Search Results (343)

Background and Objectives: Acute normovolemic hemodilution (ANH) is commonly used to minimize perioperative blood loss and transfusion requirements. While it is considered safe, the molecular effects of ANH on vital organs remain unclear. Aquaporins (AQPs), the principal cellular water transporters, may play a role in tissue adaptation or injury under hemodilution stress. This study aimed to evaluate the impact of ANH on AQP1, AQP3, and AQP4 expression profiles and their association with apoptotic and inflammatory markers in the aorta, heart, kidney, and liver. Materials and Methods: Male Hannover–Sprague Dawley rats (6 months old) were assigned to control (no procedure), sham (anesthesia only), and hemodilution (anesthesia and ANH) groups. ANH was induced using balanced crystalloid infusion. Physiological parameters, blood gases, electrolytes, and metabolic profiles were monitored. At 24 h post-ANH, tissues were harvested for immunoblot analysis of AQPs, as well as apoptotic and inflammatory markers. Results: At 24 h post-ANH, changes in potassium, calcium, and glucose levels, decreased hematocrit, increased lactate, decreased pH, base excess, and PaCO₂ were detected, indicating mild metabolic acidosis due to tissue hypoxia and impaired oxygen delivery. Apoptotic and inflammatory responses were observed across all tissues, but AQP alterations were organ-specific. In the heart, AQP1 downregulation correlated inversely with NF-κB and TNF-α levels, while AQP3 upregulation positively correlated with apoptosis. The aorta showed the opposite pattern. In the kidney, AQP4 downregulation was strongly associated with apoptosis and inflammation. Furthermore, ANH selectively increased the AQP3 expression without affecting AQP1 or AQP4 in the liver. Conclusion: ANH induces differential aquaporin expression patterns in major organs, with tissue-specific associations with apoptosis and inflammation. These findings highlight a potential mechanistic role for AQPs, particularly AQP1 and AQP3, in modulating tissue response to hemodilution. These molecular adaptations may serve as early indicators of tissue stress, suggesting clinical relevance for perioperative fluid strategies. Full article

Metabolic acidosis is a common complication of chronic kidney disease (CKD). The kidneys play a crucial role in acid–base balance, maintaining pH within the normal range (isohydria) by following mechanisms: bicarbonate reabsorption, ammogenesis, and titratable acidity. The anion gap describes the amount of unmeasured anions and is classically evaluated as the difference between the major cation (sodium) and the sum of the two major anions (chloride and bicarbonate). Metabolic acidosis can be divided into two types: normal anion gap metabolic acidosis and high anion gap metabolic acidosis. A high anion gap level is considered unfavorable in terms of prognosis as it is associated with increased mortality. Treatment of metabolic acidosis in patients with chronic kidney disease, despite available therapeutic options, is a challenge. Supplementation with bicarbonates does not improve prognosis on the one hand, and on the other hand, it may be harmful. The new KDIGO guidelines for 2024 have been significantly modified compared to 2012 after negative results of studies on bicarbonate supplementation. Bicarbonate supplementation is currently recommended only when levels are less than 18 mmol/L. This review provides an overview of the current knowledge on the pathophysiology, classification, and therapeutic options, including dietary recommendations and new pharmacology agents. Full article

