GD

ketoconazole and erythromycin, and some calcium channel blockers population at large, and this is particularly true in diabetic
in diabetic patients. 1831

(diltiazem, verapamil) compete with calcineurin inhibitors for P450 Contributing factors are the use of glucocorticoids and sirolimus and
catabolism and cause elevated levels of these immunosuppressive hypertension. Recipients of renal transplants have a high prevalence
Chapter 338 Glomerular Diseases

drugs. Analeptics, such as phenytoin and carbamazepine, will increase of coronary artery and peripheral vascular diseases. The percentage of
catabolism to result in low levels. Aspergillus (Chap. 241), Nocardia deaths from these causes has been slowly rising as the numbers of
(Chap. 199), and especially CMV (Chap. 219) infections also occur. transplanted diabetic patients and the average age of all recipients
CMV is a common and dangerous DNA virus in transplant increase. More than 50% of renal recipient mortality is attributable to
recipients. It does not generally appear until the end of the first post- cardiovascular disease. In addition to strict control of blood pressure
transplant month. Active CMV infection is sometimes associated, or and blood lipid levels, close monitoring of patients for indications
occasionally confused, with rejection episodes. Patients at highest risk of further medical or surgical intervention is an important part of
for severe CMV disease are those without anti-CMV antibodies who management.
receive a graft from a CMV antibody–positive donor (15% mortality). Hypertension may be caused by (1) native kidney disease, (2) rejec-
Valganciclovir is a cost-effective and bioavailable oral form of ganci- tion activity in the transplant, (3) renal artery stenosis if an end-to-end
clovir that has been proved effective in both prophylaxis and treatment anastomosis was constructed with an iliac artery branch, and (4) renal
of CMV disease. Early diagnosis in a febrile patient with clinical suspi- calcineurin inhibitor toxicity, which may improve with reduction in
cion of CMV disease can be made by determining CMV viral load in dose. Whereas ACE inhibitors may be useful, calcium channel block-
the blood. A rise in IgM antibodies to CMV is also diagnostic. Culture ers are more frequently used initially. Amelioration of hypertension to
of CMV from blood may be less sensitive. Tissue invasion of CMV the range of 120–130/70–80 mmHg should be the goal in all patients.
is common in the gastrointestinal tract and lungs. CMV retinopathy Hypercalcemia after transplantation may indicate failure of hyper-
occurs late in the course, if untreated. Treatment of active CMV dis- plastic parathyroid glands to regress. Aseptic necrosis of the head of
ease with valganciclovir is always indicated. In many patients immune the femur is probably due to preexisting hyperparathyroidism, with
to CMV, viral activation can occur with major immunosuppressive aggravation by glucocorticoid treatment. With improved manage-
regimens. ment of calcium and phosphorus metabolism during chronic dialysis,
The polyoma group (BK, JC, SV40) is another class of DNA viruses the incidence of parathyroid-related complications has fallen dra-
that can become dormant in kidneys and can be activated by immu- matically. Persistent hyperparathyroid activity may require subtotal
nosuppression. When reactivation occurs with BK, there is a 50% parathyroidectomy.
chance of progressive fibrosis and loss of the graft within 1 year by the Although most transplant patients have robust production of eryth-
activated virus. Risk of infection is associated with the overall degree ropoietin and normalization of hemoglobin, anemia is commonly
of immunosuppression rather than the individual immunosuppres- seen in the posttransplant period. Often the anemia is attributable
sive drugs used. Renal biopsy is necessary for the diagnosis. There to bone marrow–suppressant immunosuppressive medications such
have been variable results with leflunomide, cidofovir, and quinolone as azathioprine, mycophenolic acid, and sirolimus. Gastrointestinal
antibiotics (which are effective against polyoma helicase), but it is most bleeding is a common side effect of high-dose and long-term steroid
important to reduce the immunosuppressive load. administration. Many transplant patients have creatinine clearances of
The complications of glucocorticoid therapy are well known and 30–50 mL/min and can be considered in the same way as other
include gastrointestinal bleeding, impairment of wound healing, osteo- patients with chronic renal insufficiency for anemia management,
porosis, diabetes mellitus, cataract formation, and hemorrhagic pan- including supplemental erythropoietin.
creatitis. The treatment of unexplained jaundice in transplant patients Chronic hepatitis, particularly when due to hepatitis B virus, can
should include cessation or reduction of immunosuppressive drugs if be a progressive, fatal disease over a decade or so. Patients who are
hepatitis or drug toxicity is suspected. Therapy in such circumstances persistently hepatitis B surface antigen–positive are at higher risk,
often does not result in rejection of a graft, at least for several weeks. according to some studies, but the presence of hepatitis C virus is also
Acyclovir is effective in therapy for herpes simplex virus infections. a concern when one embarks on a course of immunosuppression in a
transplant recipient.
CHRONIC LESIONS OF THE TRANSPLANTED KIDNEY
Although 1-year transplant survival is excellent, most recipients expe-
rience progressive decline in kidney function over time thereafter.
Chronic renal transplant dysfunction can be caused by recurrent dis-
338
ease, hypertension, cyclosporine or tacrolimus nephrotoxicity, chronic
immunologic rejection, secondary focal glomerulosclerosis, or a Glomerular Diseases
combination of these pathophysiologies. Chronic vascular changes with Julia B. Lewis, Eric G. Neilson
intimal proliferation and medial hypertrophy are commonly found.
Control of systemic and intrarenal hypertension with angiotensin-
converting enzyme (ACE) inhibitors is thought to have a beneficial Two human kidneys harbor nearly 1.8 million glomerular capillary
influence on the rate of progression of chronic renal transplant dys- tufts. Each glomerular tuft resides within Bowman’s space. The cap-
function. Renal biopsy can distinguish subacute cellular rejection from sule circumscribing this space is lined by parietal epithelial cells that
recurrent disease or secondary focal sclerosis. transition into tubular epithelia forming the proximal nephron or
migrate into the tuft to replenish podocytes. The glomerular capillary
MALIGNANCY tuft derives from an afferent arteriole that forms a branching capil-
The incidence of tumors in patients on immunosuppressive therapy lary bed embedded in mesangial matrix (Fig. 338-1). This capillary
is 5–6%, or approximately 100 times greater than that in the general network funnels into an efferent arteriole, which passes filtered blood
population in the same age range. The most common lesions are can- into cortical peritubular capillaries or medullary vasa recta that supply
cer of the skin and lips and carcinoma in situ of the cervix, as well as and exchange with a folded tubular architecture. Hence the glomerular
lymphomas such as non-Hodgkin’s lymphoma. The risks are increased capillary tuft, fed and drained by arterioles, represents an arteriolar
in proportion to the total immunosuppressive load administered and portal system. Fenestrated endothelial cells resting on a glomerular
the time elapsed since transplantation. Surveillance for skin and cervi- basement membrane (GBM) line glomerular capillaries. Delicate foot
cal cancers is necessary. processes extending from epithelial podocytes shroud the outer surface
of these capillaries, and podocytes interconnect to each other by slit-
OTHER COMPLICATIONS pore membranes forming a selective filtration barrier.
Both chronic dialysis and renal transplant patients have a higher inci- The glomerular capillaries filter 120–180 L/d of plasma water con-
dence of death from myocardial infarction and stroke than does the taining various solutes for reclamation or discharge by downstream
HPIM19_Part13_p1799-1874.indd 1831 2/9/15 6:45 PM

1832
PART 13
Disorders of the Kidney and Urinary Tract
Figure 338-1 Glomerular architecture. A. The glomerular capillaries form from a branching network of renal arteries, arterioles, leading to an
afferent arteriole, glomerular capillary bed (tuft), and a draining efferent arteriole. (From VH Gattone II et al: Hypertension 5:8, 1983.) B. Scanning
electron micrograph of podocytes that line the outer surface of the glomerular capillaries (arrow shows foot process). C. Scanning electron
micrograph of the fenestrated endothelia lining the glomerular capillary. D. The various normal regions of the glomerulus on light microscopy.
(A–C: Courtesy of Dr. Vincent Gattone, Indiana University; with permission.)
tubules. Most large proteins and all cells are excluded from filtration Some glomerular diseases result from genetic mutations produc-
by a physicochemical barrier governed by pore size and negative ing familial disease or a founder effect: congenital nephrotic syn-
electrostatic charge. The mechanics of filtration and reclamation are drome from mutations in NPHS1 (nephrin) and NPHS2 (podocin)
quite complicated for many solutes (Chap. 325). For example, in affect the slit-pore membrane at birth, and TRPC6 cation channel muta-
the case of serum albumin, the glomerulus is an imperfect barrier. tions produce focal segmental glomerulosclerosis (FSGS) in adulthood;
Although albumin has a negative charge, which would tend to repel polymorphisms in the gene encoding apolipoprotein L1, APOL1, are a
the negatively charged GBM, it only has a physical radius of 3.6 nm, major risk for nearly 70% of African Americans with nondiabetic end-
while pores in the GBM and slit-pore membranes have a radius of stage renal disease, particularly FSGS; mutations in complement factor H
4 nm. Consequently, variable amounts of albumin inevitably cross associate with membranoproliferative glomerulonephritis (MPGN) or
the filtration barrier to be reclaimed by megalin and cubilin recep- atypical hemolytic uremic syndrome (aHUS), type II partial lipodystrophy
tors along the proximal tubule. Remarkably, humans with normal from mutations in genes encoding lamin A/C, or PPARγ cause a meta-
nephrons excrete on average 8–10 mg of albumin in daily voided bolic syndrome associated with MPGN, which is sometimes accompa-
urine, approximately 20–60% of total excreted protein. This amount nied by dense deposits and C3 nephritic factor; Alport’s syndrome, from
of albumin, and other proteins, can rise to gram quantities following mutations in the genes encoding for the α3, α4, or α5 chains of type IV
glomerular injury. collagen, produces split-basement membranes with glomerulosclerosis;
The breadth of diseases affecting the glomerulus is expansive and lysosomal storage diseases, such as α-galactosidase A deficiency
because the glomerular capillaries can be injured in a variety of ways, causing Fabry’s disease and N -acetylneuraminic acid hydrolase defi-
producing many different lesions. Some order to this vast subject is ciency causing nephrosialidosis, produce FSGS.
brought by grouping all of these diseases into a smaller number of Systemic hypertension and atherosclerosis can produce pressure
clinical syndromes. stress, ischemia, or lipid oxidants that lead to chronic glomeruloscle-
rosis. Malignant hypertension can quickly complicate glomeruloscle-
rosis with fibrinoid necrosis of arterioles and glomeruli, thrombotic
PATHOGENESIS OF GLOMERULAR DISEASE microangiopathy, and acute renal failure. Diabetic nephropathy is
There are many forms of glomerular disease with pathogenesis variably an acquired sclerotic injury associated with thickening of the GBM
linked to the presence of genetic mutations, infection, toxin exposure, secondary to the long-standing effects of hyperglycemia, advanced
autoimmunity, atherosclerosis, hypertension, emboli, thrombosis, or glycosylation end products, and reactive oxygen species.
diabetes mellitus. Even after careful study, however, the cause often Inflammation of the glomerular capillaries is called glomerulone-
remains unknown, and the lesion is called idiopathic. Specific or phritis. Most glomerular or mesangial antigens involved in immune-
unique features of pathogenesis are mentioned with the description of mediated glomerulonephritis are unknown (Fig. 338-2). Glomerular
each of the glomerular diseases later in this chapter. epithelial or mesangial cells may shed or express epitopes that mimic

other immunogenic proteins made elsewhere in the body. Bacteria, chemokines into the glomerular tuft, where they react with antigens 1833
fungi, and viruses can directly infect the kidney producing their own and epitopes on or near somatic cells or their structures, producing
antigens. Autoimmune diseases like idiopathic membranous glo- more cytokines and proteases that damage the mesangium, capillaries,

merulonephritis (MGN) or MPGN are confined to the kidney, whereas and/or the GBM. While the adaptive immune response is similar to
systemic inflammatory diseases like lupus nephritis or granulomatosis that of other tissues, early T cell activation plays an important role in
with polyangiitis (Wegener’s) spread to the kidney, causing second- the mechanism of glomerulonephritis. Antigens presented by class II
ary glomerular injury. Antiglomerular basement membrane disease major histocompatibility complex (MHC) molecules on macrophages
producing Goodpasture’s syndrome primarily injures both the lung and dendritic cells in conjunction with associative recognition mol-
and kidney because of the narrow distribution of the α3 NC1 domain ecules engage the CD4/8 T cell repertoire.
of type IV collagen that is the target antigen. Mononuclear cells by themselves can injure the kidney, but auto-
Local activation of Toll-like receptors on glomerular cells, deposi- immune events that damage glomeruli classically produce a humoral
tion of immune complexes, or complement injury to glomerular struc- immune response. Poststreptococcal glomerulonephritis, lupus nephri-
tures induces mononuclear cell infiltration, which subsequently leads tis, and idiopathic membranous nephritis typically are associated with
to an adaptive immune response attracted to the kidney by local release immune deposits along the GBM, while anti-GBM antibodies pro-
of chemokines. Neutrophils, macrophages, and T cells are drawn by duce the linear binding of anti-GBM disease. Preformed circulating
Basement
membrane
Subepithelial
deposit
Endothelia
Podocytes
Subendothelial
deposit Linear IgG staining IgG Lumpy-bumpy staining
A B C
N
Mθ
TH1/2 Immune
deposits
Cytokines Cytokines
Chemokines
Chemokines
Basement membrane Endocapillary Extracapillary

damage proliferation proliferation
Oxidants Proteases
C3/C5-9MAC
D
Figure 338-2 The glomerulus is injured by a variety of mechanisms. A. Preformed immune deposits can precipitate from the circulation
and collect along the glomerular basement membrane (GBM) in the subendothelial space or can form in situ along the subepithelial space.
B. Immunofluorescent staining of glomeruli with labeled anti-IgG demonstrating linear staining from a patient with anti-GBM disease or
immune deposits from a patient with membranous glomerulonephritis. C. The mechanisms of glomerular injury have a complicated patho-
genesis. Immune deposits and complement deposition classically draw macrophages and neutrophils into the glomerulus. T lymphocytes may
follow to participate in the injury pattern as well. D. Amplification mediators as locally derived oxidants and proteases expand this inflammation,
and, depending on the location of the target antigen and the genetic polymorphisms of the host, basement membranes are damaged with
either endocapillary or extracapillary proliferation.

