In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues. In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues. The 2 prototypical complement-mediated kidney diseases are atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). Atypical hemolytic uremic syndrome is an ultra-rare disease characterized by acute kidney injury, thrombocytopenia, and microangiopathic hemolytic anemia that occurs with a reported incidence of approximately 0.5 per million per year. Other diseases that can present with a similar phenotype include Shiga toxin-producing E. coli-associated hemolytic uremic syndrome (STEC-HUS), thrombotic thrombocytopenic purpura, and other multisystem disorders. Criteria have been established to facilitate the diagnosis of aHUS. At least 50% of patients with aHUS have an underlying inherited and/or acquired complement abnormality, which leads to dysregulated activity of the alternative pathway at the endothelial cell surface. There are, however, noncomplement inherited abnormalities such as mutations in DGKE, which can result in an aHUS phenotype. Until recently, the prognosis for aHUS was poor, with the majority of patients developing end-stage renal disease within 2 years of presentation. However, with the introduction of eculizumab, a humanized monoclonal antibody against C5, it is now possible to control the renal disease and prevent development of end-stage renal disease. C3G is also ultra-rare (incidence approximately 1 per million per year) and defines a group of incurable kidney diseases driven by uncontrolled activation of the complement cascade that leads to C3 deposition within the glomerulus. Most frequently, dysregulation occurs at the level of the C3 convertase of the alternative pathway in the fluid phase and is driven by genetic and/or acquired defects. Broad interindividual variability gives rise to 2 major subtypes of disease, dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), that are resolved by characteristic findings on renal biopsy. The objective of this Kidney Disease: Improving Global Outcomes (KDIGO) conference was to gather a global panel of multidisciplinary clinical and scientific expertise to identify key issues relevant to the optimal management of these 2 diseases and to propose a research agenda to resolve outstanding controversial issues. Atypical hemolytic uremic syndrome is a “thrombotic” microangiopathy (TMA), the pathological features of which represent tissue responses to endothelial injury. In some biopsies, overt thrombosis as evidenced by intraluminal fibrin or fibrin-platelet plugging is not seen. Nonthrombotic features include endothelial swelling and denudation, mesangiolysis, double contours of the glomerular basement membrane, and subendothelial accumulation of electron-lucent, flocculent material. In arteries and arterioles, intramural fibrin, myxoid intimal thickening, and concentric myointimal proliferation (onion-skinning) may occur. It is illogical to describe cases with these features and clear absence of thrombosis as thrombotic microangiopathy. We therefore suggest referring to the process as microangiopathy, with further specification of whether thrombosis is present (Table 1).Table 1Morphological features in microangiopathyActive lesionsChronic lesionsGlomeruli•Thrombi•Endothelial swelling or denudation•Fragmented red blood cells•Subendothelial flocculent material by EM•Mesangiolysis•MicroaneurysmsGlomeruli•Double contours of peripheral capillary walls by LM, with variable mesangial interposition•New subendothelial basement membrane by EM•Widening of the subendothelial zone by EMArterioles•Thrombi•Endothelial swelling or denudation•Intramural fibrin•Fragmented red blood cells•Intimal swelling•Myocyte necrosisArterioles•Hyaline depositsArteries•Thrombi•Myxoid intimal swelling•Intramural fibrin•Fragmented red blood cellsArteries•Fibrous intimal thickening with concentric lamination (onion skin)EM, electron microscopy; LM, light microscopy. Open table in a new tab EM, electron microscopy; LM, light microscopy. C5b-9 staining can be seen in microangiopathy attributed to complement abnormalities, drug toxicity, and after hematopoietic stem cell transplantation.1Chua J.S. Baelde H.J. Zandbergen M. et al.Complement factor C4d is a common denominator in thrombotic microangiopathy.J Am Soc Nephrol. 