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Effects of veverimer on serum bicarbonate and physical function in women with chronic kidney disease and metabolic acidosis: a subgroup analysis from a randomised, controlled trial.
Mathur, VS, Wesson, DE, Tangri, N, Li, E, Bushinsky, DA
BMC nephrology. 2022;(1):82
Abstract
BACKGROUND Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. METHODS This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial. RESULTS At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002). CONCLUSIONS Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018.
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Current Management of Hyperkalemia in Non-Dialysis CKD: Longitudinal Study of Patients Receiving Stable Nephrology Care.
Borrelli, S, De Nicola, L, Minutolo, R, Conte, G, Chiodini, P, Cupisti, A, Santoro, D, Calabrese, V, Giannese, D, Garofalo, C, et al
Nutrients. 2021;(3)
Abstract
BACKGROUND No study has explored the limitations of current long-term management of hyperkalemia (HK) in outpatient CKD clinics. METHODS We evaluated the association between current therapeutic options and control of serum K (sK) during 12-month follow up in ND-CKD patients stratified in four groups by HK (sK ≥ 5.0 mEq/L) at baseline and month 12: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). RESULTS We studied 562 patients (age 66.2 ± 14.5 y; 61% males; eGFR 39.8 ± 21.8 mL/min/1.73 m2, RAASI 76.2%). HK was "absent" in 50.7%, "resolving" in 15.6%, "new onset" in 16.6%, and "persistent" in 17.1%. Twenty-four hour urinary measurements testified adherence to nutritional recommendations in the four groups at either visit. We detected increased prescription from baseline to month 12 of bicarbonate supplements (from 5.0 to 14.1%, p < 0.0001), K-binders (from 2.0 to 7.7%, p < 0.0001), and non-K sparing diuretics (from 34.3 to 41.5%, p < 0.001); these changes were consistent across groups. Similar results were obtained when using higher sK level (≥5.5 mEq/L) to stratify patients. Mixed-effects regression analysis showed that higher sK over time was associated with eGFR < 60, diabetes, lower serum bicarbonate, lower use of non-K sparing diuretics, bicarbonate supplementation, and K-binder use. Treatment-by-time interaction showed that sK decreased in HK patients given bicarbonate (p = 0.003) and K-binders (p = 0.005). CONCLUSIONS This observational study discloses that one-third of ND-CKD patients under nephrology care remain with or develop HK during a 12-month period despite low K intake and increased use of sK-lowering drugs.
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Serum bicarbonate and cardiovascular events in hypertensive adults: results from the Systolic Blood Pressure Intervention Trial.
Dobre, M, Pajewski, NM, Beddhu, S, Chonchol, M, Hostetter, TH, Li, P, Rahman, M, Servilla, K, Weiner, DE, Wright, JT, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(8):1377-1384
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BACKGROUND Low serum bicarbonate level is associated with increased mortality, but its role as a predictor of cardiovascular disease (CVD) is unclear. This study evaluates the association between serum bicarbonate concentration and CVD and whether the effect of intensive blood pressure (BP) lowering on CVD outcomes is modified by serum bicarbonate level. METHODS The Systolic Blood Pressure Intervention Trial (SPRINT) randomized participants to a systolic BP target <120 mmHg (intensive treatment) or <140 mmHg (standard treatment). The primary CVD outcome was a composite of nonfatal myocardial infarction (MI), acute coronary syndrome not resulting in MI, stroke, acute decompensated heart failure and CVD death. Cox proportional hazards models adjusted for demographic, clinical and laboratory characteristics were used to evaluate the association of interest in 9334 SPRINT participants (ClinicalTrials.gov: NCT01206062). RESULTS Over a median follow-up of 3.33 years (interquartile range 2.87-3.87 years), 618 (6.6%) participants experienced a primary CVD outcome. Participants with serum bicarbonate <22 mEq/L had a significantly higher risk of the primary CVD outcome (hazard ratio 1.54; 95% confidence interval 1.11-2.14, P = 0.01), compared with participants with bicarbonate 22-26 mEq/L. The magnitude of the CVD risk reduction with intensive BP lowering was similar across bicarbonate strata (P-value for interaction = 0.97). CONCLUSIONS In hypertensive individuals, serum bicarbonate level <22 mEq/L was associated with an increased CVD risk. The effect of intensive BP lowering on CVD outcomes was not modified by the serum bicarbonate level.
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Clinical and cost-effectiveness of oral sodium bicarbonate therapy for older patients with chronic kidney disease and low-grade acidosis (BiCARB): a pragmatic randomised, double-blind, placebo-controlled trial.
