Complement C3a/C3aR and C5a/C5aR deposits accelerate the progression of advanced IgA nephropathy to end-stage renal disease

TL;DR

This study finds that deposits of complement components C3a/C3aR and C5a/C5aR in advanced IgA nephropathy patients are linked to faster progression to kidney failure.

Contribution

The study identifies a novel association between complement C3a/C3aR and C5a/C5aR deposits and progression to end-stage renal disease in stage 4 IgA nephropathy.

Findings

Higher C3a, C3aR, C5a, and C5aR expression was observed in patients who progressed to ESRD.

C3a/C3aR and C5a/C5aR deposits correlated with lower eGFR and faster kidney function decline.

C3a and C5a deposits were associated with higher histological scores in IgA nephropathy.

Abstract

IgA nephropathy (IgAN) is still one of the leading causes of end-stage kidney disease (ESRD), and complement system activation is a key to the pathogenesis of IgAN. The role of complement C3a/C3aR and C5a/C5aR in late stage of IgAN remains unknown. Renal specimens of 75 IgAN patients at the stage 4 CKD were stained using immunofluorescence and immunohistochemistry. The primary outcome was a composite of end-stage renal disease (ESRD) and death. Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses. During a median follow-up of 15.0 months, 27 patients progressed to ESRD and none died. Lower eGFR [hazards ratio (HR), 0.827, 95% confidence interval (CI), 0.732–0.935; P = 0.002] and glomerular C3 deposition (HR, 3.179, 95% CI, 1.079–9.363; P = 0.036) were predictive of time to ESRD in stage 4 CKD IgAN. Higher expression of C3a (P = 0.010), C3aR (P = 0.005), C5a (P = 0.015), and C5aR (P < 0.001) was identified in ESRD group than in non-ESRD group. Glomerular C3a/C3aR and C5a/C5aR deposits were both correlated with a lower baseline eGFR, higher baseline 24 h-urinary protein (24 h-UP) and faster decline of eGFR. Besides, C3a and C5a deposits were found in patients with high S (S1) and T (T1/2) scores, respectively. Complement C3a/C3aR and C5a/C5aR in IgAN patients with stage 4 CKD may portend a faster deterioration of kidney function.

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