www.kidney-international.

org meeting report

Atypical hemolytic uremic syndrome and C3

glomerulopathy: conclusions from a “Kidney
Disease: Improving Global Outcomes” (KDIGO) OPEN

Controversies Conference
Timothy H.J. Goodship1, H. Terence Cook2, Fadi Fakhouri3, Fernando C. Fervenza4,
Véronique Frémeaux-Bacchi5, David Kavanagh1, Carla M. Nester6,7, Marina Noris8, Matthew C. Pickering2,
Santiago Rodrı́guez de Córdoba9, Lubka T. Roumenina10,11,12, Sanjeev Sethi13 and Richard J.H. Smith6,7;
for Conference Participants14
1
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; 2Centre for Complement and Inflammation Research,
Department of Medicine, Imperial College Hammersmith Campus, London, UK; 3INSERM, UMR-S 1064, and Department of Nephrology
and Immunology, CHU de Nantes, Nantes, France; 4Department of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota,
USA; 5Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France; 6Molecular Otolaryngology and Renal
Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; 7Division of Nephrology, Department of
Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; 8IRCCS–Istituto di Ricerche Farmacologiche “Mario
Negri,” Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Ranica, Bergamo, Italy; 9Centro de Investigaciones Biológicas,
Consejo Superior de Investigaciones Científicas, Madrid, Spain; Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain;
10
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1138, Complément et Maladies, Centre de
Recherche des Cordeliers, Paris, France; 11Université Paris Descartes Sorbonne Paris-Cité, Paris, France; 12Université Pierre et Marie Curie
(UPMC-Paris-6), Paris, France; and 13Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

T
In both atypical hemolytic uremic syndrome (aHUS) and C3 he 2 prototypical complement-mediated kidney dis-
glomerulopathy (C3G) complement plays a primary role in eases are atypical hemolytic uremic syndrome (aHUS)
disease pathogenesis. Herein we report the outcome of a and C3 glomerulopathy (C3G).
2015 Kidney Disease: Improving Global Outcomes (KDIGO) Atypical hemolytic uremic syndrome is an ultra-rare dis-
Controversies Conference where key issues in the ease characterized by acute kidney injury, thrombocytopenia,
management of these 2 diseases were considered by a and microangiopathic hemolytic anemia that occurs with a
global panel of experts. Areas addressed included renal reported incidence of approximately 0.5 per million per year.
pathology, clinical phenotype and assessment, genetic Other diseases that can present with a similar phenotype
drivers of disease, acquired drivers of disease, and treatment include Shiga toxin-producing E. coli-associated hemolytic
strategies. In order to help guide clinicians who are caring uremic syndrome (STEC-HUS), thrombotic thrombocyto-
for such patients, recommendations for best treatment penic purpura, and other multisystem disorders. Criteria have
strategies were discussed at length, providing the evidence been established to facilitate the diagnosis of aHUS. At least
base underpinning current treatment options. Knowledge 50% of patients with aHUS have an underlying inherited and/
gaps were identified and a prioritized research agenda was or acquired complement abnormality, which leads to dysre-
proposed to resolve outstanding controversial issues. gulated activity of the alternative pathway at the endothelial
Kidney International (2017) 91, 539–551; http://dx.doi.org/10.1016/ cell surface. There are, however, noncomplement inherited
j.kint.2016.10.005 abnormalities such as mutations in DGKE, which can result
KEYWORDS: anti-complement therapies; atypical hemolytic uremic syn- in an aHUS phenotype. Until recently, the prognosis for
drome; C3 glomerulopathy; complement; glomerulonephritis; kidney aHUS was poor, with the majority of patients developing end-
disease stage renal disease within 2 years of presentation. However,
Copyright ª 2016, International Society of Nephrology. Published by
with the introduction of eculizumab, a humanized mono-
Elsevier Inc. This is an open access article under the CC BY-NC-SA license
(http://creativecommons.org/licenses/by-nc-sa/4.0/). clonal antibody against C5, it is now possible to control the
renal disease and prevent development of end-stage renal
disease.
Correspondence: Timothy H.J. Goodship, Institute of Genetic Medicine,
Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. C3G is also ultra-rare (incidence approximately 1 per
E-mail: [email protected]; and Richard J.H. Smith, University of million per year) and defines a group of incurable kidney
Iowa, 200 Hawkins Drive—21151 PFP, Iowa City, IA 52242, USA. E-mail: diseases driven by uncontrolled activation of the complement
[email protected] cascade that leads to C3 deposition within the glomerulus.
14
See Appendix for list of other conference participants. Most frequently, dysregulation occurs at the level of the
Received 9 August 2016; revised 10 October 2016; accepted 20 October C3 convertase of the alternative pathway in the fluid phase
2016; published online 16 December 2016 and is driven by genetic and/or acquired defects. Broad

Kidney International (2017) 91, 539–551 539

meeting report THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report

interindividual variability gives rise to 2 major subtypes of transplantation.1 However, its presence is not reliable and we
disease, dense deposit disease (DDD) and C3 glomerulone- do not know whether this variability reflects technical or
phritis (C3GN), that are resolved by characteristic findings on biological differences (Table 1).
renal biopsy. In general, it is not possible to determine etiology from
The objective of this Kidney Disease: Improving Global morphology. Because morphologic features do not allow
Outcomes (KDIGO) conference was to gather a global panel identification of etiology, it is important for the pathologist to
of multidisciplinary clinical and scientific expertise to identify provide a differential diagnosis, especially in patients with
key issues relevant to the optimal management of these 2 severe hypertension, where attributing changes to hyperten-
diseases and to propose a research agenda to resolve sion alone may lead to failure to identify other specific causes
outstanding controversial issues. such as complement dysfunction.

RENAL PATHOLOGY C3G

aHUS C3G defines a disease spectrum caused by abnormal control
Atypical hemolytic uremic syndrome is a “thrombotic” of complement activation, deposition, or degradation that
microangiopathy (TMA), the pathological features of which results in predominant glomerular C3 fragment deposition
represent tissue responses to endothelial injury. In some associated with characteristic deposits as seen by electron
biopsies, overt thrombosis as evidenced by intraluminal fibrin microscopy (EM).2 Based on EM appearance, C3G may be
or fibrin-platelet plugging is not seen. Nonthrombotic fea- subclassified as DDD (dense osmiophilic intramembranous
tures include endothelial swelling and denudation, mesan- deposits) or C3GN (light dense, amorphous mesangial, par-
giolysis, double contours of the glomerular basement amesangial, subendothelial, and subepithelial deposits)
membrane, and subendothelial accumulation of electron- (Table 2).
lucent, flocculent material. In arteries and arterioles, intra- A renal biopsy is required to diagnose C3G. The pattern
mural fibrin, myxoid intimal thickening, and concentric seen on light microscopy can be very diverse, and a diagnosis
myointimal proliferation (onion-skinning) may occur. It is of C3G can only be made on immunofluorescence (IF). The
illogical to describe cases with these features and clear absence criterion on IF with the best balance of sensitivity and spec-
of thrombosis as thrombotic microangiopathy. We therefore ificity is the presence of dominant C3 staining, with the
suggest referring to the process as microangiopathy, with intensity of C3 staining at least 2 orders of magnitude greater
further specification of whether thrombosis is present than any other immunoreactant (i.e., IgG, IgM, IgA, and
(Table 1). C1q).3 This criterion captures about 90% of DDD cases, but
Areas of controversy and gaps in knowledge. C5b-9 stain- possibly fewer C3GN cases.3 In the remaining cases, the initial
ing can be seen in microangiopathy attributed to complement kidney biopsy may not show C3-dominant glomerulone-
abnormalities, drug toxicity, and after hematopoietic stem cell phritis (GN), but subsequent biopsies may, reflecting an
evolution in disease over time and suggesting that in cases
with an atypical clinical course, repeat biopsies may be
Table 1 | Morphological features in microangiopathy
Active lesions Chronic lesions
Table 2 | Morphological features of C3G
Glomeruli Glomeruli

Thrombi
Double contours of peripheral Light microscopy

Endothelial swelling capillary walls by LM, with variable Active lesions
or denudation mesangial interposition
Mesangial expansion with or without hypercellularity

Fragmented red
New subendothelial basement
Endocapillary hypercellularity including monocytes and/or
blood cells membrane by EM neutrophils

Subendothelial flocculent
Widening of the subendothelial
Capillary wall thickening with double contours (the combination of
material by EM zone by EM capillary wall thickening and mesangial increase is referred to as a

Mesangiolysis membranoproliferative pattern)

Microaneurysms
Necrosis
Arterioles Arterioles
Cellular/fibrocellular crescents

Thrombi
Hyaline deposits Chronic lesions

Endothelial swelling
Segmental or global glomerulosclerosis
or denudation
Fibrous crescents

Intramural fibrin Immunofluorescence microscopy

Fragmented red blood cells
Typically dominant C3 staining

Intimal swelling Electron microscopy

Myocyte necrosis
DDD: Dense osmiophilic mesangial and intramembranous electron
Arteries Arteries dense deposits

Thrombi
Fibrous intimal thickening with
C3GN: Amorphous mesangial with or without capillary wall deposits

Myxoid intimal swelling concentric lamination (onion skin) including subendothelial, intramembranous and subepithelial

Intramural fibrin electron dense deposits

Fragmented red blood cells
Subepithelial “humps” may be seen in both DDD and C3GN
EM, electron microscopy; LM, light microscopy. C3G, C3 glomerulopathy; DDD, dense deposit disease; C3GN, C3 glomerulonephritis.

