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Journal of Clinical Medicine Jun 2024: Chronic kidney disease (CKD) is identified as a risk factor for the occurrence of ischemic stroke. There is substantial evidence that CKD is linked to a worse...
: Chronic kidney disease (CKD) is identified as a risk factor for the occurrence of ischemic stroke. There is substantial evidence that CKD is linked to a worse prognosis and higher mortality rates in stroke patients. This study aimed to evaluate the characteristics and factors affecting favorable outcomes and mortality in patients treated using mechanical thrombectomy (MT) for ischemic stroke, with particular emphasis on patients suffering from CKD. : The retrospective study included an analysis of data from 723 patients (139; 19.4% had CKD) with ischemic stroke treated with MT between March 2019 and July 2022. : Patients with CKD were significantly older (median age 76.5 vs. 65.65, < 0.001) and more often female (59.7% vs. 42.6%, < 0.001). CKD decreased the likelihood of achieving a favorable outcome (0-2 points in modified Rankin scale; OR: 0.56, CI95%: 0.38-0.81) and increased mortality (OR: 2.59, CI95%: 1.74-3.84) on the 90th day after stroke. In addition, CKD was associated with intracranial hemorrhage (ICH) in patients who underwent posterior circulation MT (13.85% vs. 50%, = 0.022). In patients with CKD, inter alia, higher levels of C-reactive protein (OR: 0.94, CI95%: 0.92-0.99) reduced the chance of a favorable outcome. In addition, the occurrence of ICH in patients with CKD increased mortality on the 90th day after stroke (OR: 4.18, CI95%: 1.56-11.21), which was almost twice as high as in patients without CKD (OR: 2.29, CI95%: 1.54-3.40). : Patients suffering from CKD had a lower probability of achieving a favorable outcome and had increased mortality following MT for ischemic stroke. It is crucial to understand the variations between patients with unimpaired and impaired renal function, as this could aid in predicting the outcomes of this method.
PubMed: 38930001
DOI: 10.3390/jcm13123469 -
Biomedicines Jun 2024This study aims to determine the effectiveness of administering 80 ppm nitric oxide in reducing kidney injury, mitochondrial dysfunction and regulated cell death in...
This study aims to determine the effectiveness of administering 80 ppm nitric oxide in reducing kidney injury, mitochondrial dysfunction and regulated cell death in kidneys during experimental perfusion. Twenty-four sheep were randomized into four groups: two groups received 80 ppm NO conditioning with 90 min of cardiopulmonary bypass (CPB + NO) or 90 min of CPB and hypothermic circulatory arrest (CPB + CA + NO), while two groups received sham protocols (CPB and CPB + CA). Kidney injury was assessed using laboratory (neutrophil gelatinase-associated lipocalin, an acute kidney injury biomarker) and morphological methods (morphometric histological changes in kidney biopsy specimens). A kidney biopsy was performed 60 min after weaning from mechanical perfusion. NO did not increase the concentrations of inhaled NO and methemoglobin significantly. The NO-conditioning groups showed less severe kidney injury and mitochondrial dysfunction, with statistical significance in the CPB + NO group and reduced tumor necrosis factor-α expression as a trigger of apoptosis and necroptosis in renal tissue in the CPB + CA + NO group compared to the CPB + CA group. The severity of mitochondrial dysfunction in renal tissue was insignificantly lower in the NO-conditioning groups. We conclude that NO administration is safe and effective at reducing kidney injury, mitochondrial dysfunction and regulated cell death in kidneys during experimental CPB.
PubMed: 38927505
DOI: 10.3390/biomedicines12061298 -
Brain and Behavior Jun 2024To assess changes in neurovascular coupling (NVC) by evaluating the relationship between cerebral perfusion and brain connectivity in patients with end-stage renal...
