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.