2015; 26: 2239-2247Crossref PubMed Scopus (9) Google Scholar However, its presence is not reliable and we do not know whether this variability reflects technical or biological differences (Table 1). In general, it is not possible to determine etiology from morphology. Because morphologic features do not allow identification of etiology, it is important for the pathologist to provide a differential diagnosis, especially in patients with severe hypertension, where attributing changes to hypertension alone may lead to failure to identify other specific causes such as complement dysfunction. C3G defines a disease spectrum caused by abnormal control of complement activation, deposition, or degradation that results in predominant glomerular C3 fragment deposition associated with characteristic deposits as seen by electron microscopy (EM).2Pickering M.C. D'Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Based on EM appearance, C3G may be subclassified as DDD (dense osmiophilic intramembranous deposits) or C3GN (light dense, amorphous mesangial, paramesangial, subendothelial, and subepithelial deposits) (Table 2).Table 2Morphological features of C3GLight microscopy Active lesions • Mesangial expansion with or without hypercellularity • Endocapillary hypercellularity including monocytes and/or neutrophils • Capillary wall thickening with double contours (the combination of capillary wall thickening and mesangial increase is referred to as a membranoproliferative pattern) • Necrosis • Cellular/fibrocellular crescents Chronic lesions • Segmental or global glomerulosclerosis • Fibrous crescentsImmunofluorescence microscopy • Typically dominant C3 stainingElectron microscopy • DDD: Dense osmiophilic mesangial and intramembranous electron dense deposits • C3GN: Amorphous mesangial with or without capillary wall deposits including subendothelial, intramembranous and subepithelial electron dense deposits • Subepithelial “humps” may be seen in both DDD and C3GNC3G, C3 glomerulopathy; DDD, dense deposit disease; C3GN, C3 glomerulonephritis. Open table in a new tab C3G, C3 glomerulopathy; DDD, dense deposit disease; C3GN, C3 glomerulonephritis. A renal biopsy is required to diagnose C3G. The pattern seen on light microscopy can be very diverse, and a diagnosis of C3G can only be made on immunofluorescence (IF). The criterion on IF with the best balance of sensitivity and specificity is the presence of dominant C3 staining, with the intensity of C3 staining at least 2 orders of magnitude greater than any other immunoreactant (i.e., IgG, IgM, IgA, and C1q).3Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This criterion captures about 90% of DDD cases, but possibly fewer C3GN cases.3Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In the remaining cases, the initial kidney biopsy may not show C3-dominant glomerulonephritis (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 useful.3Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The timing of the initial biopsy is crucial because C3G often presents in the context of an acute infection, and C3 dominance can be seen in self-limiting postinfectious glomerulonephritis. There are no morphological features in acute exudative GN that predict resolution or progression. Humps are no longer considered pathognomonic of postinfectious glomerulonephritis, as they are frequently found in C3G. Cases of acute exudative GN with double contours of the glomerular basement membrane should heighten suspicion for C3GN. EM should be conducted in all cases to unequivocally distinguish DDD and C3GN, as this distinction is clinically important. In addition, in light of recent descriptions of GN with masked monotypic Ig deposits,4Larsen C.P. Ambuzs J.M. Bonsib S.M. et al.Membranous-like glomerulopathy with masked IgG kappa deposits.Kidney Int. 2014; 86: 154-161Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 5Larsen C.P. Messias N.C. Walker P.D. et al.Membranoproliferative glomerulonephritis with masked monotypic immunoglobulin deposits.Kidney Int. 2015; 88: 867-873Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar staining for IgG and light chains on pronase-digested paraffin sections should be considered for all cases of C3GN on standard IF, especially in adults. There is evidence that staining for C4d can distinguish C3G from immune complex-mediated GN, though its role is not established.5Larsen C.P. Messias N.C. Walker P.D. et al.Membranoproliferative glomerulonephritis with masked monotypic immunoglobulin deposits.Kidney Int. 2015; 88: 867-873Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 6Cook H.T. C4d staining in the diagnosis of C3 glomerulopathy.J Am Soc Nephrol. 