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Outcome of C3 glomerulopathy patients: largest single-centre experience from South Asia

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Abstract

Background

C3 glomerulopathy (C3G) is related to dysfunction of alternative complement pathway (ACP) because of its hyperactivation. Triggering factors and genetic profile are likely to be different in developing countries as compared to the Western world. Data regarding C3G from South Asian is scanty.

Study design

In the present study, 115 patients of C3G from 2012 to 2017 were analyzed. Clinical details were reviewed; serological levels of C3, C4, complement factor H or B and autoantibody testing was done by nephelometry/ELISA. Limited genetics workup for CFH and CFHR5 genes was done.

Results

The prevalence of C3G was 1.52%. There was no difference in demographic and histopathologic profiles of C3G patients. Majority of patients had low functional assay and C3 levels. C3 nephritic factor was present in 47.5% of DDD and 38.6% of C3GN. Autoantibodies to CFH were present more often in the patients of C3GN (29.5%) than DDD (12.5%). Autoantibodies to CFB were equally common in both groups. Past history of infections was present in one-third patients and monoclonal paraproteins were present only in two patients. No pathogenic variants were noted in CFH/CFHR5 gene. On follow-up (3.2 + 1.6 years), complete and partial remission was achieved in one-fourth patients and 26% had resistance disease. About 40% progressed to ESRD and 18 underwent renal transplantation of which nine had a post-transplant recurrence.

Conclusions

Indian cohort had some differences in the immunological and genetic profile when compared to the Western literature; most significant was the absence of monoclonal immunoglobulins as a trigger for C3G.

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References

  1. Sethi S, Sullivan A, Smith RJ (2014) C4 dense-deposit disease. N Engl J Med 370(8):784–786

    Article  CAS  PubMed  Google Scholar 

  2. Sethi S, Fervenza FC (2011) Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. Semin Nephrol 31:341–348

    Article  CAS  PubMed  Google Scholar 

  3. Sethi S, Gamez JD, Vrana JA, Theis JD, Bergen HR, Zipfel PF, Dogan A, Smith RJH (2009) Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway. Kidney Int 75(9):952–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang Y, Meyer NC, Wang K, Nishimura C, Frees K, Jones M, Katz LM, Sethi S, Smith RJH (2012) Causes of alternative pathway dysregulation in dense deposit disease. Clin J Am Soc Nephrol 7(2):265–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sethi S, Fervenza FC, Zhang Y, Nasr SH, Leung N, Vrana J, Cramer C, Nester CM, Smith RJH (2011) Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. Clin J Am Soc Nephrol 6(5):1009–1017

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, Theis JD, Dogan A, Smith RJH (2012) C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int 82(4):465–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ravindran A, Fervenza FC, Smith RJ, De Vriese AS, Sethi S (2018) C3 Glomerulopathy: ten years’ experience at mayo clinic. Mayo Clin Proc 93(8):991–1008. https://doi.org/10.1016/j.mayocp.2018.05.019

    Article  PubMed  PubMed Central  Google Scholar 

  8. Prasto J, Kaplan BS, Russo P, Chan E, Smith RJ, Meyers KE (2014) Streptococcal infection as possible trigger for dense deposit disease (C3 glomerulopathy). Eur J Pediatr 173(6):767–772

    Article  PubMed  Google Scholar 

  9. Suga K, Kondo S, Matsuura S, Kinoshita Y, Kitano E, Hatanaka M, Kitamura H, Hidaka Y, Oda T, Kagami S (2010) A case of dense deposit disease associated with a group A streptococcal infection without the involvement of C3NeF or complement factor H deficiency. Pediatric Nephrol 25(8):1547–1550

    Article  Google Scholar 

  10. Vernon KA, de Jorge EG, Hall AE, Fremeaux-Bacchi V, Aitman TJ, Cook HT, Hangartner R, Koziell A, Pickering MC (2012) Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related Protein 5 deficiency. Am J Kidney Dis 60(1):121–125

