Department of Nephrology, Daping Hospital, Research Institute of Surgery, Army Military Medical University, Chongqing, China.
Department of Nephrology, Army 958 Hospital, Chongqing, China.
Kidney Blood Press Res. 2019;44(5):1063-1074. doi: 10.1159/000502233. Epub 2019 Sep 5.
BACKGROUND/AIMS: Stress-induced cell senescence, which contributes to cell cycle arrest and is independent of age, plays an important role in chronic kidney disease (CKD) progression. DcR2, as a senescent marker, exclusively expressed in senescent tubular epithelia. The objective of this study was to examine whether urinary DcR2 (uDcR2) could be a potential biomarker for tubulointerstitial fibrosis (TIF) in patients with immunoglobulin A nephropathy (IgAN).
This study included 210 IgAN patients and 80 healthy volunteers, with uDcR2 levels measured using enzyme-linked immunosorbent assay. We examined the relationship among uDcR2/Cr levels, renal function, and pathological parameters, using regression analysis to identify risk factors for TIF and the area under the curve (AUC) approach to predict TIF. Renal DcR2 expression was quantified by immunohistochemistry. Co-expression of DcR2 with fibrotic markers (α-smooth muscle actin [α-SMA], collagen III) was analyzed by confocal microscopy.
Levels of uDcR2/Cr were significantly higher in IgAN patients and in those with more severe TIF, compared with healthy controls. Serum DcR2 levels were similar across groups. The proportion of IgAN patients with stages 1-2 CKD and T0 was highest among those with uDcR2/Cr <130 ng/g. In contrast, the majority of those with uDcR2/Cr >201 ng/g had stages 4-5 CKD and T2. Levels of uDcR2/Cr were positively associated with urinary albumin to creatinine ratio (ACR), urinary N-acetyl-β-D-glucosaminidase (uNAG)/Cr, and TIF scores and negatively associated with estimated glomerular filtration rate (eGFR). uDcR2/Cr, uNAG, ACR, and eGFR were independent predictors for TIF, with AUC of 0.907 for uDcR2/Cr. This AUC value was higher than that observed for eGFR, uNAG/Cr, or ACR. The sensitivity and specificity of uDcR2/Cr in predicting TIF were 87.0 and 80.5%, respectively. Moreover, uDcR2/Cr levels were positively associated with the percentage of renal DcR2 expression. Renal DcR2 co-localized with α-SMA and collagen III in the kidneys of IgAN patients.
Levels of uDcR2/Cr were closely associated with the severity of TIF and renal function parameters. uDcR2/Cr represents a potential biomarker for predicting TIF in IgAN patients.
背景/目的：应激诱导的细胞衰老，其导致细胞周期停滞且与年龄无关，在慢性肾脏病（CKD）进展中起着重要作用。DcR2 作为衰老标志物，仅在衰老的肾小管上皮细胞中表达。本研究旨在探讨尿 DcR2（uDcR2）是否可作为免疫球蛋白 A 肾病（IgAN）患者小管间质纤维化（TIF）的潜在生物标志物。
本研究纳入了 210 例 IgAN 患者和 80 名健康志愿者，采用酶联免疫吸附试验检测 uDcR2 水平。通过回归分析确定 TIF 的危险因素，并采用曲线下面积（AUC）法预测 TIF，以评估 uDcR2/Cr 水平与肾功能和病理参数之间的关系。通过免疫组织化学定量检测肾组织中 DcR2 的表达。通过共聚焦显微镜分析 DcR2 与纤维化标志物（α-平滑肌肌动蛋白[α-SMA]、III 型胶原）的共表达。
与健康对照组相比，IgAN 患者和 TIF 更严重的患者 uDcR2/Cr 水平显著升高。各组血清 DcR2 水平相似。uDcR2/Cr<130ng/g 的 IgAN 患者中，CKD 1-2 期和 T0 比例最高。相比之下，uDcR2/Cr>201ng/g 的患者中，CKD 4-5 期和 T2 比例最高。uDcR2/Cr 水平与尿白蛋白与肌酐比值（ACR）、尿 N-乙酰-β-D-氨基葡萄糖苷酶（uNAG）/Cr 和 TIF 评分呈正相关，与估计肾小球滤过率（eGFR）呈负相关。uDcR2/Cr、uNAG、ACR 和 eGFR 是 TIF 的独立预测因子，uDcR2/Cr 的 AUC 为 0.907。该 AUC 值高于 eGFR、uNAG/Cr 或 ACR。uDcR2/Cr 预测 TIF 的灵敏度和特异性分别为 87.0%和 80.5%。此外，uDcR2/Cr 水平与肾组织 DcR2 表达百分比呈正相关。IgAN 患者的肾脏中，肾组织 DcR2 与 α-SMA 和 III 型胶原共定位。
uDcR2/Cr 水平与 TIF 严重程度和肾功能参数密切相关。uDcR2/Cr 可能是预测 IgAN 患者 TIF 的潜在生物标志物。
