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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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Does varying the ingestion period of sodium citrate influence blood alkalosis and gastrointestinal symptoms?
Urwin, CS, Snow, RJ, Orellana, L, Condo, D, Wadley, GD, Carr, AJ
PloS one. 2021;(5):e0251808
Abstract
OBJECTIVES To compare blood alkalosis, gastrointestinal symptoms and indicators of strong ion difference after ingestion of 500 mg.kg-1 BM sodium citrate over four different periods. METHODS Sixteen healthy and active participants ingested 500 mg.kg-1 BM sodium citrate in gelatine capsules over a 15, 30, 45 or 60 min period using a randomized cross-over experimental design. Gastrointestinal symptoms questionnaires and venous blood samples were collected before ingestion, immediately post-ingestion, and every 30 min for 480 min post-ingestion. Blood samples were analysed for blood pH, [HCO3-], [Na+], [Cl-] and plasma [citrate]. Linear mixed models were used to estimate the effect of the ingestion protocols. RESULTS For all treatments, blood [HCO3-] was significantly elevated above baseline for the entire 480 min post-ingestion period, and peak occurred 180 min post-ingestion. Blood [HCO3-] and pH were significantly elevated above baseline and not significantly below the peak between 150-270 min post-ingestion. Furthermore, blood pH and [HCO3-] were significantly lower for the 60 min ingestion period when compared to the other treatments. Gastrointestinal symptoms were minor for all treatments; the mean total session symptoms ratings (all times summed together) were between 9.8 and 11.6 from a maximum possible rating of 720. CONCLUSION Based on the findings of this investigation, sodium citrate should be ingested over a period of less than 60 min (15, 30 or 45 min), and completed 150-270 min before exercise.
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Phosphate and Calcium Control in Short Frequent Hemodialysis with the NxStage System One Cycler: Mass Balance Studies and Comparison with Standard Thrice-Weekly Bicarbonate Dialysis.
Brunati, CCM, Gervasi, F, Casati, C, Querques, ML, Montoli, A, Colussi, G
Blood purification. 2018;(4):334-342
Abstract
BACKGROUND Short frequent dialysis with NxStage System One cycler (NSO) has become increasingly popular as home hemodialysis prescription. Short dialysis sessions with NSO might not allow adequate phosphate (P) removal. METHODS Single-session and weekly balances of P and calcium (Ca) were compared in 14 patients treated with NSO (6 sessions/week) and in 14 patients on standard bicarbonate dialysis (BHD). RESULTS NSO and BHD showed similar plasma P fall, with end-dialysis plasma P slightly lower in BHD (2.2 ± 0.5 vs. 2.7 ± 0.8 mg/dL, p < 0.02). Single-session P removal was lower in NSO, but weekly removal was higher (3,488 ± 1,181 mg vs. 2,634 ± 878, p < 0.003). Plasma Ca increase was lower in NSO, with similar PTH fall. Ca balance varied according to start plasma Ca, dialysate to blood Ca gradient and net ultrafiltration. CONCLUSIONS short, frequent home hemodialysis with NSO, on a 6/week-based prescription, allows higher weekly P removal than BHD. With the dialysate Ca concentration in use (6 mg/dL), total plasma Ca and iCa concentration increase is lower in NSO.
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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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Abstract
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.
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Effects of a new bicarbonate/lactate-buffered neutral peritoneal dialysis fluid for peritoneal failure in patients undergoing peritoneal dialysis.
