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Biomedicines May 2024In chronic kidney disease (CKD) patients, several risk factors contribute to the development of endothelial dysfunction (ED), which can be described as an alteration in... (Review)
Review
In chronic kidney disease (CKD) patients, several risk factors contribute to the development of endothelial dysfunction (ED), which can be described as an alteration in the cell structure or in the function of the endothelium. Among the well-known CKD-related risk factors capable of altering the production of endothelium-derived relaxing factors, we include asymmetric dimethylarginine increase, reduced dimethylarginine dimethylamine hydrolase enzyme activity, low-grade chronic systemic inflammation, hyperhomocysteinemia, oxidative stress, insulin resistance, alteration of calcium phosphorus metabolism, and early aging. In this review, we also examined the most important techniques useful for studying ED in humans, which are divided into indirect and direct methods. The direct study of coronary endothelial function is considered the gold standard technique to evaluate if ED is present. In addition to the discussion of the main pharmacological treatments useful to counteract ED in CKD patients (namely sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonist), we elucidate innovative non-pharmacological treatments that are successful in accompanying the pharmacological ones. Among them, the most important are the consumption of extra virgin olive oil with high intake of minor polar compounds, adherence to a plant-dominant, low-protein diet (LPD), an adaptive physical activity program and, finally, ketoanalogue administration in combination with the LPD or the very low-protein diet.
PubMed: 38791047
DOI: 10.3390/biomedicines12051085 -
Biomolecules May 2024Urine free cortisol measurements are routinely performed to evaluate hypercortisolism. Despite their analytical inaccuracy, immunoassay-based methods are frequently...
INTRODUCTION
Urine free cortisol measurements are routinely performed to evaluate hypercortisolism. Despite their analytical inaccuracy, immunoassay-based methods are frequently used. Advances in liquid chromatography-high-resolution mass spectrometry (LC-HRMS) facilitate the incorporation of powerful diagnostic tools into clinical laboratories. In addition to its high analytical specificity and simultaneous analysis of different metabolites, accurate mass measurement allows for untargeted compound identification, which may help to identify clinically relevant metabolites or drugs.
METHODS
The present study aimed to validate a simple routine LC-HRMS method to quantify cortisol, cortisone, 6β-hydroxycortisol, and 18-hydroxycortisol simultaneously in human urine. Additionally, the study also validated a GC-MS method for the same steroids, evaluated their cross-reactivity with commercial cortisol immunoassays, and quantified the 24 h urine excretion in patients under clinical suspicion or follow-up for hypercortisolism.
RESULTS
The LC-HRMS method involved liquid-liquid extraction using dichloromethane, micro-LC for chromatographic separation and detection using the accurate masses of the steroids, and simultaneous high-resolution full scan acquisition. The method presented acceptable linearity, precision, and accuracy. Significant interference from 6β-hydroxycortisol and cortisone was demonstrated in the cortisol immunoassays, which impacted their reliability in the follow-up of patients with hypercortisolism and significant changes in these cortisol metabolites (i.e., due to drug-induced changes in CYP3A4 activity).
CONCLUSION
A rapid and accurate routine LC-HRMS method was validated, which is useful for the evaluation of hypercortisolism and other disorders of glucocorticoid and mineralocorticoid metabolism.
Topics: Humans; Hydrocortisone; Cortisone; Gas Chromatography-Mass Spectrometry; Chromatography, Liquid; Glucocorticoids; Cushing Syndrome; Male; Female
PubMed: 38785966
DOI: 10.3390/biom14050558 -
Journal of Comparative Effectiveness... Jun 2024To describe the epidemiological, clinical and laboratory characteristics and clinical progress of patients hospitalized with heart failure (HF) who started treatment... (Observational Study)
Observational Study
To describe the epidemiological, clinical and laboratory characteristics and clinical progress of patients hospitalized with heart failure (HF) who started treatment with empagliflozin before discharge. We performed a retrospective observational study of patients aged ≥18 years admitted to the Internal Medicine Department of University Hospital Jaen, Jaen, Spain with acute HF between 1 May 2022 and 31 May 2023. Patients had to have a life expectancy of ≥1 year and have started treatment with empagliflozin during admission. We included 112 patients (mean age, 85.2 ± 6.5 years; 67.9% women; 35.7 and 31.3% in NYHA functional classes III and IV; 73.2% with HF and preserved ejection fraction). Before admission, 80.4% were taking loop diuretics, 70.6% renin-angiotensin-aldosterone system inhibitors, 49.1% betablockers and 25% mineralocorticoid receptor antagonists. At admission, 94.6% were taking furosemide (15.2% at high doses, 36.6% at intermediate doses). The dose of furosemide was reduced at initiation of empagliflozin. At the end of follow-up, 13.4% of patients had died, 93.8% of the survivors continued treatment with empagliflozin and 26.8% had attended the emergency department with signs and symptoms of HF. Introduction of empagliflozin before discharge from hospital in patients admitted with HF made it possible to reduce the dose of diuretics during admission. The frequency of complications was as expected, and treatment was largely maintained.
