Explore the vast range of titles available.

Alkali therapy of metabolic acidosis in patients with chronic kidney disease (CKD) with plasma total CO2 (TCO2) below 22mmol/l per KDOQI guidelines appears to preserve estimated glomerular filtration rate (eGFR). Since angiotensin II mediates GFR decline in partial nephrectomy models of CKD and even mild metabolic acidosis increases kidney angiotensin II in animals, alkali treatment of CKD-related metabolic acidosis in patients with plasma TCO2 over 22mmol/l might preserve GFR through reduced kidney angiotensin II. To test this, we randomized 108 patients with stage 3 CKD and plasma TCO2 22–24mmol/l to Usual Care or interventions designed to reduce dietary acid by 50% using sodium bicarbonate or base-producing fruits and vegetables. All were treated to achieve a systolic blood pressure below 130mmHg with regimens including angiotensin converting enzyme inhibition and followed for 3 years. Plasma TCO2 decreased in Usual Care but increased with bicarbonate or fruits and vegetables. By contrast, urine excretion of angiotensinogen, an index of kidney angiotensin II, increased in Usual Care but decreased with bicarbonate or fruits and vegetables. Creatinine-calculated and cystatin C–calculated eGFR decreased in all groups, but loss was less at 3 years with bicarbonate or fruits and vegetables than Usual Care. Thus, dietary alkali treatment of metabolic acidosis in CKD that is less severe than that for which KDOQI recommends therapy reduces kidney angiotensin II activity and preserves eGFR.

Metabolic acidosis, a complication of chronic kidney disease, causes protein catabolism and bone demineralisation and is associated with adverse kidney outcomes and mortality. Veverimer, a non-absorbed, counterion-free, polymeric drug candidate selectively binds and removes hydrochloric acid from the gastrointestinal lumen. We did a multicentre, randomised, blinded, placebo-controlled, 40-week extension of a 12-week parent study at 29 sites (hospitals and specialty clinics) in seven countries (Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA). Eligible patients were those with chronic kidney disease (estimated glomerular filtration rate 20–40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate 12–20 mmol/L), who had completed the 12-week parent study, for which they were randomly assigned (4:3) to veverimer (6 g/day) or placebo as oral suspensions in water with food. Participants in the extension continued with the same treatment assignment as in the parent study. The primary endpoint was safety; the four secondary endpoints assessed the long-term effects of veverimer on serum bicarbonate concentration and physical functioning. The safety analysis set was defined as all patients who received any amount of study drug. This trial is registered at ClinicalTrials.gov, number NCT03390842, and has now completed. Participants entered the study between Dec 20, 2017, and May 4, 2018. Of the 217 patients randomly assigned to treatment in the parent study (124 to veverimer and 93 to placebo), 196 patients (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into this 40-week extension study. Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (≥4 mmol/L or normalisation) at week 52 (63% vs 38%, p=0·0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p<0·001). Veverimer resulted in improved patient-reported physical functioning (Kidney Disease and Quality of Life–Physical Function Domain) versus placebo with a mean placebo-subtracted change at end of treatment of 12·1 points (SE 3·3; p<0·0001). Time to do the repeat chair stand test improved by 4·3 s (1·2) on veverimer versus 1·4 s (1·2) on placebo (p<0·0001). In patients with chronic kidney disease and metabolic acidosis, veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function. Tricida.

Abstract Rationale Hyperlactatemia in sepsis may derive from a prevalent impairment of oxygen supply/demand and/or oxygen use. Discriminating between these two mechanisms may be relevant for the early fluid resuscitation strategy. Objectives To understand the relationship among central venous oxygen saturation (ScvO2), lactate, and base excess to better determine the origin of lactate. Methods This was a post hoc analysis of baseline variables of 1,741 patients with sepsis enrolled in the multicenter trial ALBIOS (Albumin Italian Outcome Sepsis). Variables were analyzed as a function of sextiles of lactate concentration and sextiles of ScvO2. We defined the “alactic base excess,” as the sum of lactate and standard base excess. Measurements and Main Results Organ dysfunction severity scores, physiologic variables of hepatic, metabolic, cardiac, and renal function, and 90-day mortality were measured. ScvO2 was lower than 70% only in 35% of patients. Mortality, organ dysfunction scores, and lactate were highest in the first and sixth sextiles of ScvO2. Although lactate level related strongly to mortality, it was associated with acidemia only when kidney function was impaired (creatinine >2 mg/dl), as rapidly detected by a negative alactic base excess. In contrast, positive values of alactic base excess were associated with a relative reduction of fluid balance. Conclusions Hyperlactatemia is powerfully correlated with severity of sepsis and, in established sepsis, is caused more frequently by impaired tissue oxygen use, rather than by impaired oxygen transport. Concomitant acidemia was only observed in the presence of renal dysfunction, as rapidly detected by alactic base excess. The current strategy of fluid resuscitation could be modified according to the origin of excess lactate.

