The FGF21-βKlotho endocrine axis in CKD
FGF21 is a hormone secreted from hepatocytes in response to various types of stress, such as fasting and inflammation. It binds to the βKlotho–FGFR1c complex and induces metabolic responses to fasting (i.e. lipolysis in adypocytes). FGF21 also crosses the blood-brain barrier and binds to βKlotho expressed in the suprachiasmatic nucleus activating the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis . Furthermore, FGF21 was reported to extend lifespan when overexpressed in mice, suggesting that the FGF–Klotho endocrine system has an effect on ageing processes .
Similarly to FGF23, serum levels of FGF21 also increase in patients with CKD, as early as in stage 2, and continue to rise as renal function declines. In dialysis patients, high FGF21 predicts high mortality. The osteopenia in FGF21-overexpressing transgenic mice is associated with decreased osteoblastogenesis and increased adipogenesis in the bone marrow, which may potentially contribute to the pathophysiology of CKD–MBD. Increased levels of FGF21 may also cause circadian rhythm disturbance, daily blood pressure fluctuations and depression. These symptoms are often seen in CKD patients .
The FGF19-βKlotho endocrine axis in CKD
FGF19 is a satiety hormone secreted by intestinal epithelial cells in response to primary bile acids (bile acids released from the liver) and secondary bile acids (primary bile acid metabolites produced by intestinal bacteria). FGF19 binds to the βKlotho–FGFR4 complex that is present on hepatocytes to suppress the expression of CYP7A1-gene, which encodes the rate-limiting enzyme of bile acid synthesis, cholesterol 7α-hydroxylase. Thus, the FGF19–βKlotho endocrine axis potentially affects the composition of the microbiome and vice versa. Although the connection between the FGF19–βKlotho endocrine axis and CKD is poorly understood, patients with CKD frequently show microbial imbalance in the gut and a blunted postprandial FGF19 response [3, 5].
Theory of calciprotein particles (CPPs) as a pathogen
When nephron number is decreased and FGF23 levels are increased in the context of CKD and ageing, the postprandial increase in serum inorganic phosphate levels is likely to be enhanced and prolonged. This rise in serum inorganic phosphate can potentially lead to the formation of calciprotein particles (CPPs), which are colloids comprised of deposits of calcium phosphate adsorbed onto serum protein fetuin A. CPPs can induce immune cell activation and trigger an inflammatory response, as well as contribute to arteriosclerosis by inducing vascular damage. In the vasculature, endothelial cell death and dysfunction is accompanied by osteoblastic transformation and calcification of smooth muscle cells.
As calcium phosphate nanocrystals can cause renal epithelial injury by inducing oxidative stress, the CKD associated with high FGF23 levels might be, at least in part, due to damage caused by calcium phosphate or CPPs that are generated in the proximal tubular fluid. The fact that serum CPP levels are correlated with vascular calcification/stiffness and mortality in CKD patients suggests that CPPs may serve as a ‘pathogen’ of cardiovascular complications (Figure 2) .