Prevalence, Risk Factors, and Management of Metabolic Acidosis in Chronic Kidney Disease Patients: A Multicenter Retrospective Study in Malaysia.

Background Metabolic acidosis in chronic kidney disease (CKD) patients has lately gained attention due to the growing evidence of its treatment benefits. This study aims to provide baseline data on the prevalence, risk factors, and current management of metabolic acidosis among the pre-dialysis adult Malaysian CKD population. Methodology This multicenter cross-sectional retrospective study involved pre-dialysis CKD patients above 18 years old on regular nephrology clinic follow-up at three Malaysian government hospitals with nephrology subspecialty. Demographic data, clinical information, laboratory data, and a list of concomitant medications were collected. Factors associated with the occurrence of metabolic acidosis were identified via multiple logistic regression. Results Six hundred and fifty-seven CKD patients were screened for this study, in which only 39.4% (n=259) had available bicarbonate levels. From this, a total of 86.1% (n=223) had metabolic acidosis. Higher estimated glomerular filtration rate (odds ratio (OR) 0.96, 95% confidence interval (CI) 0.93-1.00, p=0.043) and those with cardiovascular disease (OR 0.33, 95% CI 0.15-0.73; p=0.007) were significantly associated with lower odds of metabolic acidosis. There were 43.0% (n=96) on alkali therapy with sodium bicarbonate solution being the most common (n=91, 94.8%). Among those receiving alkali therapy, only 19.8% (n=19) achieved bicarbonate levels of ≥ 22 mEq/L. Conclusion Our study showed that metabolic acidosis was highly prevalent, although few achieved target levels despite supplementation, supporting the need for focused management of metabolic acidosis in the CKD population.

Modulation of mitochondrial function by extracellular acidosis in tumor cells and normal fibroblasts: Role of signaling pathways.

In many tumors pronounced extracellular acidosis resulting from glycolytic metabolism is found. Since several environmental stress factors affect the mitochondrial activity the aim of the study was to analyze the impact of acidosis on cellular oxygen consumption and which signaling pathways may be involved in the regulation. In two tumor cell lines and normal fibroblasts cellular oxygen consumption rate (OCR) and mitochondrial function were measured after 3 h at pH 6.6. Besides the activation of ERK1/2, p38 and PI3K signaling in the cytosolic and mitochondrial compartment, the mitochondrial structure and proteins related to mitochondria fission were analyzed. The acidic extracellular environment increased OCR in tumor cells but not in fibroblasts. In parallel, the mitochondrial membrane potential increased at low pH. In both tumor lines (but not in fibroblasts), the phosphorylation of ERK1/2 and PI3K/Akt was significantly increased, and both cascades were involved in OCR modulation. The activation of signaling pathways was located predominantly in the mitochondrial compartment of the cells. At low pH, the mitochondrial structure in tumor cells showed structural changes related to elongation whereas mitochondria fragmentation was reduced indicating mitochondria fusion. However, these morphological changes were not related to ERK1/2 or PI3K signaling. Acidic stress seems to induce an increased oxygen consumption, which might further aggravate tumor hypoxia. Low pH also induces mitochondria fusion that is not mediated by ERK1/2 or PI3K signaling. The mechanism by which these signaling cascades modulate the respiratory activity of tumor cells needs further investigation.

The Development of Diabetes and Diabetic Ketoacidosis Following Immunotherapy Treatment: A Systematic Review of Case Reports.

As cancer continues to be the leading cause of death worldwide, additional therapeutic options other than traditional platinum-based chemotherapy have become available that target tumor cells in innovative ways. Immunotherapies (e.g., immune checkpoint inhibitors (ICI)) ramp up the immune system to target cancer cells, providing patients with more personalized and tumor cell-specific treatment options. This new age oncological treatment option has been found to provide a more meaningful and stronger alternative to traditional chemotherapy, resulting in longer periods of remission and milder side effects. However, because ICI heightens the immune system, resultant autoimmune conditions can occur. One of the most recently shown adverse effects of ICI are extreme hyperglycemia (i.e., type 1 diabetes) and diabetic ketoacidosis (DKA). To determine the incidence of immunotherapy-induced diabetes, a systematic literature review was performed using CINHAL, EBSCO, MEDLINE, and Web of Science. A total of 403 articles were initially screened, with a final 28 case reports included. The results show that checkpoint inhibitors were found to be most commonly associated with new-onset diabetes as opposed to traditional chemotherapy. Additionally, 41% of patients developed autoimmune diabetes and DKA after being placed on a single therapy of pembrolizumab (targets PD-1: programmed cell death protein 1). However, the pathological process underlying the development of endocrinopathies after treatment with ICI continues to be under investigation.

