Low Serum Levels of Complement C3c at Diagnosis Indicate Poor Outcome in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis.

To the Editor:

We read with great interest the recent study by Lionaki et al. regarding the value of low serum complement C3 levels as an independent predictor of poor renal prognosis in patients with pauci-immune antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. We herein share our own experience with regard of low serum levels of complement C3c at diagnosis of ANCA glomerulonephritis. Although only 5 of 38 patients (13.2%) had hypocomplementemia with C3c levels below the normal range (<0.82 g/l), patients who will experience requirement of kidney replacement therapy (13 of 38) or death (1 of 38) had significantly lower C3c levels (P = 0.0265; Figure 1a). According to median serum levels of C3c (1.295 g/l), low levels of C3c were associated with worse renal function reflected by median glomerular filtration rate (9.8 vs. 24.1 ml/min, P = 0.0121), higher urinary protein-to-creatinine ratio (1492 vs. 754 mg/g, P = 0.0344), and higher ANCA renal risk score (Figure 1b). During 40 days follow-up after diagnosis, low levels of C3c were more likely associated with early requirement of kidney replacement therapy or death (P = 0.0093; Figure 1c). In conclusion and confirmatory to the observations by Lionaki et al., low C3c levels within the normal range were associated with more severe deterioration of kidney function also reflected by higher ANCA renal risk score, associated with early requirement of kidney replacement therapy or death. These observations suggest that targeting the complement system might be especially beneficial in this patient subgroup. This is especially relevant because C5a receptor inhibitor avacopan and the monoclonal C5a antibody IFX-1 are currently in clinical development for ANCA-associated vasculitis.,

Figure 1

Low serum levels of complement C3c at diagnosis indicate poor outcome in ANCA GN. (a) Serum levels of complement C3c in the total cohort and according to requirement of KRT or death during follow-up. The scatter dot plots include median ± IQR compared with one-tailed Mann–Whitney U test; the dotted lines represent upper and lower normal ranges of serum C3c levels in our institution. (b) ARRS according to low and normal levels of serum C3c. (c) Overall survival (KRT/death) within 40 days after diagnosis according to low or normal levels of serum C3c. Comparison of survival curves was performed with log-rank (Mantel-Cox) testing. ANCA GN, antineutrophil cytoplasmic antibody-associated glomerulonephritis; ARRS, antineutrophil cytoplasmic antibody renal risk score; HR, hazard ratio; IQR, interquartile range; KRT, kidney replacement therapy.