1834 immune complexes can precipitate along the subendothelial side of the the primary route to downstream tubulointerstitial injury, although
GBM, while other immune deposits form in situ on the subepithelial none of these hypotheses are mutually exclusive.
side. These latter deposits accumulate when circulating autoantibodies The simplest explanation for the effect of proteinuria on the devel-
find their antigen trapped along the subepithelial edge of the GBM. opment of interstitial nephritis is that increasingly severe proteinuria,
PART 13
Immune deposits in the glomerular mesangium may result from the carrying activated cytokines and lipoproteins producing reactive
deposition of preformed circulating complexes or in situ antigen- oxygen species, triggers a downstream inflammatory cascade in and
antibody interactions. Immune deposits stimulate the release of local around epithelial cells lining the tubular nephron. These effects induce
proteases and activate the complement cascade, producing C5–9 attack T lymphocyte and macrophage infiltrates in the interstitial spaces
complexes. In addition, local oxidants damage glomerular structures, along with fibrosis and tubular atrophy.
producing proteinuria and effacement of the podocytes. Overlapping Tubules disaggregate following direct damage to their basement
etiologies or pathophysiologic mechanisms can produce similar glo- membranes, leading to epithelial-mesenchymal transitions forming
merular lesions, suggesting that downstream molecular and cellular more interstitial fibroblasts at the site of injury. Transforming growth
responses often converge toward common patterns of injury. factor β (TGF-β), fibroblast growth factor 2 (FGF-2), hypoxemia-
inducible factor 1α (HIF-1α), and platelet-derived growth factor (PDGF)
PROGRESSION OF GLOMERULAR DISEASE are particularly active in this transition. With persistent nephritis, fibro-
Persistent glomerulonephritis that worsens renal function is always blasts multiply and lay down tenascin and a fibronectin scaffold for the
accompanied by interstitial nephritis, renal fibrosis, and tubular atro- polymerization of new interstitial collagen types I/III. These events form
phy (see Fig. 62e-27). What is not so obvious, however, is that renal scar tissue through a process called fibrogenesis. In experimental studies,
failure in glomerulonephritis best correlates histologically with the bone morphogenetic protein 7 and hepatocyte growth factor can reverse
appearance of tubulointerstitial nephritis rather than with the type of early fibrogenesis and preserve tubular architecture. When fibroblasts
inciting glomerular injury. outdistance their survival factors, apoptoses occurs, and the permanent
Loss of renal function due to interstitial damage is explained hypo- renal scar becomes acellular, leading to irreversible renal failure.
thetically by several mechanisms. The simplest explanation is that
urine flow is impeded by tubular obstruction as a result of interstitial APPROACH TO THE PATIENT:
inflammation and fibrosis. Thus, obstruction of the tubules with
debris or by extrinsic compression results in aglomerular nephrons.
Glomerular Disease
A second mechanism suggests that interstitial changes, including HEMATURIA, PROTEINURIA, AND PYURIA
interstitial edema or fibrosis, alter tubular and vascular architecture Patients with glomerular disease usually have some hematuria with
and thereby compromise the normal tubular transport of solutes and varying degrees of proteinuria. Hematuria is typically asymptom-
water from tubular lumen to vascular space. This failure increases the atic. As few as three to five red blood cells in the spun sediment
solute and water content of the tubule fluid, resulting in isosthenuria from first-voided morning urine is suspicious. The diagnosis of glo-
and polyuria. Adaptive mechanisms related to tubuloglomerular merular injury can be delayed because patients will not realize they
feedback also fail, resulting in a reduction of renin output from have microscopic hematuria, and only rarely with the exception of
the juxtaglomerular apparatus trapped by interstitial inflammation. IgA nephropathy and sickle cell disease is gross hematuria present.
Consequently, the local vasoconstrictive influence of angiotensin II When working up microscopic hematuria, perhaps accompanied
on the glomerular arterioles decreases, and filtration drops owing to by minimal proteinuria (<500 mg/24 h), it is important to exclude
a generalized decrease in arteriolar tone. A third mechanism involves anatomic lesions, such as malignancy of the urinary tract, particu-
changes in vascular resistance due to damage of peritubular capil- larly in older men. Microscopic hematuria may also appear with the
laries. The cross-sectional volume of these capillaries is decreased onset of benign prostatic hypertrophy, interstitial nephritis, papil-
by interstitial inflammation, edema, or fibrosis. These structural lary necrosis, hypercalciuria, renal stones, cystic kidney diseases,
alterations in vascular resistance affect renal function through two or renal vascular injury. However, when red blood cell casts (see
mechanisms. First, tubular cells are very metabolically active, and, Fig. 62e-34) or dysmorphic red blood cells are found in the sedi-
as a result, decreased perfusion leads to ischemic injury. Second, ment, glomerulonephritis is likely.
impairment of glomerular arteriolar outflow leads to increased intra- Sustained proteinuria >1–2 g/24 h is also commonly associated with
glomerular hypertension in less-involved glomeruli; this selective glomerular disease. Patients often will not know they have proteinuria
intraglomerular hypertension aggravates and extends mesangial scle- unless they become edematous or notice foaming urine on voiding.
rosis and glomerulosclerosis to less-involved glomeruli. Regardless of Sustained proteinuria has to be distinguished from lesser amounts of
the exact mechanism, early acute tubulointerstitial nephritis (see Fig. so-called benign proteinuria in the normal population (Table 338-1).
62e-27) suggests potentially recoverable renal function, whereas the This latter class of proteinuria is nonsustained, generally <1 g/24 h,
development of chronic interstitial fibrosis prognosticates permanent and is sometimes called functional or transient proteinuria. Fever,
loss (see Fig. 62e-30). exercise, obesity, sleep apnea, emotional stress, and congestive heart
Persistent damage to glomerular capillaries spreads to the tubu- failure can explain transient proteinuria. Proteinuria only seen with
lointerstitium in association with proteinuria. There is a hypothesis upright posture is called orthostatic proteinuria and has a benign
that efferent arterioles leading from inflamed glomeruli carry for- prognosis. Isolated proteinuria sustained over multiple clinic visits
ward inflammatory mediators, which induces downstream interstitial is found in many glomerular lesions. Proteinuria in most adults with
nephritis, resulting in fibrosis. Glomerular filtrate from injured glo- glomerular disease is nonselective, containing albumin and a mixture
merular capillaries adherent to Bowman’s capsule may also be misdi- of other serum proteins, whereas in children with minimal change
rected to the periglomerular interstitium. Most nephrologists believe, disease, the proteinuria is selective and composed largely of albumin.
however, that proteinuric glomerular filtrate forming tubular fluid is
Table 338-1 Urine Assays for Albuminuria/Proteinuria

24-Hour Albumina Albumina /Creatinine Dipstick 24-Hour Urine Proteinb
(mg/24 h) Ratio (mg/g) Proteinuria (mg/24 h)
Normal 8–10 <30 − <150
Microalbuminuria 30–300 30–300 −/Trace/1+ −
Proteinuria >300 >300 Trace−3+ >150
Albumin detected by radioimmunoassay. b Albumin represents 20–60% of the total protein excreted in the urine.
a

1835
Some patients with inflammatory glomerular disease, such as CLINICAL SYNDROMES
acute poststreptococcal glomerulonephritis or MPGN, have pyuria Various forms of glomerular injury can also be parsed into sev-
characterized by the presence of considerable numbers of leuko- eral distinct syndromes on clinical grounds (Table 338-2). These

cytes. This latter finding has to be distinguished from urine infected syndromes, however, are not always mutually exclusive. There is
with bacteria. an acute nephritic syndrome producing 1–2 g/24 h of proteinuria,
Table 338-2 Patterns of Clinical Glomerulonephritis

Glomerular Syndromes Proteinuria Hematuria Vascular Injury
Acute Nephritic Syndromes
Poststreptococcal glomerulonephritisa +/++ ++/+++ −
Subacute bacterial endocarditisa +/++ ++ −
Lupus nephritisa +/++ ++/+++ +
Antiglomerular basement membrane diseasea ++ ++/+++ −
IgA nephropathya +/++ +++c −
ANCA small-vessel vasculitisa
Granulomatosis with polyangiitis (Wegener’s) +/++ ++/+++ ++++
Microscopic polyangiitis +/++ ++/+++ ++++
Churg-Strauss syndrome +/++ ++/+++ ++++
Henoch-Schönlein purpuraa +/++ ++/+++ ++++
Cryoglobulinemiaa +/++ ++/+++ ++++
Membranoproliferative glomerulonephritisa ++ ++/+++ −
Mesangioproliferative glomerulonephritis + +/++ −
Pulmonary-Renal Syndromes
Goodpasture’s syndromea ++ ++/+++ −
Churg-Strauss syndrome +/++ ++/+++ ++++
Nephrotic Syndromes
Minimal change disease ++++ − −
Focal segmental glomerulosclerosis +++/++++ + −
Membranous glomerulonephritis ++++ + −
Diabetic nephropathy ++/++++ −/+ −
AL and AA amyloidosis +++/++++ + +/++
Light-chain deposition disease +++ + −
Fibrillary-immunotactoid disease +++/++++ + +
Fabry’s disease + + −
Basement Membrane Syndromes
Anti-GBM diseasea ++ ++/+++ –
Alport’s syndrome ++ ++ –
Thin basement membrane disease + ++ –
Nail-patella syndrome ++/+++ ++ –
Glomerular Vascular Syndromes
Atherosclerotic nephropathy + + +++
Hypertensive nephropathyb +/++ +/++ ++
Cholesterol emboli +/++ ++ +++
Sickle cell disease +/++ +++c +++
Thrombotic microangiopathies ++ ++ +++
Antiphospholipid syndrome ++ ++ +++
Churg-Strauss syndrome +++ ++/+++ ++++
AL and AA amyloidosis +++/++++ + +/++
(Continued)

1836 Table 338-2 Patterns of Clinical Glomerulonephritis (Continued)
Infectious Disease–Associated Syndromes
Poststreptococcal glomerulonephritisa +/++ ++/+++ −
PART 13
Subacute bacterial endocarditisa +/++ ++ −

HIV +++ +/++ −
Hepatitis B and C +++ +/++ −
Syphilis +++ + −
Leprosy +++ + −
Malaria +++ +/++ −
Schistosomiasis +++ +/++ −

a
Can present as rapidly progressive glomerulonephritis (RPGN); sometimes called crescentic glomerulonephritis. bCan present as a malignant hyper-
tensive crisis producing an aggressive fibrinoid necrosis in arterioles and small arteries with microangiopathic hemolytic anemia. cCan present with
gross hematuria.
Abbreviations: AA, amyloid A; AL, amyloid L; ANCA, antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane.
hematuria with red blood cell casts, pyuria, hypertension, fluid physical examination can also help determine whether the glo-
retention, and a rise in serum creatinine associated with a reduc- merulonephritis is isolated to the kidney (primary glomerulonephri-
tion in glomerular filtration. If glomerular inflammation devel- tis) or is part of a systemic disease (secondary glomerulonephritis).
ops slowly, the serum creatinine will rise gradually over many When confronted with an abnormal urinalysis and elevated
weeks, but if the serum creatinine rises quickly, particularly over serum creatinine, with or without edema or congestive heart fail-
a few days, acute nephritis is sometimes called rapidly progressive ure, one must consider whether the glomerulonephritis is acute or
glomerulonephritis (RPGN); the histopathologic term crescentic chronic. This assessment is best made by careful history (last known
glomerulonephritis is the pathologic equivalent of the clinical urinalysis or serum creatinine during pregnancy or insurance
presentation of RPGN. When patients with RPGN present with physical, evidence of infection, or use of medication or recreational
lung hemorrhage from Goodpasture’s syndrome, antineutrophil drugs); the size of the kidneys on renal ultrasound examination;
cytoplasmic antibodies (ANCA)-associated small-vessel vasculitis, and how the patient feels at presentation. Chronic glomerular
lupus erythematosus, or cryoglobulinemia, they are often diag- disease often presents with decreased kidney size. Patients who
nosed as having a pulmonary-renal syndrome. Nephrotic syndrome quickly develop renal failure are fatigued and weak and often have
describes the onset of heavy proteinuria (>3.0 g/24 h), hyperten- uremic symptoms associated with nausea, vomiting, fluid reten-
sion, hypercholesterolemia, hypoalbuminemia, edema/anasarca, tion, and somnolence. Primary glomerulonephritis presenting with
and microscopic hematuria; if only large amounts of proteinuria are renal failure that has progressed slowly, however, can be remark-
present without clinical manifestations, the condition is sometimes ably asymptomatic, as are patients with acute glomerulonephritis
called nephrotic-range proteinuria. The glomerular filtration rate without much loss in renal function. Once this initial information is
(GFR) in these patients may initially be normal or, rarely, higher collected, selected patients who are clinically stable, have adequate
than normal, but with persistent hyperfiltration and continued blood clotting parameters, and are willing and able to receive treat-
nephron loss, it typically declines over months to years. Patients ment are encouraged to have a renal biopsy.
with a basement membrane syndrome either have genetically
abnormal basement membranes (Alport’s syndrome) or an autoim-
RENAL PATHOLOGY
mune response to basement membrane collagen IV (Goodpasture’s
A renal biopsy in the setting of glomerulonephritis quickly identifies
syndrome) associated with microscopic hematuria, mild to heavy
the type of glomerular injury and often suggests a course of treatment.
proteinuria, and hypertension with variable elevations in serum
The biopsy is processed for light microscopy using stains for hema-
creatinine. Glomerular–vascular syndrome describes patients with
toxylin and eosin (H&E) to assess cellularity and architecture, periodic
vascular injury producing hematuria and moderate proteinuria.
acid–Schiff (PAS) to stain carbohydrate moieties in the membranes of
Affected individuals can have vasculitis, thrombotic microangi-
the glomerular tuft and tubules, Jones-methenamine silver to enhance
opathy, antiphospholipid syndrome, or, more commonly, a systemic
basement membrane structure, Congo red for amyloid deposits, and
disease such as atherosclerosis, cholesterol emboli, hypertension,
Masson’s trichrome to identify collagen deposition and assess the
sickle cell anemia, and autoimmunity. Infectious disease–associated
degree of glomerulosclerosis and interstitial fibrosis. Biopsies are also
syndrome is most important if one has a global perspective. Save
processed for direct immunofluorescence using conjugated antibodies
for subacute bacterial endocarditis in the Western Hemisphere,
against IgG, IgM, and IgA to detect the presence of “lumpy-bumpy”
malaria and schistosomiasis may be the most common causes of
immune deposits or “linear” IgG or IgA antibodies bound to GBM,
glomerulonephritis throughout the world, closely followed by HIV
antibodies against trapped complement proteins (C3 and C4), or spe-
and chronic hepatitis B and C. These infectious diseases produce a
cific antibodies against a relevant antigen. High-resolution electron
variety of inflammatory reactions in glomerular capillaries, ranging
microscopy can clarify the principal location of immune deposits and
from nephrotic syndrome to acute nephritic injury, and urinalyses
the status of the basement membrane.
that demonstrate a combination of hematuria and proteinuria.
Each region of a renal biopsy is assessed separately. By light micros-
These six general categories of syndromes are usually deter-
copy, glomeruli (at least 10 and ideally 20) are reviewed individually
mined at the bedside with the help of a history and physical
for discrete lesions; <50% involvement is considered focal, and >50%
examination, blood chemistries, renal ultrasound, and urinaly-
is diffuse. Injury in each glomerular tuft can be segmental, involving
sis. These initial studies help frame further diagnostic workup
a portion of the tuft, or global, involving most of the glomerulus.
that typically involves testing of the serum for the presence of
Glomeruli having proliferative characteristics show increased cellular-
various proteins (HIV and hepatitis B and C antigens), anti-
ity. When cells in the capillary tuft proliferate, it is called endocapillary,
bodies (anti-GBM, antiphospholipid, antistreptolysin O [ASO],
and when cellular proliferation extends into Bowman’s space, it is
anti-DNAse, antihyaluronidase, ANCA, anti-DNA, cryoglobulins,
called extracapillary. Synechiae are formed when epithelial podocytes
anti-HIV, and anti-hepatitis B and C antibodies) or depletion of
attach to Bowman’s capsule in the setting of glomerular injury; cres-
complement components (C3 and C4). The bedside history and
cents, which in some cases may be the extension of synechiae, develop

when fibrocellular/fibrin collections fill all or part of Bowman’s space; immune complexes, and activation of complement in association with 1837
and sclerotic glomeruli show acellular, amorphous accumulations of cell-mediated injury. Many candidate antigens have been proposed
proteinaceous material throughout the tuft with loss of functional over the years; candidates from nephritogenic streptococci of interest

