, Neilson EG, Wilson CB,
5. Saxena R, Bygren P, Rasmussen N, Wieslander J: Circulating auto- Hudson BG: Molecular architecture of the Goodpasture autoantigen
antibodies in patients with extracapillary glomerulonephritis. Nephrol in anti-GBM nephritis. N Engl J Med 363: 343–354, 2010
Dial Transplant 6: 389 –397, 1991 21. Lionaki S, Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic
6. Salama AD, Dougan T, Levy JB, Cook HT, Morgan SH, Naudeer S, (ANCA) and anti-glomerular basement membrane (GBM) autoanti-
Maidment G, George AJ, Evans D, Lightstone L, Pusey CD: Good- bodies in necrotizing and crescentic glomerulonephritis. Semin Im-
pasture’s disease in the absence of circulating anti-glomerular base- munopathol 29: 459 – 474, 2007
ment membrane antibodies as detected by standard techniques. Am J 22. Salant DJ: Goodpasture’s disease: New secrets revealed. N Engl
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Section 18: CASE PRESENTATION cytoplasmic antibodies (P-ANCA; 1:320) with specificity
for anti-myeloperoxidase (MPO; 971 AU/ml; normal range
A 47-year-old man with history of psoriasis presents with 0 to 19). Other serologies are negative or normal, including
cough, headache, chills, and a petechial rash of the lower anti-nuclear antibody, anti– double stranded DNA antibody,
extremities. Laboratory evaluation reveals acute renal fail- hepatitis B surface antigen, hepatitis C antibody, and serum
ure with serum creatinine level of 4.8 mg/dl (increased from complement C3 and C4 levels. Magnetic resonance imaging
baseline value of 0.9 mg/dl 2 months earlier). Urinalysis reveals leptomeningeal enhancement, and chest x-ray shows
reveals microhematuria with red blood cell (RBC) casts and increased interstitial markings. Skin biopsy of the leg re-
3⫹ proteinuria; 24-hour urine protein excretion is 2.0 g. veals a leukocytoclastic vasculitis. A renal biopsy is
Serologic studies reveal positive perinuclear anti-neutrophil performed.
Figure 1. Figure 2.
Figure 3. Figure 4.
Figure 5. Figure 6. Fibrin

379
What is the BEST diagnosis? segmental glomerular fibrinoid necrosis and crescent
A. Henoch-Schönlein purpura nephritis formation, without significant immune deposits by
B. Goodpasture syndrome immunofluorescence or electron microscopy. More
C. Diffuse proliferative lupus nephritis than 85% of pauci-immune GN cases are associated
D. Cryoglobulinemic glomerulonephritis (GN) with serum ANCA, in which case the term ANCA-
E. Pauci-immune necrotizing and crescentic GN associated GN is used synonymously. This entity rep-
resents small-vessel vasculitis that may be either lim-
Answer ited to the kidney (renal-limited pauci-immune GN) or
The renal biopsy findings are most consistent associated with a systemic disease such as Wegener
with ANCA-associated pauci-immune necrotizing and granulomatosis (more recently referred to as “Granu-
crescentic GN with necrotizing arteritis (answer E). Of lomatosis with Polyangiitis (Wegner’s)”), microscopic
the 26 glomeruli sampled for light microscopy, five polyangiitis, or Churg-Strauss syndrome. All these
are globally sclerotic with evidence of old fibrous variants share certain clinical and pathologic features
crescents, and nine (35%) have foci of necrosis and/or and require prompt institution of immunosuppressive
cellular crescents. Figure 1 (Jones methenamine silver therapy.
[JMS], ⫻400) shows segmental fibrinoid necrosis of
the glomerular tuft with rupture of glomerular base- Clinical presentation
ment membranes (GBMs) and extravasation of fibrin Pauci-immune GN is the most common cause of
into the urinary space, associated with a nearly cir- crescentic GN, especially in individuals who are older
cumferential cellular crescent (Figure 1). Figure 2 than 65 years (1,2) and very elderly patients who are
(JMS, ⫻400) illustrates severe segmental destruction older than 80 years (3,4). The disease is more common
of the tuft by a voluminous cellular crescent with in Caucasians and males. In addition to the renal
broad rupture of Bowman’s capsule and periglomeru- manifestations of rapidly progressive GN, most pa-
lar inflammation (Figure 2). The earliest lesion is a tients report a prodrome of fever, arthralgias, myal-
small segmental focus of fibrinoid necrosis with rup- gias, and “flu-like” illness. These symptoms are prob-
ture of the GBM and mild segmental proliferation of ably due in part to antecedent infections and elevated
the overlying glomerular epithelial cells, forming an levels of proinflammatory cytokines. In the presence
incipient crescent (Figure 3, JMS, ⫻400). The pre- of systemic vasculitis, the symptoms vary on the basis
served glomeruli have no evidence of mesangial or of the organ involvement and include pulmonary hem-
endocapillary proliferation (Figure 4, periodic acid– orrhage and hemoptysis (alveolar capillaritis), mono-
Schiff, ⫻400). There was prominent interstitial inflam- neuritis multiplex (peripheral nerve arteritis), palpable
mation by lymphocytes, monocytes, and plasma cells skin purpura (leukocytoclastic vasculitis), abdominal
associated with focal acute tubular injury. Several RBC pain, and occult blood in the stool (intestinal arteritis
casts were identified. Two interlobular arteries show and ischemia) (5). Although all ANCA-associated
necrotizing vasculitis with fibrinoid necrosis of the in- GN can be considered “vasculitis” of the glomerular
tima and transmural inflammation (Figure 5, JMS, capillaries, associated systemic small-vessel vascu-
⫻400). Except for sparse focal segmental glomerular tuft litis often manifests as distinct syndromes. Patients
staining for IgM and C3, no significant immune deposits with Wegener granulomatosis typically have necro-
were identified by immunofluorescence microscopy. tizing granulomatous inflammation of the upper and
However, there is intense (3⫹) staining for fibrin/fibrin- lower respiratory tracts, resulting in sinusitis, otitis
ogen in the distribution of the necrotizing lesions and media, saddle nose deformity, subglottic stenosis,
crescents (Figure 6, immunofluorescence for fibrin, and/or cavitary nodular lung lesions. Microscopic
⫻400). On electron microscopy, no glomerular or vas- polyangiitis also presents as pulmonary-renal syn-
cular immune-type electron-dense deposits were seen. drome but lacks granulomatous inflammation. Pa-
tients with Churg-Strauss syndrome often have a
Pauci-immune Crescentic GN history of asthma and blood eosinophilia (⬎10%) that
Pauci-immune crescentic GN usually presents may precede the renal symptoms by many years.
with rapidly progressive renal failure, hematuria, and Renal involvement occurs commonly in We-
subnephrotic proteinuria. Renal biopsy reveals focal gener granulomatosis and microscopic polyangiitis
(ⱖ80% of cases) but less frequently in Churg-Strauss More than one fourth of patients with anti-GBM
syndrome (⬍50%) (2). Urinalysis reveals hematuria, disease have ANCA in addition to anti-GBM antibod-
mild subnephrotic proteinuria, and RBC casts. Ne- ies. When compared with patients with anti-GBM
phrotic-range proteinuria is seen in a minority of cases nephritis alone, these patients have better prognosis
but is more common in those with a coexistent defined and renal survival rates that are intermediate between
immune complex–mediated disease (e.g., IgA ne- anti-GBM disease and ANCA vasculitis, but they are
phropathy, lupus nephritis) or nonspecific associated prone to relapses of ANCA disease (11,12). When a
immune deposits (6). Higher serum creatinine level at patient with positive ANCA serology has a mixed
biopsy, African American race, higher percentage of picture of necrotizing and crescentic GN with immune
total glomerular involvement, and more arteriosclero- deposits, overlaps with membranous nephropathy, IgA
nephropathy, lupus nephritis, and acute postinfectious
sis are negative predictors of renal survival (3,7,8).
GN should be considered (13–15).
ANCA serology. The diagnosis of pauci-immune
GN was advanced by the introduction of ANCA sero- Pathology
logic testing in the late 1980s. The predictive value of
Light microscopy. The early lesions of pauci-im-
ANCA positivity depends to a large extent on the
mune GN include focal and segmental glomerular
pretest probability of ANCA-associated vasculitis. In
fibrinoid necrosis with GBM rupture, sparse neutro-
the appropriate clinical context, positive ANCA has a
phil infiltration, and nuclear fragmentation (pyknosis
very high positive predictive value, but a negative
and karyorrhexis), followed by the rapid formation of
ANCA does not rule out pauci-immune GN (approx-
cellular crescents. The extent and severity of glomer-
imately 15% of cases are ANCA negative). Without ular involvement vary, but approximately two thirds of
clinical support for pauci-immune GN, a negative patients have ⬎50% crescents, qualifying as crescen-
ANCA has a high negative predictive value, whereas a tic GN (16). A brisk inflammatory infiltrate is often
positive test is a poor predictor of ANCA-associated seen adjacent to foci of glomerular necrosis and in-
disease. cludes lymphocytes, monocytes, plasma cells, neutro-
ANCA are autoantibodies that target proteins phils, and variable eosinophils. Glomeruli spared by
within neutrophil granules and monocyte lysosomes. the crescentic process usually appear unremarkable,
The more specific ELISA uses two purified substrates without evidence of mesangial or endocapillary pro-
that correspond to myeloperoxidase (MPO) and proliferation. Conversely, if ANCA-associated GN is su-
teinase 3 (PR3). The less specific (but more sensitive) perimposed on an immune complex–mediated disease,
indirect immunofluorescence method detects ANCA then variable glomerular proliferation may occur. Cir-
in patients’ serum using alcohol-fixed human neutro- cumferential crescents that cause destruction of Bow-
phils as substrate. Two patterns of neutrophil staining man’s capsule may result in periglomerular inflammation
are identified: Cytoplasmic staining corresponding to centered on the glomerulus, mimicking granulomas. Ep-
PR3-ANCA and perinuclear staining corresponding to ithelioid histiocytes and multinucleated giant cells may
MPO-ANCA. ANCA do not definitively distinguish contribute to the periglomerular inflammatory infiltrate.
categories of pauci-immune GN because of extensive However, true interstitial necrotizing granulomas are rare
overlap, but, in general, Wegener granulomatosis is in pauci-immune GN and are uncommon even in We-
more likely to be PR3-ANCA positive (75%), whereas gener granulomatosis and Churg-Strauss syndrome.
Churg-Strauss syndrome, microscopic polyangiitis, In addition to glomeruli, ANCA-associated small-
and renal limited disease more often tend to be MPO- vessel vasculitis can involve arterioles, interlobular arter-
ANCA positive (60, 50, and 60%, respectively) (9). ies, venules, and capillaries (16). Affected arteries show
Patients in all categories can have negative ANCA fibrinoid necrosis of the intima and media with mural
serologies, but Churg-Strauss syndrome has the high- inflammation and disruption of elastic lamellae. In-
est frequency of negativity. Although ANCA titers volvement of medullary vasa recta can cause necro-
correlate with disease activity in a high proportion of tizing interstitial capillaritis, medullary hemorrhage,
patients, it is not always predictive of relapses. In fact, and even papillary necrosis.
some patients have undergone successful renal trans- The chronic phase has segmental and global
plantation despite persistently high ANCA titers (10). glomerulosclerosis with evidence of old fibrous or
fibrocellular crescents. The presence of ruptured or Pathogenesis