Background/Objectives: Increasing evidence indicates that a vegetarian diet may provide renal protection and improve metabolic health in patients with chronic kidney disease (CKD). However, transitioning from an omnivorous to a vegetarian diet can be challenging. A more practical alternative could be to increase the consumption of plant protein. In this cross-sectional study, we investigated the association between increased plant protein intake and adherence to a low-protein diet (LPD) and the effect on biochemical parameters, body composition, and muscle strength in patients with non-dialysis CKD stages 3–5. Methods: The daily dietary intake of 377 patients, aged 68.5 ± 12.1 years, was evaluated using a quantitative food frequency questionnaire. Plant protein intake percentage was calculated as (daily plant protein intake/total protein intake) × 100%, and the potential renal acid load (PRAL) was estimated. A LPD was defined as a diet with a daily protein intake of <0.8 g/kg of body weight. Anthropometric measurements, body composition, and handgrip strength were assessed in a subgroup comprising 260 patients. The lean tissue index (LTI) and fat tissue index (FTI) were calculated by dividing lean mass and fat mass (kg) by the height in m², respectively. Results: Of the included 377 patients, 69.5% adhered to the LPD. Further, a 10% increase in plant protein intake was associated with a 20% increase in the likelihood of LPD adherence (OR, 1.20, 95% CI, 1.06 to 1.37), lower PRAL (β = −1.10 per 10% increase, 95% CI, −1.63 to −0.57), and higher serum bicarbonate levels (β = 0.24, 95% CI, 0.02 to 0.45). Analysis of the 260-patient subgroup revealed that a 10% increase in plant protein intake was associated with lower body mass index (β = −0.82, 95% CI, −1.05 to −0.59), FTI (β = −0.71, 95% CI, −1.01 to −0.40), waist circumference (β = −2.11, 95% CI, −2.80 to −1.41), hip circumference (β = −1.25, 95% CI, −1.75 to −0.75), waist-to-hip ratio (β = −0.91, 95% CI, −1.44 to −0.38), and waist-to-height ratio (β = −1.25, 95% CI, −1.71 to −0.80). There was no significant association between increased plant protein intake and LTI and handgrip strength. Conclusions: Increased intake of plant protein can reduce dietary acid load, alleviate metabolic acidosis, and potentially improve adiposity parameters without compromising lean mass and handgrip strength. Full article

Intracellular alkalosis and extracellular acidosis are two pathological features associated with malignant cells. They offer advantages in terms of invasiveness and proliferation. Extracellular acidification is the consequence of intracellular metabolic changes associated with a higher metabolic rate of cancer cells, potentially inducing dangerous intracellular acidification. To overcome this menace, malignant cells adapt themselves to export hydrogen ions. Therefore, it is reasonable that targeting intracellular alkalinization and extracellular acidification to prompt the reversal of such a pH gradient towards a condition comparable to normal, untransformed cells may represent a strategy helping to contrast malignant behavior. In the present study, we investigated in vitro, in prostate cancer cell models, the biological activity towards intracellular, extracellular and organelle pH of systems of molecules of vegetal origin. A few of these systems were shown to promote intracellular acidification in vitro, whereas others were shown to prevent extracellular acidification and promote lysosomal alkalinization in a cell type-dependent manner. This result clearly indicates that these systems may function as agents interfering with malignant cells inverted pH gradient. Further analysis would be necessary to unravel the cell type specificity of their effects, as well as their mechanism of action. Nevertheless, our proof-of-principle study provides evidence that such systems of molecules can be considered interesting agents in co-adjuvating anti-cancer therapies. Full article

Oxidative and glycolytic metabolism produce energy in the form of ATP and produce intermediates for biomass production. Oxidative metabolism predominates under normoxic conditions and in quiescent or slowly proliferating cells. On the other hand, under hypoxic or pseudohypoxic conditions and in rapidly proliferating cells, glycolysis becomes the predominant pathway. The balance between oxidative and glycolytic metabolism is finely tuned in physiological conditions and becomes dysregulated in many pathological conditions, most notably cancer. In this article we summarize the evidence that has been gathered over the last few years on the mechanisms underlying this balance and the consequences of their dysregulation. We discuss first the non-metabolic factors (mitochondria, cell cycle, cell type, tissue type), then molecules that are at the intersection between glycolytic and oxidative metabolism and those molecules that are inherent to oxidative or glycolytic metabolism that affect the equilibrium between the two energy-producing pathways. Eventually, we discuss pharmacologic or genetic means that allow manipulating this equilibrium. As will be seen, lactic acidosis has taken center stage in this field and lactate has been shown to fuel oxidative metabolism. This suggests that if glycolytic metabolism predominates, as has often been shown in cancer, mechanisms come into work that reestablish a metabolic heterogeneity. Thus, while one pathway may be predominant over the other, it seems as if fail-safe mechanisms are at work that avoid the possibility that it becomes the only energy-producing pathway. Eventually, we discuss possible therapeutic consequences that may derive from this expanding knowledge, in particular, as regards tumor therapy. Full article