2015; 26: 2609-2611Crossref PubMed Scopus (0) Google Scholar, 7Sethi S. Nasr S.H. De Vriese A.S. et al.C4d as a diagnostic tool in proliferative GN.J Am Soc Nephrol. 2015; 26: 2852-2859Crossref PubMed Scopus (9) Google Scholar Further studies on both frozen and paraffin sections are required. There are numerous knowledge gaps. Broadly, correlations between renal biopsy appearances, etiology, and clinical outcome including response to therapy are ill defined. IF staining is subjective and semiquantitative, and reliability and reproducibility have not been studied. While the EM appearance of DDD is well-defined and is used as a standard against which to assess the role of IF,3Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar it is not clear whether EM appearances in C3GN are characteristic and can confirm the diagnosis if IF is equivocal. The significance of some EM findings, such as the hump-like subepithelial deposits, is uncertain, and in some cases, distinguishing DDD and C3GN by EM is difficult. While it is possible to objectively assess the density of deposits on EM, the value of this approach requires further study. It is possible to identify different C3 breakdown products in glomeruli by IF8West C.D. Witte D.P. McAdams A.J. Composition of nephritic factor-generated glomerular deposits in membranoproliferative glomerulonephritis type 2.Am J Kidney Dis. 2001; 37: 1120-1130Abstract Full Text PDF PubMed Google Scholar or mass spectrometry after laser capture microdissection.9Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 10Sethi S. Gamez J.D. Vrana J.A. et al.Glomeruli of Dense Deposit Disease contain components of the alternative and terminal complement pathway.Kidney Int. 2009; 75: 952-960Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar This methodology can also be used to detect other complement components (i.e., factor H-related proteins, C5–C9). It is not known whether some of these complement components in specific tissue compartments (e.g., C5b-9) might identify a subset of patients likely to benefit from a specific type of therapy (e.g., anti-C5 therapy). An increased understanding of the significance of different complement components would be facilitated by detailed IF studies using well-characterized antibodies. The term aHUS has been used historically to define any HUS not caused by STEC-HUS. Current classifications reflect an increased understanding of disease mechanisms including the impact of genetic background and etiologic triggers.11Loirat C. Fakhouri F. Ariceta G. et al.An international consensus approach to the management of atypical hemolytic uremic syndrome in children.Pediatr Nephrol. 2016; 31: 15-39Crossref PubMed Scopus (0) Google Scholar As a result, some clinicians now use the term “primary aHUS” when an underlying abnormality of the alternative pathway of complement is strongly suspected and other causes of secondary aHUS have been excluded (Figure 1). However, even in some of these patients, a complement abnormality will not be identified. In many patients with an underlying complement risk factor, a trigger is required for aHUS to manifest.12Caprioli J. Noris M. Brioschi S. et al.Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.Blood. 2006; 108: 1267-1279Crossref PubMed Scopus (383) Google Scholar Triggers include autoimmune conditions, transplants, pregnancy, infections, drugs, and metabolic conditions.13Kavanagh D. Goodship T.H. Richards A. Atypical hemolytic uremic syndrome.Semin Nephrol. 2013; 33: 508-530Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar It may be difficult to show unequivocally that a trigger unmasks latent complement defects. Additional work is required to define the impact of complement risk factors in these subgroups. In general, we do not understand the time course of a clinical episode of aHUS and whether disease activity persists. However, many patients appear to be at life-long risk for the recurrent acute presentation of aHUS. Disease penetrance for an acute episode of aHUS is age-related, and by age 70 may be as high as 64%,14Sansbury F.H. Cordell H.J. Bingham C. et al.Factors determining penetrance in familial atypical haemolytic uraemic syndrome.J Med Genet. 