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Distal renal tubular acidosis (dRTA) is characterized by a primary defect in proton secretion by α-intercalated cells of the collecting duct, leading to impaired urine acidification and resulting in metabolic acidosis, hypokalemia, and hypercalciuria. Inherited forms of dRTA are currently associated with variants in five genes (SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, and WDR72), each being associated with specific extra-renal manifestations. Acquired forms can result from autoimmune diseases or drug side effects. Classical complications include nephrolithiasis, nephrocalcinosis, reduced glomerular filtration rate (GFR), bone demineralization, and growth failure. Treatment focuses on correcting the acid-base imbalance through alkali supplementation (potassium, sodium, or magnesium bicarbonate or citrate) to reduce renal disease progression and promote normal growth and mineralization. Traditional treatments (alkali and potassium supplementation) often suffer from poor adherence due to frequent day and night administrations, gastrointestinal discomfort, and unpleasant taste. A novel investigational drug, ADV7103, which contains potassium citrate and potassium bicarbonate in an extended-release formulation, has recently been approved by the European Medicine Agency (EMA) for dRTA. Recent studies support its use as a first-line treatment, given its efficacy and safety profile., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Hyperaldosteronism (HA) is a common cause of secondary hypertension and may contribute to resistant hypertension (RH). The authors sought to determine and characterize HA screening, positivity rates, and mineralocorticoid receptor antagonist (MRA) use among patients with RH., Methods: A cross-sectional study was performed within Kaiser Permanente Southern California (7/1/2012-6/30/2017). Using contemporary criteria, RH was defined as blood pressure uncontrolled (≥ 130/80) on ≥ 3 medications or requiring ≥ 4 antihypertensive medications. The primary outcome was screening rate for HA defined as any aldosterone and plasma renin activity measurement. Secondary outcomes were HA screen positive rates and MRA use among all patients with RH. Multivariable logistic regression analysis was used to estimate odds ratio (with 95% confidence intervals) for factors associated with HA screening and for patients that screened positive., Results: Among 102,480 patients identified as RH, 1977 (1.9%) were screened for HA and 727 (36.8%) screened positive for HA. MRA use was 6.5% among all patients with RH (22.5% among screened, 31.2% among screened positive). Black race, potassium < 4, bicarbonate > 29, chronic kidney disease, obstructive sleep apnea, and systolic blood pressure were associated with HA screening, but only Black race (1.55 [1.20-2.01]), potassium (1.82 [1.48-2.24]), bicarbonate levels (1.39 [1.10-1.75]), and diastolic blood pressure (1.15 [1.03-1.29]) were associated with positive screenings., Conclusion: The authors' findings demonstrate low screening rates for HA among patients with difficult-to-control hypertension yet a high positivity rate among those screened. Factors associated with screening did not always correlate with screening positive. Screening and targeted use of MRA may lead to improved blood pressure control and outcomes among patients with RH., Competing Interests: Conflict of InterestNone declared

Significance Statement: Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated., Background: Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate., Methods: In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20-40 ml/min per 1.73 m 2 ) and metabolic acidosis (serum bicarbonate of 12-20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure., Results: The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m 2 , and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups., Conclusions: Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis., Clinical Trial Registry Name and Registration Number: VALOR-CKD, NCT03710291 ., (Copyright © 2024 by the American Society of Nephrology.)

