Associations of Growth Differentiation Factor 15 in Chronic Kidney Disease

Anorexia is common in chronic kidney disease (CKD), yet the underlying mechanisms remain poorly defined. Growth differentiation factor-15 (GDF-15) suppresses appetite in cancer, where anti-GDF-15 therapy improves appetite.

NURTuRE-CKD is a prospective, multicentre cohort study of 2996 individuals with non-dialysis-dependent CKD. At baseline, circulating GDF-15 was measured and appetite was assessed using a questionnaire. Muscle function and estimated muscle mass were evaluated using handgrip strength (kg) and creatinine muscle index (estimated glomerular filtration rate [eGFR] cystatinC × serum creatinine). CKD progression (≥ 40% decline in eGFR, incident eGFR < 15 ml/min per 1.73 m², or dialysis initiation) and all-cause mortality were ascertained longitudinally. Multivariable logistic regression evaluated associations between GDF-15 and poor appetite, adjusting for eGFR, urea, nutritional and metabolic markers, CRP, comorbidities, and smoking. Cox models assessed associations with CKD progression (adjusted for Kidney Failure Risk Equation components) and all-cause mortality (additionally adjusted for CRP, comorbidities, and smoking).

GDF-15 was measured in 2929 participants. The median concentration was 2503 pg/ml (interquartile range 1605-3851). Participants with poor appetite (n = 786, 27%) had higher GDF-15 (2965 vs. 2,350 pg/ml; P < 0.001). In adjusted analyses, each doubling of GDF-15 was associated with higher odds of poor appetite (odds ratio [OR] 1.44, 95% CI 1.28-1.62). GDF-15 correlated negatively with handgrip strength (ρ = -0.18; P < 0.001) and creatinine muscle index (ρ= -0.40; P < 0.001), but not with body mass index. Over a median follow-up of 50 (41-56) months, 893 (32%) experienced CKD progression and 527 (18%) died. Adjusted hazard ratios per doubling of GDF-15 were 1.30 (95% CI, 1.18-1.42) for CKD progression and 1.72 (95% CI, 1.58-1.89) for all-cause mortality.

Among individuals with non-dialysis CKD, higher circulating GDF-15 concentrations were independently associated with poor appetite, sarcopenia markers, CKD progression, and all-cause mortality.