Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD

Labonté, Eric D.; Carreras, Christopher W.; Leadbetter, Michael R.; Kozuka, Kenji; Kohler, Jill; Koo-McCoy, Samantha; He, Liyu; Dy, Edward; Black, Debra; Zhong, Ziyang; Langsetmo, I.; Spencer, Andrew; Bell, Noah; Deshpande, Desiree; Navre, Marc; Lewis, Jason G.; Jacobs, J. W.; Charmot, Dominique

doi:10.1681/asn.2014030317

Cited by 89 publications

(78 citation statements)

References 36 publications

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“…However, tenapanor is able to effectively reduce serum phosphate concentration, despite having no direct effect on NPT2b 23,24 and without directly binding intestinal phosphate. Studies in healthy volunteers and patients with CKD stage 5D have shown that tenapanor treatment increased stool sodium 23,25,26 and phosphorus 26 content, and concomitantly, it reduced urinary sodium 23,26 and phosphorus content, 26 consistent with reduced sodium and phosphate absorption.…”

Section: Discussionmentioning

confidence: 93%

“…Tenapanor acts in the gut to reduce the absorption of sodium and phosphate, with minimal systemic drug exposure. [23][24][25][26] In healthy volunteers, increases in stool phosphorus up to 14.2 mmol/d relative to placebo were observed with tenapanor dosing, with concomitant reductions in urinary phosphorus. 26 The mechanism by which tenapanor reduces GI phosphate uptake is under active investigation; it does not seem to involve direct inhibition of intestinal phosphate transporters type 1 or sodium-dependent phosphate transport protein 2B (NaPi2b, also known as NPT2b).…”

mentioning

confidence: 99%

“…26 The mechanism by which tenapanor reduces GI phosphate uptake is under active investigation; it does not seem to involve direct inhibition of intestinal phosphate transporters type 1 or sodium-dependent phosphate transport protein 2B (NaPi2b, also known as NPT2b). 24 Changes in intestinal and urinary phosphorus elimination seen in healthy volunteers suggested that tenapanor could have a role in treating hyperphosphatemia in patients with advanced CKD. The aim of this double-blind, placebo-controlled study was to assess the short-term safety, efficacy, and dose-response of tenapanor in patients with hyperphosphatemia receiving maintenance hemodialysis.…”

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confidence: 99%

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Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis

Block

Rosenbaum

Leonsson-Zachrisson

et al. 2017

JASN

110

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Hyperphosphatemia is common among patients with CKD stage 5D and is associated with morbidity and mortality. Current guidelines recommend lowering serum phosphate concentrations toward normal. Tenapanor is a minimally absorbed small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 that functions in the gut to reduce sodium and phosphate absorption. This randomized, double-blind, placebocontrolled trial assessed the effects of tenapanor on serum phosphate concentration in patients with hyperphosphatemia receiving hemodialysis. After a 1-to 3-week washout of phosphate binders, we randomly assigned 162 eligible patients (serum phosphate =6.0 to ,10.0 mg/dl and a 1.5-mg/dl increase from before washout) to one of six tenapanor regimens (3 or 30 mg once daily or 1, 3, 10, or 30 mg twice daily) or placebo for 4 weeks. The primary efficacy end point was change in serum phosphate concentration from baseline (randomization) to end of treatment. In total, 115 patients (71%) completed the study. Mean serum phosphate concentrations at baseline (after washout) were 7.32-7.92 mg/dl for tenapanor groups and 7.87 mg/dl for the placebo group. Tenapanor provided dose-dependent reductions in serum phosphate level from baseline (least squares mean change: tenapanor =0.47-1.98 mg/dl; placebo =0.54 mg/dl; P=0.01). Diarrhea was the most common adverse event (tenapanor =18%-68%; placebo =12%) and frequent at the highest tenapanor doses. In conclusion, tenapanor treatment resulted in statistically significant, dose-dependent reductions in serum phosphate concentrations in patients with hyperphosphatemia receiving hemodialysis. Additional studies are required to clarify the optimal dosing of tenapanor in patients with CKD-related hyperphosphatemia. 28: 193328: -194228: , 201728: . doi: https://doi.org/10.1681 Disorders of mineral metabolism are common among persons with CKD. 1 Impaired kidney function reduces urinary phosphate excretion, the principal mechanism by which normal phosphate balance is maintained. 2 Modulation of tubular reabsorption of phosphate, mediated in large part by parathyroid hormone (PTH) and the phosphatonin fibroblast growth factor 23 (FGF23), allows for maintenance of serum phosphate concentrations within a physiologic range, despite wide variation in phosphate intake on a day to day basis. However, in advanced CKD, dietary phosphate intake generally exceeds excretory capacity; for patients on dialysis, even with dietary phosphate restriction, hyperphosphatemia is almost inevitable without specific treatment. 3 Among patients receiving dialysis, evidence from observational studies, 1,4 retrospective database analyses, 5,6 and to a lesser extent, prospective controlled trials 7,8 has shown that hyperphosphatemia is associated with mortality, 1,4-6 fractures, 5 and cardiovascular disease, including vascular calcification 8 and left ventricular hypertrophy. 7 J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis

