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Journal of Intensive Care Medicine 2019In the 1920s, guanidine, the active component of , was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1... (Review)
Review
In the 1920s, guanidine, the active component of , was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1 dimethylbiguanide) is the most well-known and currently the only marketed biguanide in the United States, United Kingdom, Canada, and Australia for the treatment of non-insulin-dependent diabetes mellitus. Although phenformin was removed from the US market in the 1970s, it is still available around the world and can be found in unregulated herbal supplements. Adverse events associated with therapeutic use of biguanides include gastrointestinal upset, vitamin B deficiency, and hemolytic anemia. Although the incidence is low, metformin toxicity can lead to hyperlactatemia and metabolic acidosis. Since metformin is predominantly eliminated from the body by the kidneys, toxicity can occur when metformin accumulates due to poor clearance from renal insufficiency or in the overdose setting. The dominant source of metabolic acidosis associated with hyperlactatemia in metformin toxicity is the rapid cytosolic adenosine triphosphate (ATP) turnover when complex I is inhibited and oxidative phosphorylation cannot adequately recycle the vast quantity of H+ from ATP hydrolysis. Although metabolic acidosis and hyperlactatemia are markers of metformin toxicity, the degree of hyperlactatemia and severity of acidemia have not been shown to be of prognostic value. Regardless of the etiology of toxicity, treatment should include supportive care and consideration for adjunct therapies such as gastrointestinal decontamination, glucose and insulin, alkalinization, extracorporeal techniques to reduce metformin body burden, and metabolic rescue.
Topics: Acidosis; Biguanides; Diabetes Mellitus, Type 2; Humans; Hyperlactatemia; Hypoglycemic Agents; Kidney; Metformin; Renal Insufficiency
PubMed: 30126348
DOI: 10.1177/0885066618793385 -
Minerva Endocrinologica Dec 2019Metabolic acidosis is defined as a pathologic process that, when unopposed, increases the concentration of hydrogen ions (H+) in the body and reduces the bicarbonate... (Review)
Review
Metabolic acidosis is defined as a pathologic process that, when unopposed, increases the concentration of hydrogen ions (H+) in the body and reduces the bicarbonate (HCO3-) concentration. Metabolic acidosis can be of a kidney origin or an extrarenal cause. Assessment of urinary ammonium excretion by calculating the urine anion gap or osmolal gap is a useful method to distinguish between these two causes. Extrarenal processes include increased endogenous acid production and accelerated loss of bicarbonate from the body. Metabolic acidosis of renal origin is due to a primary defect in renal acidification with no increase in extrarenal hydrogen ion production. This situation can occur because either the renal input of new bicarbonate is insufficient to regenerate the bicarbonate lost in buffering endogenous acid as with distal renal tubular acidosis (RTA) or the RTA of renal insufficiency, or the filtered bicarbonate is lost by kidney wasting as in proximal RTA. In either condition, because of loss of either NaHCO3 (proximal RTA) or NaA (distal RTA), effective extracellular volume is reduced and as a result the avidity for chloride reabsorption derived from the diet is increased and results in a hyperchloremic normal gap metabolic acidosis. The RTA of renal insufficiency is also characterized by a normal gap acidosis, however, with severe reductions in the glomerular filtration rate an anion gap metabolic acidosis eventually develops.
Topics: Acid-Base Equilibrium; Acidosis; Acidosis, Renal Tubular; Aldosterone; Ammonia; Bicarbonates; Buffers; Chlorides; Diarrhea; Glomerular Filtration Rate; Humans; Hypokalemia; Kidney; Kidney Tubules; Models, Biological; Postoperative Complications; Protons; Renal Insufficiency, Chronic; Urinary Diversion
PubMed: 31347344
DOI: 10.23736/S0391-1977.19.03059-1 -
The Journal of Emergency Medicine Dec 2021Alcoholic ketoacidosis (AKA) is defined by metabolic acidosis and ketosis in a patient with alcohol use. This is a common presentation in the emergency department (ED)... (Review)
Review
BACKGROUND
Alcoholic ketoacidosis (AKA) is defined by metabolic acidosis and ketosis in a patient with alcohol use. This is a common presentation in the emergency department (ED) and requires targeted therapies.
OBJECTIVE
This narrative review evaluates the pathogenesis, diagnosis, and management of AKA for emergency clinicians.
