Episode Description:
Fibroblast Growth Factor 23 (FGF23) is a phosphaturic hormone secreted by osteocytes and osteoblasts. Its main physiological role is to regulate phosphate homeostasis and vitamin D metabolism. Under normal conditions, FGF23 promotes renal excretion of phosphate and suppresses the activation of vitamin D, ensuring stable blood phosphate levels and limiting excessive dietary phosphate absorption. In Chronic Kidney Disease however FGF23 levels become abnormally elevated, leading to significant adverse outcomes, including accelerated CKD progression, cardiovascular complications, and increased mortality.
FGF23 interacts with its co-receptor, klotho, to bind fibroblast growth factor receptors in the kidneys, regulating phosphate balance by reducing renal phosphate reabsorption and active vitamin D production, which in turn limits intestinal phosphate absorption. It also suppresses parathyroid hormone secretion, contributing to mineral balance. In CKD, impaired kidney function leads to reduced phosphate excretion, causing phosphate retention and a compensatory overproduction of FGF23. This creates a cycle of phosphate retention and further FGF23 elevation.
Elevated FGF23 levels in CKD result from the kidneys’ reduced ability to excrete phosphate and are compounded by decreased klotho expression, impairing FGF23 signaling and contributing to toxic cardiovascular and renal effects. FGF23 also suppresses 1α-hydroxylase, reducing active vitamin D levels and disrupting calcium-phosphate balance, further exacerbating CKD complications.
One of the most severe consequences of elevated FGF23 in CKD is its cardiovascular impact. FGF23 is implicated in left ventricular hypertrophy (LVH) through direct activation of hypertrophic pathways in cardiomyocytes via FGFR4, independent of klotho. Elevated FGF23 also contributes to vascular calcification, worsened by chronic hyperphosphatemia, and impairs endothelial function, leading to arterial stiffness and increased cardiovascular risk. Studies consistently link elevated FGF23 with cardiovascular mortality in CKD patients.
FGF23 also accelerates CKD progression. High levels stimulate profibrotic signaling pathways, leading to tubulointerstitial fibrosis and renal decline. Increased markers of systemic inflammation associated with elevated FGF23 further aggravate renal injury. This interplay between FGF23, inflammation, and renal fibrosis creates a feedback loop that drives disease progression.
Addressing FGF23 dysregulation is a key therapeutic goal in CKD. Phosphate binders, such as sevelamer and lanthanum carbonate, reduce dietary phosphate absorption and indirectly lower FGF23 levels. Active vitamin D analogues suppress PTH and help regulate FGF23 but must be used cautiously to avoid hypercalcemia. Experimental treatments, such as FGF23-neutralizing antibodies, show promise in reducing LVH and inflammation in preclinical studies but require careful monitoring due to potential hyperphosphatemia. Therapies aimed at restoring klotho expression, including gene therapies and recombinant klotho protein, are also under investigation.
Renes Care Radio is a podcast designed for nephrology professionals, offering in-depth scientific explorations of key topics. It equips kidney care providers with the essential knowledge needed for advanced patient care.
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This podcast is for informational purposes only and is not intended to replace professional medical advice, diagnosis, or treatment.