2014; 51: 756-764Crossref PubMed Scopus (0) Google Scholar an observation that supports the existence of additional disease modifiers. A small percentage (3%–5%) of patients carry more than 1 pathogenic genetic variant, supporting a relationship between mutation burden and penetrance.15Bresin E. Rurali E. Caprioli J. et al.Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype.J Am Soc Nephrol. 2013; 24: 475-486Crossref PubMed Scopus (97) Google Scholar Presentation in later life is consistent with the need for an environmental trigger. Discordance between the pathological and clinical manifestations of the disease is sometimes seen. For instance, a thrombotic microangiopathy can sometimes be present on renal biopsy in the absence of thrombocytopenia. The introduction of eculizumab has changed the natural history of aHUS. Prior to eculizumab, most patients with aHUS progressed to end-stage renal disease, at which time the TMA process usually ceased.16Noris M. Remuzzi G. Hemolytic uremic syndrome.J Am Soc Nephrol. 2005; 16: 1035-1050Crossref PubMed Scopus (0) Google Scholar With complement inhibitory therapy, glomerular perfusion and function are maintained. How the renal endothelium is altered and interacts with the complement system following withdrawal of complement inhibitors is unclear and may be informed by clinical trials. In contrast to the acute presentation of aHUS, in the majority of patients with C3G, the disease follows a chronic, indolent course with persistent alternative pathway activation resulting in a 10-year renal survival of approximately 50%.17Servais A. Noel L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar However, cases of C3G presenting as a rapidly progressive GN are well recognized.18Fervenza F.C. Smith R.J. Sethi S. Association of a novel complement factor H mutation with severe crescentic and necrotizing glomerulonephritis.Am J Kidney Dis. 2012; 60: 126-132Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19Sandhu G. Bansal A. Ranade A. et al.C3 glomerulopathy masquerading as acute postinfectious glomerulonephritis.Am J Kidney Dis. 2012; 60: 1039-1043Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 20Vernon K.A. Goicoechea de Jorge E. Hall A.E. et al.Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency.Am J Kidney Dis. 2012; 60: 121-125Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Extrarenal manifestations are reported in up to 20% of patients with aHUS (Supplementary Table S1). It is unclear whether these manifestations are a direct consequence of complement activation, TMA, or other factors such as severe hypertension and uremia. Interestingly, despite sharing many of the same rare genetic variants in CFH21Yu Y. Triebwasser M.P. Wong E.K. et al.Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration.Hum Mol Genet. 2014; 23: 5283-5293Crossref PubMed Scopus (8) Google Scholar and CFI22Kavanagh D. Yu Y. Schramm E.C. et al.Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels.Hum Mol Genet. 2015; 24: 3861-3870PubMed Google Scholar described in age-related macular degeneration, drusen formation is not commonly reported in aHUS.23Recalde S. Tortajada A. Subias M. et al.Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases.J Am Soc Nephrol. 2016; 27: 1305-1311Crossref PubMed Scopus (16) Google Scholar In C3G (DDD and C3GN), acquired partial lipodystrophy24Misra A. Peethambaram A. Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature.Medicine (Baltimore). 2004; 83: 18-34Crossref PubMed Scopus (114) Google Scholar and retinal drusen25Dalvin L.A. Fervenza F.C. Sethi S. Pulido J.S. Shedding light on fundus drusen associated with membranoproliferative glomerulonephritis: breaking stereotypes of types I, II, and III.Retin Cases Brief Rep. 2016; 10: 72-78Crossref PubMed Google Scholar, 26Duvall-Young J. MacDonald M.K. McKechnie N.M. Fundus changes in (type II) mesangiocapillary glomerulonephritis simulating drusen: a histopathological report.Br J Ophthalmol. 