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Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement

2012; Elsevier BV; Volume: 83; Issue: 2 Linguagem: Inglês

10.1038/ki.2012.384

1523-1755

Sanjeev Sethi, Fernando C. Fervenza, Yuzhou Zhang, Ladan Zand, Nicole C. Meyer, Nicolò Ghiringhelli Borsa, Samih H. Nasr, Richard J. Smith,

SARS-CoV-2 and COVID-19 Research

Postinfectious glomerulonephritis is a common disorder that develops following an infection. In the majority of cases, there is complete recovery of renal function within a few days to weeks following resolution of the infection. In a small percentage of patients, however, the glomerulonephritis takes longer to resolve, resulting in persistent hematuria and proteinuria, or even progression to end-stage kidney disease. In some cases of persistent hematuria and proteinuria, kidney biopsies show findings of a postinfectious glomerulonephritis even in the absence of any evidence of a preceding infection. The cause of such ‘atypical’ postinfectious glomerulonephritis, with or without evidence of preceding infection, is unknown. Here we show that most patients diagnosed with this ‘atypical’ postinfectious glomerulonephritis have an underlying defect in the regulation of the alternative pathway of complement. These defects include mutations in complement-regulating proteins and antibodies to the C3 convertase known as C3 nephritic factors. As a result, the activated alternative pathway is not brought under control even after resolution of the infection. Hence, the sequela is continual glomerular deposition of complement factors with resultant inflammation and development of an ‘atypical’ postinfectious glomerulonephritis. Postinfectious glomerulonephritis is a common disorder that develops following an infection. In the majority of cases, there is complete recovery of renal function within a few days to weeks following resolution of the infection. In a small percentage of patients, however, the glomerulonephritis takes longer to resolve, resulting in persistent hematuria and proteinuria, or even progression to end-stage kidney disease. In some cases of persistent hematuria and proteinuria, kidney biopsies show findings of a postinfectious glomerulonephritis even in the absence of any evidence of a preceding infection. The cause of such ‘atypical’ postinfectious glomerulonephritis, with or without evidence of preceding infection, is unknown. Here we show that most patients diagnosed with this ‘atypical’ postinfectious glomerulonephritis have an underlying defect in the regulation of the alternative pathway of complement. These defects include mutations in complement-regulating proteins and antibodies to the C3 convertase known as C3 nephritic factors. As a result, the activated alternative pathway is not brought under control even after resolution of the infection. Hence, the sequela is continual glomerular deposition of complement factors with resultant inflammation and development of an ‘atypical’ postinfectious glomerulonephritis. Postinfectious glomerulonephritis is a type of glomerulonephritis seen in both children and adults after an infection. The glomerulonephritis is manifested by the development of a nephritic syndrome within 1–3 weeks of an infectious episode.1.Rodriguez-Iturbe B. Musser J.M. The Current state of poststreptococcal glomerulonephritis.J Am Soc Nephrol. 2008; 19: 1855-1864Crossref PubMed Scopus (165) Google Scholar, 2.Rodriguez-Iturbe B. Batsford S. Pathogenesis of poststreptococcal glomerulonephritis a century after Clemens von Pirquet.Kidney Int. 2007; 71: 1094-1104Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 3.Nadasdy T. Hebert L.A. Infection-related glomerulonephritis: understanding mechanisms.Sem Nephrol. 2011; 31: 369-375Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar The infection is often mild and typically resolves by the time the glomerulonephritis is diagnosed. The pathogenesis of postinfectious glomerulonephritis is thought to be due to (1) glomerular in situ deposition of bacterial antigens with subsequent antibody buildup and formation of in situ immune complexes and/or (2) glomerular deposition of circulating immune complexes.2.Rodriguez-Iturbe B. Batsford S. Pathogenesis of poststreptococcal glomerulonephritis a century after Clemens von Pirquet.Kidney Int. 2007; 71: 1094-1104Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 3.Nadasdy T. Hebert L.A. Infection-related glomerulonephritis: understanding mechanisms.Sem Nephrol. 