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Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD.

ABSTRACT: BACKGROUND AND OBJECTIVES:Metabolic acidosis is common in patients with CKD and has significant adverse effects on kidney, muscle, and bone. We tested the efficacy and safety of TRC101, a novel, sodium-free, nonabsorbed hydrochloric acid binder, to increase serum bicarbonate in patients with CKD and metabolic acidosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:One hundred thirty-five patients were enrolled in this randomized, double-blind, placebo-controlled, multicenter, in-unit study (designated the TRCA-101 Study). Patients had a mean baseline eGFR of 35 ml/min per 1.73 m2, a mean baseline serum bicarbonate of 17.7 mEq/L, and comorbidities, including hypertension (93%), diabetes (70%), and heart failure (21%). Patients ate a controlled diet and were treated for 14 days with placebo or one of four TRC101 dosing regimens (1.5, 3, or 4.5 g twice daily or 6 g once daily). After treatment, patients were discharged and followed for 7-14 days. RESULTS:All TRC101 treatment groups had a mean within-group increase in serum bicarbonate of ?1.3 mEq/L (P<0.001) within 72 hours of the first dose and a mean increase in serum bicarbonate of 3.2-3.9 mEq/L (P<0.001) at the end of treatment compared with placebo, in which serum bicarbonate did not change. In the combined TRC101 treatment group, serum bicarbonate was normalized (22-29 mEq/L) at the end of treatment in 35% of patients and increased by ?4 mEq/L in 39% of patients. After discontinuation of TRC101, serum bicarbonate decreased nearly to baseline levels within 2 weeks. All adverse events were mild or moderate, with gastrointestinal events most common. All patients completed the study. CONCLUSIONS:TRC101 safely and significantly increased the level of serum bicarbonate in patients with metabolic acidosis and CKD.

SUBMITTER: Bushinsky DA

PROVIDER: S-EPMC5753317 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD.

Bushinsky David A DA Hostetter Thomas T Klaerner Gerrit G Stasiv Yuri Y Lockey Claire C McNulty Sarah S Lee Angela A Parsell Dawn D Mathur Vandana V Li Elizabeth E Buysse Jerry J Alpern Robert R

Clinical journal of the American Society of Nephrology : CJASN 20171104 1

<h4>Background and objectives</h4>Metabolic acidosis is common in patients with CKD and has significant adverse effects on kidney, muscle, and bone. We tested the efficacy and safety of TRC101, a novel, sodium-free, nonabsorbed hydrochloric acid binder, to increase serum bicarbonate in patients with CKD and metabolic acidosis.<h4>Design, setting, participants, & measurements</h4>One hundred thirty-five patients were enrolled in this randomized, double-blind, placebo-controlled, multicenter, in-u ...[more]

PMID: 29102959

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Project description:BACKGROUND:Previous studies have shown that sodium bicarbonate ingestion may enhance intense exercise performance, but may also cause severe gastrointestinal distress. The purpose of this study was to determine whether a modified sodium bicarbonate (SB) ingestion protocol would elevate serum bicarbonate concentration more than previous methods without causing gastrointestinal distress. METHODS:In randomized order, seven (5 men, 2 women) elite middle-distance runners ingested either placebo, Modified SB (600?mg·kg-?1 over 19.5?h), or Acute SB (300?mg·kg-?1) in opaque gelatin capsules. Baseline and post-ingestion blood samples were analyzed for bicarbonate, pH, sodium, hematocrit, and lactate. Repeated measures ANOVA (2 time points ×?3 conditions) were analyzed to determine differences in serum bicarbonate, lactate, sodium, blood pH, and hematocrit. Gastrointestinal distress was assessed via self-report on a Likert scale of 1-10. Simple (condition) and repeated (time) within-participant contrasts were used to determine the location of any statistically significant main and interaction effects (p???0.05). RESULTS:Both Modified SB (7.6?mmol·L-?1, p?<?0.01) and Acute SB (5.8?mmol·L-?1, p?<?0.01) increased serum bicarbonate concentration compared to the placebo (p???0.05). Post-ingestion serum bicarbonate concentration was significantly higher for the Modified SB (34.7?±?2.2?mmol·L-?1, 28.0% increase) trials than the Acute SB (33.5?±?2.0?mmol·L-?1, 20.9% increase) trials (p?=?0.05). There was no reported severe GI distress in the Modified SB trials, but two cases in the Acute SB trials. CONCLUSIONS:Modified SB elevated serum bicarbonate concentration more than Acute SB, without any severe gastrointestinal side effects. Consequently, it is recommended that future experimentation involving SB by researchers and athletes use the novel ingestion protocol described in this study due to its potential for improved effectiveness and reduced gastrointestinal impact. TRIAL REGISTRATION:ClinicalTrials.gov , NCT03813329 . Registered 23 January 2019 - Retrospectively registered.