1989; 73: 297-302Crossref PubMed Google Scholar are reported and appear to be direct consequences of complement activation. Acquired partial lipodystrophy is most commonly seen in individuals with C3 nephritic factors. Factor D, required for formation of the C3 convertase, is highly expressed in adipocytes, which undergo C3 nephritic factor–induced complement-dependent lysis.27Mathieson P.W. Wurzner R. Oliveria D.B. et al.Complement-mediated adipocyte lysis by nephritic factor sera.J Exp Med. 1993; 177: 1827-1831Crossref PubMed Google Scholar Drusen, the accumulation of lipids and complement-rich proteins between Bruch’s membrane and the retinal pigment epithelium, are commonly seen in age-related macular degeneration but occur at an earlier age in C3G.28Fritsche L.G. Chen W. Schu M. et al.Seven new loci associated with age-related macular degeneration.Nat Genet. 2013; 45: 433-439Crossref PubMed Scopus (287) Google Scholar Once routine biochemical and hematological analysis has demonstrated a TMA, investigations should focus on determining the underlying etiology and excluding other diagnoses (Supplementary Table S2, Figure 1). The most urgent requirement is to measure ADAMTS13 activity to diagnose or exclude thrombotic thrombocytopenic purpura. Because the incidence of thrombotic thrombocytopenic purpura is much lower in children than in adults, expert opinion recommends that in children, treatment with eculizumab should not be delayed while ADAMTS13 activity is being determined; however, signs of nonresponse should be carefully monitored. By contrast, in adults, measuring ADAMTS13 activity is recommended prior to eculizumab initiation. Investigation for STEC-HUS should be routine in all patients with presumed aHUS, as approximately 5% of STEC-HUS cases have no prodromal diarrhea, whereas 30% of complement-mediated aHUS cases have concurrent diarrhea or gastroenteritis (Figure 1).29Gerber A. Karch H. Allerberger F. et al.Clinical course and the role of shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997-2000, in Germany and Austria: a prospective study.J Infect Dis. 2002; 186: 493-500Crossref PubMed Scopus (0) Google Scholar Serum or plasma levels of complement proteins should be measured in all patients with primary aHUS and C3G prior to plasma therapy. C3 levels will be low in 30% to 50% of aHUS cases and up to 75% of C3G cases.9Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 17Servais A. Noel L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar Low C3 levels are also seen in the acute phase of STEC-HUS and pneumoccocal aHUS.11Loirat C. Fakhouri F. Ariceta G. et al.An international consensus approach to the management of atypical hemolytic uremic syndrome in children.Pediatr Nephrol. 2016; 31: 15-39Crossref PubMed Scopus (0) Google Scholar CD46 surface expression should be evaluated by flow cytometry for suspected aHUS. Complement functional assays and activation markers can also be obtained. The clinical interpretation of these tests requires further study.30Angioi A. Fervenza F.C. Sethi S. et al.Diagnosis of complement alternative pathway disorders.Kidney Int. 2016; 89: 278-288Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar (Supplementary Table S3). Studies of hundreds of patients with aHUS have provided an excellent understanding of genetic drivers of disease and have informed genotype–phenotype correlations that predict progression of disease, response to therapy, and the risk of recurrence after transplantation. This level of understanding supports an individualized approach to patient management and treatment based on expert interpretation of genetic profiles, and mandates genetic screening and molecular diagnostics in every patient. Delays in obtaining results from genetic or molecular diagnostic studies should not prevent a clinical diagnosis or postpone treatment, as early anti-complement treatment is crucial to preserve renal function and avoid irreversible sequelae.31Zuber J. Fakhouri F. Roumenina L.T. et al.Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies.Nat Rev Nephrol. 2012; 8: 643-657Crossref PubMed Scopus (210) Google Scholar Our understanding of the genetics of C3G is not yet comparable to that of aHUS, and more data are required to inform genotype–phenotype correlations. This knowledge gap can be addressed by screening large numbers of patients with C3G, studying the effects of disease-associated variants on function, and correlating these data with clinical outcomes (Supplementary Table S4).32Bu F. Borsa N.G. 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Buil A. et al.Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene c
