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

@article{Labont2015GastrointestinalIO,
  title={Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.},
  author={Eric D. Labont{\'e} and Christopher W. Carreras and Michael R. Leadbetter and K. Kozuka and Jill Kohler and Samantha Koo-McCoy and Limin He and Edward Dy and Deborah Black and Ziyang Zhong and Ingrid Langsetmo and Andrew G. Spencer and Noah Bell and Desiree Deshpande and Marc Navre and Jason Gustaf Lewis and Jeffrey W. Jacobs and Dominique Campbell Charmot},
  journal={Journal of the American Society of Nephrology : JASN},
  year={2015},
  volume={26 5},
  pages={
          1138-49
        }
}
In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in… Expand

Paper Mentions

Blog Post
Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability
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It is determined that tenapanor reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition. Expand
Small Intestinal Phosphate Absorption: Novel Therapeutic Implications
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Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease, and Tenapanor is a first-in-class, non-phosphate binder that inhibits the sodium-hydrogen exchanger 3 or solute carrier family 9 member 3 (SLC9A3) encoded by the SLC8A3 gene, and blocks parACEllular phosphate absorption. Expand
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Intestinal phosphate absorption: The paracellular pathway predominates?
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It is argued herein that the paracellular phosphate absorption route is the predominant pathway mediating intestinal phosphate absorption in humans consuming a “Western” diet. Expand
Pharmacological Npt2a Inhibition Causes Phosphaturia and Reduces Plasma Phosphate in Mice with Normal and Reduced Kidney Function.
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Npt2a inhibition causes a dose-dependent increase in phosphate, sodium and chloride excretion associated with reductions in plasma phosphate and PTH levels in normal mice and in a CKD mouse model. Expand
Control of phosphate balance by the kidney and intestine
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The regulation of type II sodium-dependent Pi co-transporters by the kidney and intestine is described, including the regulation of Pi transport, circadian rhythm, and the vicious circle between salivary Pi secretion and intestinal Pi absorption in animals with and without CKD. Expand
The importance of intake: a gut feeling.
TLDR
Even if the tenapanor-induced reduction in sodium adsorption is limited in humins, combination ofTenapanor therapy with diuretics may be an interesting option in selected patients. Expand
Targeting Gastrointestinal Transport Proteins to Control Hyperphosphatemia in Chronic Kidney Disease
TLDR
The latest preclinical and clinical data for two candidates in this novel drug class are reviewed: tenapanor, a small-molecule inhibitor of the sodium/hydrogen ion-exchanger isoform 3, and nicotinamide, an inhibitor of sodium–phosphate-2b cotransporters. Expand
Mechanisms and Regulation of Intestinal Phosphate Absorption.
TLDR
Physiologically, the contribution of NaPi-IIb to the maintenance of phosphate balance appears to be mostly relevant during periods of low phosphate availability, and its role in individuals living in industrialized societies with high phosphate intake is probably less relevant. Expand
Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD.
TLDR
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 andFGF23 levels that will be tested in the COMBINE Study. Expand
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References

SHOWING 1-10 OF 41 REFERENCES
Sevelamer hydrochloride attenuates kidney and cardiovascular calcifications in long-term experimental uremia.
TLDR
In long-term experimental CRF, treatment with the phosphate-binder sevelamer attenuates vascular and kidney calcification and causes less deterioration in renal function with an associated lower serum creatinine, higher Creatinine clearance, and less proteinuria. Expand
The treatment of hyperphosphataemia in CKD: calcium-based or calcium-free phosphate binders?
  • M. Cozzolino, S. Mazzaferro, V. Brandenburg
  • Medicine
  • Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
  • 2011
TLDR
In the light of overall rather disappointing results of interventional trials in patients with end-stage renal disease (ESRD), the idea that primary prophylaxis may be promising is fascinating and a more integrative and translational approach to this crucial question is suggested. Expand
PHOSPHORUS METABOLISM AND MANAGEMENT IN CHRONIC KIDNEY DISEASE: Phosphate Metabolism in the Setting of Chronic Kidney Disease: Significance and Recommendations for Treatment
TLDR
Among predialysis patients with chronic kidney disease (CKD), phosphaturic hormones enhance renal PO4 excretion to maintain serum PO4 levels within the high‐normal laboratory range, and suggests treatment strategies for moderating serumPO4 levels. Expand
The role of the gastrointestinal tract in phosphate homeostasis in health and chronic kidney disease
TLDR
It is suggested that consumption of processed foods containing phosphate preservatives may lead to excessive phosphate exposure, toxicity, and cardiovascular disease in the general population, as well as in patients with declining renal function, and establishing more effective ways of targeting the intestine to limit dietary phosphate absorption could have wide-reaching health benefits. Expand
Latest findings in phosphate homeostasis.
TLDR
The role played by the FGF23-klotho axis in phosphate homeostasis and its involvement in the pathophysiology of phosphate disturbances in chronic kidney disease is described. Expand
Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy?
TLDR
Prospective and long-term studies are necessary to confirm the effects of sevelamer on serum FGF23 and the benefits of this decrease on outcomes and the positive effects of early prescription of phosphate binders on PTH control. Expand
Phosphate in early chronic kidney disease: Associations with clinical outcomes and a target to reduce cardiovascular risk
TLDR
The epidemiological and experimental evidence highlighting the relationship between excess phosphate and adverse outcomes, and the clinical studies required to address this problem are outlined, are outlined. Expand
Effects of phosphate binders in moderate CKD.
TLDR
In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. Expand
Lanthanum Carbonate Reduces Urine Phosphorus Excretion: Evidence of High-Capacity Phosphate Binding
TLDR
Evidence suggests that LC is a very effective phosphate binder in terms of binding per tablet, and the amount of reduction of dietary phosphate absorption by LC is estimated. Expand
Intestinal Inhibition of the Na+/H+ Exchanger 3 Prevents Cardiorenal Damage in Rats and Inhibits Na+ Uptake in Humans
TLDR
An inhibitor of intestinal NHE3 reduces absorption of dietary sodium in rats and humans and prevents salt-induced cardiorenal injury in nephrectomized rats and suggests that therapeutic alteration of sodium transport in the gastrointestinal tract instead of the kidney could lead to improved sodium management in renal disease. Expand
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