Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy

Abstract

IgA Nephropathy (IgAN) is the most prevalent glomerular disease worldwide. Complement system activation is crucial in its pathogenesis. Few studies correlated serum C3 and C4 with disease activity and prognosis. This retrospective study investigated the prognostic value of serum complement at the time of diagnosis in patients with IgAN. Specifically we evaluated whether adding serum C3 and C4 levels to established predictive models-one based on variables related to chronic kidney disease (CKD) progression and another incorporating variables from the International IgA Prediction Tool (IntIgAPT)-enhances the accuracy of outcome prediction. A composite renal outcome was defined as 50% decline in eGFR or onset of kidney failure. 101 patients were stratified according to baseline C3 levels in three groups (Low, Medium and High). During a median follow-up of 54 months, the Low group exhibited higher incidence of primary outcome (16.3 events vs 2.9 and 1.7 events × 100 pts/year, p = 0.0026). Model-1 (M1), consisting of CKD progression variables, and Model-3 (M3), comprising IntIgANPT variables, were implemented with baseline C3 and C4 to create Model-2 (M2) and Model-4 (M4), respectively. M2 demonstrated better predictive performance over M1, showing higher discrimination (lower AIC and BIC, higher C-index and NR2). Similarly, M4 outperformed M3, showing enhanced outcome prediction when C3 and C4 levels were added. Implementation of serum C3 and C4 can enhance prediction accuracy of already-validated prognostic models in IgAN. Lower C3 and higher C4 levels were associated with poorer prognosis, highlighting a more 'Complement-Pathic' subset of patients.

Keywords: C3; C4; Complement; Glomerulonephritis; IgA nephropathy; MEST.

Figure 1

Results from the correlation analysis showing the relationship between baseline variables. In particular, (A) shows the positive relation between C3 a C4. (B) The negative relation between C3 and IgM and panel C shows the negative relation between C4 and IgM.

Figure 2

Incidence of outcome expressed as incidence rate ratio (100 patients[pts]/year) stratified by baseline C3. Low group had a higher incidence, 16.3 events (95% CI 7.3–36.3) compared with Medium (2.9 events 95% CI 1.4–6.1) and High group (1.7 events 95% CI 0.2–11.8).