The progressively increasing prevalence of the Metabolic Syndrome (MetS) has emerged as a major global health concern since the MetS is associated with an increased risk for cardiovascular morbidity and mortality. Central obesity represents a key feature of the MetS and is strongly related to all MetS comorbidities. Dysregulation of adipose tissue-derived proteins, so called adipokines, has been implied to partially contribute to these effects. Recently, fibroblast growth factor-21 (FGF-21) has been introduced as a novel insulin sensitizing and weight reducing adipokine with potential therapeutic properties. However, data on FGF-21 elimination are rather limited. Therefore, FGF-21 regulation in relation to renal function has been investigated in a patient population with chronic kidney disease (CKD, study population 1), as well as one with acute kidney impairment (study population 2). In study population 1 (n = 499), patients were distributed into five CKD subgroups according to estimated glomerular filtration rate (eGFR). Median FGF-21 serum concentrations progressively increased from CKD stage 1 to stage 5 and highest values of FGF-21 were detected in stage 5 (1: 86.4 ng/l; 2: 206.4 ng/l; 3: 289.8 ng/l; 4: 591.3 ng/l; 5: 1918.1 ng/l). Furthermore, eGFR remained the strongest predictor for FGF-21 levels in multivariate analysis. For study population 2 (n = 32), blood samples were obtained before elective unilateral partial or total nephrectomy, as well as within 30 hours after surgery. In this population FGF-21 levels significantly increased after surgery (325.0 ng/l) as compared to before surgery (255.5 ng/l). Furthermore, relative changes of FGF-21 were independently and positively predicted by relative changes of creatinine in this cohort. These results are in accordance with the hypothesis that FGF-21 is eliminated by the kidneys and that the extent of kidney dysfunction substantially contributes to serum FGF-21 levels. However, additional animal experiments and prospective clinical studies are needed to further elucidate the role of the kidneys in FGF-21 physiology.