Aerobic-anaerobic transition boosts poly(3-hydroxybutyrate-co-3-hydroxyvalerate) synthesis in Rhodospirillum rubrum: the key role of carbon dioxide.

BACKGROUND: Microbially produced bioplastics are specially promising materials since they can be naturally synthesized and degraded, making its end-of-life management more amenable to the environment. A prominent example of these new materials are polyhydroxyalkanoates. These polyesters serve manly as carbon and energy storage and increase the resistance to stress. Their synthesis can also work as an electron sink for the regeneration of oxidized cofactors. In terms of biotechnological applications, the co-polymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate), or PHBV, has interesting biotechnological properties due to its lower stiffness and fragility compared to the homopolymer poly(3-hydroxybutyrate) (P3HB). In this work, we explored the potentiality of Rhodospirillum rubrum as a producer of this co-polymer, exploiting its metabolic versatility when grown in different aeration conditions and photoheterotrophically. RESULTS: When shaken flasks experiments were carried out with limited aeration using fructose as carbon source, PHBV production was triggered reaching 29 ± 2% CDW of polymer accumulation with a 75 ± 1%mol of 3-hydroxyvalerate (3HV) (condition C2). Propionate and acetate were secreted in this condition. The synthesis of PHBV was exclusively carried out by the PHA synthase PhaC2. Interestingly, transcription of cbbM coding RuBisCO, the key enzyme of the Calvin-Benson-Bassham cycle, was similar in aerobic and microaerobic/anaerobic cultures. The maximal PHBV yield (81% CDW with 86%mol 3HV) was achieved when cells were transferred from aerobic to anaerobic conditions and controlling the CO2 concentration by adding bicarbonate to the culture. In these conditions, the cells behaved like resting cells, since polymer accumulation prevailed over residual biomass formation. In the absence of bicarbonate, cells could not adapt to an anaerobic environment in the studied lapse. CONCLUSIONS: We found that two-phase growth (aerobic-anaerobic) significantly improved the previous report of PHBV production in purple nonsulfur bacteria, maximizing the polymer accumulation at the expense of other components of the biomass. The presence of CO2 is key in this process demonstrating the involvement of the Calvin-Benson-Bassham in the adaptation to changes in oxygen availability. These results stand R. rubrum as a promising producer of high-3HV-content PHBV co-polymer from fructose, a PHBV unrelated carbon source.

Effects of short bout small-sided game training on acid-based balance markers in youth male soccer players.

This study aimed to compare the effects of 1 × 1 small-sided games (SSGs) with different bout durations on external (ETL) and internal training loads (ITL) in youth soccer players. Twenty U18 players were divided into two groups performing six 1 × 1 SSGs with 30 and 45 s bout durations on a playing field of 10 by 15 m. ITL indices, including the percentage of maximum heart rate (HR), blood lactate (BLa) level, pH, bicarbonate (HCO3-) level, and base excess (BE) level, were measured at rest, after each SSG bout, and 15 and 30 min after the entire exercise protocol. ETL (Global Positioning System metrics) was recorded during all six SSG bouts. The analysis showed that the 45 s SSGs had a greater volume (large effect) but a lower training intensity (small to large effect) than the 30 s SSGs. A significant time effect (p < 0.05) was observed in all ITL indices and a significant group effect (F1, 18 = 8.84, p = 0.0082, ƞ2 = 0.33) in the HCO3- level only. Finally, the changes in the HR and HCO3- level were smaller in the 45 s SSGs than in the 30 s SSGs. In conclusion, 30-s games, characterized by a higher intensity of training effort, are more physiologically demanding than 45-s games. Secondly during short-bout SSG training the HR and BLa level have limited diagnostic value for ITL. Extending ITL monitoring using other indicators, such as the HCO3- and BE levels, appears reasonable.

A retrospective study on comparison of clinical characteristics and outcomes of diabetic ketoacidosis patients with and without acute pancreatitis.

