Fibroblast growth factor 21 in chronic kidney disease

Abstract

Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF family that acts as a metabolic regulator of both glucose and lipid metabolism. Similar to fibroblast growth factor 23 (FGF23), serum FGF21 levels rise progressively with the loss of renal function, reaching 20 times normal values in end-stage renal disease. In patients with chronic kidney disease (CKD), higher serum FGF21 levels correlate with poorer metabolic profile, higher inflammatory markers, more comorbidities, and higher mortality. The high serum FGF21 levels are above and beyond what can be explained by the loss of FGF21 renal clearance, suggesting increased production and/or impaired non-renal clearance. In diabetic nephropathy, serum FGF21 levels correlate with the severity of albuminuria and faster loss of glomerular filtrate rate and can potentially be a biomarker of poor prognostic. The observational and associative human data contrast sharply with in vitro and in vivo preclinical experimental data, which is more in line with a protective role of FGF21 in chronic nephropathies. We here review the physiology of FGF21, and the literature regarding its behavior in CKD with particular focus on diabetic nephropathy. Finally, we speculate on the role of FGF21 in CKD.

Keywords: Chronic kidney disease; Diabetic nephropathy; FGF21.

Fig. 1

Physiological actions of FGF21. Free fatty acids stimulate FGF21 secretion by the liver. Circulating FGF21 acts mainly on white adipose tissue to stimulate glucose uptake, lipolysis, β-oxidation of fat and adiponectin secretion. Furthermore, FGF21 induces browning and thermogenesis. In the brain, FGF21 regulates the circadian cycle, increases release of corticotropin-releasing factor, sympathetic nerve activity, while decreasing the release of gonadotropin-releasing hormone. FGF21 can be inactivated by FAP cleavage and excreted into the urine

Fig. 2

FGF21 actions in pathophysiological situations. In fatty liver disease, FGF21 expression and secretion are increased and act in a paracrine loop reducing lipotoxicity and inflammation. In mitochondrial myopathies, skeletal muscles become a source of FGF21 acting in a paracrine loop that increases glucose uptake and β-oxidation. In cardiomyopathy or after acute myocardial infarction, FGF21 expression increases and protects cardiomyocytes through a paracrine loop increasing β-oxidation and autophagy, while it decreases lipotoxicity, inflammation and apoptosis. In diabetic nephropathy, FGF21 protects against lipotoxicity and inflammation, and reduces fibrosis. Fatty liver disease and mitochondrial myopathies increase serum FGF21 levels, but it is not known if cardiomyopathy, diabetes nephropathy and pancreatitis can do the same

Fig. 3

Mechanism of FGF21 elevation in chronic kidney disease. The loss of renal function contributes to decreased FGF21 clearance but probably not enough to explain the higher FGF21 levels in CKD patients. Beyond the liver, adipose tissue and skeletal muscles might become sources of FGF21 in CKD due to FGF21 resistance, insulin resistance, mitochondrial dysfunction, oxidative stress, inflammation, and actions of uremic toxins. Moreover, the FGF21 cleavage mediated by FAP might be altered in CKD

Fig. 4

Pathobiological significance of FGF21 elevation in CKD. Three models are proposed. Left panel: FGF21 elevation and adverse consequences in CKD are serendipitous and the correlation is by chance. FGF21 can still be a co-varying biomarker. Middle panel: High FGF21 is maladaptive and is a pathogenic intermediate that exacerbates outcomes in CKD. Right panel: High FGF21 is adaptive and alleviates outcomes in CKD but the compensation is not sufficient