DISCUSSION
AKA is frequently evaluated and managed in the ED. The underlying pathophysiology is related to poor glycogen stores and elevated nicotinamide adenine dinucleotide and hydrogen. This results in metabolic acidosis with elevated beta-hydroxybutyrate levels. Patients with AKA most commonly present with a history of alcohol use (acute or chronic), poor oral intake, gastrointestinal symptoms, and ketoacidosis on laboratory assessment. Patients are generally dehydrated, and serum glucose can be low, normal, or mildly elevated. An anion gap metabolic acidosis with ketosis and electrolyte abnormalities are usually present on laboratory evaluation. Management includes fluid resuscitation, glucose and vitamin supplementation, electrolyte repletion, and evaluation for other conditions.
CONCLUSIONS
Emergency clinician knowledge of the evaluation and management of AKA is essential in caring for these patients.
Topics: Acidosis; Alcoholism; Fluid Therapy; Glucose; Humans; Ketosis
PubMed: 34711442
DOI: 10.1016/j.jemermed.2021.09.007 -
Emergency Medicine Clinics of North... May 2022This article reviews the background, metabolism, clinical effects, and treatment of toxic alcohols, specifically ethylene glycol, methanol, diethylene glycol, propylene... (Review)
Review
This article reviews the background, metabolism, clinical effects, and treatment of toxic alcohols, specifically ethylene glycol, methanol, diethylene glycol, propylene glycol, and isopropyl alcohol. This article also reviews the importance of an anion gap metabolic acidosis in relation to toxic alcohols and explores both the utility and the limitations of the osmol gap in patient management.
Topics: Acidosis; Alcoholic Intoxication; Alcohols; Ethylene Glycol; Humans; Methanol; Poisoning
PubMed: 35461626
DOI: 10.1016/j.emc.2022.01.012 -
Advances in Pediatrics Aug 2022Chronic kidney disease (CKD) in children has a significant impact on morbidity, mortality, and quality of life. The degree of renal dysfunction should be calculated... (Review)
Review
Chronic kidney disease (CKD) in children has a significant impact on morbidity, mortality, and quality of life. The degree of renal dysfunction should be calculated using pediatric-specific formulas and the degree of CKD staged; this allows for appropriate dosing of medications based on renal function and monitoring for progression and comorbid conditions including metabolic acidosis, bone disease, anemia, cardiovascular complications, malnutrition and electrolyte abnormalities, growth failure, and psychosocial issues. Treatment strategies include treating the underlying disease and using general renal protective measures. Effective management of these complex issues requires a specialized multidisciplinary team approach.
Topics: Acidosis; Anemia; Child; Humans; Kidney; Quality of Life; Renal Insufficiency, Chronic
PubMed: 35985704
DOI: 10.1016/j.yapd.2022.03.008 -
American Journal of Kidney Diseases :... Oct 2021The anion gap (AG) is a mathematical construct that compares the blood sodium concentration with the sum of the chloride and bicarbonate concentrations. It is a helpful... (Review)
Review
The anion gap (AG) is a mathematical construct that compares the blood sodium concentration with the sum of the chloride and bicarbonate concentrations. It is a helpful calculation that divides the metabolic acidoses into 2 categories: high AG metabolic acidosis (HAGMA) and hyperchloremic metabolic acidosis-and thereby delimits the potential etiologies of the disorder. When the [AG] is compared with changes in the bicarbonate concentration, other occult acid-base disorders can be identified. Furthermore, finding that the AG is very small or negative can suggest several occult clinical disorders or raise the possibility of electrolyte measurement artifacts. In this installment of AJKD's Core Curriculum in Nephrology, we discuss cases that represent several very common and several rare causes of HAGMA. These case scenarios highlight how the AG can provide vital clues that direct the clinician toward the correct diagnosis. We also show how to calculate and, if necessary, correct the AG for hypoalbuminemia and severe hyperglycemia. Plasma osmolality and osmolal gap calculations are described and when used together with the AG guide appropriate clinical decision making.
