DISCUSSION
Although the risk factors affecting the poor prognosis of patients with IgAN have been described[17], the most influential factor in endpoint outcomes of patients with IgAN remains unclear. In the present study, we assessed 136 patients with IgAN, including 102 patients in C3low group and 34 patients in C3high group, to investigate whether glomerular C3 deposition has the value of evaluating clinical prognosis and predicting kidney outcome according to an average of 105 months of follow-up. We found that glomerular C3 deposition was associated with deterioration of renal function and prognosis in patients with IgAN.
Complement regulatory proteins are expressed on the surface of almost all resident kidney cells[18]. Of all the complement proteins co-deposited with IgA1, C3 is the most abundant. Many studies have previously showed that glomerular C3 deposition and complement activation was involved in pathogenesis of patients with various kidney disease including IgAN[19-21], lupus nephritis[22], C3 glomerulopathy[23], and antineutrophil cytoplasmic antibody (ANCA)-mediated crescentic glomerulonephritis[24]. The intensity of glomerular C3 deposition has been negatively correlated with renal survival in a cohort study of 111 kidney transplant recipients with transplant glomerulopathy[25]. Interestingly, extraglomerular C3 deposits also affects clinical outcomes in IgAN patients[26]. The classical, alternative and lectin pathways are three known pathways for complement system activation. Each pathway has its own triggering mechanism; however, once the C3 convertases is created, all pathways will be unified. Thus, glomerular C3 deposition in IgAN highlights the pathophysiological role of activation of complement fragments.
In this study, we found that with patients with heavy glomerular C3 deposition suffered higher proteinuria level and lower eGFR, higher percentage of mesangial hypercellularity, segmental glomerulosclerosis, severe tubular atrophy/interstitial fibrosis, crescents, severe arterial wall thickening, severe arterial hyalinosis. According to the follow-up data, patients in C3high group had a significantly higher risk of Scr doubling and ESRD than those in C3low group, which was consistent with the previous studies. Nam et al. showed that the glomerular C3 and C4d (especially C3) deposition was an independent risk factor for progression of IgAN [27]. Kim et al. found decreased circulating C3 levels and mesangial C3 deposition predicted renal outcome in patients with IgAN according to 53.7 months follow-up. They also showed a remarkable negative relevant relation between serum C3 levels and mesangial C3 deposition [28]. In our study, although we excluded patients who had received glucocorticoids or immunosuppressants treatment before renal biopsy, we did not find the negative relevant relation serum C3 levels and mesangial C3 deposition in IgAN patients. Besides the histopathlogical and clinical parameters, we further found C3high group contained more interstitial macrophages, T lymphocytes and mast cells infiltration than the C3low group. It suggested glomerular C3 deposition might be related to the activation of local immune response in the progression of IgAN.
There are several limitations of our study. First, the cohort was not large enough. In the future, large prospective studies and repeat biopsy after glucocorticoids therapy of IgAN patients are expected. Second, we cannot dissect individual role of alternative and lectin pathways. Other complement components were not available in our current research.
In conclusion, our study suggested the clinical significance of glomerular C3 deposition in clinical practice and indicated that high density C3 deposition in kidney were associated with severe renal lesions and the activation of local immune response in the progression of IgAN. Based on an average of 105 months of follow-up, glomerular C3 deposition were independently associated with poor renal outcome in patients with IgAN. Thus, these findings suggest that glomerular C3 deposition are potentially served as a predictor factor of poor prognosis in patients with IgAN.