Kidney Medicine (Dec 2024)
Circulating Protein and Metabolite Correlates of Histologically Confirmed Diabetic Kidney Disease
Abstract
Rationale & Objective: 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. Study Design: A cross-sectional study. Setting & Participants: A total of 434 Boston Kidney Biopsy Cohort participants. Predictors: Histopathological diagnosis of DKD on biopsy. Outcomes: Proteins and metabolites associated with DKD. Analytical Approach: 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. Results: 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; P = 0.008). Limitations: A cross-sectional approach and lack of an external validation cohort. Conclusions: Distinct proteins and biological pathways are correlated with a histopathological diagnosis of DKD. Plain-Language Summary: 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.
