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Kidney & Blood Pressure Research 2024Clinical studies on differences among changes in cerebral and hepatic oxygenation during hemodialysis (HD) in patients with and without intradialytic hypotension (IDH)...
INTRODUCTION
Clinical studies on differences among changes in cerebral and hepatic oxygenation during hemodialysis (HD) in patients with and without intradialytic hypotension (IDH) are limited. We investigated changes in intradialytic cerebral and hepatic oxygenation before systolic blood pressure (SBP) reached the nadir during HD and compared these differences between patients with and without symptomatic IDH.
METHODS
We analyzed data from 109 patients with (n = 23) and without (n = 86) symptomatic IDH who were treated with HD. Cerebral and hepatic regional oxygen saturation (rSO2), as a marker of tissue oxygenation and circulation, was monitored during HD using an INVOS 5100c oxygen saturation monitor. Changes in cerebral or hepatic rSO2 when SBP reached the nadir during HD were compared between the groups of patients.
RESULTS
The cerebral rSO2 before HD in patients with and without symptomatic IDH was 49.7 ± 11.2% and 51.3 ± 9.1% (p = 0.491). %Changes in cerebral rSO2 did not significantly differ between the two groups from 60 min before the SBP nadir during HD. Hepatic rSO2 before HD in patients with and without symptomatic IDH was 58.5 ± 15.4% and 57.8 ± 15.9% (p = 0.869). The %changes in hepatic rSO2 were significantly lower in patients with symptomatic IDH than in those without throughout the observational period (p < 0.001). We calculated the area under the receiver operating characteristic curve (AUC) and estimated cutoff values for changes in hepatic rSO2 as a symptomatic IDH predictor. The predictive ability at 5 and 40 min before symptomatic IDH onset was excellent, with AUCs and cutoff values of 0.847 and 0.841, and -10.9% and -5.0%, respectively.
CONCLUSIONS
Hepatic oxygenation significantly decreased more in patients with symptomatic IDH before its onset, than in those without symptomatic IDH, whereas changes in cerebral oxygenation did not differ. Evaluating changes in hepatic oxygenation during HD might help to predict symptomatic IDH.
Topics: Humans; Hypotension; Male; Female; Middle Aged; Aged; Liver; Renal Dialysis; Oxygen; Brain; Oxygen Saturation; Blood Pressure
PubMed: 38735278
DOI: 10.1159/000539277 -
International Journal of Molecular... Apr 2024Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body... (Review)
Review
Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.
Topics: Humans; Hepatolenticular Degeneration; Copper; Iron; Ferroptosis; Reactive Oxygen Species; Liver; Animals
PubMed: 38731973
DOI: 10.3390/ijms25094753 -
Frontiers in Nutrition 2024Chronic kidney disease (CKD) is a common public health problem, which is characterized as impairment of renal function. The associations between blood metabolites and...
BACKGROUND
Chronic kidney disease (CKD) is a common public health problem, which is characterized as impairment of renal function. The associations between blood metabolites and renal function remained unclear. This study aimed to assess the causal effect of various circulation metabolites on renal function based on metabolomics.
METHODS
We performed a two-sample Mendelian randomization (MR) analysis to estimate the causality of genetically determined metabolites on renal function. A genome-wide association study (GWAS) of 486 metabolites was used as the exposure, while summary-level data for creatinine-based estimated glomerular filtration rate (eGFR) or CKD occurrence were set the outcomes. Inverse variance weighted (IVW) was used for primary causality analysis and other methods including weight median, MR-egger, and MR-PRESSO were applied as complementary analysis. Cochran Q test, MR-Egger intercept test, MR-PRESSO global test and leave-one-out analysis were used for sensitivity analysis. For the identified metabolites, reverse MR analysis, linkage disequilibrium score (LDSC) regression and multivariable MR (MVMR) analysis were performed for further evaluation. The causality of the identified metabolites on renal function was further validated using GWAS data for cystatin-C-based eGFR. All statistical analyses were performed in R software.