capillaries and normal mesangium. Since age-related glomerulosclero- at the moment are: a cationic cysteine proteinase known as strepto-
sis is common in adults, one can estimate the background percentage coccal pyrogenic exotoxin B (SPEB) that is generated by proteolysis
of sclerosis by dividing the patient’s age in half and subtracting 10. of a zymogen precursor (zSPEB), and NAPlr, the nephritis-associated
Immunofluorescent and electron microscopy can detect the presence plasmin receptor. These two antigens have biochemical affinity for
and location of subepithelial, subendothelial, or mesangial immune plasmin, bind as complexes facilitated by this relationship, and activate
deposits, or reduplication or splitting of the basement membrane. In the alternate complement pathway. The nephritogenic antigen, SPEB,
the other regions of the biopsy, the vasculature surrounding glomeruli has been demonstrated inside the subepithelial “humps” on biopsy.
and tubules can show angiopathy, vasculitis, the presence of fibrils, or The classic presentation is an acute nephritic picture with hematuria,
thrombi. The tubules can be assessed for adjacency to one another; pyuria, red blood cell casts, edema, hypertension, and oliguric renal
separation can be the result of edema, tubular dropout, or collagen failure, which may be severe enough to appear as RPGN. Systemic
deposition resulting from interstitial fibrosis. Interstitial fibrosis is an symptoms of headache, malaise, anorexia, and flank pain (due to
ominous sign of irreversibility and progression to renal failure. swelling of the renal capsule) are reported in as many as 50% of cases.
Five percent of children and 20% of adults have proteinuria in the
ACUTE NEPHRITIC SYNDROMES nephrotic range. In the first week of symptoms, 90% of patients will
have a depressed CH50 and decreased levels of C3 with normal levels of
Acute nephritic syndromes classically present with hypertension, hema-
C4. Positive rheumatoid factor (30–40%), cryoglobulins and circulating
turia, red blood cell casts, pyuria, and mild to moderate proteinuria.
immune complexes (60–70%), and ANCA against myeloperoxidase
Extensive inflammatory damage to glomeruli causes a fall in GFR and
(10%) are also reported. Positive cultures for streptococcal infection
eventually produces uremic symptoms with salt and water retention,
are inconsistently present (10–70%), but increased titers of ASO (30%),
leading to edema and hypertension.
anti-DNAse, (70%), or antihyaluronidase antibodies (40%) can help
POSTSTREPTOCOCCAL GLOMERULONEPHRITIS confirm the diagnosis. Consequently, the diagnosis of poststreptococcal
Poststreptococcal glomerulonephritis is prototypical for acute endo- glomerulonephritis rarely requires a renal biopsy. A subclinical disease
capillary proliferative glomerulonephritis. The incidence of poststrep- is reported in some series to be four to five times as common as clini-
tococcal glomerulonephritis has dramatically decreased in developed cal nephritis, and these latter cases are characterized by asymptomatic
countries and in these locations is typically sporadic. Acute poststrep- microscopic hematuria with low serum C3 complement levels.
tococcal glomerulonephritis in underdeveloped countries is epidemic Treatment is supportive, with control of hypertension, edema,
and usually affects children between the ages of 2 and 14 years, but in and dialysis as needed. Antibiotic treatment for streptococcal infec-
developed countries is more typical in the elderly, especially in asso- tion should be given to all patients and their cohabitants. There
ciation with debilitating conditions. It is more common in males, and is no role for immunosuppressive therapy, even in the setting of
the familial or cohabitant incidence is as high as 40%. Skin and throat crescents. Recurrent poststreptococcal glomerulonephritis is rare
infections with particular M types of streptococci (nephritogenic despite repeated streptococcal infections. Early death is rare in chil-
strains) antedate glomerular disease; M types 47, 49, 55, 2, 60, and 57 dren but does occur in the elderly. Overall, the prognosis is good,
are seen following impetigo and M types 1, 2, 4, 3, 25, 49, and 12 with with permanent renal failure being very uncommon, less than 1% in
pharyngitis. Poststreptococcal glomerulonephritis due to impetigo children. Complete resolution of the hematuria and proteinuria in the
develops 2–6 weeks after skin infection and 1–3 weeks after streptococ- majority of children occurs within 3–6 weeks of the onset of nephritis
cal pharyngitis. but 3–10% of children may have persistent microscopic hematuria,
The renal biopsy in poststreptococcal glomerulonephritis demon- nonnephrotic proteinuria, or hypertension. The prognosis in elderly
strates hypercellularity of mesangial and endothelial cells, glomerular patients is worse with a high incidence of azotemia (up to 60%),
infiltrates of polymorphonuclear leukocytes, granular subendothelial nephrotic-range proteinuria, and end-stage renal disease.
immune deposits of IgG, IgM, C3, C4, and C5–9, and subepithelial
deposits (which appear as “humps”) (see Fig. 62e-6). (See Glomerular SUBACUTE BACTERIAL ENDOCARDITIS
Schematic 1.) Poststreptococcal glomerulonephritis is an immune- Endocarditis-associated glomerulonephritis is typically a complica-
mediated disease involving putative streptococcal antigens, circulating tion of subacute bacterial endocarditis, particularly in patients who
remain untreated for a long time, have negative blood cultures, or
have right-sided endocarditis. Glomerulonephritis is unusual in acute
Glomerular schematic 1 bacterial endocarditis because it takes 10–14 days to develop immune
complex–mediated injury, by which time the patient has been treated,
Hump
often with emergent surgery. Grossly, the kidneys in subacute bacte-
rial endocarditis have subcapsular hemorrhages with a “flea-bitten”
appearance, and microscopy on renal biopsy reveals focal prolif-
eration around foci of necrosis associated with abundant mesangial,
subendothelial, and subepithelial immune deposits of IgG, IgM, and
C3. Patients who present with a clinical picture of RPGN have cres-
cents. Embolic infarcts or septic abscesses may also be present. The
Poly pathogenesis hinges on the renal deposition of circulating immune
complexes in the kidney with complement activation. Patients present
with gross or microscopic hematuria, pyuria, and mild proteinuria or,
less commonly, RPGN with rapid loss of renal function. A normocytic
Mesangial anemia, elevated erythrocyte sedimentation rate, hypocomplement-
deposits emia, high titers of rheumatoid factor, type III cryoglobulins, circulat-
ing immune complexes, and ANCAs may be present. Levels of serum
creatinine may be elevated at diagnosis, but with modern therapy
there is little progression to chronic renal failure. Primary treatment
POST- is eradication of the infection with 4–6 weeks of antibiotics, and if
STREPTOCOCCAL accomplished expeditiously, the prognosis for renal recovery is good.
GLOMERULONEPHRITIS ANCA-associated vasculitis sometimes accompanies or is confused

1838 with subacute bacterial endocarditis (SBE) and should be ruled out, as Table 338-3 Classification for Lupus Nephritis
the treatment is different.
Class I Minimal mesangial Normal histology with mesangial
As variants of persistent bacterial infection in blood-associated deposits
glomerulonephritis, postinfectious glomerulonephritis can occur in
Class II Mesangial proliferation Mesangial hypercellularity with
PART 13
patients with ventriculoatrial and ventriculoperitoneal shunts; pul- expansion of the mesangial matrix
monary, intraabdominal, pelvic, or cutaneous infections; and infected
Class III Focal nephritis Focal endocapillary ± extracapillary
vascular prostheses. In developed countries, a significant proportion proliferation with focal subendo-
of cases afflict adults, especially the immunocompromised, and the thelial immune deposits and mild
predominant organism is Staphylococcus. The clinical presentation mesangial expansion
of these conditions is variable and includes proteinuria, microscopic Class IV Diffuse nephritis Diffuse endocapillary ± extracapillary
hematuria, acute renal failure, and hypertension. Serum complement proliferation with diffuse subendo-
levels are low, and there may be elevated levels of C-reactive proteins, thelial immune deposits and mesan-
rheumatoid factor, antinuclear antibodies, and cryoglobulins. Renal gial alterations
lesions include membranoproliferative glomerulonephritis (MPGN), Class V Membranous nephritis Thickened basement membranes
diffuse proliferative and exudative glomerulonephritis (DPGN), or with diffuse subepithelial immune
deposits; may occur with class III or
mesangioproliferative glomerulonephritis, sometimes leading to
IV lesions and is sometimes called
RPGN. Treatment focuses on eradicating the infection, with most mixed membranous and proliferative
patients treated as if they have endocarditis. The prognosis is guarded. nephritis
Class VI Sclerotic nephritis Global sclerosis of nearly all glomeru-
LUPUS NEPHRITIS lar capillaries
Lupus nephritis is a common and serious complication of systemic Note: Revised in 2004 by the International Society of Nephrology-Renal Pathology Society
lupus erythematosus (SLE) and most severe in African-American Study Group.
female adolescents. Thirty to 50% of patients will have clinical mani-
festations of renal disease at the time of diagnosis, and 60% of adults
and 80% of children develop renal abnormalities at some point in the with proliferation or scarring, often involving only a segment of the
course of their disease. Lupus nephritis results from the deposition of glomerulus (see Fig. 62e-12). Class III lesions have the most varied
circulating immune complexes, which activate the complement cas- course. Hypertension, an active urinary sediment, and proteinuria
cade leading to complement-mediated damage, leukocyte infiltration, are common with nephrotic-range proteinuria in 25–33% of patients.
activation of procoagulant factors, and release of various cytokines. Elevated serum creatinine is present in 25% of patients. Patients with
In situ immune complex formation following glomerular binding of mild proliferation involving a small percentage of glomeruli respond
nuclear antigens, particularly necrotic nucleosomes, also plays a role well to therapy with steroids alone, and fewer than 5% progress to renal
in renal injury. The presence of antiphospholipid antibodies may also failure over 5 years. Patients with more severe proliferation involving a
trigger a thrombotic microangiopathy in a minority of patients. greater percentage of glomeruli have a far worse prognosis and lower
The clinical manifestations, course of disease, and treatment remission rates. Treatment of those patients is the same as that for class
of lupus nephritis are closely linked to renal pathology. The most IV lesions. Many nephrologists believe that class III lesions are simply
common clinical sign of renal disease is proteinuria, but hematuria, an early presentation of class IV disease. Others believe severe class
hypertension, varying degrees of renal failure, and active urine sedi- III disease is a discrete lesion requiring aggressive therapy. Class IV
ment with red blood cell casts can all be present. Although significant describes global, diffuse proliferative lesions involving the vast majority
renal pathology can be found on biopsy even in the absence of major of glomeruli. Patients with class IV lesions commonly have high anti-
abnormalities in the urinalysis, most nephrologists do not biopsy DNA antibody titers, low serum complement, hematuria, red blood
patients until the urinalysis is convincingly abnormal. The extrarenal cell casts, proteinuria, hypertension, and decreased renal function; 50%
manifestations of lupus are important in establishing a firm diagnosis of patients have nephrotic-range proteinuria. Patients with crescents
of systemic lupus because, while serologic abnormalities are common on biopsy often have a rapidly progressive decline in renal function
in lupus nephritis, they are not diagnostic. Anti-dsDNA antibodies (see Fig. 62e-12). Without treatment, this aggressive lesion has the
that fix complement correlate best with the presence of renal dis- worst renal prognosis. However, if a remission—defined as a return to
ease. Hypocomplementemia is common in patients with acute lupus near-normal renal function and proteinuria ≤330 mg/dL per day—is
nephritis (70–90%) and declining complement levels may herald a achieved with treatment, renal outcomes are excellent. Current evi-
flare. Although urinary biomarkers of lupus nephritis are being identi- dence suggests that inducing a remission with administration of high-
fied to assist in predicting renal flares, renal biopsy is the only reliable dose steroids and either cyclophosphamide or mycophenolate mofetil
method of identifying the morphologic variants of lupus nephritis. for 2–6 months, followed by maintenance therapy with lower doses of
The World Health Organization (WHO) workshop in 1974 first steroids and mycophenolate mofetil or azathioprine, best balances the
outlined several distinct patterns of lupus-related glomerular injury; likelihood of successful remission with the side effects of therapy. There
these were modified in 1982. In 2004 the International Society of is no consensus on use of high-dose intravenous methylprednisolone
Nephrology in conjunction with the Renal Pathology Society again versus oral prednisone, monthly intravenous cyclophosphamide versus
updated the classification. This latest version of lesions seen on biopsy daily oral cyclophosphamide, or other immunosuppressants such as
(Table 338-3) best defines clinicopathologic correlations, provides cyclosporine, tacrolimus, rituximab, or belimumab. Nephrologists tend
valuable prognostic information, and forms the basis for modern treat- to avoid prolonged use of cyclophosphamide in patients of childbearing
ment recommendations. Class I nephritis describes normal glomerular age without first banking eggs or sperm.
histology by any technique or normal light microscopy with minimal The class V lesion describes subepithelial immune deposits produc-
mesangial deposits on immunofluorescent or electron microscopy. ing a membranous pattern; a subcategory of class V lesions is associated
Class II designates mesangial immune complexes with mesangial with proliferative lesions and is sometimes called mixed membranous
proliferation. Both class I and II lesions are typically associated with and proliferative disease (see Fig. 62e-11); this category of injury is
minimal renal manifestation and normal renal function; nephrotic treated like class IV glomerulonephritis. Sixty percent of patients pres-
syndrome is rare. Patients with lesions limited to the renal mesangium ent with nephrotic syndrome or lesser amounts of proteinuria. Patients
have an excellent prognosis and generally do not need therapy for their with lupus nephritis class V, like patients with idiopathic membranous
lupus nephritis. nephropathy, are predisposed to renal-vein thrombosis and other
The subject of lupus nephritis is presented under acute nephritic thrombotic complications. A minority of patients with class V will
syndromes because of the aggressive and important proliferative present with hypertension and renal dysfunction. There are conflict-
lesions seen in class III–V renal disease. Class III describes focal lesions ing data on the clinical course, prognosis, and appropriate therapy for

patients with class V disease, which may reflect the heterogeneity of this plasmapheresis and can be lifesaving. Treated patients with less severe 1839
group of patients. Patients with severe nephrotic syndrome, elevated disease typically respond to 8–10 treatments of plasmapheresis accom-
serum creatinine, and a progressive course will probably benefit from panied by oral prednisone and cyclophosphamide in the first 2 weeks.

