Article | Published:

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis


Complement factor C4d was recently observed in renal biopsies from patients who had IgA nephropathy and a poor prognosis. We previously reported that C4d is a common denominator in microangiopathies. In this retrospective cohort study, we investigated whether C4d is a marker of microangiopathy in both IgA nephropathy and IgA vasculitis with nephritis, and whether patients with C4d and microangiopathy have poor renal outcome. We examined 128 renal biopsies from adult and pediatric patients, including normotensive and hypertensive patients, who presented with IgA nephropathy or IgA vasculitis with nephritis. Biopsies were re-evaluated in accordance with the Oxford classification, scored for additional lesions, and stained for complement proteins using immunohistochemistry, including C4d and C5b-9. Clinical data were collected with a mean (±SD) follow-up period of 51 ± 39 months. Changes in estimated glomerular filtration rate over time were compared using linear mixed-effects models. Renal survival was analyzed using multivariable Cox regression. Microangiopathic lesions were present in 20% of all biopsies (23% and 9% of patients with IgA nephropathy and IgA vasculitis with nephritis, respectively). Microangiopathy was associated with C4d and C5b-9 deposits, a higher number of chronic lesions, and hypertension (all p < 0.05). Patients with C4d and microangiopathic lesions had significantly poorer renal survival than patients without these findings, corrected for hypertension (p < 0.01). In conclusion, patients with IgA nephropathy or IgA vasculitis with nephritis with a combination of C4d positivity and microangiopathy comprise a clinical subgroup with an increased number of chronic lesions, lower estimated glomerular filtration rate, and poorer renal survival, even when corrected for hypertension. These data suggest that complement activation is involved in the development of microangiopathy in patients with IgA nephropathy and IgA vasculitis with nephritis, and that complement-mediated microangiopathy contributes to disease progression.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013;368:2402–14.

  2. 2.

    Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 2009;76:534–45.

  3. 3.

    Trimarchi H, Barratt J, Cattran DC, Cook HT, Coppo R, Haas M, et al. Oxford classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017;91:1014–21.

  4. 4.

    Chang A, Kowalewska J, Smith KD, Nicosia RF, Alpers CE. A clinicopathologic study of thrombotic microangiopathy in the setting of IgA nephropathy. Clin Nephrol. 2006;66:397–404.

  5. 5.

    El Karoui K, Hill GS, Karras A, Jacquot C, Moulonguet L, Kourilsky O, et al. A clinicopathologic study of thrombotic microangiopathy in IgA nephropathy. J Am Soc Nephrol. 2012;23:137–48.

  6. 6.

    Sethi S, Fervenza FC. Standardized classification and reporting of glomerulonephritis. Nephrol Dial Transplant. 2018;34:193–9.

  7. 7.

    Maillard N, Wyatt RJ, Julian BA, et al. Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol. 2015;26:1503–12.

  8. 8.

    Daha MR, van Kooten C. Role of complement in IgA nephropathy. J Nephrol. 2015;29:1–4.

  9. 9.

    Wyatt RJ, Julian BA, Galla JH. Properdin deficiency with IgA nephropathy. N Engl J Med. 1981;305:1097.

  10. 10.

    Wyatt RJ, Julian BA, Weinstein A, Rothfield NF, McLean RH. Partial H (beta 1H) deficiency and glomerulonephritis in two families. J Clin Immunol. 1982;2:110–7.

  11. 11.

    Wyatt RJ, Schneider PD, Alpers CE, Hudson EC, Julian BA. C4B deficiency in two siblings with IgA nephropathy. Am J Kidney Dis. 1990;15:66–71.

  12. 12.

    Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43:321–7.

  13. 13.

    Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M, et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet. 2014;46:1187–96.

  14. 14.

    Kiryluk K, Novak J. The genetics and immunobiology of IgA nephropathy. J Clin Invest. 2014;124:2325–32.

  15. 15.

    Ring T, Pedersen BB, Salkus G, Goodship TH. Use of eculizumab in crescentic IgA nephropathy: proof of principle and conundrum? Clin Kidney J. 2015;8:489–91.

  16. 16.

    Rosenblad T, Rebetz J, Johansson M, Bekassy Z, Sartz L, Karpman D. Eculizumab treatment for rescue of renal function in IgA nephropathy. Pediatr Nephrol. 2014;29:2225–8.