PURPOSE
To assess changes in neurovascular coupling (NVC) by evaluating the relationship between cerebral perfusion and brain connectivity in patients with end-stage renal disease (ESRD) undergoing hemodialysis versus in healthy control participants. And by exploring brain regions with abnormal NVC associated with cognitive deficits in patients, we aim to provide new insights into potential preventive and therapeutic interventions.
MATERIALS AND METHODS
A total of 45 patients and 40 matched healthy controls were prospectively enrolled in our study. Montreal Cognitive Assessment (MoCA) was used to assess cognitive function. Arterial spin labeling (ASL) was used to calculate cerebral blood flow (CBF), and graph theory-based analysis of results from resting-state functional magnetic resonance imaging (rs-fMRI) was used to calculate brain network topological parameters (node betweenness centrality [BC], node efficiency [Ne], and node degree centrality [DC]). Three NVC biomarkers (CBF-BC, CBF-Ne, and CBF-DC coefficients) at the whole brain level and 3 NVC biomarkers (CBF/BC, CBF/Ne, and CBF/DC ratios) at the local brain region level were used to assess NVC. Mann-Whitney U tests were used to compare the intergroup differences in NVC parameters. Spearman's correlation analysis was used to evaluate the relationship among NVC dysfunctional pattern, cognitive impairment, and clinical characteristics multiple comparisons were corrected using a voxel-wise false-discovery rate (FDR) method (p < .05).
RESULTS
Patients showed significantly reduced global coupling coefficients for CBF-Ne (p = .023) and CBF-BC (p = .035) compared to healthy controls. Coupling ratios at the local brain region level were significantly higher in patients in 33 brain regions (all p values < .05). Coupling ratio changes alone or accompanied by changes in CBF, node properties, or both CBF and node properties were identified. In patients, negative correlations were seen between coupling ratios and MoCA scores in many brain regions, including the left dorsolateral superior frontal gyrus, the bilateral median cingulate and paracingulate gyri, and the right superior parietal gyrus. The correlations remained even after adjusting for hemoglobin and hematocrit levels.
CONCLUSION
Disrupted NVC may be one mechanism underlying cognitive impairment in dialysis patients.
Topics: Humans; Male; Female; Middle Aged; Magnetic Resonance Imaging; Neurovascular Coupling; Kidney Failure, Chronic; Cognitive Dysfunction; Brain; Adult; Cerebrovascular Circulation; Renal Dialysis; Neuroimaging; Aged; Prospective Studies; Mental Status and Dementia Tests; Nerve Net
PubMed: 38923330
DOI: 10.1002/brb3.3598 -
JCI Insight Jun 2024The immune benefits of vitamin D3 supplementation beyond calcium and phosphate maintenance are highly clinically debated. Kidney expression of CYP27B1 is the source of...
The immune benefits of vitamin D3 supplementation beyond calcium and phosphate maintenance are highly clinically debated. Kidney expression of CYP27B1 is the source of endocrine, circulating 1,25(OH)2D3 (active form of vitamin D) that maintains serum calcium and phosphate. 1,25(OH)2D3 may also be made by the CYP27B1 enzyme in non-renal cells, like immune cells, in a process driven by cellular availability of 25(OH)D3 and inflammation. Due to the endocrine nature of 1,25(OH)2D3 in circulation, it is difficult to discern between these two sources. We recently created a regulatory deletion model of Cyp27b1 (M1/M21-DIKO) where mice have normal inflammatory-regulated Cyp27b1 expression in non-renal tissues (unlike global Cyp27b1-KO), but no expression within kidney. Here, utilizing on-tissue chemical derivatization and Matrix Assisted Laser Desorption Ionization-Mass Spectrometry Imaging (MALDI-MSI), we investigated the distribution of 1,25(OH)2D3 and 25(OH)D3 in the kidney, liver, spleen, and thymus. MALDI-MSI demonstrated increased 1,25(OH)2D3 in non-renal tissues such as the spleen after vitamin D3 supplementation in M1/M21-DIKO mice. Additionally, from this we found increased Il4 and decreased Tnfa in the spleen after vitamin D3 supplementation. Taken together, these data demonstrate non-renal production of 1,25(OH)2D3 in vivo and provide a consequence of vitamin D3 supplementation and non-renal 1,25(OH)2D3 production in cytokine changes.