    Article  PubMed  PubMed Central  Google Scholar 

  11. Nada R, Kumar A, Agrawal P, Ramachandran R, Sethi S (2018) Renal and pulmonary dense deposit disease presenting as a pulmonary-renal syndrome. Kidney Int Rep 3(3):755–761. https://doi.org/10.1016/j.ekir.2018.01.005

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bharati J, Tiewsoh K, Kumar A, Nada R, Rathi M, Gupta KL, Kohli HS, Jha V, Ramachandran R (2018) Usefulness of mycophenolate mofetil in Indian patients with C3 glomerulopathy. Clin Kidney J 12(4):483–487. https://doi.org/10.1093/ckj/sfy127

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kumar A, Bharati J, Nada R, Singh S, Sharma A, Gupta K, Ramachandran R (2019) Utility of plasma exchange in early recurrent C3 glomerulopathy. Indian J Transplant 13(2):122–126. https://doi.org/10.4103/ijot.ijot_78_18

    Article  Google Scholar 

  14. Medjeral-Thomas NR, O’Shaughnessy MM, O’Regan JA, Traynor C, Flanagan M, Wong L, Teoh CW, Awan A, Waldron M, Cairns T (2014) C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol 9(1):46–53. https://doi.org/10.2215/CJN.04700513

    Article  CAS  PubMed  Google Scholar 

  15. Pickering MC, D’agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M (2013) C3 glomerulopathy: consensus report. Kidney Int 84(6):1079–1089

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhang Y, Nester CM, Martin B, Skjoedt M-O, Meyer NC, Shao D, Borsa N, Palarasah Y, Smith RJ (2014) Defining the complement biomarker profile of C3 glomerulopathy. Clin J Am Soc Nephrol 9(11):1876–1882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bomback AS, Santoriello D, Avasare RS, Regunathan-Shenk R, Canetta PA, Ahn W, Radhakrishnan J, Marasa M, Rosenstiel PE, Herlitz LC (2018) C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney Int 93(4):977–985

    Article  PubMed  Google Scholar 

  18. Habib R, Gubler MC, Loirat C, Maiz HB, Levy M (1975) Dense deposit disease: a variant of membranoproliferative glomerulonephritis. Kidney Int 7(4):204–215

    Article  CAS  PubMed  Google Scholar 

  19. Lu DF, Moon M, Lanning LD, McCarthy AM, Smith RJ (2012) Clinical features and outcomes of 98 children and adults with dense deposit disease. Pediatr Nephrol 27(5):773–781. https://doi.org/10.1007/s00467-011-2059-7

    Article  PubMed  Google Scholar 

  20. Smith RJ, Harris CL, Pickering MC (2011) Dense deposit disease. Mol Immunol 48(14):1604–1610. https://doi.org/10.1016/j.molimm.2011.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Grünfeld JP, Lesavre P, Noël LH, Fakhouri F (2007) Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet 44(3):193–199

    Article  CAS  PubMed  Google Scholar 

  22. Nasr SH, Valeri AM, Appel GB, Sherwinter J, Stokes MB, Said SM, Markowitz GS, D’Agati VD (2009) Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol 4(1):22–32

    Article  PubMed  PubMed Central  Google Scholar 

  23. Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82(4):454–464

    Article  CAS  PubMed  Google Scholar 

  24. Smith RJH, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT, de Córdoba SR, Hageman GS, Jokiranta TS, Kimberling WJ (2007) New approaches to the treatment of dense deposit disease. J Am Soc Nephrol 18(9):2447–2456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abrera-Abeleda MA, Nishimura C, Frees K, Jones M, Maga T, Katz LM, Zhang Y, Smith RJ (2011) Allelic variants of complement genes associated with dense deposit disease. J Am Soc Nephrol 22(8):1551–1559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Servais A, Noël LH, Dragon-Durey MA, Gübler MC, Rémy P, Buob D, Cordonnier C, Makdassi R, Jaber W, Boulanger E (2011) Heterogeneous pattern of renal disease associated with homozygous Factor H deficiency. Hum Pathol 42(9):1305–1311