RESULTS
In this MR analysis, a total of 44 suggestive associations corresponding to 34 known metabolites were observed. After complementary analysis and sensitivity analysis, robust causative associations between two metabolites (betaine and N-acetylornithine) and renal function were identified. Reverse MR analysis showed no causal effects of renal function on betaine and N-acetylornithine. MVMR analysis revealed that genetically predicted betaine and N-acetylornithine could directly influence independently of each other. The causal effects of betaine and N-acetylornithine were also found on cystatin-C-based eGFR.
CONCLUSION
Our study provided evidence to support the causal effects of betaine and N-acetylornithine on renal function. These findings required further investigations to conduct mechanism exploration and drug target selection of these identified metabolites.
PubMed: 38721027
DOI: 10.3389/fnut.2024.1371995 -
Resuscitation Plus Jun 2024Post-cardiac arrest (CA) shock is associated with multiple organ failure, including acute kidney injury, and is the leading cause of early death among patient...
BACKGROUND
Post-cardiac arrest (CA) shock is associated with multiple organ failure, including acute kidney injury, and is the leading cause of early death among patient successfully resuscitated from CA. Arginine-vasopressin (AVP) may be an interesting therapeutic alternative or complement to noradrenaline (NAD) to both control shock and preserve regional, especially renal, organ perfusions.
METHODS
18 swine (24-39 kg) were submitted to 14 min of ventricular fibrillation and cardio-pulmonary resuscitation. After return of spontaneous circulation (ROSC), animals randomly received either AVP, NAD or AVP-NAD combination for maintaining a targeted mean arterial pressure of 70 ± 5 mmHg for 6 h. Haemodynamic and biological parameters, including kidney function biomarkers and diuresis, were monitored throughout the follow-up.
RESULTS
Targeted mean arterial pressure was successfully obtained in the NAD ( = 6) and the AVP-NAD ( = 6) groups, but not in the AVP group ( = 6), where 4 animals died. As compared to NAD alone, renal blood flow (2.9 ± 1.15 4.36 ± 0.64 mL//kg/min in NAD and AVP-NAD groups) and diuresis were higher in the AVP-NAD group. This was associated with a reduction of carotid blood flow and a more severe metabolic acidosis during the first 3 h of follow-up in the AVP-NAD group as compared to NAD group.
CONCLUSION
Combination of AVP and NAD improved renal perfusion and diuresis but reduced carotid blood flow as compared to NAD alone in a porcine model of post-resuscitation syndrome. AVP alone failed to manage shock and led to mortality.
PubMed: 38716382
DOI: 10.1016/j.resplu.2024.100654 -
Chemosphere Jul 2024Per- and polyfluoroalkyl substances (PFAS) are a large class of stable toxic chemicals which have ended up in the environment and in organisms in significant...
Per- and polyfluoroalkyl substances (PFAS) are a large class of stable toxic chemicals which have ended up in the environment and in organisms in significant concentrations. Toxicokinetic models are needed to facilitate extrapolation of bioaccumulation data across PFAS congeners and species. For the present study, we carried out an inventory of accumulation processes specific for PFAS, deviating from traditional Persistent Organic Pollutants (POPs). In addition, we reviewed toxicokinetic models on PFAS reported in literature, classifying them according to the number of compartments distinguished as a one-compartment model (1-CM), two-compartment model (2- CM) or a multi-compartment model, (multi-CM) as well as the accumulation processes included and the parameters used. As the inventory showed that simple 1-CMs were lacking, we developed a generic 1-CM of ourselves to include PFAS specific processes and validated the model for legacy perfluoroalkyl acids. Predicted summed elimination constants were accurate for long carbon chains (>C6), indicating that the model properly represented toxicokinetic processes for most congeners. Results for urinary elimination rate constants were mixed, which might be caused by the exclusion of reabsorption processes (renal reabsorption, enterohepatic circulation). The 1-CM needs to be improved further in order to better predict individual elimination pathways. Besides that, more data on PFAS-transporter specific processes are needed to extrapolate across PFAS congeners and species.