therapy with steroids in combination with other immunosuppressive Kidney transplantation is possible, but because there is risk of recur-
agents. Therapy with inhibitors of the renin-angiotensin system also rence, experience suggests that patients should wait for 6 months and
may attenuate the proteinuria. Antiphospholipid antibodies present in until serum antibodies are undetectable.
lupus may result in glomerular microthromboses and complicate the
course in up to 20% of lupus nephritis patients. The renal prognosis is IgA NEPHROPATHY
worse even with anticoagulant therapy. Berger first described the glomerulonephritis now termed IgA
Patients with any of the above lesions also can transform to another nephropathy. It is classically characterized by episodic hematuria asso-
lesion; hence patients often require reevaluation, including repeat ciated with the deposition of IgA in the mesangium. IgA nephropathy
renal biopsy. Lupus patients with class VI lesions have greater than is one of the most common forms of glomerulonephritis worldwide.
90% sclerotic glomeruli and end-stage renal disease with interstitial There is a male preponderance, a peak incidence in the second and
fibrosis. As a group, approximately 20% of patients with lupus nephri- third decades of life, and rare familial clustering. There are geographic
tis will reach end-stage disease, requiring dialysis or transplantation. differences in the prevalence of IgA nephropathy, with 30% preva-
Systemic lupus tends to become quiescent once there is renal failure, lence along the Asian and Pacific Rim and 20% in southern Europe,
perhaps due to the immunosuppressant effects of uremia. However, compared to a much lower prevalence in northern Europe and North
patients with lupus nephritis have a markedly increased mortality America. It was initially hypothesized that variation in detection, in
compared with the general population. Renal transplantation in renal part, accounted for regional differences. With clinical care in nephrol-
failure from lupus, usually performed after approximately 6 months ogy becoming more uniform, this variation in prevalence more likely
of inactive disease, results in allograft survival rates comparable to reflects true differences among racial and ethnic groups.
patients transplanted for other reasons. IgA nephropathy is predominantly a sporadic disease but suscep-
tibility to it has been shown uncommonly to have a genetic compo-
ANTIGLOMERULAR BASEMENT MEMBRANE DISEASE nent depending on geography and the existence of “founder effects.”
Patients who develop autoantibodies directed against glomerular Familial forms of IgA nephropathy are more common in northern
basement antigens frequently develop a glomerulonephritis termed Italy and eastern Kentucky. No single causal gene has been identified.
antiglomerular basement membrane (anti-GBM) disease. When they Clinical and laboratory evidence suggests close similarities between
present with lung hemorrhage and glomerulonephritis, they have a Henoch-Schönlein purpura and IgA nephropathy. Henoch-Schönlein
pulmonary-renal syndrome called Goodpasture’s syndrome. The target purpura is distinguished clinically from IgA nephropathy by promi-
epitopes for this autoimmune disease lie in the quaternary structure nent systemic symptoms, a younger age (<20 years old), preceding
of α3 NC1 domain of collagen IV. Indeed, anti-GBM disease may infection, and abdominal complaints. Deposits of IgA are also found
be considered an autoimmune “conformeropathy” that involves in the glomerular mesangium in a variety of systemic diseases, includ-
the perturbation of quaternary structure of the α 345NC1 hexamer. ing chronic liver disease, Crohn’s disease, gastrointestinal adenocar-
MHC-restricted T cells initiate the autoantibody response because cinoma, chronic bronchiectasis, idiopathic interstitial pneumonia,
humans are not tolerant to the epitopes created by this quaternary dermatitis herpetiformis, mycosis fungoides, leprosy, ankylosing spon-
structure. The epitopes are normally sequestered in the collagen IV dylitis, relapsing polychondritis, and Sjögren’s syndrome. IgA deposi-
hexamer and can be exposed by infection, smoking, oxidants, or sol- tion in these entities is not usually associated with clinically significant
vents. Goodpasture’s syndrome appears in two age groups: in young glomerular inflammation or renal dysfunction and thus is not called
men in their late twenties and in men and women in their sixties and IgA nephropathy.
seventies. Disease in the younger age group is usually explosive, with IgA nephropathy is an immune complex–mediated glomerulo-
hemoptysis, a sudden fall in hemoglobin, fever, dyspnea, and hematu- nephritis defined by the presence of diffuse mesangial IgA deposits
ria. Hemoptysis is largely confined to smokers, and those who present often associated with mesangial hypercellularity. (See Glomerular
with lung hemorrhage as a group do better than older populations Schematic 2.) IgM, IgG, C3, or immunoglobulin light chains may be
who have prolonged, asymptomatic renal injury; presentation with codistributed with IgA. IgA deposited in the mesangium is typically
oliguria is often associated with a particularly bad outcome. The per- polymeric and of the IgA1 subclass, the pathogenic significance of
formance of an urgent kidney biopsy is important in suspected cases of which is not clear. Abnormalities have been described in IgA pro-
Goodpasture’s syndrome to confirm the diagnosis and assess progno- duction by plasma cells, particularly secretory IgA; in IgA clearance,
sis. Renal biopsies typically show focal or segmental necrosis that later, predominately by the liver; in mesangial IgA clearance and recep-
with aggressive destruction of the capillaries by cellular proliferation, tors for IgA; and in growth factor and cytokine-mediated events.
leads to crescent formation in Bowman’s space (see Fig. 62e-14). As Currently, however, abnormalities in the O -glycosylation of the hinge
these lesions progress, there is concomitant interstitial nephritis with region of IgA seem to best account for the pathogenesis of sporadic
fibrosis and tubular atrophy. IgA nephropathy. Despite the presence of elevated serum IgA levels
The presence of anti-GBM antibodies and complement is recognized in 20–50% of patients, IgA deposition in skin biopsies in 15–55% of
on biopsy by linear immunofluorescent staining for IgG (rarely IgA). patients, or elevated levels of secretory IgA and IgA-fibronectin com-
In testing serum for anti-GBM antibodies, it is particularly important plexes, a renal biopsy is necessary to confirm the diagnosis. Although
that the α3 NC1 domain of collagen IV alone be used as the target. the immunofluorescent pattern of IgA on renal biopsy defines IgA
This is because nonnephritic antibodies against the α1 NC1 domain nephropathy in the proper clinical context, a variety of histologic
are seen in paraneoplastic syndromes and cannot be discerned from lesions may be seen on light microscopy (see Fig. 62e-8), including
assays that use whole basement membrane fragments as the binding DPGN; segmental sclerosis; and, rarely, segmental necrosis with cellular
target. Between 10 and 15% of sera from patients with Goodpasture’s crescent formation, which typically presents as RPGN.
syndrome also contain ANCA antibodies against myeloperoxidase. The two most common presentations of IgA nephropathy are
This subset of patients has a vasculitis-associated variant, which has a recurrent episodes of macroscopic hematuria during or immediately
surprisingly good prognosis with treatment. Prognosis at presentation following an upper respiratory infection often accompanied by pro-
is worse if there are >50% crescents on renal biopsy with advanced teinuria or persistent asymptomatic microscopic hematuria. Nephrotic
fibrosis, if serum creatinine is >5–6 mg/dL, if oliguria is present, or if syndrome is uncommon. Proteinuria can also first appear late in the
there is a need for acute dialysis. Although frequently attempted, most course of the disease. Rarely patients present with acute renal failure
of these latter patients will not respond to plasmapheresis and steroids. and a rapidly progressive clinical picture. IgA nephropathy is a benign
Patients with advanced renal failure who present with hemoptysis disease for the majority of patients, and 5–30% of patients may go
should still be treated for their lung hemorrhage, as it responds to into a complete remission, with others having hematuria but well

1840 Glomerular schematic 2 receive urgent treatment. Induction therapy usually includes some
combination of plasmapheresis, methylprednisolone, and cyclo-
phosphamide. Monthly “pulse” IV cyclophosphamide to induce
remission of ANCA-associated vasculitis is as effective as daily oral
PART 13
cyclophosphamide but may be associated with increased relapses.

Steroids are tapered soon after acute inflammation subsides, and
patients are maintained on cyclophosphamide or azathioprine for up
to a year to minimize the risk of relapse. Benefit with using mycophe-
nolate mofetil or rituximab has not been proven.
Granulomatosis with Polyangiitis Patients with this disease classically
present with fever, purulent rhinorrhea, nasal ulcers, sinus pain, poly-
arthralgias/arthritis, cough, hemoptysis, shortness of breath, micro-
scopic hematuria, and 0.5–1 g/24 h of proteinuria; occasionally there
may be cutaneous purpura and mononeuritis multiplex. Presentation
without renal involvement is termed limited granulomatosis with
polyangiitis, although some of these patients will show signs of renal
Mesangial deposits injury later. Chest x-ray often reveals nodules and persistent infiltrates,
plus more sometimes with cavities. Biopsy of involved tissue will show a small-
mesangial cells IgA vessel vasculitis and adjacent noncaseating granulomas. Renal biopsies
NEPHROPATHY
during active disease demonstrate segmental necrotizing glomerulo-
nephritis without immune deposits (see Fig. 62e-13). The disease
is more common in patients exposed to silica dust and those with
α1-antitrypsin deficiency, which is an inhibitor of PR3. Relapse after
achieving remission is common and is more common in patients with
granulomatosis with polyangiitis than the other ANCA-associated vas-
culitis, necessitating diligent follow-up care. Although associated with
an unacceptable high mortality rate without treatment, the greatest
threat to patients, especially elderly patients in the first year of therapy,
preserved renal function. In the minority of patients who have progres-
is from adverse events, which are often secondary to treatment, rather
sive disease, progression is slow, with renal failure seen in only 25–30%
than active vasculitis.
of patients with IgA nephropathy over 20–25 years. This risk varies
considerably among populations. Cumulatively, risk factors for the loss Microscopic Polyangiitis Clinically, these patients look somewhat simi-
of renal function identified thus far account for less than 50% of the lar to those with granulomatosis with polyangiitis, except they rarely
variation in observed outcome but include the presence of hyperten- have significant lung disease or destructive sinusitis. The distinction
sion or proteinuria, the absence of episodes of macroscopic hematuria, is made on biopsy, where the vasculitis in microscopic polyangiitis is
male sex, older age of onset, and extensive glomerulosclerosis or inter- without granulomas. Some patients will also have injury limited to the
stitial fibrosis on renal biopsy. Several analyses in large populations of capillaries and venules.
patients found persistent proteinuria for 6 months or longer to have
the greatest predictive power for adverse renal outcomes. Churg-Strauss Syndrome When small-vessel vasculitis is associated
There is no agreement on optimal treatment. Both large studies that with peripheral eosinophilia, cutaneous purpura, mononeuritis,
include patients with multiple glomerular diseases and small studies asthma, and allergic rhinitis, a diagnosis of Churg-Strauss syndrome
of patients with IgA nephropathy support the use of angiotensin- is considered. Hypergammaglobulinemia, elevated levels of serum
converting enzyme (ACE) inhibitors in patients with proteinuria or IgE, or the presence of rheumatoid factor sometimes accompanies the
declining renal function. Tonsillectomy, steroid therapy, and fish allergic state. Lung inflammation, including fleeting cough and pulmo-
oil have all been suggested in small studies to benefit select patients nary infiltrates, often precedes the systemic manifestations of disease
with IgA nephropathy. When presenting as RPGN, patients typically by years; lung manifestations are rarely absent. A third of patients may
receive steroids, cytotoxic agents, and plasmapheresis. have exudative pleural effusions associated with eosinophils. Small-
vessel vasculitis and focal segmental necrotizing glomerulonephritis can
be seen on renal biopsy, usually absent eosinophils or granulomas.
ANCA SMALL-VESSEL VASCULITIS
The cause of Churg-Strauss syndrome is autoimmune, but the inciting
A group of patients with small-vessel vasculitis (arterioles, capillar-
factors are unknown.
ies, and venules; rarely small arteries) and glomerulonephritis have
serum ANCA; the antibodies are of two types, anti-proteinase 3
(PR3) or anti-myeloperoxidase (MPO) (Chap. 385); Lamp-2 anti- MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
bodies have also been reported experimentally as potentially patho- MPGN is sometimes called mesangiocapillary glomerulonephritis or
genic. ANCA are produced with the help of T cells and activate lobar glomerulonephritis. It is an immune-mediated glomerulonephri-
leukocytes and monocytes, which together damage the walls of tis characterized by thickening of the GBM with mesangioprolifera-
small vessels. Endothelial injury also attracts more leukocytes and tive changes; 70% of patients have hypocomplementemia. MPGN is
extends the inflammation. Granulomatosis with polyangiitis, micro- rare in African Americans, and idiopathic disease usually presents in
scopic polyangiitis, and Churg-Strauss syndrome belong to this childhood or young adulthood. MPGN is subdivided pathologically
group because they are ANCA-positive and have a pauci-immune into type I, type II, and type III disease. Type I MPGN is commonly
glomerulonephritis with few immune complexes in small vessels and associated with persistent hepatitis C infections, autoimmune diseases
glomerular capillaries. Patients with any of these three diseases can like lupus or cryoglobulinemia, or neoplastic diseases (Table 338-4).
have any combination of the above serum antibodies, but anti-PR3 Types II and III MPGN are usually idiopathic, except in patients with
antibodies are more common in granulomatosis with polyangiitis complement factor H deficiency, in the presence of C3 nephritic factor
and anti-MPO antibodies are more common in microscopic poly- and/or in partial lipodystrophy producing type II disease, or comple-
angiitis or Churg-Strauss. Although each of these diseases has some ment receptor deficiency in type III disease. MPGN has been proposed
unique clinical features, most features do not predict relapse or to be reclassified into immunoglobulin-mediated disease (driven by
progression, and as a group, they are generally treated in the same the classical complement pathway) and non–immunoglobulin-medi-
way. Since mortality is high without treatment, virtually all patients ated disease (driven by the alternative complement pathway).

Table 338-4 Membranoproliferative Glomerulonephritis diagnosis, and 90% have renal insufficiency after 20 years. Nephrotic 1841
syndrome, hypertension, and renal insufficiency all predict poor
Type I Disease (Most Common)
outcome. In the presence of proteinuria, treatment with inhibitors