Hoshino, T, Ishii, H, Kitano, T, Shindo, M, Miyazawa, H, Yamada, H, Ito, K, Ueda, Y, Kaku, Y, Hirai, K, et al
Discovery medicine. 2016;(114):81-8
Abstract
BACKGROUND The highly concentrated lactate in peritoneal dialysis fluid (PDF) has been considered to contribute to peritoneal failure in patients undergoing PD. A new PDF containing a lower lactate concentration, physiological bicarbonate concentration, and neutral pH (bicarbonate/lactate-buffered neutral PDF) was recently developed. We compared the clinical effects of this bicarbonate/lactate-buffered neutral PDF and a lactate-buffered neutral PDF. METHODS AND DESIGN Patients undergoing PD were changed from a lactate-buffered neutral PDF to a bicarbonate/lactate-buffered neutral PDF. We then investigated the changes in peritoneal functions as estimated by a peritoneal equilibration test (PET) and the following surrogate markers of peritoneal membrane failure in the drained dialysate: fibrin degradation products (FDP), vascular endothelial growth factor (VEGF), cancer antigen 125 (CA125), interleukin-6 (IL-6), and transforming growth factor beta 1 (TGF-β1). RESULTS Fourteen patients undergoing PD were enrolled. The PET results were not different before and after use of the bicarbonate/lactate-buffered neutral PDF. The FDP concentration significantly decreased from 15.60 ± 13.90 to 6.04 ± 3.49 μg/mL (p = 0.02) and the VEGF concentration significantly decreased from 37.83 ± 15.82 to 27.70 ± 3.80 pg/mL (p = 0.02), while the CA125 and IL-6 concentrations remained unchanged before and after use of the bicarbonate/lactate-buffered neutral PDF. TGF-β1 was not detected in most patients. CONCLUSION The bicarbonate/lactate-buffered neutral PDF decreased the FDP and VEGF concentrations in the drained dialysate. These results suggest that the decreased lactate level achieved by administration of bicarbonate with a neutral pH in PDF may contribute to decreased peritoneal membrane failure in patients undergoing PD.
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High-volume online haemodiafiltration improves erythropoiesis-stimulating agent (ESA) resistance in comparison with low-flux bicarbonate dialysis: results of the REDERT study.
Panichi, V, Scatena, A, Rosati, A, Giusti, R, Ferro, G, Malagnino, E, Capitanini, A, Piluso, A, Conti, P, Bernabini, G, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2015;(4):682-9
Abstract
BACKGROUND In haemodialysis (HD) patients, anaemia is associated with reduced survival. Despite treatment with erythropoiesis-stimulating agents (ESAs), a large number of patients with chronic kidney disease show resistance to this therapy and require much higher than usual doses of ESAs in order to maintain the recommended haemoglobin (Hb) target, and recent studies suggest that hepcidin (HEP) may mediate the ESA resistance index (ERI). High-volume online haemodiafiltration (HV-OL-HDF) has been shown to improve anaemia and to reduce the need for ESAs in HD patients; this effect is associated with a reduced inflammatory state in these patients. The aim of the REDERT study (role of haemodiafiltration on ERI) was to investigate the effect of different dialysis techniques on ERI and HEP levels in chronic dialysis patients. METHODS A single cross-over, randomized, multicentre study (A-B or B-A) was designed. Forty stable HD patients from seven different dialysis units (male 65%, mean age 67.6 ± 14.7 years and mean dialytic age 48 ± 10 months) were enrolled. Patients were randomized to the standard bicarbonate dialysis (BHD) with low-flux polysulfone (PS) membrane group or to the HV-OL-HDF group with high-flux PS membranes and exchange volume of >20 L/session. After 6 months, patients were shifted to the other dialytic group for a further 6 months. Clinical data, Hb, ESA doses and iron metabolism were recorded every month. HEP, beta2-microglobulin (b2MG) and C-reactive protein (CRP) were determined every 3 months, and ERI was calculated monthly as the weekly ESA dose per kilogram of body weight divided by Hb level. Data were analysed using paired-samples t-test, Wilcoxon signed-rank test and Spearman's correlation coefficient. RESULTS Dialysis efficiency for small molecules assessed as Kt/V was significantly increased in HV-OL-HDF from 1.47 ± 0.24 to 1.49 ± 0.16; P < 0.01. A significant reduction of b2MG was obtained in HV-OL-HDF from month 3 whereas CRP values were not significantly changed during the study period either in BHD or HV-OL-HDF.ERI was significantly reduced in HV-OL-HDF at month 3 and 6 (from 9.1 ± 6.4 UI/weekly/Kg/Hb to 6.7 ± 5.3 UI/weekly/Kg/Hb; P < 0.05) due to a higher ESA consumption in BHD in spite of similar Hb levels. HEP levels were reduced in HV-OL-HDF with respect to BHD after 3 and 6 months. Iron consumption was not significantly different during BHD or HV-OL-HDF treatment as well as transferrin, ferritin and TSAT levels. A significant positive linear correlation between HEP and ERI (r(2) = 0.258, P < 0.001) was observed. CONCLUSIONS In a uraemic patient population with low-grade inflammation treated with HV-OL-HDF, we observed a significant reduction of ERI values as well as HEP levels. The positive correlation between these two parameters supports a role for HEP in the development of ERI in the dialytic population. Moreover, the lower b2MG and the higher Kt/V achieved in HV-OL-HDF confirms the better depurative effect of this technique in comparison with BHD with respect to middle molecules and small-molecular-weight molecules.