When lactic acidosis accompanies low-flow states or sepsis, mortality rates increase sharply. This review summarizes our current understanding of the pathophysiological aspects of lactic acidosis, as well as the approaches to its diagnosis and management. Lactic acidosis results from the accumulation of lactate and protons in the body fluids and is often associated with poor clinical outcomes. The effect of lactic acidosis is governed by its severity and the clinical context. Mortality is increased by a factor of nearly three when lactic acidosis accompanies low-flow states or sepsis, 1 and the higher the lactate level, the worse the outcome. 2 Although hyperlactatemia is often attributed to tissue hypoxia, it can result from other mechanisms. Control of the triggering conditions is the only effective means of treatment. However, advances in understanding its pathophysiological features and the factors causing . . .

Metabolic acidosis (MA) is common in patients with chronic kidney disease (CKD) and is associated with adverse effects. Despite guidelines recommending treatment, reports from Western countries have suggested that MA is often underdiagnosed and undertreated. However, the situation in Asia remains unclear. This study aims to assess the serum bicarbonate measurement rate and the prevalence, diagnosis, and treatment rates of MA in Asian CKD patients using the Japan chronic kidney disease database (J-CKD-DB-Ex). Patients included were aged 18 years or older and had an estimated glomerular filtration rate (eGFR) between 15 and 60 mL/min/1.73 m². We evaluated the rate of serum bicarbonate measurement in each year from 2014 to 2021. Among patients with at least one serum bicarbonate measurement during the study period, we assessed the prevalence of MA (serum bicarbonate < 22 mEq/L), and the diagnosis and treatment rates, based on ICD-10 codes and sodium bicarbonate prescriptions. The annual measurement rate of serum bicarbonate was consistently less than 10%. The prevalence of MA among patients with at least one serum bicarbonate measurement was 44.2%. Diagnosis and treatment rates in patients with MA were 8.6 and 7.5%, respectively. This study demonstrated that MA may be inadequately assessed and treated in Japanese patients with CKD.

Acute acidaemia is frequently observed during critical illness. Sodium bicarbonate infusion for the treatment of severe metabolic acidaemia is a possible treatment option but remains controversial, as no studies to date have examined its effect on clinical outcomes. Therefore, we aimed to evaluate whether sodium bicarbonate infusion would improve these outcomes in critically ill patients. We did a multicentre, open-label, randomised controlled, phase 3 trial. Local investigators screened eligible patients from 26 intensive care units (ICUs) in France. We included adult patients (aged ≥18 years) who were admitted within 48 h to the ICU with severe acidaemia (pH ≤7·20, PaCO2 ≤45 mm Hg, and sodium bicarbonate concentration ≤20 mmol/L) and with a total Sequential Organ Failure Assessment score of 4 or more or an arterial lactate concentration of 2 mmol/L or more. We randomly assigned patients (1:1), by stratified randomisation with minimisation via a restricted web platform, to receive either no sodium bicarbonate (control group) or 4·2% of intravenous sodium bicarbonate infusion (bicarbonate group) to maintain the arterial pH above 7·30. Our protocol recommended that the volume of each infusion should be within the range of 125–250 mL in 30 min, with a maximum of 1000 mL within 24 h after inclusion. Randomisation criteria were stratified among three prespecified strata: age, sepsis status, and the Acute Kidney Injury Network (AKIN) score. The primary outcome was a composite of death from any cause by day 28 and the presence of at least one organ failure at day 7. All analyses were done on data from the intention-to-treat population, which included all patients who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02476253. Between May 5, 2015, and May 7, 2017, we enrolled 389 patients into the intention-to-treat analysis in the overall population (194 in the control group and 195 in the bicarbonate group). The primary outcome occurred in 138 (71%) of 194 patients in the control group and 128 (66%) of 195 in the bicarbonate group (absolute difference estimate −5·5%, 95% CI −15·2 to 4·2; p=0·24). The Kaplan-Meier method estimate of the probability of survival at day 28 between the control group and bicarbonate group was not significant (46% [95% CI 40–54] vs 55% [49–63]; p=0·09. In the prespecified AKIN stratum of patients with a score of 2 or 3, the Kaplan-Meier method estimate of survival by day 28 between the control group and bicarbonate group was significant (37% [95% CI 28–48] vs 54% [45–65]; p=0·0283). Metabolic alkalosis, hypernatraemia, and hypocalcaemia were observed more frequently in the bicarbonate group than in the control group, with no life-threatening complications reported. In patients with severe metabolic acidaemia, sodium bicarbonate had no effect on the primary composite outcome. However, sodium bicarbonate decreased the primary composite outcome and day 28 mortality in the a-priori defined stratum of patients with acute kidney injury. French Ministry of Health and the Société Française d'Anesthésie Réanimation.