Idiopathic of the renin-angiotensin system is prudent. Evidence for treatment
Subacute bacterial endocarditis with dipyridamole, Coumadin (warfarin), or cyclophosphamide is not
Systemic lupus erythematosus strongly established. There is some evidence supporting the efficacy
Hepatitis C ± cryoglobulinemia of treatment of primary MPGN with steroids, particularly in children,
Mixed cryoglobulinemia as well as reports of efficacy with plasma exchange and other immu-
Hepatitis B
nosuppressive drugs. If defects in the complement pathway are found,
treatment with eculizumab is of hypothetical but unproven benefit. In
Cancer: Lung, breast, and ovary (germinal)
secondary MPGN, treating the associated infection, autoimmune dis-
Type II Disease (Dense Deposit Disease) ease, or neoplasms is of demonstrated benefit. In particular, pegylated
Idiopathic interferon and ribavirin are useful in reducing viral load. Although
C3 nephritic factor–associated all primary renal diseases can recur over time in transplanted renal
Partial lipodystrophy allografts, patients with MPGN are well known to be at risk for not
Type III Disease only a histologic recurrence but also a clinically significant recurrence
Idiopathic
with loss of graft function.
Complement receptor deficiency MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS
Mesangioproliferative glomerulonephritis is characterized by expan-
sion of the mesangium, sometimes associated with mesangial hyper-
Type I MPGN, the most proliferative of the three types, shows cellularity; thin, single contoured capillary walls; and mesangial
mesangial proliferation with lobular segmentation on renal biopsy immune deposits. Clinically, it can present with varying degrees of
and mesangial interposition between the capillary basement mem- proteinuria and, commonly, hematuria. Mesangioproliferative disease
brane and endothelial cells, producing a double contour sometimes may be seen in IgA nephropathy, Plasmodium falciparum malaria,
called tram-tracking (see Fig. 62e-9). (See Glomerular Schematic 3.) resolving postinfectious glomerulonephritis, and class II nephritis
Subendothelial deposits with low serum levels of C3 are typical, from lupus, all of which can have a similar histologic appearance.
although 50% of patients have normal levels of C3 and occasional With these secondary entities excluded, the diagnosis of primary
intramesangial deposits. Low serum C3 and a dense thickening of the mesangioproliferative glomerulonephritis is made in less than 15% of
GBM containing ribbons of dense deposits and C3 characterize type II renal biopsies. As an immune-mediated renal lesion with deposits of
MPGN, sometimes called dense deposit disease (see Fig. 62e-10). IgM, C1q, and C3, the clinical course is variable. Patients with isolated
Classically, the glomerular tuft has a lobular appearance; intramesan- hematuria may have a very benign course, and those with heavy pro-
gial deposits are rarely present and subendothelial deposits are gener- teinuria occasionally progress to renal failure. There is little agreement
ally absent. Proliferation in type III MPGN is less common than the on treatment, but some clinical reports suggest benefit from use of
other two types and is often focal; mesangial interposition is rare, and inhibitors of the renin-angiotensin system, steroid therapy, and even
subepithelial deposits can occur along widened segments of the GBM cytotoxic agents.
that appear laminated and disrupted.
Type I MPGN is secondary to glomerular deposition of circulating NEPHROTIC SYNDROME
immune complexes or their in situ formation. Types II and III MPGN Nephrotic syndrome classically presents with heavy proteinuria, mini-
may be related to “nephritic factors,” which are autoantibodies that mal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and
stabilize C3 convertase and allow it to activate serum C3. MPGN can hypertension. If left undiagnosed or untreated, some of these syndromes
also result from acquired or genetic abnormalities in the alternative will progressively damage enough glomeruli to cause a fall in GFR, pro-
complement pathway. Patients with MPGN present with proteinuria, ducing renal failure. Multiple studies have noted that the higher the 24-h
hematuria, and pyuria (30%); systemic symptoms of fatigue and mal- urine protein excretion, the more rapid is the decline in GFR.
aise that are most common in children with type I disease; or an acute Therapies for various causes of nephrotic syndrome are noted
nephritic picture with RPGN and a speedy deterioration in renal func- under individual disease headings below. In general, all patients with
tion in up to 25% of patients. Low serum C3 levels are common. Fifty hypercholesterolemia secondary to nephrotic syndrome should be
percent of patients with MPGN develop end-stage disease 10 years after treated with lipid-lowering agents because they are at increased risk
for cardiovascular disease. Edema secondary to salt and water reten-
tion can be controlled with the judicious use of diuretics, avoiding
intravascular volume depletion. Venous complications secondary to
Glomerular schematic 3
the hypercoagulable state associated with nephrotic syndrome can
be treated with anticoagulants. The losses of various serum binding
proteins, such as thyroid-binding globulin, lead to alterations in func-
tional tests. Lastly, proteinuria itself is hypothesized to be nephrotoxic,
Subendothelial and treatment of proteinuria with inhibitors of the renin-angiotensin
Widened deposits
mesangial
system can lower urinary protein excretion.
Mesangial MINIMAL CHANGE DISEASE
interposition
Minimal change disease (MCD), sometimes known as nil lesion, causes
70–90% of nephrotic syndrome in childhood but only 10–15% of
nephrotic syndrome in adults. Minimal change disease usually presents
as a primary renal disease but can be associated with several other con-
Macrophage and
mesangial cells
ditions, including Hodgkin’s disease, allergies, or use of nonsteroidal
anti-inflammatory agents; significant interstitial nephritis often accom-
panies cases associated with nonsteroidal drug use. Minimal change
disease on renal biopsy shows no obvious glomerular lesion by light
MEMBRANOPROLIFERATIVE microscopy and is negative for deposits by immunofluorescent micros-
GLOMERULONEPHRITIS TYPE I copy, or occasionally shows small amounts of IgM in the mesangium

1842 Glomerular schematic 4 mofetil, are saved for frequent relapsers, steroid-dependent patients,
or steroid-resistant patients. Cyclosporine can induce remission, but
relapse is also common when cyclosporine is withdrawn. The long-
term prognosis in adults is less favorable when acute renal failure or
PART 13
steroid resistance occurs.
FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Focal segmental glomerulosclerosis (FSGS) refers to a pattern of
renal injury characterized by segmental glomerular scars that involve
some but not all glomeruli; the clinical findings of FSGS largely
manifest as proteinuria. When the secondary causes of FSGS are
eliminated (Table 338-5), the remaining patients are considered to

have primary FSGS. The incidence of this disease is increasing, and
it now represents up to one-third of cases of nephrotic syndrome
in adults and one-half of cases of nephrotic syndrome in African
Americans, in whom it is seen more commonly. The pathogenesis
of FSGS is probably multifactorial. Possible mechanisms include a
T cell–mediated circulating permeability factor, increased soluble
MINIMAL urokinase receptor levels, TGF-β–mediated cellular proliferation
CHANGE DISEASE and matrix synthesis, and podocyte abnormalities associated with
genetic mutations. Risk polymorphisms at the APOL1 locus encoding
apolipoprotein L1 expressed in podocytes substantially explain the
(see Fig. 62e-1). (See Glomerular Schematic 4.) Electron microscopy, increased burden of FSGS among African Americans with or without
however, consistently demonstrates an effacement of the foot process HIV-associated disease.
supporting the epithelial podocytes with weakening of slit-pore mem- The pathologic changes of FSGS are most prominent in glomeruli
branes. The pathophysiology of this lesion is uncertain. Most agree located at the corticomedullary junction (see Fig. 62e-2), so if the renal
there is a circulating cytokine, perhaps related to a T cell response that biopsy specimen is from superficial tissue, the lesions can be missed,
alters capillary charge and podocyte integrity. The evidence for cyto- which sometimes leads to a misdiagnosis of MCD. In addition to focal
kine-related immune injury is circumstantial and is suggested by the and segmental scarring, other variants have been described, including
presence of preceding allergies, altered cell-mediated immunity during cellular lesions with endocapillary hypercellularity and heavy protein-
viral infections, and the high frequency of remissions with steroids. uria; collapsing glomerulopath y (see Fig. 62e-3) with segmental or
Minimal change disease presents clinically with the abrupt onset global glomerular collapse and a rapid decline in renal function; a hilar
of edema and nephrotic syndrome accompanied by acellular urinary stalk lesion (see Fig. 62e-4); or the glomerular tip lesion (see Fig. 62e-5),
sediment. Average urine protein excretion reported in 24 h is 10 g which may have a better prognosis. (See Glomerular Schematic 5.)
with severe hypoalbuminemia. Less common clinical features include FSGS can present with hematuria, hypertension, any level of pro-
hypertension (30% in children, 50% in adults), microscopic hematuria teinuria, or renal insufficiency. Nephrotic-range proteinuria, African-
(20% in children, 33% in adults), atopy or allergic symptoms (40% in American race, and renal insufficiency are associated with a poor
children, 30% in adults), and decreased renal function (<5% in chil- outcome, with 50% of patients reaching renal failure in 6–8 years.
dren, 30% in adults). The appearance of acute renal failure in adults is FSGS rarely remits spontaneously, but treatment-induced remission
often seen more commonly in patients with low serum albumin and of proteinuria significantly improves prognosis. Treatment of patients
intrarenal edema (nephrosarca) that is responsive to intravenous albu- with primary FSGS should include inhibitors of the renin-angiotensin
min and diuretics. This presentation must be distinguished from acute system. Based on retrospective studies, patients with nephrotic-range
renal failure secondary to hypovolemia. Acute tubular necrosis and proteinuria can be treated with steroids but respond far less often and
interstitial inflammation are also reported. In children, the abnormal
urine principally contains albumin with minimal amounts of higher-
molecular-weight proteins, and is sometimes called selective protein- Table 338-5 Focal Segmental Glomerulosclerosis
uria. Although up to 30% of children have a spontaneous remission, all Primary focal segmental glomerulosclerosis
children today are treated with steroids; only children who are nonre- Secondary focal segmental glomerulosclerosis
sponders are biopsied in this setting. Primary responders are patients Viruses: HIV/hepatitis B/parvovirus
who have a complete remission (<0.2 mg/24 h of proteinuria) after a
Hypertensive nephropathy
single course of prednisone; steroid-dependent patients relapse as their
Reflux nephropathy
steroid dose is tapered. Frequent relapsers have two or more relapses
in the 6 months following taper, and steroid-resistant patients fail to Cholesterol emboli
respond to steroid therapy. Adults are not considered steroid-resistant Drugs: Heroin/analgesics/pamidronate
until after 4 months of therapy. Ninety to 95% of children will develop Oligomeganephronia
a complete remission after 8 weeks of steroid therapy, and 80–85% of Renal dysgenesis
adults will achieve complete remission, but only after a longer course Alport’s syndrome
of 20–24 weeks. Patients with steroid resistance may have FSGS on
Sickle cell disease
repeat biopsy. Some hypothesize that if the first renal biopsy does not
Lymphoma
have a sample of deeper corticomedullary glomeruli, then the correct
diagnosis of FSGS may be missed. Radiation nephritis
Relapses occur in 70–75% of children after the first remission, and Familial podocytopathies
early relapse predicts multiple subsequent relapses, as do high levels of NPHS1 mutation/nephrin
basal proteinuria. The frequency of relapses decreases after puberty. NPHS2 mutation/podocin
There is an increased risk of relapse following the rapid tapering of TRPC6 mutation/cation channel
steroids in all groups. Relapses are less common in adults but are
ACTN4 mutation/actinin
more resistant to subsequent therapy. Prednisone is first-line therapy,
α-Galactosidase A deficiency/Fabry’s disease
either given daily or on alternate days. Other immunosuppressive
drugs, such as cyclophosphamide, chlorambucil, and mycophenolate N -acetylneuraminic acid hydrolase deficiency/nephrosialidosis

Glomerular schematic 5 1843

Detachment
of cell from
GBM
Collapsed
capillary
and scar
Proliferation of
subepithelial cells
FOCAL
SCLEROSING
GLOMERULONEPHRITIS
Efferent
Afferent arteriole
arteriole
after a longer course of therapy than patients with MCD. Proteinuria predictive of progression than is the stage of glomerular disease.
remits in only 20–45% of patients receiving a course of steroids over The presence of subendothelial deposits or the presence of tubulore-
6–9 months. Limited evidence suggests the use of cyclosporine in ste- ticular inclusions strongly points to a diagnosis of membranous lupus
roid-responsive patients helps ensure remissions. Relapse frequently nephritis, which may precede the extrarenal manifestations of lupus.
occurs after cessation of cyclosporine therapy, and cyclosporine itself Work in Heyman nephritis, an animal model of MGN, suggests that
can lead to a deterioration of renal function due to its nephrotoxic glomerular lesions result from in situ formation of immune complexes
effects. A role for other agents that suppress the immune system has with megalin receptor–associated protein as the putative antigen.
not been established. Primary FSGS recurs in 25–40% of patients given This antigen is not found in human podocytes. Human antibod-
allografts at end-stage disease, leading to graft loss in half of those ies have been described against neutral endopeptidase expressed by
cases. The treatment of secondary FSGS typically involves treating the podocytes in infants whose mothers lack this protein. In most adults,
underlying cause and controlling proteinuria. There is no role for ste- autoantibodies against the M-type phospholipase A2 receptor (PLA2R)
roids or other immunosuppressive agents in secondary FSGS. circulate and bind to a conformational epitope present in the recep-
tor on human podocytes, producing in situ deposits characteristic
MEMBRANOUS GLOMERULONEPHRITIS of idiopathic membranous nephropathy. Other renal diseases and
Membranous glomerulonephritis (MGN), or membranous nephropa- secondary membranous nephropathy do not appear to involve such
thy as it is sometimes called, accounts for approximately 30% of cases
of nephrotic syndrome in adults, with a peak incidence between the
ages of 30 and 50 years and a male to female ratio of 2:1. It is rare in
childhood and the most common cause of nephrotic syndrome in the Table 338-6 Membranous Glomerulonephritis
elderly. In 25–30% of cases, MGN is associated with a malignancy Primary/idiopathic membranous glomerulonephritis
(solid tumors of the breast, lung, colon), infection (hepatitis B, malaria, Secondary membranous glomerulonephritis
schistosomiasis), or rheumatologic disorders like lupus or rarely rheu- Infection: Hepatitis B and C, syphilis, malaria, schistosomiasis, leprosy,
matoid arthritis (Table 338-6). filariasis
Uniform thickening of the basement membrane along the periph- Cancer: Breast, colon, lung, stomach, kidney, esophagus, neuroblastoma
eral capillary loops is seen by light microscopy on renal biopsy (see Drugs: Gold, mercury, penicillamine, nonsteroidal anti-inflammatory
Fig. 62e-7); this thickening needs to be distinguished from that agents, probenecid
seen in diabetes and amyloidosis. (See Glomerular Schematic 6.) Autoimmune diseases: Systemic lupus erythematosus, rheumatoid arthritis,
Immunofluorescence demonstrates diffuse granular deposits of IgG primary biliary cirrhosis, dermatitis herpetiformis, bullous pemphigoid, myas-
and C3, and electron microscopy typically reveals electron-dense thenia gravis, Sjögren’s syndrome, Hashimoto’s thyroiditis
subepithelial deposits. While different stages (I–V) of progressive Other systemic diseases: Fanconi’s syndrome, sickle cell anemia, diabetes,
membranous lesions have been described, some published analyses Crohn’s disease, sarcoidosis, Guillain-Barré syndrome, Weber-Christian disease,
indicate the degree of tubular atrophy or interstitial fibrosis is more angiofollicular lymph node hyperplasia

1844 Glomerular schematic 6 the presence or absence of clinically significant nephropathy. The
composition of the GBM is altered notably with a loss of heparan
Foot process
fusion
sulfate moieties that form the negatively charged filtration barrier.
This change results in increased filtration of serum proteins into the
PART 13
urine, predominately negatively charged albumin. The expansion of

the mesangium due to the accumulation of extracellular matrix cor-
Subepithelial relates with the clinical manifestations of diabetic nephropathy (see
deposits stages in Fig. 62e-20). This expansion in mesangial matrix is associ-
ated with the development of mesangial sclerosis. Some patients also
develop eosinophilic, PAS+ nodules called nodular glomerulosclero-
sis or Kimmelstiel-Wilson nodules. Immunofluorescence microscopy
often reveals the nonspecific deposition of IgG (at times in a linear

