Although the detailed mechanism of IgAN still remains unknown, the role of oxidative stress in the pathogenesis has attracted more and more attention [2, 11, 12]. It was reported that the activation of intracellular signaling in mesangial cells cultured with aberrantly glycosylated IgA and in renal biopsies of IgAN patients basically results in oxidative stress. Advanced oxidation protein products (AOPPs) are considered to be important mediators of inflammation [13, 14], which could activate monocytes to release myeloperoxidase and synthesize reactive oxygen species. Increased AOPPs levels were observed in IgAN patients [4, 13, 15]. Bilirubin, as a powerful endogenous antioxidant, plays an important role in oxidative stress. It can inhibit NADPH oxidase and further inflammatory reaction . However, it is still do not know whether bilirubin has a role in IgAN progression.
In this study, in a cohort of 1492 patients with biopsy-proven IgAN, it was observed that a higher serum bilirubin level was beneficial to the outcome of IgAN. In the current study, it was found that the long-term renal outcome of IgAN patients with higher serum bilirubin level were better than those with lower serum bilirubin level. In the unmatched cohort, 16.2% (122/753) low-bilirubin group patients and 9.1% (67/739) high-bilirubin group patients progressed to the renal endpoints, and the Kaplan–Meier analysis revealed significant difference (p < 0.001). The result was consistent in the matched cohort (p = 0.039), including 77 (14.6%) patients in low bilirubin group and 57 (10.1%) patients in high bilirubin group reached the endpoints.
In order to simulate randomization and improve balance on baseline variables, propensity score matching analysis was carried out. Multivariate Cox regression analysis was performed with several models consisted of demographics, clinical, pathological indexes and serum bilirubin level, which could contain more confounders to reduce selective bias. The results showed that serum bilirubin level was an independent risk factor in every model in both unmatched and matched cohort. Based on these results, serum bilirubin level could be recognized as a protective factor for long term prognosis of patients with IgAN. Previously, it was reported that serum bilirubin level was associated with the progression of IgAN [16, 17]. However, previous studies did not analyze the pathological changes, moreover, selective bias were not adjusted by PSM. Therefore, the results of this study are more reliable than previous studies.
Many studies focused on the relationship between serum bilirubin levels and some oxidative stress diseases including cardiovascular disease, diabetes, obesity[7–9]. The antioxidative characteristics of bilirubin might protect not only against the progression of CKD but also against loss of residual kidney function (RKF) in PD patients . Elevated bilirubin concentrations were consistently associated with reduced vascular resistance [19, 20], improved eGFR , renal tubular function, and slowing of the progression of kidney damage . In the animal experiments, the bilirubin-treated mice showed less fibrosis in the unilateral ureteral obstruction (UUO) model and bilirubin treatment decreased fibronectin expression in tubular epithelial cells . Besides, it is reported that bilirubin interferes with vascular cell adhesion molecule1 (VCAM-1) and intercellular adhesion molecule1 (ICAM-1) to regulate atherosclerotic lesion formation and vascular inflammation both in animal and human models [9, 24]. Furthermore, bilirubin participates in immune response at several levels including modulation of regulatory T cells and T helper type 17 (Th17) cells, inhibition of the Toll-like receptor 4/nuclear factor kappaB signaling pathway, down-regulation of NLRP3 inflammasome[8, 24–26], which has been proved to be very important for IgA nephropathy in a previous study by our team .
However, there were still some limitations in our study. First, this was a single center study in China, the patients were mainly Han, Tibetan and Yi Chinese living in the southwest region of China, so it was not known whether our results had distinctive demographic or ethic characters. Second, we merely observed the level of serum total bilirubin without conjugated bilirubin and unconjugated bilirubin. Third, the sample size was limited which may not avoiding all bias.