Advertisement
Mayo Clinic Proceedings Home

C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic

      Abstract

      Objective

      To describe the clinicopathological features, complement abnormalities, triggers, treatment, and outcomes of C3 glomerulopathy.

      Patients and Methods

      A total of 114 patients with C3 glomerulopathy seen at Mayo Clinic from January 1, 2007, through December 31, 2016, were evaluated in this study.

      Results

      The mean age at diagnosis for the entire cohort was 40.4±22.3 years, with a median serum creatinine level and proteinuria value of 1.6 mg/dL (range: 0.3-14.7) (to convert to mmol/L, multiply by 0.0259) and 2605 mg/24 h (range: 233-24,165), respectively. Hematuria was present in 100 patients (87.7%). The C3 and C4 levels were low in 50 of 112 (44.6%) and 13 of 110 (11.8%) patients, respectively. A history of infection, positive autoimmune findings, and monoclonal gammopathy (MIg) were present in 33 of 114 (28.9%), 28 of 114 (24.6%), and 36 of 95 (37.9%) patients, respectively. However, 28 of 43 patients 50 years or older (65.1%) had MIg. A genetic variant in complement genes, C3 nephritic factor (C3Nef), and other autoantibodies was present in 26 of 70 (37.1%), 30 of 69 (43.5%), and 9 of 67 (13.4%) patients, respectively. Membranoproliferative and mesangial proliferative glomerulonephritis were the common patterns of injury. Patients without MIg were younger (mean age, 32.3±20.6 years), with a median serum creatinine level and proteinuria value of 1.4 mg/dL (range: 0.3-7.9) and 2450 mg/24 h (range: 250-24, 165) and with low C3 and C4 levels in 38 of 77 (49.4%) and 9 of 75 (12.0%) patients, respectively. Most patients received corticosteroids and other immunosuppressive drugs. In patients without MIg, at a median follow-up of 22.3 months (range: 0.1-201.1), the median serum creatinine level and proteinuria value were 1.4 mg/dL (range: 0.3-3.7) and 825.5 mg/24 h (range: 76-22, 603), and 7 patients (9.2%) had progression to end-stage renal disease.

      Conclusion

      C3 glomerulopathy is a heterogeneous disease entity with complex triggering events and abnormalities of the alternative pathway of complement. The disease tends to be progressive and exhibits a variable response to immunosuppressive therapy.

      Abbreviations and Acronyms:

      AP (alternative pathway), C3G (C3 glomerulopathy), C3GN (C3 glomerulonephritis), C3Nef (C3 nephritic factor), C5Nef (C5 nephritic factor), CFB (complement factor B), CFH (complement factor H), CR (complete remission), DDD (dense deposit disease), eGFR (estimated glomerular filtration rate), ESRD (end-stage renal disease), FB (factor B), FH (factor H), MIg (monoclonal immunoglobulin), MMF (mycophenolate mofetil), NR (no response), PR (partial remission)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Pickering M.C.
        • D'Agati V.D.
        • Nester C.M.
        • et al.
        C3 glomerulopathy: consensus report.
        Kidney Int. 2013; 84: 1079-1089
        • 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: 465-473
        • De Vriese A.S.
        • Sethi S.
        • Van Praet J.
        • Nath K.A.
        • Fervenza F.C.
        Kidney disease caused by dysregulation of the complement alternative pathway: an etiologic approach.
        J Am Soc Nephrol. 2015; 26: 2917-2929
        • Angioi A.
        • Fervenza F.C.
        • Sethi S.
        • et al.
        Diagnosis of complement alternative pathway disorders.
        Kidney Int. 2016; 89: 278-288
        • Servais A.
        • Noël 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: 454-464
        • Appel G.B.
        • Cook H.T.
        • Hageman G.
        • et al.
        Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.
        J Am Soc Nephrol. 2005; 16: 1392-1403
        • Sethi S.
        • Nester C.M.
        • Smith R.J.
        Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.
        Kidney Int. 2012; 81: 434-441
        • Servais A.
        • Frémeaux-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: 193-199
        • 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: 1009-1017
        • Nasr S.H.
        • Valeri A.M.
        • Appel G.B.
        • et al.
        Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
        Clin J Am Soc Nephrol. 2009; 4: 22-32
        • Rabasco C.
        • Cavero T.
        • Román E.
        • et al.
        • Spanish Group for the Study of Glomerular Diseases (GLOSEN)
        Effectiveness of mycophenolate mofetil in C3 glomerulonephritis.
        Kidney Int. 2015; 88: 1153-1160
        • Avasare R.S.
        • Canetta P.A.
        • Bomback A.S.
        • et al.
        Mycophenolate mofetil in combination with steroids for treatment of C3 glomerulopathy: a case series.
        Clin J Am Soc Nephrol. 2018; 13: 406-413
        • Custodio Martinez R.L.M.
        Diagnostics for Choosing between Log-Rank and Wilcoxon Tests [dissertation].
        Western Michigan University, Kalamazoo, MI2007
        • Bu F.
        • Borsa N.G.
        • Jones M.B.
        • et al.
        High-throughput genetic testing for thrombotic microangiopathies and C3 glomerulopathies.
        J Am Soc Nephrol. 2016; 27: 1245-1253
        • Davydov E.V.
        • Goode D.L.
        • Sirota M.
        • Cooper G.M.
        • Sidow A.
        • Batzoglou S.
        Identifying a high fraction of the human genome to be under selective constraint using GERP++.
        PLoS Comput Biol. 2010; 6: e1001025
        • Cooper G.M.
        • Stone E.A.
        • Asimenos G.
        • et al.
        Distribution and intensity of constraint in mammalian genomic sequence.
        Genome Res. 2005; 15: 901-913
        • Schwarz J.M.
        • Cooper D.N.
        • Schuelke M.
        • Seelow D.
        MutationTaster2: mutation prediction for the deep-sequencing age.
        Nat Methods. 2014; 11: 361-362
        • Adzhubei I.A.
        • Schmidt S.
        • Peshkin L.
        • et al.
        A method and server for predicting damaging missense mutations.
        Nat Methods. 2010; 7: 248-249
        • Kumar P.
        • Henikoff S.
        • Ng P.C.
        Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.
        Nat Protoc. 2009; 4: 1073-1081
        • Chun S.
        • Fay J.C.
        Identification of deleterious mutations within three human genomes.
        Genome Res. 2009; 19: 1553-1561
        • 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: 265-274
        • Zhang Y.
        • Meyer N.C.
        • Fervenza F.C.
        • et al.
        C4 nephritic factors in C3 glomerulopathy: a case series.
        Am J Kidney Dis. 2017; 70: 834-843
        • Sethi S.
        • D'Agati V.D.
        • Nast C.C.
        • et al.
        A proposal for standardized grading of chronic changes in native kidney biopsy specimens.
        Kidney Int. 2017; 91: 787-789
      1. Ravindran A, Fervenza FC, Smith RJ, Sethi S. C3 glomerulopathy associated with monoclonal Ig: a distinct subtype [published online ahead of print May 2, 2018]. Kidney Int. https://doi.org/10.1016/j.kint.2018.01.037.

