Sevelamer Carbonate | ScienceGate

Background: 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. Summary: 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 <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 <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]. Key Messages: 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.

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Effects of Sevelamer Carbonate on Advanced Glycation End Products and Antioxidant/Pro-Oxidant Status in Patients with Diabetic Kidney Disease

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.07750814 ◽

2015 ◽

Vol 10 (5) ◽

pp. 759-766 ◽

Cited By ~ 40

Author(s):

Elena M. Yubero-Serrano ◽

Mark Woodward ◽

Leonid Poretsky ◽

Helen Vlassara ◽

Gary E. Striker

Keyword(s):

Kidney Disease ◽

Advanced Glycation End Products ◽

Diabetic Kidney Disease ◽

Advanced Glycation ◽

Diabetic Kidney ◽

Sevelamer Carbonate ◽

Glycation End Products ◽

End Products ◽

Oxidant Status

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Sevelamer-associated ischemic colitis with perforation

Gastroenterology Insights ◽

10.4081/gi.2015.6116 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 4

Author(s):

Rachel Hudacko ◽

Peter Kaye

Keyword(s):

Ischemic Colitis ◽

End Stage Renal Disease ◽

Subtotal Colectomy ◽

Bowel Necrosis ◽

Drug Induced ◽

Colonic Injury ◽

Colonic Wall ◽

Sevelamer Carbonate ◽

Stage Renal Disease ◽

End Stage

We present a case of an 83-year-old woman with end-stage renal disease and hyperphosphatemia treated with sevelamer carbonate, who underwent subtotal colectomy for diffuse bowel necrosis and two perforations in the transverse colon. Histologic examination revealed ischemic colitis with crystals consistent with sevelamer carbonate embedded in ulcer debris and within the colonic wall in areas of transmural necrosis. This is a novel cause of drug-induced ischemic colitis with subsequent perforation that has not yet been reported in the literature. Clinicians and pathologists should be aware of the potential complications of sevelamer use and the histologic features of sevelamer-induced colonic injury.

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SEVELAMER CARBONATE MODULATES THE NLRP3 AND NLRP6 INFLAMMASOME EXPRESSION IN PATIENTS WITH DIABETIC NEPHROPATHY

Romanian Archives of Microbiology and Immunology ◽

10.54044/rami.2021.02.02 ◽

2021 ◽

Vol 80 (2) ◽

pp. 125-132

Author(s):

Grațiela Grădișteanu Pîrcălăbioru ◽

Mariana-Carmen Chifiriuc ◽

Roxana Adriana Stoica

Keyword(s):

Diabetic Nephropathy ◽

Nlrp3 Inflammasome ◽

Treatment Plan ◽

Innate Immune ◽

Pentraxin 3 ◽

Quantitative Real Time Pcr ◽

Blood Samples ◽

Sevelamer Carbonate

Interaction of microorganisms with the host innate immune system is a crucial factor that could modify diabetes and its associated complications. Recent reports have elucidated the role of NLRP3 inflammasome in diabetes, but to our knowledge there is no data regarding the role of other inflammasomes in diabetes-induced inflammation. To investigate this, blood samples were collected from type 2 diabetes (T2DM) patients with nephropathy as well as from healthy volunteers. After red blood cell lysis, RNA was isolated from all collected blood samples. The expression of NLRP 6, NLRP3, ASC, PRO-IL1Β, and PRO-IL18 was assessed by quantitative Real Time PCR (qRT-PCR). Patients with diabetic nephropathy showed higher NLRP3 inflammasome expression compared to healthy controls whereas no significant differences were observed in case of NLRP6 inflammasome. In addition, Pentraxin 3 expression was elevated in patients with diabetic nephropathy. A detailed analysis of the patient’s clinical data revealed the fact that subjects receiving sevelamer carbonate in their treatment plan harboured low expression of Pentraxin 3 (PTX3) and NLRP3 associated genes.

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Sevelamer Carbonate Reduces Inflammation and Endotoxemia in an Animal Model of Uremia

Blood Purification ◽

10.1159/000319850 ◽

2010 ◽

Vol 30 (3) ◽

pp. 153-158 ◽

Cited By ~ 19

Author(s):

Aline B. Hauser ◽

Iuly R.F. Azevedo ◽

Simone Gonçalves ◽

Andréa Stinghen ◽

Carlos Aita ◽

...

Keyword(s):

Animal Model ◽

Sevelamer Carbonate

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

AJP Renal Physiology ◽

10.1152/ajprenal.00137.2020 ◽

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.

