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

Abstract

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.

Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response

“…While these results are intriguing, more studies are needed to establish the connection between FGF proteins and diabetes complication development in T2D, as the data on this relationship remain scant. Here, those FGFs associated with diabetes complications showed a complex picture; FGF16 is cardioprotective 65 and therefore the decrease seen here in controls may be detrimental and, similarly, FGF20 is protective for renal function decline 76 and therefore its fall here may be detrimental. However, FGF23 elevation has been associated with increased cardiovascular disease events 79 and here was lower, suggesting a potential beneficial effect.…”

“…Baseline FGF20 was lower in T2D, at hypoglycaemia and throughout the post‐hypoglycaemia time course. FGF20 has been associated with protection against renal function and a decline in end stage renal disease 76 . The SomaScan platform was used for proteomic analysis in two longitudinal exploratory studies of patients with type 1 diabetes and T2D with CKD stage‐3 compared with those with normal renal function 76 .…”

“…FGF20 has been associated with protection against renal function and a decline in end stage renal disease 76 . The SomaScan platform was used for proteomic analysis in two longitudinal exploratory studies of patients with type 1 diabetes and T2D with CKD stage‐3 compared with those with normal renal function 76 . Data from that study suggested that ANGPT1, TNFRSF12 and FGF20 showed a strong, additive protective effect against decline in renal function.…”

“…A meta‐analysis of patients undergoing bariatric surgery revealed an increase in circulating levels of FGF19, implying a beneficial role post‐procedure. In patients with diabetes and impaired renal function, FGF20 has been associated with protection of renal function and a decline in end stage renal disease 76 . FGF23 has a role in phosphate, calcium and vitamin D homeostasis 77 and increased levels of FGF23 have been found in patients with chronic kidney disease (CKD) 78 .…”

The Multiple Roles of Fibroblast Growth Factor in Diabetic Nephropathy

“…Meanwhile, FGF20 can be used as biomarkers to predict the risk of DN progression to ESRD and delay or prevent ESRD. 131 FGF20 is selectively expressed in the brain and is almost absent in healthy peripheral tissues. There are few studies on it in the kidney, but some studies have found that FGF20 can maintain the stem cell characteristics of embryonic nephron progenitor cells and maintain normal kidney development.…”