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Bicarbonate-controlled reduction of oxygen by the QA semiquinone in Photosystem II in membranes.
Fantuzzi, A, Allgöwer, F, Baker, H, McGuire, G, Teh, WK, Gamiz-Hernandez, AP, Kaila, VRI, Rutherford, AW
Proceedings of the National Academy of Sciences of the United States of America. 2022;(6)
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Abstract
Photosystem II (PSII), the water/plastoquinone photo-oxidoreductase, plays a key energy input role in the biosphere. [Formula: see text], the reduced semiquinone form of the nonexchangeable quinone, is often considered capable of a side reaction with O2, forming superoxide, but this reaction has not yet been demonstrated experimentally. Here, using chlorophyll fluorescence in plant PSII membranes, we show that O2 does oxidize [Formula: see text] at physiological O2 concentrations with a t1/2 of 10 s. Superoxide is formed stoichiometrically, and the reaction kinetics are controlled by the accessibility of O2 to a binding site near [Formula: see text], with an apparent dissociation constant of 70 ± 20 µM. Unexpectedly, [Formula: see text] could only reduce O2 when bicarbonate was absent from its binding site on the nonheme iron (Fe2+) and the addition of bicarbonate or formate blocked the O2-dependant decay of [Formula: see text] These results, together with molecular dynamics simulations and hybrid quantum mechanics/molecular mechanics calculations, indicate that electron transfer from [Formula: see text] to O2 occurs when the O2 is bound to the empty bicarbonate site on Fe2+ A protective role for bicarbonate in PSII was recently reported, involving long-lived [Formula: see text] triggering bicarbonate dissociation from Fe2+ [Brinkert et al, Proc. Natl. Acad. Sci. U.S.A. 113, 12144-12149 (2016)]. The present findings extend this mechanism by showing that bicarbonate release allows O2 to bind to Fe2+ and to oxidize [Formula: see text] This could be beneficial by oxidizing [Formula: see text] and by producing superoxide, a chemical signal for the overreduced state of the electron transfer chain.
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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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Extracellular buffer choice influences acid-base responses and gastrointestinal symptoms.
Peacock, J, Sparks, SA, Middlebrook, I, Hilton, NP, Tinnion, D, Leach, N, Saunders, B, McNaughton, LR
Research in sports medicine (Print). 2021;(6):505-516
Abstract
To compare the bicarbonate kinetics and gastrointestinal (GI) symptom responses between an equal dose of sodium bicarbonate and sodium citrate using delayed-release capsules. Thirteen active males (age 20.5 ± 2.1 y, height 1.8 ± 0.1 m and body mass [BM] 76.5 ± 9.6 kg) consumed either 0.3 g.kg-1 BM sodium bicarbonate, sodium citrate or a placebo, using a double-blind, randomized crossover design. Blood bicarbonate ion (HCO3-) concentration, pH and GI symptoms were measured pre-consumption and every 10 min for 180 min post-consumption. Blood HCO3- concentration (P < 0.001) and pH (P = 0.040) were significantly higher in the sodium bicarbonate condition compared with sodium citrate condition up to 3 h post-consumption. Peak blood HCO3- concentration was significantly higher with the sodium bicarbonate compared with citrate (P < 0.001). Mean GI symptom scores were lower (P = 0.037) for sodium citrate (1.5 ± 1.8 AU) than bicarbonate (2.6 ± 3.1 AU), with considerable inter-individual variability. No GI symptoms were reported following consumption of the placebo. Both substances increase HCO3- values significantly, with sodium bicarbonate causing significantly higher pH and HCO3- values than the same dose of sodium citrate, but results in slightly more severe GI symptoms.
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Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study.
Tyson, CC, Luciano, A, Modliszewski, JL, Corcoran, DL, Bain, JR, Muehlbauer, M, Ilkayeva, O, Pourafshar, S, Allen, J, Bowman, C, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021;(1):38-47
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Abstract
RATIONALE & OBJECTIVE Patients with CKD are at elevated risk of metabolic acidosis due to impaired net acid excretion (NAE). Identifying early markers of acidosis may guide prevention in chronic kidney disease (CKD). This study compared NAE in participants with and without CKD, as well as the NAE, blood pressure (BP), and metabolomic response to bicarbonate supplementation. STUDY DESIGN Randomized order, cross-over study with controlled feeding. SETTING & PARTICIPANTS Participants consisted of 8 patients with CKD (estimated glomerular filtration rate 30-59mL/min/1.73m2 or 60-70mL/min/1.73m2 with albuminuria) and 6 patients without CKD. All participants had baseline serum bicarbonate concentrations between 20 and 28 mEq/L; they did not have diabetes mellitus and did not use alkali supplements at baseline. INTERVENTION Participants were fed a fixed-acid-load diet with bicarbonate supplementation (7 days) and with sodium chloride control (7 days) in a randomized order, cross-over fashion. OUTCOMES Urine NAE, 24-hour ambulatory BP, and 24-hour urine and plasma metabolomic profiles were measured after each period. RESULTS During the control period, mean NAE was 28.3±10.2 mEq/d overall without differences across groups (P=0.5). Urine pH, ammonium, and citrate were significantly lower in CKD than in non-CKD (P<0.05 for each). Bicarbonate supplementation reduced NAE and urine ammonium in the CKD group, increased urine pH in both groups (but more in patients with CKD than in those without), and increased; urine citrate in the CKD group (P< 0.2 for interaction for each). Metabolomic analysis revealed several urine organic anions were increased with bicarbonate in CKD, including 3-indoleacetate, citrate/isocitrate, and glutarate. BP was not significantly changed. LIMITATIONS Small sample size and short feeding duration. CONCLUSIONS Compared to patients without CKD, those with CKD had lower acid excretion in the form of ammonium but also lower base excretion such as citrate and other organic anions, a potential compensation to preserve acid-base homeostasis. In CKD, acid excretion decreased further, but base excretion (eg, citrate) increased in response to alkali. Urine citrate should be evaluated as an early and responsive marker of impaired acid-base homeostasis. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases and the Duke O'Brien Center for Kidney Research. TRIAL REGISTRATION Registered at ClinicalTrials.gov with study number NCT02427594.