Chloride, long considered a passive extracellular anion, has emerged as a key determinant in the pathophysiology and management of heart failure (HF) and cardiorenal syndrome. In contrast to sodium, which primarily reflects water balance and vasopressin activity, chloride exerts broader effects on neurohormonal activation, acid–base regulation, renal tubular function, and diuretic responsiveness. Its interaction with With-no-Lysine (WNK) kinases and chloride-sensitive transporters underscores its pivotal role in electrolyte and volume homeostasis. Hypochloremia, frequently observed in HF patients treated with loop diuretics, is independently associated with adverse outcomes, diuretic resistance, and arrhythmic risk. Conversely, hyperchloremia—often iatrogenic—may contribute to renal vasoconstriction and hyperchloremic metabolic acidosis. Experimental data also implicate chloride dysregulation in myocardial electrical disturbances and an increased risk of sudden cardiac death. Despite mounting evidence of its clinical importance, serum chloride remains underappreciated in contemporary risk assessment models and treatment algorithms. This review synthesizes emerging evidence on chloride’s role in HF, explores its diagnostic and therapeutic implications, and advocates for its integration into individualized care strategies. Future studies should aim to prospectively validate these associations, evaluate chloride-guided therapeutic interventions, and assess whether incorporating chloride into prognostic models can improve risk stratification and outcomes in patients with heart failure and cardiorenal syndrome. Full article

Background/Objectives: Acetazolamide is widely used for acute mountain sickness (AMS) prophylaxis. Whilst generally safe, acute kidney injury (AKI) is a rare but serious adverse event. We present a case of anuric AKI following minimal exposure to acetazolamide, contributing to the limited literature on its nephrotoxicity at prophylactic doses. Methods: A 54-year-old previously healthy male ingested 250 mg/day of oral acetazolamide for two days. He developed acute anuria and lumbar pain. Diagnostic evaluation included laboratory tests, imaging, microbiological cultures, autoimmune panels, and diuretic response. No signs of infection, urinary tract obstruction, or systemic disease were found. Results: The patient met KDIGO 2012 criteria for stage 3 AKI, with peak serum creatinine of 10.6 mg/dL and metabolic acidosis. Imaging confirmed non-obstructive nephrolithiasis. Conservative treatment failed; intermittent hemodialysis was initiated. Renal function recovered rapidly, with the normalization of serum creatinine and urinary output by day 4. Conclusions: This case represents the lowest cumulative dose of acetazolamide reported to cause stage 3 AKI. The findings support a pathophysiological mechanism involving sulfonamide-induced crystalluria and intratubular obstruction. Physicians should consider acetazolamide in the differential diagnosis of AKI, even with short-term prophylactic use. Full article

Background/Objectives: Diabetic ketoacidosis (DKA) is an acute and severe complication of diabetes mellitus, marked by hyperglycemia, ketosis, and acidosis. It is associated with significant metabolic and inflammatory adjustments that can impact multiple biochemical pathways. This study aimed to determine the serum sphingolipid profile in DKA and investigate its relationship with neutral sphingomyelinase (N-SMase), pro-inflammatory cytokines, β-hydroxybutyrate (β-OHB), and lactate levels. Methods: Thirty-three participants were divided into three groups: control (BMI ≤ 30, no health issues), obese (BMI > 30), and DKA (BMI ≤ 30). Sphingomyelins (16:0–24:0 SMs) and ceramides (C16–C24 CERs) were measured using ultra-fast liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). N-SMase, interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) levels were assessed by enzyme-linked immunosorbent assay. Evaluations were done in the DKA group before and after standard clinical treatment for DKA (post-DKA group), which included intravenous insulin therapy, fluid resuscitation, and electrolyte replacement, as per established clinical guidelines. Results: β-OHB levels were significantly higher in the DKA group than in the control, obese, and post-DKA groups. Although β-OHB levels decreased in the post-DKA group, they remained elevated compared to the control and obese groups. Lactate levels were also higher in the DKA group, with a significant decrease in the post-DKA group. TNF-α and IL-1β were higher in the obese group compared to control and DKA groups, and TNF-α decreased significantly in the post-DKA group compared to DKA. N-SMase, 16:0–18:0 SMs, and C18-C24 CER levels were lower in the DKA and post-DKA groups compared to obese and control groups. Serum β-OHB and lactate levels were significantly correlated with S1P, total CER, total SM, and N-SMase values. Conclusions: The study reveals significant metabolic and inflammatory differences in DKA and post-DKA states, suggesting a relationship between sphingolipids, N-SMase, and these alterations, which could offer insights into DKA pathophysiology and therapeutic targets. Full article