The co-existence of diabetic ketoacidosis (DKA) with acute pancreatitis (AP) is associated with unfavorable clinical outcomes. However, diagnosing AP in DKA patients is challenging and often missed due to overlapping symptoms. The aim of this retrospective observational study was to compare the clinical characteristics and outcomes of patients with concomitant DKA and AP or DKA alone. Data of patients with DKA admitted between January 2015 to August 2021 to four hospitals in Qatar was extracted from the electronic health record (Cerner). American Diabetes Association criteria and Atlanta criteria were used for DKA and AP diagnosis, respectively. Independent T-test or Mann-Whitney U test was used to analyze continuous variables, whereas categorical variables were analyzed via Chi-square or Fischer exact tests as appropriate. Univariate and multivariate logistic regression models were generated to assess the correlations. A p-value of < 0.05 was considered statistically significant. Of 936 patients with DKA, 84 (9.0%) had coexisting AP. AP was most common in the Asian race (66%, p < 0.001). Patients with DKA and AP were older, had higher admission anion-gap, white cell count, hemoglobin (hb), neutrophil/lymphocyte ratio, urea, creatinine, maximum blood glucose during the episode, total cholesterol and triglyceride level (TGL) (p < 0.05). They had a lower admission venous pH and bicarbonate at 6 h. Patients in the DKA with AP group also had a longer length of stay (LOS), DKA duration and a higher rate of ICU admission (p-values ≤ 0.001). In-hospital mortality, 3-month all-cause readmission, 6-month and 12-month DKA recurrence did not differ between the two groups. Univariate logistic regression analysis showed age, Asian ethnicity, male gender, T2D, admission WBC count, hb, urea, creatinine, potassium, venous pH, bicarbonate, anion gap, total cholesterol, TGL and LDL level were significantly associated with the development of DKA with AP (p < 0.05). In multivariate logistic regression analysis, age and total cholesterol level were associated with concomitant DKA and AP (p < 0.05). Patients with concomitant DKA and AP have more severe derangement in markers of DKA severity, inflammation, kidney injury and metabolic profile, along with a longer DKA duration, LOS and requirement for ICU support compared to DKA patients without AP. This highlights the clinical significance of diagnosing the co-existence of DKA with AP, as the combination results in significantly worse clinical outcomes and greater healthcare utilization than in patients with only DKA.

Burden and severity of deranged electrolytes and kidney function in children seen in a tertiary hospital in Kano, northern Nigeria.

INTRODUCTION: Derangement in serum electrolytes and kidney function is often overlooked, especially in resource-constrained settings, and associated with increased risk of morbidity and mortality. This study aimed to describe the burden of derangements in serum electrolytes and kidney function in children presenting to a tertiary hospital in Nigeria. METHODS: The laboratory records of all children who had serum electrolytes urea and creatinine ordered on their first presentation to hospital between January 1 and June 30, 2017 were retrospectively reviewed. Basic demographic data including admission status (inpatient or outpatient) were recordedandserum levels of sodium, potassium, chloride and bicarbonate were assessed for derangements usingnormal values from established reference ranges. Results of repeat samples were excluded. Kidney function was classified based on the serum creatinine relative to normal values for age and sex. RESULTS: During the study period, 1909 children (60.3% male); median (IQR) age 42 (11.9) months had serum chemistry and 1248 (65.4%) were admitted. Results of their first samples were analyzed. Electrolyte derangements were present in 78.6% of the samples most commonly hyponatraemia (41.1%), low bicarbonate(37.2%), hypochloraemia (33.5%) and hypokalemia(18.9%). Azotaemia was found in 20.1% of the results. Elevated serum creatinine levels were found in 399 children (24.7%), 24.1% of those being in the severe category. Children aged 5 years and younger accounted for 76.4% of those with derangement in kidney function. One hundred and eight outpatients (17.8%) had deranged kidney function. CONCLUSION: Deranged serum electrolytes and kidney function were common in this cohort.

Sodium zirconium cyclosilicate and metabolic acidosis: Potential mechanisms and clinical consequences.