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A low serum bicarbonate concentration as a risk factor for mortality in peritoneal dialysis patients.
Chang, TI, Oh, HJ, Kang, EW, Yoo, TH, Shin, SK, Kang, SW, Choi, KH, Han, DS, Han, SH
PloS one. 2013;(12):e82912
Abstract
BACKGROUND AND AIM Metabolic acidosis is common in patients with chronic kidney disease and is associated with increased mortality in hemodialysis patients. However, this relationship has not yet been determined in peritoneal dialysis (PD) patients. METHODS This prospective observational study included a total of 441 incident patients who started PD between January 2000 and December 2005. Using time-averaged serum bicarbonate (TA-Bic) levels, we aimed to investigate whether a low serum bicarbonate concentration can predict mortality in these patients. RESULTS Among the baseline parameters, serum bicarbonate level was positively associated with hemoglobin level and residual glomerular filtration rate (GFR), while it was negatively associated with albumin, C-reactive protein (CRP) levels, peritoneal Kt/V urea, and normalized protein catabolic rate (nPCR) in a multivariable linear regression analysis. During a median follow-up of 34.8 months, 149 deaths were recorded. After adjustment for age, diabetes, coronary artery disease, serum albumin, ferritin, CRP, residual GFR, peritoneal Kt/V urea, nPCR, and percentage of lean body mass, TA-Bic level was associated with a significantly decreased risk of mortality (HR per 1 mEq/L increase, 0.83; 95% CI, 0.76-0.91; p < 0.001). In addition, compared to patients with a TA-Bic level of 24-26 mEq/L, those with a TA-Bic level < 22 and between 22-24 mEq/L conferred a 13.10- and 2.13-fold increased risk of death, respectively. CONCLUSIONS This study showed that a low serum bicarbonate concentration is an independent risk factor for mortality in PD patients. This relationship between low bicarbonate levels and adverse outcome could be related to enhanced inflammation and a more rapid loss of RRF associated with metabolic acidosis. Large randomized clinical trials to correct acidosis are warranted to confirm our findings.
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Oral treatment of metabolic acidosis in hemodialyzed patients and the implications on the hemodynamic status.
Checheriţă, IA, David, C, Ciocâlteu, A, Lascăr, I, Budală, L
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie. 2013;(3):539-43
Abstract
UNLABELLED Metabolic acidosis slowly develops during renal impairment natural evolution towards ESRD and represents an important contributing factor of CKD progression. Although, several clinical and experimental trials reported the major impact of metabolic acidosis on CKD evolution, the pathophysiology mechanism remains a matter of debate. Furthermore, international guidelines do not impose a specific treatment scheme for metabolic acidosis in CKD patients, and metabolic acidosis is not fully compensated once hemodialysis starts. Therefore, the aim of our study was to determine an adequate follow-up of metabolic acidosis therapy benefits and risks in HD patients. PATIENTS AND METHODS 164 HD patients were evaluated according to the following protocol: bioumoral laboratory tests, the measure of different important parameters (residual diuresis, UF, BP, LVMI, volemia status). The assessed data were statistic analyzed using non-paired Student's t-test for continuous variables and chi-square (χ²) test for qualitative parameters (p-value <0.05 was considered statistically significant). RESULTS HD individuals were followed-up depending on their predialysis-alkaline reserve value. After therapy started, predialysis-alkaline reserve mean level increased from 19.4 mEq/L to 22.6 mEq/L (p<0.001). Furthermore, we observed a significant decrease of nitrogenous waste products values (T=10.87<1.66) and intradialytic hypotension events (p<0.001). CONCLUSIONS Our findings emphasize the beneficial effects of correcting metabolic acidosis using the proposed treatment scheme with direct impact on hemodynamic status improvement.