2011; 31: 369-375Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 4.Eison T. Ault B. Jones D. et al.Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis.Pediat Nephrol. 2011; 26: 165-180Crossref PubMed Scopus (103) Google Scholar, 5.Yousif Y. Okada K. Batsford S. et al.Induction of glomerulonephritis in rats with staphylococcal phosphatase: new aspects in post-infectious ICGN.Kidney Int. 1996; 50: 290-297Abstract Full Text PDF PubMed Scopus (21) Google Scholar, 6.Peake P. Pussell B. Karplus T. et al.Post-streptococcal glomerulonephritis: studies on the interaction between nephritis strain-associated protein (NSAP), complement and the glomerulus.APMIS. 1991; 99: 460-466Crossref PubMed Scopus (29) Google Scholar The characteristic features of postinfectious glomerulonephritis on kidney biopsy are a proliferative glomerulonephritis on light microscopy (LM), bright C3 staining with or without immunoglobulins on immunofluorescence (IF) microscopy, and subepithelial deposits called ‘humps’ on electron microscopy (EM).3.Nadasdy T. Hebert L.A. Infection-related glomerulonephritis: understanding mechanisms.Sem Nephrol. 2011; 31: 369-375Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 7.Montseny J.-J. Meyrier A. Kleinknecht D. et al.The current spectrum of infectious glomerulonephritis: experience with 76 patients and review of the literature.Medicine (Baltimore). 1995; 74: 63-73Crossref PubMed Scopus (136) Google Scholar, 8.Nasr S.H. Markowitz G.S. Stokes M.B. et al.Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature.Medicine (Baltimore). 2008; 87: 21-32Crossref PubMed Scopus (141) Google Scholar It should be pointed out that in some cases, the diagnosis of postinfectious glomerulonephritis is made on the basis of these biopsy findings even in the absence of any clinical, bacterial, or serological evidence of a preceding infection. The majority of patients achieve complete remission of the nephritic syndrome after postinfectious glomerulonephritis. However, in a small percentage, the disease takes longer to resolve or persists with renal dysfunction evidenced by continuing hematuria and proteinuria. A smaller percentage still progresses to end-stage kidney disease.1.Rodriguez-Iturbe B. Musser J.M. The Current state of poststreptococcal glomerulonephritis.J Am Soc Nephrol. 2008; 19: 1855-1864Crossref PubMed Scopus (165) Google Scholar, 4.Eison T. Ault B. Jones D. et al.Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis.Pediat Nephrol. 2011; 26: 165-180Crossref PubMed Scopus (103) Google Scholar, 7.Montseny J.-J. Meyrier A. Kleinknecht D. et al.The current spectrum of infectious glomerulonephritis: experience with 76 patients and review of the literature.Medicine (Baltimore). 1995; 74: 63-73Crossref PubMed Scopus (136) Google Scholar, 8.Nasr S.H. Markowitz G.S. Stokes M.B. et al.Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature.Medicine (Baltimore). 2008; 87: 21-32Crossref PubMed Scopus (141) Google Scholar, 9.Hoy W.E. White A.V. Dowling A. et al.Post-streptococcal glomerulonephritis is a strong risk factor for chronic kidney disease in later life.Kidney Int. 2012; 81: 1026-1032Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 10.Nasr S.H. Fidler M.E. Valeri A.M. et al.Postinfectious glomerulonephritis in the elderly.J Am Soc Nephrol. 2011; 22: 187-195Crossref PubMed Scopus (121) Google Scholar The terms ‘persistent’, ‘resolving’, or ‘chronic’ postinfectious glomerulonephritis have been used to describe these entities. During an infection that triggers the development of postinfectious glomerulonephritis, there is activation of the alternative pathway (AP) of complement.4.Eison T. Ault B. Jones D. et al.Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis.Pediat Nephrol. 2011; 26: 165-180Crossref PubMed Scopus (103) Google Scholar, 11.Ferreira V.P. Pangburn M.K. Cortés C. Complement control protein factor H: The good, the bad, and the inadequate.Mol Immunol. 2010; 47: 2187-2197Crossref PubMed Scopus (278) Google Scholar, 12.Skattum L. van Deuren M. van der Poll T. et al.Complement deficiency states and associated infections.Mol Immunol. 