Extracellular acidification reveals the antiarrhythmic properties of amiodarone related to late sodium current-induced atrial arrhythmia.

BACKGROUND: Amiodarone (AMIO) is an antiarrhythmic drug with the pKa in the physiological range. Here, we explored how mild extracellular pH (pHe) changes shape the interaction of AMIO with atrial tissue and impact its pharmacological properties in the classical model of sea anemone sodium channel neurotoxin type 2 (ATX) induced late sodium current (INa-Late) and arrhythmias. METHOD: Isolated atrial cardiomyocytes from male Wistar rats and human embryonic kidney cells expressing SCN5A Na+ channels were used for patch-clamp experiments. Isolated right atria (RA) and left atria (LA) tissue were used for bath organ experiments. RESULTS: A more acidophilic pHe caused negative inotropic effects on isolated RA and LA atrial tissue, without modification of the pharmacological properties of AMIO. A pHe of 7.0 changed the sodium current (INa) related components of the action potential (AP), which was enhanced in the presence of AMIO. ATXinduced arrhythmias in isolated RA and LA. Also, ATX prolonged the AP duration and enhanced repolarization dispersion in isolated cardiomyocytes in both pHe 7.4 and pHe 7.0. Pre-incubation of the isolated RA and LA and isolated atrial cardiomyocytes with AMIO prevented arrhythmias induced by ATX only at a pHe of 7.0. Moreover, AMIO was able to block INa-Late induced by ATX only at a pHe of 7.0. CONCLUSION: The pharmacological properties of AMIO concerning healthy rat atrial tissue are not dependent on pHe. However, the prevention of arrhythmias induced by INa-Late is pHe-dependent. The development of drugs analogous to AMIO with charge stabilization may help to create more effective drugs to treat arrhythmias related to the INa-Late.

Sodium bicarbonate and intubation in severe diabetic ketoacidosis: are we too quick to dismiss them?

Management of diabetic ketoacidosis (DKA) has internationally established guidelines. However, management of severe, refractory DKA with multiple contributors to acidosis, and management of DKA in patients with altered mentation, remain ambiguous. Use of sodium bicarbonate and intubation in DKA are unpopular treatment practices, but warrant consideration in these unique clinical scenarios. This paper describes a 61-year-old Sri Lankan female who presented with severe DKA, seizures and altered level of consciousness. In her case, the acidosis was secondary to DKA, hyperlactatemia, hyperchloraemic acidosis and acute kidney injury (AKI). Intravenous sodium bicarbonate was used in the management of acidosis. She was intubated due to altered level of consciousness with inadequate respiratory drive to compensate for metabolic acidosis. The outcome in her case was favorable. Intravenous sodium bicarbonate in DKA should be considered for patients with severe, refractory acidosis with hemodynamic instability, hyperkalemia and compounding acidosis due to normal anion gap acidosis or AKI. Intubation should be considered for patients with obtunded mentation unable to achieve respiratory compensation and obtunded mentation where reversal of DKA is unlikely to improve consciousness. Both strategies should be personalized with consideration of individual risk vs benefit.

Urinary Chloride Excretion Postcardiopulmonary Bypass in Pediatric Patients-A Pilot Study.