Block

Rosenbaum

Leonsson-Zachrisson

et al. 2017

JASN

110

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“…When an inhibitor of intestinal sodium-hydrogen exchanger-3 that also blocked dietary phosphate absorption 78 was administered to rats with CKD, it decreased urinary phosphate excretion, reduced serum phosphate and FGF23 levels, attenuated vascular calcification, and reduced heart mass. 79 Nicotinamide may also promote phosphaturia. Intra-peritoneal delivery of nicotinamide increased urinary phosphate excretion without changing urinary excretion of creatinine, potassium, sodium, calcium, or urinary flow rates in rats.…”

Section: Phosphate Bindersmentioning

confidence: 99%

Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD

Isakova

Sprague

et al. 2015

Journal of the American Society of Nephrology

123

127

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Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3-4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE study.

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“…A study has demonstrated that this compound is also able to reduce phosphate uptake and reduce ectopic calcification in an animal model of CKD. 150 These novel drugs, particularly in combination with established therapies such as phosphate binders, might contribute to the future management of dysregulated phosphate homeostasis in patients with CKD, and possibly also in renal transplant recipients.…”

Section: Pharmacologic Interventionsmentioning

confidence: 99%

Phosphate and FGF-23 homeostasis after kidney transplantation

Baia

Heilberg²,

Navis

et al. 2015

Nat Rev Nephrol

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Dysregulated phosphate metabolism is a common consequence of chronic kidney disease, and is characterized by a high circulating level of fibroblast growth factor (FGF)-23, hyperparathyroidism, and hyperphosphataemia. Kidney transplantation can elicit specific alterations to phosphate metabolism that evolve over time, ranging from severe hypophosphataemia (<0.5 mmol/l) to hyperphosphataemia (>1.50 mmol/l) and high FGF-23 levels. The majority of renal transplant recipients develop hypophosphataemia during the first 3 months after transplantation as a consequence of relatively slow adaptation of FGF-23 and parathyroid hormone levels to restored renal function, and the influence of immunosuppressive drugs. By 3-12 months after transplantation, phosphate homeostasis is at least partially restored in the majority of recipients, which is paralleled by a substantially reduced risk of cardiovascular-associated morbidity and mortality compared with the pre-transplantation setting. Many renal transplant recipients, however, exhibit persistent abnormalities in phosphate homeostasis, which is often due to multifactorial causes, and may contribute to adverse outcomes on the cardiovascular system, kidney, and bone. Dietary and pharmacologic interventions might improve phosphate homeostasis in renal transplant recipients, but additional insight into the pathophysiology of transplantation-associated abnormalities in phosphate homeostasis is needed to further optimize disease management and improve prognosis for renal transplant recipients.

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Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD

Cited by 89 publications

References 36 publications

Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis

Effect of Tenapanor on Serum Phosphate in Patients Receiving Hemodialysis

Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD

Phosphate and FGF-23 homeostasis after kidney transplantation

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