540 Kidney International (2017) 91, 539–551

THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report meeting report

useful.3 The timing of the initial biopsy is crucial because secondary aHUS have been excluded (Figure 1). However,
C3G often presents in the context of an acute infection, and even in some of these patients, a complement abnormality
C3 dominance can be seen in self-limiting postinfectious will not be identified. In many patients with an underlying
glomerulonephritis. There are no morphological features in complement risk factor, a trigger is required for aHUS to
acute exudative GN that predict resolution or progression. manifest.12 Triggers include autoimmune conditions, trans-
Humps are no longer considered pathognomonic of post- plants, pregnancy, infections, drugs, and metabolic condi-
infectious glomerulonephritis, as they are frequently found in tions.13 It may be difficult to show unequivocally that a trigger
C3G. Cases of acute exudative GN with double contours of unmasks latent complement defects. Additional work is
the glomerular basement membrane should heighten suspi- required to define the impact of complement risk factors in
cion for C3GN. EM should be conducted in all cases to these subgroups.
unequivocally distinguish DDD and C3GN, as this distinction Acute versus chronic disease? In general, we do not
is clinically important. In addition, in light of recent understand the time course of a clinical episode of aHUS and
descriptions of GN with masked monotypic Ig deposits,4,5 whether disease activity persists. However, many patients
staining for IgG and light chains on pronase-digested appear to be at life-long risk for the recurrent acute presen-
paraffin sections should be considered for all cases of C3GN tation of aHUS. Disease penetrance for an acute episode of
on standard IF, especially in adults. aHUS is age-related, and by age 70 may be as high as 64%,14
Areas of controversy and gaps in knowledge. There is evi- an observation that supports the existence of additional dis-
dence that staining for C4d can distinguish C3G from ease modifiers. A small percentage (3%–5%) of patients carry
immune complex-mediated GN, though its role is not more than 1 pathogenic genetic variant, supporting a rela-
established.5–7 Further studies on both frozen and paraffin tionship between mutation burden and penetrance.15 Pre-
sections are required. sentation in later life is consistent with the need for an
There are numerous knowledge gaps. Broadly, correlations environmental trigger. Discordance between the pathological
between renal biopsy appearances, etiology, and clinical and clinical manifestations of the disease is sometimes seen.
outcome including response to therapy are ill defined. IF For instance, a thrombotic microangiopathy can sometimes
staining is subjective and semiquantitative, and reliability and be present on renal biopsy in the absence of
reproducibility have not been studied. While the EM thrombocytopenia.
appearance of DDD is well-defined and is used as a standard The introduction of eculizumab has changed the natural
against which to assess the role of IF,3 it is not clear whether history of aHUS. Prior to eculizumab, most patients with
EM appearances in C3GN are characteristic and can confirm aHUS progressed to end-stage renal disease, at which time
the diagnosis if IF is equivocal. The significance of some EM the TMA process usually ceased.16 With complement
findings, such as the hump-like subepithelial deposits, is inhibitory therapy, glomerular perfusion and function are
uncertain, and in some cases, distinguishing DDD and C3GN maintained. How the renal endothelium is altered and
by EM is difficult. While it is possible to objectively assess the interacts with the complement system following withdrawal
density of deposits on EM, the value of this approach requires of complement inhibitors is unclear and may be informed
further study. by clinical trials.
It is possible to identify different C3 breakdown products
in glomeruli by IF8 or mass spectrometry after laser capture C3G
microdissection.9,10 This methodology can also be used to In contrast to the acute presentation of aHUS, in the majority
detect other complement components (i.e., factor H-related of patients with C3G, the disease follows a chronic, indolent
proteins, C5–C9). It is not known whether some of these course with persistent alternative pathway activation resulting
complement components in specific tissue compartments in a 10-year renal survival of approximately 50%.17 However,
(e.g., C5b-9) might identify a subset of patients likely to cases of C3G presenting as a rapidly progressive GN are well
benefit from a specific type of therapy (e.g., anti-C5 therapy). recognized.18–20
An increased understanding of the significance of different
complement components would be facilitated by detailed IF Extrarenal manifestations of aHUS and C3G
studies using well-characterized antibodies. Extrarenal manifestations are reported in up to 20% of
patients with aHUS (Supplementary Table S1). It is unclear
CLINICAL PHENOTYPE AND ASSESSMENT whether these manifestations are a direct consequence of
aHUS complement activation, TMA, or other factors such as severe
The term aHUS has been used historically to define any HUS hypertension and uremia. Interestingly, despite sharing many
not caused by STEC-HUS. Current classifications reflect an of the same rare genetic variants in CFH21 and CFI22
increased understanding of disease mechanisms including the described in age-related macular degeneration, drusen for-
impact of genetic background and etiologic triggers.11 As a mation is not commonly reported in aHUS.23
result, some clinicians now use the term “primary aHUS” In C3G (DDD and C3GN), acquired partial lipodys-
when an underlying abnormality of the alternative pathway of trophy24 and retinal drusen25,26 are reported and appear to be
complement is strongly suspected and other causes of direct consequences of complement activation. Acquired

Kidney International (2017) 91, 539–551 541

meeting report THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report

TMA
Hb LDH
Plts Haptoglobin
MAHA

TTP
ADAMTS13 activity <10%
HUS ADAMTS13 AutoAb

STEC- HUS ESRD

Stool/Swab Culture
Stx detection
Serology/ PCR

Cobalamin C Pneumococcal Autoimmune Drug-induced BMT Infection Malignancy Posttransplant Pregnancy 1ary
aHUS aHUS aHUS aHUS aHUS aHUS aHUS aHUS aHUS aHUS

Homocysteine Bacterial Culture ANA HIV C3, C4, FH, FI

Factor H Ab
Methionine S. Pneumoniae Anti-ds DNA Hep A & C Anti-FH Ab
Methyl urinary antigen Anti-phospholipid CMV CD46 FACS
-malonic acid +ve Coombs Anti-Scl70 Influenza H1N1 CFH,CFI,CD46,
MMACHC T-antigen ACA EBV C3,CFB, DGKE
genetics detection RNA polymerase III genetics
MLPA

Figure 1 | TMA diagnostic flow chart. Following the diagnosis of a TMA, clinical and laboratory evaluation is required to establish the etiology.
ADAMTS13 activity is urgently required to exclude TTP prior to treatment with eculizumab in adults but is not a prerequisite in children.
Investigation for STEC-HUS should be undertaken in all individuals with suspected aHUS. In all pediatric aHUS, plasma and urinary evaluation for
cblC deficiency is mandatory. All individuals with suspected primary aHUS should have a complete evaluation for complement-mediated aHUS.
Individuals with pregnancy-associated aHUS and de novo transplantation associated aHUS should also have a full complement evaluation due
to the high prevalence of rare genetic variants described in these subgroups. In other secondary cases of aHUS, insufficient evidence exists to
recommend a full genetic evaluation, although it is noted that rare genetic variants have been described in many of these cases. Rarely, in
severe cases of STEC-HUS resulting in ESRD, rare genetic variants have been described following HUS recurrence in a subsequent renal
transplant. In cases where the role of complement is as yet unclear, the clinician should decide on the evaluation based on the clinical
consequences of positive result (e.g., listing for renal transplantation as demonstrated by the dotted line). Factor H autoantibodies have been
reported in non–small cell lung cancer, although a causative association with malignancy associated aHUS has yet to be made.107 1ary, primary;
Ab, antibody; ACA, anticentromere antibody; aHUS, atypical hemolytic uremic syndrome; ANA antinuclear antibody; anti-Scl-70, anti-topo-
isomerase I antibody; BMT, bone marrow transplant; CMV, cytomegalovirus; DGKE, diacylglycerol kinase ε; EBV, Epstein-Barr virus; ESRD, end-
stage renal disease; FACS, flow cytometry; Hb, hemoglobin; Hep, hepatitis; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase;
MAHA, microangiopathic hemolytic anemia; MLPA, multiplex ligation-dependent probe amplification; PCR, polymerase chain reaction; Plts,
platelets; STEC-HUS, Shiga toxin E. coli HUS; Stx, Shiga toxin; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.

