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Current Opinion in Nephrology and... Mar 2024Continuous renal replacement therapy (CRRT) is a vital medical intervention used in critically ill patients with acute kidney injury (AKI). One of the key components of... (Review)
Review
PURPOSE OF REVIEW
Continuous renal replacement therapy (CRRT) is a vital medical intervention used in critically ill patients with acute kidney injury (AKI). One of the key components of adequate clearance with CRRT is the use of anticoagulants to prevent clotting of the extracorporeal circuit. Regional citrate anticoagulation is the most often recommended modality. The term 'citrate toxicity' is used to describe potential adverse effects of accumulation of citrate and subsequent hypocalcemia. However, citrate is itself not inherently toxic. The term and diagnosis of citrate toxicity are questioned in this review.
RECENT FINDINGS
Citrate is being increasingly used for regional anticoagulation of the CRRT circuit. Citrate accumulation is infrequent and can cause hypocalcemia and metabolic alkalosis, which are potential adverse effects. Citrate itself, however, is not a toxic molecule. The term 'citrate toxicity' has been used to denote hypocalcemia and metabolic acidosis. However, citrate administration is well known to cause systemic and urinary alkalinization and under certain circumstances, metabolic alkalosis, but is not associated itself with any 'toxic' effects.We review the existing literature and debunk the perceived toxicity of citrate. We delve into the metabolism and clearance of citrate and question current data suggesting metabolic acidosis occurs as the result of citrate accumulation.
SUMMARY
In conclusion, this article calls into question prevailing concerns about 'citrate toxicity'. We emphasize the need for a more nuanced understanding of its safety profile. We recommend discarding the term 'citrate toxicity' in favor of another frequently used, but more meaningful term: 'citrate accumulation'.
Topics: Humans; Acidosis; Acute Kidney Injury; Alkalosis; Anticoagulants; Citrates; Hypocalcemia; Renal Replacement Therapy
PubMed: 37962170
DOI: 10.1097/MNH.0000000000000953 -
Clinical Toxicology (Philadelphia, Pa.) Dec 2023
Topics: Humans; Acidosis; Ketosis; Gastric Inhibitory Polypeptide; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Glucagon-Like Peptide-2 Receptor
PubMed: 37938168
DOI: 10.1080/15563650.2023.2277337 -
Acta Neurologica Taiwanica Mar 2024A 13-year and 4-month-old girl was brought to the emergency department due to fever, dizziness,vomiting, and blurred vision. Laboratory data revealed hyperglycemia with...
A 13-year and 4-month-old girl was brought to the emergency department due to fever, dizziness,vomiting, and blurred vision. Laboratory data revealed hyperglycemia with an HbA1C of 7.3 percent, ketonuria, and lactic acidosis. The initial impression was diabetic ketoacidosis. During admission, recurrent focal impaired awareness seizures were noted, and magnetic resonance imaging of the brain revealed multiple brain infarctions in the bilateral cerebrum. Mitochondrial gene report showed A3243 G with 64 percent heteroplasmy, and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes was diagnosed. At 16 years and 7 months old, recurrence of vomiting and onset of right hemianopia and mild right limb weakness were observed and follow-up T2 images showed massive edema in her left parieto-occipital region. At 16 years and 10 months old, she developed clonus in her left hand associated with an unsteady gait and blurred vision. MRI of the brain revealed recurrent brain infarction, and T2 images showed massive edema of the right parieto-occipital region. MELAS is a rare disease entity and occasionally comorbid with mitochondrial diabetes in childhood. Characteristic radiological features of MELAS include infarction-like lesions over the parieto-occipital or parieto-temporal areas, which help distinguish MELAS from childhood ischemic stroke.
Topics: Humans; Female; Infant; MELAS Syndrome; Diabetic Ketoacidosis; Stroke; Acidosis, Lactic; Ketosis; Edema; Vomiting; Diabetes Mellitus
PubMed: 37853548
DOI: No ID Found -
Biomedicine & Pharmacotherapy =... Sep 2023β-hydroxybutyrate (β-HB), the most abundant ketone body, is produced primarily in the liver and acts as a substitute energy fuel to provide energy to extrahepatic... (Review)
Review
β-hydroxybutyrate (β-HB), the most abundant ketone body, is produced primarily in the liver and acts as a substitute energy fuel to provide energy to extrahepatic tissues in the event of hypoglycemia or glycogen depletion. We now have an improved understanding of β-HB as a signal molecule and epigenetic regulatory factor as a result of intensive research over the last ten years. Because β-HB regulates various physiological and pathological processes, it may have a potential role in the treatment of metabolic diseases. The liver is the most significant metabolic organ, and the part that β-HB plays in liver disorders is receiving increasing attention. In this review, we summarize the therapeutic effects of β-HB on liver diseases and its underlying mechanisms of action. Moreover, we explore the prospects of exogenous supplements and endogenous ketosis including fasting, caloric restriction (CR), ketogenic diet (KD), and exercise as adjuvant nutritional therapies to protect the liver from damage and provide insights and strategies for exploring the treatment of various liver diseases.
