scholarly journals Small Intestinal Phosphate Absorption: Novel Therapeutic Implications

2021 ◽  
pp. 1-9
Author(s):  
Jerry Yee ◽  
David Rosenbaum ◽  
Jeffrey W. Jacobs ◽  
Stuart M. Sprague
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Paracellular Pathway ◽  
Phosphate Binders ◽  
Phosphate Absorption ◽  
Therapeutic Implications ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Dietary Phosphate ◽  
Intestinal Phosphate Absorption

<b><i>Background:</i></b> Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention and, eventually, hyperphosphatemia. As hyperphosphatemia is associated with numerous adverse outcomes, including increased cardiovascular mortality, reduction in phosphorus concentrations is a guideline-recommended, established clinical practice. Dietary phosphate restriction, dialysis, and phosphate binders are currently the only options for phosphate management. However, many patients with hyperphosphatemia have phosphorus concentrations &#x3e;5.5 mg/dL, despite treatment. <b><i>Summary:</i></b> This review pre­sents recent advances in the understanding of intestinal phosphate absorption and therapeutic implications. Dietary phosphate is absorbed in the intestine through two distinct pathways, paracellular absorption and transcellular transport. Recent evidence indicates that the paracellular route accounts for 65–80% of total phosphate absorbed. Thus, the paracellular pathway is the dominant mechanism of phosphate absorption. 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 SLC9A3 gene, and blocks paracellular phosphate absorption. <b><i>Key Messages:</i></b> Targeted inhibition of sodium-hydrogen exchanger 3 effectively reduces paracellular permeability of phosphate. Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease.

scholarly journals Intestinal phosphate absorption: The paracellular pathway predominates?

2019 ◽  
Vol 244 (8) ◽  
pp. 646-654 ◽  
Author(s):  
Matthew Saurette ◽  
R Todd Alexander
Keyword(s):  
Kidney Disease ◽  
Animal Studies ◽  
Western Diet ◽  
Phosphate Absorption ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Gradient Based ◽  
Intestinal Phosphate Absorption ◽  
Stage Renal Disease ◽  
End Stage

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.

Phosphate binders in patients with chronic kidney disease: Between the new and the old.

2019 ◽  
pp. 2-3
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Estimated Glomerular Filtration Rate ◽  
Chronic Kidney Disease Stage ◽  
Disease Stage ◽  
Phosphate Binders ◽  
Advanced Chronic Kidney Disease ◽  
Phosphate Retention ◽  
Stage 4 ◽  
Dietary Phosphate

Impaired phosphate excretion by the kidney leads to Hyperphosphatemia. It is an independent predictor of cardiovascular disease and mortality in patients with advanced chronic kidney disease (stage 4 and 5) particularly in case of dialysis. Phosphate retention develops early in chronic kidney disease (CKD) due to the reduction in the filtered phosphate load. Overt hyperphosphatemia develops when the estimated glomerular filtration rate (eGFR) falls below 25 to 40 mL/min/1.73 m2. Hyperphosphatemia is typically managed with oral phosphate binders in conjunction with dietary phosphate restriction. These drugs aim to decrease serum phosphate by binding ingested phosphorus in the gastrointestinal tract and its transformation to non-absorbable complexes [1].

scholarly journals Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats

2020 ◽  
Author(s):  
Andrew J. King ◽  
Jill Kohler ◽  
Cyra Fung ◽  
Zhengfeng Jiang ◽  
Allison Quach ◽  
...  
Keyword(s):  
Male Rats ◽  
Phosphate Binders ◽  
Phosphate Absorption ◽  
Phosphorus Excretion ◽  
Sevelamer Carbonate ◽  
Sodium Hydrogen Exchanger ◽  
Intestinal Phosphate Absorption ◽  
Urinary Phosphorus Excretion ◽  
Dose Levels ◽  
Nhe3 Inhibitor

The majority of patients with chronic kidney disease (CKD) receiving dialysis do not reach target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a non-binder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This pre-clinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-hour urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer (0-3% w/w). We also evaluated the effect of the addition of tenapanor or vehicle on 24-hour urinary phosphorus excretion to rats on a stable dose of sevelamer (1.5% w/w). When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose (1.5% w/w) reduced mean (±standard error of the mean) urinary phosphorus excretion by 42±3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37±6% (P < 0.05). While both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.

scholarly journals Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality

2021 ◽  
pp. 1-10
Author(s):  
Peter A. McCullough
Keyword(s):  
Calcium Acetate ◽  
Paracellular Pathway ◽  
Ferric Citrate ◽  
Morbidity And Mortality ◽  
Phosphate Binders ◽  
Phosphate Absorption ◽  
Phosphate Retention ◽  
Sevelamer Carbonate ◽  
Prescribing Information ◽  
Phosphate Control

<b><i>Background:</i></b> Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality. <b><i>Summary:</i></b> Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to &#x3c;5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels &#x3c;5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. <b><i>Key Messages:</i></b> Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.

scholarly journals Effects of Dietary Phosphate on Adynamic Bone Disease in Rats with Chronic Kidney Disease – Role of Sclerostin?

PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e79721 ◽  
Author(s):  
Juliana C. Ferreira ◽  
Guaraciaba O. Ferrari ◽  
Katia R. Neves ◽  
Raquel T. Cavallari ◽  
Wagner V. Dominguez ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Bone Disease ◽  
Adynamic Bone Disease ◽  
Dietary Phosphate ◽  
Adynamic Bone
Sign in / Sign up

Export Citation Format

Share Document