  17. 17.

    Herzog AL, Wanner C, Amann K, Lopau K. First treatment of relapsing rapidly progressive IgA nephropathy with Eculizumab after living kidney donation: a case report. Transplant Proc. 2017;49:1574–7.

  18. 18.

    Nakamura H, Anayama M, Makino M, Makino Y, Tamura K, Nagasawa M. Atypical hemolytic uremic syndrome associated with complement factor H mutation and IgA nephropathy: a case report successfully treated with Eculizumab. Nephron. 2018;138:324–7.

  19. 19.

    Espinosa M, Ortega R, Sanchez M, Segarra A, Salcedo MT, Gonzalez F, et al. Association of C4d deposition with clinical outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2014;9:897–904.

  20. 20.

    Chua JS, Baelde HJ, Zandbergen M, Wilhelmus S, van Es LA, de Fijter JW, et al. Complement factor C4d is a common denominator in thrombotic microangiopathy. J Am Soc Nephrol. 2015;26:2239–47.

  21. 21.

    Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010;69:798–806.

  22. 22.

    Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr., et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–72.

  23. 23.

    Falkner B, Daniels SR, Flynn JT, Gidding S, Green LA, Ingelfinger JR, et al. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114:555–76.

  24. 24.

    Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–70.

  25. 25.

    Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20:629–37.

  26. 26.

    Haas M, Verhave JC, Liu Z-H, Alpers CE, Barratt J, Becker JU, et al. A multicenter study of the predictive value of crescents in IgA nephropathy. J Am Soc Nephrol. 2017;28:691–701.

  27. 27.

    Goodship THJ, Cook HT, Fakhouri F, Fervenza FC, Frémeaux-Bacchi V, Kavanagh D, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2017;91:539–51.

  28. 28.

    Pencina MJ, D’Agostino RB. Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation. Stat Med. 2004;23:2109–23.

  29. 29.

    Nasri H, Mortazavi M, Ghorbani A, Shahbazian H, Kheiri S, Baradaran A, et al. Oxford-MEST classification in IgA nephropathy patients: a report from Iran. J Nephropathol. 2012;1:31–42.

  30. 30.

    Oruc M, Durak H, Yalin SF, Seyahi N, Altiparmak MR, Trabulus S. A rare presentation of immunoglobulin A nephropathy: acute kidney injury. Nephron. 2017;137:8–14.

  31. 31.

    Zhang Y, Sun L, Zhou S,  Xu Q, Xu Q, Liu D, et al. Intrarenal arterial lesions are associated with higher blood pressure, reduced renal function and poorer renal outcomes in patients with IgA nephropathy. Kidney Blood Press Res. 2018;43:639–50.

  32. 32.

    Sinniah R, Gan HC, Yoon KH. Primary antiphospholipid antibody syndrome and mesangial IgA glomerulonephritis. Am J Nephrol. 2001;21:134–40.

  33. 33.

    Silva MF, Pimentel FL, Faria MS, Carvalho-Costa AE, Nunes JP. IgA nephropathy and antiphospholipid syndrome. Nephron. 1999;83:95–6.

  34. 34.

    Sevillano AM, Cabrera J, Gutierrez E, Morales E, Merida E, Huerta A, et al. Malignant hypertension: a type of IgA nephropathy manifestation with poor prognosis. Nefrologia. 2015;35:42–9.

  35. 35.

    Dvanajscak Z, Karl BE, Sanchez AP, Walavalkar V. IgA-dominant glomerulopathy and thrombotic microangiopathy after chemotherapy. Kidney Int Rep. 2018;3:492–7.

  36. 36.

    Surmeli-Doven S, Delibas A, Gurses I, Kayacan UR, Coskun-Yilmaz B, Esen K, et al. Hemolytic uremic syndrome and IgA nephropathy in a child: coincidence or not? Turk J Pediatr. 2018;60:81–5.

  37. 37.

    Tomita M, Ochiai M, Shu S, Yamauchi Y, Shihara H, Ogata A, et al. A case of thrombotic microangiopathy with glomerular subendothelial IgA deposition due to bevacizumab. Nihon Jinzo Gakkai Shi. 2014;56:612–7.