fragmented GBM embedded in the segmental scars First reported by Davies et al. in 1982 (17),
and focal disruption of Bowman’s capsule in areas of ANCA are now thought to play a central pathogenic
subcapsular fibrosis are helpful indicators of a previ- role in the mediation of pauci-immune GN and asso-
ous necrotizing and crescentic process. Chronic arteri- ciated vasculitis (12,18). Multiple lines of evidence
tis displays eccentric scars of the media with rupture of support this view. Transplacental transfer of ANCA
elastic membrane. There is variable tubular atrophy, IgG from a mother with active microscopic polyangi-
interstitial fibrosis, and chronic interstitial inflamma- itis has been reported to cause a pulmonary-renal
tion. Whereas some patients have purely active or syndrome in the newborn (12). In vitro studies have
purely chronic disease on renal biopsy, it is common demonstrated that MPO- and PR3-ANCA bind to
for acute and chronic lesions to coexist. neutrophils via Fab⬘2 and Fc receptor engagement,
A recently proposed histologic classification of causing activation of neutrophils and enhanced endo-
ANCA has prognostic value in predicting 1- and thelial cell binding. The activated neutrophils undergo
5-year renal survival (8). The four categories of le- a respiratory burst and degranulation, releasing reac-
sions include focal (ⱖ50% normal glomeruli), cres- tive oxygen species and lytic enzymes that result in
centic (ⱖ50% cellular crescents), sclerotic (ⱖ50% endothelial cell apoptosis and necrosis. A mouse
globally sclerosed glomeruli), and mixed (all others). model of ANCA-associated pauci-immune GN and
Inclusion of tubulointerstitial parameters did not add vasculitis has been produced by passive transfer of
significantly to the predictive value of this glomerular MPO-ANCA IgG (19). Using this model, investigators
classification. On the basis of the study cohort, focal have shown that ANCA disease is neutrophil depen-
lesions have the best prognosis and sclerotic lesions dent, requires Fc␥ receptors, and requires alternative
have the worst. Surprisingly, renal survival in the pathway complement activation (20,21). Animal mod-
crescentic category is favorable (84% at 1 year and els of PR3-ANCA have been less successful in induc-
76% at 5 years), indicating that when treated promptly, tion of GN (12,18,22), possibly because of the greater
even highly active disease has a good likelihood of role of T cell–mediated immunity (22).
functional recovery. ANCA-associated GN is an autoimmune disease
influenced by genetic and environmental factors. Ge-
Immunofluorescence. By definition, pauci-im-
netically determined expression levels of ANCA anti-
mune GN shows a paucity or absence of immune-type
gens on neutrophils, allelic variations, and gene poly-
deposits by immunofluorescence. Nonspecific entrap-
morphisms increase an individual’s susceptibility to
ment of immunoglobulins and activation of comple-
autoimmune responses. A defective allele in ␣-1 anti-
ment C3 in areas of necrosis or sclerosis may result in
trypsin, a physiologic inhibitor of PR3, is a risk factor
low-intensity staining (ⱕ2⫹). Foci of necrosis or
for development of PR3-ANCA–associated disease
cellular crescents are highlighted by staining for fibrin/
(12,23). Environmental factors such as silica exposure
fibrinogen. The immunofluorescence findings differ and drugs (e.g., propylthiouracil, hydralazine) are
when there is concurrent immune complex–mediated known to induce ANCA formation in susceptible in-
disease (showing specific granular deposits character- dividuals.
istic of the underlying disease) or anti-GBM nephritis Although both MPO and PR3 are cytoplasmic
(showing linear GBM staining for IgG). antigens inaccessible to antibody binding, activation
Electron microscopy. Glomeruli with necrotizing events lead to increased surface expression, allowing
lesions have broad ruptures of the GBM associated binding to circulating ANCA. Cytokines such as IFN
with endocapillary and extracapillary fibrin tactoids and TNF-␣ can prime neutrophils in vitro, causing
and endothelial injury. Cellular crescents contain pro- increased surface expression of MPO/PR3 (5,12,18).
liferations of plump glomerular epithelial cells and Similarly, an antecedent upper respiratory tract infec-
infiltrating leukocytes admixed with fibrin, causing tion may serve as a priming event in vivo. In the
obliteration of the urinary space and compression of absence of such cytokine priming, aberrant surface
the tuft. No immune-type electron-dense deposits are expression of MPO/PR3 may be genetically deter-
identified in the majority of cases. Uninvolved glom- mined (23). Some studies suggested a role for altered
eruli are usually unremarkable. transcriptional regulation of these genetic loci via
epigenetic modifications such as loss of DNA meth- and that cotrimazole therapy reduces the number of
ylation that result in increased surface expression of relapses (34). Thus, multiple lines of evidence support
MPO/PR3 (20,23,24). a role for infection in inciting and perpetuating
ANCA-mediated autoimmunity may be initiated ANCA-associated GN in genetically susceptible indi-
by anti-idiotypic antibodies, especially in PR3-ANCA viduals.
disease (22,25–27). The complementary peptide of
PR3, generated by the antisense DNA strand of PR3, References
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3. Bomback AS, Appel GB, Radhakrishnan J, Shirazian S, Herlitz LC,
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also sequence homology between complementary PR3 immune deposits are associated with increased proteinuria in patients
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18: 524 –531, 2003
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tis. Ann Intern Med 143: 621– 631, 2005
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1550, 1999
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bodies in necrotizing and crescentic glomerulonephritis. Semin Im-
pathogens extracellularly by releasing chromatin fi-
munopathol 29: 459 – 474, 2007
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Section 19: CASE PRESENTATION history of hypertension, and BP is 110/60 mmHg. Serum
creatinine level is 1.2 mg/dl. All serologies are negative
A 72-year-old Caucasian woman presents with new onset or normal, including anti-nuclear antibody, C3, C4, hep-
of lower extremity edema for 1 month and is found to have atitis B surface antigen, hepatitis C antibody, and anti-
nephrotic syndrome (24-hour urine protein is 11.0 g, serum neutrophil cytoplasmic antibody. Serum protein electro-
albumin is 2.0 g/dl, serum cholesterol is 302 mg/dl). Her phoresis shows no evidence of a monoclonal spike. The
past medical history is notable for a diagnosis of diabetes 2 patient weighs 140 lb, body mass index is 27.3, and
years earlier. She has no evidence of diabetic retinopathy, kidney size is 11.5 cm bilaterally. A kidney biopsy is
and most recent hemoglobin A1c is 7.0. She has no performed.
Figure 1. Figure 2.
Figure 4.
Figure 3.
Figure 5. Figure 6.
385
What is the BEST diagnosis? confined to one organ or affect multiple organs, and
A. Diabetic glomerulosclerosis renal involvement is common in systemic amyloido-
B. Renal amyloidosis, AL ␭ type sis.
C. Fibrillary glomerulonephritis More than 26 amyloid precursor proteins have
D. Immunotactoid glomerulonephritis been identified, 12 of which may involve the kidney
E. Light-chain deposition disease (LCDD), ␭ type (1,2). These include light-chain amyloid (AL), heavy-
chain amyloid (AH), light- and heavy-chain amyloid
Answer (ALH), amyloid A (AA), ␤2 microglobulin, transthy-
The glomeruli appear normocellular. Mesangial retin, fibrinogen Aa, apolipoprotein A-I, apolipopro-
areas are moderately expanded by deposits of homo- tein A-II, lysozyme, cystatin C, gelsolin, and leuko-
geneous pale eosinophilic material (Figure 1, ⫻400). cyte chemotactic factor 2 (ALect2) (1) ALect2 is a
This material is weakly periodic acid–Schiff (PAS) newly recognized form of renal amyloidosis caused by
positive and segmentally thickens some glomerular deposition of leukocyte chemotactic factor 2 (LECT2)
capillary walls, without associated endocapillary pro- peptide, which is encoded by a distinct genetic poly-
liferation (Figure 2, ⫻400). The mesangial deposits morphism more prevalent in Mexican Americans (3).
are Congo red positive and give the typical apple- The most common form of renal amyloidosis (53
green birefringence of amyloid when viewed under to 63%) is derived from monoclonal Ig light chains
polarized light (Figure 3, Congo red, polarized light, (AL amyloid) (4,5). The second most common form is
⫻600). Immunofluorescence shows light-chain re- AA amyloidosis derived from deposition of serum
striction with negativity for ␬ light chain and intense amyloid A, an acute-phase reactant produced by the
staining for ␭ light chain in the distribution of the liver in chronic inflammatory states. Together, these
expanded mesangium and thickened glomerular cap- two etiologies account for ⬎95% of renal amyloidosis
illary walls (Figure 4, immunofluorescence staining encountered on renal biopsy. All forms of renal amy-
for ␬ and ␭ light chains, ⫻400). There was no loidosis appear similar by light microscopy and elec-
glomerular staining for immunoglobulins or com- tron microscopy. Diagnosis of a specific etiology re-
plement. Similar staining for ␭ light chain was seen quires demonstration of the precursor protein by
in some vessel walls. Electron microscopy reveals immunostaining using specific antisera to the patho-
fibrillar deposits infiltrating the glomerular base-
genic protein. In difficult cases, mass spectrometry can
ment membrane (GBM), forming focal subepithelial
be performed on tissue deposits extracted by laser
projections (Figure 5, ⫻25,000). Similar fibrillar de-
capture microdissection (6).
posits infiltrate the mesangial matrix (not shown). On
high-power magnification, the fibrils appear randomly
oriented and measure 8 to 12 nm in thickness Clinical Characteristics
(Figure 6, ⫻60,000). The biopsy findings are diagnos- AL amyloidosis typically affects older individu-
tic of renal amyloidosis, AL ␭ type (answer B). als (⬎50 years), reflecting the incidence of plasma cell
dyscrasia, with a male preponderance (5,7). In the
Renal Amyloidosis Mayo Clinic series of 474 patients with AL, the mean
The amyloidoses are a diverse group of diseases age was 64 years, and 69% were male (7). Most (73%)
characterized by extracellular tissue deposition of patients had proteinuria, 25% had nephrotic syndrome,
fibrillar proteins with mean diameter of 10 nm. Al- and 50% presented with renal insufficiency. The uri-
though the precursor proteins vary, all amyloid pro- nary sediment is typically bland, and microhematuria
teins share an antiparallel ␤-pleated sheet structure on is uncommon. In an Italian study of 237 patients with
x-ray diffraction. In addition, all forms of amyloid AL, nephrotic syndrome was present in 59% and renal
contain amyloid P component, a member of the pen- insufficiency in 54% (8). In a renal biopsy series at
traxin family of serum proteins that plays a role in Columbia University, amyloidosis was the second
fibrillogenesis. The gold standard for pathologic diag- most common cause of nephrotic syndrome in very
nosis is the demonstration of characteristic apple- elderly patients who were older than 80 years (9).
green birefringence with Congo red stain when exam- Extrarenal manifestations of AL amyloid include re-
ined under polarized light (1). Amyloid may be strictive cardiomyopathy, orthostatic hypotension, pe-
ripheral neuropathy, carpal tunnel syndrome, hepato- Pathology

splenomegaly, and macroglossia. Light Microscopy. Grossly, kidneys affected by AL
Most (⬎90%) patients with AL have evidence of are large, pale, and firm. Although amyloid deposits
plasma cell dyscrasia on the basis of the results of have the potential to deposit in any or all renal com-
serum and urine immunofixation and bone marrow partments (including glomeruli, vessels, interstitium,
examination. Serum free light chain (FLC) assay is and tubular basement membranes), glomerular in-
abnormal in 87% of cases, and FLC burden correlates volvement is the most typical in patients who present
with patient survival (10,11). FLC assay is more sen- with proteinuria. Glomerular amyloid deposits usually
sitive than immunofixation and allows quantification begin in the mesangium and subsequently involve the
of light-chain synthesis; thus, serial FLC measure- GBMs, causing progressive narrowing and oblitera-
ments are helpful in monitoring response to therapy in tion of glomerular capillaries. Amyloid deposits are
AL (12–16). A combination of FLC assay and serum acellular and lightly eosinophilic and have the fol-
and urine immunofixation will be abnormal in 99% of lowing histochemical appearance: salmon orange-red
AL cases. Only a minority of patients (10 to 18%) with Congo red stain when viewed under standard bright
have coexistent multiple myeloma (7,8). The more field light (Figure 7); green birefringence when viewed
rare form of AH amyloid caused by deposition of a under polarized light (Figure 3); weak PAS reaction
monoclonal Ig heavy chain alone is more difficult to (Figure 2); negative silver staining; lavender/blue-gray
detect by serum and urine immunofixation. with trichrome; and magenta with crystal violet stain.
Treatment of AL is directed at eliminating the In addition, amyloid deposits fluoresce with thioflavin
neoplastic B cell clone. The introduction of high-dose T and S stains. Deposits may form subepithelial spic-
melphalan followed by autologous stem cell transplan- ules perpendicular to the outer surface of the capillary
tation (HDM/SCT) in the mid-1990s has been associ- loop, forming hair-like projections best appreciated
ated with complete hematologic response rates of 25 to with PAS or silver stain (Figure 8). An interesting
67% in AL (17). There has been a steady increase in feature is the lack of significant cellular reaction to the
overall survival of patients with AL in the past few glomerular amyloid infiltration. The glomeruli appear
decades, from 21% (1977 through 1986) to 33% (1997 normocellular or even hypocellular, without leukocyte
through 2006), but whether this reflects changing infiltration. Tubulointerstitial and vessel wall deposits
therapies remains unclear (18). Unfortunately, HDM/ are variably present and rarely occur in the absence of
SCT has significant treatment-related morbidity and glomerular deposits. An exception is the occasional
mortality and is not suitable for all patients. Oral patient who presents with renal insufficiency and min-
melphalan plus dexamethasone may be an option for imal or no proteinuria, in whom exclusive or predom-
patients who are poor candidates for stem cell trans-
plantation (19). Other treatment options include dexa-
methasone, thalidomide, lenalidomide, and bort-
ezomib-based regimens (20,21).
In the pre-HDM/SCT era, approximately 40% of
patients with AL progressed to ESRD, and the survival
of those with renal involvement was poor (median 27
months) (22). Interestingly, patients who presented
with renal involvement had longer survival than those
without renal disease, reflecting the greater prevalence
of cardiac disease in the latter group. After the intro-
duction of HDM/SCT for AL, renal response (defined
as ⱖ50% reduction in proteinuria, with ⬍25% decline
in renal function) has been reported in 36% (23) and
Figure 7. A glomerulus from the index case stained for
60% (24) of patients. Renal response was linked to
Congo red shows salmon-orange staining in the distribution
hematologic response (23) and was associated with of the amyloid deposits viewed by light microscopy without
better patient survival in one study (24). polarization. Magnification, ⫻600 (Congo red).
inant involvement of the vessels or tubulointerstitial uniform, the deposits of AL amyloid are usually more
compartment may occur. Some of these cases have chunky, localized, and irregular.
disproportionately severe involvement of the medul- Electron Microscopy. Amyloid deposits are com-
lary interstitium. When vessels are affected, there is a posed of randomly oriented, nonbranching fibrils of
tendency for the amyloid to replace medial myocytes, indeterminate length, which usually measure 8 to 12
causing the media to appear hypocellular (Figure 9). nm in average thickness (Figures 5 and 6). Fibrils
Immunofluorescence. In AL amyloid, immunohis- typically deposit first in the mesangium, followed by
tochemical stains show monotypic light chain (␭ light GBM deposits. In early cases with small focal depos-
chain in 75% of cases). Rarely, deposits stain for a its, demonstration of the fibrillar deposits may be
single Ig heavy chain (␥, ␣, or ␮; AH), or a single light difficult without careful search. Fibrils often infiltrate
chain and heavy chain. By immunofluorescence, am- the entire GBM thickness and can aggregate in parallel
yloid deposits have a “smudged” appearance, which is to form perpendicular spicular projections toward the
distinct from the more granular texture of immune urinary space, corresponding to the hair-like projec-
complex deposits. Unlike Randall-type LCDD, in tions seen by light microscopy. Podocyte foot process
which the deposits tend to be linear, diffuse, and effacement is variable and tends to be most severe
overlying glomerular capillary walls infiltrated by am-
yloid. At the ultrastructural level, amyloid fibrils look
similar regardless of the renal compartment involved
and the precursor protein.
Special Studies. Positive Congo red staining is
diagnostic of amyloidosis and excludes other dis-
eases that give rise to acellular glomerular deposits,
such as diabetic glomerulosclerosis, LCDD, fibril-
lary glomerulonephritis, immunotactoid glomeru-
lopathy, fibronectin glomerulopathy, and collageno-
fibrotic glomerulopathy. For best results, Congo red
stain should be performed on thick tissue sections (at
least 6 ␮m). In most cases of AL, the Congo red stain
is unequivocal. Interpretation may be difficult in cases
Figure 8. The amyloid fibrils infiltrate some GBMs, form- in which only small deposits are present. In such cases,
ing spicular projections that mimic spikes (arrows). Magni- electron microscopy may be diagnostic. The major
fication, ⫻600 (Jones methenamine silver).
cause of a false-positive Congo red stain is confusion
with interstitial collagen, which gives a yellow bire-
fringence under polarized light. Thus, interpretation of
Congo red stain is best performed by an experienced
observer.
Diagnosis of AL and AA amyloid can usually be
made by immunofluorescence staining for ␬ and ␭
light chain and immunohistochemical staining for se-
rum amyloid A. Of note, a minority of AL cases do not
stain with commercial antibodies for Ig or light chains
(up to 35% in one series) (25). This occurs when the
truncated monoclonal light chains contain only the
variable region, which cannot be detected with com-
mercial antisera raised against the constant domain of
Figure 9. Arterial walls are replaced by amyloid deposits,
the light-chain molecule (1). In addition, up to 25% of
which appear blue-gray with trichrome stain. Magnification, patients with hereditary forms of amyloidosis have an
⫻200 (trichrome). unrelated monoclonal gammopathy (26). This may
lead to nonspecific trapping of the circulating mono- Most cases of AL (with or without kidney
clonal light chain in the amyloid deposits. Similarly, involvement) are derived from ␭ light chain. A
because of the “stickiness” of the amyloid deposits, recent study suggested that AL ␭ has a higher
AA amyloidosis may exhibit nonspecific immunoflu- incidence of nephrotic syndrome compared
orescence staining for circulating plasma proteins, with AL ␬, whereas AL ␬ shows more cardiac and
including immunoglobulins, light chains, and comple- liver involvement (11). Although overall survival is
ment components, making interpretation difficult. similar in AL ␬ and ␭, renal involvement is more
Thus, careful clinical correlation, staining for other common with AL ␭ and has worse outcomes (22).
amyloid proteins (e.g., transthyretin, fibrinogen Aa, Cardiac involvement is the major determinant of sur-
apolipoprotein AI and AII, lysozyme) (1), mass spec- vival in AL (31), but renal involvement is an indepen-
trometry, and genetic testing all are helpful in cases in dent predictor of mortality (22).
which an unequivocal diagnosis of AL or AA is not
possible. Etiology and Pathogenesis
Although renal biopsy expectedly has the highest AL is caused by release of an amyloidogenic
yield for diagnosing renal AL amyloidosis, there are monoclonal light chain or light chain fragment from a
less invasive means of tissue diagnosis. Subcutaneous neoplastic plasma cell clone in the bone marrow or
fat biopsy (via either fine-needle aspiration or core less commonly a neoplastic B cell clone in the lym-
biopsy) is a highly sensitive and specific technique for phoid tissue. Amino acid substitutions in AL light
diagnosing systemic amyloidosis (27,28). In addition, chains are thought to promote abnormal protein fold-
fat biopsies are a safe and easy method of obtaining ing favoring fibrillogenesis, and clones derived from
tissue for amyloid typing and novel investigations, the 6a (␭VI) germline gene are more likely to cause
such as proteomic studies (29). Renal involvement by renal involvement (32).
AA amyloid occurs in three settings: Chronic
AL amyloidosis can be inferred if amyloid is detected
infection, autoimmune inflammatory conditions, and
by biopsy of a nonrenal tissue, there is ⱖ0.5 g of
familial Mediterranean fever. Infectious causes in-
albumin in a 24-hour urine collection, and there is no
clude chronic bronchiectasis, osteomyelitis, decubitus
other explanation for the albuminuria (e.g., diabetes,
ulcers, tuberculosis, and intravenous drug use when
hypertension) (30).
the user resorts to skin popping. Autoimmune condi-
tions associated with AA amyloid include rheumatoid
Clinical-Pathologic Correlation arthritis, juvenile rheumatoid arthritis, inflammatory
Most patients who have AL and undergo renal bowel disease, and ankylosing spondylitis. Familial
biopsy for indications of heavy proteinuria or ne- Mediterranean fever is an autosomal recessive cause
phrotic syndrome exhibit significant glomerular amy- of AA amyloid with highest prevalence in Sephardic
loid deposits, with or without tubulointerstitial and Jews, Turks, Armenians, and Arabs and manifesting
vessel wall deposits. Interestingly, the amount of recurrent episodes of fever and serositis. Regardless of
glomerular amyloid deposition does not correlate the cause, the precursor protein in AA amyloid is the
well with the severity of proteinuria; occasional amino terminal region of serum amyloid A (SAA)
cases show minimal amyloid deposits despite ne- protein, an acute-phase reactant that is produced by the
phrotic-range proteinuria. Conversely, the level of liver and circulates in association with HDL.
renal insufficiency tends to correlate with the overall The factors that determine the potential for amy-
degree of amyloid infiltration, particularly when it loidogenesis in AL and AA include macrophage-de-
leads to glomerular obliteration, vascular narrowing, pendent processing to generate amyloid precursors,
and tubulointerstitial replacement. Cases with predom- the ␤-pleated sheet structure of the precursor proteins,
inant tubulointerstitial involvement are more likely to capacity for amyloidogenic protein folding, stabiliza-
present with renal insufficiency than proteinuria and tion by amyloid P protein, and interaction with spe-
may develop specific tubular defects, such as renal cific sulfated glycosaminoglycans and proteoglycans.
tubular acidosis and nephrogenic diabetes insipidus. The factors governing tissue and organ tropisms are
Cases of AL amyloid tend to have less interstitial unknown. The pathogenic light chains have been
inflammation than cases of AA amyloid. shown in vitro to have proapoptotic effects on mesan-
gial cells, inhibit mesangial cell synthesis of TGF-␤, nostic in patients with primary systemic amyloidosis undergoing
peripheral blood stem cell transplantation. Blood 107: 3378 –3383,
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Section 20: CASE PRESENTATION nuclear antibody, anti-DNA antibody, hepatitis B surface
antigen, hepatitis C antibody, HIV serology, and serum
A 60-year-old Caucasian man with a history of morbid complements C3 and C4. Serum protein electrophoresis
obesity, hypertension, hyperlipidemia, and sleep apnea with immunofixation electrophoresis shows hypogam-
presents with nephrotic syndrome and renal insufficiency. maglobulinemia with no evidence of a monoclonal spike,
On physical examination, he is normotensive (on antihyper- and urinary protein electrophoresis is negative for a mono-
tensive medications) with 2⫹ pitting lower extremity clonal protein. Serum free light chain testing shows elevated
edema. Urinalysis shows 4⫹ protein, 1⫹ heme, and bland free ␬ light chains and a serum ␬/␭ ratio of 75.0 (normal
urinary sediment. Laboratory workup shows serum creati- range 0.26 to 1.65). Bone marrow biopsy shows a normo-
nine level of 2.36 mg/dl, 24-hour urine protein of 3.5 g, cellular marrow without evidence of plasmacytosis, and no
serum albumin of 2.1 g/dl, and hemoglobin of 10.7 g/dl. All clonal B cell population is detected by polymerase chain
serologic studies are negative or normal, including anti- reaction for Ig heavy chain gene rearrangement.
Figure 1.
Figure 2.
Figure 3.
Figure 4. IgG