Project description:Background and objectivesStudies of adults have demonstrated an association between metabolic acidosis, as measured by low serum bicarbonate levels, and CKD progression. We evaluated this relationship in children using data from the Chronic Kidney Disease in Children study.Design, setting, participants, & measurementsThe relationship between serum bicarbonate and a composite end point, defined as 50% decline in eGFR or KRT, was described using parametric and semiparametric survival methods. Analyses were stratified by underlying nonglomerular and glomerular diagnoses, and adjusted for demographic characteristics, eGFR, proteinuria, anemia, phosphate, hypertension, and alkali therapy.ResultsSix hundred and three participants with nonglomerular disease contributed 2673 person-years of follow-up, and 255 with a glomerular diagnosis contributed 808 person-years of follow-up. At baseline, 39% (237 of 603) of participants with nonglomerular disease had a bicarbonate level of ≤22 meq/L and 36% (85 of 237) of those participants reported alkali therapy treatment. In participants with glomerular disease, 31% (79 of 255) had a bicarbonate of ≤22 meq/L, 18% (14 of 79) of those participants reported alkali therapy treatment. In adjusted longitudinal analyses, compared with participants with a bicarbonate level >22 meq/L, hazard ratios associated with a bicarbonate level of <18 meq/L and 19-22 meq/L were 1.28 [95% confidence interval (95% CI), 0.84 to 1.94] and 0.91 (95% CI, 0.65 to 1.26), respectively, in children with nonglomerular disease. In children with glomerular disease, adjusted hazard ratios associated with bicarbonate level ≤18 meq/L and bicarbonate 19-22 meq/L were 2.16 (95% CI, 1.05 to 4.44) and 1.74 (95% CI, 1.07 to 2.85), respectively. Resolution of low bicarbonate was associated with a lower risk of CKD progression compared with persistently low bicarbonate (≤22 meq/L).ConclusionsIn children with glomerular disease, low bicarbonate was linked to a higher risk of CKD progression. Resolution of low bicarbonate was associated with a lower risk of CKD progression. Fewer than one half of all children with low bicarbonate reported treatment with alkali therapy. Long-term studies of alkali therapy's effect in patients with pediatric CKD are needed.

Project description:Background and objectivesLarge, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the effect of anemia correction using erythropoiesis-stimulating agents may differ between CKD subpopulations. The Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease study, a multicenter, randomized, open-label, parallel-group study, aimed to examine the effect of targeting hemoglobin levels of 11-13 g/dl using darbepoetin alfa with reference to a low-hemoglobin target of 9-11 g/dl on kidney outcome in patients with advanced CKD without diabetes in Japan.Design, setting, participants, & measurementsWe enrolled 491 patients with CKD without diabetes, and an eGFR of 8-20 ml/min per 1.73 m2. Of these 491 patients, 239 and 240 were ultimately assigned to the high- and low-hemoglobin groups, respectively (12 patients were excluded). The primary outcome was a kidney composite end point (starting maintenance dialysis, kidney transplantation, eGFR≤6 ml/min per 1.73 m2, and 50% reduction in eGFR).ResultsMean hemoglobin levels were 11.2±1.1 and 10.0±0.9 g/dl in the high- and low-hemoglobin groups, respectively, during the mean study period of 73.5±29.7 weeks. The kidney composite end point occurred in 105 (44%) and 116 (48%) patients in the high- and low-hemoglobin groups, respectively (log-rank test; P=0.32). The adjusted Cox proportional hazards model showed that the hazard ratio for the high- versus low-hemoglobin group was 0.78 (95% confidence interval, 0.60 to 1.03; P=0.08). Cardiovascular events occurred in 19 (8%) and 16 (7%) patients in each group, respectively, with no significant between-group difference (log-rank test; P=0.66).ConclusionsTargeting a higher hemoglobin level (11-13 g/dl) with darbepoetin alfa did not improve kidney outcome compared with targeting a lower hemoglobin level (9-11 g/dl) in patients with advanced CKD without diabetes.Clinical trial registry name and registration numberPrevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease (PREDICT), NCT01581073.

