Circulating Protein and Metabolite Correlates of Histologically Confirmed Diabetic Kidney Disease

Diabetic kidney disease (DKD) is one of the leading causes of end-stage kidney disease globally. We aim to identify proteomic and metabolomic correlates of histologically confirmed DKD that may improve our understanding of its pathophysiology.A cross-sectional study.A total of 434 Boston Kidney Biopsy Cohort participants.Histopathological diagnosis of DKD on biopsy.Proteins and metabolites associated with DKD.We performed linear regression to identify circulating proteins and metabolites associated with a histopathological diagnosis of DKD (n=81) compared with normal or thin basement membrane (n=27), and other kidney diseases without diabetes (n=279). Pathway enrichment analysis was used to explore biological pathways enriched in DKD. Identified proteins were assessed for their discriminative ability in cases of DKD versus a distinct set of 48 patients with diabetes but other kidney diseases.After adjusting for age, sex, estimated glomerular filtration, and albuminuria levels, there were 8 proteins and 1 metabolite that differed between DKD and normal/thin basement membrane, and 84 proteins and 11 metabolites that differed between DKD and other kidney diseases without diabetes. Five proteins were significant in both comparisons: C-type mannose receptor 2, plexin-A1, plexin-D1, renin, and transmembrane glycoprotein NMB. The addition of these proteins improved discrimination over clinical variables alone of a histopathological diagnosis of DKD on biopsy among patients with diabetes (change in area under the curve 0.126;=0.008).A cross-sectional approach and lack of an external validation cohort.Distinct proteins and biological pathways are correlated with a histopathological diagnosis of DKD.In the following study, we aimed to identify proteins, metabolites, and biological pathways that are associated with a diagnosis of diabetic kidney disease on biopsy. After adjusting for demographic characteristics and baseline renal function, we identified 5 proteins that were significantly associated with diabetic kidney disease, both in comparison to individuals without kidney disease and those with nondiabetic kidney disease: C-type mannose receptor 2, plexin-A1, plexin-D1, renin, and transmembrane glycoprotein NMB. We also found that these proteins may enhance our ability to distinguish between diabetic kidney disease and other causes of kidney disease in a group of patients with diabetes.

糖尿病肾病（DKD）是全球终末期肾病的主要病因之一。我们旨在确定经组织学证实的DKD的蛋白质组学和代谢组学相关因素，这可能会增进我们对其病理生理学的理解。 一项横断面研究。 波士顿肾脏活检队列共434名参与者。 活检中DKD的组织病理学诊断。 与DKD相关的蛋白质和代谢物。 我们进行了线性回归分析，以确定与DKD组织病理学诊断（n = 81）相关的循环蛋白质和代谢物，并与正常或薄基底膜（n = 27）以及其他非糖尿病肾病（n = 279）进行比较。采用通路富集分析来探索DKD中富集的生物学通路。对已确定的蛋白质在DKD病例与另外48名患有糖尿病但有其他肾病的患者中的鉴别能力进行了评估。 在对年龄、性别、估算的肾小球滤过率和蛋白尿水平进行调整后，在DKD与正常/薄基底膜之间有8种蛋白质和1种代谢物存在差异，在DKD与其他非糖尿病肾病之间有84种蛋白质和11种代谢物存在差异。有5种蛋白质在两种比较中均具有显著意义：C型甘露糖受体2、丛蛋白 - A1、丛蛋白 - D1、肾素和跨膜糖蛋白NMB。添加这些蛋白质提高了在糖尿病患者中对活检组织病理学诊断DKD相对于仅临床变量的鉴别能力（曲线下面积变化为0.126；P = 0.008）。 横断面研究方法以及缺乏外部验证队列。 不同的蛋白质和生物学通路与DKD的组织病理学诊断相关。 在接下来的研究中，我们旨在确定与活检诊断糖尿病肾病相关的蛋白质、代谢物和生物学通路。在对人口统计学特征和基线肾功能进行调整后，我们确定了5种与糖尿病肾病显著相关的蛋白质，无论是与无肾病个体还是与非糖尿病肾病患者相比：C型甘露糖受体2、丛蛋白 - A1、丛蛋白 - D1、肾素和跨膜糖蛋白NMB。我们还发现这些蛋白质可能提高我们在一组糖尿病患者中区分糖尿病肾病和其他肾病病因的能力。