Metabolic acidosis is frequent in chronic kidney disease (CKD) and is associated with accelerated progression of CKD, hypercatabolism, bone disease, hyperkalemia, and mortality. Clinical guidelines recommend a target serum bicarbonate ≥ 22 mmol/L, but metabolic acidosis frequently remains undiagnosed and untreated. Sodium zirconium cyclosilicate (SZC) binds potassium in the gut and is approved to treat hyperkalemia. In clinical trials with a primary endpoint of serum potassium, SZC increased serum bicarbonate, thus treating CKD-associated metabolic acidosis. The increase in serum bicarbonate was larger in patients with more severe pre-existent metabolic acidosis, was associated to decreased serum urea and was maintained for over a year of SZC therapy. SZC also decreased serum urea and increased serum bicarbonate after switching from a potassium-binding resin in normokalemic individuals. Mechanistically, these findings are consistent with SZC binding the ammonium ion (NH4+) generated from urea by gut microbial urease, preventing its absorption and, thus, preventing the liver regeneration of urea and promoting the fecal excretion of H+. This mechanism of action may potentially result in benefits dependent on corrected metabolic acidosis (e.g., improved well-being, decreased catabolism, improved CKD mineral bone disorder, better control of serum phosphate, slower progression of CKD) and dependent on lower urea levels, such as decreased protein carbamylation. A roadmap is provided to guide research into the mechanisms and clinical consequences of the impact of SZC on serum bicarbonate and urate.

Strategies to Enhance CO2 Electrochemical Reduction from Reactive Carbon Solutions.

CO2 electrochemical reduction (CO2 ER) from (bi)carbonate feed presents an opportunity to efficiently couple this process to alkaline-based carbon capture systems. Likewise, while this method of reducing CO2 currently lags behind CO2 gas-fed electrolysers in certain performance metrics, it offers a significant improvement in CO2 utilization which makes the method worth exploring. This paper presents two simple modifications to a bicarbonate-fed CO2 ER system that enhance the selectivity towards CO. Specifically, a modified hydrophilic cathode with Ag catalyst loaded through electrodeposition and the addition of dodecyltrimethylammonium bromide (DTAB), a low-cost surfactant, to the catholyte enabled the system to achieve a FECO of 85% and 73% at 100 and 200 mA·cm-2, respectively. The modifications were tested in 4 h long experiments where DTAB helped maintain FECO stable even when the pH of the catholyte became more alkaline, and it improved the CO2 utilization compared to a system without DTAB.

Potential Novel Role of Membrane-Associated Carbonic Anhydrases in the Kidney.

Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO2) and water into bicarbonate (HCO3-) and protons (H+), thereby influencing pH, are near the core of virtually all physiological processes in the body. In the kidneys, soluble and membrane-associated CAs and their synergy with acid-base transporters play important roles in urinary acid secretion, the largest component of which is the reabsorption of HCO3- in specific nephron segments. Among these transporters are the Na+-coupled HCO3- transporters (NCBTs) and the Cl--HCO3- exchangers (AEs)-members of the "solute-linked carrier" 4 (SLC4) family. All of these transporters have traditionally been regarded as "HCO3-" transporters. However, recently our group has demonstrated that two of the NCBTs carry CO32- rather than HCO3- and has hypothesized that all NCBTs follow suit. In this review, we examine current knowledge on the role of CAs and "HCO3-" transporters of the SLC4 family in renal acid-base physiology and discuss how our recent findings impact renal acid secretion, including HCO3- reabsorption. Traditionally, investigators have associated CAs with producing or consuming solutes (CO2, HCO3-, and H+) and thus ensuring their efficient transport across cell membranes. In the case of CO32- transport by NCBTs, however, we hypothesize that the role of membrane-associated CAs is not the appreciable production or consumption of substrates but the minimization of pH changes in nanodomains near the membrane.

The Mechanism of Metal-Containing Formate Dehydrogenases Revisited: The Formation of Bicarbonate as Product Intermediate Provides Evidence for an Oxygen Atom Transfer Mechanism.

Mo/W-containing formate dehydrogenases (FDH) catalyzed the reversible oxidation of formate to carbon dioxide at their molybdenum or tungsten active sites. While in the reaction of formate oxidation, the product is CO2, which exits the active site via a hydrophobic channel; bicarbonate is formed as the first intermediate during the reaction at the active site. Other than what has been previously reported, bicarbonate is formed after an oxygen atom transfer reaction, transferring the oxygen from water to formate and a subsequent proton-coupled electron transfer or hydride transfer reaction involving the sulfido ligand as acceptor.

Association of SARS-CoV-2 viral load with biochemical profile of COVID-19 patients: A nigerian experience.

