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Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes

Global proteomics profiling identified FGF20, TNFSF12, and ANGPT1 as protective against progression of renal function decline in those with diabetes. Protecting against diabetic kidney disease Diabetic kidney disease is extensively studied, but less emphasis has been placed on factors that protect against functional decline. Md Dom and colleagues used untargeted proteomics to identify plasma proteins associated with nonprogression of renal disease in individuals with type 1 and type 2 diabetes. Elevated concentrations of three proteins—ANGPT1, FGF20, and TNFSF12—were associated with nonprogression of renal disease in three cohorts of diabetics at different stages of kidney disease. These three proteins may serve as biomarkers to identify those at lower risk of diabetic kidney disease progression and should be further investigated to understand how they may delay end-stage renal disease. Diabetic kidney disease (DKD) and its major clinical manifestation, progressive renal decline that leads to end-stage renal disease (ESRD), are a major health burden for individuals with diabetes. The disease process that underlies progressive renal decline comprises factors that increase risk as well as factors that protect against this outcome. Using untargeted proteomic profiling of circulating proteins from individuals in two independent cohorts with type 1 and type 2 diabetes and varying stages of DKD followed for 7 to 15 years, we identified three elevated plasma proteins—fibroblast growth factor 20 (OR, 0.69; 95% CI, 0.54 to 0.88), angiopoietin-1 (OR, 0.72; 95% CI, 0.57 to 0.91), and tumor necrosis factor ligand superfamily member 12 (OR, 0.75; 95% CI, 0.59 to 0.95)—that were associated with protection against progressive renal decline and progression to ESRD. The combined effect of these three protective proteins was demonstrated by very low cumulative risk of ESRD in those who had baseline concentrations above median for all three proteins, whereas the cumulative risk of ESRD was high in those with concentrations below median for these proteins at the beginning of follow-up. This protective effect was shown to be independent from circulating inflammatory proteins and clinical covariates and was confirmed in a third cohort of diabetic individuals with normal renal function. These three protective proteins may serve as biomarkers to stratify diabetic individuals according to risk of progression to ESRD and might also be investigated as potential therapeutics to delay or prevent the onset of ESRD.