PubMed: 38916957
DOI: 10.1172/jci.insight.181763 -
Frontiers in Pharmacology 2024The available evidences suggest the inherent instability and interconvertibility of [6]-gingerol and [6]-shogaol. However, limited data on their interconversion hinder...
Unraveling the interconversion pharmacokinetics and oral bioavailability of the major ginger constituents: [6]-gingerol, [6]-shogaol, and zingerone after single-dose administration in rats.
BACKGROUND
The available evidences suggest the inherent instability and interconvertibility of [6]-gingerol and [6]-shogaol. However, limited data on their interconversion hinder understanding of their influence on the pharmacokinetic profiles.
PURPOSE
This study presents the first comprehensive investigation aiming to determine the interconversion pharmacokinetics in rats, and elucidate the oral bioavailability, target distribution, biotransformation, and excretion profiles of the key ginger constituents, [6]-gingerol, [6]-shogaol, and zingerone.
METHODS
The pharmacokinetics was investigated through single intravenous (3 mg/kg) or oral (30 mg/kg) administration of [6]-gingerol, [6]-shogaol, or zingerone, followed by the determination of their tissue distribution after oral dosing (30 mg/kg). Intravenous pharmacokinetics was leveraged to evaluate the interconversion, circumventing potential confounders associated with the oral route.
RESULTS
All rats tolerated these compounds throughout the pharmacokinetic study. The parent compounds exhibited rapid but partial absorption, and extensive organ distribution with substantial biotransformation, thereby limiting the oral bioavailability of each compound to below 2% when administered as pure compounds. Conversion of [6]-gingerol to [6]-shogaol after intravenous administration, demonstrated a significantly larger clearance compared to the reverse conversion ([6]-shogaol to [6]-gingerol). The irreversible metabolic clearance for both compounds was significantly greater than their reversible bioconversions. Furthermore, [6]-gingerol underwent biotransformation to zingerone. Conjugated glucuronides were eliminated partly through renal excretion, with minimal fecal excretion.
CONCLUSION
This investigation demonstrates the influence of interconversion on the disposition kinetics of [6]-gingerol, [6]-shogaol, and zingerone, as evidenced by the findings in the systemic circulation. The study further highlights the importance of considering this interconversion and tissue distribution when determining the administration dosage of ginger constituent combinations for therapeutic benefits and clinical applications.
PubMed: 38904001
DOI: 10.3389/fphar.2024.1391019 -
Nutrients May 2024Vitamin D is a crucial micronutrient, critical to human health, and influences many physiological processes. Oral and skin-derived vitamin D is hydroxylated to form... (Review)
Review
Vitamin D is a crucial micronutrient, critical to human health, and influences many physiological processes. Oral and skin-derived vitamin D is hydroxylated to form calcifediol (25(OH)D) in the liver, then to 1,25(OH)D (calcitriol) in the kidney. Alongside the parathyroid hormone, calcitriol regulates neuro-musculoskeletal activities by tightly controlling blood-ionized calcium concentrations through intestinal calcium absorption, renal tubular reabsorption, and skeletal mineralization. Beyond its classical roles, evidence underscores the impact of vitamin D on the prevention and reduction of the severity of diverse conditions such as cardiovascular and metabolic diseases, autoimmune disorders, infection, and cancer. Peripheral target cells, like immune cells, obtain vitamin D and 25(OH)D through concentration-dependent diffusion from the circulation. Calcitriol is synthesized intracellularly in these cells from these precursors, which is crucial for their protective physiological actions. Its deficiency exacerbates inflammation, oxidative stress, and increased susceptibility to metabolic disorders and infections; deficiency also causes premature deaths. Thus, maintaining optimal serum levels above 40 ng/mL is vital for health and disease prevention. However, achieving it requires several times more than the government's recommended vitamin D doses. Despite extensive published research, recommended daily intake and therapeutic serum 25(OH)D concentrations have lagged and are outdated, preventing people from benefiting. Evidence suggests that maintaining the 25(OH)D concentrations above 40 ng/mL with a range of 40-80 ng/mL in the population is optimal for disease prevention and reducing morbidities and mortality without adverse effects. The recommendation for individuals is to maintain serum 25(OH)D concentrations above 50 ng/mL (125 nmol/L) for optimal clinical outcomes. Insights from metabolomics, transcriptomics, and epigenetics offer promise for better clinical outcomes from vitamin D sufficiency. Given its broader positive impact on human health with minimal cost and little adverse effects, proactively integrating vitamin D assessment and supplementation into clinical practice promises significant benefits, including reduced healthcare costs. This review synthesized recent novel findings related to the physiology of vitamin D that have significant implications for disease prevention.
