长期随访RASAL1甲基化与肾间质纤维化及肾功能减退的关系

Long-term longitudinal study of the effect of RASAL1 hypermethylation on renal fibrosis and renal function deterioration

目的分析RASAL1基因启动子甲基化与慢性肾脏病(chronic kidney disease,CKD)患者肾间质纤维化及预后的关系。方法本研究是单中心回顾性队列研究,纳入33例行肾活检病理检查的CKD患者,于2012年10月至2013年1月入组,并随访至2021年12月。焦磷酸测序法检测患者肾组织及外周血单个核细胞(peripheral blood mononuclear cells,PBMC)RASAL1基因启动子的甲基化水平。分析RASAL1甲基化水平与肾功能、肾脏病理损伤指标及肾脏预后的关系。结果33例CKD患者肾组织RASAL1甲基化率为1.57%(1.14%,2.29%)。Spearman相关分析提示,肾组织及PBMC的RASAL1甲基化率与估算肾小球滤过率(estimated glomerular filtration rate,eGFR)呈负相关(ρ=‒0.598和‒0.590,P<0.01)。肾组织RASAL1甲基化率预测基线肾功能减退的ROC曲线下面积为0.942(P<0.01)。肾组织RASAL1高甲基化组患者肾间质纤维化比例明显高于低甲基化组(83.3%vs.38.1%,P<0.05)。6例患者随访过程中eGFR较基线下降超过20%,肾组织RASAL1高甲基化组患者发生eGFR进一步下降的概率高于低甲基化组(P<0.01)。结论CKD患者肾脏RASAL1甲基化与肾间质纤维化及eGFR下降相关。

Objective To analyze the effect of RASAL1 gene promoter methylation on renal fibrosis and renal function deterioration in patients with chronic kidney disease(CKD).Methods This study is a monocentric retrospective cohort study,including 33 patients with CKD who underwent renal biopsy from Oct 2012 to Jan 2013.Patients were followed up until Dec 2021.The methylation level of RASAL1 gene promoter in renal biopsy tissue and peripheral blood mononuclear cells(PBMCs)were measured by pyrosequencing.Results The mean methylation rate of RASAL1 gene promoter in renal tissue was 1.57%(1.14%,2.29%).Spearman correlation analysis showed that renal tissue(ρ=-0.598,P<0.01)and PBMCs(ρ=-0.590,P<0.01)RASAL1 methylation were negatively correlated with estimated glomerular filtration rate(eGFR).The AUC of renal tissue RASAL1 methylation rate for predicting baseline renal function impairment was 0.942(P<0.01).In RASAL1 hypermethylation group,the proportion of patients with renal interstitial fibrosis was significantly higher than patients with hypomethylation(83.3%vs.38.1%,P<0.05).Six patients had a decrease in eGFR of more than 20%during the follow-up.The probability of eGFR decline events in patients with RASAL1 hypermethylation was higher than hypomethylated group(P<0.01).Conclusion RASAL1 hypermethylation is associated with renal interstitial fibrosis and renal function deterioration in patients with CKD.