Circulating fibroblast growth factor 21 level predicts the progression of diabetic nephropathy in patients with type 2 diabetes

Abstract

Objective: Fibroblast Growth Factor 21 (FGF21) is a metabolic hormone produced by the liver, but also expressed in the other tissues including the adipose tissues, pancreas and kidney. Beneficial effects on body weight, carbohydrate and lipids metabolism have been observed in animals treated with recombinant FGF21. However, paradoxical increases in circulating FGF21 levels are found in obesity and diabetes. Elevated levels are also found in patients with impaired renal function. Its correlation with urinary albumin excretion in patients with diabetic nephropathy, even in the stage of microalbuminuria, suggests it to be an early indicator of subclinical diabetic nephropathy. Here we investigate whether serum FGF21 level can be usefully employed in the prediction of disease progression in patients with diabetic nephropathy. Research Design and Methods: Baseline plasma FGF21 levels were measured with an ELISA in type 2 diabetic subjects, recruited from the Hong Kong West Diabetes Registry. The role of FGF21 in predicting chronic kidney disease (CKD) over a median follow-up of 4 years was analyzed using Cox regression analysis. CKD progression was defined as a deterioration in CKD staging and a 25% or greater drop in estimated glomerular filtration rate (eGFR) from baseline, as defined by International Society of Nephrology statements. Results: At baseline, serum FGF21 levels increased progressively with CKD staging (P for trend <0.001; n=1136). Amongst 1071 subjects with baseline CKD stage ≤ 3, serum FGF21 levels were significantly higher in those with CKD progression (n=171) during follow-up than those with no progression (n=900) (P<0.001). On multivariable Cox regression analysis, serum FG21 was independently associated with CKD progression (hazard ratio [HR]: 1.24; 95% CI: 1.05-1.47; P=0.012), after adjustment for age, duration of diabetes, hypertension, C-reactive protein and eGFR. Serum FGF21 remained an independent predictor of CKD progression in a subgroup of subjects with normoalbuminuria and CKD stage 1 or 2 at baseline (HR 1.4; 95% CI 1.04-1.88; p=0.028; n=559) Conclusions: Elevated FGF21 levels may represent a compensatory change to the metabolic derangement and renal injury in diabetic patients with renal disease and appear to be a useful biomarker for predicting disease progression in type 2 diabetic patients at early stages of diabetic nephropathy. Supported by: the Hong Kong Research Grant Council (CRF HKU 02/12R)