Is there a role in acute kidney injury for FGF23 and Klotho?

Abstract

Cardio-renal syndrome is a clinical condition that has recently been well defined. In acute kidney disease, this interaction might trigger chronic processes determining the onset of cardiovascular events and the progression of chronic kidney disease. Moreover, the high mortality rate of acute kidney injury (AKI) is also linked to the fact that this condition is often complicated by dysfunctions of other organs such as lungs or heart, or is associated with septic episodes. In this context the role and the potential link between bone, heart and kidney is becoming an important topic of research. The aim of this review is to describe the cardiac alterations in the presence of AKI (cardiorenal syndrome type 3) and explore how bone can interact with heart and kidney in determining and influencing the trend of AKI in the short and long term. The main anomalies of mineral metabolism in patients with AKI will be reported, with specific reference to the alterations of fibroblast growth factor 23 and Klotho as a link between the bone-kidney-heart axis.

Keywords: CKDMBD; FGF23; Klotho; acute kidney injury; mineral metabolism.

Graphical Abstract

Figure 1:

Interconnection between AKI and heart function impairment. AKI triggers cardiac dysfunction through various pathophysiological mechanisms, including volume overload, electrolyte and acid–base imbalances, accumulation of uremic toxins, enhanced immune response and activation of sympathetic nervous system and RAAS. HF: heart failure, GFR: glomerular filtration rate; SNS: sympathetic nervous system.

Figure 2:

Effect on cardiomyocytes of kidney damage increased FGF23 levels and hypoxia. Kidney damage induces the production of NGAL and G-3-P, while an hypoxic milieu stimulates the production of DAMPs. Together these molecules induce the production of several pro-inflammatory cytokines by immune cells (IL-1, IL-6, TNF-α). This creates a pro-inflammatory environment which increases the production of NO and ROS and activates several transcription factor in cardiomyocytes, which lead to further production of pro-inflammatory mediators and TGF-β, which promotes further fibrosis and kidney damage. Moreover, in the context of renal hypoperfusion, as previously seen, there is an increase in SNS and RAAS activity. In addition, there is an increase in FGF23 levels, which binds directly on specific receptor on heart cells. These mechanisms act synergistically in augmenting intracellular Ca²⁺ levels by binding to RR and activating RR–CaMKII complex (especially FGF23), leading to calcium efflux from sarcoplasmic reticulum to cytoplasm. The increase in cytoplasmic calcium can lead to conduction abnormalities and predisposition to cardiac arrhythmias. FGF23 also contributes in increasing the synthesis of sarcomeric proteins, such as actin and myosin, thus inducing cardiac hypertrophy. DAMPs: damage-associated molecular pattern; G-3-P: galectin-3-phosphate; NGAL: neutrophil gelatinase-associated lipocalin; TGF-β: transforming growth factor β; Ald: aldosteron; MR: mineralcorticoid receptor; ATII: angiotensin II; AT-1: receptor for angiotensin II; NO: nitric oxide; ROS: reactive oxygen species; RR: ryanodine receptors.

Figure 3:

FGF23–Klotho effects on tubular absorption mechanisms. FGF23–Klotho signaling in the kidney. In proximal renal tubules, blood-borne FGF23 binds to a receptor complex consisting of FGFRs and αKlotho (Klotho), and activates a signaling cascade involving ERK1/2 and SGK1. SGK1 in turn phosphorylates NHERF-1, leading to internalization and degradation of NaPi-2a. FGF23-induced phosphorylation of NHERF-1 decreases the membrane abundance of NaPi-2a, and leads to increased urinary phosphate excretion. The FGF23 signaling–induced mechanisms downstream of ERK1/2 which suppress the transcription of 1α-hydroxylase in proximal renal tubules are unknown. In distal renal tubules, FGF23 circulating in blood binds to the FGFR–Klotho receptor complex, and activates ERK1/2, SGK1 and the WNK1/4 complex. Activation of WNK signaling increases the luminal membrane abundance of glycosylated TRPV5 and of NCC, leading to increased distal tubular calcium and sodium reabsorption. ERK 1/2: Extracellular signal-regulated kinases 1/2; SGK1: Serum and glucocorticoid‐inducible kinase 1; WNK 1/4: Lysine Deficient Protein Kinase 1/4; NHERF-1: sodium–hydrogen exchanger regulatory factor; TRPV5: Transient Receptor Potential Vanilloid 5; NCC: Na+–Cl^– cotransporter.