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

Lactic acidosis associated with metformin treatment is a rare but important adverse event, and unravelling the problem is critical. First, this potential event still influences treatment strategies in type 2 diabetes mellitus, particularly in the many patients at risk of kidney failure, in those presenting contraindications to metformin and in the elderly. Second, the relationship between metformin and lactic acidosis is complex, since use of the drug may be causal, co-responsible or coincidental. The present review is divided into three parts, dealing with the incidence, management and prevention of lactic acidosis occurring during metformin treatment. In terms of incidence, the objective of this article is to counter the conventional view of the link between metformin and lactic acidosis, according to which metformin-associated lactic acidosis is rare but is still associated with a high rate of mortality. In fact, the direct metformin-related mortality is close to zero and metformin may even be protective in cases of very severe lactic acidosis unrelated to the drug. Metformin has also inherited a negative class effect, since the early biguanide, phenformin, was associated with more frequent and sometimes fatal lactic acidosis. In the second part of this review, the objective is to identify the most efficient patient management methods based on our knowledge of how metformin acts on glucose/lactate metabolism and how lactic acidosis may occur (at the organ and cellular levels) during metformin treatment. The liver appears to be a key organ for both the antidiabetic effect of metformin and the development of lactic acidosis; the latter is attributed to mitochondrial impairment and subsequent adenosine triphosphate depletion, acceleration of the glycolytic flux, increased glucose uptake and the generation of lactate, which effluxes into the circulation rather than being oxidized further. Haemodialysis should systematically be performed in severe forms of lactic acidosis, since it provides both symptomatic and aetiological treatment (by eliminating lactate and metformin). In the third part of the review (prevention), the objective is to examine the list of contraindications to metformin (primarily related to renal and cardiovascular function). Diabetes is above all a vascular disease and metformin is a vascular drug with antidiabetic properties. Given the importance of the liver in lactate clearance, we suggest focusing on the severity of and prognosis for liver disease; renal dysfunction is only a prerequisite for metformin accumulation, which may only be dangerous per se when associated with liver failure. Lastly, in view of metformin’s impressive overall effectiveness profile, it would be paradoxical to deny the majority of patients with long-established diabetes access to metformin because of the high prevalence of contraindications. The implications of these contraindications are discussed.

Cancer cells are characterized by a metabolic shift in cellular energy production, orchestrated by the transcription factor HIF-1α, from mitochondrial oxidative phosphorylation to increased glycolysis, regardless of oxygen availability (Warburg effect). The constitutive upregulation of glycolysis leads to an overproduction of acidic metabolic products, resulting in enhanced acidification of the extracellular pH (pHe ~ 6.5), which is a salient feature of the tumor microenvironment. Despite the importance of pH and tumor acidosis, there is currently no established clinical tool available to image the spatial distribution of tumor pHe. The purpose of this review is to describe various imaging modalities for measuring intracellular and extracellular tumor pH. For each technique, we will discuss main advantages and limitations, pH accuracy and sensitivity of the applied pH-responsive probes and potential translatability to the clinic. Particular attention is devoted to methods that can provide pH measurements at high spatial resolution useful to address the task of tumor heterogeneity and to studies that explored tumor pH imaging for assessing treatment response to anticancer therapies.

Background Sodium bicarbonate is commonly used to correct metabolic acidosis in pediatric patients, yet its efficacy remains controversial. This study aims to assess its effectiveness in treating non-lactic and lactic metabolic acidosis and its impact at various chloride levels. Methods A retrospective cohort study was conducted by screening pediatric patients diagnosed with metabolic acidosis from a paediatric intensive care database. Patients were categorized into two groups: lactate patients (lactate > 2.0 mmol/L) and non-lactate patients (lactate ≤ 2.0 mmol/L). The risk of death in patients who received sodium bicarbonate was assessed. Results Sodium bicarbonate treatment did not significantly affect in-hospital mortality in either overall lactate patients or non-lactate patients, with adjusted OR of 1.044 (95% CI: 0.829–1.315, p  = 0.714) and 0.838 (95% CI: 0.548–1.281, p  = 0.414), respectively. In lactate patients, those receiving sodium bicarbonate had a higher risk of in-hospital death when chloride was < 107 mmol/L (adjusted OR = 2.195, 95% CI: 1.536–3.135, p  < 0.001), whereas the risk of in-hospital death decreased when chloride was ≥ 113 mmol/L (adjusted OR = 0.365, 95% CI: 0.217–0.614, p  < 0.001). Similar findings were observed in non-lactate patients. Conclusions Sodium bicarbonate treatment does not improve the survival of pediatric patients with lactate or non-lactate metabolic acidosis. However, it can reduce the odds of mortality in pediatric patients with hyperchloremia, regardless of their lactate levels. Prospective studies are needed to further confirm these findings.