2011; 48: 1643-1655Crossref PubMed Scopus (155) Google Scholar After elimination of the infection, immune complexes are cleared, the AP activity is controlled, and glomerulonephritis resolves.11.Ferreira V.P. Pangburn M.K. Cortés C. Complement control protein factor H: The good, the bad, and the inadequate.Mol Immunol. 2010; 47: 2187-2197Crossref PubMed Scopus (278) Google Scholar,13.Zipfel P.F. Skerka C. Complement regulators and inhibitory proteins.Nat Rev Immunol. 2009; 9: 729-740Crossref PubMed Scopus (891) Google Scholar We hypothesized that in patients who take longer to resolve, develop persistent proteinuria and hematuria, or progress to end-stage kidney disease, there is a defect in the regulating mechanisms of the AP of complement that prevents its downregulation after resolution of the infection. The consequence is excessive deposition of complement proteins and breakdown products in the glomeruli seen as the pathognomonic bright C3 staining on IF microscopy on kidney biopsy. An inflammatory response ensues with the development of persistent proliferative glomerulonephritis. We define such cases as ‘atypical’ postinfectious glomerulonephritis, to highlight the presence of an abnormality in the AP of complement. To test this hypothesis, we evaluated the AP of complement in 11 patients with persistent hematuria and proteinuria diagnosed with postinfectious glomerulonephritis on kidney biopsy to determine whether an underlying abnormality of the AP of complement could be identified. The study included six cases with a kidney biopsy diagnosis of postinfectious glomerulonephritis, even though there was no evidence of a preceding infection. (Table 1) Our study included 11 patients who fulfilled the diagnostic criteria of ‘atypical’ postinfectious glomerulonephritis. The diagnostic criteria of ‘atypical’ postinfectious glomerulonephritis were as follows: (1) persistent hematuria and proteinuria, with or without a history of preceding infection; (2) renal biopsy showing features of postinfectious glomerulonephritis—(a) proliferative glomerulonephritis on LM, including patterns of diffuse or focal endocapillary proliferative and exudative glomerulonephritis, and mesangial proliferative glomerulonephritis; (b) mesangial and/or capillary wall C3 with or without immunoglobulin staining on IF microscopy; and (c) subepithelial ‘hump-like’ deposits on EM—(3) abnormalities of the AP of complement.Table 1Clinical features and laboratory evaluationPatientAge/sex at presentationSerum creatinine at presentation mg/dlUrinalysis RBC/HPFUrinary protein (mg/24h)C3/C4 mg/dlSerum creatinine at follow-up171/F1.741–50, 25% dRBC638976/26aC3 levels at outside laboratory at presentation had normal range listed as 90–150mg/dl.1.1 (15 m)314/M1.321–30, >25% dRBC15,76019/131.3 (30 m)460/M1.150–100, >25% dRBC87457/351.4 (48 m)547/F3.121–30, No report on dRBC204, While on dialysis56/47On dialysis, 4 m after presentation622/M2.050–100, No report on dRBC10,39012/Normal1.6 (4 m)722/M1.850–100, No report dRBC800135/371.2 (6 m)817/F0.7Hematuria UA reportbUA presentation not available, low or normal C3/C4 as per notes or laboratory result values not given.1156115/200.7 (12 m)92.5/M0.550–100, >25% dRBC3+, Not quantitated81/230.4 (Recent patient, 4 m)1020/M1.331–40, <25% dRBC12,4003/Normal1.65 (8 m)1161/F0.831–40, G, p.Arg567Gly and c.3350A>G, p.Asn1117Ser. The single missense variant in CFHR5 was c.646–647AA>TT,p.Asn216Phe. None of the missense variants is reported in NHLBI Exome Sequencing Project, a database of over 10,000 chromosomes.Table 3Complement abnormalitiesPatientCFHCFHR5FH antibodiesaNormal titer <1:50.Hemolytic assaybNormal <3%.APFAcNormal 65–130%.C3NeFsMACdNormal TT, p.Asn216PheNegative0%, Normal63%, AbnormalNegative0.21 mg/l3No mutationsNo mutationsNegative1%, Normal63%, AbnormalPositive (C3CSAPeC3 convertase stabilizing assay with properdin.)ND4No mutationsNo mutationsNegative0%, Normal1% AbnormalPositive (IFE)1.23 mg/l5No mutationsNo mutationsNegative12% Abnormal34% AbnormalPositive (IFE)0.48 mg/l6No mutationsNo mutationsNegative0%, Normal14% AbnormalPositive (both assays)ND7c.3350A>G, p.Asn1117SerNo mutationsNegative0% Normal80%NegativeND8No mutationsNo mutationsNegative0% Normal123%Negative0.13 mg/l9No mutationsNo mutationsNegative9% Abnormal77%Positive (both assays)ND10c.1699A>G, p.Arg567GlyNo