A. Nodular diabetic glomerulosclerosis
B. Heavy-chain deposition disease (HCDD)
C. Amyloidosis
D. Dense-deposit disease
Figure 5. E. Fibrillary glomerulonephritis
393
Answer heavy chains detected with antisera to IgG, IgM, and

The renal biopsy findings are most consistent IgA, respectively, and for the ␬ and ␭ light chains.
with heavy chain deposition disease (HCDD) (answer Strong linear staining for a single light chain without
B). Of 16 glomeruli sampled, two were globally scle- a heavy-chain component defines light-chain deposi-
rosed. All remaining glomeruli have accentuated lobu- tion disease (LCDD), which is the most common
larity as a result of marked mesangial expansion by variety. Staining for a single light chain and a single
nodular sclerosis and hypercellularity (Figures 1 heavy chain defines light- and heavy-chain deposition
through 3). Highly eosinophilic material typical of disease (LHCDD). Staining for a single heavy chain,
deposits globally expands the mesangium (Figure 1, with no staining for either light chain, is diagnostic of
hematoxylin and eosin, ⫻400) and stains red (fuchsi- HCDD, as was seen in the index case. Positivity for a
nophilic) with trichrome stain (Figure 2, ⫻400). Silver monoclonal ␬ chain accounts for the vast majority of
stain highlights the prominent mesangial sclerosis (sil- cases of LCDD (1). Approximately 10 to 20% of
ver positive) admixed with paler deposits (Figure 3, patients with MIDD have LHCDD, and fewer than 5%
Jones methenamine silver, ⫻400). The nodular mes- have HCDD (1–3).
angial expansion is accompanied by foci of circum- Regardless of their composition, these portions
ferential mesangial interposition and some infiltrating of monoclonal Igs preferentially deposit in the base-
mononuclear leukocytes (Figures 2 and 3). Immuno- ment membranes of the kidney, typically resulting in a
fluorescence staining reveals intense (3⫹) staining for nodular sclerosing glomerulopathy with thickening of
IgG in the distribution of the mesangial nodules ac- TBMs and vascular basement membranes. Although
companied by diffuse linear positivity involving Bow- amyloidosis may also deposit as a monoclonal light
man’s capsules, glomerular basement membrane chain, a monoclonal heavy chain, or a combined
(GBM), tubular basement membrane (TBM), and ar- monoclonal light and heavy chain, MIDD is distin-
teriolar basement membranes (Figure 4, ⫻200). guished by the nonfibrillar ultrastructural appearance
Weaker semilinear staining for C3 is present in the of the deposits and the diffuse distribution of the linear
same distribution as IgG (not shown). No staining was staining by immunofluorescence (4). First described
observed for the other heavy chains (IgA, IgM) or by Randall et al. in 1976 (4), MIDD is often referred
either light chain (␬ or ␭), indicating ␥ heavy-chain to as “Randall-type” MIDD to differentiate it from
restriction. Staining using fluoresceinated antisera to other forms of dysproteinemia-related renal disease.
the ␥ heavy-chain constant domains CH1, CH2, and
CH3 revealed negativity for CH1 and positivity for Clinical presentation
CH2 and CH3, consistent with a truncated heavy chain MIDD occurs most frequently in older men, and
with CH1 deletion (data not shown). Ultrastructural the average age at presentation is 55 to 60 years.
examination shows characteristic band-like, finely Patients with HCDD tend to be slightly younger,
granular electron-dense deposits along the lamina rara and rare cases of MIDD have been reported in the
interna of the GBM (Figure 5, ⫻8000). third decade of life (5,6). Patients with MIDD usu-
ally present with proteinuria and renal insufficiency,
Heavy-Chain Deposition Disease accompanied by more variable hypertension and
Monoclonal Ig deposition disease (MIDD) is a microhematuria (3,7,8). Nephrotic-range protein-
systemic disorder characterized by tissue deposition of uria is common, but full nephrotic syndrome occurs
monoclonal light and/or heavy chains that appear lin- in only one quarter of patients, particularly those
ear by immunofluorescence and produce punctate with well-developed nodular glomerulosclerosis (3).
granular (nonfibrillar) electron-dense deposits. Renal Subnephrotic proteinuria (⬍1 g/d) is found at pre-
involvement often predominates, although multiple sentation in approximately 25% of patients, in
organ systems (e.g., heart, liver, and peripheral nerves) which case renal biopsy may reveal predominantly
may be involved. tubulointerstitial (rather than glomerular) involve-
There are three major types of MIDD, depending ment. Approximately one third of cases of LCDD
on the composition of the monoclonal paraprotein. occur in association with light chain (or myeloma)
Proper characterization requires careful evaluation of cast nephropathy and present with acute renal fail-
immunofluorescence staining for the ␥, ␮, and ␣ ure (3). Hypocomplementemia (reduced C3 and/or
C4) may occur in cases of HCDD or LHCDD diomyopathy, myocardial infarction, conduction de-
because of the complement-fixing ability of the fects, and arrhythmias.
heavy chains (particularly ␥1 or ␥3), which resides
in the CH2 domain (3,5). Pathology
Because the urine dipstick detects albumin but is Light microscopy. Nodular sclerosing glomeru-
insensitive to light and heavy chains, there is often a lopathy is the most characteristic histologic finding in
discrepancy between the quantification of proteinuria MIDD (3,15). The mesangium is diffusely and glo-
by dipstick and by a 24-hour urine collection. Immu- bally expanded by increased matrix admixed with
nofixation electrophoresis is superior to routine serum deposits, associated with milder mesangial hypercel-
and urine protein electrophoresis for the identification lularity. The mesangial expansion and presence of
of monoclonal light or heavy chains. This is particu- variable membranoproliferative features (focal mesan-
larly important in MIDD, in which the concentration gial interposition and duplication of GBMs) narrow
of monoclonal Ig in urine or serum may be low as a the capillary lumina. The deposits typically stain
result of strong tissue avidity. Overall, a monoclonal brightly eosinophilic, strongly periodic acid–Schiff
serum or urine protein can be identified in approxi- (PAS) positive, trichrome red, and weakly argyro-
mately 80% of patients with LCDD and 60% of philic. Some of the nodules are surrounded by glomer-
patients with HCDD (3). In some cases of HCDD, the ular capillary microaneurysms, resembling those seen
truncated heavy chain can be detected only on serum in diabetic nephropathy. However, the nodules of
fractionation and Western blotting (2,9). Even in cases MIDD tend to be more symmetrically distributed and
have different staining characteristics than diabetic
in which pathogenic light chains were undetectable in
nodules, which typically stain exclusively for extra-
serum or urine, in vitro biosynthetic labeling experi-
cellular matrix (ECM) as trichrome blue and strongly
ments have confirmed their secretion by bone marrow
argyrophilic. In contrast to amyloidosis, the deposits
plasma cells (1,10,11). The recent introduction of
of MIDD are Congo red negative.
serum free ␬ and ␭ light-chain quantification is prov-
There is ribbon-like thickening of the GBMs,
ing to be an extremely sensitive assay (12). Because
TBMs, and vascular basement membranes by PAS-
the vast majority of paraproteinemias are due to light-
positive material. In the arteries, the deposits have the
chain overproduction, this test has the potential to
distinctive feature of ringing the individual myocytes,
capture virtually all cases of LCDD or LHCDD.
producing a thick pericellular cuff (Figure 6). A rare
A bone marrow biopsy performed for documen- pattern of LCDD has been described with massive
tation of hematologic malignancy shows variable find- thickening of glomerular capillary walls, mimicking
ings. The criteria for multiple myeloma are met in 40 membranoproliferative glomerulonephritis, without
to 50% of cases of LCDD and 25% of cases of HCDD evidence of nodular glomerulosclerosis (16). Cres-
(1,3,13,14), whereas others have a mild plasma cell cents are uncommon in LCDD but may occur in up to
dyscrasia, often requiring immunohistochemical con- one third of cases of HCDD. Rarely, the deposits form
firmation. When MIDD is associated with cast ne- interstitial PAS-positive aggregates that are confluent
phropathy, multiple myeloma is diagnosed in ⬎90% with the thickened TBMs (Figure 7). Giant cell reac-
of cases. Waldenstrom macroglobulinemia and tion may form to some of the larger interstitial depos-
chronic lymphocytic leukemia are more rare causes of its. In more advanced cases, there is severe tubular
MIDD. atrophy and interstitial fibrosis.
MIDD is a systemic disease with clinically evi- Crystalline or fractured casts dominate the histo-
dent extrarenal involvement most commonly affecting logic picture in cases of MIDD with coexistent my-
the liver and heart. Other possible sites of involvement eloma cast nephropathy. Most such cases are due to
include the lymph nodes, salivary glands, spleen, gas- LCDD with ␬ light-chain restriction (3). Usually, the
trointestinal tract, lung, skin, thyroid gland, adrenal renal biopsies show no obvious nodular glomerulo-
glands, and peripheral nerves (4). Hepatic involvement sclerosis by light microscopy, although linear deposits
may present as cholestatic jaundice, elevated liver of MIDD are evident by immunofluorescence. In ad-
function tests, portal hypertension, and rarely liver dition, these cases usually lack identifiable electron-
failure. Cardiac manifestations include restrictive car- dense deposits at the ultrastructural level.
Figure 6. An arteriole contains strongly eosinophilic depos- Figure 8. A case of ␥-HCDD illustrates positivity for IgG
its that form rings around the individual myocytes in a case that rings the individual myocytes of a small artery, pro-
of LCDD. Magnification, ⫻600 (hematoxylin and eosin). ducing a net-like pattern. Magnification, ⫻400 (immuno-
fluorescence, IgG).
Although rarely examined, MIDD deposits in