Background: Acetazolamide has been used for diuretic-induced metabolic alkalosis, but the preferred dose, route, and frequency of administration remain unknown., Objective: The purpose of this study was to characterize dosing strategies and determine the effectiveness of intravenous (IV) and oral (PO) acetazolamide for patients with heart failure (HF) with diuretic-induced metabolic alkalosis., Methods: This was a multicenter, retrospective cohort study comparing the use of IV versus PO acetazolamide in patients with HF receiving at least 120 mg of furosemide for the treatment of metabolic alkalosis (serum bicarbonate CO 2 ≥32). The primary outcome was the change in CO 2 on the first basic metabolic panel (BMP) within 24 hours of the first dose of acetazolamide. Secondary outcomes included laboratory outcomes, such as change in bicarbonate, chloride, and incidence of hyponatremia and hypokalemia. This study was approved by the local institutional review board., Results: IV acetazolamide was given in 35 patients and PO acetazolamide was given in 35 patients. Patients in both groups were given a median of 500 mg of acetazolamide in the first 24 hours. For the primary outcome, there was a significant decrease in CO 2 on the first BMP within 24 hours after patients received the IV acetazolamide (-2 [interquartile range, IQR: -2, 0] vs 0 [IQR: -3, 1], P = 0.047). There were no differences in secondary outcomes., Conclusion and Relevance: IV acetazolamide resulted in significantly decreased bicarbonate within 24 hours of administration. IV acetazolamide may be preferred to treat diuretic-induced metabolic alkalosis in patients with HF., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background & Aims: Non-alcoholic fatty liver disease is increasingly gaining epidemiological ground in liver diseases. Among the proposed non-pharmacologic interventions, dietary interventions have been widely used. Several patients suffering from it complain of gastrointestinal symptoms unrelated to organic gastrointestinal tract disease. However, the role of drinking water quality modifications in this regard has not been investigated in depth., Methods: Patients with upper or lower functional gastrointestinal symptoms were enrolled and divided into groups based on bright liver ultrasound relief's presence (SP) or absence (NSP). These patients were asked to drink bicarbonate-sulphate-calcium-magnesium and sodium-low drinkable water (Fonte Essenziale ®) for six months. Participants were assessed at baseline (T0), at the end of six months of drinking water intake (T6), and after an additional six months of washout (T12) by questionnaires designed to evaluate lower and upper gastrointestinal symptoms (Leeds dyspepsia score, short form) severity and frequency., Results: A total of 61 patients were enrolled. In the SP population, the severity of lower gastrointestinal symptoms improved between T0-T6 (Z: -2.437; ES: 0.312) and worsened after the water washout (Z: -2.492; ES: 0.319). The same was for the Leeds score severity sub score in T0-T6 (Z: -2.850; ES: 0.364) and T6-T12 (Z: -2.921; ES: 0.374). These improvements seem unrelated to the severity of liver steatosis at baseline. Furthermore, no safety issues were recorded while taking the water nor during the six-month follow-up afterwards., Conclusion: Regular six-month intake of 400 mL of Fonte Essenziale® water was associated, in the absence of dietary regimen modifications, with an improvement in some qualitative and quantitative features of upper and lower functional gastrointestinal symptoms in both an SP and NSP sample., (Copyright © 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: The use of sodium bicarbonate to treat metabolic acidosis is intuitive, yet data suggest that not all patients benefit from this therapy., Objective: In this narrative review, we describe the physiology behind commonly encountered nontoxicologic causes of metabolic acidosis, highlight potential harm from the indiscriminate administration of sodium bicarbonate in certain scenarios, and provide evidence-based recommendations to assist emergency physicians in the rational use of sodium bicarbonate., Discussion: Sodium bicarbonate can be administered as a hypertonic push, as a resuscitation fluid, or as an infusion. Lactic acidosis and cardiac arrest are two common scenarios where there is limited benefit to routine use of sodium bicarbonate, although certain circumstances, such as patients with concomitant acute kidney injury and lactic acidosis may benefit from sodium bicarbonate. Patients with cardiac arrest secondary to sodium channel blockade or hyperkalemia also benefit from sodium bicarbonate therapy. Recent data suggest that the use of sodium bicarbonate in diabetic ketoacidosis does not confer improved patient outcomes and may cause harm in pediatric patients. Available evidence suggests that alkalinization of urine in rhabdomyolysis does not improve patient-centered outcomes. Finally, patients with a nongap acidosis benefit from sodium bicarbonate supplementation., Conclusions: Empiric use of sodium bicarbonate in patients with nontoxicologic causes of metabolic acidosis is not warranted and likely does not improve patient-centered outcomes, except in select scenarios. Emergency physicians should reserve use of this medication to conditions with clear benefit to patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Acetazolamide inhibits proximal tubular sodium and bicarbonate re-absorption and improved decongestive response in acute heart failure in the ADVOR trial. It is unknown whether bicarbonate levels alter the decongestive response to acetazolamide., Methods and Results: This is a sub-analysis of the randomized, double-blind, placebo-controlled ADVOR trial that randomized 519 patients with acute heart failure and volume overload in a 1:1 ratio to intravenous acetazolamide (500 mg/day) or matching placebo on top of standardized intravenous loop diuretics (dose equivalent of twice oral maintenance dose). The primary endpoint was complete decongestion after 3 days of treatment (morning of day 4). Impact of baseline HCO3 levels on the treatment effect of acetazolamide was assessed. : Of the 519 enrolled patients, 516 (99.4%) had a baseline HCO3 measurement. Continuous HCO3 modelling illustrated a higher proportional treatment effect for acetazolamide if baseline HCO3 ≥ 27 mmol/l. A total of 234 (45%) had a baseline HCO3 ≥ 27 mmol/l. Randomization towards acetazolamide improved decongestive response over the entire range of baseline HCO3- levels (P = 0.004); however, patients with elevated baseline HCO3 exhibited a significant higher response to acetazolamide [primary endpoint: no vs. elevated HCO3; OR 1.37 (0.79-2.37) vs. OR 2.39 (1.35-4.22), P-interaction = 0.065), with higher proportional diuretic and natriuretic response (both P-interaction < 0.001), greater reduction in congestion score on consecutive days (treatment × time by HCO3-interaction <0.001) and length of stay (P-interaction = 0.019). The larger proportional treatment effect was mainly explained by the development of diminished decongestive response in the placebo arm (loop diuretics only), both with regard to reaching the primary endpoint of decongestion as well as reduction in congestion score. Development of elevated HCO3 further worsened decongestive response in the placebo arm (P-interaction = 0.041). A loop diuretic only strategy was associated with an increase in the HCO3 during the treatment phase which was prevented by acetazolamide (day 3: placebo 74.8% vs. acetazolamide 41.3%, P < 0.001)., Conclusion: Acetazolamide improves decongestive response over the entire range of HCO3- levels; however, the treatment response is magnified in patients with baseline or loop diuretic-induced elevated HCO3 (marker of proximal nephron NaHCO3 retention) by specifically counteracting this component of diuretic resistance., Competing Interests: Conflict of interest P.M.: received consultancy fees from CLS Vifor Pharma. F.H.V.: none. J.D.: none. P.N.: none. E.M.: FWO research grant—1SF6822N. S.N.A.: none. J.M.T.M.: received consultancy fees from Boehringer Ingelheim and a Personal grant from the Dutch Heart Foundation. L.H.: none. K.D.: speakers fee from Abbott, Boehringer ingelheim and Astrazeneca and fees for participation in DSMB of FIRE1, REPREIVE, SEQUANA Medical. A.M.: none. G.F.: grants from the European Commission, and speaker fees or DSMB fees from Bayer and Boehringer Ingelheim and fees from the Heart Failure Association. Serves as committee member for Medtronics, Bayer, Boehringer Ingelhein, Vifor, Amgen, Servier, Novartis. F.R.: not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years. The Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research, educational and/or travel grants from Abbott, Amgen, Astra Zeneca, Bayer, Berlin Heart, B. Braun, Biosense Webster, Biosensors Europe AG, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, Cardinal Health Switzerland, Corteria, Daiichi, Diatools AG, Edwards Lifesciences, Fresenius, Guidant Europe NV (BS), Hamilton Health Sciences, Kaneka Corporation, Kantar, Labormedizinisches Zentrum, Medtronic, MSD, Mundipharma Medical Company, Novartis, Novo Nordisk, Orion, Pfizer, Quintiles Switzerland Sarl, Sahajanand IN, Sanofi, Sarstedt AG, Servier, SIS Medical, SSS International Clinical Research, Terumo Deutschland, Swiss National Foundation, Trama Solutions, V-Wave, Vascular Medical, Vifor, Wissens Plus, ZOLL. The research and educational grants do not impact on Prof. Ruschitzka’s personal remuneration. The Department of Cardiology received consultancy fees form AstraZeneca (IMC), Bayer, Boehringer Ingelheim, Citi Research, Klub Class, Novo Nordisk, Radcliffe Group, Stiftung Pfizer Forschungspreis, Vifor. The Department of Cardiology (University Hospital of Zurich/University of Zurich) reports speaker fees from Abbott, Amgen, AstraZeneca (A + Science AB), Bayer (At the Limits), Boehringer Ingelheim, Boston Scientific (CCE Services), Brigham and Women’s Hospital Boston, C.T.I. GmbH, Hôpitaux Universitaires des Genève (GECORE), Luzerner Kantonsspital, Sanofi-Aventis, Servier, Medscape (WebMD), Medtronic, Medworld, Novartis, Roche, Ruwag, Swiss Heart Failure Academy, The Hong Kong Heart Failure Society, Trama Solutions SL, Inselspital Bern, Charité—Universitätsmedizin Berlin (Medical Education Global Solutions), Romanian Society of Cardiology, ÖKG—Österreichische Gesellschaft für Kardiologie. W.H.W.T.: received grants from NIH and consultancy fees from Owkin, Relypsa, ProCardia, Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, Whiteswell, Boston Scientific, Kiniksa Pharmaceuticals, CardiaTec Biosciences, Applier Therapeutics. M.D.: received consultancy fees from Astra Zeneca and Boehringer Ingelheim. W.M.: speakers fees from Medtronic, Abbott, Novartis, Vifor Pharma, AstraZenica, Boehringer Ingelheim, Pfizer, Novo Nordisk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Bupropion cardiotoxicity widens QRS complexes by inhibiting cardiac gap junctions. Sodium bicarbonate is the standard treatment for QRS widening from sodium channel blockade, but its effect on QRS widening in bupropion cardiotoxicity is not well-studied., Methods: This is a retrospective cohort study of bupropion overdoses from 10 hospitals between January 2010 and June 2022. Patients with documented administration of sodium bicarbonate and QRS duration > 100 milliseconds on pre-bicarbonate electrocardiogram were included. Patients with no electrocardiogram within four hours of treatment or with baseline pre-overdose wide QRS and < 10 milliseconds widening from baseline were excluded. The primary outcome was a change in QRS duration between the pre-bicarbonate electrocardiogram and the first electrocardiogram after initial bicarbonate administration. Secondary outcomes included prevalence of post-bicarbonate QRS < 100 milliseconds, change in electrocardiogram intervals after total bicarbonate administration, and change in metabolic parameters and hemodynamics. Wilcoxon signed-rank testing was performed on the primary outcome. Linear regression modeling was performed to test for an association between change in QRS and bicarbonate dosing., Results: Thirteen patients were included for final analysis. The median age was 32 years, and 54% were male. Six patients developed seizures; one developed ventricular tachycardia, and four received vasopressors. The median QRS and QTc pre-bicarbonate were 116 and 495 milliseconds, respectively. The median change in QRS duration was -2.0 milliseconds, which was not statistically significant ( P  = 0.42). The median bicarbonate dose administered before the first post-bicarbonate electrocardiogram was 100 milliequivalents. We did not identify an association between QRS change and bicarbonate dosing ( P  = 0.9, R-squared = 0.001). No patient had a QRS duration < 100 milliseconds after the initial bicarbonate dose. There was minimal change in QTc, electrolytes, heart rate, or blood pressure; alkalemia post-bicarbonate was achieved in eight patients., Conclusion: Sodium bicarbonate did not significantly decrease QRS duration in this small retrospective cohort of bupropion overdoses.