mutationsNegative0%, Normal0% AbnormalPositive (both assays)2.03 mg/l11No mutationsNo mutationsNegative0%, Normal130%Positive (C3CSAP)0.21 mg/lAbbreviations: APFA, alternative pathway functional assay; IFE, immunofixation electrophoresis; ND, not done; sMAC, soluble membrane attack complex.a Normal titer <1:50.b Normal <3%.c Normal 65–130%.d Normal <0.3mg/l.e C3 convertase stabilizing assay with properdin. Open table in a new tab Abbreviations: APFA, alternative pathway functional assay; IFE, immunofixation electrophoresis; ND, not done; sMAC, soluble membrane attack complex. Six of the eleven patients were treated with ACE inhibitors and angiotensin II blockers (renin–angiotensin system blockade), in addition to corticosteroid therapy, ranging from 4 weeks to 1 year. Two patients were treated conservatively with renin–angiotensin system blockade only and did not receive steroids or other forms of immunosuppressive therapy. One patient with crescents received cyclophosphamide followed by mycophenolate mofetil with stabilization of renal function. One patient was on dialysis within 4 months of presentation and one patient received no treatment. Follow-up ranged from 4 to 48 months. In general, patients did well with no significant decline in renal function, both in the short and long term. On presentation, the mean serum creatinine and estimated glomerular filtration rate (excluding patient 5) were 1.96mg/dl and 58ml/min, respectively; follow-up means were 1.06mg/dl and 72ml/min, respectively (mean follow-up, 14.9 months). Only three patients had 24-h urinary protein quantification at last follow-up, which ranged from 900 to 7000mg/24h (mean, 3900mg/24h). In three patients, proteinuria was present but not quantified, and in four patients, proteinuria data were not available (one patient was on dialysis). The patient who progressed to dialysis presented with a serum creatinine of 3.1mg/dl. Repeat C3 levels normalized in four patients, whereas they remained low in three patients (follow-up from 1 year to 23 months). Postinfectious glomerulonephritis is a relatively common glomerulonephritis that affects both children and adults.1.Rodriguez-Iturbe B. Musser J.M. The Current state of poststreptococcal glomerulonephritis.J Am Soc Nephrol. 2008; 19: 1855-1864Crossref PubMed Scopus (165) Google Scholar, 8.Nasr S.H. Markowitz G.S. Stokes M.B. et al.Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature.Medicine (Baltimore). 2008; 87: 21-32Crossref PubMed Scopus (141) Google Scholar, 9.Hoy W.E. White A.V. Dowling A. et al.Post-streptococcal glomerulonephritis is a strong risk factor for chronic kidney disease in later life.Kidney Int. 2012; 81: 1026-1032Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 10.Nasr S.H. Fidler M.E. Valeri A.M. et al.Postinfectious glomerulonephritis in the elderly.J Am Soc Nephrol. 2011; 22: 187-195Crossref PubMed Scopus (121) Google Scholar Patients typically present with nephritic syndrome or acute renal failure, which rapidly resolve. In a minority of patients, however, hematuria and proteinuria persist or there is progression to end-stage kidney disease.10.Nasr S.H. Fidler M.E. Valeri A.M. et al.Postinfectious glomerulonephritis in the elderly.J Am Soc Nephrol. 2011; 22: 187-195Crossref PubMed Scopus (121) Google Scholar,14.Moroni G. Pozzi C. Quaglini S. et al.Long-term prognosis of diffuse proliferative glomerulonephritis associated with infection in adults.Nephrol Dialysis Transplant. 2002; 17: 1204-1211Crossref PubMed Scopus (64) Google Scholar The cause of persistent hematuria and proteinuria is not known. Kidney biopsy performed in such cases shows features of postinfectious glomerulonephritis, i.e., proliferative glomerulonephritis on LM, bright glomerular C3 staining with or without immunoglobulins on IF, and subepithelial humps on EM. We also include cases of persistent hematuria and proteinuria that show features of postinfectious glomerulonephritis on kidney biopsy, but have no evidence of a preceding infection. We classify these patients as ‘atypical’ postinfectious glomerulonephritis, and they form the basis of our study. Thus, patients with persistent hematuria and proteinuria, and kidney biopsy findings of a postinfectious glomerulonephritis, with or without a preceding infection, are included in the study. In this study, we show that such