Hypocomplementemia is associated with more severe renal disease and worse renal outcomes in patients with ANCA-associated vasculitis: a retrospective cohort study

Abstract

Background: The complement system has been recently proposed to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). This study evaluated the value of serum and kidney deposited C3 in predicting renal outcomes in AAV. Methods: This was a retrospective study of 47 patients with AAV, who were categorized according to their serum C3 levels as hypo-or normo-complementemic and to those with positive or negative kidney biopsy immunofluorescence (IF) for C3. Baseline characteristics as well as progression to end-stage renal disease (ESRD) between the 2 groups were compared. Results: In total, 23% (11/47) were hypo-complementemic; these patients were older (74 vs. 65 years, p ¼ 0.013), had higher creatinine levels (4.9 vs. 2.2 mg/dL, p ¼ 0.006), were more often hemodialysis dependent (64% vs. 19%, p ¼ 0.009) and progressed more often to ESRD (55% vs. 11%, p ¼ 0.01) compared to normo-complementemic patients (n ¼ 36). On multivariate analysis, serum creatinine at diagnosis (HR ¼ 16.8, 95%CI: 1.354-208.62, p ¼ 0.028) and low serum C3 (HR ¼ 2.492; 95% CI: 1.537-11.567; p ¼ 0.044) were independent predictors for ESRD. Among 25 patients with an available kidney biopsy, 56% had C3 deposition by IF and displayed more often a mixed histological pattern (72% vs. 27%, p ¼ 0.033), low serum C3 levels (42% vs. 18%, p < 0.001) and serious infections during follow-up (57% vs. 18%, p ¼ 0.047) compared to those with negative (n ¼ 11) IF staining. Conclusion: Almost one of four patients with AAV has low C3 levels at diagnosis which is associated with more severe renal disease and worse renal outcomes (ESRD). This should be taken into account in therapeutic and monitoring strategies.

Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis

“…Furthermore, hypocomplementemia was only detectable in a minor subset of ANCA GN and not correlated with renal or extrarenal AAV manifestations, in line with previous reports [26]. However, low levels of circulating C3c correlated with AKI severity in ANCA GN independent of systemic disease activity or extrarenal AAV manifestation, again in line with independent reports [27]. By systematic scoring of glomerular and tubulointerstitial lesions in association with circulating complement components C3c and C4, we here provide further insights into the mechanistic role of complement system activation in kidney injury to different renal compartments in ANCA GN.…”

Long-Term Renal Survival in Antineutrophil Cytoplasmic Antibody–Associated Glomerulonephritis With Complement C3 Deposition

“…The major novel findings of this study, which included 142 Japanese patients with ANCA-GN, are as follows: glomerular complement deposition was detected in web 4C=FPO approximately 40% of the ANCA-GN kidney biopsy specimens by routine IF and C3-positive patients with ANCA-GN had both worse renal and overall survival at 5 years. The association between C3 deposition and poor renal and overall survival persisted after considering the previously reported predictors of renal outcomes in ANCA-GN 16,20,[23][24][25][26] and after changing the definition of outcomes or analyzing the patient subgroups. To the best of our knowledge, this is the largest study to date that investigated the glomerular deposition of Igs and complement using IF and the first study that evaluated the prognostic significance of C3 deposition.…”

“…11,13 Likewise, recent studies have reported that patients with AAV with low serum C3 level at diagnosis had poorer renal and overall survival rates. [14][15][16] Although data from humans have supported the complement activation involvement in human ANCA-GN, the clinicopathologic significance of complement deposition in patients with ANCA-GN is yet unclear. Most clinical studies 11,12,[14][15][16] investigating complement deposition in renal histopathology and/or serum complement level were limited because of small sample size or fewer kidney biopsy specimens.…”

“…[14][15][16] Although data from humans have supported the complement activation involvement in human ANCA-GN, the clinicopathologic significance of complement deposition in patients with ANCA-GN is yet unclear. Most clinical studies 11,12,[14][15][16] investigating complement deposition in renal histopathology and/or serum complement level were limited because of small sample size or fewer kidney biopsy specimens. Moreover, studies analyzing complement deposition in renal histopathology [10][11][12][13] were cross-sectional, and the longterm outcomes of ANCA-GN patients with complement deposition on IF remain unclear.…”

“…R Oba et al: Long-Term Renal Survival in ANCA-GN CLINICAL RESEARCH HRs of composite end points between the C3-positive and -negative groups. The prognostic factors of renal outcomes in ANCA-GN16,20,[23][24][25][26] were included in multivariable analyses. The treatments were divided into the following 3 categories: none, prednisolone only, and prednisolone þ other immunosuppressors.…”