Background and Clinical Significance: Diabetic ketoacidosis (DKA) is a serious and potentially life-threatening condition, often triggered by infections or undiagnosed diabetes. Spontaneous pneumomediastinum (SPM) and pneumothorax are rare but recognized complications of DKA, possibly due to alveolar rupture from increased respiratory effort or vomiting. Sometimes, acute pancreatitis (AP) may further complicate DKA, but the co-occurrence of these three conditions remains exceptionally rare. Case Presentation: We describe the case of a 60-year-old woman without a known history of diabetes who arrived at the emergency department with abdominal pain, fatigue, vomiting, and altered mental status. Initial laboratory findings showed metabolic acidosis, hyperglycemia, and elevated anion gap, consistent with DKA. Imaging revealed spontaneous pneumomediastinum and subsequently a left-sided pneumothorax, without evidence of trauma or esophageal rupture. Epigastric pain, along with elevated serum lipase and CT findings, also confirmed acute pancreatitis. Despite the complexity of her condition, the patient responded well to supportive treatment, including oxygen therapy, fluid resuscitation, insulin infusion, and antibiotics. She was discharged in good condition after 28 days, with a confirmed diagnosis of type 2 diabetes, without further complications. Conclusions: This case highlights an unusual combination of DKA complicated by spontaneous pneumomediastinum, pneumothorax and acute pancreatitis in a previously undiagnosed diabetic patient. Because prompt intervention can lead to favorable outcomes even in complex, multisystem cases, early recognition of atypical DKA complications is critical in order to avoid misdiagnosis. Full article

Background/Objectives: In diabetic ketoacidosis (DKA), absolute insulin deficiency and elevation of counter-regulatory hormones may cause osmotic diuresis and water and electrolyte loss, which may lead to dehydration and renal failure. Fluids with high Na content are preferred in the DKA fluid therapy algorithm due to the association of Na with β-Hydroxybutyrate (β-HB) and the renal excretion of Na-β-HB. However, these fluids may cause hyperchloremic metabolic acidosis due to their high chloride concentration. In the literature, base-excess chloride (BE_Cl) has been suggested as a better approach for assessing the effect of chloride on acid–base status. Our aim in this study was to investigate the effect of fluids with BE_Cl values less than zero versus those with values equal to or greater than zero on the metabolic acid–base status in the first 6 h of DKA. Methods: This retrospective study included DKA cases managed in the tertiary intensive care units of five hospitals in the last 10 years. Patients were divided into two groups according to the Na-Cl difference of the administered fluids during the first 6 h of treatment: Group I [GI, fluids with Na-Cl difference = 0, chloride-rich group] and Group II [GII, fluids with Na-Cl difference > 32 mmol, chloride non-rich group]. Demographic data, blood gas analysis results, types and amounts of administered fluids, urea–creatinine values, and urine ketone levels were recorded. Results: Thirty-five patients with DKA in the ICU were included in the study (GI; 22 patients, GII; 13 patients). There was no difference between the patients in the two groups in terms of age, gender, and LOS-ICU. According to the distribution of the administered fluids, the main fluid administered in GI was 0.9% NaCl, whereas in the GII, it was bicarbonate, Isolyte-S, and 0.9% NaCl. In GI, the chloride load administered was higher; the BE_Cl level of the fluids was lower than in GII. At the end of the first 6 h, although sodium and strong ion gap values were similar, patients in GI were more acidotic due to iatrogenic hyperchloremia and, as a result, were more hypocapnic than GII. Conclusions: In conclusion, administering chloride-rich fluids in DKA may help reduce unmeasured anion acidosis. Still, risks cause iatrogenic hyperchloremic acidosis, which can hinder the expected resolution of acidosis and increase respiratory workload. Therefore, it is suggested that DKA guidelines be revised to recommend an individualized approach that avoids chloride-rich fluids and includes monitoring of metabolic parameters like Cl and BE_Cl. Full article

