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Effect of Tenapanor on Interdialytic Weight Gain in Patients on Hemodialysis.

ABSTRACT: BACKGROUND AND OBJECTIVES:Interdialytic weight gain in patients on hemodialysis is associated with adverse cardiovascular outcomes and increased mortality. The degree of interdialytic weight gain is influenced by sodium intake. We evaluated the effects of tenapanor (AZD1722 and RDX5791), a minimally systemically available inhibitor of the sodium/hydrogen exchanger isoform 3, on interdialytic weight gain in patients with CKD stage 5D treated with hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:This phase 2, randomized, double-blind study (NCT01764854; conducted January to September of 2013) enrolled adults on maintenance hemodialysis with interdialytic weight gain ?3.0% of postdialysis weight and ?2 kg. Patients were randomly assigned (1:1) to receive tenapanor or placebo. The primary end point was change in mean interdialytic weight gain (percentage of baseline postdialysis weight) from baseline (mean across a 2-week run-in period) to week 4. In a subgroup of inpatients, 24-hour stool sodium and stool weight were assessed for 1 week. RESULTS:Sixteen patients received 1 week of inpatient treatment (tenapanor, eight; placebo, eight), and 72 patients received 4 weeks of treatment in an outpatient setting (tenapanor, 37; placebo, 35; completers: tenapanor, 31; placebo, 33). In the outpatient cohort, no significant effect on interdialytic weight gain was detected; least squares mean changes in relative interdialytic weight gain from baseline to week 4 were tenapanor, -0.26% (95% confidence interval, -0.57% to 0.06%) and placebo, -0.23% (95% confidence interval, -0.54% to 0.07%; P=0.46). During week 1 (inpatient cohort only), compared with placebo, tenapanor treatment resulted in higher stool sodium content (mean [±SD]: tenapanor, 36.6 [±21.8] mmol/d; placebo, 2.8 [±2.7] mmol/d; P<0.001) and higher stool weight (tenapanor, 172.5 [±68.1] g/d; placebo, 86.3 [±30.0] g/d; P<0.01). A similar safety profile was observed across treatment groups with the exception of diarrhea, which occurred more frequently with tenapanor treatment. CONCLUSIONS:Tenapanor treatment increased stool sodium and weight over placebo in patients undergoing hemodialysis. However, over 4 weeks of treatment, there was no difference in interdialytic weight gain between patients treated with tenapanor and those receiving placebo.

SUBMITTER: Block GA

PROVIDER: S-EPMC5012484 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Effect of Tenapanor on Interdialytic Weight Gain in Patients on Hemodialysis.

Block Geoffrey A GA Rosenbaum David P DP Leonsson-Zachrisson Maria M Stefansson Bergur V BV Rydén-Bergsten Tina T Greasley Peter J PJ Johansson Susanne A SA Knutsson Mikael M Carlsson Björn C BC

Clinical journal of the American Society of Nephrology : CJASN 20160623 9

<h4>Background and objectives</h4>Interdialytic weight gain in patients on hemodialysis is associated with adverse cardiovascular outcomes and increased mortality. The degree of interdialytic weight gain is influenced by sodium intake. We evaluated the effects of tenapanor (AZD1722 and RDX5791), a minimally systemically available inhibitor of the sodium/hydrogen exchanger isoform 3, on interdialytic weight gain in patients with CKD stage 5D treated with hemodialysis.<h4>Design, setting, particip ...[more]