partial lipodystrophy is most commonly seen in individuals however, signs of nonresponse should be carefully monitored.
with C3 nephritic factors. Factor D, required for formation of By contrast, in adults, measuring ADAMTS13 activity is
the C3 convertase, is highly expressed in adipocytes, which recommended prior to eculizumab initiation. Investigation
undergo C3 nephritic factor–induced complement- for STEC-HUS should be routine in all patients with pre-
dependent lysis.27 Drusen, the accumulation of lipids and sumed aHUS, as approximately 5% of STEC-HUS cases have
complement-rich proteins between Bruch’s membrane and no prodromal diarrhea, whereas 30% of complement-
the retinal pigment epithelium, are commonly seen in age- mediated aHUS cases have concurrent diarrhea or gastroen-
related macular degeneration but occur at an earlier age in teritis (Figure 1).29
C3G.28

Laboratory investigations Complement investigations of aHUS and C3G

Once routine biochemical and hematological analysis has Serum or plasma levels of complement proteins should be
demonstrated a TMA, investigations should focus on deter- measured in all patients with primary aHUS and C3G prior to
mining the underlying etiology and excluding other diagnoses plasma therapy. C3 levels will be low in 30% to 50% of aHUS
(Supplementary Table S2, Figure 1). The most urgent cases and up to 75% of C3G cases.9,17 Low C3 levels are also
requirement is to measure ADAMTS13 activity to diagnose or seen in the acute phase of STEC-HUS and pneumoccocal
exclude thrombotic thrombocytopenic purpura. Because the aHUS.11 CD46 surface expression should be evaluated by flow
incidence of thrombotic thrombocytopenic purpura is much cytometry for suspected aHUS. Complement functional
lower in children than in adults, expert opinion recommends assays and activation markers can also be obtained. The
that in children, treatment with eculizumab should not be clinical interpretation of these tests requires further study.30
delayed while ADAMTS13 activity is being determined; (Supplementary Table S3).

542 Kidney International (2017) 91, 539–551

THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report meeting report

GENETIC DRIVERS OF DISEASE In C3G, we recommend that all planned recipients of a

aHUS living-related kidney be screened and if a genetic abnormality
Studies of hundreds of patients with aHUS have provided an is found, the donor should be tested to exclude that genetic
excellent understanding of genetic drivers of disease and have abnormality. If the donor is found to carry the same genetic
informed genotype–phenotype correlations that predict pro- abnormality as the recipient, current evidence would suggest
gression of disease, response to therapy, and the risk of that while this finding may not constitute an absolute
recurrence after transplantation. This level of understanding contraindication to donation, each case should be evaluated
supports an individualized approach to patient management on an individual basis by experts in this area, taking into
and treatment based on expert interpretation of genetic account the family history and specific genetic abnormality.
profiles, and mandates genetic screening and molecular The theoretical risks that donation may trigger disease onset
diagnostics in every patient. Delays in obtaining results from must be discussed with the donor.
genetic or molecular diagnostic studies should not prevent a Genetic testing is recommended for patients in whom
clinical diagnosis or postpone treatment, as early anti- discontinuation of anticomplement therapies is being
complement treatment is crucial to preserve renal function considered.
and avoid irreversible sequelae.31 Understanding genetic variants. Genetic variants should
be classified as benign, likely benign, variant of uncertain
C3G significance, likely pathogenic, or pathogenic following
Our understanding of the genetics of C3G is not yet com- international guidelines.57
parable to that of aHUS, and more data are required to In aHUS, pathogenic variants specifically impair the
inform genotype–phenotype correlations. This knowledge capacity to protect host endothelial cells and platelets from
gap can be addressed by screening large numbers of patients complement damage or activation.58–67 It is clear that the
with C3G, studying the effects of disease-associated variants combination of different pathogenic variants and/or the
on function, and correlating these data with clinical outcomes combination of pathogenic variants and common risk vari-
(Supplementary Table S4).32–35 ants in CFH and MCP determine overall individual risk/
There is no clear benefit to performing genetic analysis in predisposition to aHUS.14,15,43,47,68–71 Genetic makeup also
every case of C3G, however genetic results may assist in influences disease progression, response to therapies, and
treatment decisions (i.e., anti-complement therapy vs. recurrence after transplantation (Supplementary
immunosuppression) and should be undertaken in familial Table S5).56,72,73
cases and when there is suspicion of a genetic defect.36–40 C3G, in contrast, appears mechanistically more complex
than aHUS, with massive C3 activation in plasma and com-
Genetic testing plement dysregulation on surfaces, including the glycocalyx
The minimum set of genes that should be screened in aHUS overlying the glomerular endothelial pores.2,17,38,51,55,74–78 We
and C3G includes CFH, CD46, CFI, C3, CFB, THBD, CFHR1, have limited information about genotype-phenotype corre-
CFHR5, and DGKE.41–46 Because of the frequent concurrence lations to distinguish different C3G subtypes, inform prog-
of genetic risk factors in aHUS, this analysis should also nosis, and/or recommend treatment.
include genotyping for the risk haplotypes CFH-H3 and It is highly recommended that genetic results be inter-
MCPggaac.47 Genetic analyses must include suitable technol- preted by a laboratory with expertise in aHUS and C3G
ogies to detect copy number variation, hybrid genes, and (Supplementary Tables S6 and S7).
other complex genomic rearrangements in the CFH/CFHRs
genomic region.48–53 ACQUIRED DRIVERS OF DISEASE
The identification of a pathogenic genetic variant in a aHUS
patient with aHUS reinforces the diagnosis and establishes In aHUS, the best studied are FH autoantibodies, which are
with accuracy the cause of the disease, facilitating patient typically associated with homozygosity for delCFHR3-
management, effective treatment, and genetic counseling. In CFHR1. Positive results should be confirmed in a second
C3G, however, present knowledge is insufficient except in sample at least 4 weeks after the initial sample. Testing should
cases of CFHR rearrangements leading to fusion genes (such also be performed in the prerenal transplant period. In pe-
as CFHR5 nephropathy), FH or FI deficiency, or with C3 diatric patients, FH autoantibody assays should be performed
mutations.36–40,54,55 following consensus guidelines: at diagnosis and, if positive, at
Genetic analysis is essential in living-related kidney donor days 7, 14, and 28, monthly, and at 1 year.11 Relapses of anti-
transplantation.56 The general recommendation in aHUS is FH–associated HUS occur in about 20% to 25% of patients.
that transplantation from living-related kidney donors should
only be considered if causative genetic (or acquired) factors C3G
are clearly identified in the recipient and the related donor is In C3G, C3 nephritic factors, FH autoantibodies and, in older
free of these factors. In this setting, the presence in the donor adults, free light chains should be assayed (Supplementary
of CFH or MCP aHUS risk haplotypes is not a contraindi- Table S8). The results of autoantibody assays require expert
cation to donation. interpretation, with their relevance to disease interpreted in