    Article  CAS  PubMed  Google Scholar 

  27. Michael A, Drummond K, Good R, Vernier R (1966) Acute poststreptococcal glomerulonephritis: immune deposit disease. J Clin Investig 45(2):237–248

    Article  PubMed  Google Scholar 

  28. Sawanobori E, Umino A, Kanai H, Matsushita K, Iwasa S, Kitamura H, Oda T, Yoshizawa N, Sugita K, Higashida K (2009) A prolonged course of Group A streptococcus-associated nephritis: a mild case of dense deposit disease (DDD)? Clin Nephrol 71(6):703–707

    Article  CAS  PubMed  Google Scholar 

  29. Pirozzi N, Stoppacciaro A, Menè P (2018) Dominant C3 glomerulopathy: new roles for an old actor in renal pathology. J Nephrol 31(4):503–510

    Article  PubMed  Google Scholar 

  30. Barbour TD, Pickering MC, Cook HT (2013) Dense deposit disease and C3 glomerulopathy. In: Seminars in nephrology, Elsevier, pp 493–507

  31. Józsi M, Licht C, Strobel S, Zipfel SL, Richter H, Heinen S, Zipfel PF, Skerka C (2008) Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111(3):1512–1514

    Article  PubMed  Google Scholar 

  32. Lionet A, Provôt F, Glowacki F, Frémeaux-Bacchi V, Hazzan M (2009) A case of adult atypical haemolytic uraemic syndrome related to anti-factor H autoantibodies successfully treated by plasma exchange, corticosteroids and rituximab. NDT Plus 2(6):458–60. https://doi.org/10.1093/ndtplus/sfp109

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sinha A, Gulati A, Saini S, Blanc C, Gupta A, Gurjar BS, Saini H, Kotresh ST, Ali U, Bhatia D (2014) Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int 85(5):1151–1160

    Article  CAS  PubMed  Google Scholar 

  34. Goodship THJ, Pappworth IY, Toth T, Denton M, Houlberg K, McCormick F, Warland D, Moore I, Hunze EM, Staniforth SJ (2012) Factor H autoantibodies in membranoproliferative glomerulonephritis. Mol Immunol 52(3):200–206

    Article  CAS  PubMed  Google Scholar 

  35. Marinozzi MC, Roumenina LT, Chauvet S, Hertig A, Bertrand D, Olagne J, Frimat M, Ulinski T, Deschênes G, Burtey S (2017) Anti-Factor B and anti-C3b autoantibodies in C3 glomerulopathy and Ig-associated membranoproliferative glomerulonephritis. J Am Soc Nephrol 28(5):1603–1613. https://doi.org/10.1681/ASN.2016030343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Strobel S, Zimmering M, Papp K, Prechl J, Józsi M (2010) Anti-factor B autoantibody in dense deposit disease. Mol Immunol 47(7–8):1476

    Article  CAS  PubMed  Google Scholar 

  37. Abrera-Abeleda MA, Nishimura C, Smith JLH, Sethi S, McRae JL, Murphy BF, Silvestri G, Skerka C, Jozsi M, Zipfel PF (2006) Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet 43(7):582–589

    Article  CAS  PubMed  Google Scholar 

  38. Sozeri B, Mir S, Berdeli A, Dincel N, Sarsik B (2012) Gene polymorphism of complement factor H in a turkish patient with membranoproliferative glomerulonephritis type II. Iran J Kidney Dis 6(2):149

    PubMed  Google Scholar 

  39. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102(20):7227–7232

    Article  CAS  PubMed  Google Scholar 

  40. Tortajada A, Montes T, Martı́nez-Barricarte R, Morgan BP, Harris CL, de Córdoba SR (2009) The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity. Hum Mol Genet 18(18):3452–3461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mizuno M, Suzuki Y, Ito Y (2018) Complement regulation and kidney diseases: recent knowledge of the double-edged roles of complement activation in nephrology. Clin Exp Nephrol 22(1):3–14