PMID: 27340281

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Project description:Hypertension is common in hemodialysis patients; however, the relationship between interdialytic weight gain (IDWG) and blood pressure (BP) is incompletely characterized. This study seeks to define the relationship between IDWG and BP in prevalent hemodialysis subjects.This study used data from 32,295 dialysis sessions in 442 subjects followed up for 6 months in the Crit-Line Intradialytic Monitoring Benefit (CLIMB) Study.Mixed linear regression was used to analyze the relationship between percentage of IDWG (IDWG [%] = [current predialysis weight - previous postdialysis weight]/dry weight * 100) as the independent variable and systolic BP (SBP) and predialysis - postdialysis SBP (deltaSBP) as dependent variables.In unadjusted analyses, every 1% increase in percentage of IDWG was associated with a 1.00 mm Hg (95% confidence interval [CI], +/-0.24) increase in predialysis SBP (P < 0.0001), 0.65 mm Hg (95% CI, +/-0.24) decrease in postdialysis SBP (P < 0.0001), and 1.66 mm Hg (95% CI, +/-0.25) increase in deltaSBP (P < 0.0001). After controlling for other significant predictors of SBP, every 1% increase in percentage of IDWG was associated with a 1.00 mm Hg (95% CI, +/-0.24) increase in predialysis SBP (P < 0.0001) and a 1.08 mm Hg (95% CI, +/-0.22) increase in deltaSBP with hemodialysis (P < 0.0001). However, in subjects with diabetes as the cause of end-stage renal disease, subjects with lower creatinine levels, and older subjects, the magnitude of the association between percentage of IDWG and predialysis SBP was less pronounced. The magnitude of percentage of IDWG on deltaSBP was less pronounced in younger subjects and subjects with lower dry weights. Results were similar with diastolic BP.Hemodialysis BP measurements are imprecise estimates of BP and true hemodynamic burden in dialysis subjects.In prevalent hemodialysis subjects, increasing percentage of IDWG is associated with increases in predialysis BP and BP changes with hemodialysis; however, the magnitude of the relationship is modest and modified by other clinical factors. Thus, although overall volume status may impact on BP to a greater extent, day-to-day variations in weight gain have a modest role in BP increases in prevalent subjects with end-stage renal disease.

Project description:Although hemoglobin (Hb) levels are affected by a change in the body fluid status, the relationship between Hb levels and mortality while taking interdialytic weight gain (IDWG) at blood sampling into account has not yet been examined in hemodialysis patients.Cohort study.Data from the Miyazaki Dialysis cohort study, including 1375 prevalent hemodialysis patients (median age (interquartile range), 69 (60-77) years, 42.3% female).Patients were divided into 5 categories according to baseline Hb levels and two groups based on the median value of IDWG rates at blood sampling at pre-HD on the first dialysis session of the week.All-cause and cardiovascular mortalities during a 3-year follow-up.Hazard ratios were estimated using a Cox model for the relationship between Hb categories and mortality, and adjusted for potential confounders such as age, sex, dialysis duration, erythropoiesis-stimulating agent dosage, Kt/V, comorbid conditions, anti-hypertensive drug use, serum albumin, serum C-reactive protein, serum ferritin, and serum intact parathyroid hormone. Patients with Hb levels of 9-9.9 g/dL were set as our reference category.A total of 246 patients (18%) died of all-cause mortality, including 112 cardiovascular deaths. Lower Hb levels (<9.0g/dL) were associated with all-cause mortality (adjusted HRs 2.043 [95% CI, 1.347-3.009]), while Hb levels were not associated with cardiovascular mortality. When patients were divided into two groups using the median value of IDWG rates (high IDWG, ?5.4% and low IDWG, <5.4%), the correlation between lower Hb levels and all-cause mortality disappeared in high IDWG patients, but was maintained in low IDWG patients (adjusted HRs 3.058 [95% CI,1.575-5.934]). On the other hand, higher Hb levels (?12g/dL) were associated with cardiovascular mortality in high IDWG patients (adjusted HRs 2.724 [95% CI, 1.010-7.349]), but not in low IDWG patients.In hemodialysis patients, target Hb levels may need to be selected in consideration of IDWG at blood sampling.

