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Increased renal damage in hypocomplementemic patients with ANCA-associated vasculitis: retrospective cohort study



The complement system has an important role in the pathogenesis of vasculitis associated with antineutrophilic cytoplasmic antibody (AAV) mainly at the level of the kidneys because patients with complement deposits on the glomerular basal membrane present more aggressive disease compared with those with pauci-immune vasculitis.


To analyze the association of hypocomplementemia with the clinical manifestations, laboratory data, renal histology, progress to renal insufficiency, and mortality of patients with AAV.


Retrospective cohort study (2000–2007) included 93 patients with AAV. Hypocomplementemia is defined as having C3 values lower than 80 mg/dL or C4 values below 15 mg/dL. Demographic, statistical, clinical, hematological, serological, and histopathological characteristics of all the patients with and without diagnosis of hypocomplementemia were compared. In order to evaluate variable independence, a logistic regression analysis was used.


Ninety-three patients were studied of whom 63 (67.7%) had complement dosage at the moment of AAV diagnosis. Seven patients (11.1%) presented hypocomplementemia and a greater kidney involvement compared with normocomplementemic patients. Thirty renal biopsies were analyzed and 4 (13.3%) showed immunocomplex (IC) or complement deposits by an immunofluorescence test (IFT). Patients with “non-pauci-immune” AAV also presented terminal chronic renal disease (TCRD).


There is an association between low complement and the degree of renal damage in patients with AAV. Patients with renal biopsies confirming IC and/or complement deposits showed more aggressive renal disease.

Key Points
• The complement system has an important role in the pathogenesis of vasculitis associated to antineutrophilic cytoplasmic antibody.
• The studies in murine models confirming the complement activation by alternative pathway and particularly the receptor C5a (C5aR) is necessary for the development of glomerulonefritis.
• Complement deposit observed in the renal biopsies of patients diagnosed with AAV was correlated to greater kidney damage, greater proteinuria and major disease activity compared to patients diagnosed with typical pauci-immune vasculitis.
• The presence of hypocomplementemia at the onset of the disease was also associated with a greater organ involvement, poor prognosis and greater mortality.

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  1. 1.

    Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CGM, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DGI, Specks U, Stone JH, Takahashi K, Watts RA (2013) 2012 revised international Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65(1):1–11.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Augusto JF, Langs V, Demiselle J et al (2016) Low serum complement C3 levels at diagnosis of renal ANCA-associated vasculitis is associated with poor prognosis. PLoS One 11:1–12

    Google Scholar 

  3. 3.

    Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette JC (2007) Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol 170(1):52–64

    CAS  Article  Google Scholar 

  4. 4.

    Xing GQ, Chen M, Liu G, Heeringa P, Zhang JJ, Zheng X, E J, Kallenberg CGM, Zhao MH (2009) Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauci-immune vasculitis. J Clin Immunol 29(3):282–291.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Fukui S, Iwamoto N, Umeda M, Nishino A, Nakashima Y, Koga T, Kawashiri SY, Ichinose K, Hirai Y, Tamai M, Nakamura H, Origuchi T, Sato S, Kawakami A (2016) Antineutrophilic cytoplasmic antibody-associated vasculitis with hypocomplementemia has a higher incidence of serious organ damage and a poor prognosis. Medicine 95(37):e4871.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Molad Y, Tovar A, Ofer-Shiber S (2014) Association of low serum complement C3 with reduced patient and renal survival in antimyeloperoxidase-associated small-vessel vasculitis. Nephron Clin Pract 126(1):67–74.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Luqmani R, Bacon P, Moots R et al (1994) Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 87(11):671–678

    CAS  PubMed  Google Scholar 

  8. 8.

    Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, le Toumelin P, French Vasculitis Study Group (FVSG) (2011) The Five-Factor Score revisited assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine 90(1):19–27.

    Article  PubMed  Google Scholar 

  9. 9.

    Little MA, Pusey CD (2004) Rapidly progressive glomerulonephritis: current and evolving treatment strategies. J Nephrol 17(8):S10–S19

    PubMed  Google Scholar 

  10. 10.

    Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, Neumann I, Noël LH, Pusey CD, Waldherr R, Bruijn JA, Bajema IM (2010) Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 21(10):1628–1636.

    Article  PubMed  Google Scholar 

  11. 11.

    Díaz-Crespo F, Villacorta J, Acevedo M et al (2016) The predictive value of kidney biopsy in renal vasculitis: a multicenter cohort study. Hum Pathol 52:119–127.

    Article  PubMed  Google Scholar 

  12. 12.

    Deshayes S, Aouba A, Khoy K, Mariotte D, Lobbedez T, Martin Silva N (2018) Hypocomplementemia is associated with worse renal survival in ANCA-positive granulomatosis with polyangiitis and microscopic polyangiitis. PLoS One 13(4):e0195680.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Hirayama K, Kobayashi M, Usui J, Arimura Y, Sugiyama H, Nitta K, Muso E, Wada T, Matsuo S, Yamagata K, on behalf of the Japanese RPGN Study Group of Progressive Renal Disease, Fujimoto S, Hirawa S, Horikoshi S, Hosoya T, Itoh T, Inaguma O, Kaname S, Kawamura T, Kimura K, Maruyama S, Nakabayashi N, Ogura M, Saitoh T, Tabei T, Taguma Y, Tsuruya K, Watanabe T, Yasunaga S, Yoshida M, Yumura W, Yuzawa Y, Sada K (2015) Pulmonary involvements of anti-neutrophil cytoplasmic autoantibody-associated renal vasculitis in Japan. Nephrol Dial Transplant 30(Suppl 1):i83–i93.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Kilgore KS, Ward PA, Warren JS (1998) Neutrophil adhesion to human endothelial cells is induced by the membrane attack complex: the roles of P-selectin and platelet activating factor. Inflammation 22(6):583–598

    CAS  Article  Google Scholar 

  15. 15.

    Trouw LA, Pickering MC, Blom AM (2017) The complement system as a potential therapeutic target in rheumatic disease. Nat Rev Rheumatol 13(9):538–547.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Manenti L, Urban ML, Maritati F, Galetti M, Vaglio A (2017) Complement blockade in ANCA-associated vasculitis: an index case, current concepts and future perspectives. Intern Emerg Med 12(6):727–731.

    Article  PubMed  Google Scholar 

  17. 17.

    Tesar V, Hruskova Z (2018) Avacopan in the treatment of ANCA-associated vasculitis. Expert Opin Investig Drugs 27(5):491–496.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Haas M, Eustace JA (2004) Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int 65(6):2145–2152

    CAS  Article  Google Scholar 

  19. 19.

    Chen Y-X, Xu J, Pan X-X, Shen P-Y, Li X, Ren H, Chen X-N, Ni L-Y, Zhang W, Chen N (2017) Histopathological classification and renal outcome in patients with antineutrophil cytoplasmic antibodies-associated renal vasculitis: a study of 186 patients and metaanalysis. J Rheumatol 44(3):304–313.

    Article  PubMed  Google Scholar 

  20. 20.

    Scaglioni V, Scolnik M, Catoggio LJ et al (2017) ANCA-associated pauci-immune glomerulonephritis: always pauci-immune? Clin Exp Rheumatol 35 Suppl 103(1):55–58

    PubMed  Google Scholar 

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We would like to thank Jovanka Vukovic for helping us translate this manuscript.

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Corresponding author

Correspondence to L. García.

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The present study was approved by the Ethics Committee following recommendations of the Declaration of Helsinki. Being it a retrospective study, the informed consent was not considered necessary granting data confidentiality.



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García, L., Pena, C.E., Maldonado, R.Á. et al. Increased renal damage in hypocomplementemic patients with ANCA-associated vasculitis: retrospective cohort study. Clin Rheumatol 38, 2819–2824 (2019).

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  • ANCA vasculitis
  • Complement
  • Kidney involvement
  • Prognosis