Effect of time-weighted average 25(OH)D on the occurrence of major adverse kidney events in IgA nephropathy: from a 10-year populationbased cohort study

Fang LuChang LiuDandan SongLi QianJingfeng ZhuJingjing WuChengning ZhangZhimin HuangMing ZengBin SunBo ZhangSuyan Duan^*Yanggang YuanChangying XingHuijuan Mao

• Department of Nephrology, First Affiliated Hospital, Nanjing Medical University, Nanjing, China

Background: Vitamin D (VD) deficiency has been found to be common and associated with an increased risk of adverse outcomes in chronic kidney disease (CKD) in some studies. However, whether it is associated with the progression of IgA nephropathy (IgAN) and the efficacy of supplementation is still in debate.Methods: A total of 866 patients of IgAN were included. Identification of the baseline and timeweighted average (TWA) serum 25(OH)D level associated with the major adverse kidney events (MAKE) was executed by Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves and multivariate logistic regression analysis. Furthermore, the dataset was divided into derivation and validation cohorts using a 6:4 ratio. Internal validation was performed to assess the added value of TWA 25(OH)D level to clinical variables by ROC curves, decision curve analysis and Net reclassification improvement. An integrative analysis of genomic, scRNA-seq, and molecular docking analysis was used to reveal the potential mechanism of VD supplementation on IgAN progression.Results: During a median follow-up of 4.3 years (IQR 3.3 -5.9 years), a total of 92 (10.6%) patients occurred MAKE. Cumulative renal outcomes were significantly higher in the lower baseline and TWA 25(OH)D levels. The multivariate Cox regression analyses indicated that TWA 25(OH)D level was an independent determinant for MAKE in IgAN after adjusting important confounders.Moreover, it showed reliable predictive performance in risk stratification of MAKE, with the optimal predictive cutoff value of 44.8 nmol/L. Accordingly, a significant linear association between TWA 25(OH)D and the risk of MAKE was observed. Reclassification further confirmed the consistency of overall findings. Furthermore, in addition to routine-used clinical parameters, TWA 25(OH)D-based model had strong risk prediction power, verified internally, and demonstrated satisfactory efficacy and significant net advantages. Moreover, VD treatment may improve prognosis by regulating the process of cell chemotaxis, inflammatory response, and defense response via targeting the NFKB1 and NR4A1 expressions in proximal tubule cells in IgAN.Our findings enable more comprehensive insight into VD in IgAN and strengthen the efficacy of VD supplementation in IgAN. The long-term maintenance of optimal VD levels from early in life might be associated with reduced future risk of kidney progression in IgAN.