Kidney International (2017) 91, 539–551 543

meeting report THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report

the context of the results for all other complement assays and with some improvement, but there is a risk that delaying the
genetic screens. onset of eculizumab may lead to a suboptimal therapeutic
outcome.
TREATMENT STRATEGIES Treatment duration is controversial, and to date there is no
aHUS evidence to support lifelong therapy in all aHUS patients.
All patients with a clinical diagnosis of primary aHUS are Discontinuation of plasma therapy or complement inhibition
eligible for treatment with a complement inhibitor is feasible at least in some patients with aHUS. The consensus
(Supplementary Table S9). The dosing schedule reported in favored a minimal period of treatment to allow optimal renal
the trials is recommended, although 2 options for altered recovery without early relapse (Figure 3). Prospective studies
dosing have been considered: (i) the minimal dose required to are crucial to assess parameters predictive of relapse and to
achieve complement blockade; and (ii) a discontinuation define how genetics, quality of renal recovery, age, presence or
dosing schedule.79 No data exist to support either option, and absence of a triggering event, and biomarkers related to
both require monitoring of complement activity (Table 3). complement activation and/or endothelial cell injury inform
The treatment of FH autoantibody–driven aHUS involves the this decision.
use of anticellular therapy and is guided by antibody titer Eculizumab increases the risk of meningococcal infec-
(Figure 2). Interruption of anticomplement therapy during tion.11 Patients should receive vaccination against meningo-
intercurrent illness, a time of high-risk for aHUS relapse, is coccus, including type B; however, vaccination should not
not recommended unless an infection with an encapsulated delay the start of eculizumab. Antibiotic prophylaxis is
organism is suspected or documented. mandated during the first 2 weeks. Controversy remains as to
If access to eculizumab is unavailable, plasma therapy can whether vaccination is efficacious in patients with acute
be used. Plasma exchange should also be considered for anti- kidney injury, chronic kidney disease, and/or during immu-
FH-positive aHUS and in the emergency treatment of criti- nosuppression. It is unknown whether antimeningococcal
cally ill patients with severe TMA (e.g., coma or convulsions) antibodies are protective in the setting of complement
and a strong presumption of TTP until evidence of residual blockade; therefore, it is recommended that antibiotic pro-
ADAMTS13 activity exceeds 10%.80 The use of plasma phylaxis be maintained for the treatment duration and up to 2
exchange when eculizumab is available may be associated to 3 months after discontinuation.

Table 3 | Monitoring eculizumab therapy

CH50 (Total complement activity) Description

Measures the combined activity of all of the complement pathways

Tests the functional capability of serum complement components to lyse
50% of sheep erythrocytes in a reaction mixture

Will be low in congenital complement deficiency (C1–8) or during complement blockade

Normal range is assay dependent
Recommended goal during therapeutic complement blockade

<10% of normal
AH50 (Alternative pathway hemolytic activity) Description

Measures the combined activity of the alternative and terminal complement pathways

Tests the functional capability of alternate or terminal pathway complement
components to lyse 50% of rabbit erythrocytes in a Mg2þ-EGTA buffer

Will be low in congenital C3, FI, FB, properdin, FH, and FD deficiencies or
during terminal complement blockade

Normal range is assay dependent
Recommended goal during therapeutic complement blockade

<10% of normal
Eculizumab trough Description

May be a free or bound level

ELISA-based assay using C5 coated plates, patient sera, and an anti–human
IgG detection system

Not affected by complement deficiencies
Recommended trough level during therapeutic complement blockade

50–100mg/ml
Alternative assays The following assays are under investigation (or awaiting to be replicated in
different laboratories)62 as a means to monitor therapeutic complement blockade

Free C5
62

In vitro human microvascular endothelial cell test

sC5b-9 (also referred to as sMAC and TCC) may remain detectable in
aHUS patients in remission and therefore is not recommended as a monitoring tool
aHUS, atypical hemolytic uremic syndrome; C3, complement component 3; C5, complement component 5; EGTA, ethyleneglycol tetraacetic acid; ELISA, enzyme-linked
immunosorbent assay; FB, complement factor B; FD, complement factor D; FH, complement factor H; FI, complement factor I; sC5b-9, soluble C5b-9; sMAC, soluble mem-
brane attack complex; TCC, terminal complement complex.

544 Kidney International (2017) 91, 539–551

THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report meeting report

Clinical diagnosis
of
aHUS

High titer
FH autoantibodya

Plasma therapyb Eculizumab

Simultaneous start of Continue plasma Simultaneous start of Continue eculizumab

anticellular therapyc therapy indefinitelyd anticellular therapyc therapy indefinitelyd

Periodic monitoring of Periodic monitoring of

FH autoantibody FH autoantibody
levele levele

Discontinue therapy Discontinue therapy

when antibody titer when antibody titer
falls below a falls below a
pathogenic titer for at pathogenic titer for at
least 6 monthsf least 6 monthsf

Figure 2 | Treatment of complement factor H autoantibody-mediated aHUS. There are no prospective controlled studies in patients with
atypical hemolytic uremic syndrome (aHUS) due to anti–factor H protein (FH) antibodies, and thus the proposed management is based on a
pediatric consensus.11
a
Abnormal titer depends on the testing laboratory.
b
The decision to use plasma therapy versus eculizumab will be based on patient age and local resource availability.
c
Cyclophosphamide, rituximab, or mycophenolate mofetil.
d
The decision to continue anticomplement therapy indefinitely is not informed by data.
e
The interval may be monthly or quarterly and is based on local resources.
f
This recommendation is based on limited retrospective case reviews.108–110

Documentation of increased complement activ- complement gene and has no evidence of abnormal com-
ity11,31,79,81,82 in the setting of aHUS after an external trigger plement activation, donation is feasible.31
suggests clinical benefit of complement blockade especially in Liver transplant remains an option in patients with liver-
the setting of severe sequelae.17,77,83 However, in the absence derived complement protein abnormalities, in particular for
of trial data, complement inhibition in these forms of aHUS renal transplant recipients with uncontrolled disease activity
remains controversial. despite eculizumab therapy.85
Transplant. Kidney transplantation should be delayed
until at least 6 months after the start of dialysis because C3G
limited renal recovery may occur several months after starting A single randomized controlled trial using steroid as mono-
eculizumab.82,84 The resolution of hematological TMA fea- therapy in mesangiocapillary GN83 has been published. Given
tures and extrarenal manifestations is a prerequisite for the change in terminology and disease characterization and
transplantation. The decision to use anticomplement therapy the potential confounding effect on trial stratification, the
during transplantation should be based on recurrence risk results of this trial are of limited use in guiding current
(Table 4). treatment considerations for C3G. A retrospective study
Living-related kidney donation carries a risk for recurrence supports the effectiveness of mycophenolate mofetil in a select
in the recipient and a risk of de novo disease in the donor group.86 Outlined here is a tiered approach to treatment
should the donor carry an at-risk genetic variant.81 Potential based primarily on expert opinion, with limited support from
donors with evidence of abnormal alternative complement retrospective cohort studies87–103 (Table 5). In the absence of
pathway activity should be excluded. If the potential living- more specific data, monitoring of anticomplement therapy
related donor does not carry a pathogenic variant in a should be similar to that used in aHUS (Table 3).

Kidney International (2017) 91, 539–551 545

meeting report THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report

Clinical diagnosis
of
aHUS

Minimal period of
treatment and absence
of extrarenal disease

Adult Child Transplant

Transplant patients,
especially those who
Complete recovery of have lost previous
renal function in children allografts, are not good
>3 years of age candidates for treatment
cessation

If eculizumab is to be discontinued close periodic monitoring of renal function and

hematological parameters is mandatory. There are NO data to inform the frequency of
testing

Figure 3 | Recommendations for cessation of treatment with complement inhibitors. There are no prospective controlled studies in
patients with atypical hemolytic uremic syndrome (aHUS) to define criteria for discontinuation of eculizumab therapy. This flow diagram is
based on expert opinion.111–114 Discontinuation can be considered on a case-by-case basis in patients after at least 6 to 12 months of treatment
and at least 3 months of normalization (or stabilization in the case of residual chronic kidney disease) of kidney function. Earlier cessation
(at 3 months) may be considered in patients (especially children) with pathogenic variants in MCP if there has been rapid remission and
recovery of renal function. In patients who have undergone dialysis, eculizumab should be maintained for at least 4 to 6 months before
considering discontinuation. In this setting, the assessment of fibrotic changes in the kidney using a biopsy may be helpful. In patients who
have undergone transplant, especially patients who have lost previous allografts, discontinuation is not recommended.