Topics: Acid-Base Equilibrium; Acid-Base Imbalance; Acidosis; Adult; Aged; Curriculum; Diabetic Ketoacidosis; Female; Fluid Therapy; Humans; Male; Middle Aged; Osmolar Concentration; Young Adult
PubMed: 34400023
DOI: 10.1053/j.ajkd.2021.02.341 -
American Journal of Kidney Diseases :... Aug 2019Maintenance of normal acid-base homeostasis is one of the most important kidney functions. In chronic kidney disease, the capacity of the kidneys to excrete the daily... (Review)
Review
Maintenance of normal acid-base homeostasis is one of the most important kidney functions. In chronic kidney disease, the capacity of the kidneys to excrete the daily acid load as ammonium and titratable acid is impaired, resulting in acid retention and metabolic acidosis. The prevalence of metabolic acidosis increases with declining glomerular filtration rate. Metabolic acidosis is associated with several clinically important complications, including chronic kidney disease progression, bone demineralization, skeletal muscle catabolism, and mortality. To mitigate these adverse consequences, clinical practice guidelines suggest treating metabolic acidosis with oral alkali in patients with chronic kidney disease. However, large clinical trials to determine the efficacy and safety of correcting metabolic acidosis with oral alkali in patients with chronic kidney disease have yet to be conducted. In this Core Curriculum article, established and emerging concepts regarding kidney acid-base regulation and the pathogenesis, risk factors, diagnosis, and management of metabolic acidosis in chronic kidney disease are discussed.
Topics: Acid-Base Equilibrium; Acidosis; Female; Humans; Middle Aged; Renal Insufficiency, Chronic
PubMed: 31036389
DOI: 10.1053/j.ajkd.2019.01.036 -
American Journal of Obstetrics and... May 2023Normal birth is a eustress reaction, a beneficial hedonic stress with extremely high catecholamines that protects us from intrauterine hypoxia and assists in the rapid... (Review)
Review
Normal birth is a eustress reaction, a beneficial hedonic stress with extremely high catecholamines that protects us from intrauterine hypoxia and assists in the rapid shift to extrauterine life. Occasionally the cellular O requirement becomes critical and an O deficit in blood (hypoxemia) may evolve to a tissue deficit (hypoxia) and finally a risk of organ damage (asphyxia). An increase in H concentration is reflected in a decrease in pH, which together with increased base deficit is a proxy for the level of fetal O deficit. Base deficit (or its negative value, base excess) was introduced to reflect the metabolic component of a low pH and to distinguish from the respiratory cause of a low pH, which is a high CO concentration. Base deficit is a theoretical estimate and not a measured parameter, calculated by the blood gas analyzer from values of pH, the partial pressure of CO, and hemoglobin. Different brands of analyzers use different calculation equations, and base deficit values can thus differ by multiples. This could influence the diagnosis of metabolic acidosis, which is commonly defined as a pH <7.00 combined with a base deficit ≥12.0 mmol/L in umbilical cord arterial blood. Base deficit can be calculated as base deficit in blood (or actual base deficit) or base deficit in extracellular fluid (or standard base deficit). The extracellular fluid compartment represents the blood volume diluted with the interstitial fluid. Base deficit in extracellular fluid is advocated for fetal blood because a high partial pressure of CO (hypercapnia) is common in newborns without concomitant hypoxia, and hypercapnia has a strong influence on the pH value, then termed respiratory acidosis. An increase in partial pressure of CO causes less increase in base deficit in extracellular fluid than in base deficit in blood, thus base deficit in extracellular fluid better represents the metabolic component of acidosis. The different types of base deficit for defining metabolic acidosis in cord blood have unfortunately not been noticed by many obstetrical experts and organizations. In addition to an increase in H concentration, the lactate production is accelerated during hypoxia and anaerobic metabolism. There is no global consensus on definitions of normal cord blood gases and lactate, and different cutoff values for abnormality are used. At a pH <7.20, 7% to 9% of newborns are deemed academic; at <7.10, 1% to 3%; and at <7.00, 0.26% to 1.3%. From numerous studies of different eras and sizes, it can firmly be concluded that in the cord artery, the statistically defined lower pH limit (mean -2 standard deviations) is 7.10. Given that the pH for optimal enzyme activity differs between different cell types and organs, it seems difficult to establish a general biologically critical pH limit. The blood gases and lactate in cord blood change with the progression of pregnancy toward a mixed metabolic and respiratory acidemia because of increased metabolism and CO production in the growing fetus. Gestational age-adjusted normal reference values have accordingly been published for pH and lactate, and they associate with Apgar score slightly better than