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Short-term effects of sevelamer-carbonate on fibroblast growth factor 23 and pulse wave velocity in patients with normophosphataemic chronic kidney disease Stage 3

Clinical Kidney Journal ◽

10.1093/ckj/sfz027 ◽

2019 ◽

Vol 12 (5) ◽

pp. 678-685 ◽

Cited By ~ 5

Author(s):

Annet Bouma-de Krijger ◽

Frans J van Ittersum ◽

Tiny Hoekstra ◽

Pieter M ter Wee ◽

Marc G Vervloet

Keyword(s):

Chronic Kidney Disease ◽

Growth Factor ◽

Kidney Disease ◽

Pulse Wave Velocity ◽

Fibroblast Growth Factor ◽

Pulse Wave ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Short Term ◽

Sevelamer Carbonate

Abstract Background High concentrations of both phosphate and fibroblast growth factor 23 (FGF23) observed in chronic kidney disease (CKD) are associated with an increased risk of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a surrogate marker for cardiovascular events and all-cause mortality. It is not known whether a reduction of FGF23 or phosphate alters cardiovascular risk. Sevelamer has shown to have the ability to reduce both phosphate and FGF23 concentrations. Furthermore, reduction of PWV is reported with sevelamer use as well, but it is unclear if this is mediated by decline of phosphate or FGF23. We investigated if sevelamer induced a decline in PWV and if this was associated with a reduction in FGF23. Methods In all, 24 normophosphataemic CKD Stage 3 patients started treatment with a fixed dose of sevelamer-carbonate (Renvela®) 2.4 g twice daily, with their usual diet for 8 weeks in a single-arm study. PWV was measured and blood samples were obtained before, during and after washout of treatment with sevelamer. Vascular calcification was quantified using the Kauppila Index (KI). The primary outcome was the change of PWV from baseline to 8 weeks of treatment and the secondary endpoint was the difference of FGF23 following treatment with sevelamer. One of the linear mixed models was used to analyse the association between treatment and outcome. Mediation analysis was performed as a sensitivity analysis. The study was registered in the Dutch trial register (http://www.trialregister.nl: NTR2383). Results A total of 18 patients completed 8 weeks of treatment with sevelamer and were analysed. Overall, treatment with sevelamer did not induce a significant reduction of PWV (β = −0.36, P = 0.12). However, in patients with less vascular calcification (lower KI score), there was a statistically significant reduction of PWV, adjusted for mean arterial pressure, after treatment (β = 0.63, P = 0.02). Addition of FGF23 to the model did not alter this association. Mediation analysis yielded similar results. FGF23 did not decrease during treatment with sevelamer. Conclusion In this short-term pilot study in normophosphataemic CKD patients, treatment with sevelamer did not improve PWV. In subgroup analysis, however, PWV improved in patients with no or limited abdominal aorta calcifications. This was not associated with a decline of FGF23.

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The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial

Toxins ◽

10.3390/toxins11050279 ◽

2019 ◽

Vol 11 (5) ◽

pp. 279 ◽

Cited By ~ 3

Author(s):

Youssef Bennis ◽

Yan Cluet ◽

Dimitri Titeca-Beauport ◽

Najeh El Esper ◽

Pablo Ureña ◽

...

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Serum Levels ◽

Uremic Toxins ◽

In Vitro Experiments ◽

Double Blind ◽

Double Blind Placebo ◽

Ckd Stage ◽

Sevelamer Carbonate

High serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation of gut-derived uremic toxins. The aim of the present study was to evaluate the adsorptive effect of sevelamer carbonate on different gut-derived protein-bound uremic toxins or their precursors in vitro, and its impact on the serum levels of pCS, IS and IAA in patients with CKD stage 3b/4. For the in vitro experiments, IAA, p-cresol (precursor of pCS) and indole (precursor of IS), each at a final concentration of 1 or 10 µg/mL, were incubated in centrifugal 30 kDa filter devices with 3 or 15 mg/mL sevelamer carbonate in phosphate-buffered saline at a pH adjusted to 6 or 8. Then, samples were centrifuged and free uremic toxins in the filtrates were analyzed. As a control experiment, the adsorption of phosphate was also evaluated. Additionally, patients with stage 3b/4 CKD (defined as an eGFR between 15 and 45 mL/min per 1.73 m2) were included in a multicenter, double-blind, placebo-controlled, randomized clinical trial. The participants received either placebo or sevelamer carbonate (4.8 g) three times a day for 12 weeks. The concentrations of the toxins and their precursors were measured using a validated high-performance liquid chromatography method with a diode array detector. In vitro, regardless of the pH and concentration tested, sevelamer carbonate did not show adsorption of indole and p-cresol. Conversely, with 10 µg/mL IAA, use of a high concentration of sevelamer carbonate (15 mg/mL) resulted in a significant toxin adsorption both at pH 8 (mean reduction: 26.3 ± 3.4%) and pH 6 (mean reduction: 38.7 ± 1.7%). In patients with CKD stage 3b/4, a 12-week course of treatment with sevelamer carbonate was not associated with significant decreases in serum pCS, IS and IAA levels (median difference to baseline levels: −0.12, 0.26 and −0.06 µg/mL in the sevelamer group vs. 1.97, 0.38 and 0.05 µg/mL in the placebo group, respectively). Finally, in vitro, sevelamer carbonate was capable of chelating a gut-derived uremic toxin IAA but not p-cresol and indole, the precursors of pCS and IS in the gut. In a well-designed clinical study of patients with stage 3b/4 CKD, a 12-week course of treatment with sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS and IAA.

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