Background: Kidney involvement in coronavirus disease 2019 (COVID-19) pathology has been supported by high frequency of angiotensin-converting enzyme 2 (ACE2) expression on renal cells and reports of acute kidney injury. However, the association between host viral load and kidney function is not clear. Aim: In this study, plasma levels of renal markers (urea nitrogen, creatinine, and estimated glomerular filtration rate (eGFR)) and electrolytes (sodium, potassium, chlorine, and bicarbonate) were assessed in relation to SARS-CoV-2 viral load of COVID-19 patients. Patients and Methods: This cross-sectional study involved 144 consenting COVID-19 patients admitted to the Ogun state COVID-19 isolation center between May and December 2020. All participants presented with mild respiratory symptoms and did not require ICU admission or ventilation support. Data included reverse transcriptase polymerase chain reaction (RT-PCR) cycle threshold (CT) value, blood urea nitrogen (BUN), creatinine, sodium, potassium, chlorine, bicarbonate measurements, and glomerular filtration rate. Reference intervals were used as comparators, and multiple linear regression model was fitted. Statistical significance was set at P < 0.05. Results: BUN level and creatinine were elevated in 4 (2.8%) and 42 (29.2%) patients, respectively, with lowered eGFR observed in 37 (25.7%) patients. Hyponatremia and hypokalemia were observed in 35 (24.3%) and 21 (14.6%) patients, respectively, while hypochloremia was observed in 21 (14.6%) patients. Lowered bicarbonate was observed in 29 (20.1%) patients. Linear regression showed statistically significant association (R2 = 0.340, P = 0.032) between RT-PCR CT value and eGFR (ß = 0.006, P = 0.017) as well as HCO3 (ß = -0.262, P = 0.036). Conclusion: COVID-19 patients with mild respiratory symptoms exhibited renal abnormalities, electrolytes, and acid-base imbalances which were partly associated with SARS-CoV-2 viral load.

Polyhydroxyalkanoates and 5-aminolevulinic acid production by a mixed phototrophic culture using medium-chain carboxylic acids from winery effluents.

This work aimed to obtain polyhydroxyalkanoates (PHA) and 5-aminolevulinic acid (5-ALA) from medium-chain carboxylic acids (MCCA) using a mixed culture enriched in Rhodopseudomnas palustris. MCCA, obtained from residual wine lees, were tested in batch photofermentation experiments. First, the influence of individual MCCA (hexanoic, heptanoic, and octanoic acids) was evaluated; then, the MCCA coming directly from a fermentation reactor (LC-effluent) or after acids extraction (HC-effluent) were studied. Nutrient supplementation, bicarbonate, and acetic acid addition were also tested. Results showed that PHA production was higher in hexanoic (328 mg PHA/L) compared to heptanoic (152 mg PHA/L) and octanoic (164 mg PHA/L) acids. Bicarbonate addition and acetic acid as co-substrate improved the MCCA consumption, the PHA content and production rate. The HC-effluent, without nutrient supplementation, was allowed to increase 2.5 times the PHA content (reaching 40 % w/w and 584 mg/L) and to double 5-ALA production (7.6 µM) compared to the LC-effluent condition.

Carbon signaling protein SbtB possesses atypical redox-regulated apyrase activity to facilitate regulation of bicarbonate transporter SbtA.

The PII superfamily consists of widespread signal transduction proteins found in all domains of life. In addition to canonical PII proteins involved in C/N sensing, structurally similar PII-like proteins evolved to fulfill diverse, yet poorly understood cellular functions. In cyanobacteria, the bicarbonate transporter SbtA is co-transcribed with the conserved PII-like protein, SbtB, to augment intracellular inorganic carbon levels for efficient CO2 fixation. We identified SbtB as a sensor of various adenine nucleotides including the second messenger nucleotides cyclic AMP (cAMP) and c-di-AMP. Moreover, many SbtB proteins possess a C-terminal extension with a disulfide bridge of potential redox-regulatory function, which we call R-loop. Here, we reveal an unusual ATP/ADP apyrase (diphosphohydrolase) activity of SbtB that is controlled by the R-loop. We followed the sequence of hydrolysis reactions from ATP over ADP to AMP in crystallographic snapshots and unravel the structural mechanism by which changes of the R-loop redox state modulate apyrase activity. We further gathered evidence that this redox state is controlled by thioredoxin, suggesting that it is generally linked to cellular metabolism, which is supported by physiological alterations in site-specific mutants of the SbtB protein. Finally, we present a refined model of how SbtB regulates SbtA activity, in which both the apyrase activity and its redox regulation play a central role. This highlights SbtB as a central switch point in cyanobacterial cell physiology, integrating not only signals from the energy state (adenyl-nucleotide binding) and the carbon supply via cAMP binding but also from the day/night status reported by the C-terminal redox switch.

