Modifying Phosphate Toxicity in Chronic Kidney Disease

Abstract

Phosphate toxicity is a well-established phenomenon, especially in chronic kidney disease (CKD), where hyperphosphatemia is a frequent occurrence when CKD is advanced. Many therapeutic efforts are targeted at phosphate, and comprise dietary intervention, modifying dialysis schemes, treating uncontrolled hyperparathyroidism and importantly, phosphate binder therapy. Despite all these interventions, hyperphosphatemia persists in many, and its pathological influence is ongoing. In nephrological care, a somewhat neglected aspect of treatment—when attempts fail to lower exposure to a toxin like phosphate—is to explore the possibility of “anti-dotes”. Indeed, quite a long list of factors modify, or are mediators of phosphate toxicity. Addressing these, especially when phosphate itself cannot be sufficiently controlled, may provide additional protection. In this narrative overview, several factors are discussed that may qualify as either such a modifier or mediator, that can be influenced by other means than simply lowering phosphate exposure. A wider scope when targeting phosphate-induced comorbidity in CKD, in particular cardiovascular disease, may alleviate the burden of disease that is the consequence of this potentially toxic mineral in CKD.

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

“…In addition, FGF23 suppresses the activation of vitamin D and acts to decrease parathyroid hormone synthesis and secretion being the major trigger in the path of CKD-MBD. FGF23 needs its cofactor klotho to ensure phosphate clearance [31]. Since the expression of Klotho declines in the kidney in the earlier stage CKD, FGF23 rises due to the resistance to FGF23 signaling in the kidney [31,32].…”

“…FGF23 needs its cofactor klotho to ensure phosphate clearance [31]. Since the expression of Klotho declines in the kidney in the earlier stage CKD, FGF23 rises due to the resistance to FGF23 signaling in the kidney [31,32]. Although renal α-Klotho levels were significantly reduced and serum FGF23 levels were significantly elevated they can maintain serum phosphate within the normal range in early and intermediate stages of CKD.…”

“…Elevated serum phosphate has revealed as a non-traditional risk factor for cardiovascular events in CKD and partially explains the increased mortality risk in CKD [29,31,32].…”

“…Vascular mineralization, especially affecting the coronary artery, is strongly related to mortality of CKD patients independently from the established atherogenic markers. The rate of coronary artery mineralization in CKD patients undergoing hemodialysis treatment was reported to be five times higher than in the non-dialysis CKD patients and is associated with features of valvular calcifications sharing the same changes [16,31,36]. Moreover, valvular heart disease is one of the most common complications observed in patients with CKD [37,38] and hyperphosphatemia directly affects progression of valvular calcification.…”

“…The difference remains that only PTH has an impact on increased serum calcium. While PTH receptor (PTH1R), is present in bone and kidney, the klotho coreceptor is only expressed in the kidney [7,31]. In addition, PTH stimulates calcitriol synthesis that further contributes to increased serum calcium, whereas FGF23 has an opposite effect on vitamin D and calcium.…”