Urinary Proteomics as a tool to Identify Kidney Responders to Dipeptidyl Peptidase-4 Inhibition. A Hypothesis-Generating Analysis from the MARLINA-T2D Trial.

PURPOSE: Chronic kidney disease (CKD) is a serious complication of hyperglycemia and treatment options to slow its progression are scarce. Dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used glucose-lowering drugs in type 2 diabetes (T2D). Among these, linagliptin has been suggested to exert kidney protective effects. We investigated whether a potential effect of linagliptin on kidney function could be unmasked by characterizing the urinary proteome profile (UPP) in T2D individuals with prevalent albuminuria.

EXPERIMENTAL DESIGN: This study was performed based on data and samples available from the previously reported MARLINA-T2D trail (NCT01792518). Study participants were randomized 1:1 to receive either linagliptin 5mg or placebo for 24 weeks. A previously developed urinary proteome-based classifier, CKD273, was assessed.

RESULTS: Our results confirm previous studies of a significant correlation between CKD273 and clinical kidney parameters as well as with eGFR decline. Patient stratification using CKD273 at baseline, showed a trend towards attenuation of renal function loss in high CKD-risk patients treated with linagliptin. We further characterized linagliptin affected peptides of which the majority contained a DPP-4 target sequence and some also correlated with urinary DPP-4 activity.

CONCLUSIONS AND CLINICAL RELEVANCE: CKD273 is a promising tool for identifying patients at high risk for kidney disease progression and may unmask a potential of linagliptin to slow progressive kidney function loss in high CKD-risk patients. UPP characterization revealed a significant impact of linagliptin on urinary peptides. This article is protected by copyright. All rights reserved.