Topics: Humans; Glucosides; Female; Heart Failure; Male; Benzhydryl Compounds; Retrospective Studies; Aged; Aged, 80 and over; Sodium-Glucose Transporter 2 Inhibitors; Spain; Hospitalization; Acute Disease
PubMed: 38785682
DOI: 10.57264/cer-2024-0027 -
ESC Heart Failure May 2024Reducing sodium intake is necessary for patients with chronic heart failure (CHF). Salt substitutes (saltSubs) have become increasingly popular as recommendations by...
AIMS
Reducing sodium intake is necessary for patients with chronic heart failure (CHF). Salt substitutes (saltSubs) have become increasingly popular as recommendations by healthcare professionals (HCPs) as well as options for patients and their caregivers. However, their consumption is generally potassium based and remains poorly evaluated in CHF management. Their impact on guideline-directed medical therapies (GDMTs) also remains unknown. The primary objective of this study was to provide a description and estimate of HCP recommendations and reported use of saltSubs in France. Secondary objectives were to identify if there was an association between these recommendations by HCPs and the use of GDMTs.
METHODS AND RESULTS
A nationwide, questionnaire-based, cross-sectional, epidemiological study was conducted from September 2020 to July 2021. Data collection included baseline characteristics, the use and recommendations of saltSubs, and the use of GDMTs, which included (i) angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNis), (ii) mineralocorticoid receptor antagonists (MRAs), and/or (iii) beta-blockers (BBs). In total, 13% of HCPs advised saltSubs and 17% of patients and 22% of caregivers reported their consumption. CHF patients advised to take saltSubs did not differ in terms of left ventricular ejection fraction (EF) <40%, ischaemic origin, and New York Heart Association III-IV class, but were more recently hospitalized for acute HF (P = 0.004). HCPs who recommended saltSubs to patients were more likely to advise an anti-diabetic diet (P < 0.001), cholesterol-lowering diet (P < 0.001), and exercise (P = 0.018). In the overall population, ACEi/ARB/ARNi use was less frequent in case of saltSub recommendations (74% vs. 82%, P = 0.012). The concomitant prescription of none, one, two, or three GDMTs was less favourable in case of saltSub recommendations (P = 0.046). There was no significant difference for the presence of MRA (56% vs. 58%) and/or BB (78% vs. 82%). The under-prescription of ACEi/ARB/ARNi was found when patients had EF < 40% (P = 0.029) and/or EF ≥ 40% (P = 0.043). In the subgroup with left ventricular EF ≥ 40%, we found a higher thiazide use (P = 0.014) and a less frequent use of low EF GDMTs (P = 0.044) in case of being recommended saltSubs.
CONCLUSIONS
Beyond the well-established risk for hyperkalaemia, our preliminary results suggest a potentially negative impact of saltSubs on GDMT use, especially for ACEis/ARBs/ARNis in CHF management. saltSub recommendations and their availability from open sale outlets should be considered to avoid possible misuse or deference from GDMTs in the future. Informed advice to consumers should also be considered from HCPs or pharmacists.
PubMed: 38783593
DOI: 10.1002/ehf2.14706 -
BMC Cardiovascular Disorders May 2024Acute heart failure is the rapid onset of new or worsening symptoms and signs of heart failure. Despite the increasing burden of heart failure in developing countries... (Observational Study)
Observational Study
BACKGROUND
Acute heart failure is the rapid onset of new or worsening symptoms and signs of heart failure. Despite the increasing burden of heart failure in developing countries like Ethiopia, there is a paucity of comprehensive data regarding the clinical characteristics, treatment patterns, and outcomes of acute heart failure, especially in the selected study area. Therefore, this study aimed to assess the clinical characteristics, treatment patterns, and outcomes of hospitalized patients with acute heart failure at Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia.
METHODS
This is a retrospective cross-sectional study of 303 acute heart failure patients who were admitted to the medical wards and intensive care unit of Yekatit 12 Hospital Medical College, Addis Ababa, central Ethiopia, from July 1, 2022, to July 1, 2023. A pretested data abstraction format was used for data extraction from electronic medical records, and SPSS version 26 was used for data analysis. Descriptive analysis was used to summarize sociodemographic data, clinical characteristics, treatment patterns, and outcomes of acute heart failure. Bivariate and multivariate logistic regression models were fitted to identify factors associated with in-hospital mortality. The odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated to show the strength of the association.