Background: Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progression of CKD., Methods: The VALOR-CKD trial is an international, randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the effect of once-daily veverimer on kidney disease progression in patients with metabolic acidosis and CKD. Eligibility criteria include a serum bicarbonate in the range of 12-20 mmol/L and an estimated glomerular filtration rate (eGFR) of 20-40 mL/min/1.73 m2. The primary outcome is kidney disease progression defined as the development of end-stage kidney disease, a sustained decline in eGFR of >40% from baseline or death due to kidney failure. Key secondary endpoints include effects on physical function., Results: Between December 2018 and December 2021, 1480 participants were randomized. The mean age at baseline was 65.1 years and 42% of the patients were female. The mean baseline eGFR was 29.1 mL/min/1.73 m2 and mean serum bicarbonate was 17.5 mmol/L. The median urine albumin-to-creatinine ratio at screening was 201 mg/g and the median 5-year predicted risk of kidney failure was 32%. Diabetes and hypertension were present in 56% and 98% of participants, respectively., Conclusions: VALOR-CKD has recruited a large population of people with metabolic acidosis at high risk for CKD progression to determine the effects of veverimer on the risk of progressive loss of kidney function., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Although acute diarrhoea is a self-limiting disease, dehydration may occur in some children. Dehydration is the consequence of an increased loss of water and electrolytes (sodium, chloride, potassium, and bicarbonate) in liquid stools. When these losses are high and not replaced adequately, severe dehydration appears. Severe dehydration is corrected with intravenous solutions. The most frequently used solution for this purpose is 0.9% saline. Balanced solutions (e.g. Ringer's lactate) are alternatives to 0.9% saline and have been associated with fewer days of hospitalization and better biochemical outcomes. Available guidelines provide conflicting recommendations. It is unclear whether 0.9% saline or balanced intravenous fluids are most effective for rehydrating children with severe dehydration due to diarrhoea., Objectives: To evaluate the benefits and harms of balanced solutions for the rapid rehydration of children with severe dehydration due to acute diarrhoea, in terms of time in hospital and mortality compared to 0.9% saline., Search Methods: We used standard, extensive Cochrane search methods. The latest search date was 4 May 2022., Selection Criteria: We included randomized controlled trials in children with severe dehydration due to acute diarrhoea comparing balanced solutions, such as Ringer's lactate or Plasma-Lyte with 0.9% saline solution, for rapid rehydration., Data Collection and Analysis: We used standard Cochrane methods. Our primary outcomes were 1. time in hospital and 2., Mortality: Our secondary outcomes were 3. need for additional fluids, 4. total amount of fluids received, 5. time to resolution of metabolic acidosis, 6. change in and the final values of biochemical measures (pH, bicarbonate, sodium, chloride, potassium, and creatinine), 7. incidence of acute kidney injury, and 8., Adverse Events: We used GRADE to assess the certainty of the evidence., Main Results: Characteristics of the included studies We included five studies with 465 children. Data for meta-analysis were available from 441 children. Four studies were conducted in low- and middle-income countries and one study in two high-income countries. Four studies evaluated Ringer's lactate, and one study evaluated Plasma-Lyte. Two studies reported the time in hospital, and only one study reported mortality as an outcome. Four studies reported final pH and five studies reported bicarbonate levels. Adverse events reported were hyponatremia and hypokalaemia in two studies each. Risk of bias All studies had at least one domain at high or unclear risk of bias. The risk of bias assessment informed the GRADE assessments. Primary outcomes Compared to 0.9% saline, the balanced solutions likely result in a slight reduction of the time in hospital (mean difference (MD) -0.35 days, 95% confidence interval (CI) -0.60 to -0.10; 2 studies; moderate-certainty evidence). However, the evidence is very uncertain about the effect of the balanced solutions on mortality during hospitalization in severely dehydrated children (risk ratio (RR) 0.33, 95% CI 0.02 to 7.39; 1 study, 22 children; very low-certainty evidence). Secondary outcomes Balanced solutions probably produce a higher increase in blood pH (MD 0.06, 95% CI 0.03 to 0.09; 4 studies, 366 children; low-certainty evidence) and bicarbonate levels (MD 2.44 mEq/L, 95% CI 0.92 to 3.97; 443 children, four studies; low-certainty evidence). Furthermore, balanced solutions likely reduces the risk of hypokalaemia after the intravenous correction (RR 0.54, 95% CI 0.31 to 0.96; 2 studies, 147 children; moderate-certainty evidence). Nonetheless, the evidence suggests that balanced solutions may result in no difference in the need for additional intravenous fluids after the initial correction; in the amount of fluids administered; or in the mean change of sodium, chloride, potassium, and creatinine levels., Authors' Conclusions: The evidence is very uncertain about the effect of balanced solutions on mortality during hospitalization in severely dehydrated children. However, balanced solutions likely result in a slight reduction of the time in the hospital compared to 0.9% saline. Also, balanced solutions likely reduce the risk of hypokalaemia after intravenous correction. Furthermore, the evidence suggests that balanced solutions compared to 0.9% saline probably produce no changes in the need for additional intravenous fluids or in other biochemical measures such as sodium, chloride, potassium, and creatinine levels. Last, there may be no difference between balanced solutions and 0.9% saline in the incidence of hyponatraemia., (Copyright © 2023 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Diabetic ketoacidosis (DKA) is commonly complicated by mixed acid-base disorders. Therefore, patients with DKA can present with pH > 7.3 or bicarbonate > 18 mmol/L, which falls outside the values defined by the current traditional DKA criteria (pH ≤ 7.3 or bicarbonate ≤ 18 mmol/L)., Objective: We aimed to study the spectrum of acid-base clinical presentations of DKA and the prevalence of diabetic ketoalkalosis., Methods: This study included all adult patients at a single institution admitted in 2018-2020 with diabetes, positive beta-hydroxybutyric acid, and increased anion gap ≥ 16 mmol/L. Mixed acid-base disorders were analyzed to determine the spectrum of presentation of DKA., Results: There were 259 encounters identified under the inclusion criteria. Acid-base analysis was available in 227 cases. Traditional acidemic DKA (pH ≤ 7.3), DKA with mild acidemia (7.3 < pH ≤ 7.4), and diabetic ketoalkalosis (pH > 7.4) account for 48.9% (111/227), 27.8% (63/227), and 23.3% (53/227) of cases, respectively. Of the 53 cases with diabetic ketoalkalosis, increased anion gap metabolic acidosis was present in all, and concurrent metabolic alkalosis, respiratory alkalosis, and respiratory acidosis were present in 47.2% (25/53), 81.1% (43/53), and 11.3% (6/53) encounters, respectively. In addition, 34.0% (18/53) of those with diabetic ketoalkalosis were found to have severe ketoacidosis, defined by beta-hydroxybutyric acid ≥ 3 mmol/L., Conclusions: DKA can present as traditional acidemic DKA, DKA with mild acidemia, and diabetic ketoalkalosis. Diabetic ketoalkalosis is a common yet easily overlooked alkalemic variant of DKA associated with mixed acid-base disorders, and a high proportion of these presentations have severe ketoacidosis and thus, require the same treatment as traditional DKA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 m 2 and 89 mL/min per 1·73 m 2 , 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 m 2 (IQR -4·081 to 1·440) and mean -1·862 mL/min per 1·73 m 2 (SD 6·344) per year in the placebo group versus median -1·413 mL/min per 1·73 m 2 (IQR -4·503 to 1·139) and mean -1·830 mL/min per 1·73 m 2 (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 m 2 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., Competing Interests: Declaration of interests NM received lecture fees from Forum für Medizinische Fortbildung and Boehringer Ingelheim. AR received support for attending meetings and travel expenses from Salmon Pharma and Astellas Pharma. CAW received honoraria from Medice, Kyowa Kirin, Advicenne, and Ardelyx. RPW received honoraria from OM Pharma. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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 (NH 4 + ) 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., Competing Interests: Conflict of interest statement AO has received grants from Sanofi and consultancy or speaker fees or travel support from Advicciene, Astellas, Astrazeneca, Amicus, Amgen, Boehringer-Ingelheim, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Lilly, Menarini, Mundipharma, Kyowa Kirin, Alexion, Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk, Sysmex and Vifor Fresenius Medical Care Renal Pharma and is Director of the Catedra Mundipharma-UAM of diabetic kidney disease and the Catedra Astrazeneca-UAM of chronic kidney disease and electrolytes., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Acid-base disorders are common in the intensive care unit. By utilizing a systematic approach to their diagnosis, it is easy to identify both simple and mixed disturbances. These disorders are divided into four major categories: metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. Metabolic acidosis is subdivided into anion gap and non-gap acidosis. Distinguishing between these is helpful in establishing the cause of the acidosis. Anion gap acidosis, caused by the accumulation of organic anions from sepsis, diabetes, alcohol use, and numerous drugs and toxins, is usually present on admission to the intensive care unit. Lactic acidosis from decreased delivery or utilization of oxygen is associated with increased mortality. This is likely secondary to the disease process, as opposed to the degree of acidemia. Treatment of an anion gap acidosis is aimed at the underlying disease or removal of the toxin. The use of therapy to normalize the pH is controversial. Non-gap acidoses result from disorders of renal tubular H + transport, decreased renal ammonia secretion, gastrointestinal and kidney losses of bicarbonate, dilution of serum bicarbonate from excessive intravenous fluid administration, or addition of hydrochloric acid. Metabolic alkalosis is the most common acid-base disorder found in patients who are critically ill, and most often occurs after admission to the intensive care unit. Its etiology is most often secondary to the aggressive therapeutic interventions used to treat shock, acidemia, volume overload, severe coagulopathy, respiratory failure, and AKI. Treatment consists of volume resuscitation and repletion of potassium deficits. Aggressive lowering of the pH is usually not necessary. Respiratory disorders are caused by either decreased or increased minute ventilation. The use of permissive hypercapnia to prevent barotrauma has become the standard of care. The use of bicarbonate to correct the acidemia is not recommended. In patients at the extreme, the use of extracorporeal therapies to remove CO 2 can be considered., (Copyright © 2022 by the American Society of Nephrology.)