During periods of exercise, the primary cause of metabolic acidosis is the accumulation of lactate from anaerobic metabolism, whereas a transient increase in CO₂ triggers a mild respiratory acidosis through the production of carbonic acid (H₂CO₃). The combined effects of these reactions result in a slight acidifying shift in arterial blood pH. Proton-sensing G protein-coupled receptors (including GPR68, GPR4, GPR132, and GPR65) represent the primary receptors within the body for detecting alterations in extracellular proton concentrations. These receptors have been demonstrated to possess potential roles in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Recent studies have shown that the activation or inhibition of these receptors modulates a number of arterial functions, including angiogenesis, arterial relaxation, and arterial inflammation. It is well established that moderate exercise has a beneficial effect on the regulation of arterial function. This study examines the effect of exercise on proton concentrations in the microenvironment of the organism and its influence on proton-sensing G protein-coupled receptors located on cell membranes, as well as possible mechanisms involved in the regulation of arterial function. The objective is to present novel perspectives for the exploration of potential drug targets for the prevention and treatment of arterial dysfunction and the development of exercise regimens. Full article

Background: Acute mesenteric ischemia (AMI) is a potentially life-threatening condition that requires prompt diagnosis and treatment. The presence of air within the arterial lumen, particularly in the abdomen, is an uncommon finding with varied etiologies. This case report presents a unique instance of AMI with air in the superior mesenteric artery (SMA), highlighting the complexities in diagnosis and management. Case presentation: An 89-year-old male with a history of smoking, hypertension, dyslipidemia, and atrial fibrillation presented with chest pain and underwent coronary angiography for suspected anterior ST-elevation myocardial infarction (STEMI). Following successful thromboaspiration and admission to the coronary care unit, he developed severe abdominal pain. A contrast-enhanced computed tomography (CECT) scan revealed a thromboembolic occlusion in the SMA, along with air filling in the SMA and its branches. An endovascular thrombectomy was performed, but the patient died the next day due to complications related to AMI and metabolic acidosis. Conclusions: This case underscores the challenges in diagnosing and managing AMI, particularly when accompanied by unusual imaging findings such as air within the SMA. The presence of air in the arterial system raises questions about its origin and clinical significance in the context of AMI. Further research is needed to understand the mechanisms and implications of this rare phenomenon, which may have implications for refining diagnostic and therapeutic strategies for AMI. Full article

Background/Objectives: Critically ill patients can often present acid–base alterations. The aim of this study was to evaluate the prevalence and the time-course of acid–base alterations on intensive care unit (ICU) admission and on day one by the traditional standard base excess (SBE)-based and the Stewart methods in mechanically ventilated patients. Methods: A prospective observational study enrolling mechanically ventilated patients in the ICU was conducted. Arterial blood gas analysis, blood and urine samples were obtained on ICU admission and on day one. Plasmatic and urinary acid–base variables were compared among acidemic, alkalemic and patients with normal pH. The agreement between the SBE-based and Stewart methods was assessed at ICU admission and on day one. Results: One hundred and seventy-two patients were enrolled. On ICU admission, 55 (32%), 29 (17%) and 88 (51%) patients had acidemia, alkalemia and a normal pH, respectively. On day one, 12 (7%), 48 (28%) and 112 (65%) patients had acidemia, alkalemia and a normal pH with lower values of paCO2 and albumin. According to the SBE and Stewart approaches, the occurrence of metabolic acidosis was similar (24% vs. 35%), as well as the rate of metabolic alkalosis (16% vs. 23%) on ICU admission; on day one, the occurrence of metabolic acidosis was different (12% vs. 35%), as well as the rate of metabolic alkalosis (35% vs. 14%). The agreement between methods was estimated to be low both on ICU admission and on day one. Conclusions: Up to 50 % of mechanically ventilated patients presented acid–base derangements, mainly due to acidemia on ICU admission and to alkalemia after 24 h, secondary to alterations in carbon dioxide and plasma albumin. The agreement between the traditional and Stewart approaches was poor. The Stewart approach could be more accurate in detecting the acid–base disturbances in critically ill patients characterized by changes of mechanical ventilation and fluid administration. Full article

Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease. Full article

The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe₂S₂ iron–sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Björnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A>G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A>G variant, suggesting altered interaction between the mutant BCS1L and CIII. Full article