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BMC medicine. 2020;(1):91
Abstract
BACKGROUND Chronic kidney disease with metabolic acidosis is common in older people, but the effectiveness of oral sodium bicarbonate therapy in this group is unclear. We tested whether oral sodium bicarbonate provides net health benefit for older people with advanced chronic kidney disease and serum bicarbonate concentrations < 22 mmol/L. METHODS Pragmatic multicentre, parallel group, double-blind, placebo-controlled randomised trial. We recruited adults aged ≥ 60 years with estimated glomerular filtration rate of < 30 mL/min/1.73 m2, not receiving dialysis, with serum bicarbonate concentration < 22 mmol/L, from 27 nephrology and geriatric medicine departments in the UK. Participants received oral sodium bicarbonate (up to 3 g/day) or matching placebo given for up to 2 years, randomised in a 1:1 ratio. The primary outcome was between-group difference in the Short Physical Performance Battery (SPPB) at 12 months, adjusted for baseline values, analysed by intention to treat. Secondary outcomes included generic and disease-specific quality of life (EQ-5D and KDQoL tools), anthropometry, renal function, walk distance, blood pressure, bone and vascular health markers, and incremental cost per quality-adjusted life year gained. RESULTS We randomised 300 participants between May 2013 and February 2017, mean age 74 years, 86 (29%) female. At 12 months, 116/152 (76%) participants allocated to bicarbonate and 104/148 (70%) allocated to placebo were assessed; primary outcome data were available for 187 participants. We found no significant treatment effect for the SPPB bicarbonate arm 8.3 (SD 2.5) points, placebo arm 8.8 (SD 2.2) and adjusted treatment effect - 0.4 (95% CI - 0.9 to 0.1, p = 0.15). We found no significant treatment effect for glomerular filtration rate (0.6 mL/min/1.73 m2, 95% CI - 0.8 to 2.0, p = 0.39). The bicarbonate arm showed higher costs and lower quality of life as measured by the EQ-5D-3L tool over 1 year (£564 [95% CI £88 to £1154]); placebo dominated bicarbonate under all sensitivity analyses. Adverse events were more frequent in those randomised to bicarbonate (457 versus 400). CONCLUSIONS Oral sodium bicarbonate did not improve physical function or renal function, increased adverse events and is unlikely to be cost-effective for use by the UK NHS for this patient group. TRIAL REGISTRATION European Clinical Trials Database (2011-005271-16) and ISRCTN09486651; registered 17 February 2012.
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Impact of the dialysate acid component on haemodialysis mortality rates.
Couchoud, C, Hannedouche, T, Bauwens, M, Ecochard, R, Lassalle, M, Frimat, L, Choukroun, G, Lobbedez, T
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(7):1244-1249
Abstract
BACKGROUND No prospective study has evaluated the long-term effect on mortality of the new acid concentrates added to bicarbonate dialysate. The aim of this pharmacoepidemiological study was to evaluate the association between hydrochloric or citric acid-based dialysate and mortality on haemodialysis (HD). METHODS This study included 117 796 patients with 3 723 887 months on HD recorded in the national French Renal Epidemiology and Information Network registry. Dialysate acid components were retrospectively reconstructed for each facility. All patients on HD were associated each month with an exposure based on that at their facility of treatment. We took each patient's time-varying exposure into account to calculate the monthly mortality rates for each exposure. Incidence rate ratios (IRRs) for mortality were calculated with a Poisson regression, with acetic acid as the reference. Regressions were adjusted for initial clinical characteristics (age, gender, previous cardiovascular events, active malignancy, diabetes, pulmonary disease, mobility), dialysis technique and location (in-centre, outpatient centre, self-care unit) and ESRD vintage, updated monthly. RESULTS The crude mortality rate per 1000 patient-months with citric acid {11.5 [95% confidence interval (CI) 11.1-12.0]} was lower than with either acetic acid [12.9 (95% CI 12.8-13.1)] or hydrochloric acid [12.8 (95% CI 12.2-13.5)]. For the 2014-17 period, the IRR for mortality with citric acid [adjusted IRR 0.94 (95% CI 0.90-0.99)] and with hydrochloric acid [adjusted IRR 0.86 (95% CI 0.79-0.94)] were significantly lower than with acetic acid. CONCLUSION This post-marketing study of long-term exposure to dialysate acidifiers at the patient level found the use of citric and hydrochloric acid-based dialysates, compared with acetic acid, was associated with lower mortality.
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Long-term effects of citric acid-based bicarbonate haemodialysis on patient outcomes: a survival propensity score-matched study in western France.
