Abstract
BACKGROUND: The risk of diabetic kidney disease (DKD) progression is significant despite treatment with renin-angiotensin system (RAS) blocking agents. Current clinical tools cannot predict whether or not patients will respond to treatment with RAS inhibitors (RASi). We aimed to investigate whether proteome analysis could identify urinary peptides as biomarkers that could predict the response to angiotensin-converting enzyme inhibitor and angiotensin-receptor blockers treatment to avoid DKD progression. Furthermore, we investigated the comparability of the estimated glomerular filtration rate (eGFR), calculated using four different GFR equations, for DKD progression. METHODS: We evaluated urine samples from a discovery cohort of 199 diabetic patients treated with RASi. DKD progression was defined based on eGFR percentage slope results between visits (∼1 year) and for the entire period (∼3 years) based on the eGFR values of each GFR equation. Urine samples were analysed using capillary electrophoresis-coupled mass spectrometry. Statistical analysis was performed between the uncontrolled (patients who did not respond to RASi treatment) and controlled kidney function groups (patients who responded to the RASi treatment). Peptides were combined in a support vector machine-based model. The area under the receiver operating characteristic curve was used to evaluate the risk prediction models in two independent validation cohorts treated with RASi. RESULTS: The classification of patients into uncontrolled and controlled kidney function varies depending on the GFR equation used, despite the same sample set. We identified 227 peptides showing nominal significant difference and consistent fold changes between uncontrolled and controlled patients in at least three methods of eGFR calculation. These included fragments of collagens, alpha-1-antitrypsin, antithrombin-III, CD99 antigen and uromodulin. A model based on 189 of 227 peptides (DKDp189) showed a significant prediction of non-response to the treatment/DKD progression in two independent cohorts. CONCLUSIONS: The DKDp189 model demonstrates potential as a predictive tool for guiding treatment with RASi in diabetic patients.