Despite the controversy, sodium bicarbonate is a commonly used medication in critically ill patients of all ages. There is a lack of data on the acute impact on hemodynamic parameters, biomarker indicators of cardiac output, and changes in vasoinotropic support after sodium bicarbonate therapy. In our retrospective study on children with biventricular circulation in pediatric cardiac intensive care unit receiving bicarbonate therapy: we analyzed its effects on arterial blood gases, heart rate, blood pressure (BP), central venous pressures (CVP), cerebral and renal near-infrared spectroscopy (NIRS), changes in vasoinotropic and ventilator changes before and after sodium bicarbonate administration. Thirty-one administrations of sodium bicarbonate in 23 patients with congenital heart disease without residual shunts were analyzed. The average age was 15.4 months, weight 7.7 kg, and the average bicarbonate dose was 1 meq/kg. There was an increase in arterial pH from 7.24 to 7.30 (p = 0.14) and bicarbonate changed from 18 to 20 mEq/L (p = 0.23). No clinically significant changes were found in the following parameters: heart rate (141 ± 20.1 to 136 ± 19), systolic BP (84 ± 17 to 86 ± 14 mmHg), diastolic BP (48 ± 12 to 49 ± 12 mmHg), cerebral NIRS (64 ± 12 to 65 ± 12), renal NIRS (80 ± 10 to 81 ± 7), CVP (9 ± 3 to 10 ± 4 mmHg), paCO 2 (45 ± 26 to 42 ± 7 mmHg), paO 2 (143 ± 78 to 127 ± 59 mmHg), serum lactate (2.2 ± 2.7 to 3.6 ± 3.8 mmol/L), and vasoinotropic score (7.5 ± 5.0 to 7.7 ± 4.7). Outside of a change in serum pH and bicarbonate levels no other significant changes were noted after sodium bicarbonate administration in children with congenital heart disease with fully septated, biventricular circulation. There was no improvement in systemic oxygen delivery., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Isotonic crystalloids are the preferred solution for the initial clinical management of patients with multiple trauma, among which lactated Ringer's solution and normal saline are the most widely used, but both have clinical limitations. Bicarbonated Ringer's solution (BRS), which provides physiological levels of bicarbonate ions and electrolyte ions, can be used to supplement missing extracellular fluid and correct metabolic acidosis., Methods: A prospective, randomized controlled study enrolled 63 patients with traumatic hepatic rupture and hemorrhagic shock. They were randomly assigned to the Bicarbonated group (n = 33) or the Control group (n = 30), which received restrictive fluid resuscitation with sodium bicarbonate Ringer's solution or sodium lactate Ringer's solution, respectively. The levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, arterial blood lactic acid and potential of hydrogen (pH) were measured prior to, 1, 3, 24, and 72 hours following resuscitation. The primary outcomes were patient survival, shock-related complications, and comparison of the inflammatory factors., Results: The incidence of complications in the Bicarbonated group was significantly lower than in the Control group (15.15% vs 40.0%; P < .05). The intensive care unit length of stay and mechanical ventilation time in the Bicarbonated group were significantly shorter than in the Control group (all P < .01). The levels of IL-6 and TNF-α in the Bicarbonated group were significantly lower 1 hour following resuscitation than prior to resuscitation (P < .01), whereas these levels in the Control group were increased following 1h of resuscitation as compared with before resuscitation (P < .01). Following resuscitation, the levels of IL-6, TNF-α and lactate in the Bicarbonated group were significantly lower than in the Control group (P < .01). Moreover, in the Bicarbonated group, the lactic acid level decreased and the pH value increased significantly following resuscitation, whereas there was no difference in lactic acid levels and pH value between pre- and 1 hour post-resuscitation in the Control group (P > .05)., Conclusion: The shock-related complications were dramatically reduced from using BRS in these patients. Additionally, the BRS was found to better inhibit the expression of inflammatory factors in their peripheral blood and could correct acidosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: In cystic fibrosis (CF), renal base excretion is impaired. Accordingly, challenged urine bicarbonate excretion may be an in vivo biomarker of cystic fibrosis transmembrane conductance regulator (CFTR) function., Objective: To evaluate the association between challenged bicarbonate excretion and clinical characteristics at baseline, quantify the CFTR modulator drug elexacaftor/tezacaftor/ivacaftor-induced changes of challenged bicarbonate excretion after 6 months of treatment, and characterize the intraindividual variation in healthy adults., Design: Prospective observational study., Setting: Cystic fibrosis clinic, Aarhus University Hospital, Denmark., Patients: Fifty adult patients with CF starting CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor between May 2020 and June 2021., Measurements: Quantification of urine bicarbonate excretion after an acute oral sodium bicarbonate challenge before and 6 months after elexacaftor/tezacaftor/ivacaftor treatment., Results: At baseline, challenged urine bicarbonate excretion was associated with several CF disease characteristics. Bicarbonate excretion was higher in patients with residual function mutations. A higher bicarbonate excretion was associated with better lung function, pancreatic sufficiency, and lower relative risk for chronic pseudomonas infections. Elexacaftor/tezacaftor/ivacaftor treatment increased bicarbonate excretion by 3.9 mmol/3 h (95% CI, 1.6 to 6.1 mmol/3 h), reaching about 70% of that seen in healthy control participants. In healthy control participants, individual bicarbonate excretion at each visit correlated with the individual mean bicarbonate excretion. The median coefficient of variation was 31%., Limitation: Single-center study without a placebo-controlled group., Conclusion: Although further studies are needed to address the performance and sensitivity of this approach, this early-stage evaluation shows that challenged urine bicarbonate excretion may offer a new, simple, and safe quantification of CFTR function and the extent of its pharmacologic improvement. Elexacaftor/tezacaftor/ivacaftor partially restores renal CFTR function in patients with CF, likely resulting in decreased risk for electrolyte disorders and metabolic alkalosis., Primary Funding Source: Innovation Fund Denmark.

Metabolic alkalosis is a widespread acid-base disturbance, especially in hospitalized patients. It is characterized by the primary elevation of serum bicarbonate and arterial pH, along with a compensatory increase in Pco 2 consequent to adaptive hypoventilation. The pathogenesis of metabolic alkalosis involves either a loss of fixed acid or a net accumulation of bicarbonate within the extracellular fluid. The loss of acid may be via the gastrointestinal tract or the kidney, whereas the sources of excess alkali may be via oral or parenteral alkali intake. Severe metabolic alkalosis in critically ill patients-arterial blood pH of 7.55 or higher-is associated with significantly increased mortality rate. The kidney is equipped with sophisticated mechanisms to avert the generation or the persistence (maintenance) of metabolic alkalosis by enhancing bicarbonate excretion. These mechanisms include increased filtration as well as decreased absorption and enhanced secretion of bicarbonate by specialized transporters in specific nephron segments. Factors that interfere with these mechanisms will impair the ability of the kidney to eliminate excess bicarbonate, therefore promoting the generation or impairing the correction of metabolic alkalosis. These factors include volume contraction, low glomerular filtration rate, potassium deficiency, hypochloremia, aldosterone excess, and elevated arterial carbon dioxide. Major clinical states are associated with metabolic alkalosis, including vomiting, aldosterone or cortisol excess, licorice ingestion, chloruretic diuretics, excess calcium alkali ingestion, and genetic diseases such as Bartter syndrome, Gitelman syndrome, and cystic fibrosis. In this installment in the AJKD Core Curriculum in Nephrology, we will review the pathogenesis of metabolic alkalosis; appraise the precipitating events; and discuss clinical presentations, diagnoses, and treatments of metabolic alkalosis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The physiologic bile acid ursodeoxycholic acid (UDCA) has potent anticholestatic and weak litholytic properties and has been used for centuries as a remedy for cholestatic liver diseases. Today, UDCA at 13-15 mg/kg/day is the standard first line medication for all people with primary biliary cholangitis (PBC), the most frequent chronic cholestatic liver disease where UDCA clearly improves long-term survival. For many other chronic cholestatic conditions, anticholestatic effects are described, but long-term data are incomplete. While UDCA's litholytic properties can be explained by lowering biliary cholesterol hypersaturation, its beneficial effects in cholestatic diseases build on different mechanisms of action, namely: (i) stimulation of hepatobiliary secretion by post-transcriptional mechanisms including membrane targeting and insertion of key transporters and ion channels, (ii) stabilization of a biliary bicarbonate umbrella by stimulation of biliary chloride/bicarbonate secretion, and (iii) inhibition of hepatocyte and cholangiocyte apoptosis and reduction of endoplasmic reticulum stress induced by toxic endogenous bile acids.

Background: Contrast-induced acute kidney injury (CI-AKI) is prognostically relevant in invasive cardiological and radiological procedures. The administration of sodium bicarbonate has controversial effects. It has been hypothesised that bicarbonate is ineffective when unable to achieve adequate urine alkalinisation., Aims: We tested the hypothesis that alkaline urine status with oral or intravenous (i.v.) bicarbonate on top of hydration alone prevents CI-AKI., Methods: In a prospective, randomised, parallel-group, open-label trial, we compared 1) saline hydration alone (n=81); 2) i.v. bicarbonate (n=82); and 3) oral bicarbonate (n=78), in patients with chronic kidney disease (CKD) scheduled for the intra-arterial administration of contrast medium. The primary endpoint was the incidence of CI-AKI according to alkaline urine status achieved immediately before angiography. Secondary endpoints were the mean change of urine pH up to the time of angiography and the incidence of CI-AKI in the three groups., Results: The incidence of CI-AKI was not significantly different in the three treatment arms (20% in the hydration group, 21% in the oral bicarbonate group and 22% in the i.v. bicarbonate group; p=0.94). Patients achieving a pH >6 before angiography (n=145) had a significantly lower incidence of CI-AKI compared with the others (n=96; odds ratio [OR] 0.48, 95% confidence interval [CI]: 0.25-0.90; p=0.023, primary study hypothesis). The proportion of patients achieving a pH >6 was higher in the i.v. and oral bicarbonate groups compared with hydration alone., Conclusions: Urinary pH before administration of contrast medium is an inverse correlate of CI-AKI incidence, and bicarbonate is superior to hydration alone in achieving urinary alkalinisation. Since, however, bicarbonate did not reduce the incidence of CI-AKI, we conclude that urinary pH is a marker and not a mediator of CI-AKI (ClinicalTrials.gov: NCT02980003).

