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Complement C3a/C3aR and C5a/C5aR deposits accelerate the progression of advanced IgA nephropathy to end-stage renal
Ying Wang1, Shunlai Shang2, Shimin Jiang1
1Department of Nephrology, China-Japan Friendship Hospital, No. 2 East Yinghuayuan Street, Chaoyang District, Beijing, 100029, China.
Insights
Complement C3a/C3aR and C5a/C5aR activation in IgA nephropathy (IgAN) patients with stage 4 CKD indicates faster kidney function decline. Higher expression of these complement components predicts progression to end-stage renal disease (ESRD).
Area of Science:
- Nephrology
- Immunology
- Pathogenesis of kidney disease
Background:
- IgA nephropathy (IgAN) is a major cause of end-stage renal disease (ESRD).
- Complement system activation is implicated in IgAN pathogenesis.
- The role of C3a/C3aR and C5a/C5aR in late-stage IgAN is not well understood.
Purpose of the Study:
- To investigate the role of complement C3a/C3aR and C5a/C5aR in IgAN patients with stage 4 chronic kidney disease (CKD).
- To assess the association of these complement components with kidney function decline and progression to ESRD.
Main Methods:
- Renal specimens from 75 IgAN patients at stage 4 CKD were analyzed using immunofluorescence and immunohistochemistry.
- Clinicopathological characteristics and outcomes (ESRD, death) were assessed.
- Multivariable Cox regression and Spearman analyses were used to evaluate associations.
Main Results:
- Lower estimated glomerular filtration rate (eGFR) and glomerular C3 deposition predicted time to ESRD.
- Higher expression of C3a, C3aR, C5a, and C5aR was found in the ESRD group.
- C3a/C3aR and C5a/C5aR deposits correlated with lower baseline eGFR, higher 24-hour urinary protein, and faster eGFR decline.
Conclusions:
- Complement C3a/C3aR and C5a/C5aR activation in IgAN patients with stage 4 CKD may indicate faster kidney function deterioration.
- These complement components are associated with adverse clinical and pathological features in IgAN.
- Targeting these complement pathways could be a potential therapeutic strategy for IgAN.
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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