Topics: Humans; 3-Hydroxybutyric Acid; Ketone Bodies; Ketosis; Diet, Ketogenic; Liver Diseases
PubMed: 37487440
DOI: 10.1016/j.biopha.2023.115191 -
NeoReviews Feb 2024See Bonus NeoBriefs videos and downloadable teaching slides Metabolic acidosis can manifest in the neonatal period and cause significant morbidity and mortality in... (Review)
Review
See Bonus NeoBriefs videos and downloadable teaching slides Metabolic acidosis can manifest in the neonatal period and cause significant morbidity and mortality in neonates. Preterm infants are at an even higher risk of developing metabolic acidosis. If the acidosis results from a dysfunction of acid-base homeostasis by the renal system, the disorder is known as renal tubular acidosis (RTA). In this review, we will describe renal development and normal acid-base homeostasis by the renal system. We will also discuss the pathophysiology of the different types of RTA, laboratory findings to aid in diagnosis, and treatment considerations. Understanding RTA will help neonatal clinicians recognize and diagnose an infant affected by RTA and initiate treatment in a timely manner.
Topics: Infant; Humans; Infant, Newborn; Acidosis, Renal Tubular; Infant, Premature; Kidney; Homeostasis
PubMed: 38296789
DOI: 10.1542/neo.25-2-e99 -
The American Journal of Emergency... Oct 2023Metformin toxicity is a rare but serious condition that carries with it a high rate of morbidity and mortality. (Review)
Review
INTRODUCTION
Metformin toxicity is a rare but serious condition that carries with it a high rate of morbidity and mortality.
OBJECTIVE
This review highlights the pearls and pitfalls of metformin toxicity, including diagnosis, initial resuscitation, and management in the emergency department (ED) based on current evidence.
DISCUSSION
Metformin is a common medication used for treatment of diabetes mellitus. Metformin toxicity is a spectrum of conditions that may be differentiated into three subgroups: metformin-associated lactic acidosis (MALA), metformin-induced lactic acidosis (MILA), and metformin-unrelated lactic acidosis (MULA). MILA is a condition found predominantly in patients chronically taking metformin or those with large acute overdoses. Conversely, MULA occurs in patients on metformin but with a critical illness stemming from a separate cause. MALA is rare but the most severe form, with mortality rates that reach 50%. Differentiating these entities is difficult in the ED setting without obtaining metformin levels. Patients with metformin toxicity present with nonspecific gastrointestinal symptoms and vital sign abnormalities. Laboratory analysis will reveal a high lactate with anion gap metabolic acidosis. Patients presenting with elevated lactate levels in the setting of metformin use should be considered at risk for the most severe form, MALA. Patients with MALA require aggressive treatment with intravenous fluids, treatment of any concomitant condition, and early consideration of hemodialysis, along with specialist consultation such as nephrology and toxicology.
CONCLUSIONS
An understanding of metformin toxicity can assist emergency clinicians in diagnosing and managing this potentially deadly disease.
Topics: Humans; Metformin; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Acidosis, Lactic; Prevalence; Lactic Acid
PubMed: 37517113
DOI: 10.1016/j.ajem.2023.07.020 -
Clinical Medicine (London, England) Nov 2023Lactic acidosis is commonly associated with tissue hypoperfusion and gives rise to concern regarding hypoxia or underlying hypotension. In the cancer patient, especially...
Lactic acidosis is commonly associated with tissue hypoperfusion and gives rise to concern regarding hypoxia or underlying hypotension. In the cancer patient, especially one undergoing chemotherapy, there is always concern for sepsis; however, in the otherwise clincially stable patient with cancer, type B lactic acidosis can also be related to their underlying malignancy. It is considered a haematological emergency given its high mortality rate. However, despite the urgency to treat type B lactic acidosis in these circumstances, treatment options beyond treatment of the malignancy are limited, and its presence portends a poor prognosis. This case highlights our current understanding of type B lactic acidosis and an approach to lactic acidosis evaluation in the cancer patient.
