-
Endocrine Journal Jul 2023Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have... (Review)
Review
Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the acid-base balance in PHA2. Through a literature search published between 2008-2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0-8.6 mEq/L), whereas that of chloride (Cl) was 110 ± 3.5 mEq/L (n = 41, 100-119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cl and HCO3 levels showed significant correlations with K levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.
Topics: Adult; Humans; Child; Adolescent; Pseudohypoaldosteronism; Hypoaldosteronism; Acidosis; Mutation; Hyperkalemia
PubMed: 37081692
DOI: 10.1507/endocrj.EJ22-0607 -
Cancer Letters Apr 2024Acidosis is involved in multiple pathways in tumor cells and immune cells among the tumor microenvironment (TME). Ferroptosis is a nonapoptotic and iron-dependent form...
Acidosis is involved in multiple pathways in tumor cells and immune cells among the tumor microenvironment (TME). Ferroptosis is a nonapoptotic and iron-dependent form of cell death characterized by accumulation of lipid peroxidation involved in various cancers. The role of ferroptosis in the breast cancer (BC) acidic microenvironment remains unrevealed. Here, we reported that short-term acidosis induced ferroptosis of BC cells in the zinc finger AN1-type domain 5 (ZFAND5)/solute carrier family 3 member 2 (SLC3A2) dependent manner to suppress tumor growth using in silico and multiple biological methods. Mechanistically, we demonstrated that short-term acidosis increased total/lipid reactive oxygen species (ROS) level, decreased glutathione (GSH) level and induced the morphological changes of mitochondria. Specifically, acidosis restrained the protein stability of SLC3A2 by promoting its ubiquitination process. The prognostic analysis showed that higher expression of ZFAND5 and lower expression of SLC3A2 were correlated with longer overall survival of BC patients, respectively. Furthermore, in combination with ferroptosis agonist metformin, short-term acidosis could synergistically inhibit viability and enhance the ferroptosis of BC cells. Meanwhile, by the exploration of immune cells, short-term acidosis also induced M1 macrophage polarization, triggering processes of phagocytosis and ferroptosis in BC cells. This study demonstrated that short-term acidosis induced BC cell ferroptosis through ZFAND5/SLC3A2 signaling axis and promoted phagocytosis and ferroptosis of BC cells with M1 macrophage polarization, which might be a new mechanism for BC therapy.
Topics: Humans; Female; Breast Neoplasms; Ferroptosis; Fusion Regulatory Protein 1, Heavy Chain; Macrophages; Acidosis; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 38360142
DOI: 10.1016/j.canlet.2024.216732 -
Acta Anaesthesiologica Scandinavica Apr 2024Our 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...
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.
PubMed: 38581223
DOI: 10.1111/aas.14424 -
Journal of Lipid Research Oct 2023The potential of ketogenic approaches to regulate energy balance has recently gained attention since ketones may influence both energy expenditure and energy intake. In... (Review)
Review
The potential of ketogenic approaches to regulate energy balance has recently gained attention since ketones may influence both energy expenditure and energy intake. In this narrative review, we summarized the most relevant evidence about the role of ketosis on energy expenditure, substrate utilization, and energy intake in humans. We considered different strategies to induce ketosis, such as fasting, dietary manipulation, and exogenous ketone sources. In general, ketosis does not have a major influence on energy expenditure but promotes a shift in substrate utilization towards ketone body oxidation. The strategies to induce ketosis by reduction of dietary carbohydrate availability (e.g., ketogenic diets) do not independently influence energy intake, being thus equally effective for weight loss as diets with higher carbohydrate content. In contrast, the intake of medium-chain triglycerides and ketone esters induces ketosis and appears to increase energy expenditure and reduce energy intake in the context of high carbohydrate availability. These latter strategies lead to slightly enhanced weight loss. Unfortunately, distinguishing the effects of the various ketogenic strategies per se from the effects of other physiological responses is not possible with the available human data. Highly controlled, inpatient studies using targeted strategies to isolate the independent effects of ketones are required to adequately address this knowledge gap.
Topics: Humans; Ketone Bodies; Diet, Ketogenic; Ketones; Ketosis; Energy Metabolism; Energy Intake; Dietary Carbohydrates; Weight Loss
PubMed: 37703994
DOI: 10.1016/j.jlr.2023.100442 -
American Journal of Physiology.... Dec 2023Exercise is associated with the development of oxidative stress, but the specific source and mechanism of production of pro-oxidant chemicals during exercise has not...
