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Kidney360 Oct 2021Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia.
METHODS
In this 52-week phase 3 study (NCT03427125), participants receiving maintenance dialysis with both hyperphosphatemia (serum phosphate 6.0-10.0 mg/dl) and a 1.5 mg/dl increase after phosphate binder washout were randomized (3:1) to tenapanor 30 mg twice daily for 26 weeks (randomized treatment period) or sevelamer carbonate (52-week safety control). Participants completing 26 weeks of treatment with tenapanor were rerandomized (1:1) to tenapanor or placebo for 12 weeks (randomized withdrawal period), and were eligible to enter the 14-week safety extension period. With input from the US Food and Drug Administration, the primary efficacy end point was the difference in the change in serum phosphate from the end of the randomized treatment period to the end of the randomized withdrawal period, among participants who achieved ≥1.2 mg/dl decrease in serum phosphate during the randomized treatment period (efficacy analysis set). Efficacy was also evaluated in the intention-to-treat (ITT) analysis set.
RESULTS
Of 564 eligible participants randomized to receive tenapanor (=423) or sevelamer carbonate (=141) during the randomized treatment period, 255 (60%) in the tenapanor group subsequently were rerandomized to tenapanor (=128) or placebo (=127) during the randomized withdrawal period. In the efficacy analysis set (=131), the difference in estimated mean change in serum phosphate level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was -1.4 mg/dl (<0.0001); in the ITT analysis set (=243), the estimated mean difference was -0.7 mg/dl (=0.002). Loosened stools were the most frequently reported adverse event (53% during the randomized treatment period). Serious adverse events were reported more frequently for participants treated with sevelamer carbonate (16%-23% across the three study periods) compared with tenapanor (11%-17%).
CONCLUSIONS
Tenapanor reduced serum phosphate concentrations and maintained control of serum phosphate in participants receiving maintenance dialysis, with an acceptable safety and tolerability profile.
Topics: Humans; Isoquinolines; Phosphates; Renal Dialysis; Sulfonamides; United States
PubMed: 35372979
DOI: 10.34067/KID.0002002021 -
American Journal of Kidney Diseases :... Jan 2021Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney...
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<800-1,000mg of calcium daily, whereas CKD bone and mineral disorder guidelines do not provide clear targets, but<1,500mg 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.
Topics: Calcium; Chelating Agents; Clinical Trials as Topic; Humans; Hyperphosphatemia; Patient Care Management; Phosphates; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 32771650
DOI: 10.1053/j.ajkd.2020.05.025 -
The Cochrane Database of Systematic... Aug 2018Phosphate binders are used to reduce positive phosphate balance and to lower serum phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Phosphate binders are used to reduce positive phosphate balance and to lower serum phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of chronic kidney disease-mineral and bone disorder (CKD-MBD). This is an update of a review first published in 2011.
OBJECTIVES
The aim of this review was to assess the benefits and harms of phosphate binders for people with CKD with particular reference to relevant biochemical end-points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD of any GFR category comparing a phosphate binder to another phosphate binder, placebo or usual care to lower serum phosphate. Outcomes included all-cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum phosphate, parathyroid hormone (PTH), and FGF23.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random-effects meta-analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes.
MAIN RESULTS
We included 104 studies involving 13,744 adults. Sixty-nine new studies were added to this 2018 update.Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron-based binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)-oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow-up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty-seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty-one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium-based phosphate binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron-based binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron-based binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all binders were uncertain.In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium-based binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow-up of up to 36 months, compared to calcium-based binders. Compared with calcium-based binders, lanthanum had uncertain effects with respect to all-cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment-related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head-to-head studies of iron-based binders compared with calcium. The paucity of placebo-controlled studies in CKD G5D has led to uncertainty about the effects of phosphate binders on patient-important outcomes compared with placebo.It is uncertain whether the effects of binders on clinically-relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses.
AUTHORS' CONCLUSIONS
In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium-based binders and incur less treatment-related hypercalcaemia, while we found no clinically important benefits of any phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of binders on patient-important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron-based phosphate binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron-based binders may lead to diarrhoea.
Topics: Adult; Aged; Calcium; Calcium Compounds; Cause of Death; Chelating Agents; Chronic Disease; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Progression; Fibroblast Growth Factor-23; Humans; Hypercalcemia; Iron Compounds; Lanthanum; Middle Aged; Parathyroid Hormone; Phosphorus; Polyamines; Randomized Controlled Trials as Topic; Renal Dialysis; Sevelamer
PubMed: 30132304
DOI: 10.1002/14651858.CD006023.pub3 -
Journal of the American Society of... Jun 2021Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of action-tenapanor, an inhibitor of paracellular phosphate absorption, and phosphate binders-is safe and effective for the management of hyperphosphatemia in patients receiving maintenance dialysis.
METHODS
This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperphosphatemia (defined in this trial as serum phosphorus 5.5-10 mg/dl inclusive) despite receiving phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4.
RESULTS
Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (-0.84 versus -0.19 mg/dl, <0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively.