series, the staining involved TBMs most consistently
liver are often confined to sinusoids and basement
(100%), with less complete glomerular (87%) and
membranes of bile ducts. The cardiac deposits are
vessel wall (65%) involvement (3). The arterial
identified in arterial basement membranes and perivas-
smooth muscle basement staining tends to surround
cular areas and may also accumulate between individ-
individual myocytes producing a net-like pattern (Fig-
ual cardiac myocytes (13).
ure 8). The mesangial nodules, Bowman’s capsules,
Immunofluorescence. The immunofluorescence and, in some cases, the interstitium also stain.
findings in MIDD are distinctive for the presence of In LCDD, the monotypic light chain is predom-
diffuse linear staining of the renal basement mem- inantly ␬ (␬:␭ ratio 9:1). The monotypic Ig in LHCDD
branes throughout all compartments of the kidney. The is most commonly IgG␬ or IgG␭. In HCDD, the
deposits stain intensely (usually ⱖ2⫹) for the patho- monotypic heavy chain is usually ␥ (with all sub-
genic light and/or heavy chain, making careful immu- classes ␥1 to ␥4 described), with rare reports of ␣ or ␮
nofluorescence evaluation critical for diagnosis. In one chain (3). LCDD with minimal glomerular involve-
ment may be misdiagnosed as minimal change disease
when routine staining for light chains is not per-
formed. Rarely, the truncated light or heavy chains fail
to react well with commercially available antisera
directed to the constant domains of the light and heavy
chains because they are composed predominantly of
the variable regions. In such cases, the deposits are
seen well by electron microscopy despite the weak or
inconclusive immunofluorescence findings.
The immunofluorescence microscopy is other-
wise negative except for complement deposition in
affected renal basement membranes in cases of HCDD
composed of ␥1 and ␥3 heavy chains. Differentiating
␥ HCDD from diabetic nephropathy may pose a diag-
nostic challenge because both have glomerular nod-
Figure 7. An example of LCDD shows highly eosinophilic
deposits that thicken medullary TBMs as well as interstitial
ules and linear IgG staining along GBMs and TBMs.
capillary walls, with extension into the adjacent interstitial Typically, the staining for IgG is stronger in HCDD
collagen. Magnification, ⫻600 (hematoxylin and eosin). than in diabetic nephropathy, and there is usually some
Figure 9. Along the outer aspect of a thickened TBM, the

deposits of LCDD form linear bands of punctate, granular
electron-dense material. Magnification, ⫻8000 (electron
micrograph).
positivity (although weaker) for both light chains in

diabetic nephropathy. Staining for the IgG subtypes (1 Figure 10. A small artery from a patient with LCDD
through 4) is useful in ␥ HCDD to prove restriction to displays punctate electron-dense deposits around the medial
a single subtype, as expected for a monoclonal protein. myocytes and within the intima. Magnification, ⫻4000
(electron micrograph).
Staining with antisera directed against the constant
domains of heavy chain (CH1, CH2, and CH3) consis-
tently demonstrates deletion of CH1 domain of ␥ tologic or ultrastructural pathology or clinical renal
heavy chain in HCDD. manifestations (3,8,17).
Electron microscopy. The ultrastructure of MIDD Prognosis
deposits is one of finely granular, punctate, highly Prognosis in pure MIDD is better than in patients
electron-dense deposits that lack fibrillar substructure. with MIDD and myeloma cast nephropathy. In one study
Within the glomerulus, the deposits tend to form a of 34 patients with MIDD, renal and patient survivals
band along the inner aspect of GBM (within the were 22 and 54 months, respectively, in those with pure
lamina rara interna and extending to the inner lamina MIDD compared with 4 and 22 months, respectively, in
densa). They often have a punctate, peppery texture. those with MIDD and myeloma cast nephropathy (3).
Similar punctate deposits are seen in the expanded Thus, the presence of myeloma cast nephropathy domi-
mesangial matrix, in Bowman’s capsule, and along the nates the clinical course in the combined group. Chemo-
outer aspect of the TBMs, especially along the inter- therapy stabilized or improved renal function in 67% of
stitial interface (Figure 9). In the vessel walls, they patients who had pure MIDD and presented with a
form a ring of punctate granular material in the per- creatinine level of ⬍5.0 mg/dl. On multivariate analysis,
imyocyte matrix and in the intimal basement mem- the only predictor of outcome was initial serum creati-
branes (Figure 10). Rarely, interstitial capillary base- nine, emphasizing the importance of early detection (3).
ment membranes are also involved. In a large series of 63 patients with LCDD, patient
Occasionally, LCDD is diagnosed on immuno- survival was 66% at 1 year and 31% at 8 years despite
fluorescence only, and no corresponding electron- chemotherapy (7). By multivariate analysis, the best
dense deposits are identified. Such cases may repre- independent correlates of outcome were age and serum
sent early LCDD without the ability to form definable creatinine at presentation (7). The recent use of high-
deposits at the ultrastructural level. In some cases, this dosage melphalan with autologous stem cell transplanta-
immunofluorescence picture represents nonspecific tion has led to reduction in the levels of monoclonal
binding of a monoclonal protein to renal basement protein and improved renal function in some patients
membranes in a patient with monoclonal gammopathy (16,18). Rarely, this combined therapy has led to reversal
of undetermined significance, without producing his- of dialysis dependence (19). Because MIDD can recur in
the renal transplant, patients with ESRD should not undergo promote myofibroblastic transformation of mesangial
transplantation unless their synthesis of monoclonal protein cells, with increased mesangial synthesis of growth
has been controlled through effective therapy. factors, PDGF-␤, and TGF-␤ (28,30). Whereas the
initial activation of PDGF-␤ stimulates mesangial cell
Pathogenesis proliferation, the subsequent activation of TGF-␤ in-
MIDD is caused by tissue deposition of patho- hibits proliferation while enhancing ECM production
genic Ig light and/or heavy chains, which in turn (30). Exposure to pathogenic light chains induces
promotes accumulation of ECM to produce the char- mesangial cell synthesis of tenascin-C, a major ECM
acteristic pathologic lesions (20). Sequence analysis of component of the nodules (28,30). Other ECM pro-
the pathogenic Ig fragments has identified altered teins synthesized include laminin, collagen IV, and
structural properties that promote tissue deposition and fibronectin. It is also likely that the normal degrada-
fibrotic responses. tion of tenascin-C is compromised by ineffective mes-
The vast majority of LCDD are ␬ restricted, in angial release of matrix metalloproteinase 7 (30).
contrast to the predominance of ␭ restriction in AL Light chains deposited in the glomerular capillary wall
amyloidosis. In the course of Ig production, a B cell are thought to mediate proteinuria by interference with
clone chooses from among four possible variable do- endothelial and podocyte functions required for main-
mains of the ␬ light chain, which are denoted V␬I tenance of filtration barrier.
through IV. Patients with LCDD have an overrepre- Sequence analysis of pathogenic heavy chains in
sentation of the V␬IV variability subgroup (21), with HCDD has revealed the consistent deletion of the CH1
fewer examples of the V␬I subgroup (22). The vari- constant domain in all cases of ␥-HCDD, as well as a
able domains contain highly variable complementari- case of ␣-HCDD (5,31). Rarely, the CH2 and hinge
ty-determining regions (CDR1 through 3) that further regions are also deleted (2). The CH1 domain normally
broaden the repertoire of antigenic determinants rec- binds to a chaperone protein, heavy chain– binding
ognized. Importantly, the rare V␬IV subgroup nor- protein, for assembly of the complete Ig molecule
mally has a longer CDR1 loop containing more hy- within the endoplasmic reticulum of the plasma cell
drophobic residues than other V␬ subgroups. In (32). Heavy chains lacking a CH1 domain are prema-
LCDD, analysis of pathogenic V␬IV light chains at turely secreted into the circulation as free heavy chains
the cDNA and protein levels has identified specific in the case of HCDD or as heavy chain complexed to
amino acid substitutions (e.g., leucine, isoleucine, or light chain in the case of LHCDD. Similar to LCDD,
tyrosine at positions 27 and/or 31) that alter the light the pathogenic heavy chains often have unique amino
chain’s physiochemical properties (8). The resultant acid substitutions in the variable domain that affect
conformational changes and presence of hydrophobic charge and hydrophobicity, favoring tissue deposition
residues at sites exposed to solvent promote reduced (2,33).
protein solubility and enhanced tissue precipitation
(23) as well as ECM production (24). In addition,
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Section 21: CASE PRESENTATION 1⫹ lower extremity edema. Urinalysis showed 3⫹ protein and
10 to 20 red blood cells per high-power field. All serologies are
A 55-year-old African American woman presents with in- negative or normal, including anti-nuclear antibody, anti-DNA
creasing serum creatinine, hematuria, and proteinuria. Past antibody, anti-neutrophil cytoplasmic antibody, rheumatoid
medical history is significant for a 20-year history of type 2 factor, hepatitis B surface antigen, hepatitis C antibody, and C3
diabetes (without retinopathy) and longstanding hypertension. and C4. There is no evidence of a monoclonal spike on serum
Six months prior to biopsy, the patient had a serum creatinine protein electrophoresis or urine protein electrophoresis with
of 1.6 mg/dl. At the time of presentation, the patient has a immunofixation. The patient’s medications include meto-
creatinine of 2.6 mg/dl and a 24-hour urine protein of 2.4 g. prolol, furosemide, glipizide, and esomeprazole. A renal bi-
Physical examination is notable for a BP 155/79 mmHg and opsy is performed.
Figure 1. Figure 2.
Figure 3. Figure 4. IgG

A. Fibrillary glomerulonephritis (FGN)
C. Immunotactoid glomerulonephritis (ITG)
D. Nodular diabetic glomerulosclerosis
Figure 5. E. Amyloidosis
401
Answer association of ITG with underlying dysproteinemia and