patients have an underlying abnormality of the AP of complement. Most patients who are clinically diagnosed with postinfectious glomerulonephritis recover complete renal function and are not biopsied, and hence as a group are difficult to study. However, persistent hematuria and proteinuria, in the setting of a prior clinical diagnosis of postinfectious glomerulonephritis, is an indication for kidney biopsy. We propose that when an infection occurs, it triggers the AP, which under normal circumstances is quickly brought under control once the infection abates. However, in patients with a defect in AP regulation, there is continual AP activation with deposition of complement proteins and their breakdown products in the glomeruli, even after resolution of the infection, which leads to the development of ‘atypical’ proliferative glomerulonephritis. If the defect is mild, AP control occurs, albeit at a much slower rate than normal, and in these patients, the glomerulonephritis eventually resolves. If the defect in AP regulation is more severe, hematuria and proteinuria persist, often exacerbated by recurrent bouts of infection (Figure 2). Thus, in ‘atypical’ postinfectious glomerulonephritis, an infection unmasks the underlying AP abnormality. In our study, we had documentation of infection in only 5 of the 11 patients, raising the possibility that subclinical infections may have occurred in the remaining patients. These are the cases that showed biopsy findings of postinfectious glomerulonephritis, yet, had no clinical evidence of a preceding infection. The role of AP activity in postinfectious glomerulonephritis is supported by other studies.15.Frémeaux-Bacchi V. Weiss L. Demouchy C. et al.Hypocomplementaemia of poststreptococcal acute glomerulonephritis is associated with C3 nephritic factor (C3NeF) IgG autoantibody activity.Nephrol Dialysis Transplant. 1994; 9: 1747-1750PubMed Google Scholar As early as 1985, Meri16.Meri S. Complement activation by circulating serum factors in human glomerulonephritis.Clin Exp Immunol. 1985; 59: 276-284PubMed Google Scholar showed that sera from four patients with post-streptococcal glomerulonephritis contained factors other than immune complexes that activated the complement system. Hisano et al.17.Hisano S. Matsushita M. Fujita T. et al.Activation of the lectin complement pathway in post-streptococcal acute glomerulonephritis.Pathol Int. 2007; 57: 351-357Crossref PubMed Scopus (32) Google Scholar, by immunohistochemical staining methods, showed that glomeruli in postinfectious glomerulonephritis contained components of both the lectin and AP of complement. We have also completed laser microdissection and mass spectrometry of glomeruli of atypical postinfectious glomerulonephritis and verified the presence of AP complement proteins and their breakdown products in diseased glomeruli.18.Sethi 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 (213) Google Scholar Another indirect evidence of the role of the AP is persistently low C3 levels noted in a small percentage of patients with postinfectious glomerulonephritis, even though C3 titers typically normalize within 8 weeks of resolution of the infection.19.Payne D. Houtman P. Browning M. Acute post-streptococcal glomerulonephritis associated with prolonged hypocomplementaemia.J Clin Pathol. 2008; 61: 1133-1135Crossref PubMed Scopus (6) Google Scholar,20.Dedeoglu I. Springate J. Waz W. et al.Prolonged hypocomplementemia in poststreptococcal acute glomerulonephritis.Clin Nephrol. 1996; 46: 302-305PubMed Google Scholar In this study of ‘atypical’ postinfectious glomerulonephritis patients, we show that such patients have an underlying defect in the AP of complement. In 10 of the 11 patients, we demonstrated abnormalities in AP regulation. Five patients had C3Nefs detected by C3CSAP. C3Nefs are autoantibodies to C3 convertase that impair its control by protein regulators of complement activity, effectively prolonging the half-life of C3 convertase from a few seconds to 4–60min.21.Zhang Y. Meyer N.C. Wang K. et al.Causes of alternative pathway dysregulation in dense deposit disease.Clin J Am Soc Nephrol. 