An expert update on novel therapeutic targets for hyperphosphatemia in chronic kidney disease: preclinical and clinical innovations

Abstract

Introduction: The management of hyperphosphatemia in patients with chronic kidney disease (CKD) is complicated, requiring a multidisciplinary approach that includes dietary phosphate restriction, dialysis, and phosphate binders.Areas covered: We describe key players involved in regulating inorganic phosphate homeostasis and their differential role in healthy people and different stages of CKD. The contribution of paracellular and transcellular intestinal absorptive mechanisms are also examined. Finally, we illuminate recent therapeutic approaches for hyperphosphatemia in CKD. We searched PubMed/Medline (up to November 2019) using the following terms: chronic kidney disease, dialysis, diet, hyperphosphatemia, NaPi2b, nicotinamide, phosphate binder, secondary hyperparathyroidism, tenapanor and vascular calcification.Expert opinion: The precise mechanisms regulating intestinal phosphate absorption in humans is not completely understood. However, it is now established that this process involves two independent pathways: a) active transport (i.e. transcellular route, via specific ion transporters) and inactive transport (i.e. paracellular route across tight junctions). Dietary phosphate restriction and phosphate-binder use can lead to an undesirable maladaptive increase in phosphate uptake and promote active phosphate transport by increased expression of the gastrointestinal sodium-dependent phosphate transporter, NaPi2b. Nicotinamide may overcome these limitations through the inhibition of NaPi2b, by improved efficacy and reduced phosphate binder use and better compliance.

PF-06869206 is a selective inhibitor of renal Pitransport: evidence from in vitro and in vivo studies

“…Consistent with a minor role in renal P i reabsorption, Npt2c knockout does not impair P i homeostasis in mice but leads to disturbances in Ca 2ϩ homeostasis (46,55). In patients with late-stage CKD, hyperphosphatemia is common (17,19) and associated with increased PTH (20) and FGF-23 levels (28). This ultimately contributes to metabolic bone disease (31) and the progression of cardiovascular events including vascular calcification (50,63) and left ventricular hypertrophy (21,45).…”

Multidisciplinary Perspectives of Current Approaches and Clinical Gaps in the Management of Hyperphosphatemia

“…Important factors to consider when proposing dietary phosphate restriction include the source and bioavailability of the phosphate. 19 …”

“…Important factors to consider when proposing dietary phosphate restriction include the source and bioavailability of the phosphate. 19 Common sources of dietary phosphate include 1) organic phosphate in plant foods; 2) organic phosphate in animal protein; and 3) inorganic phosphate used to prolong shelf-life and to improve taste and texture in processed foods. 20 However, the amount of phosphate present does not necessarily reflect phosphate uptake as bioavailability varies according to the form and food source.…”

Coming out of the PiTs—novel strategies for controlling intestinal phosphate absorption in patients with CKD

“…Several established therapies as well as therapies currently in clinical test phases target intestinal phosphate absorption. 3,7 Although dietary phosphate restriction and several classes of phosphate binders aim at reducing available phosphate, novel therapies try decreasing trans-and paracellular Nicotinamide may also decrease renal NaPi-IIa expression. However, ASP-3325 given alone completely failed to alter serum phosphate levels, FGF23, or intestinal phosphate absorption in patients on hemodialysis.…”

“…In contrast, in patients on hemodialysis, nicotinamide together with phosphate binders was able to reduce serum phosphate (unpublished data from NoPhos phase III trial as shown during ERA-EDTA Congress 2019 and discussed here 7 ), as compared to patients receiving only standard care (including phosphate binders). 7 A different mode of action is used by tenapanor, an inhibitor of the sodiumproton exchanger isoform 3 (Na þ /H þexchanger NHE3), which reduces intestinal Na þ absorption. The drug leads, owing to NHE3 inhibition, to intracellular acidification, which in turn reduces paracellular phosphate fluxes.…”