Heartburn relief with bicarbonate-rich mineral water: results of the randomised, placebo-controlled phase-III trial STOMACH STILL.

OBJECTIVE: We assessed whether the bicarbonate-rich mineral water Staatl. Fachingen STILL is superior over conventional mineral water in relieving heartburn. DESIGN: Multicentre, double-blind, randomised, placebo-controlled trial STOMACH STILL in adult patients with frequent heartburn episodes since ≥6 months and without moderate/severe reflux oesophagitis. Patients drank 1.5 L/day verum or placebo over the course of the day for 6 weeks. Primary endpoint was the percentage of patients with reduction of ≥5 points in the Reflux Disease Questionnaire (RDQ) score for 'heartburn'. Secondary endpoints included symptom reduction (RDQ), health-related quality of life (HRQOL, Quality of Life in Reflux and Dyspepsia (QOLRAD)), intake of rescue medication and safety/tolerability. RESULTS: Of 148 randomised patients (verum: n=73, placebo: n=75), 143 completed the trial. Responder rates were 84.72% in the verum and 63.51% in the placebo group (p=0.0035, number needed to treat=5). Symptoms improved under verum compared with placebo for the dimension 'heartburn' (p=0.0003) and the RDQ total score (p=0.0050). HRQOL improvements under verum compared with placebo were reported for 3 of 5 QOLRAD domains, that is, 'food/drink problems' (p=0.0125), 'emotional distress' (p=0.0147) and 'vitality' (p=0.0393). Mean intake of rescue medication decreased from 0.73 tablets/day at baseline to 0.47 tablets/day in week 6 in the verum group, whereas in the placebo group it remained constant during the trial. Only three patients had treatment-related adverse events (verum: n=1, placebo: n=2). CONCLUSION: STOMACH STILL is the first controlled clinical trial demonstrating superiority of a mineral water over placebo in relieving heartburn, accompanied by an improved HRQOL. TRIAL REGISTRATION NUMBER: EudraCT 2017-001100-30.

Mathematical modelling of bicarbonate supplementation and acid-base chemistry in kidney failure patients on hemodialysis.

Acid-base regulation by the kidneys is largely missing in end-stage renal disease patients undergoing hemodialysis (HD). Bicarbonate is added to the dialysis fluid during HD to replenish the buffers in the body and neutralize interdialytic acid accumulation. Predicting HD outcomes with mathematical models can help select the optimal patient-specific dialysate composition, but the kinetics of bicarbonate are difficult to quantify, because of the many factors involved in the regulation of the bicarbonate buffer in bodily fluids. We implemented a mathematical model of dissolved CO2 and bicarbonate transport that describes the changes in acid-base equilibrium induced by HD to assess the kinetics of bicarbonate, dissolved CO2, and other buffers not only in plasma but also in erythrocytes, interstitial fluid, and tissue cells; the model also includes respiratory control over the partial pressures of CO2 and oxygen. Clinical data were used to fit the model and identify missing parameters used in theoretical simulations. Our results demonstrate the feasibility of the model in describing the changes to acid-base homeostasis typical of HD, and highlight the importance of respiratory regulation during HD.

Arterial bicarbonate is associated with hypoxic burden and uncontrolled hypertension in obstructive sleep apnea - The ESADA cohort.

