Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Division of Nephrology, Hypertension, and Endocrinology, Nihon University School of Medicine, Tokyo, Japan.
Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA.
Kidney Int. 2022 Aug;102(2):370-381. doi: 10.1016/j.kint.2022.04.022. Epub 2022 May 23.
This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated.
本研究应用大型蛋白质组学面板寻找与糖尿病肾病患者肾功能衰竭进展相关的新循环生物标志物。包含 1 型和 2 型糖尿病以及早期和晚期糖尿病肾病的 754 名个体的四个独立队列被随访以确定肾功能衰竭的进展。在十年的随访中，754 名个体中有 227 名进展为肾功能衰竭。使用 SOMAscan 蛋白质组学平台，我们测量了基线时 1129 种循环蛋白的浓度。在我们之前的出版物中，我们分析了这些蛋白质中的 334 种，这些蛋白质是参与糖尿病肾病的特定候选途径的成员，发现 35 种蛋白质与肾功能衰竭进展的风险密切相关。在这里，我们使用非靶向方法检查了其余的 795 种蛋白质。在这些剩余的蛋白质中，有 11 种与肾功能衰竭的进展显著相关。这些蛋白质以前报道的生物学过程与神经元发育有关（DLL1、MATN2、NRX1B、KLK8、RTN4R 和 ROR1），并在细胞和动物研究中与肾纤维化的发展有关（LAYN、DLL1、MAPK11、MATN2、内皮脂酶和 ROR1）。必须进一步研究这些蛋白质在糖尿病肾病进展中涉及的特定机制，以评估它们作为肾脏保护治疗靶点的价值。使用多变量 LASSO 回归分析，发现五种蛋白质（LAYN、ESAM、DLL1、MAPK11 和内皮脂酶）与肾功能衰竭进展的风险独立相关。因此，我们的研究确定了一些可能被视为新的候选预后生物标志物的蛋白质，以预测糖尿病肾病肾功能衰竭的进展风险。此外，当评估所有 SOMAscan 结果时，这三种蛋白质（DLL1、ESAM 和 MAPK11）被选为候选生物标志物。