No specific recommendation can be made for plasma with well-documented alternative complement pathway
therapy or rituximab (an anti-CD20 antibody). The confer- disease is required to identify morphological and/or immu-
ence attendees acknowledged published reports that support nohistochemical features that may distinguish between these
the effectiveness of plasma therapy in the setting of C3G groups. A longitudinal study of patients with features of
induced specifically by pathogenic variants in factor H; chronic microangiopathy on biopsy but without a history of
however, this approach appears to be beneficial to only a acute presentation is needed to define associations with
select subgroup of patients with C3G.77 clinical features, etiology, and outcome.
Transplant. No specific data are available to inform de- C3G. A comprehensive study is needed to define the
cisions surrounding transplantation in C3G. Recommenda- relationship of morphology to etiology, clinical course, and
tions reflect expert opinion and limited case reports response to therapy, which would be best achieved by a
(Supplementary Table S10). C3G recurs in allografts at a high multicenter collection of well-annotated cases, analyzed by a
rate, leading to graft loss in approximately 50% of patients. group of renal pathologists in a manner similar to that used
for the Oxford classification of IgA nephropathy.105,106 The
RESEARCH RECOMMENDATIONS study should include: light microscopy with histologic
We believe a cross-disciplinary approach should be under- markers of activity and chronicity; IF, including routine
taken for the recommendations listed below. This should studies together with staining for C3 fragments and other
include combining pathology, clinical phenotyping, genetics, complement proteins; and EM, including objective assess-
and therapy prospectively using scoring systems such as the ment of deposit density, quantity, and distribution.
MEST score in IgA nephropathy.104
Clinical phenotype and evaluation of aHUS and C3G
Renal pathology A consensus on the terminology covering TMAs and aHUS
aHUS. A comparative study of biopsies from patients should be sought as more information concerning their
with well-documented malignant hypertension and patients pathogenesis becomes available.

546 Kidney International (2017) 91, 539–551

THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report meeting report

Table 4 | Prophylaxis against aHUS recurrence in allografts Table 5 | Recommended treatment approach for C3Ga
based on a risk-assessment strategya
All patients

Optimal blood pressure control (suggested
Recurrence risk Treatment regimen blood pressure below the 90% in children
and #120/80 mm Hg in adults)
High risk (50-100%) Prophylactic eculizumabb,c B Priority agents include angiotensin converting

Previous early recurrence Note: Start on the day of
a enzyme inhibitors and angiotensin receptor

Pathogenic mutation transplantation due to blockers

Gain-of-function mutation potential for severe
Optimal nutrition for both normal growth in
recurrence and limited children and healthy weight in adults
recovery of function
Lipid control
in renal grafts compared Moderate disease Description
with native kidneys
Urine protein over 500 mg/24 h despite
supportive therapy
Moderate risk Prophylactic eculizumab or or

No mutation identified plasma exchanged
Moderate inflammation on renal biopsy

Isolated CFI mutations
or

Complement gene

Recent increase in serum creatinine suggesting
mutation of unknown significance risk for progressive disease

Persistent low titer FH autoantibody
Recommendation

Prednisone
Low risk (<10%) No prophylaxis
Mycophenolate mofetil

Isolated MCP mutations
Severe disease Description

Persistently negative FH

Urine protein over 2000 mg/24 h despite
autoantibodies immunosuppression and supportive therapy
aHUS, atypical hemolytic uremic syndrome; CFI, complement factor I gene; FH, or
complement factor H protein; MCP, membrane cofactor protein gene.
Severe inflammation represented by marked
a
Requires complete screening of all genes implicated in aHUS. endo- or extracapillary proliferation with or
b
Prophylactic regimens are based on local center protocols; no trial data exist to without crescent formation despite
support superiority of 1 protocol over another.
c immunosuppression and supportive therapy
Liver transplantation can be considered for renal transplant recipients with liver-
derived complement protein abnormalities, uncontrolled disease activity despite or
eculizumab therapy, or financial considerations regarding cost of long-term eculi-
Increased serum creatinine suggesting risk for
zumab therapy. progressive disease at onset despite
d
The decision to perform or not to perform prophylactic plasma exchange or immunosuppression and supportive therapy
complement inhibition is left to the discretion of the clinician. Recommendation

Methylprednisolone pulse dosing as well as
other anti-cellular immune suppressants have
had limited success in rapidly progressive disease
Clinical studies are required to define how complement
Data are insufficient to recommend eculizumab
biomarkers correlate with current or impending aHUS as a first-line agent for the treatment of rapidly
progressive disease
relapse and/or renal involvement, to identify risk factors for
C3G, C3 glomerulopathy.
aHUS relapse upon cessation of anti-complement therapy, to a
Based on a single, small prospective trial, case reports, and expert opinion.
identify alternative anticomplement therapeutics for aHUS, to
assess the value of proximal (at the level of the alternative
pathway) anticomplement therapy in C3G, and to determine In patients with aHUS and C3G in whom neither genetic
whether complement biomarkers can inform clinical nor acquired drivers of disease are identified, concerted
outcome in C3G patients. efforts should be made to elucidate disease triggers.

Genetic and acquired drivers of disease Treatment and clinical trial strategies for aHUS and C3G
Genetic testing should be undertaken in all persons with Despite remarkable advances in our understanding of the
suspected primary aHUS, although in cases of secondary underlying pathological mechanisms involved in C3G and
aHUS, the role of genetic testing must be clarified. Exceptions aHUS, much remains to learn about treatment. Because
include de novo posttransplant aHUS and pregnancy- eculizumab has altered the natural history of aHUS, contro-
associated aHUS, both of which require genetic testing. versy has arisen in several areas of treatment. Dosing schedule
In C3G, except for particular cases, present knowledge is and treatment duration remain controversial and should be
insufficient to establish robust phenotype–genotype correla- rigorously studied.
tions. Comprehensive genetic testing is required to fill this The treatment of C3G has not been studied thoroughly. In
knowledge gap. the absence of trial data, retrospective reviews, case studies, and
The impact of acquired autoantibodies such as C3 expert opinion inform the current approach to C3G treatment.
nephritic factor and FH autoantibody must be followed in The development and trial of complement inhibitors as
longitudinal studies to define their relevance to disease course therapeutic interventions for C3G is a high priority. For the
in the context of the results of all other complement assays purposes of selecting patients for clinical trials, the conference
and genetic screening. participants felt that only a single phenotypic parameter