Exercise is associated with the development of oxidative stress, but the specific source and mechanism of production of pro-oxidant chemicals during exercise has not been confirmed. We used equine skeletal muscle mitochondria to test the hypothesis that hyperthermia and acidosis affect mitochondrial oxygen consumption and production of reactive oxygen species (ROS). Skeletal muscle biopsies were obtained at rest, after an acute episode of fatiguing exercise, and after a 9-wk conditioning program to increase aerobic fitness. Mitochondrial oxygen consumption and ROS production were measured simultaneously using high-resolution respirometry. Both hyperthermia and acidosis increased nonphosphorylating (LEAK) respiration (5.8× and 3.0×, respectively, < 0.001) and decreased efficiency of oxidative phosphorylation. The combined effects of hyperthermia and acidosis resulted in large decreases in phosphorylating respiration, further decreasing oxidative phosphorylation efficiency from 97% to 86% ( < 0.01). Increased aerobic fitness reduced the effects of acidosis on LEAK respiration. Hyperthermia increased and acidosis decreased ROS production (2× and 0.23×, respectively, < 0.001). There was no effect of acute exercise, but an aerobic conditioning program was associated with increased ROS production during both nonphosphorylating and phosphorylating respiration. Hyperthermia increased the ratio of ROS production to O consumption during phosphorylating respiration, suggesting that high-temperature impaired transfer of energy through the electron transfer system despite relatively low mitochondrial membrane potential. These data support the role of skeletal muscle mitochondria in the development of exercise-induced oxidative stress, particularly during forms of exercise that result in prolonged hyperthermia without acidosis. The results of this study provide evidence for the role of mitochondria-derived ROS in the development of systemic oxidative stress during exercise as well as skeletal muscle diseases such as exertional rhabdomyolysis.
Topics: Animals; Horses; Reactive Oxygen Species; Mitochondria; Mitochondria, Muscle; Muscle, Skeletal; Acidosis; Oxygen Consumption; Hyperthermia; Hyperthermia, Induced
PubMed: 37811714
DOI: 10.1152/ajpregu.00177.2023 -
International Journal of Molecular... Dec 2023Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one...
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one of the most common maternally inherited mitochondrial diseases accompanied by neuronal damage due to defects in the oxidative phosphorylation system. There is no established treatment. Our previous study reported a superior restoration of mitochondrial function and bioenergetics in mitochondria-deficient cells using highly purified mesenchymal stem cells (RECs). However, whether such exogenous mitochondrial donation occurs in mitochondrial disease models and whether it plays a role in the recovery of pathological neuronal functions is unknown. Here, utilizing induced pluripotent stem cells (iPSC), we differentiated neurons with impaired mitochondrial function from patients with MELAS. MELAS neurons and RECs/mesenchymal stem cells (MSCs) were cultured under contact or non-contact conditions. Both RECs and MSCs can donate mitochondria to MELAS neurons, but RECs are more excellent than MSCs for mitochondrial transfer in both systems. In addition, REC-mediated mitochondrial transfer significantly restored mitochondrial function, including mitochondrial membrane potential, ATP/ROS production, intracellular calcium storage, and oxygen consumption rate. Moreover, mitochondrial function was maintained for at least three weeks. Thus, REC-donated exogenous mitochondria might offer a potential therapeutic strategy for treating neurological dysfunction in MELAS.
Topics: Humans; MELAS Syndrome; Mitochondria; Acidosis, Lactic; DNA, Mitochondrial; Mitochondrial Diseases; Neurons; Mesenchymal Stem Cells
PubMed: 38139018
DOI: 10.3390/ijms242417186 -
American Journal of Kidney Diseases :... Sep 2023Metformin has been recommended for some patients with advanced chronic kidney disease. However, the value of metformin in kidney transplant recipients (KTRs) with...
RATIONALE & OBJECTIVE
Metformin has been recommended for some patients with advanced chronic kidney disease. However, the value of metformin in kidney transplant recipients (KTRs) with pretransplant diabetes mellitus (DM) or posttransplant DM is uncertain. We investigated the clinical effects of metformin in KTRs.
STUDY DESIGN
Retrospective cohort study.
SETTING & PARTICIPANTS
A total of 1,995 KTRs with diabetes from 6 tertiary referral centers in the Republic of Korea.
EXPOSURE
Metformin usage was defined as the use of metformin for>90 days after kidney transplantation; 1,193 KTRs were metformin users, and 802 KTRs did not use metformin. Changing usage of metformin among those exposed for >90 days was also characterized.
OUTCOME
Primary outcomes were all-cause mortality and death-censored graft failure (DCGF). Secondary outcomes were biopsy-proven acute rejection (BPAR) and lactic acidosis events.
ANALYTICAL APPROACH
Survival analyses were conducted using multivariable Cox regression and competing risk analyses using Fine and Gray models. Changes in metformin use over time were modeled using a time-varying covariate. Metformin usage, mean daily dose, and hemoglobin A (HbA) changes were considered in the landmark analysis to address time-varying confounding.