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Metabolic acidosis is associated with increased risk of adverse kidney outcomes and mortality in patients with non-dialysis dependent chronic kidney disease: an observational cohort study.
Tangri, N, Reaven, NL, Funk, SE, Ferguson, TW, Collister, D, Mathur, V
BMC nephrology. 2021;(1):185
Abstract
BACKGROUND Management of chronic kidney disease (CKD) requires the management of risk factors, such as hypertension and albuminuria, that affect CKD progression. Identification of additional modifiable risk factors is necessary to develop new treatment strategies for CKD. We sought to quantify the association of metabolic acidosis with CKD progression and mortality in a large U.S. community-based cohort. METHODS In this longitudinal, retrospective cohort study we identified non-dialysis-dependent patients with stage 3‒5 CKD from Optum's de-identified integrated electronic health records. We selected cohorts of patients with confirmed metabolic acidosis or normal serum bicarbonate levels based on 2 consecutive serum bicarbonate values: 12 to < 22 mEq/L or 22-29 mEq/L, respectively, 28‒365 days apart. The primary composite outcome was ≥ 40 % decline in estimated glomerular filtration rate (eGFR), renal replacement therapy (chronic dialysis or kidney transplant), or all-cause mortality (DD40). Secondary outcomes included each component of the composite outcome. Cox proportional hazards models were used for the DD40 outcome and secondary outcomes, while logistic regression models were used for the DD40 outcome at 2 years. RESULTS A total of 51,558 patients qualified for the study. The unadjusted 2-year incidence of adverse renal and fatal outcomes was significantly worse among patients in the metabolic acidosis group vs. those who had normal serum bicarbonate levels: 48 % vs. 17 % for DD40, 10 % vs. 4 % for ≥ 40 % decline in eGFR, 20 % vs. 6 % for renal replacement therapy, and 31 % vs. 10 % for all-cause mortality (all P < 0.001). Over a ≤ 10-year period, for each 1-mEq/L increase in serum bicarbonate, the adjusted hazard ratio for DD40 was 0.926 (95 % confidence interval [CI], 0.922-0.930; P < 0.001); over a ≤ 2-year period, the adjusted odds ratio for DD40 was 0.873 (95 % CI, 0.866-0.879; P < 0.001). CONCLUSIONS In this large community cohort of patients with stage 3‒5 CKD, the presence of metabolic acidosis was a significant, independent risk factor for the composite adverse outcome of CKD progression, renal replacement therapy, and all-cause mortality (DD40).
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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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Modulation of the Association of Hypobicarbonatemia and Incident Kidney Failure With Replacement Therapy by Venous pH: A Cohort Study.
Kajimoto, S, Sakaguchi, Y, Asahina, Y, Kaimori, JY, Isaka, Y
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021;(1):35-43
Abstract
RATIONALE & OBJECTIVE Studies showing an association between lower bicarbonate levels and worse kidney disease prognosis have not accounted for the influence of pH. It remains unknown whether this association is consistent across a wide range of blood pH values. This study sought to assess how pH modifies the relationship between hypobicarbonatemia and incident kidney failure requiring kidney replacement therapy (KFRT). STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 1,058 Japanese patients with estimated glomerular filtration rates<60mL/min/1.73m2. EXPOSURE Baseline venous bicarbonate levels and venous pH. OUTCOME KFRT defined as initiation of kidney replacement therapy (hemodialysis, peritoneal dialysis, and kidney transplantation). ANALYTICAL APPROACH Cox proportional hazards model assessing the interaction between baseline bicarbonate levels and venous pH on incident KFRT. RESULTS In the lowest bicarbonate quartile (≤21.5 mEq/L), 59% of patients had acidemia (pH<7.32), whereas 38% had venous pH within the normal range and 3% had alkalemia (pH>7.42). During a median follow-up of 3.0 years, 374 patients developed KFRT. Venous pH modified the association between bicarbonate level and rate of KFRT (P for interaction=0.04). After adjustment for potential confounders, including capacity for respiratory compensation, the lowest (vs the highest) bicarbonate quartile was associated with a 2.29-fold (95% CI, 1.10-4.77; P=0.03) higher rate of KFRT among patients with acidemia (pH<7.32). In contrast, among patients without acidemia (pH≥7.32), no significant association was found between bicarbonate level and KFRT. In an exploratory analysis, patients with higher respiratory compensation capacity had a lower rate of KFRT (HR per 0.1 increase in respiratory compensation capacity, 0.90; 95% CI, 0.87-0.94; P<0.001). LIMITATIONS Observational study design; blood gas measurements were performed in a select patient population. CONCLUSIONS Venous pH modified the association of hypobicarbonatemia with progression of chronic kidney disease to KFRT. Measurement of venous pH may be valuable for identifying patients with chronic kidney disease and hypobicarbonatemia and may inform treatment.
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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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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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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.