The aim of this study was to describe renal chloride metabolism following cardiopulmonary bypass (CPB) surgery in pediatric patients. A prospective observational trial in a tertiary pediatric intensive care unit (PICU) with 20 recruited patients younger than 2 years following CPB surgery was conducted. Urinary electrolytes, plasma urea, electrolytes, creatinine, and arterial blood gases were collected preoperatively, on admission to PICU and at standardized intervals thereafter. The urinary and plasma strong ion differences (SID) were calculated from these results at each time point. Fluid input and output and electrolyte and drug administration were also recorded. Median chloride administration was 67.7 mmol/kg over the first 24 hours. Urinary chloride (mmol/L; median interquartile range [IQR]) was 30 (19, 52) prior to surgery, 15 (15, 65) on admission, and remained below baseline until 24 hours. Plasma chloride (mmol/L; median [IQR]) was 105 (98, 107) prior to surgery and 101 (101, 106) on admission to PICU. It then increased from baseline, but remained within normal limits, for the remainder of the study. The urinary SID increased from 49.8 (19.1, 87.2) preoperatively to a maximum of 122.7 (92.5, 151.8) at 6 hours, and remained elevated until 48 hours. Plasma and urinary chloride concentrations were not associated with the development of acute kidney injury. Urinary chloride excretion is impaired after CPB. The urinary SID increase associated with the decrease in chloride excretion suggests impaired production and/or excretion of ammonium by the nephron following CPB, with gradual recovery postoperatively.

Consensus of the Brazilian association of hematology, hemotherapy and cellular therapy on patient blood management.

Understanding the physiological concepts of oxygen delivery is essential to discern the mechanisms that influence its increase, reduction or maintenance in the body. This text explores the different mechanisms that help maintain oxygen delivery even in the face of reduced hemoglobin levels. Adequate oxygen delivery ensures tissue and metabolic balance, which is crucial to avoid harmful consequences such as metabolic acidosis and cellular dysoxia. The complex interaction between variables such as cardiac output, hemoglobin and heart rate (HR) plays a fundamental role in maintaining oxygen delivery, allowing the body to temporarily adjust to situations of anemia or high metabolic demand. It is important to emphasize that blood transfusions should not be based on fixed values, but rather on individual metabolic needs. Strategies to reduce myocardial consumption and monitor macro and micro hemodynamics help in making rational decisions. Individualizing treatment and considering factors such as blood viscosity in relation to the benefits of transfusion are increasingly relevant to optimize therapy and minimize risks, especially in complex clinical scenarios, such as neurocritical patients and trauma victims.

Serum bicarbonate levels and kidney outcomes in critically ill patients: a prospective cohort study.

BACKGROUND: The interplay between serum bicarbonate levels and kidney outcomes is not fully understood. We conducted a prospective cohort study in three intensive care units (ICUs) to evaluate the association of serum bicarbonate levels with acute kidney injury (AKI) and kidney function recovery in critically ill patients. METHODS: A prospective cohort study in three intensive care units (ICUs) was performed. The serum bicarbonate level in the first 24 h after ICU admission was categorized as low (< 22 mEq/L), normal (22-26 mEq/L), or high (> 26 mEq/L). Serum creatinine (SCr) levels according to the KDIGO AKI guideline were used for defining AKI within the first 7 days of ICU stay. At ICU admission, SCr ≥ 1.1 for women and ≥ 1.3 mg/dL for men were indicative of impaired kidney function. Mortality outcome was tracked up to 28 days, and kidney function recovery was assessed at hospital discharge. RESULTS: A total of 2732 patients (66 ± 19 years and 55% men) were analyzed, with 32% having impaired kidney function at ICU admission. Overall, 26% of patients had low bicarbonate levels, while 32% had high bicarbonate levels. Notably, patients with preserved kidney function showed a lower prevalence of low bicarbonate levels compared to those with impaired kidney function (20% vs. 39%, p < 0.001), while higher rates were observed for high bicarbonate (35% vs. 24%, p < 0.001). Compared with patients with normal serum bicarbonate levels, those with low bicarbonate were 81% more likely to develop AKI (OR = 1.81; 95% CI 1.10-2.99), whereas those with high bicarbonate were 44% less likely (OR = 0.56; 95% CI 0.32-0.98) in the adjusted model for confounders. Neither those with high nor low serum bicarbonate levels were associated with an increased risk of mortality (HR = 1.03; 95% CI 0.68-1.56 and 0.99; 95% CI 0.68-1.42, respectively). In subgroup analysis, regardless of the kidney function at ICU admission, serum bicarbonate levels were not associated with the development of AKI and all-cause mortality. Regarding kidney function recovery, higher non-recovery rates were found for those with low bicarbonate. CONCLUSION: In critically ill ICU patients, low bicarbonate levels were associated with the more likely development of AKI and subsequent non-recovery of kidney function, while high bicarbonate levels showed no such association. Therefore, low bicarbonate levels may be considered a risk factor for adverse kidney outcomes in critically ill patients.