pattern) or complement staining without immune deposits on electron
microscopy. Prominent vascular changes are frequently seen with hya-
line and hypertensive arteriosclerosis. This is associated with varying
degrees of chronic glomerulosclerosis and tubulointerstitial changes.
Renal biopsies from patients with types 1 and 2 diabetes are largely
indistinguishable.
MEMBRANOUS These pathologic changes are the result of a number of postulated
GLOMERULONEPHRITIS factors. Multiple lines of evidence support an important role for
increases in glomerular capillary pressure (intraglomerular hyper-
tension) in alterations in renal structure and function. Direct effects
of hyperglycemia on the actin cytoskeleton of renal mesangial and
autoantibodies and levels of these autoantibodies have correlated with vascular smooth-muscle cells as well as diabetes-associated changes in
the severity of MGN. Eighty percent of patients with MGN present circulating factors such as atrial natriuretic factor, angiotensin II, and
with nephrotic syndrome and nonselective proteinuria. Microscopic insulin-like growth factor (IGF) may account for this. Sustained glo-
hematuria is seen but less commonly than in IgA nephropathy or merular hypertension increases matrix production, alterations in the
FSGS. Spontaneous remissions occur in 20–33% of patients and often GBM with disruption in the filtration barrier (and hence proteinuria),
occur late in the course after years of nephrotic syndrome, which and glomerulosclerosis. A number of factors have also been identified
make treatment decisions difficult. One-third of patients continue to that alter matrix production, including the accumulation of advanced
have relapsing nephrotic syndrome but maintain normal renal func- glycosylation end products, circulating factors including growth hor-
tion, and approximately another third of patients develop renal failure mone, IGF-I, angiotensin II, connective tissue growth factor, TGF-β,
or die from the complications of nephrotic syndrome. Male gender, and dyslipidemia.
older age, hypertension, and the persistence of proteinuria are associ- The natural history of diabetic nephropathy in patients with types
ated with worse prognosis. Although thrombotic complications are 1 and 2 diabetes is similar. However, since the onset of type 1 diabetes
a feature of all nephrotic syndromes, MGN has the highest reported is readily identifiable and the onset of type 2 diabetes is not, a patient
incidences of renal vein thrombosis, pulmonary embolism, and deep newly diagnosed with type 2 diabetes may present with advanced
vein thrombosis. Prophylactic anticoagulation is controversial but has diabetic nephropathy. At the onset of diabetes, renal hypertrophy
been recommended for patients with severe or prolonged proteinuria and glomerular hyperfiltration are present. The degree of glomeru-
in the absence of risk factors for bleeding. lar hyperfiltration correlates with the subsequent risk of clinically
In addition to the treatment of edema, dyslipidemia, and hyperten- significant nephropathy. In the approximately 40% of patients with
sion, inhibition of the renin-angiotensin system is recommended. diabetes who develop diabetic nephropathy, the earliest manifestation
Therapy with immunosuppressive drugs is also recommended for is an increase in albuminuria detected by sensitive radioimmunoassay
patients with primary MGN and persistent proteinuria (>3.0 g/24 h). (Table 338-1). Albuminuria in the range of 30–300 mg/24 h is called
The choice of immunosuppressive drugs for therapy is controversial, microalbuminuria. Microalbuminuria appears 5–10 years after the
but current recommendations are to treat with steroids and cyclo- onset of diabetes. It is currently recommended to test patients with
phosphamide, chlorambucil, mycophenolate mofetil, or cyclosporine. type 1 disease for microalbuminuria 5 years after diagnosis of diabetes
In patients who relapse or fail to respond to this therapy, the use of and yearly thereafter and, because the time of onset of type 2 diabetes
rituximab, an anti-CD20 antibody directed at B cells, or synthetic is often unknown, to test type 2 patients at the time of diagnosis of
adrenocorticotropic hormone may be considered. diabetes and yearly thereafter.
Patients with small increases in albuminuria increase their levels of
DIABETIC NEPHROPATHY urinary albumin excretion, typically reaching dipstick positive levels of
Diabetic nephropathy is the single most common cause of chronic renal proteinuria (>300 mg albuminuria) 5–10 years after the onset of early
failure in the United States, accounting for 45% of patients receiving albuminuria. Microalbuminuria is a potent risk factor for cardiovas-
renal replacement therapy, and is a rapidly growing problem worldwide. cular events and death in patients with type 2 diabetes. Many patients
The dramatic increase in the number of patients with diabetic nephropa- with type 2 diabetes and microalbuminuria succumb to cardiovascular
thy reflects the epidemic increase in obesity, metabolic syndrome, and events before they progress to proteinuria or renal failure. Proteinuria
type 2 diabetes mellitus. Approximately 40% of patients with types 1 or in frank diabetic nephropathy can be variable, ranging from 500 mg
2 diabetes develop nephropathy, but due to the higher prevalence of to 25 g/24 h, and is often associated with nephrotic syndrome. More
type 2 diabetes (90%) compared to type 1 (10%), the majority of patients than 90% of patients with type 1 diabetes and nephropathy have
with diabetic nephropathy have type 2 disease. Renal lesions are more diabetic retinopathy, so the absence of retinopathy in type 1 patients
common in African-American, Native American, Polynesian, and Maori with proteinuria should prompt consideration of a diagnosis other
populations. Risk factors for the development of diabetic nephropathy than diabetic nephropathy; only 60% of patients with type 2 diabetes
include hyperglycemia, hypertension, dyslipidemia, smoking, a family with nephropathy have diabetic retinopathy. There is a significant
history of diabetic nephropathy, and gene polymorphisms affecting the correlation between the presence of retinopathy and the presence of
activity of the renin-angiotensin-aldosterone axis. Kimmelstiel-Wilson nodules (see Fig. 62e-20). Also, characteristically,
Within 1–2 years after the onset of clinical diabetes, morphologic patients with advanced diabetic nephropathy have normal to enlarged
changes appear in the kidney. Thickening of the GBM is a sensi- kidneys, in contrast to other glomerular diseases where kidney size is
tive indicator for the presence of diabetes but correlates poorly with usually decreased. Using the above epidemiologic and clinical data, and

in the absence of other clinical or serologic data suggesting another dis- different reasons, their clinicopathophysiology is quite similar and will 1845
ease, diabetic nephropathy is usually diagnosed without a renal biopsy. be discussed together. Amyloid infiltrates the liver, heart, peripheral
After the onset of proteinuria, renal function inexorably declines, with nerves, carpal tunnel, upper pharynx, and kidney, producing restric-

50% of patients reaching renal failure over another 5–10 years; thus, tive cardiomyopathy, hepatomegaly, macroglossia, and heavy protein-
from the earliest stages of microalbuminuria, it usually takes 10–20 uria sometimes associated with renal vein thrombosis. In systemic AL
years to reach end-stage renal disease. Once renal failure appears, how- amyloidosis, also called primary amyloidosis, light chains produced
ever, survival on dialysis is shorter for patients with diabetes compared in excess by clonal plasma cell dyscrasias are made into fragments by
to other dialysis patients. Survival is best for patients with type 1 diabe- macrophages so they can self-aggregate at acid pH. A disproportion-
tes who receive a transplant from a living related donor. ate number of these light chains (75%) are of the lambda class. About
Good evidence supports the benefits of blood sugar and blood pres- 10% of these patients have overt myeloma with lytic bone lesions and
sure control as well as inhibition of the renin-angiotensin system in infiltration of the bone marrow with >30% plasma cells; nephrotic
retarding the progression of diabetic nephropathy. In patients with syndrome is common, and about 20% of patients progress to dialysis.
type 1 diabetes, intensive control of blood sugar clearly prevents the AA amyloidosis is sometimes called secondary amyloidosis and also
development or progression of diabetic nephropathy. The evidence for presents as nephrotic syndrome. It is due to deposition of β-pleated
benefit of intensive blood glucose control in patients with type 2 dia- sheets of serum amyloid A protein, an acute phase reactant whose
betes is less certain, with current studies reporting conflicting results. physiologic functions include cholesterol transport, immune cell
Controlling systemic blood pressure decreases renal and cardiovas- attraction, and metalloproteases activation. Forty percent of patients
cular adverse events in this high-risk population. The vast majority of with AA amyloid have rheumatoid arthritis, and another 10% have
patients with diabetic nephropathy require three or more antihyperten- ankylosing spondylitis or psoriatic arthritis; the rest derive from other
sive drugs to achieve this goal. Drugs that inhibit the renin-angiotensin lesser causes. Less common in Western countries but more common
system, independent of their effects on systemic blood pressure, have in Mediterranean regions, particularly in Sephardic and Iraqi Jews, is
been shown in numerous large clinical trials to slow the progression familial Mediterranean fever (FMF). FMF is caused by a mutation in
of diabetic nephropathy at early (microalbuminuria) and late (protein- the gene encoding pyrin, whereas Muckle-Wells syndrome, a related
uria with reduced glomerular filtration) stages, independent of any disorder, results from a mutation in cryopyrin; both proteins are
effect they may have on systemic blood pressure. Since angiotensin II important in the apoptosis of leukocytes early in inflammation; such
increases efferent arteriolar resistance and, hence, glomerular capillary proteins with pyrin domains are part of a new pathway called the
pressure, one key mechanism for the efficacy of ACE inhibitors or inflammasome. Receptor mutations in tumor necrosis factor recep-
angiotensin receptor blockers (ARBs) is reducing glomerular hyperten- tor 1 (TNFR1)-associated periodic syndrome also produce chronic
sion. Patients with type 1 diabetes for 5 years who develop albuminuria inflammation and secondary amyloidosis. Fragments of serum amy-
or declining renal function should be treated with ACE inhibitors. loid A protein increase and self-aggregate by attaching to receptors
Patients with type 2 diabetes and microalbuminuria or proteinuria may for advanced glycation end products in the extracellular environment;
be treated with ACE inhibitors or ARBs. Evidence suggests increased nephrotic syndrome is common, and about 40–60% of patients prog-
risk for cardiovascular adverse events in some patients with a com- ress to dialysis. AA and AL amyloid fibrils are detectable with Congo
bination of two drugs (ACE inhibitors, ARBs, renin inhibitors, or red or in more detail with electron microscopy (see Fig. 62e-15). Currently
aldosterone antagonists) that suppress several components of the renin- developed serum free light chain nephelometry assays are useful in
angiotensin system. the early diagnosis and follow-up of disease progression. Biopsy of
involved liver or kidney is diagnostic 90% of the time when the pretest
probability is high; abdominal fat pad aspirates are positive about
GLOMERULAR DEPOSITION DISEASES 70% of the time, but apparently less so when looking for AA amyloid.
Plasma cell dyscrasias producing excess light chain immunoglobulin Amyloid deposits are distributed along blood vessels and in the mesan-
sometimes lead to the formation of glomerular and tubular deposits gial regions of the kidney. The treatment for primary amyloidosis,
that cause heavy proteinuria and renal failure; the same is true for the melphalan and autologous hematopoietic stem cell transplantation,
accumulation of serum amyloid A protein fragments seen in several can delay the course of disease in about 30% of patients. Secondary
inflammatory diseases. This broad group of proteinuric patients has amyloidosis is also relentless unless the primary disease can be con-
glomerular deposition disease. trolled. Some new drugs in development that disrupt the formation of
fibrils may be available in the future.
Light Chain Deposition Disease The biochemical characteristics of
nephrotoxic light chains produced in patients with light chain malig-
Fibrillary-Immunotactoid Glomerulopathy Fibrillary-immunotactoid
nancies often confer a specific pattern of renal injury; that of either cast
glomerulopathy is a rare (<1.0% of renal biopsies), morphologi-
nephropathy (see Fig. 62e-17), which causes renal failure but not heavy
cally defined disease characterized by glomerular accumulation of
proteinuria or amyloidosis, or light chain deposition disease (see Fig.
nonbranching randomly arranged fibrils. Some classify amyloid and
62e-16), which produces nephrotic syndrome with renal failure. These
nonamyloid fibril-associated renal diseases all as fibrillary glomeru-
latter patients produce kappa light chains that do not have the bio-
lopathies with immunotactoid glomerulopathy reserved for nonamy-
chemical features necessary to form amyloid fibrils. Instead, they self-
loid fibrillary disease not associated with a systemic illness. Others
aggregate and form granular deposits along the glomerular capillary
define fibrillary glomerulonephritis as a nonamyloid fibrillary dis-
and mesangium, tubular basement membrane, and Bowman’s capsule.
ease with fibrils 12–24 nm and immunotactoid glomerulonephritis
When predominant in glomeruli, nephrotic syndrome develops, and
with fibrils >30 nm. In either case, fibrillar/microtubular deposits of
about 70% of patients progress to dialysis. Light-chain deposits are not
oligoclonal or oligotypic immunoglobulins and complement appear
fibrillar and do not stain with Congo red, but they are easily detected
in the mesangium and along the glomerular capillary wall. Congo red
with anti–light chain antibody using immunofluorescence or as granu-
stains are negative. The cause of this “nonamyloid” glomerulopathy
lar deposits on electron microscopy. A combination of the light chain
is mostly idiopathic; reports of immunotactoid glomerulonephritis
rearrangement, self-aggregating properties at neutral pH, and abnor-
describe an occasional association with chronic lymphocytic leu-
mal metabolism probably contribute to the deposition. Treatment for
kemia or B cell lymphoma. Both disorders appear in adults in the
light chain deposition disease is treatment of the primary disease and,
fourth decade with moderate to heavy proteinuria, hematuria, and
if possible, autologous stem cell transplantation.
a wide variety of histologic lesions, including DPGN, MPGN, MGN,
Renal Amyloidosis Most renal amyloidosis is either the result of pri- or mesangioproliferative glomerulonephritis. Nearly half of patients
mary fibrillar deposits of immunoglobulin light chains known as develop renal failure over a few years. There is no consensus on treat-
amyloid L (AL), or secondary to fibrillar deposits of serum amyloid A ment of this uncommon disorder. The disease has been reported to
(AA) protein fragments (Chap. 137). Even though both occur for recur following renal transplantation in a minority of cases.

1846 FABRY’S DISEASE enzyme. Graft and patient survival following renal transplantation
Fabry’s disease is an X-linked inborn error of globotriaosylceramide in patients with Fabry’s are similar to other causes of end-stage renal
metabolism secondary to deficient lysosomal α-galactosidase A activ- disease.
ity, resulting in excessive intracellular storage of globotriaosylce-
PART 13
ramide. Affected organs include the vascular endothelium, heart, PULMONARY-RENAL SYNDROMES
brain, and kidneys. Classically, Fabry’s disease presents in childhood
Several diseases can present with catastrophic hemoptysis and glo-
in males with acroparesthesias, angiokeratoma, and hypohidrosis.
merulonephritis associated with varying degrees of renal failure. The
Over time male patients develop cardiomyopathy, cerebrovascular
usual causes include Goodpasture’s syndrome, granulomatosis with
disease, and renal injury, with an average age of death around 50
polyangiitis, microscopic polyangiitis, Churg-Strauss vasculitis, and,
years of age. Hemizygotes with hypomorphic mutations sometimes
rarely, Henoch-Schönlein purpura or cryoglobulinemia. Each of these
present in the fourth to sixth decade with single-organ involvement.
diseases can also present without hemoptysis and are discussed in detail
Rarely, dominant-negative α-galactosidase A mutations or female
earlier in “Acute Nephritic Syndromes.” (See Glomerular Schematic 7.)
heterozygotes with unfavorable X inactivation present with mild
Pulmonary bleeding in this setting is life-threatening and often results
single-organ involvement. Rare females develop severe manifesta-
in airway intubation, and acute renal failure requires dialysis. Diagnosis
tions including renal failure but do so later in life than males. Renal
is difficult initially because biopsies and serologic testing take time.
biopsy reveals enlarged glomerular visceral epithelial cells packed
Treatment with plasmapheresis and methylprednisolone is often empiri-
with small clear vacuoles containing globotriaosylceramide; vacuoles
cal and temporizing until results of testing are available.
may also be found in parietal and tubular epithelia (see Fig. 62e-18).
These vacuoles of electron-dense materials in parallel arrays (zebra
BASEMENT MEMBRANE SYNDROMES
bodies) are easily seen on electron microscopy. Ultimately, renal
biopsies reveal FSGS. The nephropathy of Fabry’s disease typically All kidney epithelia, including podocytes, rest on basement membranes
presents in the third decade as mild to moderate proteinuria, some- assembled into a planar surface through the interweaving of collagen
times with microscopic hematuria or nephrotic syndrome. Urinalysis IV with laminins, nidogen, and sulfated proteoglycans. Structural
may reveal oval fat bodies and birefringent glycolipid globules under abnormalities in GBM associated with hematuria are characteristic
polarized light (Maltese cross). Renal biopsy is necessary for definitive of several familial disorders related to the expression of collagen IV
diagnosis. Progression to renal failure occurs by the fourth or fifth genes. The extended family of collagen IV contains six chains, which
decade. Treatment with inhibitors of the renin-angiotensin system are expressed in different tissues at different stages of embryonic devel-
is recommended. Treatment with recombinant α-galactosidase A opment. All epithelial basement membranes early in human develop-
clears microvascular endothelial deposits of globotriaosylceramide ment are composed of interconnected triple-helical protomers rich in
from the kidneys, heart, and skin. In patients with advanced organ α1.α1.α2(IV) collagen. Some specialized tissues undergo a develop-
involvement, progression of disease occurs despite enzyme replace- mental switch replacing α1.α1.α2(IV) protomers with an α3.α4.α5(IV)
ment therapy. Variable responses to enzyme therapy may be due to the collagen network; this switch occurs in the kidney (glomerular and
occurrence of neutralizing antibodies or differences in uptake of the tubular basement membrane), lung, testis, cochlea, and eye, while an
Glomerular schematic 7
RAPIDLY
PROGRESSIVE
GLOMERULONEPHRITIS