stationary cutoffs, but they are not widely used in clinical practice. On the basis of good-quality data, it is reasonable to set a cord artery lactate cutoff (mean +2 standard deviations) at 10 mmol/L at 39 to 40 weeks' gestation. For base deficit, it is not possible to establish statistically defined reference values because base deficit is calculated with different equations, and there is no consensus on which to use. Arterial cord blood represents the fetus better than venous blood, and samples from both vessels are needed to validate the arterial origin. A venoarterial pH gradient of <0.02 is commonly used to differentiate arterial from venous samples. Reference values for pH in cord venous blood have been determined, but venous blood comes from the placenta after clearance of a surplus of arterial CO, and base deficit in venous blood then overestimates the metabolic component of fetal acidosis. The ambition to increase neonatal hemoglobin and iron depots by delaying cord clamping after birth results in falsely acidic blood gas and lactate values if the blood sampling is also delayed. Within seconds after birth, sour metabolites accumulated in peripheral tissues and organs will flood into the central circulation and further to the cord arteries when the newborn starts to breathe, move, and cry. This influence of "hidden acidosis" can be avoided by needle puncture of unclamped cord vessels and blood collection immediately after birth. Because of a continuing anaerobic glycolysis in the collected blood, it should be analyzed within 5 minutes to not result in a falsely high lactate value. If the syringe is placed in ice slurry, the time limit is 20 minutes. For pH, it is reasonable to wait no longer than 15 minutes if not in ice. Routine analyses of cord blood gases enable perinatal audits to gain the wisdom of hindsight, to maintain quality assurance at a maternity unit over years by following the rate of neonatal acidosis, to compare results between hospitals on regional or national bases, and to obtain an objective outcome measure in clinical research. Given that the intrapartum cardiotocogram is an uncertain proxy for fetal hypoxia, and there is no strong correlation between pathologic cardiotocograms and fetal acidosis, a cord artery pH may help rather than hurt a staff person subjected to a malpractice suit based on undesirable cardiotocogram patterns. Contrary to common beliefs and assumptions, up to 90% of cases of cerebral palsy do not originate from intrapartum events. Future research will elucidate whether cell injury markers with point-of-care analysis will become valuable in improving the dating of perinatal injuries and differentiating hypoxic from nonhypoxic injuries.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Lactic Acid; Reference Values; Hypercapnia; Carbon Dioxide; Ice; Acidosis; Fetal Blood; Infant, Newborn, Diseases; Fetal Diseases; Umbilical Cord; Hypoxia; Hydrogen-Ion Concentration
PubMed: 37164495
DOI: 10.1016/j.ajog.2022.07.001 -
Nature Metabolism Feb 2023The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it...
The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a 'stem-like memory' state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.
Topics: Animals; Mice; Neoplasms; Cell Differentiation; Tumor Microenvironment; Acidosis; Carbon
PubMed: 36717749
DOI: 10.1038/s42255-022-00730-6 -
Journal of Nephrology Dec 2021Renal tubular acidosis (RTA) comprises a group of disorders in which excretion of hydrogen ions or reabsorption of filtered HCO is impaired, leading to chronic metabolic... (Review)
Review
Renal tubular acidosis (RTA) comprises a group of disorders in which excretion of hydrogen ions or reabsorption of filtered HCO is impaired, leading to chronic metabolic acidosis with normal anion gap. In the current review, the focus is placed on the most common type of RTA, Type 1 RTA or Distal RTA (dRTA), which is a rare chronic genetic disorder characterized by an inability of the distal nephron to secrete hydrogen ions in the presence of metabolic acidosis. Over the years, knowledge of the molecular mechanisms behind acid secretion has improved, thereby greatly helping the diagnosis of dRTA. The primary or inherited form of dRTA is mostly diagnosed in infancy, childhood, or young adulthood, while the acquired secondary form, as a consequence of other disorders or medications, can happen at any age, although it is more commonly seen in adults. dRTA is not as "benign" as previously assumed, and can have several, highly variable long-term consequences. The present review indeed reports and summarizes both clinical symptoms and diagnosis, long-term outcomes, genetic inheritance, epidemiology and current treatment options, with the aim of shedding more light onto this rare disorder. Being a chronic condition, dRTA also deserves attention in the transition between pediatric and adult nephrology care, and as a rare disease it has a place in the European and Italian rare nephrological diseases network.
Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Adult; Biological Transport; Child; Humans; Young Adult
PubMed: 33770395
DOI: 10.1007/s40620-021-01032-y