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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 m 2 , 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 m 2 , 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.

The consequences of chronic subclinical metabolic acidosis, characterized by an increase in single nephron ammonium generation, contribute to the progression of chronic kidney disease (CKD). Therefore, sodium bicarbonate (NaHCO₃) supplementation in CKD with normal serum bicarbonate patients may reduce kidney fibrosis and slow CKD progression. This study aimed to evaluate the impact of high-dose NaHCO₃ supplementation on urinary transforming growth factor-beta (TGF-β), a biomarker of kidney fibrosis, in non-diabetic CKD patients with normal serum bicarbonate levels. We conducted a single-center, randomized, open-label controlled trial in patients with non-diabetic CKD stage 3–4 and normal serum bicarbonate (22–26 mEq/L). Participants were randomized to receive high-dose NaHCO₃ (0.8 mEq/kg/day) or standard care for 12 weeks. The primary outcome was the change in urinary TGF-β-to-creatinine ratio from baseline. Secondary outcomes included changes in urinary albumin-to-creatinine ratio (UACR), urine pH, serum electrolytes, blood pressure, and adverse events. A total of 64 participants were randomized (NaHCO₃ group: n = 32; control group: n = 32). There was no significant difference in the percentage change of urinary TGF-β (NaHCO₃: −1.86% vs. control: 5.75%; p = 0.477). However, the NaHCO₃ group demonstrated a significant increase in urine pH mean difference (0.56; 95% CI: 0.3,0.82 vs. 0,95% CI −0.24,0.24; p = 0.002) compared to the control group. Similarly, no significant differences were observed in UACR, serum electrolytes, blood pressure, or body weight between groups. No serious adverse events were reported. High-dose NaHCO₃ supplementation in non-diabetic CKD patients with normal serum bicarbonate levels did not significantly reduce urinary TGF-β over 12 weeks but effectively increased urine pH without adverse effects. These findings suggest that NaHCO₃ is safe; however, its role in modulating profibrotic biomarkers in CKD requires further investigation. Longer-term studies and alternative alkali therapies should be explored to determine the optimal strategies for preserving kidney function in this population. Clinical trial registration: TCTR20240817007 (17/08/2024).

Salt and fluid absorption and secretion are two processes that are fundamental to epithelial function and whole body fluid homeostasis, and as such are tightly regulated in epithelial tissues. The CFTR anion channel plays a major role in regulating both secretion and absorption in a diverse range of epithelial tissues, including the airways, the GI and reproductive tracts, sweat and salivary glands. It is not surprising then that defects in CFTR function are linked to disease, including life-threatening secretory diarrhoeas, such as cholera, as well as the inherited disease, cystic fibrosis (CF), one of the most common life-limiting genetic diseases in Caucasian populations. More recently, CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease (COPD), and the hyper-responsiveness in asthma, underscoring its fundamental role in whole body health and disease. CFTR regulates many mechanisms in epithelial physiology, such as maintaining epithelial surface hydration and regulating luminal pH. Indeed, recent studies have identified luminal pH as an important arbiter of epithelial barrier function and innate defence, particularly in the airways and GI tract. In this chapter, we will illustrate the different operational roles of CFTR in epithelial function by describing its characteristics in three different tissues: the airways, the pancreas, and the sweat gland.

Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients. The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m2 and 89 mL/min per 1·73 m2, stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5–4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996. Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median –0·722 mL/min per 1·73 m2 (IQR –4·081 to 1·440) and mean –1·862 mL/min per 1·73 m2 (SD 6·344) per year in the placebo group versus median –1·413 mL/min per 1·73 m2 (IQR –4·503 to 1·139) and mean –1·830 mL/min per 1·73 m2 (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m2 per year (95% CI –1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death. In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis. Swiss National Science Foundation.

Cellular and organism survival depends upon the regulation of pH, which is regulated by highly specialized cell membrane transporters, the solute carriers (SLC) (For a comprehensive list of the solute carrier family members, see: https://www.bioparadigms.org/slc/). The SLC4 family of bicarbonate (HCO3−) transporters consists of ten members, sorted by their coupling to either sodium (NBCe1, NBCe2, NBCn1, NBCn2, NDCBE), chloride (AE1, AE2, AE3), or borate (BTR1). The ionic coupling of SLC4A9 (AE4) remains controversial. These SLC4 bicarbonate transporters may be controlled by cellular ionic gradients, cellular membrane voltage, and signaling molecules to maintain critical cellular and systemic pH (acid–base) balance. There are profound consequences when blood pH deviates even a small amount outside the normal range (7.35–7.45). Chiefly, Na+-coupled bicarbonate transporters (NCBT) control intracellular pH in nearly every living cell, maintaining the biological pH required for life. Additionally, NCBTs have important roles to regulate cell volume and maintain salt balance as well as absorption and secretion of acid–base equivalents. Due to their varied tissue expression, NCBTs have roles in pathophysiology, which become apparent in physiologic responses when their expression is reduced or genetically deleted. Variations in physiological pH are seen in a wide variety of conditions, from canonically acid–base related conditions to pathologies not necessarily associated with acid–base dysfunction such as cancer, glaucoma, or various neurological diseases. The membranous location of the SLC4 transporters as well as recent advances in discovering their structural biology makes them accessible and attractive as a druggable target in a disease context. The role of sodium-coupled bicarbonate transporters in such a large array of conditions illustrates the potential of treating a wide range of disease states by modifying function of these transporters, whether that be through inhibition or enhancement.