A 7-month-old male infant was referred to us for evaluation of hypercalcemia and failure to thrive. He was the second-born child to third-degree consanguineous parents with a birth weight of 3.5 kg. The index child was severely underweight. Initial laboratory investigations showed hypercalcemia (13.6 mg/dL), hypophosphatemia, hyponatremia, hypokalemia and hypochloremia. The initial serum bicarbonate level was 20.9 mEq/L. The urine calcium: creatinine ratio (0.05) was normal. He was noted to have polyuria (6 mL/kg/hr) and required intravenous fluids to maintain intravascular volume and manage hypercalcemia, along with potassium chloride supplements. The serum calcium decreased to 9.7 mg/dL after hydration for 48 h. At this juncture, the child was noted to exhibit metabolic acidosis (serum bicarbonate 16 mEq/L) for the first time. Thereafter, fractional excretion of bicarbonate was estimated to be 16.5% while the tubular threshold maximum for phosphorus per glomerular filtration rate was 1.2 mg/dL; indicating bicarbonaturia and phosphaturia, respectively. Glycosuria with aminoaciduria were also noted. Clinical exome sequencing revealed a NM&#95;004937.3:c.809&#95;811del in exon 10 of the CTNS gene that resulted in in-frame deletion of amino acids [NP&#95;004928.2:p.Ser270del] at the protein level. The child is now growing well on oral potassium citrate, neutral phosphate and sodium bicarbonate supplements. This case was notable for absence of metabolic acidosis at admission. Instead, severe hypercalcemia was a striking presenting manifestation, that has not been reported previously in literature. Cystinosis has been earlier described in association with metabolic acidosis, hypocalcemia and hypomagnesemia. However, typical features like metabolic acidosis were masked in early stages of the disease in our case posing a diagnostic challenge. This atypical initial presentation adds to the constellation of clinical features in this condition., (© 2021. Japanese Society of Nephrology.)

Aims: To determine the effect of TTP399, a hepatoselective glucokinase activator, on the risk of ketoacidosis during insulin withdrawal in individuals with type 1 diabetes (T1D)., Materials and Methods: Twenty-three participants with T1D using insulin pump therapy were randomized to 800 mg TTP399 (n = 12) or placebo (n = 11) for 7 to 10 days. After the treatment period, an insulin withdrawal test (IWT) was performed, during which insulin pumps were removed to induce ketogenesis. The IWT was stopped after 10 hours or if blood glucose reached >399 mg/dL [22.1 mmol/L], if beta-hydroxybutyrate (BHB) was >3.0 mmol/L, or for patient discomfort. The primary endpoint was the proportion of participants who reached BHB concentrations of 1 mmol/L or greater., Results: During the 7- to 10-day treatment period, mean fasting plasma glucose was significantly reduced ( -27.6 vs. -4.4 mg/dL [-1.5 vs. -0.2 mmol/L]; P = 0.03) and there were fewer adverse events, including hypoglycaemia, in the TTP399-treated arm. During the IWT, no differences were observed between TTP399 and placebo in mean serum BHB concentration, mean duration of IWT, or BHB at termination of IWT. However, serum bicarbonate was numerically higher and urine acetoacetate was quantitatively lower in the TTP399-treated participants. As a result of higher bicarbonate values, none of the TTP399-treated participants met the prespecified criteria for diabetic ketoacidosis (DKA), defined as BHB >3 mmol/L and serum bicarbonate <18 mEq/L, compared to 42% of placebo-treated participants., Conclusions: When used as an adjunctive therapy to insulin, TTP399 improves glycaemia without increasing hypoglycaemia in individuals with T1D. During acute insulin withdrawal, TTP399 did not increase BHB concentrations and decreased the incidence of DKA., (© 2022 John Wiley & Sons Ltd.)

The quality of life and survival rates of patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) have been greatly improved by defect-repair surgery and personalized treatments. However, those who survive surgery may remain at risk of persistent PAH, the prognosis may be considerably worse than those unoperated. Dynamic monitoring of clinical measures during the perioperative period of shunt correction is therefore indispensable and of great value. In this study, we explored the plasma-metabolite profiling in 13 patients with CHD-PAH during the perioperative period of defect repair. Plasma was harvested at four time points: prior to cardiopulmonary bypass (CPB) after anesthesia (Pre), immediately after CPB (T0), 24 h (T24), and 48 h (T48) after defect repair. Untargeted metabolomics strategy based on UPLC Q-TOF MS was used to detect the metabolites. A total of 193 distinguishing metabolites were determined at different time points, enriched in pathways such as oxidation of branched-chain fatty acids. We found that 17 metabolite alterations were significantly correlated with the reduction in mean pulmonary arterial pressure (MPAP) at T48 versus Pre. Gradients in diastolic pulmonary arterial pressure (DPAP), bicarbonate in radial artery (aHCO 3 ), bicarbonate in superior vena cava (svcHCO 3 ), and the partial pressure of dissolved CO 2 gas in radial artery (aPCO 2 ) were positively correlated with MPAP gradient. Notably, these clinical-measure gradients were correlated with alterations in shunt-correction-associated metabolites. In total, 12 out of 17 identified metabolites in response to defect repair were increased at both T24 and T48 (all P < 0.05, except propionylcarnitine with P < 0.05 at T24). In contrast, galactinol dihydrate, guanosine monophosphate, and hydroxyphenylacetylglycine tended to decline at T24 and T48 (only galactinol dihydrate with P < 0.05 at T48). In conclusion, 17 metabolites that respond to shunt correction could be used as suitable noninvasive markers, and clinical measures, including DPAP, aHCO 3 , svcHCO 3 , and aPCO 2 , would be of great value in disease monitoring and evaluating future therapeutic interventions., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Purpose: To characterize the effects of commonly used transcatheter arterial chemoembolization (TACE) regimens on the immune response and immune checkpoint marker expression using a VX2 rabbit liver tumor model., Materials and Methods: Twenty-four VX2 liver tumor-bearing New Zealand white rabbits were assigned to 7 groups (n = 3 per group) undergoing locoregional therapy as follows: (a) bicarbonate infusion without embolization, (b) conventional TACE (cTACE) using a water-in-oil emulsion containing doxorubicin mixed 1:2 with Lipiodol, drug-eluting embolic-TACE with either (c) idarubicin-eluting Oncozene microspheres (40 μm) or (d) doxorubicin-eluting Lumi beads (40-90 μm). For each therapy arm (b-d), a tandem set of 3 animals with additional bicarbonate infusion before TACE was added, to evaluate the effect of pH modification on the immune response. Three untreated rabbits served as controls. Tissue was harvested 24 hours after treatment, followed by digital immunohistochemistry quantification (counts/μm 2 ± SEM) of tumor-infiltrating cluster of differentiation 3 + T-lymphocytes, human leukocyte antigen DR type antigen-presenting cells (APCs), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and programmed cell death protein-1 (PD-1)/PD-1 ligand (PD-L1) pathway axis expression., Results: Lumi-bead TACE induced significantly more intratumoral T-cell and APC infiltration than cTACE and Oncozene-microsphere TACE. Additionally, tumors treated with Lumi-bead TACE expressed significantly higher intratumoral immune checkpoint markers compared with cTACE and Oncozene-microsphere TACE. Neoadjuvant bicarbonate demonstrated the most pronounced effect on cTACE and resulted in a significant increase in intratumoral cluster of differentiation 3 + T-cell infiltration compared with cTACE alone., Conclusions: This preclinical study revealed significant differences in evoked tumor immunogenicity depending on the choice of chemoembolic regimen for TACE., (Copyright © 2022 SIR. Published by Elsevier Inc. All rights reserved.)

