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Effects of oral sodium bicarbonate in patients with CKD.

ABSTRACT: Metabolic acidosis contributes to muscle breakdown in patients with CKD, but whether its treatment improves functional outcomes is unknown. The choice of dose and tolerability of high doses remain unclear. In CKD patients with mild acidosis, this study evaluated the dose-response relationship of alkali with serum bicarbonate, its side effect profile, and its effect on muscle strength.In this single-blinded pilot study from March of 2009 to August of 2010, 20 adults with estimated GFR 15-45 ml/min per 1.73 m(2) and serum bicarbonate 20-24 mEq/L were treated during successive 2-week periods with placebo followed by escalating oral NaHCO3 doses (0.3, 0.6, and 1.0 mEq/kg per day). At each visit, handgrip strength and time required to complete 5 and 10 repetitions of a sit-to-stand test were measured.Each 0.1 mEq/kg per day increase in dose produced a 0.33 mEq/L (95% confidence interval=0.23-0.43 mEq/L) higher serum bicarbonate. Sit-to-stand time improved after 6 weeks of oral NaHCO3 (23.8±1.4 versus 22.2±1.6 seconds for 10 repetitions, P=0.002), and urinary nitrogen excretion decreased (-0.70 g/g creatinine [95% confidence interval=-1.11 to -0.30] per 0.1 mEq/kg per day higher dose). No statistically significant change was seen in handgrip strength (29.5±9.6 versus 28.4±9.4 kg, P=0.12). Higher NaHCO3 doses were not associated with increased BP or greater edema.NaHCO3 supplementation produces a dose-dependent increase in serum bicarbonate and improves lower extremity muscle strength after a short-term intervention in CKD patients with mild acidosis. Long-term studies are needed to determine if this finding translates into improved functional status.

SUBMITTER: Abramowitz MK

PROVIDER: S-EPMC3641618 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Effects of oral sodium bicarbonate in patients with CKD.

Abramowitz Matthew K MK Melamed Michal L ML Bauer Carolyn C Raff Amanda C AC Hostetter Thomas H TH

Clinical journal of the American Society of Nephrology : CJASN 20130207 5

<h4>Background and objectives</h4>Metabolic acidosis contributes to muscle breakdown in patients with CKD, but whether its treatment improves functional outcomes is unknown. The choice of dose and tolerability of high doses remain unclear. In CKD patients with mild acidosis, this study evaluated the dose-response relationship of alkali with serum bicarbonate, its side effect profile, and its effect on muscle strength.<h4>Design, setting, participants, & measurements</h4>In this single-blinded pi ...[more]

PMID: 23393105

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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:RationaleSalt sensitivity of blood pressure affects >30% of the hypertensive and >15% of the normotensive population. Variants of the electrogenic sodium bicarbonate cotransporter NBCe2 gene, SLC4A5, are associated with increased blood pressure in several ethnic groups. SLC4A5 variants are also highly associated with salt sensitivity, independent of hypertension. However, little is known about how NBCe2 contributes to salt sensitivity, although NBCe2 regulates renal tubular sodium bicarbonate transport. We hypothesized that SLC4A5 rs10177833 and rs7571842 increase NBCe2 expression and human renal proximal tubule cell (hRPTC) sodium transport and may be a cause of salt sensitivity of blood pressure.ObjectiveTo characterize the hRPTC ion transport of wild-type (WT) and homozygous variants (HV) of SLC4A5.Methods and resultsThe expressions of NBCe2 mRNA and protein were not different between hRPTCs carrying WT or HV SLC4A5 before or after dopaminergic or angiotensin (II and III) stimulation. However, luminal to basolateral sodium transport, NHE3 protein, and Cl-/HCO3- exchanger activity in hRPTCs were higher in HV than WT SLC4A5. Increasing intracellular sodium enhanced the apical location of NBCe2 in HV hRPTCs (4.24±0.35% to 11.06±1.72% (P<0.05, N = 3, 2-way ANOVA, Holm-Sidak test)) as determined by Total Internal Reflection Fluorescence Microscopy (TIRFM). In hRPTCs isolated from kidney tissue, increasing intracellular sodium enhanced bicarbonate-dependent pH recovery rate and increased NBCe2 mRNA and protein expressions to a greater extent in HV than WT SLC4A5 (+38.00±6.23% vs HV normal salt (P<0.01, N = 4, 2-way ANOVA, Holm-Sidak test)). In hRPTCs isolated from freshly voided urine, bicarbonate-dependent pH recovery was also faster in those from salt-sensitive and carriers of HV SLC4A5 than from salt-resistant and carriers of WT SLC4A5. The faster NBCe2-specific bicarbonate-dependent pH recovery rate in HV SCL4A5 was normalized by SLC4A5- but not SLC4A4-shRNA. The binding of purified hepatocyte nuclear factor type 4A (HNF4A) to DNA was increased in hRPTCs carrying HV SLC4A5 rs7571842 but not rs10177833. The faster NBCe2-specific bicarbonate-dependent pH recovery rate in HV SCL4A5 was abolished by HNF4A antagonists.ConclusionNBCe2 activity is stimulated by an increase in intracellular sodium and is hyper-responsive in hRPTCs carrying HV SLC4A5 rs7571842 through an aberrant HNF4A-mediated mechanism.