α5.α5.α6(IV) network appears in skin, smooth muscle, and esophagus not all cases are familial (perhaps a founder effect), it usually presents 1847
and along Bowman’s capsule in the kidney. This switch probably in childhood in multiple family members and is also called benign
occurs because the α3.α4.α5(IV) network is more resistant to proteases familial hematuria. Cases of TBMD have genetic defects in type IV

and ensures the structural longevity of critical tissues. When basement collagen but in contrast to Alport behave as an autosomal dominant
membranes are the target of glomerular disease, they produce moder- disorder that in ~40% of families segregates with the COL(IV) α3/
ate proteinuria, some hematuria, and progressive renal failure. COL(IV) α4 loci. Mutations in these loci can result in a spectrum
of disease ranging from TBMD to autosomal dominant or recessive
ANTI-GBM DISEASE Alport’s. The GBM shows diffuse thinning compared to normal values
Autoimmune disease where antibodies are directed against the α3 NC1 for the patient’s age in otherwise normal biopsies (see Fig. 62e-19).
domain of collagen IV produces an anti-GBM disease often associated The vast majority of patients have a benign course.
with RPGN and/or a pulmonary-renal syndrome called Goodpasture’s
syndrome. Discussion of this disease is covered earlier in “Acute NAIL-PATELLA SYNDROME
Nephritic Syndromes.” Patients with nail-patella syndrome develop iliac horns on the pelvis
and dysplasia of the dorsal limbs involving the patella, elbows, and
ALPORT’S SYNDROME nails, variably associated with neural-sensory hearing impairment,
Classically, patients with Alport’s syndrome develop hematuria, glaucoma, and abnormalities of the GBM and podocytes, leading to
thinning and splitting of the GBMs, mild proteinuria (<1–2 g/24 hematuria, proteinuria, and FSGS. The syndrome is autosomal domi-
h), which appears late in the course, followed by chronic glomeru- nant, with haploinsufficiency for the LIM homeodomain transcription
losclerosis leading to renal failure in association with sensorineural factor LMX1B; pedigrees are extremely variable in the penetrance for
deafness. Some patients develop lenticonus of the anterior lens all features of the disease. LMX1B regulates the expression of genes
capsule, “dot and fleck” retinopathy, and rarely, mental retardation encoding α3 and α4 chains of collagen IV, interstitial type III collagen,
or leiomyomatosis. Approximately 85% of patients with Alport’s podocin, and CD2AP that help form the slit-pore membranes con-
syndrome have an X-linked inheritance of mutations in the α5(IV) necting podocytes. Mutations in the LIM domain region of LMX1B
collagen chain on chromosome Xq22–24. Female carriers have vari- associate with glomerulopathy, and renal failure appears in as many
able penetrance depending on the type of mutation or the degree as 30% of patients. Proteinuria or isolated hematuria is discovered
of mosaicism created by X inactivation. Fifteen percent of patients throughout life, but usually by the third decade, and is inexplicably
have autosomal recessive disease of the α3(IV) or α4(IV) chains on more common in females. On renal biopsy there is lucent damage to
chromosome 2q35–37. Rarely, some kindred have an autosomal the lamina densa of the GBM, an increase in collagen III fibrils along
dominant inheritance of dominant-negative mutations in α3(IV) or glomerular capillaries and in the mesangium, and damage to the slit-
α4(IV) chains. pore membrane, producing heavy proteinuria not unlike that seen in
Pedigrees with the X-linked syndrome are quite variable in their congenital nephrotic syndrome. Patients with renal failure do well with
rate and frequency of tissue damage leading to organ failure. Seventy transplantation.
percent of patients have the juvenile form with nonsense or missense
mutations, reading frame shifts, or large deletions and generally GLOMERULAR-VASCULAR SYNDROMES
develop renal failure and sensorineural deafness by age 30. Patients A variety of diseases result in classic vascular injury to the glomerular
with splice variants, exon skipping, or missense mutations of α-helical capillaries. Most of these processes also damage blood vessels elsewhere
glycines generally deteriorate after the age of 30 (adult form) with in the body. The group of diseases discussed here lead to vasculitis, renal
mild or late deafness. Early severe deafness, lenticonus, or proteinuria endothelial injury, thrombosis, ischemia, and/or lipid-based occlusions.
suggests a poorer prognosis. Usually females from X-linked pedigrees
have only microhematuria, but up to 25% of carrier females have been ATHEROSCLEROTIC NEPHROPATHY
reported to have more severe renal manifestations. Pedigrees with the Aging in the developed world is commonly associated with the occlu-
autosomal recessive form of the disease have severe early disease in sion of coronary and systemic blood vessels. The reasons for this
both females and males with asymptomatic parents. include obesity, insulin resistance, smoking, hypertension, and diets
Clinical evaluation should include a careful eye examination and rich in lipids that deposit in the arterial and arteriolar circulation, pro-
hearing tests. However, the absence of extrarenal symptoms does not ducing local inflammation and fibrosis of small blood vessels. When the
rule out the diagnosis. Since α5(IV) collagen is expressed in the skin, renal arterial circulation is involved, the glomerular microcirculation
some X-linked Alport’s patients can be diagnosed with a skin biopsy is damaged, leading to chronic nephrosclerosis. Patients with GFRs <60
revealing the lack of the α5(IV) collagen chain on immunofluorescent mL/min have more cardiovascular events and hospitalizations than
analysis. Patients with mutations in α3(IV) or α4(IV) require a renal those with higher filtration rates. Several aggressive lipid disorders can
biopsy. Genetic testing can be used for the diagnosis of Alport’s syn- accelerate this process, but most of the time atherosclerotic progression
drome and the demonstration of the mode of inheritance. Early in their to chronic nephrosclerosis is associated with poorly controlled hyper-
disease, Alport’s patients typically have thin basement membranes on tension. Approximately 10% of glomeruli are normally sclerotic by age
renal biopsy (see Fig. 62e-19), which thicken over time into multilam- 40, rising to 20% by age 60 and 30% by age 80. Serum lipid profiles in
ellations surrounding lucent areas that often contain granules of vary- humans are greatly affected by apolipoprotein E polymorphisms; the
ing density—the so-called split basement membrane. In any Alport’s E4 allele is accompanied by increases in serum cholesterol and is more
kidney, there are areas of thinning mixed with splitting of the GBM. closely associated with atherogenic profiles in patients with renal fail-
Tubules drop out, glomeruli scar, and the kidney eventually succumbs ure. Mutations in E2 alleles, particularly in Japanese patients, produce a
to interstitial fibrosis. All affected members of a family with X-linked specific renal abnormality called lipoprotein glomerulopathy associated
Alport’s syndrome should be identified and followed, including moth- with glomerular lipoprotein thrombi and capillary dilation.
ers of affected males. Primary treatment is control of systemic hyper-
tension and use of ACE inhibitors to slow renal progression. Although HYPERTENSIVE NEPHROSCLEROSIS
patients who receive renal allografts usually develop anti-GBM anti- Uncontrolled systemic hypertension causes permanent damage to
bodies directed toward the collagen epitopes absent in their native the kidneys in about 6% of patients with elevated blood pressure. As
kidney, overt Goodpasture’s syndrome is rare and graft survival is good. many as 27% of patients with end-stage kidney disease have hyper-
tension as a primary cause. Although there is not a clear correlation
THIN BASEMENT MEMBRANE DISEASE between the extent or duration of hypertension and the risk of end-
Thin basement membrane disease (TBMD) characterized by persistent organ damage, hypertensive nephrosclerosis is fivefold more frequent
or recurrent hematuria is not typically associated with proteinuria, in African Americans than whites. Risk alleles associated with APOL1,
hypertension, or loss of renal function or extrarenal disease. Although a functional gene for apolipoprotein L1 expressed in podocytes

1848 substantially explains the increased burden of end-stage renal disease dialysis. Treatment is directed to reducing the frequency of painful crises
among African Americans. Associated risk factors for progression to and administering ACE inhibitors in the hope of delaying a progressive
end-stage kidney disease include increased age, male gender, race, decline in renal function. In sickle cell patients undergoing renal trans-
smoking, hypercholesterolemia, duration of hypertension, low birth plantation, renal graft survival is comparable to African Americans in
PART 13
weight, and preexisting renal injury. Kidney biopsies in patients with the general transplant population.
hypertension, microhematuria, and moderate proteinuria demonstrate
arteriolosclerosis, chronic nephrosclerosis, and interstitial fibrosis in THROMBOTIC MICROANGIOPATHIES
the absence of immune deposits (see Fig. 62e-21). Today, based on a Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic
careful history, physical examination, urinalysis, and some serologic syndrome (HUS) represent a spectrum of thrombotic microangiopa-
testing, the diagnosis of chronic nephrosclerosis is usually inferred thies. Thrombotic thrombocytopenic purpura and hemolytic-uremic
without a biopsy. Treating hypertension is the best way to avoid syndrome share the general features of idiopathic thrombocytopenic
progressive renal failure; most guidelines recommend lowering blood purpura, hemolytic anemia, fever, renal failure, and neurologic dis-
pressure to <130/80 mmHg if there is preexisting diabetes or kidney turbances. When patients, particularly children, have more evidence
disease. In the presence of kidney disease, most patients begin antihy- of renal injury, their condition tends to be called HUS. In adults with
pertensive therapy with two drugs, classically a thiazide diuretic and an neurologic disease, it is considered to be TTP. In adults there is often a
ACE inhibitor; most will require three drugs. There is strong evidence mixture of both, which is why they are often referred to as having TTP/
in African Americans with hypertensive nephrosclerosis that therapy HUS. On examination of kidney tissue, there is evidence of glomeru-
initiated with an ACE inhibitor can slow the rate of decline in renal lar capillary endotheliosis associated with platelet thrombi, damage
function independent of effects on systemic blood pressure. Malignant to the capillary wall, and formation of fibrin material in and around
acceleration of hypertension complicates the course of chronic neph- glomeruli (see Fig. 62e-23). These tissue findings are similar to what
rosclerosis, particularly in the setting of scleroderma or cocaine use is seen in preeclampsia/HELLP (hemolysis, elevated liver enzymes,
(see Fig. 62e-24). The hemodynamic stress of malignant hypertension and low platelet count syndrome), malignant hypertension, and the
leads to fibrinoid necrosis of small blood vessels, thrombotic microan- antiphospholipid syndrome. TTP/HUS is also seen in pregnancy; with
giography, a nephritic urinalysis, and acute renal failure. In the setting the use of oral contraceptives or quinine; in renal transplant patients
of renal failure, chest pain, or papilledema, the condition is treated as given OKT3 for rejection; in patients taking the calcineurin inhibi-
a hypertensive emergency. Slightly lowering the blood pressure often tors, cyclosporine and tacrolimus, or in patients taking the antiplatelet
produces an immediate reduction in GFR that improves as the vascular agents, ticlopidine and clopidogrel; or following HIV infection.
injury attenuates and autoregulation of blood vessel tone is restored. Although there is no agreement on how much they share a final
common pathophysiology, two general groups of patients are recog-
CHOLESTEROL EMBOLI nized: childhood HUS associated with enterohemorrhagic diarrhea
Aging patients with clinical complications from atherosclerosis and TTP/HUS in adults. Childhood HUS is caused by a toxin released
sometimes shower cholesterol crystals into the circulation—either by Escherichia coli 0157:H7 and occasionally by Shigella dysenteriae.
spontaneously or, more commonly, following an endovascular pro- This shiga toxin (verotoxin) directly injures endothelia, enterocytes,
cedure with manipulation of the aorta—or with use of systemic and renal cells, causing apoptosis, platelet clumping, and intravascular
anticoagulation. Spontaneous emboli may shower acutely or shower hemolysis by binding to the glycolipid receptors (Gb3). These receptors
subacutely and somewhat more silently. Irregular emboli trapped in are more abundant along endothelia in children compared to adults.
the microcirculation produce ischemic damage that induces an inflam- Shiga toxin also inhibits the endothelial production of ADAMTS13.
matory reaction. Depending on the location of the atherosclerotic In familial cases of adult TTP/HUS, there is a genetic deficiency of
plaques releasing these cholesterol fragments, one may see cerebral the ADAMTS13 metalloprotease that cleaves large multimers of
transient ischemic attacks; livedo reticularis in the lower extremities; von Willebrand’s factor. Absent ADAMTS13, these large multimers
Hollenhorst plaques in the retina with visual field cuts; necrosis of the cause platelet clumping and intravascular hemolysis. An antibody to
toes; and acute glomerular capillary injury leading to focal segmental ADAMTS13 is found in many sporadic cases of adult TTP/HUS, but
glomerulosclerosis sometimes associated with hematuria, mild protein- not all; many patients also have antibodies to the thrombospondin
uria, and loss of renal function, which typically progresses over a few receptor on selected endothelial cells in small vessels or increased lev-
years. Occasional patients have fever, eosinophilia, or eosinophiluria. els of plasminogen-activator inhibitor 1 (PAI-1). Some children with
A skin biopsy of an involved area may be diagnostic. Since tissue fixa- complement protein deficiencies express atypical HUS (aHUS), which
tion dissolves the cholesterol, one typically sees only residual, bicon- can be treated with liver transplant. The treatment of adult TTP/HUS
vex clefts in involved vessels (see Fig. 62e-22). There is no therapy is daily plasmapheresis, which can be lifesaving. Plasmapheresis is
to reverse embolic occlusions, and steroids do not help. Controlling given until the platelet count rises, but in relapsing patients it normally
blood pressure and lipids and cessation of smoking are usually recom- is continued well after the platelet count improves, and in resistant
mended for prevention. patients twice-daily exchange may be helpful. Most patients respond
within 2 weeks of daily plasmapheresis. Since TTP/HUS often has an
SICKLE CELL DISEASE autoimmune basis, there is an anecdotal role in relapsing patients for
Although individuals with SA-hemoglobin are usually asymptomatic, using splenectomy, steroids, immunosuppressive drugs, bortezomib,
most will gradually develop hyposthenuria due to subclinical infarction or rituximab, an anti-CD20 antibody. Patients with childhood HUS
of the renal medulla, thus predisposing them to volume depletion. There from infectious diarrhea are not given antibiotics, because antibiotics
is an unexpectedly high prevalence of sickle trait among dialysis patients are thought to accelerate the release of the toxin and the diarrhea is
who are African American. Patients with homozygous SS-sickle cell dis- usually self-limited. No intervention appears superior to supportive
ease develop chronic vasoocclusive disease in many organs. Polymers of therapy in children with postdiarrheal HUS.
deoxygenated SS-hemoglobin distort the shape of red blood cells. These
cells attach to endothelia and obstruct small blood vessels, producing ANTIPHOSPHOLIPID ANTIBODY SYNDROME (SEE CHAP. 379)
frequent and painful sickle cell crises over time. Vessel occlusions in the
kidney produce glomerular hypertension, FSGS, interstitial nephritis,
GLOBAL CONSIDERATIONS
and renal infarction associated with hyposthenuria, microscopic hema- INFECTIOUS DISEASE–ASSOCIATED SYNDROMES
turia, and even gross hematuria; some patients also present with MPGN. A number of infectious diseases will injure the glomerular
Renal function can be overestimated due to the increased tubular secre- capillaries as part of a systemic reaction producing an immune
tion of creatinine seen in many patients with SS-sickle cell. By the second response or from direct infection of renal tissue. Evidence of
or third decade of life, persistent vasoocclusive disease in the kidney this immune response is collected by glomeruli in the form of immune
leads to varying degrees of renal failure, and some patients end up on deposits that damage the kidney, producing moderate proteinuria and