Human kidneys are well adapted to excrete the daily acid load from diet and metabolism in order to maintain homeostasis. In approximately 30% of patients with more advanced stages of CKD, these homeostatic processes are no longer adequate, resulting in metabolic acidosis. Potential deleterious effects of chronic metabolic acidosis in CKD, including muscle wasting, bone demineralization, hyperkalemia, and more rapid progression of CKD, have been well cataloged. Based primarily upon concerns related to nutrition and bone disease, early Kidney Disease Outcomes Quality Initiative guidelines recommended treating metabolic acidosis with alkali therapy targeting a serum bicarbonate ≥22 mEq/L. More recent guidelines have suggested similar targets based upon potential slowing of CKD progression. However, appropriately powered, long-term, randomized controlled trials to study efficacy and safety of alkali therapy for these outcomes are largely lacking. As a result, practice among physicians varies, underscoring the complexity of treatment of chronic metabolic acidosis in real-world CKD practice. Novel treatment approaches and rigorous phase 3 trials may resolve some of this controversy in the coming years. Metabolic acidosis is an important complication of CKD, and where it "falls" in the priority schema of CKD care will depend upon the generation of strong clinical evidence., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Importance: No large randomised controlled trial has assessed the potential benefits on neurologic outcomes of prehospital sodium bicarbonate administration in patients with nontraumatic out-of-hospital cardiac arrest (OHCA)., Objective: To obtain information of assistance in designing a randomised controlled trial of bicarbonate therapy after OHCA in specific patient subgroups., Design: We conducted two, separate, simultaneous, retrospective studies of two distinct, unlinked datasets., Setting and Participants: One dataset was a French nationwide population-based registry (RéAC Registry, French dataset) and the other was a randomised controlled trial comparing continuous to interrupted chest compressions in North America (ROC-CCC trial, North-American dataset)., Intervention: We investigated whether prehospital bicarbonate administration was associated with better neurologic outcomes., Outcome Measures and Analyses: The main outcome measure was the functional outcome at hospital discharge. To adjust for potential confounders, we conducted a nested propensity-score-matched analysis with inverse probability-of-treatment weighting., Main Results: In the French dataset, of the 54 807 patients, 1234 (2.2%) received sodium bicarbonate and 450 were matched. After propensity-score matching, sodium bicarbonate was not associated with a higher likelihood of favourable functional outcomes on day 30 [adjusted odds ratio (aOR), 0.912; 95% confidence interval (95%CI), 0.501-1.655]. In the North-American dataset, of the 23 711 included patients, 4902 (20.6%) received sodium bicarbonate and 1238 were matched. After propensity-score matching, sodium bicarbonate was associated with a lower likelihood of favourable functional outcomes at hospital discharge (aOR, 0.45; 95% CI, 0.34-0.58)., Conclusion: In patients with OHCA, prehospital sodium bicarbonate administration was not associated with neurologic outcomes in a French dataset and was associated with worse neurologic outcomes in a North-American dataset. Given the considerable variability in sodium bicarbonate use by different prehospital care systems and the potential resuscitation-time bias in the present study, a large randomised clinical trial targeting specific patient subgroups may be needed to determine whether sodium bicarbonate has a role in the prehospital management of prolonged OHCA., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Hemodialysis (HD) with bicarbonate dialysis fluid (DF) requires the presence of an acid to prevent the precipitation of calcium and magnesium carbonate. The most used acid is acetic acid, with it several complications have been described. In a previous work we described the acute changes during an HD session with a DF with citrate instead of acetate. Now we report the results in the medium term, 16 weeks. It is a prospective, multicenter, crossover and randomized study, where 56 HD patients with bicarbonate three times a week were dialysed for 16 weeks with 3 mmol/L acetate and 16 weeks with 1 mmol/L citrate. Patients older than 18 years with a previous stay on HD of more than 3 months and with a normal functioning arteriovenous fistula were included. Epidemiological data, dialysis, bioimpedance, biochemistry before and after HD, as well as hypotensive episodes, were collected monthly. After 16 weeks of citrate treatment, preHD ionic calcium and magnesium were significantly lower and PTH higher than in the acetate period. No differences were observed in the effectiveness of dialysis. Hypotensive episodes were significantly more frequent with acetate than with citrate: 311 (14.1%) vs 238 (10.8%) sessions. The lean mass index increased by 0.96 ± 2.33 kg/m 2 when patients switched from LD with acetate to citrate. HD with citrate modifies several parameters of bone mineral metabolism, not only acutely as previously described, but also in the long term. The substitution of acetate for citrate improves hemodynamic stability, producing less hypotension and can improve nutritional status., (Copyright © 2021 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Different from Fe ions in Fenton reaction, Mn ions can function both as catalyst for chemodynamic therapy and immune adjuvant for antitumor immune responses. In Mn-mediated Fenton-like reaction, bicarbonate ([Formula: see text]), as the most important component to amplify therapeutic effects, must be present, however, intracellular [Formula: see text] is strictly limited because of the tight control by live cells., Results: Herein, Stimuli-responsive manganese carbonate-indocyanine green complexes (MnCO 3 -ICG) were designed for intracellular marriage of bicarbonate and Mn ions as "immune ion reactors" to regulate intracellular redox homeostasis and antitumor immune responses. Under the tumor acidic environment, the biodegradable complex can release "ion reactors" of Mn 2+ and [Formula: see text], and ICG in the cytoplasm. The suddenly increased [Formula: see text] in situ inside the cells regulate intracellular pH, and accelerate the generation of hydroxyl radicals for the oxidative stress damage of tumors cells because [Formula: see text] play a critical role to catalyze Mn-mediated Fenton-like reaction. Investigations in vitro and in vivo prove that the both CDT and phototherapy combined with Mn 2+ -enhanced immunotherapy effectively suppress tumor growth and realize complete tumor elimination., Conclusions: The combination therapy strategy with the help of novel immune adjuvants would produce an enhanced immune response, and be used for the treatment of deep tumors in situ., (© 2022. The Author(s).)

Background and Objectives: Kidneys play a key role in maintaining the acid−base balance. The aim of this study was to evaluate the effect of a 3-month oral sodium bicarbonate administration on arterial wall stiffness, arterial pressure and serum nutritional markers in non-dialysed patients with chronic kidney disease (CKD) stages 3−5 and metabolic acidosis. Methods: Eighteen CKD patients with eGFR < 45 mL/min/1.73 m2 and capillary blood bicarbonate (HCO3) < 22 mmol/L were enrolled in this single-centre, prospective study. Anthropometric parameters, pulse wave velocity, 24-h ambulatory blood pressure measurements, blood and urine parameters were assessed at the beginning and at the end of the study. The patients received supplementation with 2 g of sodium bicarbonate daily for three months. Results: A significant increase of pH: 7.32 ± 0.06 to 7.36 ± 0.06; p = 0.025, HCO3 from 18.7 mmol/L (17.7−21.3) to 22.2 mmol/L (20.2−23.9); p < 0.001 and a decrease in base excess from −6.0 ± 2.4 to −1.9 ± 3.1 mmol/L; p < 0.001 were found. An increase in serum total protein from 62.7 ± 6.9 to 65.8 ± 6.2; p < 0.013 and albumin from 37.3 ± 5.4 to 39.4 ± 4.8; p < 0.037 but, also, NT-pro-BNP (N-Terminal Pro-B-Type Natriuretic Peptide) from 794.7 (291.2−1819.0) to 1247.10 (384.7−4545.0); p < 0.006, CRP(C Reactive Protein) from 1.3 (0.7−2.9) to 2.8 (1.1−3.1); p < 0.025 and PTH (parathyroid hormone) from 21.5 ± 13.7 to 27.01 ± 16.3; p < 0.006 were observed, as well as an increase in erythrocyte count from 3.4 ± 0.6 to 3.6 ± 0.6; p < 0.004, haemoglobin from 10.2 ± 2.0 to 11.00 ± 1.7; p < 0.006 and haematocrit from 31.6 ± 6.00 to 33.6 ± 4.8; p < 0.009. The mean eGFR during sodium bicarbonate administration did not change significantly: There were no significant differences in pulse wave velocity or in the systolic and diastolic BP values. Conclusion: The administration of sodium bicarbonate in non-dialysed CKD patients in stages 3−5 improves the parameters of metabolic acidosis and serum nutritional markers; however, it does not affect the blood pressure and vascular stiffness.

Background: The objective of this study was to describe the differences in metabolic parameters and in time to recovery from diabetes ketoacidosis (DKA), between children and adolescents with newly diagnosed diabetes compared with established type 1 diabetes (T1DM)., Methods: This was a single-center, retrospective study. The cohort consists of 356 children and adolescents with T1DM who had DKA during 2008-2018. Data were obtained from the patients' medical files. Recovery of DKA was defined as the resolution of acidosis (pH >7.3 and bicarbonate >15 meq/L)., Results: The mean time to recovery from DKA was significantly longer in patients with newly diagnosed diabetes than in those with established diabetes (13± versus 8.5± h) (p < 0.001). This difference was maintained in an analysis according to DKA severity: mild, moderate, and severe. pH at presentation did not differ between the groups, but bicarbonate at presentation was significantly lower in patients with newly diagnosed diabetes than in those with established diabetes, 9.9± versus 12± mmol/L (p < 0.001). Potassium and phosphorus levels were lower, and sodium and chloride levels were higher in patients with newly diagnosed diabetes than in those with established diabetes (p < 0.001)., Conclusions: DKA is associated with a shorter recovery time in patients with established diabetes compared to newly diagnosed diabetes. This may have implications on the treatment of people with established diabetes., Impact: DKA is associated with a shorter recovery time in patients with established diabetes compared with newly diagnosed diabetes. Shorter recovery time in a patient with established diabetes compared with newly diagnosed diabetes was observed in any DKA severity. The time to recovery from DKA did not differ significantly between patients treated with an insulin pump and those treated with multiple daily injections. Triggers for DKA among patients with established diabetes were poor compliance with treatment, infection, pump dysfunction, and dehydration., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Diabetic ketoacidosis (DKA) is a common acute life-threatening complication of poorly controlled diabetes mellitus contributing to considerable mortality and morbidity. Use of standardized treatment protocols improves patient outcomes in the emergency department (ED) for many conditions, but variability in adult DKA treatment protocols has not been assessed across EDs. In this study, we compared DKA treatment protocols from adult EDs across Canada to highlight inconsistencies in recommended DKA management., Methods: ED staff in Canada were solicited for their treatment protocols used to guide acute ED DKA management. Information regarding initial fluid resuscitation and maintenance fluid, potassium replacement, insulin therapy and bicarbonate administration was abstracted from each protocol, collated in a table and compared., Results: Thirty-six unique protocols were obtained representing 85 institutions (40 urban and 45 rural, with a 65.1% response rate) across Canada, with no protocol use for 4 urban centres. Similarities in protocols included the intravenous insulin infusion rate and instructions for switching to subcutaneous insulin. Variability was noted in the rate, amount and type of fluid bolus given (0.5 to 2 L of normal saline or Ringer's lactate over 15 minutes to 2 hours), the criteria determining the amount, potassium supplementation at normo/hypokalemic ranges, when to add dextrose to maintenance fluid, insulin bolus inclusion and bicarbonate administration., Conclusions: This is the first comparison of adult DKA treatment protocols in Canada. Although several common approaches were identified, variability was found in initial fluid boluses, initial insulin bolus and role of bicarbonate, necessitating further study to ensure local DKA protocols reflect current evidence-based best practices for optimal patient clinical outcomes., (Copyright © 2021 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Radiation-induced mucositis (RIOM) is one of the most common side effects from head and neck radiotherapy. Several reagents have been introduced to manage the symptom; however, there is still a limited number of effective reagents. Herbal mouthwashes with payayor ( Clinacanthus nutans Lindau) and fingerroot ( Boesenbergia rotunda ) were tested their efficacies in preventing and reducing severity of RIOM in comparison with normal saline with sodium bicarbonate., Methods: One hundred twenty patients with head and neck cancer undergoing radiotherapy participated in the study and were randomly assigned into three treatment groups using block randomization method. The participants were assigned one of the three mouthwashes for use throughout their radiotherapy course and were assessed for their mucositis scores from week one to six into their radiotherapy course as well as at one-month follow-up. Body mass index was also measured for comparison of nutritional status., Results: The two mouthwashes were similarly effective in prophylaxis of RIOM in term of severity. The averaged mucositis scores were less than two for all groups. For the onset of RIOM, both herbal mouthwashes could slightly delay the symptom but not statistically significant. Patients' body mass index across the three treatment groups was also comparable. The patients were largely satisfied with all the mouthwashes with no clear preference on any of them., Conclusions: Prophylactic treatment of RIOM using herbal mouthwashes could substitute the current standard of normal saline with bicarbonate. A different formulation of the two herbs could potentially improve the prophylactic outcome., Trial Registration No: NCT03359187., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Sodium zirconium cyclosilicate (SZC) is a selective potassium (K+) binder for hyperkalemia management that provides rapid and sustained correction of hyperkalemia. The NEUTRALIZE study is investigating whether SZC, in addition to correcting hyperkalemia and maintaining normal serum K+, can provide sustained increases in serum bicarbonate (HCO3-) in patients with hyperkalemia and metabolic acidosis associated with chronic kidney disease (CKD)., Methods: This is a prospective, randomized, double-blind, placebo-controlled phase 3b study of US adults with stage 3-5 CKD not on dialysis with hyperkalemia (K+ >5.0-≤5.9 mmol/L) and low-serum HCO3- (16-20 mmol/L). In the open-label correction phase, all eligible patients receive SZC 10 g three times daily for up to 48 h. Patients who achieve normokalemia (K+ ≥3.5-≤5.0 mmol/L) are then randomized 1:1 to once-daily SZC 10 g or placebo for a 4-week, double-blind, placebo-controlled maintenance phase. The primary endpoint is the proportion of patients with normokalemia at the end of treatment (EOT) without rescue therapy for hyperkalemia. Key secondary endpoints include mean change in serum HCO3-, the proportion of patients with an increase in serum HCO3- of ≥2 or ≥3 mmol/L without rescue therapy for metabolic acidosis, and the proportion of patients with serum HCO3- ≥22 mmol/L at EOT., Conclusions: NEUTRALIZE will establish whether SZC can provide sustained increases in serum HCO3- while lowering serum K+ in patients with hyperkalemia and CKD-associated metabolic acidosis and may provide insights on the mechanism(s) underlying the increased serum HCO3- with SZC treatment., (The Author(s). Published by S. Karger AG, Basel.)