        • Medjeral-Thomas N.R.
        • O'Shaughnessy M.M.
        • O’Regan J.A.
        • et al.
        C3 glomerulopathy: clinicopathologic features and predictors of outcome.
        Clin J Am Soc Nephrol. 2014; 9: 46-53
        • Bomback A.S.
        • Santoriello D.
        • Avasare R.S.
        • et al.
        C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.
        Kidney Int. 2018; 93: 977-985
        • Sethi S.
        • Fervenza F.C.
        Membranoproliferative glomerulonephritis—a new look at an old entity.
        N Engl J Med. 2012; 366: 1119-1131
        • Dragon-Durey M.A.
        • Sethi S.K.
        • Bagga A.
        • et al.
        Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome.
        J Am Soc Nephrol. 2010; 21: 2180-2187
        • Zand L.
        • Kattah A.
        • Fervenza F.C.
        • et al.
        C3 glomerulonephritis associated with monoclonal gammopathy: a case series.
        Am J Kidney Dis. 2013; 62: 506-514
        • Sethi S.
        • Sukov W.R.
        • Zhang Y.
        • et al.
        Dense deposit disease associated with monoclonal gammopathy of undetermined significance.
        Am J Kidney Dis. 2010; 56: 977-982
        • Bridoux F.
        • Desport E.
        • Frémeaux-Bacchi V.
        • et al.
        Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?.
        Clin J Am Soc Nephrol. 2011; 6: 2165-2174
        • Lloyd I.E.
        • Gallan A.
        • Huston H.K.
        • et al.
        C3 glomerulopathy in adults: a distinct patient subset showing frequent association with monoclonal gammopathy and poor renal outcome.
        Clin Kidney J. 2016; 9: 794-799
        • Meri S.
        • Koistinen V.
        • Miettinen A.
        • Törnroth T.
        • Seppälä I.
        Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis.
        J Exp Med. 1992; 175: 939-950
        • Blanc C.
        • Togarsimalemath S.K.
        • Chauvet S.
        • et al.
        Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases.
        J Immunol. 2015; 194: 5129-5138
        • Chauvet S.
        • Frémeaux-Bacchi V.
        • Petitprez F.
        • et al.
        Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.
        Blood. 2017; 129: 1437-1447
        • Hamzi M.A.
        • Zniber A.
        • Badaoui G.E.
        • et al.
        C3 glomerulopathy associated to multiple myeloma successfully treated by autologous stem cell transplant.
        Indian J Nephrol. 2017; 27: 141-144
        • Sethi S.
        • Fervenza F.C.
        • Zhang Y.
        • et al.
        Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement.
        Kidney Int. 2013; 83: 293-299
        • Al-Ghaithi B.
        • Chanchlani R.
        • Riedl M.
        • Thorner P.
        • Licht C.
        C3 glomerulopathy and post-infectious glomerulonephritis define a disease spectrum.
        Pediatr Nephrol. 2016; 31: 2079-2086
        • Hou J.
        • Markowitz G.S.
        • Bomback A.S.
        • et al.
        Toward a working definition of C3 glomerulopathy by immunofluorescence.
        Kidney Int. 2014; 85: 450-456
        • Larsen C.P.
        • Walker P.D.
        Redefining C3 glomerulopathy: ‘C3 only’ is a bridge too far.
        Kidney Int. 2013; 83: 331-332