Project description:Supplementation with sodium acetate (NaAcet) increases milk fat production through an apparent stimulation of de novo lipogenesis in the mammary gland. Sodium acetate increases acetate supply to the mammary gland, but it also increases dietary cation-anion difference, which can also increase milk fat yield. The objective of this study was to determine if the effect of NaAcet on milk fat production was due to an increase in acetate supply or an increase in dietary cation-anion difference. The study included 12 multiparous cows in a replicated 3 × 3 Latin square design balanced for carryover effects, with 14-d experimental periods. Treatments were a basal total mixed ration (31.8% neutral detergent fiber, 14.8% crude protein, 25.5% starch, and 4.4% fatty acids on a dry matter basis) as a no-supplement control, acetate supplemented at 3.25% of dry matter as NaAcet, and sodium bicarbonate (NaHCO3) providing an equal amount of sodium to the NaAcet treatment. The NaAcet and NaHCO3 were mixed into the basal diet before feeding. Milk samples were taken at each milking during the last 3 d of each period. Plasma samples were taken every 9 h during the last 3 d (a total of 8 times) to determine concentrations of plasma metabolites and hormones. Eating behavior was monitored during the last week of each period using an automated system. The NaAcet and NaHCO3 treatments increased milk fat concentration and yield compared to the no-supplement control. The NaAcet treatment increased milk fat production predominantly by increasing the yield of de novo and mixed-source fatty acids. The NaHCO3 treatment increased the yield of preformed and de novo fatty acids, suggesting different mechanisms for the 2 treatments. The NaAcet treatment increased plasma acetate concentration in a period of the day concurrent with the highest dry matter intake. The NaAcet treatment increased milk fat production by stimulating the production of de novo fatty acids, a mechanism consistent with previous reports, possibly by increasing acetate supply to the mammary gland. The NaHCO3 treatment increased milk fat production by increasing the production of all biological categories of fatty acids, except for odd and branched-chain fatty acids, possibly by increasing overall diet digestibility.

Project description:BackgroundOral sodium bicarbonate (NaHCO3) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown.MethodsThis multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO3 over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m2 with urinary albumin/creatinine (ACR) ≥50 mg/g and serum bicarbonate 20-28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO3; 0.8 meq/kg of lean body wt per day; n=90) or lower-dose (LD-NaHCO3; 0.5 meq/kg of lean body wt per day; n=52) NaHCO3 or matching placebo (n=52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if ≥67% of participants were on full-dose and ≥80% were on ≥25% of the per-protocol dose.ResultsMean±SD baseline eGFR was 36±9 ml/min per 1.73 m2, serum bicarbonate was 24±2 meq/L, and median (IQR) ACR was 181 (25-745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO3, 96% in LD-NaHCO3, and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO3, 98% in LD-NaHCO3, and 92% in placebo were on ≥25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO3 compared with LD-NaHCO3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group.ConclusionsBoth NaHCO3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO3 may be a reasonable choice for future trials.

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Effects of oral sodium bicarbonate in patients with CKD.

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Effects of oral sodium bicarbonate in patients with CKD.

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