RESULTS
Metformin use was associated with a lower risk of DCGF (adjusted hazard ratio [AHR], 0.47 [95% CI, 0.23-0.96], P=0.038); there was no significant association with all-cause mortality (AHR, 0.94 [95% CI, 0.32-2.76], P=0.915) or BPAR (AHR 0.98 [95% CI, 0.62-1.54], P=0.942). In the subgroup analysis, metformin usage was associated with a reduced risk of all-cause mortality and a lower risk of DCGF for both pretransplantation DM and posttransplant DM groups. Metformin usage was associated with a lower risk of BPAR in the posttransplant DM group, although it was less effective in the pretransplantation DM group. There was no confirmed case of metformin-associated lactic acidosis (MALA) in the present cohort. A higher dose of metformin was correlated with lower risks of DCGF and BPAR.
LIMITATIONS
Data on newer antidiabetic drugs such as SGLT2 inhibitors are limited, and there is potential limited generalizability to other populations.
CONCLUSIONS
Metformin usage may benefit KTRs, as evidenced by its association with a reduced risk of DCGF and the absence of MALA events. Randomized controlled trials are needed to validate these observational findings.
Topics: Humans; Kidney Transplantation; Metformin; Retrospective Studies; Acidosis, Lactic; Diabetes Mellitus; Transplant Recipients; Risk Factors
PubMed: 36965829
DOI: 10.1053/j.ajkd.2023.01.446 -
JCEM Case Reports Jul 2023We report a 76-year-old man who was treated for hyperglycemia and metabolic acidosis after chemotherapy with enfortumab vedotin and pembrolizumab administered after his...
We report a 76-year-old man who was treated for hyperglycemia and metabolic acidosis after chemotherapy with enfortumab vedotin and pembrolizumab administered after his surgery for bladder cancer. He had an approximately 20-year history of diabetes. His body mass index was 18.6, and he received metformin 1000 mg/day, sitagliptin 50 mg/day, mitiglinide 30 mg/day, and voglibose 0.6 mg/day with hemoglobin A1c was approximately 7%. He underwent total cystectomy and ileal conduit reconstruction. After relapse, he received chemotherapy but later developed hyperglycemia and metabolic acidosis. His hyperglycemia was caused by enfortumab vedotin, and metabolic acidosis was attributable to the ileocecal canal. These symptoms should be remembered as important complications of this standard treatment, which prompted this case report.
PubMed: 37909003
DOI: 10.1210/jcemcr/luad092 -
PloS One 2023Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic...
Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic acid-induced bone dissolution. Bisphosphonates (BPPs) are a potential treatment for inhibiting bone dissolution; however, there are limited studies observing the use of BPPs on acidotic patients. We aimed to determine efficacy of BPPs on maintaining bone health and pH regulation in acid-exposed mice. Using a diet-induced murine model of metabolic acidosis, we examined bone structure, composition, and mechanics as well as blood gases for three groups: control, acidosis, and acidosis + bisphosphonates (acidosis+BPP). Acidosis was induced for 14 days and alendronate was administered every 3 days for the acidosis+BPP group. The administration of BPP had little to no effect on bone structure, mechanics, and composition of the acidosis bones. However, administration of BPP did cause the mice to develop more severe acidosis than the acidosis only group. Overall, we discovered that BPPs may exacerbate acidosis symptoms by inhibiting the release of buffering ions from bone. Therefore, we propose that BPP administration should be carefully considered for those with CKD and that alkali supplementation could help minimize acidifying effects.
Topics: Animals; Mice; Alendronate; Ammonium Chloride; Diphosphonates; Acidosis; Osteolysis; Renal Insufficiency, Chronic
PubMed: 37713420
DOI: 10.1371/journal.pone.0291649 -
The American Journal of the Medical... May 2024Autoimmune polyglandular syndrome (APS) is a rare group of immune-mediated disorders, which are typically, but not exclusively, related to the presence of endocrine... (Review)
Review
Autoimmune polyglandular syndrome (APS) is a rare group of immune-mediated disorders, which are typically, but not exclusively, related to the presence of endocrine abnormalities. APS type 2 is the most common subtype of the syndrome, more often observed in adulthood, with a characteristic clinical triad, which includes adrenal insufficiency, autoimmune thyroiditis and diabetes mellitus type 1. Adrenal insufficiency is an essential and necessary clinical manifestation of the syndrome, as it is observed in 100 % of the cases, while it can be accompanied by hyperchloremic metabolic acidosis. Herein, we present a 23 years-old patient with adrenal insufficiency in the context of autoimmune polyglandular syndrome type 2 with coexisting autoimmune thyroiditis and metabolic acidosis with an increased anion gap attributed to prolonged malnutrition. Additionally, we analyze the main clinical features of adrenal insufficiency, which is a central component of autoimmune polyglandular syndrome; highlight characteristics that differentiate the major APS subtypes.
PubMed: 38801948
DOI: 10.1016/j.amjms.2024.05.019