Kidney International (2017) 91, 539–551 547

meeting report THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report

warranted consideration: the EM designation as either DDD or Table S2. Investigations recommended for TMA.
C3GN. While data demonstrating that EM will predict Table S3. Complement studies for aHUS and C3G.
treatment response to current therapeutic options are lacking, Table S4. Genetic drivers in aHUS and C3G.
Table S5. Genotype-phenotype correlations in aHUS.
limited retrospective studies suggest that there is a difference in Table S6. Categorization of the genetic variants.
renal survival between the 2 groups.17 Table S7. Complement assays that should be considered in addition
Although stratification based on sC5b-9 appears to genetic screening in aHUS and C3G.
appealing,88 particularly when considering terminal comple- Table S8. Acquired drivers of disease in aHUS and C3G: screening
ment blockade therapeutics, there is a paucity of data recommendations.
to support the reliability of this assay as a true marker of Table S9. Eculizumab dosing in aHUS based on dosing goal.
disease pathology. There is also insufficient evidence to Table S10. Transplant considerations in C3G.
Supplementary material is linked to the online version of the paper at
support stratification according to C5b-9 staining of renal www.kidney-international.org.
biopsy tissue. The conference participants believed there
was sufficient evidence in other glomerular diseases to
REFERENCES
exclude patients from C3G trials if they were stable on prior
1. Chua JS, Baelde HJ, Zandbergen M, et al. Complement factor C4d is a
supportive therapy or immune suppression after a 3-month common denominator in thrombotic microangiopathy. J Am Soc
period, had rapidly progressive disease, or had more than Nephrol. 2015;26:2239–2247.
2. Pickering MC, D’Agati VD, Nester CM, et al. C3 glomerulopathy:
25% sclerosis on renal biopsy.
consensus report. Kidney Int. 2013;84:1079–1089.
3. Hou J, Markowitz GS, Bomback AS, et al. Toward a working definition of
CONCLUSION C3 glomerulopathy by immunofluorescence. Kidney Int. 2014;85:
In this report, we document the proceedings of a KDIGO 450–456.
4. Larsen CP, Ambuzs JM, Bonsib SM, et al. Membranous-like
Controversies Conference on the management of aHUS and glomerulopathy with masked IgG kappa deposits. Kidney Int. 2014;86:
C3G. We have made recommendations pertinent to the 154–161.
diagnosis and treatment of patients with these 2 diseases 5. Larsen CP, Messias NC, Walker PD, et al. Membranoproliferative
glomerulonephritis with masked monotypic immunoglobulin deposits.
based on current expert opinion practices. In addition, we Kidney Int. 2015;88:867–873.
have identified knowledge gaps and offered suggestions for 6. Cook HT. C4d staining in the diagnosis of C3 glomerulopathy. J Am Soc
future research. While there are knowledge gaps in both Nephrol. 2015;26:2609–2611.
7. Sethi S, Nasr SH, De Vriese AS, et al. C4d as a diagnostic tool in
diseases, it is clear that the evidence base for the management proliferative GN. J Am Soc Nephrol. 2015;26:2852–2859.
of patients with C3G lags behind that of aHUS, and 8. West CD, Witte DP, McAdams AJ. Composition of nephritic factor-
addressing this disparity should be a priority. Though we generated glomerular deposits in membranoproliferative
glomerulonephritis type 2. Am J Kidney Dis. 2001;37:1120–1130.
have presented these 2 diseases as distinct entities, it is clear
9. Sethi S, Fervenza FC, Zhang Y, et al. C3 glomerulonephritis:
that there is substantial overlap not only in the pathogenesis clinicopathological findings, complement abnormalities, glomerular
but also in the clinical presentation such that some patients proteomic profile, treatment, and follow-up. Kidney Int. 2012;82:465–473.
10. Sethi S, Gamez JD, Vrana JA, et al. Glomeruli of Dense Deposit Disease
may show features of both. This should not be overlooked.
contain components of the alternative and terminal complement
pathway. Kidney Int. 2009;75:952–960.
DISCLOSURE 11. Loirat C, Fakhouri F, Ariceta G, et al. An international consensus
THJG declared that his employer (Newcastle University) has received approach to the management of atypical hemolytic uremic syndrome
consultancy fees on his behalf from Akari Therapeutics and Alexion. in children. Pediatr Nephrol. 2016;31:15–39.
HTC declared having received consultancy fees from Achillion and 12. Caprioli J, Noris M, Brioschi S, et al. Genetics of HUS: the impact of MCP,
speaker honoraria from Alexion. FF declared having received CFH, and IF mutations on clinical presentation, response to treatment,
consultancy fees and speaker honoraria from Alexion. VFB declared and outcome. Blood. 2006;108:1267–1279.
13. Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic
having received consultancy fees from Alexion. DK declared having
syndrome. Semin Nephrol. 2013;33:508–530.
equity ownership/stock options on Gyroscope Therapeutics and
14. Sansbury FH, Cordell HJ, Bingham C, et al. Factors determining
received research support from Fight for Sight, Kidney Research UK, penetrance in familial atypical haemolytic uraemic syndrome. J Med
Macular Society, Medical Research Council, Northern Counties Kidney Genet. 2014;51:756–764.
Research Fund, and Wellcome Trust. CMN declared having received 15. Bresin E, Rurali E, Caprioli J, et al. Combined complement gene
consultancy fees from Achillion and royalties from UpToDate. MN mutations in atypical hemolytic uremic syndrome influence clinical
declared having received consultancy fees from Alexion and Novartis. phenotype. J Am Soc Nephrol. 2013;24:475–486.
MCP declared having received consultancy fees from Achillion and 16. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol.
research support from Alexion. SRdC declared having received 2005;16:1035–1050.
speaker honoraria from Alexion. LTR declared having received 17. Servais A, Noel LH, Roumenina LT, et al. Acquired and genetic
complement abnormalities play a critical role in dense deposit disease
research support from CSL Behring. All the other authors declared no
and other C3 glomerulopathies. Kidney Int. 2012;82:454–464.
competing interests. 18. Fervenza FC, Smith RJ, Sethi S. Association of a novel complement
The conference was sponsored by Kidney Disease: Improving factor H mutation with severe crescentic and necrotizing
Global Outcomes (KDIGO) and supported in part by unrestricted glomerulonephritis. Am J Kidney Dis. 2012;60:126–132.
educational grants from Achillion Pharmaceuticals, Akari Therapeutics, 19. Sandhu G, Bansal A, Ranade A, et al. C3 glomerulopathy masquerading
Alexion Pharmaceuticals, and Omeros. as acute postinfectious glomerulonephritis. Am J Kidney Dis. 2012;60:
1039–1043.
20. Vernon KA, Goicoechea de Jorge E, Hall AE, et al. Acute presentation
SUPPLEMENTARY MATERIAL and persistent glomerulonephritis following streptococcal infection in a
Table S1. Extrarenal manifestations reported in aHUS, DDD, and patient with heterozygous complement factor H-related protein 5
C3GN. deficiency. Am J Kidney Dis. 2012;60:121–125.

