Background: Given the association of diabetic retinopathy (DR) to diabetic kidney disease, we investigated the urinary proteome to the presence and deterioration of DR in type 1 and type 2 diabetes in a post-hoc analysis of studies investigating the effect of candesartan on the progression of DR.

Methods: Baseline urinary proteomic analysis was performed in 783 and 792 randomly chosen subjects from two RCTs: DIRECT-Protect 1 and 2. Endpoints were two-step and three-step change in DR score according to the Early Treatment of Diabetic Retinopathy Study protocol. Peptide levels were correlated to baseline DR score, using Spearman rank correlation (association presented as Rho), in a discovery set of 2/3 of participants in DIRECT-Protect 1. Identified peptide fragments were then tested cross-sectionally in a validation set of the remaining 1/3 in DIRECT-Protect 1. Thereafter, peptides identified in the discovery set were assessed in the entire DIRECT-Protect 1 and 2 cohorts in relation to baseline DR. Finally, peptides validated in the entire cohorts were tested longitudinally. Adjustment included sex, age, diabetes duration, smoking, total cholesterol, HbA1c, SBP, UAER, serum creatinine, and randomization group.

Results: Follow-up ranged from 4.0-4.7 years. 24 out of 427 investigated peptide fragments were associated with baseline DR in the discovery set after adjustment for multiple testing. Two of these (COL3A1 (seq: NTG~) and COL4A1 (seq: DGA~) were also associated to baseline DR in the validation set (Rho: -0.22, p<0.001 and Rho: -0.14, p=0.024). Neither was associated with the development of endpoints. Investigating the discovered fragments in the full cohorts, several collagen fragments were associated with baseline DR and endpoints, in both type 1 and type 2 diabetes, however without overlap.

Conclusions: Several urinary peptide fragments (mainly collagen) were associated with the presence of DR, however, they were not conclusively associated with worsening of DR.

Disclosure

V. Rotbain curovic: None. P. Magalhães: None. T. He: Employee; Self; Mosaiques Diagnostics GmbH. T. W. Hansen: Stock/Shareholder; Self; Novo Nordisk A/S. H. Mischak: Stock/Shareholder; Self; Mosaiques Diagnostics. P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd.

© 2021 by the American Diabetes Association
2021
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