Topics: Humans; Acidosis, Lactic; Neoplasms; Sepsis
PubMed: 38065594
DOI: 10.7861/clinmed.2023-0391 -
Communications Biology Jul 2023Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the...
Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.
Topics: Humans; Fructose-1,6-Diphosphatase Deficiency; Fructose-Bisphosphatase; Fructose; Acidosis, Lactic; Phenotype; Genotype; Hypoglycemic Agents
PubMed: 37507476
DOI: 10.1038/s42003-023-05160-y -
Annals of Emergency Medicine Aug 2023Our primary objective was to characterize the degree of dehydration in children with diabetic ketoacidosis (DKA) and identify physical examination and biochemical... (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVE
Our primary objective was to characterize the degree of dehydration in children with diabetic ketoacidosis (DKA) and identify physical examination and biochemical factors associated with dehydration severity. Secondary objectives included describing relationships between dehydration severity and other clinical outcomes.
METHODS
In this cohort study, we analyzed data from 753 children with 811 episodes of DKA in the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation Study, a randomized clinical trial of fluid resuscitation protocols for children with DKA. We used multivariable regression analyses to identify physical examination and biochemical factors associated with dehydration severity, and we described associations between dehydration severity and DKA outcomes.
RESULTS
Mean dehydration was 5.7% (SD 3.6%). Mild (0 to <5%), moderate (5 to <10%), and severe (≥10%) dehydration were observed in 47% (N=379), 42% (N=343), and 11% (N=89) of episodes, respectively. In multivariable analyses, more severe dehydration was associated with new onset of diabetes, higher blood urea nitrogen, lower pH, higher anion gap, and diastolic hypertension. However, there was substantial overlap in these variables between dehydration groups. The mean length of hospital stay was longer for patients with moderate and severe dehydration, both in new onset and established diabetes.
CONCLUSION
Most children with DKA have mild-to-moderate dehydration. Although biochemical measures were more closely associated with the severity of dehydration than clinical assessments, neither were sufficiently predictive to inform rehydration practice.
Topics: Child; Humans; Diabetic Ketoacidosis; Dehydration; Cohort Studies; Fluid Therapy; Hypertension; Retrospective Studies; Diabetes Mellitus
PubMed: 37024382
DOI: 10.1016/j.annemergmed.2023.01.001 -
Age and Ageing Jan 2024Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) reduce cardio-metabolic and renal outcomes in patients with type 2 diabetes (T2D) but their efficacy and safety in... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) reduce cardio-metabolic and renal outcomes in patients with type 2 diabetes (T2D) but their efficacy and safety in older or frail individuals remains unclear.
METHODS
We searched PubMed, Scopus, Web of Science, Cochrane CENTRA and Google Scholar and selected randomised controlled trials and observational studies comparing SGLT2Is versus placebo/other glucose-lowering agent for people with frailty or older individuals (>65 years) with T2D and heart failure (HF). Extracted data on the change in HbA1c % and safety outcomes were pooled in a random-effects meta-analysis model.
RESULTS
We included data from 20 studies (22 reports; N = 77,083 patients). SGLT2Is did not significantly reduce HbA1c level (mean difference -0.13, 95%CI: -0.41 to 0.14). SGLT2Is were associated with a significant reduction in the risk of all-cause mortality (risk ratio (RR) 0.81, 95%CI: -0.69 to 0.95), cardiac death (RR 0.80, 95%CI: -0.94 to 0.69) and hospitalisation for heart failure (HHF) (RR 0.69, 95%CI: 0.59-0.81). However, SGLT2Is did not demonstrate significant effect in reducing in the risk of macrovascular events (acute coronary syndrome or cerebral vascular occlusion), renal progression/composite renal endpoint, acute kidney injury, worsening HF, atrial fibrillation or diabetic ketoacidosis.
CONCLUSIONS
In older or frail patients with T2D and HF, SGLT2Is are consistently linked with a decrease in total mortality and the overall burden of cardiovascular (CV) events, including HHF events and cardiac death, but not protective for macrovascular death or renal events. Adverse events were more difficult to quantify but the risk of diabetic ketoacidosis or acute kidney injury was not significantly increase.
Topics: Humans; Aged; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Glycated Hemoglobin; Diabetic Ketoacidosis; Sodium-Glucose Transporter 2; Frail Elderly; Heart Failure; Death; Glucose; Sodium
PubMed: 38287703
DOI: 10.1093/ageing/afad254