548 Kidney International (2017) 91, 539–551

THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report meeting report

21. Yu Y, Triebwasser MP, Wong EK, et al. Whole-exome sequencing French series comparing children and adults. Clin J Am Soc Nephrol.
identifies rare, functional CFH variants in families with macular 2013;8:554–562.
degeneration. Hum Mol Genet. 2014;23:5283–5293. 44. Lemaire M, Fremeaux-Bacchi V, Schaefer F, et al. Recessive mutations in
22. Kavanagh D, Yu Y, Schramm EC, et al. Rare genetic variants in the CFI DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45:
gene are associated with advanced age-related macular degeneration 531–536.
and commonly result in reduced serum factor I levels. Hum Mol Genet. 45. Maga TK, Nishimura CJ, Weaver AE, et al. Mutations in alternative
2015;24:3861–3870. pathway complement proteins in American patients with atypical
23. Recalde S, Tortajada A, Subias M, et al. Molecular Basis of Factor H hemolytic uremic syndrome. Hum Mutat. 2010;31:E1445–E1460.
R1210C Association with Ocular and Renal Diseases. J Am Soc Nephrol. 46. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med.
2016;27:1305–1311. 2009;361:1676–1687.
24. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and 47. Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, et al. Predisposition to
autoimmune derangements in acquired partial lipodystrophy: report of atypical hemolytic uremic syndrome involves the concurrence of
35 cases and review of the literature. Medicine (Baltimore). 2004;83: different susceptibility alleles in the regulators of complement
18–34. activation gene cluster in 1q32. Hum Mol Genet. 2005;14:703–712.
25. Dalvin LA, Fervenza FC, Sethi S, Pulido JS. Shedding light on fundus 48. Challis RC, Araujo GS, Wong EK, et al. A de novo deletion in the
drusen associated with membranoproliferative glomerulonephritis: regulators of complement activation cluster producing a hybrid
breaking stereotypes of types I, II, and III. Retin Cases Brief Rep. 2016;10: complement factor H/complement factor H-related 3 gene in
72–78. atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2016;27:
26. Duvall-Young J, MacDonald MK, McKechnie NM. Fundus changes in 1617–1624.
(type II) mesangiocapillary glomerulonephritis simulating drusen: a 49. Chen Q, Wiesener M, Eberhardt HU, et al. Complement factor H-related
histopathological report. Br J Ophthalmol. 1989;73:297–302. hybrid protein deregulates complement in dense deposit disease. J Clin
27. Mathieson PW, Wurzner R, Oliveria DB, et al. Complement-mediated Invest. 2014;124:145–155.
adipocyte lysis by nephritic factor sera. J Exp Med. 1993;177: 50. Gale DP, de Jorge EG, Cook HT, et al. Identification of a mutation in
1827–1831. complement factor H-related protein 5 in patients of Cypriot origin with
28. Fritsche LG, Chen W, Schu M, et al. Seven new loci associated glomerulonephritis. Lancet. 2010;376:794–801.
with age-related macular degeneration. Nat Genet. 2013;45: 51. Tortajada A, Yebenes H, Abarrategui-Garrido C, et al. C3
433–439. glomerulopathy-associated CFHR1 mutation alters FHR oligomerization
29. Gerber A, Karch H, Allerberger F, et al. Clinical course and the role of and complement regulation. J Clin Invest. 2013;123:2434–2446.
shiga toxin-producing Escherichia coli infection in the hemolytic- 52. Valoti E, Alberti M, Tortajada A, et al. A novel atypical hemolytic uremic
uremic syndrome in pediatric patients, 1997-2000, in Germany and syndrome-associated hybrid CFHR1/CFH gene encoding a fusion
Austria: a prospective study. J Infect Dis. 2002;186:493–500. protein that antagonizes factor H-dependent complement regulation.
30. Angioi A, Fervenza FC, Sethi S, et al. Diagnosis of complement J Am Soc Nephrol. 2015;26:209–219.
alternative pathway disorders. Kidney Int. 2016;89:278–288. 53. Venables JP, Strain L, Routledge D, et al. Atypical haemolytic uraemic
31. Zuber J, Fakhouri F, Roumenina LT, et al. Use of eculizumab for atypical syndrome associated with a hybrid complement gene. PLoS Med.
haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev 2006;3:e431.
Nephrol. 2012;8:643–657. 54. Athanasiou Y, Voskarides K, Gale DP, et al. Familial C3 glomerulopathy
32. Bu F, Borsa NG, Jones MB, et al. High-Throughput genetic testing for associated with CFHR5 mutations: clinical characteristics of 91 patients
thrombotic microangiopathies and C3 glomerulopathies. J Am Soc in 16 pedigrees. Clin J Am Soc Nephrol. 2011;6:1436–1446.
Nephrol. 2016;27:1245–1253. 55. Chauvet S, Roumenina LT, Bruneau S, et al. A familial C3GN secondary
33. de Cordoba SR. Complement genetics and susceptibility to to defective C3 regulation by complement receptor 1 and factor H.
inflammatory disease. Lessons from genotype-phenotype correlations. J Am Soc Nephrol. 2016;27:1665–1677.
Immunobiology. 2016;221:709–714. 56. Noris M, Remuzzi G. Managing and preventing atypical hemolytic
34. Noris M, Brioschi S, Caprioli J, et al. Familial haemolytic uraemic uremic syndrome recurrence after kidney transplantation. Curr Opin
syndrome and an MCP mutation. Lancet. 2003;362:1542–1547. Nephrol Hypertens. 2013;22:704–712.
35. Richards A, Kemp EJ, Liszewski MK, et al. Mutations in human 57. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the
complement regulator, membrane cofactor protein (CD46), predispose interpretation of sequence variants: a joint consensus recommendation
to development of familial hemolytic uremic syndrome. Proc Natl Acad of the American College of Medical Genetics and Genomics and the
Sci U S A. 2003;100:12966–12971. Association for Molecular Pathology. Genet Med. 2015;17:405–424.
36. Ault BH, Schmidt BZ, Fowler NL, et al. Human factor H deficiency. 58. Frimat M, Tabarin F, Dimitrov JD, et al. Complement activation by heme
Mutations in framework cysteine residues and block in H protein as a secondary hit for atypical hemolytic uremic syndrome. Blood.
secretion and intracellular catabolism. J Biol Chem. 1997;272: 2013;122:282–292.
25168–25175. 59. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, et al. Gain-of-
37. Levy M, Halbwachs-Mecarelli L, Gubler MC, et al. H deficiency in two function mutations in complement factor B are associated with atypical
brothers with atypical dense intramembranous deposit disease. Kidney hemolytic uremic syndrome. Proc Natl Acad Sci U S A. 2007;104:
Int. 1986;30:949–956. 240–245.
38. Martinez-Barricarte R, Heurich M, Valdes-Canedo F, et al. Human C3 60. Manuelian T, Hellwage J, Meri S, et al. Mutations in factor H reduce
mutation reveals a mechanism of dense deposit disease pathogenesis binding affinity to C3b and heparin and surface attachment to
and provides insights into complement activation and regulation. J Clin endothelial cells in hemolytic uremic syndrome. J Clin Invest. 2003;111:
Invest. 2010;120:3702–3712. 1181–1190.
39. Montes T, Goicoechea de Jorge E, Ramos R, et al. Genetic deficiency of 61. Marinozzi MC, Vergoz L, Rybkine T, et al. Complement factor B
complement factor H in a patient with age-related macular mutations in atypical hemolytic uremic syndrome-disease-relevant or
degeneration and membranoproliferative glomerulonephritis. Mol benign? J Am Soc Nephrol. 2014;25:2053–2065.
Immunol. 2008;45:2897–2904. 62. Noris M, Galbusera M, Gastoldi S, et al. Dynamics of complement
40. Schejbel L, Schmidt IM, Kirchhoff M, et al. Complement factor H activation in aHUS and how to monitor eculizumab therapy. Blood.
deficiency and endocapillary glomerulonephritis due to paternal 2014;124:1715–1726.
isodisomy and a novel factor H mutation. Genes Immun. 2011;12:90–99. 63. Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME, et al. Clustering of
41. Abarrategui-Garrido C, Martinez-Barricarte R, Lopez-Trascasa M, et al. missense mutations in the C-terminal region of factor H in atypical
Characterization of complement factor H-related (CFHR) proteins in hemolytic uremic syndrome. Am J Hum Genet. 2001;68:478–484.
plasma reveals novel genetic variations of CFHR1 associated with 64. Roumenina LT, Jablonski M, Hue C, et al. Hyperfunctional C3
atypical hemolytic uremic syndrome. Blood. 2009;114:4261–4271. convertase leads to complement deposition on endothelial cells and
42. Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in contributes to atypical hemolytic uremic syndrome. Blood. 2009;114:
atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345–357. 2837–2845.
43. Fremeaux-Bacchi V, Fakhouri F, Garnier A, et al. Genetics and 65. Sanchez-Corral P, Perez-Caballero D, Huarte O, et al. Structural and
outcome of atypical hemolytic uremic syndrome: a nationwide functional characterization of factor H mutations associated with

