Classification of Predictors of Rapid Development of Kidney Failure and Short-Term Changes in Concentration of Circulating Proteins.

Abstract

Limited knowledge exists regarding short-term changes/increases in concentrations of circulating proteins (referred here as deltas) and rapid development of kidney failure (rapid KF) in diabetes mellitus. Concentrations of 452 circulating proteins were measured by OLINK proteomics platform at baseline and after a median interval of 3-4 years in 106 individuals with type 1 and 77 with type 2 diabetes in two case-control studies. During 10-year follow-up, 31 and 26 individuals, respectively, developed rapid KF. Deltas for 40 proteins predicted rapid KF in both studies. All were better predictors than delta urine albumin-creatinine ratio, and half were better than delta glomerular filtration rate. Comparing the delta proteins with 46 circulating proteins of which elevated baseline concentrations were predictors of rapid KF risk in our previous study, 61 unique proteins were identified. Among these proteins, 21 were good predictors of rapid KF only when measured at baseline (predictors of initiation), 15 were good predictors when measured as deltas (predictors of progression) and 25 were good predictors when both baseline and delta concentrations were used (predictors of initiation and progression). An index score, developed for the latter 25 proteins, provided superior prediction of rapid KF. A subset of these latter proteins was associated with apoptotic processes/tumor necrosis factor (TNF) receptor signaling pathways. Development of rapid KF in diabetes was preceded by elevated concentrations of multiple circulating proteins both at baseline and during short follow-up. Comparing baseline and short-term changes in concentrations of circulating proteins classified predictors of rapid KF risk into those associated with initiation, progression, or both. Predictors of both initiation & progression flagged apoptosis processes and TNF receptor signaling pathways. Multi-protein prognostic algorithms using proteins associated with both initiation and progression improved prediction of rapid KF risk beyond clinical variables.