The influence of birthweight on mortality and severe neonatal morbidity in late preterm and term infants: an Australian cohort study.

Background: The aim of this study was to detail incidence rates and relative risks for severe adverse perinatal outcomes by birthweight centile categories in a large Australian cohort of late preterm and term infants. Methods: This was a retrospective cohort study of singleton infants (≥34+0 weeks gestation) between 2000 and 2018 in Queensland, Australia. Study outcomes were perinatal mortality, severe neurological morbidity, and other severe morbidity. Categorical outcomes were compared using Chi-squared tests. Continuous outcomes were compared using t-tests. Multinomial logistic regression investigated the effect of birthweight centile on study outcomes. Findings: The final cohort comprised 991,042 infants. Perinatal mortality occurred in 1944 infants (0.19%). The incidence and risk of perinatal mortality increased as birthweight decreased, peaking for infants <1st centile (perinatal mortality rate 13.2/1000 births, adjusted Relative Risk Ratio (aRRR) of 12.96 (95% CI 10.14, 16.57) for stillbirth and aRRR 7.55 (95% CI 3.78, 15.08) for neonatal death). Severe neurological morbidity occurred in 7311 infants (0.74%), with the highest rate (19.6/1000 live births) in <1st centile cohort. There were 75,243 cases of severe morbidity (7.59% livebirths), with the peak incidence occurring in the <1st centile category (12.3% livebirths). The majority of adverse outcomes occurred in infants with birthweights between 10 and 90th centile. Almost 2 in 3 stillbirths, and approximately 3 in 4 cases of neonatal death, severe neurological morbidity or other severe morbidity occurred within this birthweight range. Interpretation: Although the incidence and risk of perinatal mortality, severe neurological morbidity and severe morbidity increased at the extremes of birthweight centiles, the majority of these outcomes occurred in infants that were apparently "appropriately grown" (i.e., birthweight 10th-90th centile). Funding: National Health and Medical Research Council, Mater Foundation, Royal Australian College of Obstetricians and Gynaecologists Women's Health Foundation - Norman Beischer Clinical Research Scholarship, Cerebral Palsy Alliance, University of Queensland Research Scholarship.

Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation study.

Background: Current labelling advises discontinuation of metformin when estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 due to increased risk of lactic acidosis. However, in real-world practice, the risk-benefit ratios remain uncertain. We examined the risk associations of discontinued-metformin use with cardiorenal and clinical outcomes in patients with type 2 diabetes (T2D) and advanced chronic kidney disease. Methods: In this territory-wide, retrospective cohort and target trial emulation study, we included Chinese patients attending the Hong Kong Hospital Authority (HA) and enrolled in the Risk-Assessment-and-Management-Programme-for-Diabetes-Mellitus (RAMP-DM) from 2002 to 2019. Patients were stratified by discontinuation of metformin within six months after reaching eGFR < 30 ml/min/1.73 m2 from January 1, 2002 to December 31, 2018, and followed up until December 31 2019. We excluded patients who had observational time <6 months from eGFR < 30 ml/min/1.73 m2, and had their eGFR measured during a hospitalisation episode due to acute kidney injury, or missing diagnosis date of diabetes. We compared the risk associations of metformin discontinuation with clinical outcomes. The primary outcomes were major adverse cardiovascular events (MACE), end-stage kidney disease (ESKD), cancer, and all-cause mortality. A Cox-model with time-dependent exposure and covariates was used to estimate the hazard ratio (HR) of outcomes in a propensity-score overlap-weighted cohort. The risk of occurrence of lactic acidosis (serum lactate > 5.0 mmol/L with a concomitant blood pH < 7.35 or ICD-9 codes of 276.2) in discontinued-metformin versus continued-metformin users was assessed in a separate register-based cohort. Findings: A total of 33,586 metformin users with new-onset eGFR < 30 ml/min/1.73 m2 were included in the study, 7500 (22.3%) of whom discontinued metformin within 6 months whereas 26,086 (77.7%) continued use of metformin. During a median follow-up of 3.8 (IQR: 2.2-6.1) years, 16.4% (5505/33,586), 30.1% (10,113/33,586), and 7.1% (2171/30,682) had incident MACE, ESKD, and cancer respectively, and 44.4% (14,917/33,586) died. Compared to continued-metformin use, discontinuation was associated with higher risk of MACE (weighted and adjusted HR = 1.40, 95% CI: 1.29-1.52), ESKD (HR = 1.52, 1.42-1.62), and death (HR = 1.22, 1.18-1.27). No association was observed for cancer (HR = 0.93, 0.85-1.01). Discontinued-metformin users had higher change in HbA1c change at 6-month of follow-up versus continued-metformin users (weighted mean HbA1c level change: 0.5% [0.4-0.6%] versus 0.2% [0.1-0.2]). In the separate register-based cohort (n = 3235), null association was observed between metformin use and risk of lactic acidosis (weighted HR = 0.94 [0.53-1.64]). Interpretation: Our results suggest that discontinuation of metformin in patients with T2D and chronic kidney disease may be associated with increased risk of cardiovascular-renal events. Use of metformin below eGFR of 30 ml/min/1.73 m2 may be associated with cardiovascular, renal, and mortality benefits that need to be weighed against the risk of lactic acidosis, but further research is needed to validate these findings. Funding: CUHK Impact Research Fellowship Scheme.