RESULTS
Of the 303 patients, 51.5% were females, and the mean age was 56.7 years. The most frequent symptom and sign were dyspnea (98.7%) and peripheral edema (79%), respectively. The commonest underlying cause and precipitating factor of acute heart failure were cor pulmonale (22.8%) and pneumonia (35.3%), respectively. The commonest anti-remodeling medications prescribed on discharge were beta-blockers (47.9%), followed by mineralocorticoid receptor antagonists (42.8%) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (38.6%), and the least prescribed were sodium-glucose cotransporter 2 inhibitors (8.3%). The in-hospital mortality rate was 8.6%, and the median length of hospital stay was 9 days. Based on the multivariate logistic regression analysis, the most important predictors of in-hospital mortality were systolic blood pressure (SBP) < 115 mmHg (adjusted odds ratio [AOR] = 6.28; 95% CI: 1.99, 19.78), chloride level < 96 mg/dL (AOR = 4.88; 95% CI: 1.30, 18.33), blood urea nitrogen (BUN) > 20 mg/dl (AOR = 5.48; 95% CI: 1.47, 20.49), and presence of dyslipidemia (AOR = 3.73, 95% CI: 1.15, 12.07).
CONCLUSIONS
This study has shown that systolic blood pressure (SBP) < 115 mmHg, blood urea nitrogen (BUN) > 20 mg/dL, chloride (Cl) level < 96 mg/dL, and the presence of dyslipidemia were statistically significant factors associated with in-hospital mortality among patients with acute heart failure. Hence, healthcare providers should stratify patients with acute heart failure upon admission based on their risk of in-hospital mortality and address those potential negative prognostic indicators accordingly.
Topics: Humans; Retrospective Studies; Heart Failure; Ethiopia; Male; Female; Middle Aged; Cross-Sectional Studies; Hospital Mortality; Aged; Acute Disease; Treatment Outcome; Risk Factors; Adult; Risk Assessment; Time Factors; Practice Patterns, Physicians'; Aged, 80 and over; Hospitalization
PubMed: 38773412
DOI: 10.1186/s12872-024-03905-z -
Disease Models & Mechanisms May 2024Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the...
Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD. Here, we knocked out the glucocorticoid receptor (GR, encoded by Nr3c1) specifically in myofibers and cardiomyocytes within wild-type and mdx52 mice to dissect its role in muscular dystrophy. Double-knockout mice showed significantly worse phenotypes than mdx52 littermate controls in measures of grip strength, hang time, inflammatory pathology and gene expression. In the heart, GR deletion acted additively with dystrophin loss to exacerbate cardiomyopathy, resulting in enlarged hearts, pathological gene expression and systolic dysfunction, consistent with imbalanced mineralocorticoid signaling. The results show that physiological GR functions provide a protective role during muscular dystrophy, directly contrasting its degenerative role in other disease states. These data provide new insights into corticosteroids in disease pathophysiology and establish a new model to investigate cell-autonomous roles of nuclear receptors and mechanisms of pharmacological corticosteroids.
Topics: Animals; Receptors, Glucocorticoid; Mice, Inbred mdx; Mice, Knockout; Dystrophin; Myocardium; Muscular Dystrophy, Duchenne; Muscle, Skeletal; Myocytes, Cardiac; Mice; Cardiomyopathies; Mice, Inbred C57BL; Muscular Dystrophy, Animal; Phenotype; Systole
PubMed: 38770680
DOI: 10.1242/dmm.050397 -
Journal of Traditional Chinese Medicine... Jun 2024OBJECTIVE:To elucidate the mechanism by which Huoxue Jiedu Huayu recipe (, HJHR) regulates angiogenesis in the contralateral kidney of unilateral ureteral obstruction...
Huoxue Jiedu Huayu recipe inhibits macrophage-secreted vascular endothelial growth factor-a on angiogenesis and alleviates renal fibrosis in the contralateral kidneys of unilateral ureteral obstruction rats.
UNLABELLED
OBJECTIVE:To elucidate the mechanism by which Huoxue Jiedu Huayu recipe (, HJHR) regulates angiogenesis in the contralateral kidney of unilateral ureteral obstruction (UUO) rats and the mechanism by which it reduces of renal fibrosis.
METHODS
Male Wistar rats were randomly divided into 4 groups: the sham group, UUO group (180 d of left ureter ligation), UUO plus eplerenone (EPL) group, and UUO plus HJHR group. After 180 d of oral drug administration, blood and contralateral kidneys were collected for analysis. Angiogenesis- and fibrosis-related indexes were detected.
RESULTS
HJHR and EPL improved structural damage and renal interstitial fibrosis in the contralateral kidney and reduced the protein expression levels of α-smooth muscle actin (α-SMA), vimentin and collagen I. Moreover, these treatments could reduce the expression of vascular endothelial growth factor-A (VEGFA) by inhibiting the infiltration of macrophages. Furthermore, HJHR and EPL significantly reduced the expression of CD34 and CD105 by downregulating VEGFA production, which inhibited angiogenesis. Finally, the coexpressions of CD34, CD105 and α-SMA were decreased in the HJHR and EPL groups, indicating that endothelial-to-mesenchymal transition was inhibited.