    Article  CAS  PubMed  Google Scholar 

  42. Prosser BE, Johnson S, Roversi P, Herbert AP, Blaum BS, Tyrrell J, Jowitt TA, Clark SJ, Tarelli E, Uhrín D (2007) Structural basis for complement factor H–linked age-related macular degeneration. J Exp Med 204(10):2277–2283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Geerdink LM, Westra D, van Wijk JA, Dorresteijn EM, Lilien MR, Davin J-C, Kömhoff M, Van Hoeck K, van der Vlugt A, van den Heuvel LP (2012) Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics. Pediatric Nephrol 27(8):1283–1291

    Article  Google Scholar 

  44. Gewurz AT, Imherr S, Strauss S, Gewurz H, Mold C (1983) C3 nephritic factor and hypocomplementaemia in a clinically healthy individual. Clin Exp Immunol 54(1):253

    CAS  PubMed  PubMed Central  Google Scholar 

  45. McRae JL, Duthy TG, Griggs KM, Ormsby RJ, Cowan PJ, Cromer BA, McKinstry WJ, Parker MW, Murphy BF, Gordon DL (2005) Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein. J Immunol 174(10):6250–6256

    Article  CAS  PubMed  Google Scholar 

  46. Sethi S, Sukov WR, Zhang Y, Fervenza FC, Lager DJ, Miller DV, Cornell LD, Krishnan SGS, Smith RJH (2010) Dense deposit disease associated with monoclonal gammopathy of undetermined significance. Am J Kidney Dis 56(5):977–982

    Article  PubMed  PubMed Central  Google Scholar 

  47. Barbour S, Gill J (2015) Advances in the understanding of complement mediated glomerular disease: implications for recurrence in the transplant setting. Am J Transplant 15(2):312–319

    Article  CAS  PubMed  Google Scholar 

  48. Salvadori M, Bertoni E (2016) Complement related kidney diseases: recurrence after transplantation. World J Transplant 6(4):632

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zand L, Lorenz EC, Cosio FG, Fervenza FC, Nasr SH, Gandhi MJ, Smith RJ, Sethi S (2014) Clinical findings, pathology, and outcomes of C3GN after kidney transplantation. J Am Soc Nephrol 25(5):1110–1117

    Article  CAS  PubMed  Google Scholar 

  50. McCaughan J, O’rourke D, Courtney A (2012) Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies. Am J Transplant 12(4):1046–1051

    Article  CAS  PubMed  Google Scholar 

  51. Regunathan-Shenk R, Avasare RS, Ahn W, Canetta PA, Cohen DJ, Appel GB, Bomback AS (2018) Kidney transplantation in C3 glomerulopathy: a case series. Am J Kidney Dis 73(3):316–323. https://doi.org/10.1053/j.ajkd.2018.09.002

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all the C3G patients to participate in this study, providing blood samples and visiting our clinics for routine follow-up. We also thank ICMR, New Delhi for providing fellowship grant to Dr. Ashwani Kumar (five years research fellowship; vide letter number 3/1/3/JRF-2012/HRD-01-10841). We thank research grant cell, Post Graduate Institute of Medical Education and Research, Chandigarh for providing intramural funding to Prof. Ritambhra Nada. (Intramural Grant-2016-18).

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Institutional research grant, Post Graduate Institute of Medical Education and Research, Chandigarh.

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Authors and Affiliations

  1. Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Ashwani Kumar, Ritambhra Nada, Charan Singh Rayat & Rakesh Kumar Vasishta

  2. Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Raja Ramachandran & Krishan Lal Gupta

  3. Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Amit Rawat & Karalanglin Tiewsoh

  4. Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Reena Das

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  1. Ashwani Kumar
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Yes, this research involve human participant for which ethical approval was taken from institute’s ethical committee vide letter number Histopath/13/2088.

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Kumar, A., Nada, R., Ramachandran, R. et al. Outcome of C3 glomerulopathy patients: largest single-centre experience from South Asia. J Nephrol 33, 539–550 (2020). https://doi.org/10.1007/s40620-019-00672-5

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