Project description:BACKGROUND:Patients with chronic kidney diseases (CKD) on haemodialysis (HD) have high morbidity and mortality rates, which are also due to the inherent risks associated with nephropathy. Non-adherence (NA) to the different demands of the treatment can have consequences for the outcome of patients undergoing HD; nevertheless, there are still doubts about such repercussions. This study was conducted to evaluate the association between NA to conventional HD and all-cause mortality and cardiovascular mortality. METHODS:We prospectively evaluated mortality in a 6-year period in a cohort of 255 patients on HD in northeast Brazil. The evaluated parameters of NA to HD were interdialytic weight gain (IDWG)???4% of dry weight (DW), hyperphosphatemia and regular attendance at treatment, assessed as the correlation between the periods on HD completed and those prescribed. We used the Cox multivariate regression model to analyse survival and the predictors of all-cause mortality and cardiovascular mortality. RESULTS:With a median follow-up period of 1493?days and a mortality rate of 9.1 per 100 people-years, there were 87 deaths, of which 54% were cardiovascular deaths. IDWG ?4% of DW was associated with a risk of all-cause mortality however presenting a borderline outcome for cardiovascular mortality, with hazard ratios of 2.02 (CI 95% 1.17-3.49, p?=?0.012) and 2.09 (CI 95% 1.01-4.35, p?=?0.047), respectively. No significant association was found between other parameters of NA and mortality. Subgroup analysis showed that for patients with IDWG ?4% of DW, malnutrition, age and diagnosis of cardiovascular and cerebrovascular diseases were associated with higher all-cause mortality. CONCLUSIONS:IDWG ?4% of DW was identified as an independent predictor of all-cause mortality and demonstrated a borderline outcome for cardiovascular mortality in patients on conventional HD. The occurrence of excessive IDWG in the presence of malnutrition represented a significant increase in the risk of death, indicating a subgroup of patients with a worse prognosis.

Project description:IntroductionPhosphate binders are used to treat hyperphosphatemia. Some patients have inappropriately controlled serum phosphorus levels, which may occur for many reasons, including a high pill burden and adverse events (AEs). Tenapanor selectively inhibits the passive paracellular transfer of phosphate in the gastrointestinal tract, thereby reducing serum phosphorus levels. This novel mechanism of action may contribute to improved phosphate management. The efficacy and safety of tenapanor have not been evaluated in Japanese patients with high serum phosphorus levels despite treatment with phosphate binders. This study aimed to assess the efficacy and safety of add-on tenapanor therapy for reducing serum phosphorus levels in this population.MethodsThis multicenter, double-blind, randomized, placebo-controlled trial enrolled patients with refractory hyperphosphatemia undergoing hemodialysis. Patients were randomly assigned in a 1:1 ratio to receive tenapanor or placebo as an add-on to their phosphate binder regimen for 6 weeks. Change in serum phosphorus levels at week 6 (day 43) compared with the baseline value (day 1, week 0) (primary endpoint), achievement of target serum phosphorus levels (serum phosphorus level ≤6.0 or ≤5.5 mg/dL), and safety, based on all AEs and drug-related AEs, were among the outcomes evaluated.ResultsIn total, 24 patients were randomly assigned to the placebo group and 23 to the tenapanor group. The mean serum phosphorus level decreased from 7.01 mg/dL on day 1 to 6.69 mg/dL on day 43 in the placebo group and from 6.77 mg/dL on day 1 to 4.67 mg/dL on day 43 in the tenapanor group. In the placebo and tenapanor groups (modified intent-to-treat population), the mean (standard deviation) change in the serum phosphorus level at day 43 (last observation carried forward [LOCF]) was 0.08 (1.52) mg/dL and -1.99 (1.24) mg/dL, respectively, with a between-group difference of -2.07 (95% confidence interval: -2.89, -1.26; p < 0.001). The target achievement rate (serum phosphorus level ≤6.0 mg/dL at week 6 [LOCF]) was 37.5 and 87.0% in the placebo and tenapanor groups, respectively. Diarrhea was the most common drug-related AE, and it occurred in 8.3 and 65.2% of patients in the placebo and tenapanor groups, respectively. No specific AEs were observed with add-on tenapanor or with phosphate binders.Discussion/conclusionTherapy with existing phosphate binders and add-on tenapanor resulted in a significant decrease in serum phosphorus level compared with the placebo group in patients with refractory hyperphosphatemia despite treatment with phosphate binders. No new safety signals were raised, and add-on tenapanor was generally well tolerated.

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Effect of Tenapanor on Interdialytic Weight Gain in Patients on Hemodialysis.

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Effect of Tenapanor on Interdialytic Weight Gain in Patients on Hemodialysis.

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