Pseudo-Hypobicarbonatemia in Patients With Hypertriglyceridemia.

Hypobicarbonatemia with an elevated anion gap on a metabolic panel is frequently the initial marker of a life-threatening condition such as diabetic ketoacidosis in a patient with epigastric pain. The two commonly used means of measuring bicarbonate levels are direct measurement from a metabolic panel and calculated measurement from arterial blood gas. In this case report, we would like to highlight a potentially serious deficiency in one of these two means and how it may lead to a dangerous misdiagnosis and subsequent mismanagement. We also shine a light on potential measures to counteract or prevent this undesirable outcome.

Linezolid Toxicity: A Clinical Case Report.

Linezolid plays a clinically important role; however, it is responsible for severe pharmacological interactions and side effects, such as myelosuppression, serotonin syndrome, and lactic acidosis. We report a case of an 80-year-old man treated with venlafaxine for depression. He was admitted with a right femur fracture and submitted to surgical intervention, complicated by local infection. In collected pus was identified multiple microorganisms including Enterococcus faecium resistant to vancomycin. The therapeutic was adjusted to linezolid. On the 36th day of treatment, he developed hypertension, poor peripheral perfusion, and generalized tremor. He was disoriented, with marbled skin, myoclonus, and sinus tachycardia; and apyretic, with no signs of respiratory distress or joint/surgical wound inflammatory signs. Blood tests showed hyperlacticemia and discrete elevation of C-reactive protein but in a decrescent trend, with no other relevant alterations. The diagnosis of lactic acidosis and probable serotonin syndrome secondary to linezolid was made, supported by improvement after the drug suspension.

Emergent Management of Severe Hypothermia, Acidemia, and Coagulopathy in Operative Penetrating Ballistic Cranial Trauma.

Hypothermia in a trauma patient has been associated with increased morbidity and mortality and is more frequently seen in those sustaining traumatic brain injuries (TBIs). Acidosis is an important consequence of hypothermia that leads to derangements across the spectrum of the coagulation cascade. Here, we present a case of a 31-year-old male presented after suffering a right parietal penetrating ballistic injury with an associated subdural hematoma and 7 mm midline shift requiring decompressive craniectomy and external ventricular drain (EVD) placement in the setting of severe hypothermia (28°C) and acidosis (pH 7.12). With aggressive rewarming intraoperatively, the use of full-body forced-air warming, warmed IV fluids, and increasing the ambient room temperature, the patient's acidosis and hypothermia improved to pH 7.20 and 34°C. Despite these aggressive attempts to rewarm the patient, he developed coagulopathy in the setting of concurrent hypothermia and acidosis. This case highlights the importance of prompt reversal of hypothermia due to its potentially fatal effects, particularly in the setting of severe TBIs. We discuss the critical aspects of surgical management of the injury and anesthetic management of hypothermia, acidosis, and coagulopathy perioperatively.