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Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate-balanced solution.
Davies, PG, Venkatesh, B, Morgan, TJ, Presneill, JJ, Kruger, PS, Thomas, BJ, Roberts, MS, Mundy, J
Critical care (London, England). 2011;(1):R21
Abstract
INTRODUCTION As even small concentrations of acetate in the plasma result in pro-inflammatory and cardiotoxic effects, it has been removed from renal replacement fluids. However, Plasma-Lyte 148 (Plasma-Lyte), an electrolyte replacement solution containing acetate plus gluconate is a common circuit prime for cardio-pulmonary bypass (CPB). No published data exist on the peak plasma acetate and gluconate concentrations resulting from the use of Plasma-Lyte 148 during CPB. METHODS Thirty adult patients were systematically allocated 1:1 to CPB prime with either bicarbonate-balanced fluid (24 mmol/L bicarbonate) or Plasma-Lyte 148. Arterial blood acetate, gluconate and interleukin-6 (IL-6) levels were measured immediately before CPB (T1), three minutes after CPB commencement (T2), immediately before CPB separation (T3), and four hours post separation (T4). RESULTS Acetate concentrations (normal 0.04 to 0.07 mmol/L) became markedly elevated at T2, where the Plasma-Lyte group (median 3.69, range (2.46 to 8.55)) exceeded the bicarbonate group (0.16 (0.02 to 3.49), P < 0.0005). At T3, levels had declined but the differential pattern remained apparent (Plasma-Lyte 0.35 (0.00 to 1.84) versus bicarbonate 0.17 (0.00 to 0.81)). Normal circulating acetate concentrations were not restored until T4. Similar gluconate concentration profiles and inter-group differences were seen, with a slower T3 decay. IL-6 increased across CPB, peaking at T4, with no clear difference between groups. CONCLUSIONS Use of acetate containing prime solutions result in supraphysiological plasma concentrations of acetate. The use of acetate-free prime fluid in CPB significantly reduced but did not eliminate large acetate surges in cardiac surgical patients. Complete elimination of acetate surges would require the use of acetate free bolus fluids and cardioplegia solutions. TRIAL REGISTRATION Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000267055.
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Metabolic effects of citrate- vs bicarbonate-based substitution fluid in continuous venovenous hemofiltration: a prospective sequential cohort study.
Aman, J, Nurmohamed, SA, Vervloet, MG, Groeneveld, AB
Journal of critical care. 2010;(1):120-7
Abstract
BACKGROUND Studies investigating the metabolic effects of citrate-based substitution fluids are lacking. This study aims to compare the effect of citrate- vs bicarbonate-based substitution fluid used during continuous venovenous hemofiltration (CVVH) for acute kidney injury on acid-base balance and electrolytes in critically ill patients. METHODS This was a prospective sequential cohort study in patients with a contraindication for systemic anticoagulation. The first cohort was treated by bicarbonate-based CVVH (n = 10) and the second cohort was treated by CVVH with citrate-based substitution fluid (n = 19). Flow of the latter was coupled to blood flow, and ionized calcium concentrations were monitored and kept constant by calcium-glubionate infusion. RESULTS No major differences between the 2 groups were found in baseline acid-base parameters. In both groups, arterial pH increased after initiation of treatment and normalized on the average within 18 hours in either group. No differences were found in bicarbonate concentrations. Electrolyte control was comparable for the groups. CONCLUSION Citrate-based substitution fluid is comparable to bicarbonate-based substitution fluid during CVVH in critically ill patients with acute kidney injury, concerning acid-base balance and electrolyte control. This implies complete conversion of citrate to bicarbonate in the patients studied.