A representative glomerulus exhibits global mes- lymphoproliferative disorders.
angial expansion by increased cells and matrix with
irregular thickening of the glomerular basement mem- Clinical Characteristics
branes (GBMs; Figure 1; hematoxylin and eosin, The most common presenting symptoms of FGN
⫻400). In Figure 2 (⫻400), a glomerulus stained with are nephrotic range proteinuria, microscopic hematu-
Masson’s trichrome shows mesangial expansion by ria, and renal insufficiency. On the basis of a compi-
fuchsinophilic (red) material admixed with blue-stain- lation of the three largest published series comprising
ing mesangial matrix, producing a purple-gray color. 115 patients (1–3), the mean age of presentation in
This color reaction is often seen when immune depos- FGN is 53.4 years, 62.6% of affected patients are
its are closely intermingled with extracellular matrix. female, and approximately 90% are Caucasian. At the
With Jones methenamine silver, the normally black- time of presentation, the mean serum creatinine is 3.3
staining mesangial matrix is infiltrated by nonargyro- mg/dl and the mean 24-h urine protein is 6.1 g/d.
philic (pink) material (Figure 3, ⫻400). There is also Approximately half of patients have full nephrotic
irregular segmental thickening and duplication of syndrome, and 62% have microhematuria. Serologic
some glomerular capillary walls, associated with par- testing for markers of autoimmune disease is generally
tial mesangial interposition (arrows). Congo red stain negative, and serum complement levels are usually
for amyloid is negative (not shown). Immunofluores- normal. There is a low incidence of underlying non-
cence staining for IgG shows 3⫹ mesangial and seg- hematologic malignancies and lymphoproliferative
mental capillary wall positivity with a smudged (as disorders (1–3). Associations with HCV infection and
opposed to granular) texture (Figure 4, ⫻600). Similar rheumatoid arthritis have also been reported in a mi-
smudged glomerular staining is seen for C3 (2⫹), C1q nority of cases (3).
(trace), and ␬ (3⫹) and ␭ (2⫹) light chains (not
shown). There is no glomerular staining for IgM or Pathology
IgA. No extraglomerular deposits are identified. Elec- Light Microscopy. FGN exhibits a spectrum of glo-
tron microscopy shows global infiltration of the mes- merular involvement (1–3). Most common is a mem-
angium by randomly oriented fibrils measuring 18 nm branoproliferative pattern of glomerulonephritis (MPGN)
in mean diameter (Figure 5, ⫻12,000). In the setting of with mesangial expansion, partial or circumferential
negative serologies and Congo red negativity, the glo- mesangial interposition, and duplication of GBMs. This
merular deposits of polyclonal IgG with 18-nm fibrillar is the form seen in the index case presented. As the name
substructure are diagnostic of fibrillary glomerulonephri- implies, the mesangial proliferative pattern (MES) is
tis (FGN) (answer A). characterized by purely mesangial proliferation and ma-
trix expansion, with patent capillary lumina and no pe-
Fibrillary Glomerulonephritis ripheral capillary wall involvement. The diffuse prolifera-
FGN is an uncommon disease seen in approxi- tive pattern (DPGN) exhibits mesangial and endocapillary
mately 0.5 to 1.0% of native kidney biopsies. It is one of proliferation and has the highest incidence of crescent
the renal disorders with an organized substructure by formation. Uncommonly, FGN can manifest a membra-
electron microscopy. FGN is defined by glomerular im- nous pattern (MGN) with minimal mesangial involve-
mune deposits composed of randomly oriented non- ment and prominent subepithelial deposits separated by
branching fibrils ranging from 16 to 24 nm in diameter. basement membrane spikes. A diffuse sclerosing pattern
The diagnosis of FGN requires identification of the (DS) has also been described and has been defined by the
characteristic fibrils by electron microscopy as well as presence of at least 70% global glomerulosclerosis (3).
the absence of reactivity with histochemical stains for Regardless of the histologic pattern, the deposits in FGN
amyloid, such as Congo red and thioflavin-T. The ma- are typically weakly eosinophilic, weakly periodic acid–
jority of cases of FGN are idiopathic; however, associa- Schiff positive, gray-purple with trichrome stain, and
tions with hepatitis C virus (HCV) infection and rarely nonargyrophilic (silver negative). Because the color re-
dysproteinemia have been reported. FGN is differenti- action seen with the routine stains resembles that of
ated from ITG by its ultrastructural appearance; this amyloidosis, it is especially important to rule out amy-
distinction is important because of the much greater loidosis by Congo red stain. Correlating with the high
incidence of renal insufficiency at the time of diagnosis, a mean of 44, 20, and 7 months, respectively. These
most cases of FGN exhibit at least mild tubular atrophy, outcomes were significantly worse than for the MES
interstitial fibrosis, and interstitial inflammation. (80 months) and MGN (87 months) groups. In this
Immunofluorescence. With rare exceptions, the study, 45% of patients reached ESRD at a mean
fibrillar immune deposits of FGN stain dominantly follow-up time of 23 months, including 18% of the
with antisera to IgG. The texture of the staining is patients with a presenting creatinine level of ⬍1.5
often “smudged,” resembling the staining quality in mg/dl and 72% of the patients with a presenting
amyloidosis. This smudgy appearance differs from the creatinine level of ⬎2.0 mg/dl. In multivariate analy-
typical granular or linear staining observed in other sis, only serum creatinine at biopsy and the degree of
immune complex–mediated processes. Early studies interstitial fibrosis significantly correlated with out-
on the IgG subtypes found that the deposits of FGN come. Similarly, Iskander et al. (1) and Fogo et al. (2)
were mainly or exclusively composed of IgG4 (1). A reported a 52 and 44% incidence of ESRD over a
more recent series noted oligotypic deposits staining mean follow-up of 24 months.
for both IgG1 and IgG4 in the majority of cases, with Fibrillary Glomerulonephritis and HCV Infection.
occasional cases staining for only IgG1 or IgG4 (3). HCV infection is present in a subset of patients with
These findings support the presence of subtype-re- FGN (5), including up to 17% of patients in the largest
stricted IgG deposits, which may predispose to fibril- available series (3). Cases of HCV-associated FGN
logenesis. The fibrillar deposits in FGN are usually exhibit no distinguishing pathologic features when
polyclonal, with staining for both ␬ and ␭ light chains; compared with other FGN, and serum complement
however, occasional cases show light-chain restriction levels are typically normal. Of note, there is a single
(typically ␬). Staining for complement component C3 case of FGN and concurrent HCV infection in which
is typically strong, whereas staining for C1q is less proteinuria and renal insufficiency improved after
frequent and weaker. Low-intensity positivity for IgM treatment of HCV with ␣-IFN, supporting a pathoge-
is found in approximately half of cases, whereas IgA is netic association (6).
rarely identified (1,3).
Differential Diagnosis. Because of its broad range of
Electron Microscopy. Electron microscopy is re- histologic appearances, FGN is easily confused with
quired to establish a definitive diagnosis of FGN. The other glomerulonephritides. Immunofluorescence helps
diagnostic ultrastructural feature is the presence of to narrow the differential diagnosis to entities associated
randomly oriented fibrils typically measuring between with IgG-dominant staining; however, definitive diagno-
16 and 24 nm in diameter. The distribution of the sis requires electron microscopy. At the ultrastructural
deposits mimics the findings by light microscopy, with level, FGN must be distinguished from other diseases
mesangial fibrils predominating in the MES pattern that have organized fibrillar deposits, such as amyloido-
and mesangial and capillary wall fibrils seen in the sis, ITG, and, rarely, cryoglobulinemic glomerulonephri-
MPGN, DPGN, and MGN patterns. In the MPGN and tis and lupus nephritis. The fibrillar deposits of FGN
DPGN patterns, the fibrils typically diffusely permeate typically measure 16 to 24 nm in diameter, which is
the GBM, extending from the subendothelial to sub- approximately twice the diameter of amyloid fibrils (8 to
epithelial region and obscuring the lamina densa. In 12 nm). Importantly, Congo red and thioflavin T staining
some cases, the fibrils are admixed with nonorganized are positive in amyloidosis and negative in FGN. In
granular electron-dense deposits. Extraglomerular de- addition, immunofluorescence shows light-chain restric-
posits are extremely unusual (4). tion and negative staining for IgG in AL amyloidosis,
Clinical-Pathologic Correlation. Rosenstock et al. whereas FGN deposits are composed of polyclonal IgG
(3) examined the relationship among histologic pat- and complement.
terns of FGN, presenting features, and clinical out- ITG is a rare glomerular disease that can be con-
comes. The MPGN, DPGN, and DS patterns are as- fused with FGN because of its similar clinical presenta-
sociated with a higher serum creatinine level and a tion and similar light microscopic and immunofluorescence
greater degree of proteinuria at the time of biopsy findings. Differentiation requires electron microscopy,
compared with the MES and MGN patterns. Similarly, which reveals larger 30- to 50-nm microtubular depos-
the MPGN, DPGN, and DS patterns reached ESRD at its with a hollow center in ITG. Unlike FGN, the
Figure 6. Comparison of the organized deposits in amyloidosis (A), FGN (B), and ITG (C). Magnification, ⫻80,000.
microtubular deposits of ITG often align to form contain IgG, ␬, ␭, C3, and amyloid P component (8).
parallel stacks in the subepithelial and/or subendothe- Amyloid P component is a normal serum glycoprotein
lial regions without infiltrating the GBM itself. Figure that can be found deposited in all types of amyloidosis.
6 shows the characteristic fibrils of amyloidosis (A), As in amyloidosis, it is likely that amyloid P plays a
FGN (B), and ITG (C), all photographed at ⫻80,000 role in fibrillogenesis and resistance to proteolysis.
magnification. In many cases, the IgG deposits of ITG The ability of cryoglobulins to produce orga-
are monoclonal, staining for a single light chain and a nized glomerular deposits of immunoglobulins raises
single IgG subtype. The distinction between FGN and the question whether the fibrillar deposits in FGN
ITG is clinically relevant because of the greater asso- represent a type of “slow” cryoglobulin. Rostango et
ciation of ITG with lymphoproliferative disorders, al. (9) studied a patient who had biopsy-proven FGN
monoclonal gammopathy, and hypocomplementemia. and whose serum formed a fibrillar precipitate after
Cryoglobulinemic glomerulonephritis occasionally prolonged cold storage at 4°C. Unlike cryoglobulin
exhibits deposits with an organized fibrillar substructure. precipitates, the fibrils did not dissolve on rewarming.
These deposits are more commonly microtubular and Using immunoelectron microscopy, amino acid se-
thus more likely to be confused with ITG than FGN. quencing, and immunoblotting, they demonstrated that
Therefore, cryoglobulin studies should be performed to the fibrils were composed of immunoglobulins, amy-
exclude the possibility of cryoglobulinemic glomerulo- loid P, and fibronectin. Fibronectin is found in plasma
nephritis in cases of FGN and ITG. In lupus nephritis, and extracellular matrix, shows a wide range of li-
organized fibrillar or microtubular structures may be seen gand-binding interactions, and is known to be associ-
focally in otherwise granular deposits. This finding prob- ated with immune complexes and cryoprecipitates.
ably reflects the presence of type 3 (mixed) cryoglobulins Study of additional cases is needed to determine the
in some patients with lupus nephritis. Electron micros- specificity of these findings for FGN.
copy is required to distinguish the MGN pattern of FGN The immunoelectron microscopic studies support
from membranous nephropathy (7). that IgG is an integral component of the fibrillary depos-
A variety of disorders of extracellular matrix also its. On the basis of the restricted IgG subtype staining, it
manifest organized fibrillar glomerular deposits, includ- has been proposed that the deposits may represent an
ing collagen type 3 glomerulopathy, fibronectin glomeru- oligoclonal immune response to an antigenic challenge
lopathy, nail-patella syndrome, and fibrillosis of scarring (e.g., to viral infection in the case of HCV) and that their
(as seen in diabetic nodules and nonspecific glomerulo- homogeneous composition favors fibrillogenesis.
sclerosis). These entities can be differentiated from FGN
on the basis of their negative staining for IgG and the References
collagenous appearance of the deposits. 1. Iskandar SS, Falk RJ, Jennette JC: Clinical and pathologic features of
fibrillary glomerulonephritis. Kidney Int 42: 1401–1407, 1992
Etiology and Pathogenesis 2. Fogo A, Qureshi N, Horn RG: Morphologic and clinical features of
The pathogenesis of FGN is poorly understood, fibrillary glomerulonephritis versus immunotactoid glomerulopathy.
Am J Kidney Dis 22: 367–377, 1993
in part because of the absence of an animal model. 3. Rosenstock JL, Markowitz GS, Valeri AM, Sacchi G, Appel GB,
Immunoelectron microscopy has shown that the fibrils D’Agati VD: Fibrillary and immunotactoid glomerulonephritis: Dis-
tinct entities with different clinical and pathologic features. Kidney Int 7. Muller-Hocker J, Weiss M, Sitter M, Samtleben W: Fibrillary glomer-
63: 1450 –1461, 2003 ulonephritis mimicking membranous nephropathy: A diagnostic pit-
4. Adeyi OA, Sethi S, Rennke HG: Fibrillary glomerulonephritis: A fall. Pathol Res Pract 205: 265–271, 2009
report of 2 cases with extensive glomerular and tubular deposits. Hum 8. Yang GC, Nieto R, Stachura I, Gallo GR: Ultrastructural immunohis-
Pathol 32: 660 – 663, 2001 tochemical localization of polyclonal IgG, C3, and amyloid P compo-
5. Markowitz GS, Cheng JT, Colvin RB, Trebbin WM, D’Agati VD: nent on the Congo-red negative amyloid-like fibrils of fibrillary
Hepatitis C viral infection is associated with fibrillary glomerulone- glomerulopathy. Am J Pathol 141: 409 – 419, 1992
phritis and immunotactoid glomerulopathy. J Am Soc Nephrol 9: 9. Rostango A, Vidal R, Asok K, Chuba J, Niederman G, Gold L,
2244 –2252, 1998 Frangione B, Ghiso J, Gallo G: Fibrillary glomerulonephritis related to
6. Coroneos E, Truong L, Olivero J: Fibrillary glomerulonephritis associated serum fibrillar immunoglobulin-fibronectin complexes. Am J Kidney
with hepatitis C viral infection. Am J Kidney Dis 29: 132–135, 1997 Dis 28: 676 – 684, 1996
Section 22: CASE PRESENTATION reveals 2⫹ peripheral edema and BP of 130/90 mmHg.
Urinalysis shows 4⫹ protein, more than five red blood cells
A 57-year-old man with a history of hypertension for 25 per high-power field, more than five white blood cells per
years, 40 pack-years of smoking, hepatitis C infection for 20 high-power field, but no cellular casts. Laboratory evalua-
years, and type 2 diabetes for 10 years presents with slowly tion reveals hemoglobin A1c of 7.4, serum albumin level of
progressive renal failure and worsening proteinuria. He was 2.9 g/dl, positive hepatitis C antibody, negative hepatitis B
treated briefly with interferon 5 years earlier but is currently surface antigen, negative anti-nuclear antibody, negative
on no antiviral medications. Serum creatinine level rose anti-neutrophil cytoplasmic antibody, negative cryoglobu-
from 2.5 mg/dl 10 years ago to 4.0 mg/dl at presentation. lins, normal C3 and C4, and no monoclonal spike on serum
Proteinuria rose from 6.0 g/day 3 months earlier to 10.0 protein electrophoresis or urinary protein electrophoresis.
g/day. Medications include valsartan, hydrochlorothiazide, Hepatitis C viral titer is low, and liver function tests are
doxazosin, insulin, and esomeprazole. Physical examination normal. Renal biopsy is performed.
Figure 1. Figure 2.
Figure 3. Figure 4.
Figure 5. Albumin. Figure 6.