2012; 7: 265-274Crossref PubMed Scopus (154) Google Scholar In two patients, immunofixation electrophoresis was positive. This assay does not detect antibodies, but rather measures the presence of C3c in the serum as an indication of C3 convertase dysregulation. Four patients also had novel variants in complement-regulatory genes. CFH, which carried variants in three patients, is the most important fluid-phase regulator of the AP. It competes with factor B for binding to C3b to control the formation of C3 convertase, promotes decay of formed C3 convertase, and serves as a cofactor for factor I to degrade C3b. We also detected a novel variant in CFHR5, a member of the factor H gene family, which is also a regulator of the C3 convertase. None of these variants is reported in NHLBI Exome Sequencing Project, a database of over 10,000 chromosomes, and current data suggest that rare variants such as those reported here make an important contribution to human phenotypic variation and disease susceptibility.22.Tennessen J.A. Bigham A.W. O’ Connor T.D. et al.Evolution and functional impact of rare coding variation from deep sequencing of human exomes.Science. 2012; 337: 64-69Crossref PubMed Scopus (1213) Google Scholar Consistent with this possible functional effect, when we applied three commonly used algorithms (SIFT, PolyPhen2, and BLOSUM) to predict the consequence of the nonsynonymous variants, we identified that in each case at least two of these three programs classified these variants as damaging (predicted to have an effect on function).22.Tennessen J.A. Bigham A.W. O’ Connor T.D. et al.Evolution and functional impact of rare coding variation from deep sequencing of human exomes.Science. 2012; 337: 64-69Crossref PubMed Scopus (1213) Google Scholar, 23.Henikoff S. Henikoff J.G. Amino acid substitution matrices from protein blocks.Proc Natl Acad Sci. 1992; 89: 10915-10919Crossref PubMed Scopus (4311) Google Scholar, 24.Liu X. Jian X. Boerwinkle E. dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions.Hum Mutat. 2011; 32: 894-899Crossref PubMed Scopus (511) Google Scholar Our results are also supported by a case report showing persistent glomerulonephritis, following streptococcal infection in a patient with CFHR5 deficiency.25.Vernon 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 (75) Google Scholar Nevertheless, functional testing of the isolated mutant proteins was not performed, and therefore the pathological significance of these variants remains speculative. Recent studies have shown that dysregulation of the AP also results in a proliferative glomerulonephritis called C3 glomerulonephritis (C3GN). C3GN is characterized by glomerular C3 deposition and the presence of numerous deposits in the mesangium and capillary walls, including subepithelial deposits.18.Sethi 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 (213) Google Scholar, 26.Sethi S. Nester C.M. Smith R.J.H. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 27.Servais A. Fremeaux-Bacchi V. Lequintrec M. et al.Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.J Med Genet. 2007; 44: 193-199Crossref PubMed Scopus (239) Google Scholar, 28.Sethi S. Fervenza F.C. Zhang Y. et al.Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.Clin J Am Soc Nephrol. 2011; 6: 1009-1017Crossref PubMed Scopus (121) Google Scholar, 29.Sethi S. Fervenza F.C. Membranoproliferative glomerulonephritis-a new look at an old entity.N Engl J Med. 2012; 366: 1119-1131Crossref PubMed Scopus (347) Google Scholar Thus, there is considerable overlap in the biopsy findings of patients with ‘atypical’ postinfectious glomerulonephritis and C3GN.26.Sethi S. Nester C.M. Smith R.J.H. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar This overlap is not surprising, as both ‘atypical’ postinfectious glomerulonephritis and C3GN are due to abnormalities of the AP of complement. However, differences include the diffuse proliferative pattern of glomerulonephritis with ‘atypical’ postinfectious glomerulonephritis, as opposed to the membranoproliferative glomerulonephritis most commonly seen with C3GN, and the possible presence of Igs in ‘atypical’ postinfectious glomerulonephritis, which are typically absent in C3GN. On EM, ‘atypical’ postinfectious glomerulonephritis shows numerous subepithelial humps with mesangial and subendothelial deposits, whereas in C3GN, there are numerous mesangial and subendothelial deposits and only occasional subepithelial deposits (Table 4). It should be pointed out that subepithelial