Topics: Humans; Vitamin D; Vitamin D Deficiency; Dietary Supplements; Cardiovascular Diseases
PubMed: 38892599
DOI: 10.3390/nu16111666 -
International Journal of Molecular... Jun 2024An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a...
An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a vascular receptor blocker. No human or veterinary studies regarding the effect of ARNI on renal haemodynamics in the absence of cardiac or renal issues exist. Therefore, we investigated the effect of ARNI on renal haemodynamics in five healthy dogs. ARNI was administered to all five dogs at an oral dose of 20 mg/kg twice daily for 4 weeks. Renal haemodynamics were assessed on the day before ARNI administration (BL), on Day 7, and on Day 28. The glomerular filtration rate (GFR) significantly increased on Day 28 compared to BL and Day 7, whereas renal plasma flow increased on Day 7 and Day 28 compared to BL. Systolic blood pressure significantly decreased between BL and Day 28. Plasma atrial natriuretic peptide (ANP) concentrations increased on Day 7 compared to BL. Additionally, ANP concentrations increased on Day 28 in three of the five dogs. Different ANP concentrations were observed in the remaining two dogs. Both urine output volume and heart rate remained relatively stable and did not exhibit significant change. In conclusion, ARNI may enhance renal haemodynamics in healthy dogs. ARNI could be a valuable drug for treating both heart and kidney disease in dogs.
Topics: Animals; Dogs; Neprilysin; Hemodynamics; Angiotensin Receptor Antagonists; Kidney; Valsartan; Male; Aminobutyrates; Blood Pressure; Atrial Natriuretic Factor; Glomerular Filtration Rate; Female; Drug Combinations; Biphenyl Compounds; Tetrazoles; Renal Circulation
PubMed: 38892356
DOI: 10.3390/ijms25116169 -
The Journal of Extra-corporeal... Jun 2024The usage of cardiopulmonary bypass (CPB) in cardiothoracic surgery contributes to the activation of the inflammatory response. In certain cases, the systemic...