407
What is the BEST diagnosis? accounting for ⬎40% of all new cases (1). Type 1
A. Hepatitis C–associated membranoproliferative glomer- diabetes, which is caused by autoimmune destruction
ulonephritis of the pancreatic islets, typically has its onset in
B. Smoking-related glomerulopathy childhood and manifests insulin deficiency. Type 2
C. Light-chain deposition disease diabetes is more common in older adults but is also
D. Nodular diabetic glomerulosclerosis (NDG) increasingly recognized in young adults and children
E. Hypertensive arterionephrosclerosis with metabolic syndrome (including insulin resistance,
obesity, hyperlipidemia, and hypertension). The risk
Answer for developing nephropathy in type 1 and type 2
A representative glomerulus appears enlarged diabetes is similar. It has been estimated that approx-
with global nodular mesangial sclerosis, mild mesan- imately 30 to 40% of patients with type 1 and type 2
gial hypercellularity, and uniform thickening of the diabetes will develop nephropathy. Renal disease be-
glomerular basement membranes (GBMs; Figure 1; gins with microalbuminuria (albumin excretion 30 to
periodic acid–Schiff [PAS], ⫻400). The adjacent pre- 300 mg/24 h). Approximately 15% of individuals with
glomerular arteriole (arrow) shows mural hyalinosis. microalbuminuria develop heavier proteinuria and
Another glomerulus contains an eccentric large mes- progressive renal insufficiency (2– 4). The cumulative
angial nodule composed of acellular lamellated PAS- incidence of ESRD as a result of diabetic nephropathy
positive extracellular matrix (Figure 2, PAS, ⫻400). is 50% in type 1 diabetes (5) and 3 to 11% in type 2
Bowman’s capsule appears thickened and lamellated. diabetes (6). However, most cases of ESRD are due to
Silver stain reveals global silver-positive mesangial type 2 diabetes, reflecting its much greater prevalence.
sclerosis with segmental capillary microaneurysm for- NDG, characterized by acellular nodular accu-
mation (arrowheads). Mesangial interposition sur- mulations of mesangial matrix (also termed Kimmel-
rounds some of the nodules. (Figure 3, Jones methe- stiel-Wilson nodules), is the histologic hallmark of
namine silver, ⫻400). Forty percent of glomeruli were diabetic renal disease and is present in up to 40% of
globally sclerotic with prominent hyalinosis. Tubular renal biopsies from patients with diabetes (7). The
atrophy and interstitial fibrosis occupied approxi- other major pattern of glomerular involvement in di-
mately 60% of the cortex. An arteriole shows severe abetic nephropathy is diffuse mesangial sclerosis
hyalinosis (Figure 4, Jones methenamine silver, (without nodularity), which is termed “diffuse diabetic
⫻400). Immunofluorescence (IF) microscopy reveals glomerulosclerosis.” Both diffuse and nodular forms
diffuse linear staining of GBMs and tubular basement of diabetic nephropathy also exhibit GBM thickening,
membranes (TBMs) with antisera to albumin (1 to 2⫹; tubulointerstitial scarring, arteriosclerosis, and arteri-
Figure 5, ⫻100) and IgG (trace to 1⫹; data not olar hyalinosis. Similar glomerular lesions are found
shown), without significant positivity for other im- in patients with type 1 and type 2 diabetes. In addition,
mune reactants. By electron microscopy (EM), the nondiabetic kidney disease (NDKD) is not uncom-
mesangium is expanded by nodular accumulations of mon, either alone or superimposed on diabetic ne-
matrix material that compress the mesangial cells and phropathy (see NDKD in Patients with Diabetes sec-
narrow the glomerular capillaries, associated with uni- tion). NDKD is more frequently detected in patients
form thickening of GBMs (Figure 6, electron micro- with type 2 diabetes, reflecting the greater prevalence
graph, ⫻4000). No immune-type electron-dense de- of comorbid conditions, such as systemic hyperten-
posits or endothelial tubuloreticular inclusions were sion, cardiovascular disease, and older age.
identified. These findings are consistent with nodular Compared with diffuse diabetic glomerulosclerosis,
diabetic glomerulosclerosis (NDG) (answer D). It is NDG is characterized by longer duration of diabetes,
possible that longstanding hypertension and smoking heavier proteinuria, greater renal insufficiency, more fre-
contributed to the vascular disease and glomeruloscle- quent diabetic retinopathy, more severe chronic patho-
rosis. logic changes, and worse prognosis (8,9), consistent with
a more advanced stage of diabetic nephropathy (9).
Nodular Diabetic Glomerulosclerosis Nonetheless, it remains uncertain whether NDG evolves
Diabetic kidney disease (diabetic nephropathy) is from diffuse mesangial sclerosis or arises ab initio via
the single leading cause of ESRD in the United States, distinct pathogenetic pathways.
Clinical Characteristics flecting their composition from extracellular matrix. Of-

Hyperfiltration is a feature of early diabetes and ten, the nodules have a concentric, lamellated appear-
is thought to be a hemodynamic effect of hyperglyce- ance. Typically, only one or two nodules are present per
mia on GFR. NDG is usually diagnosed after 10 to 20 glomerulus, and adjacent segments display milder mes-
years of type 1 diabetes but may occur earlier in type angial sclerosis. When nodules are numerous, they cause
2 diabetes, possibly reflecting subclinical disease of accentuation of the glomerular lobularity. Larger nodules
unknown duration (10). Indeed, approximately 3% of are frequently associated with microaneurysms (balloon-
patients with type 2 diabetes have clinical evidence of ing and confluence of peripheral capillaries resulting
nephropathy at the time of initial diagnosis (11). The from detachment of the GBM reflection to the underlying
incidences of diabetes and diabetic ESRD are higher in mesangium) and mesangiolysis (dissolution of the mes-
African Americans, Native Americans, and Hispanics angial matrix, producing clear, non-argyrophilic areas).
(particularly Mexican Americans) compared with Additional findings include “insudative” lesions repre-
Caucasians, reflecting racially determined genetic presenting entrapment of plasma proteins as hyalinosis.
disposition. Glomerular hyalinosis can occur in the subendothelial
Most patients with NDG have heavy proteinuria, region of peripheral capillaries (i.e., “fibrin cap”) and/or
with or without full nephrotic syndrome. Of note, the between the parietal epithelium and Bowman’s capsule
level of proteinuria is typically suppressed in patients (i.e., capsular drop lesion). Unlike matrix material, insu-
who receive angiotensin-converting enzyme inhibitor dative lesions often contain clear vacuoles of entrapped
or angiotensin receptor blocker therapy but can worsen lipid and are brightly eosinophilic, trichrome red, and
rapidly upon reduction or discontinuation of renin- non-argyrophilic. Although hyalinosis is a characteristic
angiotensin system blockade. Renal insufficiency is feature of diabetic nephropathy, it is not pathognomonic
usually present and may be chronic or acute-on- and can also occur in hypertensive nephrosclerosis and in
chronic. Microhematuria is present in up to 48% of primary and secondary FSGS, among other conditions.
cases (12). Diabetic retinopathy (diagnosed by an In addition to the presence of nodular sclerosis,
ophthalmologist) is present in 90 to 94% of patients glomeruli are usually enlarged and display a back-
with NDG, and proliferative retinopathy is more ground of variable mesangial sclerosis and mild mes-
strongly associated with NDG than background reti- angial hypercellularity. Mesangial interposition and
nopathy (8,9). Atypical clinical features that should duplication of GBMs may surround some nodules.
suggest the presence of NDKD include short history of GBMs, Bowman’s capsule, and TBMs are diffusely
diabetes (particularly for patients with type 1 diabe- thickened, a finding best appreciated with PAS or
tes), rapid increase in proteinuria or sudden onset of silver stains. Lesions of segmental and global glomer-
nephrotic syndrome, rapid deterioration in kidney ulosclerosis commonly supervene and may be due in
function, azotemia with minimal proteinuria, active part to coexistent hypertensive arterionephrosclerosis.
urinary sediment, macroscopic hematuria, abnormal The globally sclerotic glomeruli of NDG are often
serologic tests, and absence of retinopathy. distinctive because they remain large with residual
lobular accentuation and prominent hyalinosis.
Pathology Whereas thickening of the TBMs of atrophic
Light Microscopy. In the hyperfiltration phase, tubules is common in any chronic renal disease, dia-
glomeruli are hypertrophied without obvious mesan- betic nephropathy is one of the few conditions to
gial alterations. Well-developed diabetic nephropathy exhibit diffuse thickening of the TBMs of nonatrophic
can be divided into diffuse and nodular forms. Both tubules. Proximal tubules often contain intracytoplas-
have generalized mesangial sclerosis, but this process mic protein and lipid resorption droplets. Rarely seen
is focally accentuated to form mesangial nodules in in the modern era is clearing of the cytoplasm of the
NDG. proximal tubule of the pars recta owing to glycogen
The characteristic lesion of NDG is nodular expan- accumulation (the Armanni-Ebstein lesion), a finding
sion of the mesangial matrix, producing an acellular core more common in patients with untreated diabetes and
surrounded by mesangial cells (Kimmelstiel-Wilson le- episodes of ketoacidosis. There is variable tubuloin-
sion). Nodules are oval or round, eosinophilic, PAS terstitial scarring and chronic interstitial inflammation.
positive, and strongly argyrophilic (silver positive), re- Arteries often display moderate to severe intimal and
tally thinned in areas of capillary microaneurysm for-