hematuria. A high prevalence of many of these infectious diseases in Other Viruses Other viral infections are occasionally associated with 1849
undeveloped countries results in infection-associated renal disease glomerular lesions, but cause and effect are not well established.
being the most common cause of glomerulonephritis in many parts of These viral infections and their respective glomerular lesions include:

the world. cytomegalovirus producing MPGN; influenza and anti-GBM disease;
measles-associated endocapillary proliferative glomerulonephritis,
Poststreptococcal Glomerulonephritis This form of glomerulonephritis
with measles antigen in the capillary loops and mesangium; parvovirus
is one of the classic complications of streptococcal infection. The
causing mild proliferative or mesangioproliferative glomerulonephri-
discussion of this disease can be found earlier, in the section “Acute
tis or FSGS; mumps and mesangioproliferative glomerulonephritis;
Nephritic Syndromes.”
Epstein-Barr virus producing MPGN, diffuse proliferative nephritis,
Subacute Bacterial Endocarditis Renal injury from persistent bactere- or IgA nephropathy; dengue hemorrhagic fever causing endocapillary
mia absent the continued presence of a foreign body, regardless of proliferative glomerulonephritis; and coxsackievirus producing focal
cause, is treated presumptively as if the patient has endocarditis. The glomerulonephritis or DPGN.
discussion of this disease can be found earlier, in the section “Acute
Syphilis Secondary syphilis, with rash and constitutional symptoms,
Nephritic Syndromes.”
develops weeks to months after the chancre first appears and occa-
Human Immunodeficiency Virus Renal disease is an important com- sionally presents with the nephrotic syndrome from MGN caused by
plication of HIV disease. The risk of development of end-stage renal subepithelial immune deposits containing treponemal antigens. Other
disease is much higher in HIV-infected African Americans than in HIV- lesions have also rarely been described including interstitial syphilitic
infected whites. About 50% of HIV-infected patients with kidney disease nephritis. The diagnosis is confirmed with nontreponemal and trepo-
have HIV-associated nephropathy (HIVAN) on biopsy. The lesion nemal tests for Treponema pallidum. The renal lesion responds to
in HIVAN is FSGS, characteristically revealing a collapsing glomeru- treatment with penicillin or an alternative drug, if allergic. Additional
lopathy (see Fig. 62e-3) with visceral epithelial cell swelling, microcystic testing for other sexually transmitted diseases is an important part of
dilatation of renal tubules, and tubuloreticular inclusion. Renal epithelial disease management.
cells express replicating HIV virus, but host immune responses also play
a role in the pathogenesis. MPGN and DPGN have also been reported Leprosy Despite aggressive eradication programs, approximately
but more commonly in HIV-infected whites and in patients coinfected 400,000 new cases of leprosy appear annually worldwide. The diagnosis
with hepatitis B or C. HIV-associated TTP has also been reported. Other is best made in patients with multiple skin lesions accompanied by
renal lesions include DPGN, IgA nephropathy, and MCD. Renal biopsy sensory loss in affected areas, using skin smears showing paucibacil-
may be indicated to distinguish between these lesions. lary or multibacillary infection (WHO criteria). Leprosy is caused by
HIV patients with FSGS typically present with nephrotic-range infection with Mycobacterium leprae and can be classified by Ridley-
proteinuria and hypoalbuminemia, but unlike patients with other Jopling criteria into various types: tuberculoid, borderline tuberculoid,
etiologies for nephrotic syndrome, they do not commonly have mid-borderline and borderline lepromatous, and lepromatous. Renal
hypertension, edema, or hyperlipidemia. Renal ultrasound also reveals involvement in leprosy is related to the quantity of bacilli in the body,
large, echogenic kidneys despite the finding that renal function in and the kidney is one of the target organs during splanchnic localiza-
some patients declines rapidly. Treatment with inhibitors of the renin- tion. In some series, all cases with borderline lepromatous and leproma-
angiotensin system decreases the proteinuria. Effective antiretroviral tous types of leprosy have various forms of renal involvement including
therapy benefits both the patient and the kidney and improves survival FSGS, mesangioproliferative glomerulonephritis, or renal amyloido-
of HIV-infected patients with chronic kidney disease (CKD) or end- sis; much less common are the renal lesions of DPGN and MPGN.
stage renal disease. In HIV-infected patients not yet on therapy, the Treatment of the infection can cause remission of the renal disease.
presence of HIVAN is an indication to initiate therapy. Following the Malaria There are 300–500 million incident cases of malaria each year
introduction of antiretroviral therapy, survival on dialysis for the HIV- worldwide, and the kidney is commonly involved. Glomerulonephritis is
infected patient has improved dramatically. Renal transplantations in due to immune complexes containing malarial antigens that are implanted
HIV-infected patients without detectable viral loads or histories of in the glomerulus. In malaria from P. falciparum, mild proteinuria is
opportunistic infections provide a better survival benefit over dialysis. associated with subendothelial deposits, mesangial deposits, and mesan-
Following transplantation, patient and graft survival are similar to the gioproliferative glomerulonephritis that usually resolve with treatment. In
general transplant population despite frequent rejections. quartan malaria from infection with Plasmodium malariae, children are
Hepatitis B and C Typically infected patients present with microscopic more commonly affected and renal involvement is more severe. Transient
hematuria, nonnephrotic or nephrotic-range proteinuria, and hyper- proteinuria and microscopic hematuria can resolve with treatment of the
tension. There is a close association between hepatitis B infection and infection. However, resistant nephrotic syndrome with progression to
polyarteritis nodosa with vasculitis appearing generally in the first renal failure over 3–5 years does happen, as <50% of patients respond to
6 months following infection. Renal manifestations include renal steroid therapy. Affected patients with nephrotic syndrome have thicken-
artery aneurysms, renal infarction, and ischemic scars. Alternatively, ing of the glomerular capillary walls, with subendothelial deposits of IgG,
the hepatitis B carrier state can produce a MGN that is more common IgM, and C3 associated with a sparse membranoproliferative lesion. The
in children than adults, or MPGN that is more common in adults than rare mesangioproliferative glomerulonephritis reported with Plasmodium
in children. Renal histology is indistinguishable from idiopathic MGN vivax or Plasmodium ovale typically has a benign course.
or type I MPGN. Viral antigens are found in the renal deposits. There Schistosomiasis Schistosomiasis affects more than 300 million people
are no good treatment guidelines, but interferon α-2b and lamivudine worldwide and primarily involves the urinary and gastrointestinal tracts.
have been used to some effect in small studies. Children have a good Glomerular involvement varies with the specific strain of schistoso-
prognosis, with 60–65% achieving spontaneous remission within miasis; Schistosoma mansoni is most commonly associated with clinical
4 years. In contrast, 30% of adults have renal insufficiency and 10% renal disease, and the glomerular lesions can be classified: Class I is a
have renal failure 5 years after diagnosis. mesangioproliferative glomerulonephritis; class II is an extracapillary pro-
Up to 30% of patients with chronic hepatitis C infection have some liferative glomerulonephritis; class III is a membranoproliferative glomer-
renal manifestations. Patients often present with type II mixed cryo- ulonephritis; class IV is a focal segmental glomerulonephritis; and class V
globulinemia, nephrotic syndrome, microscopic hematuria, abnormal is amyloidosis. Classes I–II often remit with treatment of the infection,
liver function tests, depressed C3 levels, anti–hepatitis C virus (HCV) but classes III and IV lesions are associated with IgA immune deposits
antibodies, and viral RNA in the blood. The renal lesions most com- and progress despite antiparasitic and/or immunosuppressive therapy.
monly seen, in order of decreasing frequency, are cryoglobulinemic
glomerulonephritis, MGN, and type I MPGN. Treatment with pegylated Other Parasites Renal involvement with toxoplasmosis infections
interferon and ribavirin is typical to reduce the viral load. is rare. When it occurs, patients present with nephrotic syndrome

1850 and have a histologic picture of MPGN. Fifty percent of patients with AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
leishmaniasis will have mild to moderate proteinuria and microscopic Etiology and Pathogenesis (Fig. 339-1) ADPKD is characterized by
hematuria, but renal insufficiency is rare. Acute DPGN, MGN, and progressive formation of epithelial-lined cysts in the kidney. Although
mesangioproliferative glomerulonephritis have all been observed on cysts only occur in 5% of the tubules in the kidney, the enormous
PART 13
biopsy. Filariasis and trichinosis are caused by nematodes and are growth of these cysts ultimately leads to the loss of normal surround-
sometimes associated with glomerular injury presenting with protein- ing tissues and loss of renal function. The cellular defects in ADPKD
uria, hematuria, and a variety of histologic lesions that typically resolve that have been known for a long time are increased cell proliferation
with eradication of the infection. and fluid secretion, decreased cell differentiation, and abnormal extra-
cellular matrix. ADPKD is caused by mutations in PKD1 and PKD2,
which, respectively, code for polycystin-1 (PC1) and polycystin-2
(PC2). PC1 is a large 11-transmembrane protein that functions like a G
protein–coupled receptor. PC2 is a calcium-permeable six-transmem-

brane protein that structurally belongs to the transient receptor poten-
tial (TRP) cation channel family. PC1 and PC2 are widely expressed in
almost all tissues and organs. PC1 expression is high in development
and low in the adult, whereas PC2 expression is relatively constant.
339
PC1 and PC2 are found on the primary cilium, a hair-like structure
Polycystic Kidney Disease and present on the apical membrane of a cell, in addition to the cell mem-
Other Inherited Disorders of branes and cell-cell junctions of tubular epithelial cells. Defects in the
primary cilia are linked to a wide spectrum of human diseases, col-
Tubule Growth and Development lectively termed ciliopathies. The most common phenotype shared by
Jing Zhou, Martin R. Pollak many ciliopathies is kidney cysts. PC1 and PC2 bind to each other via
their respective C-terminal tails to form a receptor-channel complex
and regulate each other’s function. The PC1/2 protein complex serves
The polycystic kidney diseases are a group of genetically heteroge- as a mechanosensor or chemical sensor and regulates calcium and
neous disorders and a leading cause of kidney failure. The autosomal G-protein signaling. The PC1/2 protein complex may also directly
dominant form of polycystic kidney disease (ADPKD) is the most regulate a number of cellular functions including the cell cycle, the
common life-threatening monogenic disease, affecting 12 million actin cytoskeleton, planar cell polarity (PCP), and cell migration. This
people worldwide. The autosomal recessive form of polycystic kidney protein complex has also been implicated in regulating a number of
disease (ARPKD) is rarer but affects the pediatric population. Kidney signaling pathways, including Wnt, mammalian target of rapamycin
cysts are often seen in a wide range of syndromic diseases. Recent stud- (mTOR), STAT3, cMET, phosphoinositide 3-kinase (PI3K)/AKT,
ies have shown that defects in the structure or function of the primary G protein–coupled receptor (GPCR), and epidermal growth factor
cilia may underlie this group of genetic diseases collectively termed receptor (EGFR), as well as in the localization and activity of cystic
ciliopathies (Table 339-1). fibrosis transmembrane conductance (CFTR). One hypothesis is
TABLE 339-1 Inherited Diseases Commonly Associated with a Cystic Phenotype

Mode of Renal
Disease Inheritance Abnormalities Other Clinical Features Genes
Autosomal dominant AD Cortical and medul- Liver, pancreatic cysts, hypertension, PKD1, PKD2
polycystic kidney disease lary cysts subarachnoid hemorrhage
Autosomal recessive AR Distal and collect- Oligohydramnios if severe, hypertension, PKHD1
polycystic kidney disease ing duct cysts ascending cholangitis, liver fibrosis
Medullary cystic kidney AD Small fibrotic In adults, gout MCKD1, MCKD2/UMOD
kidneys; medullary
cysts
Nephronophthisis AR Small fibrotic Growth retardation, anemia (visual loss, liver NPHP1-4, IQCB1, CEP290, GLIS2, RPGRIP1L,
kidneys; medullary fibrosis, cerebellar ataxia if associated with NEK8, SDCCAG8, TMEM67, TTC21B
cysts another syndrome)
Senior-Løken syndrome AR Renal cysts Juvenile nephronophthisis, Leber’s amaurosis NPHP1-6, SDCCAG8
Leber’s congenital amaurosis AR Renal cysts Visual impairment in first year of life, GUCY2D, RPE65, LCA3-14 (including LCA10,
pigmentary retinopathy CEP290)
Meckel-Gruber syndrome AR Cortical and CNS anomalies, polydactyly, congenital MKS1, TMEM216, TMEM67, CEP290,
medullary cysts heart defects RPGRIP1L, CC2D2A, TCTN2, B9D1, B9D2,
NPHP3
Bardet-Biedl syndrome AR Renal cysts Obesity, polydactyly, retinitis pigmentosa, BBS1, 2, ARL6, BBS4,5, MKKS, BBS7, TTC8,
anosmia, congenital heart defects, mental BBS9, 10, TRIM32, BBS12, MKS1, CEP290,
retardation C2ORF86; modifiers MKS1, MKS3,
CCDC28B
Oral-facial-digital AR Renal cysts Oral cavity, face, and digit anomalies; CNS OFD1
syndrome type I abnormalities; cystic kidney disease; X-linked
with male lethality, primary ciliary dyskinesia
Cranioectodermal dysplasia AR Renal cysts Skeletal dysplasia, thoracic deformities, poly- IFT80
(Sensenbrenner’s syndrome) dactyly, renal cysts, retinitis pigmentosa
Tuberous sclerosis AD Renal cysts Angiomyolipomas, renal cell carcinoma, facial TSC1, TSC2
angiofibromas, CNS hamartomas
Von Hippel-Lindau disease AD Renal cysts Renal cell carcinoma, retinal angiomas, CNS VHL
hemangioblastomas, pheochromocytomas
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system.

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ketoconazole and erythromycin, and some calcium channel blockers population at large, and this is particularly true in diabetic

in diabetic patients. 1831

Chapter 338 Glomerular Diseases

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Chapter 338 Glomerular Diseases

Basement membrane Endocapillary Extracapillary

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Table 338-1 Urine Assays for Albuminuria/Proteinuria

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Chapter 338 Glomerular Diseases

Table 338-2 Patterns of Clinical Glomerulonephritis

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Subacute bacterial endocarditisa +/++ ++ −

Schistosomiasis +++ +/++ −

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Chapter 338 Glomerular Diseases

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Chapter 338 Glomerular Diseases

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cyclophosphamide but may be associated with increased relapses.

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Chapter 338 Glomerular Diseases

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steroid resistance occurs.

FOCAL SEGMENTAL GLOMERULOSCLEROSIS

eliminated (Table 338-5), the remaining patients are considered to

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Chapter 338 Glomerular Diseases

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urine, predominately negatively charged albumin. The expansion of

often reveals the nonspecific deposition of IgG (at times in a linear

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Chapter 338 Glomerular Diseases

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Chapter 338 Glomerular Diseases

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Chapter 338 Glomerular Diseases

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protein–coupled receptor. PC2 is a calcium-permeable six-transmem-

TABLE 339-1 Inherited Diseases Commonly Associated with a Cystic Phenotype

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