Association between hypomagnesemia and serum lactate levels in patients with sepsis: a retrospective observational study.

BACKGROUND: Sepsis-3 emphasizes the recognition of sepsis-induced cellular metabolic abnormalities, and utilizes serum lactate level as a biomarker of cellular metabolic abnormalities. Magnesium plays an important role as a cofactor in glucose metabolism, although it is not well known that magnesium deficiency causes elevated serum lactate levels. Additionally, it remains unclear how magnesium status affects the role of serum lactate levels as a marker of metabolic abnormalities in sepsis. Thus, this study aimed to investigate the association between serum magnesium and lactate levels in patients with sepsis and explore this relationship from the perspectives of time course and circulatory abnormalities. METHODS: This retrospective observational study of adult patients with sepsis was performed at the 16-bed intensive care unit of Jichi Medical University Hospital between June 2011 and December 2017. The relationship between serum magnesium and lactate levels for 5 days from intensive care unit admission was investigated along the time course. Multivariate logistic regression analysis was performed to evaluate the association between serum magnesium and lactate levels during intensive care unit admission. RESULTS: Among 759 patients included, 105 had hypomagnesemia (magnesium level < 1.6 mg/dL), 558 had normal serum magnesium levels (1.6-2.4 mg/dL), and 96 had hypermagnesemia (magnesium level > 2.4 mg/dL) at intensive care unit admission. From intensive care unit admission to day 5, the hypomagnesemia group had higher serum lactate levels and a higher frequency of lactic acidosis than the normal magnesium level and hypermagnesemia groups (70% vs. 51.6% vs. 50%; P < 0.001). Hypomagnesemia at intensive care unit admission was independently associated with lactic acidosis, i.e., lactic acid level > 2 mmol/L (odds ratio, 2.76; 95% confidence interval, 1.60-4.76; P < 0.001). CONCLUSIONS: Hypomagnesemia was associated with serum lactate levels in the early and post-resuscitation phases of sepsis. Further studies are needed to elucidate whether the magnesium status is associated with sepsis-induced cellular and metabolic abnormalities.

Umbilical artery eucapnic pH to assess fetal well being.

BACKGROUND: Umbilical artery gas results help obstetricians to assess fetal well being during the course of labor and guide screening decisions on eligibility for therapeutic hypothermia or also know as whole body or head cooling. The accuracy of results, especially base deficit on arterial cord gas analysis, in predicting brain injury is questioned. A novel biomarker specifically calculated for fetal acid-base physiology and response to asphyxia-neonatal eucapnic pH as a marker of neonatal metabolic acidosis-has the potential to be an accurate predictor of hypoxic-ischemic encephalopathy. OBJECTIVES: We aimed to compare false-negative rates of hypoxic-ischemic encephalopathy for umbilical artery pH, base deficit, and neonatal eucapnic pH in assessing fetal acid-base balance as a marker of fetal well being and predicting acute brain injury. STUDY DESIGN: This is a retrospective single-center cohort study of newborns ≥ 35 weeks' gestation diagnosed with hypoxic-ischemic encephalopathy. We compared false-negative rates for any grade of hypoxic-ischemic encephalopathy using unilateral paired χ2 statistical analysis based on cut-off values for umbilical artery pH ≤ 7.00, base deficit ≥ 16 mmol/L, base deficit ≥ 12 mmol/L and neonatal eucapnic pH ≤ 7.14. We performed analysis of variance between umbilical artery pH, base deficit, and neonatal eucapnic pH for each hypoxic-ischemic encephalopathy grade. RESULTS: We included 113 newborns. False-negative rate for hypoxic-ischemic encephalopathy was significantly higher for base deficit < 16 mmol/ (n=78/113; 69.0%) compared to base deficit < 12 mmol/L (n=46/113; 40.7%), pH > 7.00 (n=41/113; 36.3%) or neonatal eucpanic pH > 7.14 (n=35/113; 31.0%) (p<0.0001). All true positive cases were identified using only umbilical artery pH and neonatal eucapnic pH. Base deficit ≥16 or ≥12 mmol/L did not add any value in identifying newborns with hypoxic-ischemic encephalopathy when using umbilical artery pH and neonatal eucapnic pH. No association emerged between any marker and hypoxic-ischemic encephalopathy severity grading. CONCLUSION: Our findings support the accuracy of neonatal eucapnic pH to assess fetal well being during labor and to improve predictive performance for acute brain injury. Neonatal eucpanic pH, in addition to umbilical artery pH, may be a viable alternative in identifying newborns at risk for hypoxic-ischemic encephalopathy.

