Abstract
Mesangial C4d deposits have been associated with worse outcomes in Western patients with IgA nephropathy (IgAN), but there is limited data in Asians. Previously, a high proportion of stained glomeruli was often required for the classification of C4d positive (C4d+ve). Positive staining in lower proportion of staining would be classified as C4d-ve. This retrospective study evaluated the prognostic value of C4d+ve using a less stringent definition (one C4d+ve glomerulus) in Thai patients with IgAN (n = 120). Baseline findings and outcomes were compared between those with more extensive C4d staining patterns and those with more restricted staining. Clinico-pathologic parameters and risk for kidney outcomes (kidney failure or decline GFR50%) were compared between C4d+ve versus C4d-ve, and between different patterns: Focal (< 50%) versus Diffuse (≥ 50% of glomeruli); or Global (≥ 50) versus Segmental (< 50% of mesangial area). The hazard ratios were estimated using Cox proportional hazard models for Model 1 (Oxford score+ C4d) and Model 2 (Model 1+ clinical factors). C4d+ve (n = 81) had lower eGFR, more global sclerosis, and interstitial fibrosis than C4d-ve at baseline. The 5-year kidney survival for C4d+ve was lower (53.7%) than C4d-ve (89.7%); P = 0.0255. By univariate analysis, T1, T2, C4d+ve, eGFR<60, proteinuria were predictors of kidney outcome. By multivariate analysis, proteinuria, T1, T2 and C4d+ve were independent predictors (Model 2 HR (95% CI) C4d+ve: 3.24 (1.09–9.58), p = 0.034). Segmental had lower eGFR, higher tubulointerstitial fibrosis, and segmental sclerosis compared to Global pattern. Clinicopathological parameters were not different between Focal and Diffuse patterns. Outcomes were similar between staining patterns. In conclusion, C4d staining may be a valuable marker of poor prognosis in Asian patients with IgAN. Less stringent criteria for C4d+ve should be considered as no differences in outcomes were observed between more extensive staining with less extensive patterns. More studies are needed to identify the optimum criteria for C4d+ve.
Highlights
IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide with Asian countries having among the highest prevalence [1]
C4d positive (C4d+ve) patients had lower estimated glomerular filtration rate (eGFR), more global sclerosis, and interstitial fibrosis compared to C4d negative (C4d-ve) patients
We showed that C4d+ve patients defined as positive mesangial C4d in at least one glomerulus were more likely to have interstitial fibrosis, global sclerosis, and lower eGFR at presentation than C4d-ve patients
Summary
IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide with Asian countries having among the highest prevalence [1]. IgAN is defined by the predominant deposition of IgA in the glomerular mesangium, and is characterized by a highly variable course ranging from asymptomatic patients to those with progressive deterioration of kidney function to kidney failure). Several clinical factors including hypertension, proteinuria, low baseline kidney function, and adverse kidney histological features are associated with poor outcome in IgAN [2, 3]. The Oxford classification of the histopathological findings has been widely used to predict outcomes in IgAN patients. Current clinicopathologic parameters cannot fully predict the progression of IgAN. New prognostic markers may be useful to guide treatment of IgAN
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