Case Description: An 11-year-old sexually intact male Shih Tzu diagnosed with acute kidney injury and left-sided congestive heart failure that had nonelective mitral valve surgery., Clinical Findings: Metabolic alkalosis developed postoperatively, and plasma bicarbonate concentration peaked 2 days after surgery (40.2 mmol/L; pH, 7.550)., Treatment and Outcome: Acetazolamide administration increased the urinary excretion of bicarbonate and contributed to the improvement of the dog's acid-base status and oxygenation capacity. Metabolic alkalosis persisted for 4 days after surgery, and no treatment was required after resolution. Plasma urea nitrogen and creatinine concentrations normalized 2 days after surgery., Clinical Relevance: Severe metabolic alkalosis can occur as a complication following mitral valve surgery. Acetazolamide may be suitable for the treatment of severe metabolic alkalosis.

Distal renal tubular acidosis (DRTA) is a rare disease resulting from a failure in the normal urine acidification process at the distal tubule and collecting duct level. It is characterised by persistent hyperchloremic metabolic acidosis, with a normal anion gap in plasma, in the presence of high urinary pH and low urinary excretion of ammonium. To date, 5 genes whose mutations give rise to primary DRTA have been described. Alterations in the ATP6V1B1 and ATP6V0A4 genes are inherited recessively and are associated with forms of early onset and, in many cases, with neurosensorial deafness. Pathogenic variants in the SLC4A1 gene are habitually inherited dominantly and give rise to milder symptoms, with a later diagnosis and milder electrolytic alterations. Nonetheless, evolution to nephrocalcinosis and lithiasis, and the development of chronic kidney disease in the medium to long term has been described in a similar manner in all 3 groups. Lastly, recessive forms of DTRA associated to mutations in the FOXI1 and WDR72 genes have also been described. The clinical management of DTRA is based on bicarbonate or citrate salts, which do not succeed in correcting all cases of the metabolic alterations described and, thus, the consequences associated with them. Recently, a new treatment based on slow-release bicarbonate and citrate salts has received the designation of orphan drug in Europe for the treatment of DTRA., (Copyright © 2020 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: A new prolonged-release formulation of potassium citrate and potassium bicarbonate, ADV7103, has been shown to improve metabolic control, palatability, and gastrointestinal safety in patients with distal renal tubular acidosis (dRTA) when compared to standard of care (SoC) treatments. The present work evaluates safety and efficacy of ADV7103 during 24 months., Methods: Thirty pediatric and adult patients were included in an open-label extension study after a phase II/III trial. Safety and tolerability were assessed. Plasma bicarbonate and potassium levels, as well as urine parameters, were evaluated over time. Acceptability, adherence, and quality of life were also assessed. The evolution of clinical consequences of dRTA in the cohort was explored., Results: There were 104 adverse events (AEs) reported, but only 9 gastrointestinal events observed in five patients (17%) were considered to be related to ADV7103 treatment. There were no AEs leading to treatment discontinuation. Plasma bicarbonate and potassium levels were in the normal ranges at the different visits, respectively, in 69-86% and 83-93% of patients. Overall adherence rates were ≥ 75% throughout the whole study in 79% patients. An average improvement of quality of life of 89% was reported at 24 months of study., Conclusions: Common AEs concerned metabolism and gastrointestinal disorders; the former being related to the disease. Less than half of the gastrointestinal AEs were related to ADV7103 treatment and they were mostly mild in severity. Metabolic parameters were maintained in the normal ranges in most patients. Patient satisfaction was high and adherence to treatment was good and remained stable., Trial Registration Number: Registered as EudraCT 2013-003828-36 on the 3rd of September 2013.

Background: Sodium zirconium cyclosilicate (SZC) binds potassium and ammonium in the gastrointestinal tract. In addition to serum potassium reduction, Phase 2 trial data have shown increased serum bicarbonate with SZC, which may be clinically beneficial because maintaining serum bicarbonate ≥22 mmol/L preserves kidney function. This exploratory analysis examined serum bicarbonate and urea, and urine pH data from three SZC randomized, placebo-controlled Phase 3 studies among patients with hyperkalaemia [ZS-003 (n = 753), HARMONIZE (n = 258) and HARMONIZE-Global (n = 267)]., Methods: In all studies, patients received ≤10 g SZC 3 times daily (TID) for 48 h to correct hyperkalaemia, followed by randomization to maintenance therapy with SZC once daily (QD) versus placebo for ≤29 days among those achieving normokalaemia., Results: Significant dose-dependent mean serum bicarbonate increases from baseline of 0.3 to 1.5 mmol/L occurred within 48 h of SZC TID in ZS-003 (all P < 0.05), which occurred regardless of chronic kidney disease (CKD) stage. Similar acute increases in HARMONIZE and HARMONIZE-Global were maintained over 29 days. With highest SZC maintenance doses, patient proportions with serum bicarbonate <22 mmol/L fell from 39.4% at baseline to 4.9% at 29 days (P = 0.005) in HARMONIZE and from 87.9% to 70.1%, (P = 0.006) in HARMONIZE-Global. Path analyses demonstrated that serum urea decreases (but not serum potassium or urine pH changes) were associated with SZC effects on serum bicarbonate., Conclusions: SZC increased serum bicarbonate concentrations and reduced patient proportions with serum bicarbonate <22 mmol/L, likely due to SZC-binding of gastrointestinal ammonium. These SZC-induced serum bicarbonate increases occurred regardless of CKD stage and were sustained during ongoing maintenance therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Congenital heart disease is a leading cause of death in newborns and infants. The feasibility of fetal cardiac surgery is linked to extracorporeal circulation (ECC); therefore, cardioplegic solutions need to be effective and long-lasting., Methods: Eighteen pregnant sheep were divided into an ECC-only group, St. Thomas' Hospital cardioplegic solution (STH1) group (STH group), and HTK preservation solution (Custodiol®) group (HTK group). Markers of myocardial injury including troponin I (cTnI), troponin T (cTnT) and creatine kinase myocardial band (CKMB) were measured at specific time points (T1: pre-ECC, T2: 30 min of ECC, T3: 60 min of ECC, T4: 60 min post-ECC, T5: 120 min post-ECC). Myocardial tissue was removed from the fetal sheep at T5, and apoptosis was detected by TUNEL staining., Results: Changes in the serum cTnI, cTnT and CKMB concentrations were not significantly different among the three groups before and during the ECC(T1,T2,T3). At 60 min after ECC shutdown(T4), cTnI and cTnT concentrations were significantly higher in the STH group than before the start of ECC. The concentration of cTnI was higher in the STH group than in the HTK and ECC-only groups. The concentration of cTnT was higher in the STH group than in the ECC-only group. At 120 min after ECC shutdown(T5), cTnI and cTnT concentrations were significantly higher in the ECC and HTK groups than before the start of ECC, and CKMB concentration was significantly higher in STH and HTK groups. The concentrations of cTnT, cTnI and CKMB was higher in the STH group than in the HTK and ECC-only groups. The number of TUNEL-positive cells in the HTK and STH groups was higher than in the ECC-only group. The number of TUNEL-positive cells in the STH group was higher than in the HTK group. There was no statistically significant difference among the groups in the heart rate and mean arterial pressure after ECC., Conclusion: The HTK preservation solution was significantly better than STH1 in reducing the release of cardiomyocyte injury markers and the number of apoptotic cells in fetal sheep ECC. Fetal sheep receiving ECC-only had an advantage in all indicators, which suggests ECC-only fetal heart surgery is feasible.