mation or around the larger nodules. Mesangial areas
show nodular expansion by acellular matrix material
with the same density as normal mesangial matrix.
Occasionally, the expanded mesangial matrix contains
bundles of collagenous fibrils ranging from 10 to 25
nm in thickness (“diabetic fibrillosis”) (15). These
fibrils differ from those of fibrillary glomerulonephri-
tis by their lack of characteristic IF staining for IgG
and C3 and by their typically parallel (nonrandom)
wavy alignment and close apposition to mesangial
Figure 7. A glomerular capillary shows marked uniform cells, without capillary wall involvement. In areas of
thickening of the GBM by matrix material associated with mesangiolysis, the matrix has a loose, “empty” appear-
mesangial sclerosis and moderate foot process effacement. ance, leading to detachment of the GBM reflection
Magnification, ⫻8000 (electron micrograph).
from the mesangium. Foot process effacement varies
medial sclerosis, and arterioles show prominent hya- in severity but is rarely complete. Insudative lesions
linosis. A characteristic feature of diabetic kidney consist of amorphous electron-dense subendothelial or
disease is the presence of arteriolar hyalinosis involv- mesangial deposits that may be difficult to distinguish
ing both the afferent and efferent arterioles, whereas from immune deposits but generally have a more
hypertensive arteriolonephrosclerosis specifically tar- homogeneous texture typical of hyaline, with focal
gets the afferent arterioles. lipid droplets. TBMs are thickened and lamellated and
A recently proposed pathologic classification of frequently contain extracellular electron-lucent lipid
diabetic glomerulosclerosis distinguishes NDG (class inclusions.
III) from cases with nonspecific glomerular alterations Differential Diagnosis. The differential diagnosis
by light microscopy but ultrastructural evidence of of NDG includes other conditions that can produce
GBM thickening defined as ⬎395 nm in females and nodular mesangial expansion. These include amyloid-
⬎430 nm in males who are older than 9 years (class I), osis, monoclonal Ig deposition disease, glomerulopa-
cases with diffuse mesangial sclerosis by light micros- thies with organized deposits (e.g., fibrillary glomer-
copy (class II), and cases with ⬎50% global glomerulonephritis, immunotactoid glomerulopathy, fibronectin
ulosclerosis (class IV). The clinical and prognostic glomerulopathy, type III collagenofibrotic glomeru-
significance of this classification awaits independent lopathy), nodular glomerulosclerosis associated with
validation (13). chronic hypoxia or ischemia (e.g., cyanotic congenital
Immunofluorescence. A common, nonspecific heart disease, Takayasu arteritis with renal artery ste-
finding in diabetic kidneys is diffuse linear staining of nosis, cystic fibrosis), and nodular glomerulosclerosis
GBMs and TBMs for albumin (Figure 5), with weaker related to longstanding cigarette smoking and hyper-
linearity for IgG and ␬ and ␭ light chains. Linear tension (16,17). Diffuse linear staining of all renal
staining for IgG is attributed to its charge-dependent basement membranes for a single light chain should
affinity for the GBM, rather than anti-GBM activity suggest monoclonal Ig deposition disease, and EM
(14). Segmental glomerular staining for IgM and C3 is will demonstrate the characteristic punctate granular
common in areas of hyalinosis. Similar positivity for electron densities in most cases. Similarly, IF and EM
IgM and C3 is seen in areas of arteriolar sclerosis and will identify cases of AL amyloidosis, fibrillary glo-
hyalinosis. Glomerular capillary microaneurysms of- merulonephritis, and immunotactoid glomerulopathy,
ten stain for fibrin/fibrinogen. whereas immunohistochemical stains for amyloid A
Electron Microscopy. GBMs are usually diffusely protein, fibronectin, and type III collagen are neces-
thickened by matrix material with a homogeneous or sary to confirm the diagnoses of AA amyloidosis,
vaguely lamellated texture (Figure 7, ⫻3000). GBM fibronectin glomerulopathy, and type III collagenofi-
thickness exceeds 400 nm and may reach thicknesses brotic glomerulopathy, respectively. Nodular sclerosis
of ⬎1200 nm. By contrast, the GBM may be segmen- related to longstanding cigarette smoking and hyper-
tension closely resembles NDG but usually has more onset of full nephrotic syndrome and whose biopsies
neovascularization by small capillaries within the mes- show only mild diabetic changes with severe foot
angial nodules and extending outward from the glo- process effacement and podocyte microvillous trans-
merular hilus (16). formation (24). IgA-dominant post-staphylococcal in-
NDKD in Patients with Diabetes. NDKD, either fectious glomerulonephritis is not uncommon in older
alone or superimposed on diabetic nephropathy, is not patients with diabetes and cellulitis or other suppura-
uncommon in patients with diabetes. The likelihood of tive infections (22). Tubulointerstitial diseases include
finding NDKD depends on clinical variables that in- acute tubular necrosis, acute interstitial nephritis, py-
elonephritis, and myeloma cast nephropathy, among
fluence the decision to biopsy, such as short duration
others. Vascular diseases include cholesterol emboli-
of diabetes, absence of retinopathy, active urine sedi-
zation and thrombotic microangiopathy.
ment, hypocomplementemia or other serologic abnor-
malities, sudden onset of heavy proteinuria, or rapidly
deteriorating kidney function. In a biopsy study of 34
Pathogenesis
The pathogenesis of NDG is multifactorial and
patients with type 2 diabetes and microalbuminuria,
complex. Genetic predisposition seems to play a role
41% showed absent or only mild diabetic changes and
in both type 1 and type 2 diabetes. Elevation in
disproportionately severe tubulointerstitial or vascular
intracellular glucose levels leads to glucose oxidation
disease, which correlated with poor glycemic control
in the tricarboxylic acid cycle, generation of more
(18). In a series of 51 patients with type 2 diabetes and
electron donors to the electron transport chain, and
⬎300 mg/d albuminuria, 68% of biopsies showed
overproduction of mitochondrial superoxide (25).
diabetic glomerulosclerosis, 18% showed normal glo-
These perturbations in turn activate a number of del-
merular structure, and 14% had NDKD (19). Among eterious metabolic pathways, including protein kinase
233 unselected patients who had type 2 diabetes and C, the polyol pathway, and the hexosamine pathway,
underwent renal biopsy, 28% had pure diabetic ne- all of which have been linked to hyperfiltration, endo-
phropathy, 19% had concurrent diabetic nephropathy thelial injury, microvascular disease, and albuminuria.
and NDKD, and 53% had NDKD alone, including a Importantly, hyperglycemia causes nonenzy-
broad variety of glomerular diseases (20). In an un- matic glycation of extracellular matrix proteins and
published series of 168 consecutive native kidney lipids, which are converted through the Maillard reac-
biopsies from patients with type 2 diabetes at our tion into Schiff bases, Amadori products, and ulti-
institution (74% of whom had nephrotic-range protein- mately advanced glycation end products (AGE), pro-
uria), diabetic nephropathy alone was seen in 86 moting irreversible cross-linking of matrix proteins.
(51%) cases, diabetic nephropathy with superimposed Although the GBMs become thickened, the reduction
NDKD in 39 (23%) cases, and NDKD alone in 43 in heparan sulfate proteoglycan content is thought to
(26%) cases. Clinical correlates of NDKD alone in- be important in the induction of albuminuria (26).
cluded shorter duration of diabetes (5 versus 10 years) AGE have been identified by immunohistochemistry
and less frequent diabetic retinopathy (17 versus in the thickened renal basement membranes of human
38%). Cases with combined diabetic nephropathy and diabetic nephropathy (27). Interaction with RAGE, a
NDKD were more likely to have active urinary sedi- multiligand receptor for AGE, in turn activates proin-
ment and rapid progression than those with diabetic flammatory and profibrotic pathways. RAGE is ex-
nephropathy alone. pressed on podocytes and glomerular endothelial cells,
NDKD in patients with diabetes comprises a where interaction with AGE generates podocyte oxi-
broad spectrum of glomerular, tubulointerstitial, and dative stress, endothelial dysfunction, proinflamma-
vascular diseases (21). Glomerular diseases include tory and profibrotic cytokine production, altered glo-
minimal change disease, acute postinfectious glomer- merular filtration barrier, and eventual podocyte
ulonephritis (22), pauci-immune crescentic glomeru- apoptosis (28).
lonephritis (23), IgA nephropathy, membranous ne- The hyperglycemic milieu also activates pro-
phropathy, and fibrillary glomerulonephritis, to name renin to generate angiotensin II (29). In addition to its
a few. Minimal change disease should be considered hemodynamic effects, angiotensin II promotes local
in patients who have diabetes and present with abrupt profibrotic cytokine production and glomerular matrix
expansion. Recent evidence has focused on the roles with retinopathy. The Collaborative Study Group. Nephrol Dial
Transplant 13: 2547–2552, 1998
of high fructose intake and elevated uric acid in the 9. Hong D, Zheng T, Jia-qing S, Jian W, Zhi-hong L, Lei-shi L: Nodular
stimulation of NF-␬B–induced endothelial injury, ma- glomerular lesion: A later stage of diabetic nephropathy? Diabetes
trix production, and systemic hypertension in patients Res Clin Pract 78: 189 –195, 2007
10. Fioretto P, Caramori ML, Mauer M: The kidney in diabetes: Dynamic
with type 2 diabetes (30). pathways of injury and repair. The Camillo Golgi Lecture 2007.
The pathogenesis of nodules is thought to in- Diabetologia 51: 1347–1355, 2008
volve repeated episodes of mesangiolysis and endo- 11. Gall MA, Rossing P, Skott P, Damsbo P, Vaag A, Bech K, Dejgaard
A, Lauritzen M, Lauritzen E, Hougaard P, Beck-Nielsen H, Parving
thelial injury and repair, as evidenced by their frequent HH: Prevalence of micro- and macroalbuminuria, arterial hyperten-
association with microaneurysm formation, entrapped sion, retinopathy and large vessel disease in European type 2 (non-
red blood cells and fibrin, and increased glomerular insulin-dependent) diabetic patients. Diabetologia 34: 655– 661,
1991
expression of plasminogen activator inhibitor 1 (31). 12. Mogensen CE, Schmitz O: The diabetic kidney: From hyperfiltration
In a mouse model of diabetic nephropathy, control of and microalbuminuria to end-stage renal failure. Med Clin North Am
systemic BP ameliorated the formation of NDG but 72: 1465–1492, 1988
13. Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT,
not diffuse mesangial sclerosis (32). Of note, reversal Drachenberg CB, Ferrario F, Fogo AB, Haas M, de Heer E, Joh K,
of NDG has been demonstrated after pancreas trans- Noel LH, Radhakrishnan J, Seshan SV, Bajema IM, Bruijn JA:
plantation, indicating the potential for regression of Pathologic classification of diabetic nephropathy. J Am Soc Nephrol
21: 556 –563, 2010
established diabetic lesions upon sustained euglycemia
14. Gallo GR: Elution studies in kidneys with linear deposition of
(33). Progression of diabetic glomerulosclerosis in- immunoglobulin in glomeruli. Am J Pathol 61: 377–394, 1970
volves podocyte loss and adhesions to Bowman’s 15. Gonul II, Gough J, Jim K, Benediktsson H: Glomerular mesangial
fibrillary deposits in a patient with diabetes mellitus. Int Urol Neph-
capsule. Adhesions often develop first at the tubular
rol 38: 767–772, 2006
pole, producing atubular glomeruli that have lost com- 16. Nasr SH, D’Agati VD: Nodular glomerulosclerosis in the nondiabetic
munication with the proximal tubules (34). Lesions smoker. J Am Soc Nephrol 18: 2032–2036, 2007
17. Markowitz GS, Lin J, Valeri AM, Avila C, Nasr SH, D’Agati VD:
often progress through stages of segmental to global
Idiopathic nodular glomerulosclerosis is a distinct clinicopathologic
glomerulosclerosis. Similar to other chronic renal dis- entity linked to hypertension and smoking. Hum Pathol 33: 826 – 835,
eases, irreversible podocyte stress and depletion are 2002
18. Fioretto P, Mauer M, Brocco E, Velussi M, Frigato F, Muollo B,
now recognized as important mediators of progressive
Sambataro M, Abaterusso C, Baggio B, Crepaldi G, Nosadini R:
glomerulosclerosis in diabetic nephropathy (35,36). Patterns of renal injury in NIDDM patients with microalbuminuria.
Diabetologia 39: 1569 –1576, 1996
19. Christensen PK, Larsen S, Horn T, Olsen S, Parving HH: Causes of
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Kidney Disease and End-Stage Renal Disease, Bethesda, National athy. Kidney Int 58: 1719 –1731, 2000
Institute of Diabetes and Digestive and Kidney Diseases, 2010 20. Pham TT, Sim JJ, Kujubu DA, Liu IL, Kumar VA: Prevalence of
2. Hovind P, Tarnow L, Rossing P, Jensen BR, Graae M, Torp I, Binder nondiabetic renal disease in diabetic patients. Am J Nephrol 27:
C, Parving HH: Predictors for the development of microalbuminuria 322–328, 2007
and macroalbuminuria in patients with type 1 diabetes: Inception 21. Gambara V, Mecca G, Remuzzi G, Bertani T: Heterogeneous nature
cohort study. BMJ 328: 1105, 2004 of renal lesions in type II diabetes. J Am Soc Nephrol 3: 1458 –1466,
3. Amin R, Widmer B, Prevost AT, Schwarze P, Cooper J, Edge J, 1993
Marcovecchio L, Neil A, Dalton RN, Dunger DB: Risk of microalbu- 22. Nasr SH, Share DS, Vargas MT, D’Agati VD, Markowitz GS: Acute
minuria and progression to macroalbuminuria in a cohort with child- poststaphylococcal glomerulonephritis superimposed on diabetic glo-
hood onset type 1 diabetes: Prospective observational study. BMJ merulosclerosis. Kidney Int 71: 1317–1321, 2007
336: 697–701, 2008 23. Nasr SH, D’Agati VD, Said SM, Stokes MB, Appel GB, Valeri AM,
4. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR: Markowitz GS: Pauci-immune crescentic glomerulonephritis super-
Development and progression of nephropathy in type 2 diabetes: The imposed on diabetic glomerulosclerosis. Clin J Am Soc Nephrol 3:
United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney 1282–1288, 2008
Int 63: 225–232, 2003 24. Stokes MB, Kwakye J, D’Agati VD: Nephrotic syndrome and ARF
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8. Schwartz MM, Lewis EJ, Leonard-Martin T, Lewis JB, Batlle D: nephropathy and nondiabetic renal disease. J Am Soc Nephrol 11:
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Nephrology Self-Assessment Program
Examination Questions
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414
Volume 10, Number 4, July 2010 —Renal Pathology and Examination Questions
夝 1. Which ONE of the following statements C. Immunotactoid glomerulopathy

about antibodies against M-type phospho- D. Waldenstrom macroglobulinemic glomeru-
lipase A2 receptor (PLA2R) is CORRECT? lonephritis
A. PLA2R antibodies are seen in the majority E. Proliferative glomerulonephritis with
of patients with class IV lupus nephritis. monoclonal IgG deposits
B. PLA2R antibodies are most commonly of
the IgG2 subclass. 3. A 44-year-old woman presents with nephrotic
C. PLA2R antibodies are present in the ma- syndrome and microhematuria. Serologic
jority of patients with membranous ne- workup reveals evidence of HCV infection,
phropathy, including primary and second- depressed C3 and C4 complement levels, and
ary forms of disease. cryoglobulinemia. Renal biopsy is performed,
and light microscopy reveals a membranopro-
D. PLA2R antibodies appear to be specific for
liferative pattern of glomerulonephritis.
primary membranous nephropathy.
Which ONE of the following statements
E. PLA2R antibodies predict a poor outcome
about the renal biopsy findings in this case
in the setting of pauci-immune crescentic
is MOST likely to be CORRECT?
glomerulonephritis.
A. Immunofluorescence will reveal mesangial
2. A 68-year-old man presents with nephrotic syn- and capillary wall deposits that stain domi-
drome, microhematuria, and renal insufficiency. nantly for IgA.
Serologic evaluation reveals normal serum com- B. Immunofluorescence will reveal mesangial
plements and negative serologies including anti- and capillary wall deposits that stain domi-
nuclear antibody (ANA), hepatitis C virus (HCV) nantly for IgM.
antibody, hepatitis B surface antigen, anti-neutro- C. Electron microscopy will reveal global
phil cytoplasmic antibody (ANCA), and serum subepithelial deposits.
cryoglobulins. Light microscopy reveals a diffuse
D. Immunofluorescence will reveal abundant
proliferative glomerulonephritis with membrano-
deposits in tubular basement membranes
proliferative features. Immunofluorescence reveals
and the interstitium.
global mesangial and subendothelial deposits that
stain 3⫹ for IgG; 2⫹ for C3; 3⫹ for ␬; and E. No deposits will be found by immunofluo-
negative for IgM, IgA, C1, and ␭. Immunoflu- rescence or electron microscopy.
orescence staining for subtypes of IgG reveals
3⫹ positivity for IgG3. Staining for IgG1, IgG2, 4. A 19-year-old man is found to have vasculitis
and IgG4 is negative. Electron microscopy re- of the lower extremity. Subsequent workup
veals global mesangial and subendothelial de- reveals a 24-hour urine protein of 1.7 g, mi-
posits. No deposit substructure or fibril forma- crohematuria with rare red blood cell (RBC)
tion is noted. The patient is subsequently found casts, and a creatinine level of 1.3 mg/dl. The
to have a monoclonal serum spike. patient describes intermittent abdominal pain
and arthralgias. Serologic evaluation discloses
Which ONE of the following is the COR-
a negative ANA and ANCA, negative HCV
RECT diagnosis?
antibody, normal serum complements, and no
A. Fibrillary glomerulonephritis evidence of cryoglobulinemia. Renal biopsy is
B. Amyloidosis, light- and heavy-chain type performed, and light microscopy reveals a
415
mesangial proliferative glomerulonephritis. diffuse tubular injury and atypical, distal tubular
Electron microscopy reveals global mesangial casts that stain brightly with the hematoxylin
deposits. and eosin stain, appear pale with the periodic
The mesangial deposits seen by immunoflu- acid–Schiff stain, and are associated with adher-
orescence are likely to stain dominantly for ent monocytes and rare giant cells.
which ONE of the following immune reac- Which ONE of the following pathologic
tants? findings is MOST likely to be seen upon
A. IgG further evaluation?
B. IgM A. By immunofluorescence, the tubular casts
C. IgA stain similarly for ␬ and ␭ light chains.
D. C3 B. By immunofluorescence, the tubular casts
E. ␬ light chain stain dominantly for a single light chain
(␬ or ␭) and with minimal intensity for the
reciprocal light chain.
夝 5. An 18-year-old Asian woman is found to have
microhematuria, a 24-hour urine protein of C. Electron microscopy reveals abundant
1.5 g, a serum creatinine of 0.8 mg/dl, an ANA mesangial randomly oriented fibrils with a
titer of 1:80, and a negative anti-DNA antibody. mean diameter of 8 to 12 nm.
Renal biopsy reveals a diffuse mesangial and D. Electron microscopy reveals global subepi-
focal endocapillary proliferative glomerulone- thelial electron-dense deposits.
phritis. By immunofluorescence, the global E. Immunofluorescence reveals linear staining
mesangial and segmental subendothelial depos- for ␭ in glomerular basement membranes
its stain co-dominantly for IgG and IgA (each (GBMs) and tubular basement membranes,
3⫹). Thus, the differential diagnosis includes
Bowman’s capsule, and blood vessels.
mainly lupus nephritis and IgA nephropathy
(IgAN).
夝 7. A 62-year-old woman with a 6-month history of
Which ONE of the following findings would
smoldering multiple myeloma is found to have a
favor the diagnosis of IgAN in this patient?
24-hour urine protein of 5 g, serum albumin
A. The ultrastructural finding of multiple en- level of 3.4 g/dl, creatinine of 1.4 mg/dl, and mild
dothelial tubuloreticular inclusions edema. Renal biopsy is performed, and light mi-
B. The serologic finding of normal serum croscopy reveals a nodular pattern of glomerulo-
complement levels sclerosis. Immunofluorescence reveals linear
C. The immunofluorescence finding of tubu- staining for ␬ light chain in glomerular and tubular
lar basement membrane and vessel wall basement membranes, Bowman’s capsule, and
deposits blood vessels. Electron microscopy reveals finely
D. The immunofluorescence finding of 2⫹ granular, nonfibrillar, punctate deposits in glomer-
global mesangial positivity for C1q ular and tubular basement membranes, the mesan-
E. The immunofluorescence finding of 2⫹ gium, and vessel walls.
global mesangial positivity for IgM, C3, These findings are diagnostic of which ONE
and C1q (i.e., a “full house”) of the following disease entities?
A. Light chain deposition disease
6. An 82-year-old woman presents with back pain, B. Amyloidosis
hypercalcemia, anemia, and acute renal failure
C. Light chain Fanconi syndrome
with a creatinine level of 5.1 mg/dl. She has a
24-hour urine protein of 4 g. Urinalysis reveals D. Proliferative glomerulonephritis with
1⫹ protein and a bland urine sediment. Renal monoclonal IgG deposits
biopsy is performed. Light microscopy reveals E. Nodular diabetic glomerulosclerosis
8. A 23-year-old woman is found to have micro- C. Lupus nephritis