OBJECTIVE: Blood bicarbonate concentration plays an important role for obstructive sleep apnea (OSA) patients to maintain acid-base balance. We investigated the association between arterial standard bicarbonate ([HCO3-]) and nocturnal hypoxia as well as comorbid hypertension in OSA. METHODS: A cross-sectional analysis of 3329 patients in the European Sleep Apnea Database (ESADA) was performed. Arterial blood gas analysis and lung function test were performed in conjunction with polysomnographic sleep studies. The 4% oxygen desaturation index (ODI), mean and minimum oxygen saturation (SpO2), and percentage of time with SpO2 below 90% (T90%) were used to reflect nocturnal hypoxic burden. Arterial hypertension was defined as a physician diagnosis of hypertension with ongoing antihypertensive medication. Hypertensive patients with SBP/DBP below or above 140/90 mmHg were classified as controlled-, uncontrolled hypertension, respectively. RESULTS: The [HCO3-] level was normal in most patients (average 24.0 ± 2.5 mmol/L). ODI, T90% increased whereas mean and minimum SpO2 decreased across [HCO3-] tertiles (ANOVA, p = 0.030, <0.001, <0.001, and <0.001, respectively). [HCO3-] was independently associated with ODI, mean SpO2, minimum SpO2, and T90% after adjusting for confounders (ß value [95%CI]: 1.21 [0.88-1.54], -0.16 [-0.20 to -0.11], -0.51 [-0.64 to -0.37], 1.76 [1.48-2.04], respectively, all p < 0.001). 1 mmol/L elevation of [HCO3-] was associated with a 4% increased odds of uncontrolled hypertension (OR: 1.04 [1.01-1.08], p = 0.013). CONCLUSION: We first demonstrated an independent association between [HCO3-] and nocturnal hypoxic burden as well as uncontrolled hypertension in OSA patients. Bicarbonate levels as an adjunctive measure provide insight into the pathophysiology of hypertension in OSA.

Sodium bicarbonate for kidney transplant recipients with metabolic acidosis in Switzerland: a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Swiss National Science Foundation.

The effects of immersion in 42℃ radon, natrium, calcium, bicarbonate content thermal-mineral water on chronic low back pain. Controlled, follow-up study.

In our minimized follow-up trial with 137 participants with chronic low back pain, one group of participants received regular outpatient care, and the other group received balneotherapy by immersion in 42℃ thermal-mineral water in addition to regular outpatient care on 15 occasions for 3 weeks. Pain on movement and at rest on the 0-100 mm visual analogue scale (VAS), Oswestry index, the number of participants evaluating the symptoms clinically acceptable (Patient Acceptable Symptom State, PASS) and the EuroQol-5D-5L (EQ-5D-5L) quality of life questionnaire were assessed at basal time (at week 0) and after balneotherapy (at weeks 3 and 12). The VAS pain scores, the Oswestry index, the EQ-5D-5L index and the EQ-VAS significantly improved in the balneotherapy group after treatment at week 3 (p < 0.001) and week 12 (p < 0.001) compared to baseline, with a significant between group difference at week 3 (p < 0.001) and week 12 (p < 0.001). The pain VAS score on movement was 66.82 ± 11.48, 26.69 ± 21.49, and 20.09 ± 23.29 in the balneotherapy group, and 63.67 ± 14.77, 67.35 ± 15.44, and 70.23 ± 18.26 in the control group at the consecutive visits. The PASS increased in both groups at week 3 and week 12 compared to the baseline, with a significant between-group difference at week 3 and week 12 for the balneotherapy group. Our results suggest the therapeutic efficacy of immersion in 42℃ thermal mineral water on chronic low back pain.ClinicalTrials.gov Identifier: NCT05342051.

Pendrin regulation is prioritized by anion in high-potassium diets.