Potier, J, Dolley-Hitze, T, Hamel, D, Landru, I, Cardineau, E, Queffeulou, G, Zagdoun, E, Renaudineau, E, Molinari, N, Gamon, L, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(7):1228-1236
Abstract
BACKGROUND Citric acid-based bicarbonate haemodialysis (CIT-HD) has gained more clinical acceptance over the last few years in France and is a substitute for other acidifiers [e.g. acetic acid (CH3COOH) and hydrochloric acid (HCl)]. This trend was justified by several clinical benefits compared with CH3COOH as well as the desire to avoid the consequences of the corrosive action of HCl, but a nationwide clinical report raised concerns about the long-term safety of CIT-HD. The aim of this study was to assess the long-term effects of CIT-HD exposure on patient outcomes in western France. METHODS This is a population-based retrospective multicentre observational study performed in 1132 incident end-stage kidney disease patients in five sanitary territories in western France who started their renal replacement therapy after 1 January 2008 and followed up through 15 October 2018. Relevant data, collected prospectively with the same medical software, were anonymously aggregated for the purposes of the study. The primary goal of this study was to investigate the effects of citrate exposure on all-cause mortality. To provide a control group to CIT-HD one, propensity score matching (PSM) at 2:1 was performed in two steps: the first analysis was intended to be exploratory, comparing patients who received citrate ≤80% of the time (CIT-HD ≤80) versus those who received citrate >80% of the time (CIT-HD >80), while the second analysis was intended to be explanatory in comparing patients with 0% (CIT-HD0) versus 100% citrate time exposure (CIT-HD100). RESULTS After PSM, in the exploratory part of the analysis, 432 CIT-HD ≤80 patients were compared with 216 CIT-HD >80 patients and no difference was found for all-cause mortality using the Kaplan-Meier model (log-rank 0.97), univariate Cox regression analysis {hazard ratio [HR] 1.01 [95% confidence interval (CI) 0.71-1.40]} and multivariate Cox regression analysis [HR 1.11 (95% CI 0.76-1.61)] when adjusted for nine variables with clinical pertinence and high statistical relevance in the univariate analysis. In the explanatory part of the analysis, 316 CIT-HD0 patients were then compared with 158 CIT-HD100 patients and no difference was found using the Kaplan-Meier model (log-rank 0.06), univariate Cox regression analysis [HR 0.69 (95% CI 0.47-1.03)] and multivariate Cox regression analysis [HR 0.87 (95% CI 0.57-1.33)] when adjusted for seven variables with clinical pertinence and high statistical relevance in the univariate analysis. CONCLUSIONS Findings of this study support the notion that CIT-HD exposure ≤6 years has no significant effect on all-cause mortality in HD patients. This finding remains true for patients receiving high-volume online haemodiafiltration, a modality most frequently prescribed in this cohort.
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Association between change in serum bicarbonate and change in thyroid hormone levels in patients receiving conventional or more frequent maintenance haemodialysis.
Molfino, A, Beck, GJ, Li, M, Lo, JC, Kaysen, GA, ,
Nephrology (Carlton, Vic.). 2019;(1):81-87
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AIM: Correction of metabolic acidosis in patients with chronic kidney disease has been associated with improvement in thyroid function. We examined whether changes in bicarbonate were associated with changes in thyroid function in patients with end-stage renal disease receiving conventional or more frequent haemodialysis. METHODS In the Frequent Hemodialysis Network Trials, the relationship between changes in serum bicarbonate, free triiodothyronine (FT3) and free thyroxine (FT4) was examined among 147 and 48 patients with endogenous thyroid function who received conventional (3×/week) or more frequent (6×/week) haemodialysis (Daily Trial) or who received conventional or more frequent nocturnal haemodialysis (Nocturnal Trial). Equilibrated normalized protein catabolic rate (enPCR) was examined to account for nutritional factors affecting both acid load and thyroid function. RESULTS Increasing dialysis frequency was associated with increased bicarbonate level. Baseline bicarbonate level was not associated with baseline FT3 and FT4. Change in bicarbonate level was not associated with changes in FT3 and FT4 in the Daily Trial nor for FT4 in the Nocturnal Trial (r ≤ 0.14, P > 0.21). While, a significant correlation between change in serum bicarbonate and change in FT3 (r = 0.44, P = 0.02) was observed in the Nocturnal Trial; findings were no longer significant after adjusting for change in enPCR (r = 0.37, P = 0.08). For participants with baseline bicarbonate <23 mmol/L, no association between change in bicarbonate and change in thyroid indices were seen in the Daily Trial; for the Nocturnal Trial, findings were also not significant for change in FT3 and the association between change in bicarbonate and change in FT4 (r = 0.54, P = 0.03) was no longer significant after adjusting for enPCR (r = 0.45, P = 0.11). CONCLUSION Changes in bicarbonate were not associated with changes in thyroid hormone levels after adjusting for enPCR, as a marker of nutritional status. Future studies should examine whether improvement in acid base status improves thyroid function in haemodialysis patients with evidence of thyroid hypofunction.
