Npt2a as a target for treating hyperphosphatemia

Hyperphosphatemia results from an imbalance in phosphate (P(i)) homeostasis. In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications. The current mainstays in the management of hyperphosphatemia are oral P(i) binder and dietary P(i) restriction. Although these options are employed in patients with chronic kidney disease (CKD), they seem inadequate to correct elevated plasma P(i) levels. In addition, a paradoxical increase in expression of intestinal P(i) transporter and uptake may occur. Recently, studies in rodents targeting the renal Na(+)/P(i) cotransporter 2a (Npt2a), responsible for ∼70% of P(i) reabsorption, have been proposed as a potential treatment option. Two compounds (PF-06869206 and BAY-767) have been developed which are selective for Npt2a. These Npt2a inhibitors significantly increased urinary P(i) excretion consequently lowering plasma P(i) and PTH levels. Additionally, increases in urinary excretions of Na(+), Cl(−) and Ca(2+) have been observed. Some of these results are also seen in models of reduced kidney function. Responses of FGF23, a phosphaturic hormone that has been linked to the development of left ventricular hypertrophy in CKD, are ambiguous. In this review, we discuss the recent advances on the role of Npt2a inhibition on P(i) homeostasis as well as other pleiotropic effects observed with Npt2a inhibition.