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 m 2 , 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.

Purpose: High-dose methotrexate (HD-MTX) requires urine alkalinization to pH ≥ 7 for adequate excretion to prevent toxicity. Due to shortages of IV sodium bicarbonate (IV-NaHCO3), few reports have demonstrated utility of oral bicarbonate (PO-NaHCO3); however, the addition of acetazolamide (Acet) has not been well described. Our study compares outcomes between alkalinization methods of IV-NaHCO3 monotherapy versus IV-NaHCO2 + Acet and PO-NaHCO3 + Acet., Methods: A single-center, IRB exempt, retrospective review was conducted from Jan 2016 to Sept 2019 of adults receiving HD-MTX ≥ 500 mg/m 2 . The primary outcome was time from start of alkalinization to pH ≥ 7. Secondary outcomes included time from start of alkalinization to initiation of HD-MTX, time to MTX clearance, length of stay (LOS), percentage of urine pH assessments < 7, and incidence of MTX toxicity. Statistical analysis was performed using SAS9.4 with alpha 0.05., Results: Overall demographics (n = 196 HD-MTX cycles for 55 patients) include a mean age 55 years, HD-MTX dose ~ 5400 mg/m 2 , and 69% with a diagnosis of lymphoma. Adjusting for baseline demographic differences among groups, median time from first dose alkalinization to pH ≥ 7 and to start of HD-MTX was longer for those receiving IV-NaHCO3 (n = 41) vs either IV-NaHCO3 + Acet (n = 70) or PO-NaHCO3 + Acet (n = 76) (p = 0.0001). HD-MTX clearance to a level < 0.1 μmol/L was not improved with the addition of Acet. No difference existed among groups for pH results < 7, LOS, or incidence of MTX toxicity (p > 0.05)., Conclusions: Addition of Acet to NaHCO3 reduces time to pH ≥ 7 and initiation of HD-MTX but does not appear to improve LOS, MTX toxicities, or time to MTX clearance.

Background: Del Nido cardioplegia (DNC) has been proven safe and effective in pediatric patients. However, the use of DNC in adult undergoing cardiovascular surgery lacks support with substantial evidence. This study aimed to evaluate the efficacy of DNC as a cardioplegia of prophylaxis to ventricular arrhythmias associated to cardiovascular surgery in adult patients., Methods: This study recruited nine hundred fifty-four patients who underwent cardiopulmonary bypass surgeries in Nanjing Hospital affiliated to Nanjing Medical University between January 2019 and December 2019. Among 954 patients, 324 patients were treated with DNC (DNC group), and 630 patients were treated with St. Thomas cardioplegia (STH group). The incidence of postoperative arrhythmia as well as other cardiovascular events relavant to the surgery were investigated in both groups., Results: In DNC group, the incidence of postoperative ventricular arrhythmias was lower (12.4% vs. 17.4%, P = 0.040), and the length of ICU stay was shorter (1.97 ± 1.49 vs. 2.26 ± 1.46, P = 0.004). Multivariate logistic regression demonstrated that the use of DNC helped to reduce the incidence of postoperative ventricular arrhythmias (adjusted odds ratio 0.475, 95% CI 0.266-0.825, P = 0.010). The propensity score-based analysis and subgroup analysis indicated that DNC has the same protecting effects towards myocardial in all kinds of cardiopulmonary bypass surgeries., Conclusions: Del Nido cardioplegia may potentially reduce the incidence of postoperative ventricular arrhythmias, shorten the length of ICU stay and improve the overall outcome of the patients undergoing cardiovascular surgery.

Acidic extracellular pH (pHe) is characteristic of the tumor microenvironment. Several reports suggest that increasing pHe improves the response of immune checkpoint inhibitors in murine models. To increase pHe, either sodium bicarbonate (NaHCO 3 ) or citric acid/potassium-sodium citrate (KNa-cit) was chronically administered to mice. It is hypothesized that bicarbonate ions (HCO 3 - ), produced from these alkalinizing agents in vivo, increased pHe in the tumor, and excess HCO 3 - eliminated into urine increased urinary pH values. However, there is little published information on the effect of changing serum HCO 3 - concentrations, urinary HCO 3 - concentrations and urinary pH values on the therapeutic outcomes of immunotherapy. In this study, we report that oral administration of either NaHCO 3 or KNa-cit increased responses to anti-programmed cell death-1 (PD-1) antibody, an immune checkpoint inhibitor, in a murine B16 melanoma model. In addition, we report that daily oral administration of an alkalinizing agent increased blood HCO 3 - concentrations, corresponding to increasing the tumor pHe. Serum HCO 3 - concentrations also correlated with urinary HCO 3 - concentrations and urinary pH values. There was a clear relationship between urinary pH values and the antitumor effects of immunotherapy with anti-PD-1 antibody. Our results imply that blood HCO 3 - concentrations, corresponding to tumor pHe and urinary pH values, may be important factors that predict the clinical outcomes of an immunotherapeutic agent, when combined with alkalinizing agents such as NaHCO 3 and KNa-cit.

Background: Oral rehydration solution (ORS) is a simple intervention that can prevent childhood deaths from severe diarrhea and dehydration. In a previous study, we mapped the use of ORS treatment subnationally and found that ORS coverage increased over time, while the use of home-made alternatives or recommended home fluids (RHF) decreased, in many countries. These patterns were particularly striking within Senegal, Mali, and Sierra Leone. It was unclear, however, whether ORS replaced RHF in these locations or if children were left untreated, and if these patterns were associated with health policy changes., Methods: We used a Bayesian geostatistical model and data from household surveys to map the percentage of children with diarrhea that received (1) any ORS, (2) only RHF, or (3) no oral rehydration treatment between 2000 and 2018. This approach allowed examination of whether RHF was replaced with ORS before and after interventions, policies, and external events that may have impacted healthcare access., Results: We found that RHF was replaced with ORS in most Sierra Leone districts, except those most impacted by the Ebola outbreak. In addition, RHF was replaced in northern but not in southern Mali, and RHF was not replaced anywhere in Senegal. In Senegal, there was no statistical evidence that a national policy promoting ORS use was associated with increases in coverage. In Sierra Leone, ORS coverage increased following a national policy change that abolished health costs for children., Conclusions: Children in parts of Mali and Senegal have been left behind during ORS scale-up. Improved messaging on effective diarrhea treatment and/or increased ORS access such as through reducing treatment costs may be needed to prevent child deaths in these areas.

Despite the possible benefit from avoiding stone surgery with all its possible complications, oral chemolysis is rarely performed in patients with urinary stones suspected of uric acid content. Among the reasons for its limited use is the sparse and low-quality data on its efficacy and the lack of reliable factors predicting its outcome. We thus performed a retrospective single-center cohort study of 216 patients (median patient age 63 years) with 272 renal (48%) and/or ureteral (52%) stones treated with oral chemolysis from 01/2010 to 12/2019. Patients with low urine pH (< 6), low stone density upon non-contrast enhanced computed tomography (NCCT), radiolucent urinary stones on plain radiography, and/or a history of uric acid urolithiasis were included. Potassium citrate and/or sodium/magnesium bicarbonate were used for alkalization (target urine pH 6.5-7.2). Median stone size was 9 mm, median stone density 430 Hounsfield Units. Patients with ureteral stones < 6 mm were excluded since stones this small are very likely to pass spontaneously. The stone-free status of each patient was evaluated after 3 months using NCCT. Oral chemolysis was effective with a complete and partial response rate of stones at 3 months of 61% and 14%, respectively; 25% of stones could not be dissolved. Lower stone density (OR = 0.997 [CI 0.994-0.999]; p = 0.008) and smaller stone size (OR = 0.959 [CI 0.924-0.995]; p = 0.025) significantly increased the success rate of oral chemolysis in multivariate logistic regression analysis. More precise stone diagnostics to exclude non-uric-acid stones could further improve outcome.