Clinical Potential of Targeting Fibroblast Growth Factor-23 and αKlotho in the Treatment of Uremic Cardiomyopathy

Abstract

Chronic kidney disease is highly prevalent, affecting 10% to 15% of the adult population worldwide and is associated with increased cardiovascular morbidity and mortality. As chronic kidney disease worsens, a unique cardiovascular phenotype develops characterized by heart muscle disease, increased arterial stiffness, atherosclerosis, and hypertension. Cardiovascular risk is multifaceted, but most cardiovascular deaths in patients with advanced chronic kidney disease are caused by heart failure and sudden cardiac death. While the exact drivers of these deaths are unknown, they are believed to be caused by uremic cardiomyopathy: a specific pattern of myocardial hypertrophy, fibrosis, with both diastolic and systolic dysfunction. Although the pathogenesis of uremic cardiomyopathy is likely to be multifactorial, accumulating evidence suggests increased production of fibroblast growth factor-23 and αKlotho deficiency as potential major drivers of cardiac remodeling in patients with uremic cardiomyopathy. In this article we review the increasing understanding of the physiology and clinical aspects of uremic cardiomyopathy and the rapidly increasing knowledge of the biology of both fibroblast growth factor-23 and αKlotho. Finally, we discuss how dissection of these pathological processes is aiding the development of therapeutic options, including small molecules and antibodies, directly aimed at improving the cardiovascular outcomes of patients with chronic kidney disease and end-stage renal disease.

Keywords: FGF23; cardiorenal syndrome; fibroblast growth factor; growth factor; kidney; treatment; αKlotho.

Figure 1. Potential mechanisms of fibroblast growth factor‐23 (FGF23) signal transduction and signaling pathways.

Fibroblast growth factor‐23 (FGF23) acts on cells that constitutively express fibroblast growth factor receptor‐1 (FGFR1) and its coreceptor αKlotho. In cells that do not constitutively express αKlotho, such as cardiac myocytes and fibroblasts, circulating αKlotho is thought to perform a role similar to membrane‐bound αKlotho. Circulating FGF23 can also bind to other FGFR1 and other FGFR independently of αKlotho. In cardiac myocytes, this is thought to be FGFR4 predominantly. The binding of FGF23 to an FGFR1‐αKlotho complex activates MAPK (mitogen‐activated protein kinase), upregulating early growth response protein‐1 (EGR1), thereby modulating physiological gene expression. In the absence of αKlotho, FGF23 binding to either FGFR1 or FGFR4 activates phospholipase Cγ1 (PLCγ1), increasing intracellular calcium. This in turn activates calcineurin to dephosphorylate (P, in red) nuclear factor of activated T‐cells (NFAT), which induces pathophysiological gene transcription.

Figure 2. Dynamic interplay of fibroblast growth factor‐23–αKlotho axis.

Dietary phosphate (Pi) ingestion and absorption leads to osteocytes secreting fibroblast growth factor‐23 (FGF23). It is not clear how osteocytes detect circulating phosphate, but the sensing of calciprotein particles (nanoparticles consisting of calcium, phosphate, and fetuin A) has been proposed as a potential mechanism. Increased FGF23 leads to increased phosphate excretion by downregulating sodium‐dependent phosphate cotransporter IIa/c, via mitogen‐activated protein kinase signaling, in the renal proximal tubules expressing FGF‐receptor 1 (FGFR1) in an αKlotho‐dependent manner. In addition, FGF23 lowers renal vitamin D hydroxylation and decreases parathyroid hormone (PTH) secretion, both actions also being αKlotho‐dependent, reducing calcium entry into the circulation. In the context of reducing renal function, FGF23 production increases to compensate for reduced renal phosphate excretion, decreased activated vitamin D levels, and rising PTH secretion. High levels of circulating FGF23 have been implicated in the development of uremic cardiomyopathy through αKlotho‐independent mechanisms via either the FGFR1 or, more likely, FGFR4. Circulating αKlotho may mitigate some of the pathophysiological actions of FGF23 on the myocardium. However, the kidneys are the main source of circulating αKlotho and levels decrease with reducing renal function.