CONCLUSIONS
A dual-mechanism treatment using both tenapanor and phosphate binders improved control of hyperphosphatemia in patients undergoing maintenance dialysis compared with phosphate binders alone.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
AMPLIFY, NCT03824587.
Topics: Adult; Aged; Chelating Agents; Diarrhea; Double-Blind Method; Drug Therapy, Combination; Female; Fibroblast Growth Factor-23; Humans; Hyperphosphatemia; Isoquinolines; Male; Middle Aged; Phosphorus; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer; Sodium-Hydrogen Exchanger 3; Sulfonamides
PubMed: 33766811
DOI: 10.1681/ASN.2020101398 -
Renal Failure Dec 2023This study was designed to examine the relative safety and efficacy of sevelamer in the treatment of chronic kidney disease (CKD) patients in comparison to placebo,... (Meta-Analysis)
Meta-Analysis Review
This study was designed to examine the relative safety and efficacy of sevelamer in the treatment of chronic kidney disease (CKD) patients in comparison to placebo, calcium carbonate (CC), or lanthanum carbonate (LC). The PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were searched for articles published through 18 June 2022. The quality of relevant studies was independently analyzed by two investigators who also extracted data from these manuscripts as per Cochrane Collaboration Handbook 5.3. The safety and efficacy of sevelamer as a treatment for hyperphosphatemia in CKD patients were then examined through a meta-analysis, with the primary patient-level outcomes of interest in this analysis being all-cause mortality and the incidence of gastrointestinal adverse effects. Vascular calcification score was also examined as an intermediate outcome, while serum biochemical parameters including levels of phosphate (P), calcium (Ca), intact parathyroid hormone (iPTH), lipids, C-reactive protein (CRP), or fibroblast growth factor-23 (FGF-23) were additionally assessed. In total, this meta-analysis incorporated data from 34 randomized controlled trials (RCTs) enrolling 2802 patients. Sevelamer was associated with reduced all-cause mortality (RR 0.28, CI 0.19 - 0.41, ) and Vessel calcification score (RR -0.58, CI -1.11 to -0.04, ) and induced less hypercalcemia (MD -0.28, CI 0.40 to -0.16, ) and hyperphosphatemia (MD -0.22, CI -0.32 to -0.13, ) when compared with Ca-based binders in CKD5D individuals. No significant differences in gastrointestinal adverse events (GAEs) incidence were observed. These data suggest that sevelamer may represent a beneficial means of protecting CKD patients against death and vessel calcification when used to treat hyperphosphatemia, while we found no clinically important benefits in decreasing gastrointestinal adverse effects.
Topics: Humans; Sevelamer; Hyperphosphatemia; Chelating Agents; Phosphates; Renal Insufficiency, Chronic; Renal Dialysis
PubMed: 37272189
DOI: 10.1080/0886022X.2023.2210230 -
Case Reports in Gastrointestinal... 2020Hyperphosphatemia is a common and well-described complication of end-stage renal disease. Despite strict dietary constraints and compliance, phosphate binders such as...
Hyperphosphatemia is a common and well-described complication of end-stage renal disease. Despite strict dietary constraints and compliance, phosphate binders such as calcium acetate and/or sevelamer carbonate are also needed to treat secondary hyperparathyroidism. This case vignette describes an underrecognized adverse effect of a phosphate binder, sevelamer carbonate, inducing colitis in a 47-year-old male with insulin-dependent diabetes complicated by end-stage renal disease. He presented for recurrent abdominal pain with associated nausea and was found to have multiple circumferential lesions on computed tomography including distal ascending, transverse, and proximal descending colon. Colonoscopy demonstrated nearly obstructing lesions worrisome for colonic ischemia or inflammatory bowel disease. Pathological review of histology demonstrated ragged colonic mucosa with ulcerative debris and nonpolarizing crystalline material at the sites of ulceration, morphologically consistent with the phosphate binder, sevelamer carbonate. Sevelamer carbonate was discontinued, and the patient was transitioned to calcium carbonate with strict dietary restrictions. His symptoms improved with the cessation of sevelamer, and he was subsequently discharged home. He eventually underwent renal transplant without redevelopment of symptoms. Recognition of this underreported complication of sevelamer carbonate, phosphate binder, is of utmost importance in directing appropriate therapy with cessation of this medication in the setting of gastrointestinal complaints or more specifically enteritis and colitis. Clinicians providing care to end-stage renal patients taking either sevelamer and/or sodium polystyrene sulfonate should have increased awareness of the possible gastrointestinal side effects.
PubMed: 32774946
DOI: 10.1155/2020/4646732 -
Frontiers in Cardiovascular Medicine 2021Sevelamer hydrochloride is a phosphate binder used to treat hyperphosphatemia in chronic kidney disease (CKD) patients that can reduce valvular and vascular...
