Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Lab of Kidney Disease and Blood Purification in Hunan, Changsha, China.
Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Lab of Kidney Disease and Blood Purification in Hunan, Changsha, China,
Kidney Blood Press Res. 2019;44(2):245-263. doi: 10.1159/000498962. Epub 2019 May 9.
BACKGROUND/AIMS: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. Microalbuminuria (MA) is widely used to predict early progressive renal function decline (ERFD) of DN in type 2 diabetes mellitus (T2D) patients, but the sensitivity and specificity of MA have been questioned. Here, we determined the urine metabolites differences between T2D patients with MA who maintained stable renal function and those who progressed to ERFD in order to identify specific biomarkers of the progression of renal dysfunction.
A total of 102 T2D patients with MA and normal renal function at baseline were followed up for 5-6 years. Of these, 52 patients were selected and classified into two groups according to the later renal function; 25 patients who experienced ERFD were regarded as the progressive group, while 27 patients who maintained stable renal function were considered as the stable group. In the pilot study, untargeted, broad-spectrum urine metabolomics was performed on the urine of 12 subjects from the progressive group (5 patients as "progressors") and stable group (7 patients as "non-progressors") to discover candidate markers. We then used a targeted metabolomics analysis to identify the selected markers in the urine of an additional 40 patients (20 from the progressive group as cases, and 20 from the stable group as controls) in the validation study.
A total of 318 known metabolites were detected in the pilot study and 6 metabolites with significant difference between progressors and non-progressors were identified. The levels of 4 metabolites, including azelaic acid, adipic acid, 5-hydroxyhexanoic acid, and L-tryptophan decreased significantly, while levels of L-pyroglutamic acid and D-norvaline increased observably in the progressors compared with non-progressors. Furthermore, in the validation study, 6 metabolites were confirmed by quantitative measurements and their concentrations were consistent with the changes in the pilot study. Concentrations of L-pyroglutamic acid and D-norvaline still increased in the cases, but were not statistically significant. Of the 4 metabolites with decreased concentrations among the cases, only 5-hydroxyhexanoic acid remained statistically significant while the other 3 metabolites did not differ between cases and controls.
We have identified urine metabolites and shown that 5-hydroxyhexanoic acid can be used as a predictor of progression of ERFD in T2D patients with MA. This finding provides the new perspective that 5-hydroxyhexanoic acid may be useful to identify T2D patients with MA who are at risk of ERFD.
背景/目的：糖尿病肾病（DN）是终末期肾病的主要原因。微量白蛋白尿（MA）广泛用于预测 2 型糖尿病（T2D）患者 DN 的早期进行性肾功能下降（ERFD），但 MA 的敏感性和特异性受到质疑。在这里，我们确定了 MA 维持肾功能稳定的 T2D 患者与进展为 ERFD 的患者之间的尿液代谢物差异，以确定肾功能障碍进展的特定生物标志物。
共纳入 102 例基线时 MA 且肾功能正常的 T2D 患者，随访 5-6 年。其中，选择了 52 例患者，并根据后期肾功能将其分为两组；25 例发生 ERFD 的患者为进展组，27 例肾功能稳定的患者为稳定组。在初步研究中，对进展组（5 例为“进展者”）和稳定组（7 例为“非进展者”）的 12 例患者的尿液进行了非靶向、广谱尿液代谢组学分析，以发现候选标志物。然后，我们在验证研究中，对另外 40 例患者（进展组 20 例为病例，稳定组 20 例为对照）的尿液进行了靶向代谢组学分析，以鉴定所选标志物。
在初步研究中检测到 318 种已知代谢物，鉴定出 6 种在进展者和非进展者之间有显著差异的代谢物。与非进展者相比，进展者中 4 种代谢物（壬二酸、己二酸、5-羟基己酸和 L-色氨酸）的水平显著降低，而 L-焦谷氨酸和 D-正缬氨酸的水平明显升高。此外，在验证研究中，通过定量测量确认了 6 种代谢物，其浓度与初步研究中的变化一致。病例组 L-焦谷氨酸和 D-正缬氨酸的浓度仍升高，但无统计学意义。在浓度降低的 4 种代谢物中，只有 5-羟基己酸仍有统计学意义，而其他 3 种代谢物在病例组和对照组之间无差异。
我们已经确定了尿液代谢物，并表明 5-羟基己酸可用于预测 MA 的 T2D 患者 ERFD 的进展。这一发现提供了新的视角，即 5-羟基己酸可能有助于识别 MA 的 T2D 患者，这些患者有发生 ERFD 的风险。