CONCLUSIONS
These findings confirm that HJHR alleviates contralateral renal fibrosis by inhibiting VEGFA-induced angiogenesis, encourage the use of HJHR against renal interstitial fibrosis and provide a theoretical basis for the clinical management of patients with CKD.
Topics: Animals; Male; Ureteral Obstruction; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A; Fibrosis; Kidney; Macrophages; Drugs, Chinese Herbal; Humans; Neovascularization, Pathologic; Kidney Diseases; Angiogenesis
PubMed: 38767629
DOI: 10.19852/j.cnki.jtcm.20240423.005 -
Journal of Diabetes Jun 2024Asians bear a heavier burden of chronic kidney disease (CKD), a common comorbidity of type 2 diabetes mellitus (T2DM), than non-Asians. Nonsteroidal mineralocorticoid... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Asians bear a heavier burden of chronic kidney disease (CKD), a common comorbidity of type 2 diabetes mellitus (T2DM), than non-Asians. Nonsteroidal mineralocorticoid receptor antagonists (MRAs) have garnered attention for their potential advantages in renal outcomes. Nevertheless, the impact on diverse ethnic groups remains unknown.
METHODS
The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang database, and clinical trial registries were searched through August 2023 with the following keywords: nonsteroidal MRAs (finerenone, apararenone, esaxerenone, AZD9977, KBP-5074), CKD, T2DM, and randomized controlled trial (RCT). A random effects model was used to calculate overall effect sizes.
RESULTS
Seven RCTs with 14 997 participants were enrolled. Nonsteroidal MRAs reduced urinary albumin to creatinine ratio (UACR) significantly more in Asians than non-Asians: (weighted mean difference [WMD], -0.59, 95% CI, -0.73 to -0.45, p < .01) vs (WMD, -0.29, 95% CI, -0.32 to -0.27, p < .01), respectively. The average decline of estimated glomerular filtration rate (eGFR) was similar in Asians and non-Asians (p > .05). Regarding systolic blood pressure (SBP), nonsteroidal MRAs had a better antihypertension performance in Asians (WMD, -5.12, 95% CI, -5.84 to -4.41, p < .01) compared to non-Asians (WMD, -3.64, 95% CI, -4.38 to -2.89, p < .01). A higher incidence of hyperkalemia and eGFR decrease ≥30% was found in Asians than non-Asians (p < .01).
CONCLUSIONS
Nonsteroidal MRAs exhibited significant renal benefits by decreasing UACR and lowering SBP in Asian than that of non-Asian patients with CKD and T2DM, without increase of adverse events except hyperkalemia and eGFR decrease ≥30%.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus, Type 2; Renal Insufficiency, Chronic; Asian People; Glomerular Filtration Rate; Diabetic Nephropathies; Randomized Controlled Trials as Topic; Kidney; Naphthyridines; Pyrroles; Sulfones
PubMed: 38753662
DOI: 10.1111/1753-0407.13566 -
Physiological Reports May 2024We have previously reported that the subfornical organ (SFO) does not contribute to the chronic hypertensive response to DOCA-salt in rats, and yet the organum...
We have previously reported that the subfornical organ (SFO) does not contribute to the chronic hypertensive response to DOCA-salt in rats, and yet the organum vasculosum of the lamina terminalis (OVLT) plays a significant role in the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Since efferent fibers of the OVLT project to and through the median preoptic nucleus (MnPO), the present study was designed to test the hypothesis that the MnPO is necessary for DOCA-salt hypertension in the rat. Male Sprague-Dawley rats underwent SHAM (MnPOsham; n = 5) or electrolytic lesion of the MnPO (MnPOx; n = 7) followed by subsequent unilateral nephrectomy and telemetry instrumentation. After recovery and during the experimental protocol, rats consumed a 0.1% NaCl diet and 0.9% NaCl drinking solution. Mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg/rat; SQ). The chronic pressor response to DOCA was attenuated in MnPOx rats by Day 11 of treatment and continued such that MAP increased 25 ± 3 mmHg in MnPOsham rats by Day 21 of DOCA compared to 14 ± 3 mmHg in MnPOx rats. These results support the hypothesis that the MnPO is an important brain site of action and necessary for the full development of DOCA-salt hypertension in the rat.
Topics: Animals; Male; Rats, Sprague-Dawley; Desoxycorticosterone Acetate; Preoptic Area; Hypertension; Rats; Sodium Chloride, Dietary; Blood Pressure
PubMed: 38749925
DOI: 10.14814/phy2.16046