Cardiometabolic protein expression levels and pathways associated with kidney function decline in older European adults with advanced kidney disease

Background. Cardiovascular disease and chronic kidney disease (CKD) progression pathophysiology are similar. We investigated associations of cardiometabolic protein expression and pathways with kidney function decline in older adults with advanced CKD referred for nephrology assessment. Methods. Two plasma proteomic panels analysed at baseline (Olink^® cardiometabolic T96 and cardiovascular II T96, Uppsala, Sweden) and longitudinal estimated glomerular filtration rate (eGFR) data from European adults aged >65 years with a single eGFR of <20 mL/min/1.73 m² [European Quality (EQUAL) Study] were used to explore mechanisms of CKD progression. Protein-slope associations were estimated using generalized linear mixed-effects models and with a false-discovery rate P < .05 taken to validation to verify the effect size of the association. Proteins were further modularized into biological pathways using pathway enrichment analysis. Results. A discovery sub-cohort of 238 complete-case participants from Germany, the UK and Poland (median age 76 years, 41% female sex, median baseline eGFR 17.8 mL/min/1.73 m²) were included and 246 participants from Sweden formed the validation sub-cohort (median age 75 years, 28% female, median baseline eGFR 17.5 mL/min/1.73 m²). Of the 175 analysed proteins, higher expression levels of Receptor-type tyrosine-protein phosphatase S [–15.4% change in eGFR per year per doubling of protein expression; 95% confidence interval (CI) –23.5%, –7.6%], Insulin-like growth factor binding protein 6 (–7.9%; 95% CI –12.3%, –3.5%) and Ficolin 2 (–7.4%; 95% CI –12.0%, –2.8%) showed a validated association with eGFR decline. Conclusions. Higher expression levels of proteins and biological pathways involving fibrogenesis and the complement cascade were found to be associated with kidney function loss. However, study limitations and unavailability of concurrent kidney cellular proteomic signatures necessitate further study.