Novel Protein Biomarkers to Monitor Kidney Function Decline and Treatment Response in Individuals With Normoalbuminuria and Type 2 Diabetes

Kidney function can decline in individuals with type 2 diabetes despite normal urinary albumin-to-creatinine ratio (UACR), which may not adequately capture this process. We evaluated whether biomarkers reflecting inflammation, tubular injury, regenerative capacity, and fibrosis improve risk stratification and treatment monitoring beyond UACR in normoalbuminuric individuals with type 2 diabetes. We measured plasma tumor necrosis factor receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1), urinary epidermal growth factor normalized to creatinine (uEGF/Cr), and serum matrix metalloproteinase-7 (MMP-7) at baseline and year one in banked samples from normoalbuminuric participants of the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial. We assessed associations of baseline UACR and biomarkers with a composite kidney outcome (sustained ≥40% decline in kidney function, kidney failure, or renal death) and compared longitudinal trajectories by outcome and treatment (canagliflozin vs. placebo). Of 2,573 participants, 53 (2.1%) experienced the composite kidney outcome (28 [3.3%] placebo, 25 [1.5%] canagliflozin). Baseline UACR was not associated with the composite kidney outcome, whereas TNFR-1, TNFR-2, KIM-1, and MMP-7 were each independently associated. Among participants who experienced the composite kidney outcome, TNFR-1, TNFR-2, and KIM-1 increased irrespective of treatment, while uEGF/Cr declined. Canagliflozin attenuated the rise in KIM-1 and the decline in uEGF/Cr, and fully suppressed MMP-7 elevation observed with placebo. In normoalbuminuric individuals with type 2 diabetes, biomarkers reflecting inflammation, tubular injury, regenerative capacity, and fibrosis independently identified individuals at risk for chronic kidney disease progression and showed divergent trajectories by outcome and treatment, supporting their potential clinical utility for risk stratification and treatment monitoring. Article Highlights Kidney function can decline in individuals with type 2 diabetes despite normal albuminuria, yet current risk stratification relies heavily on urinary albumin-to-creatinine ratio (UACR), which may inadequately capture this process. We investigated whether biomarkers reflecting inflammation, tubular injury, regenerative capacity, and fibrosis improve risk prediction and treatment monitoring beyond UACR in these individuals. Baseline UACR did not predict the composite kidney outcome, whereas TNFR-1, TNFR-2, KIM-1, and MMP-7 were independently associated. In those who developed the outcome, these biomarkers and uEGF/Cr showed divergent trajectories, unlike UACR. Biomarkers capturing pathways beyond glomerular injury may improve risk stratification and treatment monitoring in these normoalbuminuric patients.