humps can be present occasionally in Henoch–Schonlein purpura and Dense Deposit Disease.Table 4Kidney biopsy features of postinfectious glomerulonephritis, ‘atypical’ postinfectious glomerulonephritis, and C3 glomerulonephritisPostinfectious glomerulonephritis (PIGN)‘Atypical’ postinfectious glomerulonephritis (aPIGN)C3 glomerulonephritis (C3GN)LMDiffuse proliferative, less commonly mesangial proliferative, or crescenticDiffuse proliferative, less commonly mesangial proliferative, or crescenticMembranoproliferative and less commonly mesangial proliferativeIFBright mesangial and capillary wall C3, usually with Igs (garland pattern)Bright mesangial and capillary wall C3, usually without Igs. If present IgG (trace to 1+)Bright mesangial and capillary wall C3, usually without IgsEMNumerous subepithelial humps, few mesangial, and subendothelial depositsNumerous subepithelial humps, many mesangial and subendothelial deposits, and ±intramembranous depositsMany mesangial and subendothelial deposits, ±few intramembranous, and subepithelial humpsAbbreviations: EM, electron microscopy; IF, immunofluorescence; Ig, immunoglobulin; LM, light microscopy. Open table in a new tab Abbreviations: EM, electron microscopy; IF, immunofluorescence; Ig, immunoglobulin; LM, light microscopy. Finally, we speculate that postinfectious and ‘atypical’ postinfectious glomerulonephritis are conceptually similar to the hemolytic uremic syndrome (HUS) and atypical HUS (aHUS) in that both HUS and postinfectious glomerulonephritis are caused by an infection, whereas in aHUS and ‘atypical’ postinfectious glomerulonephritis, although there may be an infectious trigger, it is the underlying abnormality of the AP that drives the disease process. To summarize, we define the entity of ‘atypical’ postinfectious glomerulonephritis that mimics postinfectious glomerulonephritis on kidney biopsy, yet behaves differently in that these patients have persistent proteinuria and hematuria and may progress to end-stage kidney disease. We show that patients with ‘atypical’ postinfectious glomerulonephritis have an underlying abnormality in the AP of complement. On the basis of our data, we recommend testing for abnormalities in the AP of complement in all patients with ‘atypical’ postinfectious glomerulonephritis. Novel treatment strategies that target the underlying complement defect should also be considered in patients with progressive renal failure. Renal biopsies from 11 Mayo Clinic patients were evaluated. In all cases, routine workup, including LM, IF microscopy, and EM, was performed. Clinical information was obtained from the charts. The Institutional Review Boards at the Mayo Clinic and University of Iowa approved the study. C3Nefs and factor H autoantibodies were detected, and the hemolytic assay, alternative pathway functional assay, and soluble membrane attack complex were completed, as previously described.18.Sethi 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 (213) Google Scholar,21.Zhang Y. Meyer N.C. Wang K. et al.Causes of alternative pathway dysregulation in dense deposit disease.Clin J Am Soc Nephrol. 2012; 7: 265-274Crossref PubMed Scopus (154) Google Scholar All functional assays were repeated three times. Coding regions and intron–exon boundary junctions of CFH (MIM no. 134370; NM_000186), CFHR5 (MIM no. 608593; NM_030787.3), CFI (MIM no. 217030; NM_000204.3), CD46 (MIM no. 120920; NM_002389.3), CFB (MIM no. 138470; NM_001710.5), and C3 (MIM no. 120700; NM_000064.2) were amplified and screened for mutations and polymorphisms using bidirectional sequencing as previously described.30.Abrera-Abeleda M.A. Nishimura C. Frees K. et al.Allelic variants of complement genes associated with dense deposit disease.J Am Soc Nephrol. 2011; 22: 1551-1559Crossref PubMed Scopus (77) Google Scholar Multiplex-ligation probe amplification to detect the deletion of CFHR3-CFHR1 was completed as described.31.Maga T.K. Meyer N.C. Belsha C. et al.A novel deletion in the RCA gene cluster causes atypical hemolytic uremic syndrome.Nephrol Dialysis Transplant. 2011; 26: 739-741Crossref PubMed Scopus (35) Google Scholar This research was supported in part by NIH grant DK074409 to SS and RJHS, and Fulk Family Foundation award (Mayo Clinic) to SS. We thank Amy Weaver for help with putting the complement evaluation together.