Purpose Enteric-coated sodium bicarbonate (NaHCO 3 ) can attenuate gastrointestinal (GI) symptoms following acute bicarbonate loading, although the subsequent effects on exercise performance have not been investigated. The purpose of this study was to examine the effects of enteric-coated NaHCO 3 supplementation on high-intensity exercise performance and GI symptoms. Methods Eleven trained male cyclists completed three 4 km time trials after consuming; a placebo or 0.3 g∙kg –1 body mass NaHCO 3 in enteric-coated or gelatin capsules. Exercise trials were timed with individual peak blood bicarbonate ion concentration ([HCO 3 – ]). Blood acid–base balance was measured pre-ingestion, pre-exercise, and post-exercise, whereas GI symptoms were recorded pre-ingestion and immediately pre-exercise. Results Pre-exercise blood [HCO3 − ] and potential hydrogen (pH) were greater for both NaHCO 3 conditions ( P  < 0.0005) when compared to placebo. Performance time was faster with enteric-coated (− 8.5 ± 9.6 s, P  = 0.044) and gelatin (− 9.6 ± 7.2 s, P  = 0.004) NaHCO 3 compared to placebo, with no significant difference between conditions (mean difference = 1.1 ± 5.3 s, P  = 1.000). Physiological responses were similar between conditions, although blood lactate ion concentration was higher with gelatin NaHCO 3 (2.4 ± 1.7 mmol∙L –1 , P  = 0.003) compared with placebo. Furthermore, fewer participants experienced GI symptoms with enteric-coated ( n  = 3) compared to gelatin ( n  = 7) NaHCO 3 . Discussion Acute enteric-coated NaHCO 3 consumption mitigates GI symptoms at the onset of exercise and improves subsequent 4 km cycling TT performance. Athletes who experience GI side-effects after acute bicarbonate loading may, therefore, benefit from enteric-coated NaHCO 3 supplementation prior to exercise performance.

Hydration is one of the most significant issues for combat sports as athletes often use water restriction for quick weight loss before competition. It appears that alkaline water can be an effective alternative to sodium bicarbonate in preventing the effects of exercise-induced metabolic acidosis. Therefore, the main aim of the present study was to investigate, in a double blind, placebo controlled randomized study, the impact of mineral-based highly alkaline water on acid-base balance, hydration status, and anaerobic capacity. Sixteen well trained combat sport athletes (n = 16), were randomly divided into two groups; the experimental group (EG; n = 8), which ingested highly alkaline water for three weeks, and the control group (CG; n = 8), which received regular table water. Anaerobic performance was evaluated by two double 30 s Wingate tests for lower and upper limbs, respectively, with a passive rest interval of 3 minutes between the bouts of exercise. Fingertip capillary blood samples for the assessment of lactate concentration were drawn at rest and during the 3rd min of recovery. In addition, acid-base equilibrium and electrolyte status were evaluated. Urine samples were evaluated for specific gravity and pH. The results indicate that drinking alkalized water enhances hydration, improves acid-base balance and anaerobic exercise performance.

Among high-risk patients undergoing angiography, there was no benefit of intravenous sodium bicarbonate over sodium chloride or of oral acetylcysteine over placebo for the prevention of death, dialysis, or contrast-associated acute kidney injury.

Objectives To assess the efficacy and safety of bicarbonate infusion in children with Acute Diarrhea and Severe Dehydration (ADSD) having severe Non-Anion Gap Metabolic Acidemia (sNAGMA). Methods Children (aged 1–144 mo) with ADSD and sNAGMA (pH ≤7.2 and/or serum bicarbonate ≤15 mEq/L) were enrolled in an open-label randomized design. Controls (n = 25) received WHO-recommended rehydration therapy with Ringer Lactate, while intervention group (n = 25) received additional bicarbonate deficit correction. Primary outcome was time taken to resolve metabolic acidemia (pH >7.30 and/or bicarbonate >15 mEq/L). Secondary outcome measures were adverse outcome [composite of pediatric intensive care unit (PICU) transfer and deaths], acute care area free days in 5 d (ACAFD 5 ), hospital stay, and adverse effects. Results Time taken to resolve metabolic acidemia was significantly lesser with intervention [median (IQR); 8 h (4, 12) vs. 12 h (8, 24); p  = 0.0067]. Intervention led to acidemia resolution in significantly more children by 8 h and 16 h (17/25 vs. 9/25, p  = 0.035 and 23/25 vs. 17/24, p  = 0.018, respectively). Patients with fluid refractory shock needed lesser inotropes in intervention group [median Vasoactive Inotrope Score (VIS), 10.5 vs. 34]. Intervention led to significantly lesser adverse outcome (0/25 vs. 5/25, p  = 0.049), and noticeably more ACAFD 5 [median (IQR); 2 (1, 2) vs. 1 (1, 2); p  = 0.12]. Two patients died in the control group while none in the intervention group. No adverse effect was documented. Conclusions Additional calculated dose of bicarbonate infusion led to significantly early resolution of metabolic acidemia, lesser utilization of critical care facilities, and lesser adverse outcome in children with ADSD and sNAGMA, compared to standard therapy, with no adverse effect.

Percutaneously absorbed carbon dioxide enhances blood flow. The mechanism by which it does so is unclear, but we hypothesized that it involves bicarbonate ions. BALB/c mice were bathed in neutral bicarbonate ionized water (NBIW) and showed increased blood bicarbonate levels and blood flow via phosphorylation of peripheral vascular endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO). Phosphorylation of eNOS and NO production were also increased in human umbilical vein endothelial cells cultured in medium containing NBIW, and NBIW showed reactive oxygen species scavenging activity. In a double-blind, randomized study in men and women aged 30 to 59 years with subjective cold intolerance, bathing in NBIW elevated body temperature faster than bathing in a control solution and improved chills and sleep quality. Taken together, our results show that percutaneously absorbed carbon dioxide changes to bicarbonate ions, which act directly on endothelial cells to increase NO production by phosphorylation of eNOS and thus improve blood flow.