Kidney International (2017) 91, 539–551 549

meeting report THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report

atypical hemolytic uremic syndrome. Am J Hum Genet. 2002;71: 88. Bomback AS, Smith RJ, Barile GR, et al. Eculizumab for dense deposit
1285–1295. disease and C3 glomerulonephritis. Clin J Am Soc Nephrol. 2012;7:
66. Schramm EC, Roumenina LT, Rybkine T, et al. Mapping interactions 748–756.
between complement C3 and regulators using mutations in atypical 89. Bonucchi D, Leonelli M, Damiano F, et al. [Post-transplant recurrence of
hemolytic uremic syndrome. Blood. 2015;125:2359–2369. glomerulonephritis: a complex clinical case]. G Ital Nefrol. 2010;27 Suppl
67. Stahl AL, Vaziri-Sani F, Heinen S, et al. Factor H dysfunction in patients 52:S82–S84.
with atypical hemolytic uremic syndrome contributes to complement 90. Daina E, Noris M, Remuzzi G. Eculizumab in a patient with dense-
deposition on platelets and their activation. Blood. 2008;111: deposit disease. N Engl J Med. 2012;366:1161–1163.
5307–5315. 91. Garnier AS, Augusto JF, Pellier I, et al. Successful long-term outcome of
68. Bernabeu-Herrero ME, Jimenez-Alcazar M, Anter J, et al. Complement kidney transplantation in a patient with X-linked thrombocytopenia:
factor H, FHR-3 and FHR-1 variants associate in an extended haplotype 9-year follow-up. Transplantation. 2014;98:e57–e58.
conferring increased risk of atypical hemolytic uremic syndrome. Mol 92. Gurkan S, Fyfe B, Weiss L, et al. Eculizumab and recurrent C3
Immunol. 2015;67:276–286. glomerulonephritis. Pediatr Nephrol. 2013;28:1975–1981.
69. Caprioli J, Castelletti F, Bucchioni S, et al. Complement factor H 93. Herlitz LC, Bomback AS, Markowitz GS, et al. Pathology after eculizumab
mutations and gene polymorphisms in haemolytic uraemic in dense deposit disease and C3 GN. J Am Soc Nephrol. 2012;23:
syndrome: the C-257T, the A2089G and the G2881T polymorphisms 1229–1237.
are strongly associated with the disease. Hum Mol Genet. 2003;12: 94. Inman M, Prater G, Fatima H, et al. Eculizumab-induced reversal of
3385–3395. dialysis-dependent kidney failure from C3 glomerulonephritis. Clin
70. Harris CL, Heurich M, Rodriguez de Cordoba S, et al. The complotype: Kidney J. 2015;8:445–448.
dictating risk for inflammation and infection. Trends Immunol. 2012;33: 95. Kerns E, Rozansky D, Troxell ML. Evolution of immunoglobulin
513–521. deposition in C3-dominant membranoproliferative glomerulopathy.
71. Pickering MC, de Jorge EG, Martinez-Barricarte R, et al. Spontaneous Pediatr Nephrol. 2013;28:2227–2231.
hemolytic uremic syndrome triggered by complement factor H lacking 96. Le Quintrec M, Lionet A, Kandel C, et al. Eculizumab for treatment of
surface recognition domains. J Exp Med. 2007;204:1249–1256. rapidly progressive C3 glomerulopathy. Am J Kidney Dis. 2015;65:
72. Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement 484–489.
abnormalities in sporadic and familial aHUS and their impact on clinical 97. McCaughan JA, O’Rourke DM, Courtney AE. Recurrent dense deposit
phenotype. Clin J Am Soc Nephrol. 2010;5:1844–1859. disease after renal transplantation: an emerging role for
73. Sanchez Chinchilla D, Pinto S, Hoppe B, et al. Complement mutations in complementary therapies. Am J Transplant. 2012;12:1046–1051.
diacylglycerol kinase-epsilon-associated atypical hemolytic uremic 98. Oosterveld MJ, Garrelfs MR, Hoppe B, et al. Eculizumab in pediatric
syndrome. Clin J Am Soc Nephrol. 2014;9:1611–1619. Dense Deposit Disease. Clin J Am Soc Nephrol. 2015;10:1773–1782.
74. Abrera-Abeleda MA, Nishimura C, Frees K, et al. Allelic variants of 99. Ozkaya O, Nalcacioglu H, Tekcan D, et al. Eculizumab therapy in a
complement genes associated with dense deposit disease. J Am Soc patient with dense-deposit disease associated with partial lipodystropy.
Nephrol. 2011;22:1551–1559. Pediatr Nephrol. 2014;29:1283–1287.
75. Barbour TD, Ruseva MM, Pickering MC. Update on C3 glomerulopathy. 100. Radhakrishnan S, Lunn A, Kirschfink M, et al. Eculizumab and refractory
Nephrol Dial Transplant. 2016;31:717–725. membranoproliferative glomerulonephritis. N Engl J Med. 2012;366:
76. Goicoechea de Jorge E, Caesar JJ, Malik TH, et al. Dimerization of 1165–1166.
complement factor H-related proteins modulates complement 101. Rousset-Rouviere C, Cailliez M, Garaix F, et al. Rituximab fails where
activation in vivo. Proc Natl Acad Sci U S A. 2013;110:4685–4690. eculizumab restores renal function in C3nef-related DDD. Pediatr
77. Licht C, Heinen S, Jozsi M, et al. Deletion of Lys224 in regulatory domain Nephrol. 2014;29:1107–1111.
4 of Factor H reveals a novel pathomechanism for dense deposit 102. Sanchez-Moreno A, De la Cerda F, Cabrera R, et al. Eculizumab in dense-
disease (MPGN II). Kidney Int. 2006;70:42–50. deposit disease after renal transplantation. Pediatr Nephrol. 2014;29:
78. Wong EK, Anderson HE, Herbert AP, et al. Characterization of a factor H 2055–2059.
mutation that perturbs the alternative pathway of complement in a 103. Vivarelli M, Pasini A, Emma F. Eculizumab for the treatment of dense-
family with membranoproliferative GN. J Am Soc Nephrol. 2014;25: deposit disease. N Engl J Med. 2012;366:1163–1165.
2425–2433. 104. Barbour SJ, Espino-Hernandez G, Reich HN, et al. The MEST score
79. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor provides earlier risk prediction in lgA nephropathy. Kidney Int. 2016;89:
eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 167–175.
2013;368:2169–2181. 105. Cattran DC, Coppo R, Cook HT, et al. The Oxford classification of IgA
80. Mannucci PM, Cugno M. The complex differential diagnosis between nephropathy: rationale, clinicopathological correlations, and
thrombotic thrombocytopenic purpura and the atypical hemolytic classification. Kidney Int. 2009;76:534–545.
uremic syndrome: Laboratory weapons and their impact on treatment 106. Roberts IS, Cook HT, Troyanov S, et al. The Oxford classification of IgA
choice and monitoring. Thromb Res. 2015;136:851–854. nephropathy: pathology definitions, correlations, and reproducibility.
81. Donne RL, Abbs I, Barany P, et al. Recurrence of hemolytic Kidney Int. 2009;76:546–556.
uremic syndrome after live related renal transplantation associated 107. Amornsiripanitch N, Hong S, Campa MJ, et al. Complement factor H
with subsequent de novo disease in the donor. Am J Kidney Dis. autoantibodies are associated with early stage NSCLC. Clin Cancer Res.
2002;40:E22. 2010;16:3226–3231.
82. Povey H, Vundru R, Junglee N, et al. Renal recovery with eculizumab in 108. Dragon-Durey MA, Sethi SK, Bagga A, et al. Clinical features of anti-
atypical hemolytic uremic syndrome following prolonged dialysis. Clin factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc
Nephrol. 2014;82:326–331. Nephrol. 2010;21:2180–2187.
83. Tarshish P, Bernstein J, Tobin JN, et al. Treatment of mesangiocapillary 109. Khandelwal P, Gupta A, Sinha A, et al. Effect of plasma exchange and
glomerulonephritis with alternate-day prednisone–a report of the immunosuppressive medications on antibody titers and outcome in
International Study of Kidney Disease in Children. Pediatr Nephrol. anti-complement factor H antibody-associated hemolytic uremic
1992;6:123–130. syndrome. Pediatr Nephrol. 2015;30:451–457.
84. Licht C, Greenbaum LA, Muus P, et al. Efficacy and safety of eculizumab 110. Sinha A, Gulati A, Saini S, et al. Prompt plasma exchanges and
in atypical hemolytic uremic syndrome from 2-year extensions of phase immunosuppressive treatment improves the outcomes of anti-factor H
2 studies. Kidney Int. 2015;87:1061–1073. autoantibody-associated hemolytic uremic syndrome in children.
85. Coppo R, Bonaudo R, Peruzzi RL, et al. Liver transplantation for Kidney Int. 2014;85:1151–1160.
aHUS: still needed in the eculizumab era? Pediatr Nephrol. 2016;31: 111. Sheerin NS, Kavanagh D, Goodship TH, et al. A national specialized
759–768. service in England for atypical haemolytic uraemic syndrome-the first
86. Rabasco C, Cavero T, Roman E, et al. Effectiveness of mycophenolate year’s experience. QJM. 2016;109:27–33.
mofetil in C3 glomerulonephritis. Kidney Int. 2015;88:1153–1160. 112. Wetzels JF, van de Kar NC. Discontinuation of eculizumab maintenance
87. Besbas N, Gulhan B, Gucer S, et al. A novel CFHR5 mutation associated treatment for atypical hemolytic uremic syndrome. Am J Kidney Dis.
with C3 glomerulonephritis in a Turkish girl. J Nephrol. 2014;27:457–460. 2015;65:342.

550 Kidney International (2017) 91, 539–551

THJ Goodship et al.: aHUS and C3 glomerulopathy: a KDIGO conference report meeting report

113. Ardissino G, Possenti I, Tel F, et al. Discontinuation of eculizumab Linda Burke, USA; Thomas D. Cairns, UK; Mireya Carratala, Spain;
treatment in atypical hemolytic uremic syndrome: an update. Am J Vivette D. D’Agati, USA; Mohamed R. Daha, The Netherlands; An
Kidney Dis. 2015;66:172–173. S. De Vriese, Belgium; Marie-Agnès Dragon-Durey, France; Agnes
114. Ardissino G, Testa S, Possenti I, et al. Discontinuation of eculizumab B. Fogo, USA; Miriam Galbusera, Italy; Daniel P. Gale, UK; Hermann
maintenance treatment for atypical hemolytic uremic syndrome: a
Haller, Germany; Sally Johnson, UK; Mihály Józsi, Hungary; Diana
report of 10 cases. Am J Kidney Dis. 2014;64:633–637.
Karpman, Sweden; Lynne Lanning, USA; Moglie Le Quintrec,
France; Christoph Licht, Canada; Chantal Loirat, France; Francisco
Monfort, Spain; B. Paul Morgan, UK; Laure-Hélène Noël, France;
APPENDIX Michelle M. O’Shaughnessy, USA; Marion Rabant, France; Eric
Other Conference Participants Rondeau, France; Piero Ruggenenti, Italy; Neil S. Sheerin, UK; Jenna
Charlie E. Alpers, USA; Gerald B. Appel, USA; Gianluigi Ardissino, Smith, USA; Fabrizio Spoleti, Italy; Joshua M. Thurman, USA; Nicole
Italy; Gema Ariceta, Spain; Mustafa Arici, Turkey; Arvind Bagga, C.A.J. van de Kar, The Netherlands; Marina Vivarelli, Italy; Peter
India; Ingeborg M. Bajema, The Netherlands; Miguel Blasco, Spain; F. Zipfel, Germany

Kidney International (2017) 91, 539–551 551