Abstract
Introduction
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.
Aim
To analyze the association of hypocomplementemia with the clinical manifestations, laboratory data, renal histology, progress to renal insufficiency, and mortality of patients with AAV.
Methods
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.
Results
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).
Conclusion
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. |
Similar content being viewed by others
References
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. https://doi.org/10.1002/art.37715
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
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
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. https://doi.org/10.1007/s10875-008-9268-2
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. https://doi.org/10.1097/MD.0000000000004871
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. https://doi.org/10.1159/000357154
Luqmani R, Bacon P, Moots R et al (1994) Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 87(11):671–678
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. https://doi.org/10.1097/MD.0b013e318205a4c6
Little MA, Pusey CD (2004) Rapidly progressive glomerulonephritis: current and evolving treatment strategies. J Nephrol 17(8):S10–S19
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. https://doi.org/10.1681/ASN.2010050477
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. https://doi.org/10.1016/j.humpath.2016.01.015
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. https://doi.org/10.1371/journal.pone.0195680
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. https://doi.org/10.1093/ndt/gfu385
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
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. https://doi.org/10.1038/nrrheum.2017.125
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. https://doi.org/10.1007/s11739-017-1636-6
Tesar V, Hruskova Z (2018) Avacopan in the treatment of ANCA-associated vasculitis. Expert Opin Investig Drugs 27(5):491–496. https://doi.org/10.1080/13543784.2018.1472234
Haas M, Eustace JA (2004) Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int 65(6):2145–2152
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. https://doi.org/10.3899/jrheum.160866
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
Acknowledgments
We would like to thank Jovanka Vukovic for helping us translate this manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Disclosures
None.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1007/s10067-019-04636-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10067-019-04636-9