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Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD.
Bushinsky, DA, Hostetter, T, Klaerner, G, Stasiv, Y, Lockey, C, McNulty, S, Lee, A, Parsell, D, Mathur, V, Li, E, et al
Clinical journal of the American Society of Nephrology : CJASN. 2018;(1):26-35
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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.
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Serum Bicarbonate Concentration and Cognitive Function in Hypertensive Adults.
Dobre, M, Gaussoin, SA, Bates, JT, Chonchol, MB, Cohen, DL, Hostetter, TH, Raphael, KL, Taylor, AA, Lerner, AJ, Wright, JT, et al
Clinical journal of the American Society of Nephrology : CJASN. 2018;(4):596-603
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BACKGROUND AND OBJECTIVES Cognitive function worsens as kidney function declines, but mechanisms contributing to this association are not completely understood. Metabolic acidosis, a common complication of CKD, leads to neural networks overexcitation and is involved in cerebral autoregulation. We aimed to evaluate the association between serum bicarbonate concentration as a measure of metabolic acidosis, and cognitive function in hypertensive adults with and without CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Five cognitive summary scores were measured (global cognitive function, executive function, memory, attention/concentration, and language) in 2853 participants in the Systolic BP Intervention Trial (SPRINT). Multivariable linear regression models adjusted for demographics, comorbidities, systolic BP, medications, eGFR and albuminuria evaluated the cross-sectional association between bicarbonate and cognition at SPRINT baseline. In a subset (n=681) who underwent brain magnetic resonance imaging, the models were adjusted for white matter hyperintensity volume, vascular reactivity, and cerebral blood flow. RESULTS The mean age (SD) was 68 (8.5) years. Global cognitive and executive functions were positively associated with serum bicarbonate (estimate [SEM]: 0.014 [0.006]; P=0.01, and 0.018 [0.006]; P=0.003, respectively). Each 1 mEq/L lower bicarbonate level had a similar association with global cognitive and executive function as being 4.3 and 5.4 months older, respectively. The association with global cognition persisted after magnetic resonance imaging findings adjustment (estimate [SEM]: 0.03 [0.01]; P=0.01). There was no association between serum bicarbonate level and memory, attention/concentration, and language. CONCLUSIONS In a large cohort of hypertensive adults, higher serum bicarbonate levels were independently associated with better global cognitive and executive performance. (ClinicalTrials.gov: NCT01206062).
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A Phase 4, multicentre, randomized, single-blind clinical trial to evaluate the immunogenicity of the live, attenuated, oral rotavirus vaccine (116E), ROTAVAC®, administered simultaneously with or without the buffering agent in healthy infants in India.
Ella, R, Bobba, R, Muralidhar, S, Babji, S, Vadrevu, KM, Bhan, MK
Human vaccines & immunotherapeutics. 2018;(7):1791-1799
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BACKGROUND The World Health Organization recommends that rotavirus vaccines should be included in all national immunization programs. Some currently licensed oral rotavirus vaccines contain a buffering agent (either as part of a ready-to-use liquid formulation or added during reconstitution) to reduce possible degradation of the vaccine virus in the infant gut, which poses several programmatic challenges (the large dose volume or the reconstitution requirement) during vaccine administration. Because ROTAVAC®, a WHO prequalified vaccine, was derived from the 116E neonatal strain, we evaluated the immunogenicity and safety of ROTAVAC® without buffer and ROTAVAC® with buffer in a phase 4, multicentre, single-blind, randomized clinical trial in healthy infants in India. METHODS 900 infants, approximately 6, 10 and 14 weeks of age, were assigned to 3 groups to receive ROTAVAC® (0.5 mL dose) orally: (i) 2.5 mL of citrate-bicarbonate buffer 5 minutes prior to administration of ROTAVAC® (Group I), (ii) ROTAVAC®, alone, without any buffer (Group II), or (iii) ROTAVAC®, mixed with buffer immediately before administration (Group III). Non-inferiority was compared among the groups for differences in serological responses (detected by serum anti-rotavirus IgA) and safety. RESULTS Geometric mean titers post vaccination at day 84 (28 days after dose 3) were 19.6 (95%CI: 17.0, 22.7), 20.7 (95%CI: 17.9, 24) and 19.2 (95%CI: 16.8, 22.1) for groups I, II and III respectively. Further, seroconversion rates and distribution of adverse events were similar among groups. CONCLUSIONS Administration of ROTAVAC® at a 0.5 mL dose volume without buffering agent was shown to be well tolerated and immunogenic. Given the homologous nature of the strain, it is plausible that ROTAVAC® replicates well and confers immunity even without buffer administration.