  38. 38.

    Mathew RO, Nayer A, Asif A. The endothelium as the common denominator in malignant hypertension and thrombotic microangiopathy. J Am Soc Hypertens. 2016;10:352–9.

  39. 39.

    Timmermans S, Abdul-Hamid MA, Vanderlocht J, Damoiseaux J, Reutelingsperger CP, van Paassen P, et al. Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities. Kidney Int. 2017;91:1420–5.

  40. 40.

    Coppo R, Peruzzi L, Loiacono E et al. Defective gene expression of the membrane complement inhibitor CD46 in patients with progressive immunoglobulin A nephropathy. Nephrol Dial Transplant. 2018. Epub ahead of print:

  41. 41.

    Schmitt R, Krmar RT, Kristoffersson A, Soderberg M, Karpman D. IgA nephropathy associated with a novel N-terminal mutation in factor H. Eur J Pediatr. 2011;170:107–10.

  42. 42.

    Zhu L, Guo WY, Shi SF, Liu LJ, Lv JC, Medjeral-Thomas NR, et al. Circulating complement factor H-related protein 5 levels contribute to development and progression of IgA nephropathy. Kidney Int. 2018;94:150–8.

  43. 43.

    Matsumura D, Tanaka A, Nakamura T, Sato E, Node K. Coexistence of atypical hemolytic uremic syndrome and crescentic IgA nephropathy treated with eculizumab: a case report. Clin Nephrol Case Stud. 2016;4:24–8.

  44. 44.

    Fabiano RCG, de Almeida Araujo S, Bambirra EA, Oliveira EA, Simoes ESAC, Pinheiro SVB. Mesangial C4d deposition may predict progression of kidney disease in pediatric patients with IgA nephropathy. Pediatr Nephrol. 2017;32:1211–20.

  45. 45.

    Segarra A, Romero K, Agraz I, Ramos N, Madrid A, Carnicer C, et al. Mesangial C4d deposits in early IgA nephropathy. Clin J Am Soc Nephrol. 2018;13:258–64.

  46. 46.

    Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, van Gijlswijk-Janssen DJ, et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol. 2006;17:1724–34.

  47. 47.

    Coppo R. C4d deposits in IgA nephropathy: where does complement activation come from? Pediatr Nephrol. 2017;32:1097–101.

  48. 48.

    Paunas TIF, Finne K, Leh S, Marti HP, Mollnes TE, Berven F, et al. Glomerular abundance of complement proteins characterized by proteomic analysis of laser-captured microdissected glomeruli associates with progressive disease in IgA nephropathy. Clin Proteomics. 2017;14:30–41.

  49. 49.

    Yin W, Ghebrehiwet B, Weksler B,  Peerschke EI. Classical pathway complement activation on human endothelial cells. Mol Immunol. 2007;44:2228–34.

  50. 50.

    Oikonomopoulou K, Ricklin D, Ward PA, Lambris JD. Interactions between coagulation and complement—their role in inflammation. Semin Immunopathol. 2012;34:151–65.

  51. 51.

    Brocklebank V, Kavanagh D. Complement C5-inhibiting therapy for the thrombotic microangiopathies: accumulating evidence, but not a panacea. Clin Kidney J. 2017;10:600–24.

  52. 52.

    Mengel M, Chan S, Climenhaga J, Kushner YB, Regele H, Colvin RB et al. Banff initiative for quality assurance in transplantation (BIFQUIT): reproducibility of C4d immunohistochemistry in kidney allografts. Am J Transplant. 2013;13:1235–45.

  53. 53.

    Coppo R. Biomarkers and targeted new therapies for IgA nephropathy. Pediatr Nephrol. 2017;32:725–31.

Download references


We are grateful to Annelies E. Berden, Marjolijn van Buren, Jade Chantharasy, Karlien Cransberg, Hans C. Ablij, Stefan P. Berger, Bas A. Gabreëls, Hans G. Peltenburg, and Yvo W.J. Sijpkens for their help obtaining the clinical data that were used in this study. The results presented in this paper have not been published previously except in abstract form at Kidney Week 2015, the Annual American Society of Nephrology Conference.

Author information

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Jamie S. Chua.

Supplementary information

Supplemental Tables and Figures

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2
Fig. 3