Phosphate Balance and CKD-Mineral Bone Disease

Abstract

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a common comorbidity in patients with CKD. Characterized by laboratory abnormalities, bone abnormality, and vascular calcification, CKD-MBD encompasses a group of mineral and hormone disturbances that are strongly associated with increased cardiovascular (CV) morbidity and mortality. Abnormal serum phosphate concentrations are an independent risk factor for CV morbidity and mortality, and overall mortality. Phosphate retention plays a central role in initiating and driving many other disturbances in CKD-MBD (e.g., increased parathyroid hormone and fibroblast growth factor 23 concentrations, hypocalcemia, low vitamin D) that are also linked to increased CV risk. Thus, effective phosphate control is a logical therapeutic target for CKD-MBD treatment. Current phosphate management strategies (dietary restrictions, dialysis, phosphate binders) are insufficient to consistently achieve and maintain target phosphate concentrations in patients on dialysis. Phosphate binders reduce available phosphate for intestinal absorption but do not impair the dominant phosphate absorption pathway. Novel therapies that consider new mechanistic understandings of intestinal phosphate absorption are needed. One such therapy is tenapanor, a targeted sodium-hydrogen exchanger isoform 3 inhibitor that has been shown to reduce serum phosphate concentrations in multiple clinical trials. Tenapanor has a novel mechanism of action that reduces intestinal phosphate absorption in the primary paracellular phosphate absorption pathway.

Keywords: chronic kidney disease mineral bone disorder; fibroblast growth factor 23; hyperphosphatemia; parathyroid hormone; phosphate absorption; vascular calcification.

Figure 1

Physiology of chronic kidney disease (CKD)–mineral bone disorder (MBD). Phosphate retention leads to an increase of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels.^, FGF23 decreases the levels of calcitriol, leading to reduced absorption of calcium in the gastrointestinal tract. An association between reduced calcitriol and reduced intestinal phosphate absorption has been shown in animal models. Increased PTH leads to higher bone turnover, releasing calcium and phosphate,^, and increased FGF23 concentrations. Both FGF23 and PTH lead to increased calcium reabsorption as well as decreased phosphate reabsorption in the kidneys.^,, This, in turn, causes calcium concentrations to increase and inhibits phosphate retention.