hematuria, a 24-hour urine protein of 3.3 g, and D. Dense deposit disease
a creatinine level of 2.0 mg/dl. Family history
E. Amyloidosis
includes a maternal grandfather with ESRD.
Renal biopsy is performed and reveals findings
suggestive of hereditary nephritis (HN). In an 11. A renal biopsy reveals glomerular and vascular
effort to confirm the diagnosis, staining for sub- fibrin thrombi. Glomeruli also exhibit mesangioly-
types of type IV collagen is performed and sis, endothelial swelling, and GBM duplication
reveals 3⫹ staining of all renal basement mem- with mesangial interposition. Multiple arteries dis-
branes for the ␣-1 chain of type IV collagen. play mucoid intimal edema. No immune-type de-
Staining of the ␣-3 and ␣-5 chains is entirely posits are identified by immunofluorescence or
negative. electron microscopy.
Which ONE of the following is the COR- This pattern of renal injury is seen in which
RECT interpretation of the staining results? ONE of the following conditions?
A. The lack of staining for ␣-3 and ␣-5 ar- A. Henoch-Schönlein purpura
gues against the diagnosis of HN. B. Hereditary nephritis/Alport syndrome
B. The lack of staining for ␣-3 and ␣-5 sup- C. Renal atheroembolic disease
ports the diagnosis of HN. D. Wegener granulomatosis
C. The findings are noncontributory. E. Hemolytic uremic syndrome
D. The findings favor the diagnosis of thin
basement membrane nephropathy 12. Which ONE of the following is the MOST
over HN. common cause of acute interstitial nephritis?
A. IgG4 immune complex tubulointerstitial
9. Which ONE of the following statements is nephritis
CORRECT regarding secondary causes of
B. Viral infection
glomerular disease?
C. Pharmacologic agents
A. Carcinomas are most commonly associated
with FSGS. D. Systemic, presumed autoimmune condi-
tions including systemic lupus erythemato-
B. HCV infection is most commonly associ-
sus, Sjögren syndrome, and sarcoidosis
ated with minimal change disease.
E. Tubulointerstitial nephritis with uveitis
C. Rheumatoid arthritis is most commonly
syndrome
associated with AA amyloidosis.
D. Nonsteroidal anti-inflammatory drugs are
13. Multiple glomerular diseases are associated with
most commonly associated with IgAN.
crescent formation.
E. HIV infection is most commonly associ-
In which ONE of the following glomerular
ated with membranous nephropathy.
diseases is crescent formation typically
MOST extensive, with more than 80% of
10. Excessive activation of the alternative com- cases exhibiting crescents in more than 50%
plement pathway can occur as a result of of glomeruli?
multiple mechanisms, including formation
A. Lupus nephritis class IV
of C3 nephritic factor or reduced activity of
factor H or factor I. These observations are B. Pauci-immune crescentic glomerulonephri-
central to the pathogenesis of which ONE of tis associated with ANCA seropositivity
the following conditions? C. Fibrillary glomerulonephritis
A. IgA nephropathy D. Anti-GBM disease
B. FSGS E. Acute postinfectious glomerulonephritis
14. In which ONE of the following conditions is the A. Membranoproliferative glomerulonephritis

pathogenesis thought to involve neutrophil ac- type 1
tivation, often the result of a recent upper re- B. Membranous nephropathy
spiratory tract infection, leading to surface ex-
C. FSGS
pression of enzymes that are normally confined
to the cytoplasm of neutrophils? D. Minimal change disease.
A. Minimal change disease E. Monoclonal immunoglobulin deposition
disease
B. Acute postinfectious glomerulonephritis
C. Pauci-immune crescentic glomerulonephri- 17. A 17-year-old Caucasian boy is found to have
tis related to ANCA seropositivity microhematuria, a creatinine level of 1.1 mg/dl,
D. Anti-GBM disease and a 24-hour urine protein of 2.3 g. The elec-
E. Cryoglobulinemic glomerulonephritis tron microscopic findings are provided.
15. In which ONE of the following dysproteine-

mia-associated renal diseases is the monoclo-
nal light chain present within the renal pa-
renchyma more commonly composed of ␭
than ␬?
A. Light chain cast nephropathy (a.k.a.
myeloma cast nephropathy)
B. Light chain Fanconi syndrome
C. Light chain deposition disease
D. Light chain (AL) amyloidosis
16. A 45-year-old Hispanic woman presents with

abrupt onset of full nephrotic syndrome. She has a Which ONE of the following statements is
creatinine level of 0.9 mg/dl, 24-hour urine protein MOST likely to be CORRECT in regard to
of 9 g, serum albumin of 2.8 g/dl, and a bland urine this patient?
sediment. Sampling for light microscopy and im- A. The patient has a history of recent infec-
munofluorescence is limited to medulla. The elec- tion.
tron microscopic findings are provided. B. The patient has a maternal grandfather
with ESRD.
C. The patient has a paternal grandfather with
ESRD.
D. The patient has a history of Grave’s dis-
ease.
E. The patient has a history of monoclonal
gammopathy.
夝18. A 25-year-old African American man presents

with full nephrotic syndrome including
edema, a 24-hour urine protein of 13.0 g, and
a serum albumin of 2.6 g/dl. The patient has a
creatinine level of 1.8 mg/dl and a bland urine
Which ONE of the following is the COR- sediment. The light microscopic findings are
RECT diagnosis? provided.
C. The patient has a history of diabetes

mellitus.
D. The patient has a history of monoclonal
gammopathy and peripheral neuropathy.
E. The patient has hemoptysis.
20. An 85-year-old Caucasian woman presents with

florid nephrotic syndrome and acute renal fail-
ure. The patient has a 24-hour urine protein of
15.0 g, serum albumin level of 1.5 g/dl, 2⫹
peripheral edema, bland urine sediment, and an
increase in creatinine from 0.8 to 2.5 mg/dl over
2 weeks. The electron microscopic findings are
provided.
Which ONE of the following serologic tests

is MOST likely to provide the diagnosis?
A. ANCA
B. Anti-GBM antibody
C. ANA
D. Antibody to HIV
E. Hepatitis B surface antigen
19. A 60-year-old Caucasian man presents with ne-

phrotic syndrome and mild renal insufficiency.
The electron microscopic findings are provided.

RECT diagnosis?
A. Minimal change disease
C. Amyloidosis
D. Light chain deposition disease
E. IgA nephropathy
夝21. The following image is from the renal biopsy

of a patient with systemic lupus erythemato-
Which ONE of the following statements is sus.
MOST likely to be CORRECT about this
If the majority of the glomeruli in this bi-
patient?
opsy have a similar appearance, then which
A. The patient has metastatic cancer of the ONE of the following would be the appro-
lung. priate classification of this biopsy on the
B. The patient has a history of anti-phospho- basis of the 2003 ISN/RPS Classification of
lipid syndrome. lupus nephritis?

RECT diagnosis?
A. Hereditary nephritis
B. Light and heavy chain deposition disease
C. Anti-GBM disease
D. Acute postinfectious glomerulonephritis
E. Pauci-immune necrotizing and crescentic
glomerulonephritis related to ANCA sero-
positivity
23. A 37-year-old man presents with gross hema-

turia, a creatinine level of 1.7 mg/dl, and a
24-hour urine protein of 2.0 g. The patient is
found to have depressed serum complements
and an active urine sediment with RBC casts.
A. Lupus nephritis class II Light microscopy reveals a diffuse prolifera-
B. Lupus nephritis class III tive and exudative glomerulonephritis. Immu-
C. Lupus nephritis class V nofluorescence reveals global mesangial and
D. Lupus nephritis class IV-S capillary wall deposits which stain 3⫹ for C3
and 2⫹ for IgG, ␬, and ␭.
E. Lupus nephritis class IV-G
22. A 50-year-old Caucasian woman presents with

acute renal failure and a creatinine level of 7.0
mg/dl. Urinalysis reveals 3⫹ protein and an
active urine sediment with many RBC casts.
Renal biopsy is performed emergently, and light
microscopy reveals a diffuse necrotizing and
crescentic glomerulonephritis. The result of im-
munofluorescence staining for IgG is provided.
Similar findings were seen with staining for ␬
and ␭ light chains.
The ultrastructural findings are MOST

characteristic of which ONE of the follow-
ing conditions?
A. Acute post-streptococcal glomerulonephritis
B. Diffuse proliferative lupus nephritis
(class IV)
C. Diffuse proliferative glomerulonephritis
related to HCV infection.
D. Henoch-Schönlein purpura nephritis
E. Fibrillary glomerulonephritis
24. A 39-year-old Caucasian man presents with abrupt image of a representative glomerulus from the
onset of nephrotic syndrome. The light micro- biopsy is provided. Immunofluorescence was
scopic findings are provided. Immunofluorescence negative for all immune reactants, and electron
was negative, and electron microscopy revealed microscopy confirmed the absence of deposits.
complete foot process effacement.
Which ONE of the following is the COR- On the basis of these findings, which ONE of
RECT diagnosis? the following statement is CORRECT regard-
A. Minimal change disease ing the serologic workup on this patient?
B. FSGS, collapsing variant A. The probability of a positive anti-GBM
antibody is ⬎50%.
C. FSGS, cellular variant
B. The probability of a positive ANCA
D. FSGS, tip lesion variant
is ⬎75%.
E. Amyloidosis
C. The probability of a positive ANCA is 98
to 100%.
25. A 79-year-old woman is found to have a creat-
inine level of 4.4 mg/dl, an active urine sediment D. The probability of a positive ANA
with RBC casts, and subnephrotic proteinuria. is ⬎50%.
Renal biopsy is performed while awaiting re- E. The probability of hypocomplementemia
ceipt of the results of serologic studies. An is ⬎75%.
NephSAP
®
Reverse Table of Contents
Section 1: Membranous nephropathy. . . . . . . . . . . . . . . . . . .273

Section 2: Collapsing focal segmental glomerulosclerosis . .279
Section 3: Proliferative glomerulonephritis with monoclonal
IgG deposits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .285
Section 4: HCV-associated cryoglobulinemic
glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .291
Section 5: IgA nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . .297
Section 6: Myeloma cast nephropathy. . . . . . . . . . . . . . . . . .305
Section 7: Hereditary nephritis (Alport syndrome) . . . . . . . .311
Section 8: Thin basement membrane nephropathy . . . . . . . .317
Section 9: Membranoproliferative glomerulonephritis . . . . .323
Section 10: Dense deposit disease . . . . . . . . . . . . . . . . . . . . .329
Section 11: Catastrophic antiphospholipid antibody syndrome
& thrombotic microangiopathy . . . . . . . . . . . . . . . . . . . . .335
Section 12: Acute interstitial nephritis. . . . . . . . . . . . . . . . . .341
Section 13: Minimal change disease . . . . . . . . . . . . . . . . . . .347
Section 14: Focal segmental glomerulosclerosis, tip variant
(“glomerular tip lesion”). . . . . . . . . . . . . . . . . . . . . . . . . . .353
Section 15: Lupus nephritis . . . . . . . . . . . . . . . . . . . . . . . . . .359
Section 16: Acute post-infectious glomerulonephritis. . . . . .367
Section 17: Anti-glomerular basement membrane (anti-GBM)
nephritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .373
Section 18: Pauci-immune necrotizing and crescentic
glomerulonephritis (ANCA-associated) . . . . . . . . . . . . . . .379
Section 19: Amyloidosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . .385
Section 20: Monoclonal immunoglobulin deposition disease . . . .393
Section 21: Fibrillary glomerulonephritis . . . . . . . . . . . . . . .401
Section 22: Diabetic nephropathy . . . . . . . . . . . . . . . . . . . . .407
422

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What is the purpose of NephSAP?

What is the purpose of NephSAP?

What are the goals of NephSAP?

What are the goals of NephSAP?

Volume 10 • Number 4 • July 2011

Nephrology Self-Assessment Program

CME Self-Assessment Questions . . . . . . . . . . . . . . . . . . . . . 415

Reverse Table of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . 422

Glomerular, Vascular, and Tubulointerstital Diseases—

Renal Bone Disease, Disorders of Divalent Ions, and

End-Stage Disease and Dialysis—

Program Mission and Objectives

Accreditation and Credit Designation

Continuing Medical Education (CME) Information

Instructions to Obtain American Board of Internal Medicine (ABIM) Maintenance of Certification

What is the BEST diagnosis?

Answer HbsAg, and hepatitis C virus antibody studies. Workup for

What is the BEST diagnosis?

Answer the glomerular tuft accompanied by overlying glomer-

What is the BEST diagnosis? Proliferative Glomerulonephritis with Monoclonal

Figure 3. Figure 4. IgM

What is the BEST diagnosis?

Answer HCV infection is cryoglobulinemic GN with features

Pathology HIV-associated nephropathy, may display only mild

sosomes of intracapillary macrophages. Of note, de- Etiology and Pathogenesis

Figure 1. Figure 2. IgA

What is the BEST diagnosis?

Answer rare in individuals of African descent. The biopsy

Figure 4. A glomerulus displays endocapillary proliferation

Figure 7. A glomerulus contains a segmental scar (segmen-

Table 1. Oxford-MEST classification of IgAN(7)

dardize the reporting of pathologic features in IgAN polymorphisms of atherosclerosis-associated genes

Section 6: CASE PRESENTATION cutaneous manifestations. His medications include Atripla

What is the BEST diagnosis?

Answer tion, radiocontrast, infection, or nonsteroidal anti-

hard appearance with sharp edges and lines of fracture. Pathogenesis

by morphologic changes reminiscent of ATN (19,20).

MM at the time of diagnosis or subsequently. How-

Section 7: CASE PRESENTATION disease. Physical examination reveals a BP of 140/80

What is the BEST diagnosis?

Answer earliest manifestation of disease and persists through-

Table 1. Usual expression patterns of ␣ subunits of type IV collagen

and higher rates of hearing loss and ocular disease (4).

What is the BEST diagnosis?

Answer life. Although unusual in children, mild proteinuria

Figure 3. C3 Figure 4. IgG

Pathology cated (or double contoured) appearance of the glomer-

small, low-affinity, and cationic immune complexes

What is the BEST diagnosis? Clinical Characteristics

C1q. In more chronic cases, nonspecific positivity for Clinical-Pathologic Correlation

Etiology and Pathogenesis References

Answer patient’s plasma is diluted 1:1 with normal plasma, a

wall). Of note, acute TMA is seen in only one third of

inciting event. Thus, the renal pathology of these condi- References

What is the BEST diagnosis?

A. Lymphoma of the kidney

Answer to 30% of cases (4 –7). Much of these data come from

of renal biopsy in one large series (23). In that series,

What is the BEST diagnosis?

Answer significant glomerular abnormalities by light micros-