Phosphate Absorption and Hyperphosphatemia Management in Kidney Disease: A Physiology-Based Review

Fishbane, Steven; Nigwekar, Sagar U.

doi:10.1016/j.xkme.2021.07.003

Cited by 11 publications

(5 citation statements)

References 67 publications

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“… 2 , 35 – 39 In brief, the transcellular absorption pathway uses specific phosphate transporters such as the sodium-dependent phosphate cotransporter 2b (NaPi2b) and type-III inorganic phosphate (Pi) transporters PiT-1 and PiT-2, whereas the paracellular pathway relies on the passive transport of phosphate through tight junction complexes between cells according to concentration gradients. 2 , 40 Because these therapies have different mechanisms of action from that of phosphate binders, there is hope that they will provide necessary therapeutic innovation.…”

Section: New Classes Of Phosphate Management Therapies Would Give Pat...mentioning

confidence: 99%

Managing Phosphate Burden in Patients Receiving Dialysis: Beyond Phosphate Binders and Diet

Kalantar-Zadeh,

Forfang,

Bakris

et al. 2023

Kidney360

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Most patients receiving dialysis rely on dietary restriction and phosphate binders to minimize the risk of hyperphosphatemia, which is associated with increased mortality. However, dietary restriction is difficult due to “hidden” phosphate additives in processed foods and medications. Restriction of dietary phosphate sources such as protein may increase the risk of malnutrition. Phosphate binders, the only pharmacologic option for phosphate management since aluminum salts were introduced several decades ago, are often insufficient for binding the 1,400-2,500 mg of phosphate potentially consumed daily. Over the last decade, serum phosphate levels in the US have risen and >69% of patients receiving dialysis exhibited a most recent phosphate level >4.5 mg/dL (above the normal range), indicating an urgent need for new, more effective therapies to manage phosphate burden. Novel, non-binder therapies such as transcellular and paracellular phosphate absorption inhibitors may be used for phosphate management, and future studies should examine whether they allow fewer dietary restrictions for patients receiving dialysis, potentially improving patient quality of life and nutritional status. It is imperative that we collaborate to move beyond the restrictive approaches available today and provide patients and clinicians with an array of strategies so that they may choose the most appropriate patient-centered therapy.

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Section: New Classes Of Phosphate Management Therapies Would Give Pat...mentioning

confidence: 99%

Managing Phosphate Burden in Patients Receiving Dialysis: Beyond Phosphate Binders and Diet

Kalantar-Zadeh,

Forfang,

Bakris

et al. 2023

Kidney360

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“…Tenapanor is a new phosphate-lowering agent which blocks paracellular phosphate absorption in the gut (but is awaiting FDA approval for this indication). It operates via the sodium-hydrogen exchanger (NHE3) and closes paracellular tight junctions [30]. Pergola et al proved the efficacy of tenapanor in the AMPLIFY study [31].…”

Section: ? Nak Atpasementioning

confidence: 99%

Disordered minerals and disease of soft tissue and bones in chronic kidney disease

Swanepoel

2023

AJN

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This article briefly reviews the mineral and bone disorder (MBD) found in patients with chronic kidney disease (CKD) and should provide a useful summary for trainees in nephrology and internal medicine. The storage of minerals is one of the principal roles of our bones, which are alive and are constantly being remodelled under the influence of vitamin D and parathyroid hormone (PTH), aided and abetted by calcium and phosphates. This occurs in a controlled fashion in healthy individuals. In patients with CKD, this control is lost and either an exaggerated, ineffectual remodelling takes place, resulting in the removal (in the case of high-turnover bone disease) or inadequate (in low-turnover bone disease) deposition of minerals. Vascular (and other soft tissue) calcification accompanies MBD, with phosphate and calcium playing major roles in the pathogenesis of the condition.

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“…Current strategies to treat hyperphosphatemia focus on reducing intestinal phosphate absorption to balance the decrease in renal phosphate excretion. Intestinal phosphate is absorbed through paracellular diffusion and active transporter mediated transcellular transport [13]. Currently available approaches to reduce intestinal phosphate absorption include restricting dietary phosphate content and the use of various phosphate binders.…”

Section: Introductionmentioning

confidence: 99%

“…However, these approaches have limitations, including the high phosphate content of a typical Western diet, limited binding capacity of phosphate binders, and poor patient compliance. As a result, the majority of dialysis patients are unable to maintain serum phosphate at desired levels [13].…”

Section: Introductionmentioning

confidence: 99%

Effect of an NHE3 inhibitor in combination with an NPT2b inhibitor on gastrointestinal phosphate absorption in Rodent models

Wang,

Yu,

Gavardinas

et al. 2024

PLoS ONE

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Many of the pathological consequences of chronic kidney disease can be attributed to an elevation in serum phosphate levels. Current therapies focused on decreasing intestinal phosphate absorption to treat hyperphosphatemia are inadequate. The most effective therapeutic strategy may be to target multiple absorptive pathways. In this study, the ability of a novel inhibitor of the intestinal sodium hydrogen exchanger 3 (NHE3), LY3304000, which inhibits paracellular, diffusional uptake of phosphate, to work in combination with an inhibitor of the active transporter, sodium dependent phosphate cotransporter 2b (NPT2b), LY3358966, was explored. LY3304000 modestly inhibited the acute uptake of phosphate into plasma of rats, while surprisingly, it doubled the rate of phosphate uptake in mice, an animal model dominated by NPT2b mediated acute phosphate uptake. In rats, LY3004000 and LY3358966 work in concert to inhibit acute phosphate uptake. On top of LY3358966, LY3304000 further decreased the acute uptake of phosphate into plasma. Studies measuring the recovery of radiolabeled phosphate in the intestine demonstrated LY3304000 and LY3358966 synergistically inhibited the absorption of phosphate in rats. We hypothesize the synergism is because the NHE3 inhibitor, LY3304000, has two opposing effects on intestinal phosphate absorption in rats, first it decreases diffusion mediated paracellular phosphate absorption, while second, it simultaneously increases phosphate absorption through the NPT2b pathway. NHE3 inhibition decreases proton export from enterocytes and raises the cell surface pH. In vitro, NPT2b mediated phosphate transport is increased at higher pHs. The increased NPT2b mediated transport induced by NHE3 inhibition is masked in rats which have relatively low levels of NPT2b mediated phosphate transport, by the more robust inhibition of diffusion mediated phosphate absorption. Thus, the inhibition of NPT2b mediated phosphate transport in rats in the presence of NHE3 inhibition has an effect that exceeds its effect in the absence of NHE3 inhibition, leading to the observed synergism on phosphate absorption between NPT2b and NHE3 inhibition.

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Phosphate Absorption and Hyperphosphatemia Management in Kidney Disease: A Physiology-Based Review

Cited by 11 publications

References 67 publications

Managing Phosphate Burden in Patients Receiving Dialysis: Beyond Phosphate Binders and Diet

Managing Phosphate Burden in Patients Receiving Dialysis: Beyond Phosphate Binders and Diet

Disordered minerals and disease of soft tissue and bones in chronic kidney disease

Effect of an NHE3 inhibitor in combination with an NPT2b inhibitor on gastrointestinal phosphate absorption in Rodent models

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