Intestinal phosphate transport: a therapeutic target in chronic kidney disease and beyond?

Abstract

Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD), contributing to the increased cardiovascular morbidity and mortality seen in this patient group. Results from retrospective studies suggest that small increases in serum phosphate concentration, within the normal or near-normal range, also correlate with increased cardiovascular morbidity and mortality and have led to the suggestion that detection and preventative treatment of positive phosphate balance is important in healthy individuals as well as in those with CKD. Phosphate homeostasis is maintained by the crosstalk between intestinal phosphate absorption and renal phosphate excretion; however, relatively little is known about the mechanisms of intestinal phosphate transport. Our current understanding is that the intestinal type II sodium phosphate cotransporter, NaPi-IIb, plays a significant role in absorption. It may also be involved in the sensing of dietary phosphate composition and the release of hormonal factors that modulate renal phosphate reabsorption to achieve phosphate balance. Interestingly, studies using NaPi-IIb knockout mice with adenine-induced CKD show only partial attenuation of hyperphosphatemia, suggesting that an additional sodium-independent pathway is involved in phosphate absorption. The aim of this review is to discuss our current knowledge of the processes and role of the intestine in phosphate homeostasis and to provide evidence that this organ could be targeted for the treatment of hypophosphatemia and hyperphosphatemia.

Importance of Dietary Phosphorus for Bone Metabolism and Healthy Aging

“…In conditions of abundant dietary P i intake, 70% of intestinal P i uptake occurs primarily by passive paracellular diffusion, while only 30% occurs via sodium (Na + )-dependent, carrier-mediated transcellular transport [ 21 , 23 , 24 , 25 , 26 ]. However, in experimental animals, it is estimated that the two pathways contribute roughly equally to intestinal P i absorption [ 27 ].…”

Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability

“…NaPi2b has a high affinity for phosphate ( K M , 10 to 100 μM); thus, it is saturated under most dietary phosphate concentrations (3, 29). The type III sodium-dependent phosphate transporters PiT1 (SLC20A1) and PiT2 (SLC20A2) are also expressed in the intestine, although their contribution to intestinal phosphate absorption is limited, as shown by the minimal transcellular sodium-dependent phosphate uptake remaining in NaPi2b knockout (KO) mice (26, 27, 30, 31).…”

Intestinal Depletion of NaPi-IIb/Slc34a2 in Mice: Renal and Hormonal Adaptation

“…(12) There are also some indications for overexpression of NaPi-IIb in breast and epithelial ovarian cancers. (13,14) Absorption of dietary Pi occurs through a combination of passive and active transport processes across the intestinal epithelia (15) (for review see Lee and Marks (16) and Marks and colleagues (17) ). The intrinsic properties of NaPi-IIb parallel the kinetic and regulatory features of the active component: its expression is regulated by the dietary content of Pi as well as by the circulating levels of the steroid hormone 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), whereas its activity is reduced by high luminal pH.…”