Project description:BackgroundMany medications are formulated with acid salts. Their effect on acid-base balance in CKD is unclear.MethodsWe calculated the acid load (meq/d) from medications prescribed to 74 United States veterans with diabetes and CKD to identify agents with high potential acid load. We also determined cross-sectional associations between the acid load from medications and acid-base parameters after adjusting for demographics, eGFR, protein intake, and other confounders.ResultsOf the 125 medications prescribed, 31 (25%) contained an acid salt. Metformin hydrochloride (15.4 meq/d at 2550 mg/d) and gabapentin hydrochloride (13.0 meq/d at 2700 mg/d) were identified as agents with a high potential acid load. Mean daily acid load from medications was 6.6 meq/d in the overall cohort, 14.2 meq/d in the high medication acid load group (≥7.7 meq/d, n=29), and 1.6 meq/d in the low medication acid load group (<7.7 meq/d, n=45). After adjusting for potential confounders, those in the high acid load group had 1.7 meq/L lower total carbon dioxide (CO2) and 2.2 meq/L higher anion gap than those in the low acid load group. Use of gabapentin alone was not associated with differences in total CO2 or anion gap. Use of metformin alone was associated with 0.7 meq/L lower total CO2 and 1.0 meq/L higher anion gap. Use of metformin with gabapentin was associated with 1.8 meq/L lower total CO2 and 2.4 meq/L higher anion gap. The higher anion gap was not explained by higher serum lactate levels. The acid load from medications was not associated with differences in urinary ammonium, titratable acid, or pH.ConclusionsMedications containing acid salts, particularly metformin hydrochloride and gabapentin hydrochloride, are sources of an exogenous acid load. These agents may influence serum total CO2 levels and serum anion gap in individuals with CKD.Clinical trial registry name and registration numberInvestigations of the Optimum Serum Bicarbonate Level in Renal Disease, NCT01574157.

Project description:Aims/hypothesis: Dietary restriction (DR) reduces adiposity and improves metabolism in patients with one or more symptoms of the metabolic syndrome. Nonetheless, it remains elusive whether the benefits of DR in humans are mediated by calorie or nutrient restriction. This study was conducted to identify whether isocaloric dietary protein restriction is sufficient to confer the beneficial effects of dietary restriction in patients with metabolic syndrome. Methods: We performed a prospective, randomized controlled dietary intervention under constant nutritional and medical supervision. A total of 21 individuals diagnosed with the metabolic syndrome was randomly assigned for caloric restriction (CR; n = 11, mean age 49 ± 8.5 years, female 63%; diet of 5,941 ± 686 KJ per day) or isocaloric dietary protein restriction (PR; n = 10, mean age 51.6 ± 8.9 years, female 50%; diet of 8,409 ± 2,360 KJ per day) and followed for 27 days. Results: Like CR, PR promoted weight loss (-6.6%, P= 0.0041) due to reduction in adiposity (-9.9%, P= 0.0007), associated with reductions in blood glucose (-52.7%, P= 0.0002), lipid levels (cholesterol, -35.4%, P= 0.0010; triglycerides, -39.5% P= 0.0022) and blood pressure (systolic, -37.7 P< 0.0001; diastolic, -73.2% P< 0.0001). PR resulted in enrichment of metabolic pathways related to the immune system such as B cell proliferation, lymphocyte proliferation and leukocyte proliferation in subcutaneous adipose tissue. Hence, a reduction in calorie intake or changes in the gut microbiome are not necessary to confer the metabolic benefits of DR. Instead, a reduction in protein intake with a mild increase in carbohydrate intake to maintain the isocaloric balance of the diet is sufficient to improve metabolic control. Conclusions/interpretation: Protein restriction is sufficient to confer almost the same clinical outcomes as calorie restriction without the need for a reduction in calorie intake. The isocaloric characteristic of the PR intervention makes this approach a more attractive and less drastic dietary strategy in clinical settings and has greater potential to be used as adjuvant therapy for people with the metabolic syndrome.

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Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD.

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Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD.

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