The usage of cardiopulmonary bypass (CPB) in cardiothoracic surgery contributes to the activation of the inflammatory response. In certain cases, the systemic inflammatory response may be immoderate, leading to organ dysfunction, such as acute renal failure or multiorgan dysfunction. This study aimed to examine the effect of haemoadsorption (HA) therapy on inflammatory markers and renal damage indices during cardiopulmonary bypass and in the early postoperative period. We conducted a retrospective analysis of prospectively collected data in a single tertiary care center on patients operated between January 2021 and May 2022. The levels of inflammatory markers and renal parameters in blood samples (Interleukin (IL) 6, C-reactive protein (CRP), white blood cells, lactate, procalcitonin (PCT), and NT-proBNP, urea, creatinine, glomerular filtration rate (GFR), mechanical ventilation days and intensive care unit (ICU) days) were compared between the three groups. Data from the Jafron HA 330 (n = 20) and CytoSorb300 (n = 20) groups were compared with those from the control group (n = 20). All patients underwent cardiopulmonary bypass for more than 120 min. Baseline patient characteristics were similar in all three groups. Acute kidney injury (AKI) was diagnosed in 17 patients (28.3%); seven patients were in the Jafron HA 330, two in the CytoSorb300, and eight in the control group. We found that IL1α, IL 6, IL8, Lactate dehydrogenase, PCT, NT-proBNP, CRP, Leukocyte, and TNFα had no significant or clinical difference between the CytoSorb 300 and Jafron HA 330 adsorber groups. Our results indicate that haemoadsorption therapy does not significantly reduce the risk of AKI after prolonged CPB, but decreases the need for renal replacement therapy.
Topics: Humans; Acute Kidney Injury; Cardiopulmonary Bypass; Male; Female; Middle Aged; Retrospective Studies; Aged; Incidence; Biomarkers
PubMed: 38888547
DOI: 10.1051/ject/2024004 -
Cureus May 2024Abernethy syndrome is a rare congenital malformation stemming from a portosystemic shunt. Diagnosis proves challenging due to nonspecific clinical symptoms, with...
Abernethy syndrome is a rare congenital malformation stemming from a portosystemic shunt. Diagnosis proves challenging due to nonspecific clinical symptoms, with presentation varying based on age and disease severity. Consequences include hepatic, cardiovascular, renal, gastrointestinal, and neurological complications, and growth retardation. We report the case of a child presenting with perioral and digital cyanosis, observed in early childhood. Clinical examination revealed low saturation, telangiectasias, digital clubbing, and collateral venous circulation in the thorax. Imaging confirmed the diagnosis of Abernethy syndrome.
PubMed: 38883064
DOI: 10.7759/cureus.60501 -
Circulation Jun 2024Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of...
BACKGROUND
Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide. Although most mouse models of atherosclerosis develop lesions in the aorta and carotid arteries, they do not develop advanced coronary artery lesions. Moreover, they do not undergo spontaneous plaque rupture with MI and stroke or do so at such a low frequency that they are not viable experimental models to study late-stage thrombotic events or to identify novel therapeutic approaches for treating atherosclerotic disease. This has stymied the development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Here, we describe a diet-inducible mouse model that develops widespread advanced atherosclerosis in coronary, brachiocephalic, and carotid arteries with plaque rupture, MI, and stroke.
METHODS
We characterized a novel mouse model with a C-terminal mutation in the scavenger receptor class B, type 1 (SR-BI), combined with knockout (designated SR-BI/). Mice were fed Western diet (WD) for 26 weeks and analyzed for MI and stroke. Coronary, brachiocephalic, and carotid arteries were analyzed for atherosclerotic lesions and indices of plaque stability. To validate the utility of this model, SR-BI/ mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme produced by activated neutrophils that predicts rupture of human atherosclerotic lesions.
RESULTS
SR-BI/ mice show high (>80%) mortality rates after 26 weeks of WD feeding because of major adverse cardiovascular events, including spontaneous plaque rupture with MI and stroke. Moreover, WD-fed SR-BI/ mice displayed elevated circulating high-sensitivity cardiac troponin I and increased neutrophil extracellular trap formation within lesions compared with control mice. Treatment of WD-fed SR-BI/ mice with AZM198 showed remarkable benefits, including >90% improvement in survival and >60% decrease in the incidence of plaque rupture, MI, and stroke, in conjunction with decreased circulating high-sensitivity cardiac troponin I and reduced neutrophil extracellular trap formation within lesions.
CONCLUSIONS
WD-fed SR-BI/ mice more closely replicate late-stage clinical events of advanced human atherosclerotic disease than previous models and can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.
PubMed: 38881440
DOI: 10.1161/CIRCULATIONAHA.123.067931