The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia

Block, Geoffrey A.; Rosenbaum, David P.; Yan, Andrew T.; Greasley, Peter J.; Chertow, Glenn M.; Wolf, Myles

doi:10.1093/ndt/gfy061

Cited by 30 publications

(21 citation statements)

References 40 publications

(56 reference statements)

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“…Tenapanor retains efficacy at high luminal phosphate concentrations, and this translates to reduced intestinal phosphate absorption in healthy humans. We have recently reported that tenapanor significantly reduces serum phosphate and FGF-23 in ESRD patients with hyperphosphatemia receiving dialysis (58, 59); further investigation is ongoing to determine whether tenapanor offers a new approach to serum phosphate control in the clinical setting (60, 61).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption. Because tenapanor also reduces intestinal phosphate absorption, it may have potential as a therapy for hyperphosphatemia. We investigated the mechanism by which tenapanor reduces gastrointestinal phosphate uptake, using in vivo studies in rodents and translational experiments on human small intestinal stem cell-derived enteroid monolayers to model ion transport physiology. We found that tenapanor produces its effect by modulating tight junctions, which increases transepithelial electrical resistance (TEER) and reduces permeability to phosphate, reducing paracellular phosphate absorption. NHE3-deficient monolayers mimicked the phosphate phenotype of tenapanor treatment, and tenapanor did not affect TEER or phosphate flux in the absence of NHE3. Tenapanor also prevents active transcellular phosphate absorption compensation by decreasing the expression of NaPi2b, the major active intestinal phosphate transporter. In healthy human volunteers, tenapanor (15 mg, given twice daily for 4 days) increased stool phosphorus and decreased urinary phosphorus excretion. We determined that tenapanor reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…89 Given that increases in intact FGF-23 accompanying CKD and hyperphosphatemia have deleterious effects, a secondary analysis of the phase 2 placebo-controlled, randomized clinical trial was carried out to assess the effect of tenapanor on FGF-23. 90 Following washout of Pi binders and four weeks of treatment with tenapanor, serum Pi and intact FGF-23 levels were significantly reduced. Further, the magnitude of reduction in FGF-23 was correlated to the magnitude of reduction of serum Pi levels.…”

Section: Introductionmentioning

confidence: 92%

Intestinal phosphate absorption: The paracellular pathway predominates?

Saurette

Alexander

2019

Exp Biol Med (Maywood)

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Hyperphosphatemia is nearly universal in patients with advanced chronic kidney disease and end stage renal disease. Given the considerable negative sequelae associated with hyperphosphatemia, i.e. increased cardiovascular disease, hastening of renal failure and death, reducing serum phosphate is a goal of therapy. In the absence of sufficient renal function, intestinal phosphate absorption is the remaining target to reduce plasma phosphate levels. Much work has been done with respect to understanding transcellular phosphate absorption. Both animal studies using inducible or intestinal NaPi-2b knockout mice and specific NaPi-2b inhibitors revealed this transporter as the primary mechanism mediating transcellular phosphate absorption in the intestine. However, this has not translated into effective phosphate lowering therapies in patients with kidney disease. More recently, it was observed that inhibition of the epithelial sodium hydrogen exchanger, sodium–hydrogen exchanger isoform 3 (NHE3), or its genetic deletion, decreases intestinal phosphate absorption. The mechanism mediating this effect is through increased transepithelial resistance and reduced paracellular phosphate permeability. Thus, NHE3 inhibition reduces paracellular phosphate permeability in the intestine. The transepithelial potential difference across intestinal epithelium is lumen negative and phosphate commonly exists as a divalent anion. Further, consumption of the typical Western diet provides a large lumen to blood phosphate concentration gradient. Based on these observations we argue herein that the paracellular phosphate absorption route is the predominant pathway mediating intestinal phosphate absorption in humans. Impact statement This review summarizes the work on transcellular intestinal phosphate absorption, arguing why this pathway is not the predominant pathway in humans consuming a “Western” diet. We then highlight the recent evidence which is strongly consistent with paracellular intestinal phosphate absorption mediating the bulk of intestinal phosphate absorption in humans.

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“…In short-term studies sponsored by the manufacturer, tenapanor shows reduction in serum phosphate levels over 8 weeks in patients receiving hemodialysis of~1 mg/ dL 61,62 and modest reductions in FGF-23 levels (by 10%-30%). [61][62][63] At the time of writing, only short-term studies are available and tenapanor remains experimental and in phase 3 studies. With the limited binding efficacy of many phosphate binders, particularly if taken incorrectly, 64 these treatments may be important adjuvants for phosphate control in the future.…”

Section: Beyond Binders In Phosphate Managementmentioning

confidence: 99%

State-of-the-Art Management of Hyperphosphatemia in Patients With CKD: An NKF-KDOQI Controversies Perspective

Scialla

Kendrick

Uribarri

et al. 2021

American Journal of Kidney Diseases

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Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney disease (CKD). In patients with CKD glomerular filtration rate category 3a (G3a) or worse, including those with kidney failure who are receiving dialysis, clinical practice guidelines suggest "lowering elevated phosphate levels towards the normal range" with possible strategies including dietary phosphate restriction or use of binders. Additionally, guidelines suggest restricting the use of oral elemental calcium often contained in phosphate binders. Nutrition guidelines in CKD suggest <800-1,000 mg of calcium daily, whereas CKD bone and mineral disorder guidelines do not provide clear targets, but <1,500 mg in maintenance dialysis patients has been previously recommended. Many different classes of phosphate binders are now available and clinical trials have not definitively demonstrated the superiority of any class of phosphate binders over another with regard to clinical outcomes. Use of phosphate binders contributes substantially to patients' pill burden and out-of-pocket costs, and many have side effects. This has led to uncertainty regarding the use and best choice of phosphate binders for patients with CKD or kidney failure. In this controversies perspective, we discuss the evidence base around binder use in CKD and kidney failure with a focus on comparisons of available binders.Complete author and article information provided before references.

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The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia

Cited by 30 publications

References 40 publications

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

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

Intestinal phosphate absorption: The paracellular pathway predominates?

State-of-the-Art Management of Hyperphosphatemia in Patients With CKD: An NKF-KDOQI Controversies Perspective

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