Plasma Growth Differentiation Factor-15 Independently Predicts All-Cause and Cardiovascular Mortality As Well As Deterioration of Kidney Function in Type 1 Diabetic Patients With Nephropathy

OBJECTIVE: Growth deferentiation factor-15 (GDF-15) is involved in inflammation and apoptosis. Expression is induced in the heart in response to ischemia and in atherosclerotic plaques. The aim of this study was to investigate GDF-15 levels in relation to all-cause mortality, cardiovascular mortality and morbidity, decline in glomerular filtration rate (GFR), and progression toward end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS: The study was a prospective observational follow-up study including 451 type 1 diabetic patients with diabetic nephropathy (274 men, aged 42.1 +/- 0.5 years means +/- SD, diabetes duration 28.3 +/- 8.9 years, GFR 76 +/- 33 ml/min/1.73 m(2)) and a control group of 440 patients with longstanding type 1 diabetes and persistent normoalbuminuria (232 men, aged 45.4 +/- 11.5 years, duration of diabetes 27.7 +/- 10.1 years). The patients were followed for 8.1 (0.0-12.9) years (median range). RESULTS: Among normoalbuminuric patients, GDF-15 above the median predicted an adjusted (age, systolic blood pressure sBP, and estimated GFR) increased risk of all-cause mortality (hazard ratio HR 3.6 95% CI 1.3-10.3; P = 0.014). Among patients with diabetic nephropathy, higher (fourth quartile) versus lower (first quartile) GDF-15 levels predict all-cause mortality (covariate-adjusted sex, age, smoking, blood pressure, A1C, cholesterol, GFR, N-terminal prohormone B-type natriuretic peptide, antihypertensive treatment, and previous cardiovascular events; HR 4.86 95% CI 1.37-17.30) as well as fatal and nonfatal cardiovascular events (adjusted HR 5.59 1.23-25.43 and 3.55 1.08-11.64, respectively). In addition, higher GDF-15 levels predict faster decline in GFR (P < 0.001) but not development of ESRD. CONCLUSIONS: Higher levels of GDF-15 are a predictor of all-cause and cardiovascular mortality and morbidity in patients with diabetic nephropathy. Furthermore, higher levels of GDF-15 are associated with faster deterioration of kidney function.