A novel approach to pH-Responsive targeted cancer Therapy: Inhibition of FaDu cancer cell proliferation with a pH low insertion Peptide-Conjugated DGAT1 inhibitor.

Targeting enzymes involved in lipid metabolism is increasingly recognized as a promising anticancer strategy. Efficient inhibition of diacylglycerol O-transferase 1 (DGAT1) can block fatty acid (FA) storage. This, in turn, triggers an increase in free polyunsaturated FA concentration, leading to peroxidation and ferroptosis. In this study, we report the development of a pH-sensitive peptide (pHLIP)-drug conjugate designed to selectively deliver DGAT1 inhibitors to cancer cells nested within the acidic microenvironment of tumors. We utilized two previously established pHLIP sequences for coupling with drugs. The study of DGAT1 conjugates in large unilamellar vesicles (LUVs) of different compositions did not reveal enhanced pH-dependent insertion compared to POPC LUVs. However, using in vitro 3D tumor spheroids, significant antiproliferative effects were observed upon exposure to pHLIP-T863 (DGAT1 inhibitor) conjugates, surpassing the inhibitory activity of T863 alone. In conclusion, our study provides the first evidence that pHLIP-based conjugates with DGAT1 inhibitors have the potential to specifically target the acidic compartment of tumors. Moreover, it sheds light on the limitations of LUV models in capturing the pH-dependency of such conjugates.

Tumoral acidosis promotes adipose tissue depletion by fostering adipocyte lipolysis.

OBJECTIVE: Tumour progression drives profound alterations in host metabolism, such as adipose tissue depletion, an early event of cancer cachexia. As fatty acid consumption by cancer cells increases upon acidosis of the tumour microenvironment, we reasoned that fatty acids derived from distant adipose lipolysis may sustain tumour fatty acid craving, leading to the adipose tissue loss observed in cancer cachexia. METHODS: To evaluate the pro-lipolytic capacities of acid-exposed cancer cells, primary mouse adipocytes from subcutaneous and visceral adipose tissue were exposed to pH-matched conditioned medium from human and murine acid-exposed cancer cells (pH 6.5), compared to naive cancer cells (pH 7.4). To further address the role of tumoral acidosis on adipose tissue loss, a pH-low insertion peptide was injected into tumour-bearing mice, and tumoral acidosis was neutralised with a sodium bicarbonate buffer. Prolipolytic mediators were identified by transcriptomic approaches and validated on murine and human adipocytes. RESULTS: Here, we reveal that acid-exposed cancer cells promote lipolysis from subcutaneous and visceral adipocytes and that dampening acidosis in vivo inhibits adipose tissue depletion. We further found a set of well-known prolipolytic factors enhanced upon acidosis adaptation and unravelled a role for ß-glucuronidase (GUSB) as a promising new actor in adipocyte lipolysis. CONCLUSIONS: Tumoral acidosis promotes the mobilization of fatty acids derived from adipocytes via the release of soluble factors by cancer cells. Our work paves the way for therapeutic approaches aimed at tackling cachexia by targeting the tumour acidic compartment.

Distal renal tubular acidosis as a rare complication of vesicoureteral reflux in children: a case report and literature review.