Sevelamer hydrochloride is a phosphate binder used to treat hyperphosphatemia in chronic kidney disease (CKD) patients that can reduce valvular and vascular calcification. The aim of this study was to examine the effects of sevelamer treatment on calcification in bioprosthetic heart valves (BHVs). Wister rats were randomly divided into three groups according to sevelamer intake and implantation (sham-sham operation; implant-implantation and normal diet, implant+S implantation, and sevelamer diet). Two kinds of BHVs-bovine pericardium treated with glutaraldehyde (GLUT) or non-GLUT techniques-were implanted in rat dorsal subcutis at 4 weeks. After implantation, sevelamer was administered to the implant+S group. The animals were executed at days 0 (immediately after implantation), 7, 14, 28, and 56. Calcium levels were determined by atomic absorption spectroscopy and von Kossa staining. Serum biochemistry analysis, Western blotting, real-time quantitative polymerase chain reaction, alkaline phosphatase activity measurement, histopathologic analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were conducted to identify the anti-calcification mechanism of sevelamer. Non-GLUT crosslinking attenuates BHV calcification. Serum phosphate and calcium remained unreactive to sevelamer after a 14-day treatment. However, the mean calcium level in the implant+S group was significantly decreased after 56 days. In addition, the PTH level, inflammatory cell infiltration, system and local inflammation, and expression of Bmp2, Runx2, Alp, IL-1β, IL-6, and TNF-α were significantly reduced in the implant+S group. Sevelamer treatment significantly attenuated the calcification of BHVs and had anti-inflammation effects that were independent from serum calcium and phosphate regulation. Thus, sevelamer treatment might be helpful to improve the longevity of BHVs.
PubMed: 34660741
DOI: 10.3389/fcvm.2021.740038 -
Kidney International May 2009Hyperphosphatemia is an inevitable consequence of end-stage chronic kidney disease and is present in the majority of dialysis patients. Hyperphosphatemia is... (Review)
Review
Hyperphosphatemia is an inevitable consequence of end-stage chronic kidney disease and is present in the majority of dialysis patients. Hyperphosphatemia is observationally and statistically associated with increased cardiovascular mortality among dialysis patients. Dietary restriction of phosphate and current dialysis modalities are not sufficiently effective to maintain serum phosphate levels within the recommended range, so the majority of dialysis patients require oral phosphate binders. However, the benefits of achieving the recommended range have yet to be shown prospectively. Unfortunately, conventional phosphate binders are not reliably effective and are associated with a range of limitations and side effects. Aluminum-containing agents are highly efficient but no longer widely used because of proven toxicity. Calcium-based salts are inexpensive, effective, and most widely used, but there is now concern about their association with hypercalcemia and vascular calcification. Sevelamer hydrochloride is associated with fewer adverse effects, but a large pill burden and high cost are limiting factors to its wider use. Lanthanum carbonate is another non-aluminum, calcium-free phosphate binder. Preclinical and clinical studies have shown a good safety profile, and it appears to be well tolerated and effective in reducing phosphate levels in dialysis patients; however, it is similarly expensive. Data on its safety profile over 6 years of treatment are now published. Achievement of opinion-based guidelines appears to have become an end in itself. Dialysis patient outcomes are worse than outcomes for many types of cancer, yet prospective, outcome-based randomized controlled trials are not being undertaken for reasons that are difficult to explain.
Topics: Chelating Agents; Humans; Hyperphosphatemia; Lanthanum; Phosphates; Polyamines; Renal Dialysis; Sevelamer
PubMed: 19279554
DOI: 10.1038/ki.2009.60 -
Archives of Pathology & Laboratory... Dec 2021With the increasing development and use of iatrogenic agents, pathologists are encountering more novel foreign materials in retrieved gastrointestinal specimens. These...
CONTEXT.—
With the increasing development and use of iatrogenic agents, pathologists are encountering more novel foreign materials in retrieved gastrointestinal specimens. These colorful and unusual-appearing foreign materials can pose a diagnostic dilemma to those unaware of their morphology, especially if the relevant clinical history is lacking.
OBJECTIVE.—
To discuss the histopathologic features, clinical scenarios and significance, and differential diagnosis of relatively recently described, yet quickly expanding, family of iatrogenic agents that can present as foreign materials in gastrointestinal specimens-pharmaceutical fillers (crospovidone and microcrystalline cellulose), submucosal lifting agents (Eleview and ORISE), lanthanum carbonate, hydrophilic polymers, OsmoPrep, yttrium 90 microspheres (SIR-Sphere and TheraSphere), and resins (sodium polystyrene sulfonate, sevelamer, and bile acid sequestrants).
DATA SOURCES.—
We collate the findings of published literature, including recently published research papers, and authors' personal experiences from clinical sign-out and consult cases.
CONCLUSIONS.—
Correct identification of these iatrogenic agents is important because the presence of some novel agents can explain the histopathologic findings seen in the background specimen, and specific novel agents can serve as diagnostic clues to prompt the pathologist to consider other important and related diagnoses. Awareness of even biologically inert agents is important for accurate diagnosis and to avoid unnecessary and expensive diagnostic studies.
Topics: Acrylic Resins; Foreign Bodies; Humans; Iatrogenic Disease; Microspheres; Pharmaceutical Preparations
PubMed: 33571357
DOI: 10.5858/arpa.2020-0535-RA