The Cl-/[Formula: see text] exchanger pendrin in the kidney maintains acid-base balance and intravascular volume. Pendrin is upregulated in models associated with high circulating aldosterone concentration, such as dietary NaCl restriction or an aldosterone infusion. However, it has not been established if pendrin is similarly regulated by aldosterone with a high-K+ diet because the effects of accompanying anions have not been considered. Here, we explored how pendrin is modulated by different dietary potassium salts. Wild-type (WT) and aldosterone synthase (AS) knockout (KO) mice were randomized to control, high-KHCO3, or high-KCl diets. Dietary KCl and KHCO3 loading increased aldosterone in WT mice to the same extent but had opposite effects on pendrin abundance. KHCO3 loading increased pendrin protein and transcript abundance. Conversely, high-KCl diet feeding caused pendrin to decrease within 8 h of switching from the high-KHCO3 diet, coincident with an increase in plasma Cl- and a decrease in [Formula: see text]. In contrast, switching the high-KCl diet to the high-KHCO3 diet caused pendrin to increase in WT mice. Experiments in AS KO mice revealed that aldosterone is necessary to optimally upregulate pendrin protein in response to the high-KHCO3 diet but not to increase pendrin mRNA. We conclude that pendrin is differentially regulated by different dietary potassium salts and that its regulation is prioritized by the dietary anion, providing a mechanism to prevent metabolic alkalosis with high-K+ base diets and safeguard against hyperchloremic acidosis with consumption of high-KCl diets.NEW & NOTEWORTHY Regulation of the Cl-/[Formula: see text] exchanger pendrin has been suggested to explain the aldosterone paradox. A high-K+ diet has been proposed to downregulate a pendrin-mediated K+-sparing NaCl reabsorption pathway to maximize urinary K+ excretion. Here, we challenged the hypothesis, revealing that the accompanying anion, not K+, drives pendrin expression. Pendrin is downregulated with a high-KCl diet, preventing acidosis, and upregulated with an alkaline-rich high-K+ diet, preventing metabolic alkalosis. Pendrin regulation is prioritized for acid-base balance.

Base (HCO3-/CO32-) Transport Properties of SLC4 Proteins: New Insights in Acid-Base Kidney Physiology.

H+ or base transporters and channels in the mammalian genome play important roles in the maintenance of numerous cellular biochemical and physiologic processes throughout the body. Among the known base transporters, those within the SLC4 and SLC26 gene families are involved in cell, transepithelial, and whole organ function. Whether the functional properties of these transporters involve HCO3-, CO32-, or HCO3-/CO32- stimulated H+ (or OH-) transport has not received widespread attention in the literature. Accordingly, "bicarbonate" is the term typically used in most textbooks without greater specificity. Moreover, clinicians and physiologists have historically focused on the blood HCO3- concentration as the base term in the Henderson-Hasselbalch equation in the analysis of clinical acid-base abnormalities, thus, bicarbonate has been assumed to be the species reabsorbed along the nephron as required to maintain the blood [HCO3-] at approximately 25 mM. However, accumulating data in the literature suggest that carbonate, rather than bicarbonate, is the species absorbed across the proximal tubule basolateral membrane, whereas in the collecting duct, bicarbonate is indeed transported. Various experimental approaches leading to this new concept are herein reviewed.

Role of the luminal composition on intestinal metal toxicity, bioavailability and bioreactivity: An in vitro approach based on the cell line RTgutGC.

The bioavailability of metal complexes is poorly understood. To evaluate bioavailability and toxicity of neutral and charged complexes as well as free metal ions, Visual Minteq, a chemical equilibrium model, was used to design media containing different metal species. Two non-essential (silver and cadmium) and two essential (copper and zinc) metals were selected. The rainbow trout (Oncorhynchus mykiss) gut cell line (RTgutGC) was used to investigate bioavailability, bioreactivity and toxicity of the different metal species. Toxicity was measured using a multiple endpoint cytotoxicity assay, bioavailability by measuring intracellular metal concentration, and bioreactivity by quantification of mRNA level of the metal responsive genes, metallothionein (MT), glutathione reductase (GR) and zinc transporter 1 (ZnT1). Speciation calculations showed that silver and cadmium preferentially bind chloride, copper phosphate and bicarbonate, and zinc remained primarily as a free ion. Cysteine avidly complexed with all metals reducing toxicity, bioavailability and bioreactivity. Silver and copper toxicity was not affected by inorganic metal speciation, whereas cadmium and zinc toxicity was decreased by chloride complexation. Moreover, reduction of calcium concentration in the medium increased toxicity and bioavailability of cadmium and zinc. Bioavailability of silver and zinc was reduced by low chloride while cadmium bioavailability was increased by low chloride and in presence of bicarbonate. Copper bioavailability was not affected by the medium composition. Cadmium and silver were more bioreactive, independently from the medium composition, in comparison to copper and zinc (i.e., higher induction of MT and GR). Cadmium was the only metal able to induce MT in presence of cysteine. ZnT1 was induced by cadmium in low-chloride, by zinc in low-chloride low-calcium and by cadmium and copper in the bicarbonate media. Overall, this study demonstrates that metal complexation alone is not sufficient to explain metal toxicity, and that anion exchange mechanisms play a role in metal uptake and bioreactivity.