Uremic Cardiomyopathy: A New Piece in the Chronic Kidney Disease-Mineral and Bone Disorder Puzzle

Abstract

Cardiovascular diseases are the main cause of death in chronic kidney disease (CKD) patients. In dialysis patients, sudden cardiac death accounts for 40% of all deaths. In these patients, sudden cardiac death is usually secondary to an underlying cardiomyopathy, which is clinically identified by the high prevalence of left ventricular hypertrophy and the resultant mechanical and electrical dysfunction. CKD-related cardiomyopathy has a multifactorial pathophysiology. Recent evidence has highlighted the central pathophysiological role of chronic kidney disease-mineral and bone disorder (CKD-MBD) with hyperphosphatemia and high fibroblast growth factor 23 (FGF23) levels in these patients. Further, since CKD is known to be an αKlotho deficiency state, experimental studies have demonstrated that the deleterious effects of FGF23 can be minimized by reestablishing adequate soluble Klotho levels. Herein, we present a review that addresses not only the development of the understanding of CKD-related cardiomyopathy pathophysiology, but also explores the recent data that identify the triad of hyperphosphatemia, high FGF23 levels and αKlotho deficiency as playing a central role on it. Taken together, the data suggest that the uremic cardiomyopathy can be considered a new piece in the CKD-DMO puzzle.

Keywords: FGF23; Klotho; chronic kidney disease; chronic kidney disease-mineral and bone disorder; uremic cardiomyopathy.

Figure 1

Schematic representation of sudden cardiac death pathophysiology in dialysis patients. Uremic cardiomyopathy serves as the arrhythmogenic substrate and triggers related to dialysis or cardiomyocyte metabolism may lead to a fatal arrhythmia.

Figure 2

Uremic Cardiomyopathy related factors. Beyond uremic toxins such as indoxil sulfate, marionobufagenin, β2-microglobulin and homocysteine and other CKD-related factors such as hypervolemia, hypertension, anemia, insulin resistance, inflammation and oxidative stress, the CDK-MBD has recently been stood out as major player related to uremic cardiomyopathy. IS, Indoxyl sulfate; MBG, Marionobufagenin; P, Phosphate; B2M, β2-Microglobulin; PTH, parathyroid hormone; FGF23, Fibroblast growth factor 23.

Figure 3

Schematic representation of how FGF23 can induce cardiomyocyte hypertrophy. The high circulating FGF23 levels in CKD patients can activate FGFR4 in cardiac myocytes and, through calcineurin/NFAT signaling pathway, activates cardiac remodeling genes, leading to hypertrophy and fibrosis. On the other hand, FGFR4 blockade by anti-FGFR4 can attenuate cardiac hypertrophy. FGF23, Fibroblast growth factor 23; FGFR4, type 4 Fibroblast growth factor 23 receptor; PLCγ, Phospholipase Cγ; NFAT, Nuclear factor of activated T-cells. Adapted from Grabner et al. (55).

Figure 4

Schematic representation of soluble klotho pleiotropic functions and FGF23 – sKlotho interactions. Soluble klotho can modulate several signaling pathways by receptor or soluble factor biding. In relation to circulating FGF23, soluble klotho can bind it and act in three different ways: First, as decoy receptor leading to FGF23 inactivation or excretion; second, as a bona fide co-receptor, favoring FGF23 biding to FGFR1c, and third, soluble klotho can also serve as a on demand co-receptor to FGFR1c on cardiomyocyte membrane, changing the signaling pathway through FGF23 can act on myocardium. FGF23, Fibroblast growth factor 23; FGFR4, Type 4 fibroblast growth factor receptor; NFAT, Nuclear factor of activated T-cells; FGFR1c, Type 1c fibroblast growth factor receptor; IGF1R, Insulin growth factor 1 receptor; TGFβRII, Type II transforming growth factor β.