Distal renal tubular acidosis (dRTA) is a clinical picture of hyperchloremic hypokalemic metabolic acidosis with a normal anion gap. It can be caused by a variety of conditions including obstructive uropathy such as vesicoureteral reflux (VUR). We report a rare case of dRTA secondary to VUR in a 4-year-old girl with a history of meningomyelocele, neurogenic bladder and recurrent urinary tract infections. She was admitted to the hospital with complaints of polydipsia, polyuria, and inability to gain weight for the last 1 year. She was on prophylactic antibiotic treatment with clean intermittent catheterization and anticholinergic drug. She had a history of subureteral injection of various agents and botulin toxin injection into the bladder. Her voiding cystourethrogram revealed grade 5 VUR in the left kidney, tortuosity in the left ureter, and the bladder had a dome-like appearance and was trabeculated. When all laboratory values of the patient since birth were examined, it was observed that urine pH was high despite hypokalemic hyperchloremic metabolic acidosis for the last year; these abnormalities became more severe in the last few months. In conclusion, the development of hypokalemia and nephrolithiasis/nephrocalcinosis along with metabolic acidosis in a patient diagnosed with VUR should be considered as an indicator of impaired tubular functions. Also, the possibility of an underlying VUR in the presence of recurrent urinary tract infection in a patient diagnosed with dRTA should not be ignored.

Perioperative urinary ketosis and metabolic acidosis in patients fasted for undergoing gynecologic surgery.

BACKGROUND: Our bodies have adaptive mechanisms to fasting, in which glycogen stored in the liver and muscle protein are broken down, but also lipid mobilisation is triggered. As a result, glycerol and fatty acids are released into the bloodstream, increasing the production of ketone bodies in liver. However, there are limited studies on the incidence of perioperative urinary ketosis, the intraoperative blood glucose changes and metabolic acidosis after fasting for surgery in non-diabetic adult patients. METHODS: We conducted a retrospective cohort study involving 1831 patients undergoing gynecologic surgery under general anesthesia from January to December 2022. Ketosis was assessed using a postoperative urine test, while blood glucose levels and acid-base status were collected from intraoperative arterial blood gas analyses. RESULTS: Of 1535 patients who underwent postoperative urinalysis, 912 (59.4%) patients had ketonuria. Patients with ketonuria were younger, had lower body mass index, and had fewer comorbidities than those without ketonuria. After adjustments, younger age, higher body mass index and surgery starting late afternoon were significant risk factors for postoperative ketonuria. Of the 929 patients assessed with intraoperative arterial blood gas analyses, 29.0% showed metabolic acidosis. Multivariable logistic regression revealed that perioperative ketonuria and prolonged surgery significantly increased the risk for moderate-to-severe metabolic acidosis. CONCLUSION: Perioperative urinary ketosis and intraoperative metabolic acidosis are common in patients undergoing gynecologic surgery, even with short-term preoperative fasting. The risks are notably higher in younger patients with lower body mass index. Optimization of preoperative fasting strategies including implementation of oral carbohydrate loading should be considered for reducing perioperative metabolic derangement due to ketosis.

[Risk of neonatal acidosis in preterm induction of labor for fetal growth restriction]. / Risque d'acidose en cas de déclenchement pour PAG avant 37 SA.

OBJECTIVE: If a small for gestational age (SGA) foetus needs to be delivered because of severity (< 3rd centile) attempting induction of labor theoretically increases the risk of caesarean section and neonatal acidosis, but these risks are poorly understood. This article aims to assess the risk of caesarean section and neonatal acidosis in attempted vaginal birth of a moderately preterm foetus in the setting of severe SGA. METHOD: A single-centre hospital-based observational study conducted over a period of 17 consecutive years in mothers with a single foetus in cephalic presentation with severe SGA (< 3rd centile) needing foetal extraction. Neonatal acidosis was considered moderate if pH<7.10 and severe if pH<7.0. The degree of severity of SGA was estimated according to the birth weight ratio. RESULTS: Four hundred and thirty-fourfoetuses with severe SGA were included during the period, 140 of whom were born after induction (32.3%). In this group, 66.4 % of women achieved a vaginal birth (66.4% CI95[58.0-74.2]) and the risk of moderate or severe acidosis was doubled compared with the group of foetuses who had undergone a planned caesarean section (7.9% vs 3.1%, OR=2.7 [1.1-6.7]). Neither gestational age nor the degree of growth restriction was significantly related to the risk of caesarean section or to the risk of moderate or severe neonatal acidosis Conclusion: In cases of severe SGA before 37 weeks' gestation, induction of labour allows vaginal delivery in two-thirds of cases. It is accompanied by a doubling of the risk of moderate or severe neonatal acidosis.