Topics: Fluorocarbons; Humans; Bioaccumulation; Toxicokinetics; Persistent Organic Pollutants; Environmental Monitoring; Environmental Pollutants; Models, Biological
PubMed: 38714250
DOI: 10.1016/j.chemosphere.2024.142253 -
Clinical and Applied... 2024In unfractionated heparin (UFH) monitoring during extracorporeal circulation, the traditional measures of activated clotting time (ACT) or activated partial... (Observational Study)
Observational Study
In unfractionated heparin (UFH) monitoring during extracorporeal circulation, the traditional measures of activated clotting time (ACT) or activated partial thromboplastin time (APTT) may diverge, confounding anticoagulant adjustments. We aimed to explore the factors explaining this discrepancy in children and young adults. This retrospective observational study, conducted at an urban regional tertiary hospital, included consecutive pediatric patients who received UFH during extracorporeal circulation (continuous kidney replacement therapy or extracorporeal membrane oxygenation) between April 2017 and March 2021. After patients whose ACT and APTT were not measured simultaneously or who were also taking other anticoagulants were excluded, we analyzed 94 samples from 23 patients. To explain the discrepancy between ACT and APTT, regression equations were created using a generalized linear model (family = gamma, link = logarithmic) with ACT as the response variable. Other explanatory variables included age, platelet count, and antithrombin. Compared to APTT alone as an explanatory variable, the Akaike information criterion and pseudo-coefficient of determination improved from 855 to 625 and from 0.01 to 0.42, respectively, when these explanatory variables were used. In conclusion, we identified several factors that may explain some of the discrepancy between ACT and APTT in the routinely measured tests. Evaluation of these factors may aid in appropriate adjustments in anticoagulation therapy.
Topics: Humans; Heparin; Female; Male; Child; Retrospective Studies; Extracorporeal Circulation; Adolescent; Partial Thromboplastin Time; Child, Preschool; Young Adult; Adult; Infant; Anticoagulants; Blood Coagulation; Whole Blood Coagulation Time
PubMed: 38711321
DOI: 10.1177/10760296241252838 -
The Journal of Vascular Access May 2024An accessible tool is required to analyze volume flow trends in arteriovenous fistulas for hemodialysis. Earlybird, an easy-to-place ultrasound Doppler device, has shown...
Assessment of volume flow rate in arteriovenous fistulas with a novel ultrasound Doppler device (earlybird): Trend analysis, comparison of methods, and inter- and intra-rater reliability.
BACKGROUND
An accessible tool is required to analyze volume flow trends in arteriovenous fistulas for hemodialysis. Earlybird, an easy-to-place ultrasound Doppler device, has shown comparable accuracy to duplex ultrasound. In this study, we compared volume flow measurements obtained with duplex ultrasound and the dilution technique to an enhanced earlybird device, featuring a dual Doppler probe system, eliminating the requirement for a known insonation angle.
METHODS
Nine patients with a distal radiocephalic arteriovenous fistula were monitored for 12 months with regular volume flow measurements. Correlation and inter- and intra-class reliability analyses were conducted.
RESULTS
An overall moderate correlation was observed between earlybird and duplex ultrasound or dilution technique (intraclass correlation coefficient = 0.606 (95% confidence interval 0.064, 0.721) and 0.581 (0.039, 0.739), respectively). Duplex ultrasound compared to dilution measurements, demonstrated an overall moderate correlation (0.725 (0.219, 0.843)). Correlation between earlybird and duplex ultrasound was stronger for the arteriovenous fistula (0.778 (0.016, 0.901)) than the brachial artery (0.381 (-0.062, 0.461)). For earlybird, inter-rater reliability was excellent for the arteriovenous fistula (0.907 (0.423, 0.930)) and poor for the brachial artery (0.430 (0.241, 0.716)). Duplex ultrasound showed a good inter-rater reliability (arteriovenous fistula: 0.843 (0.610, 0.871), brachial artery: 0.819 (0.477, 0.864)). The overall intra-rater reliability was good for duplex ultrasound (rater A: 0.893 (0.727, 0.911); rater B: 0.853 (0.710, 0.891)), while excellent for earlybird (rater A: 0.905 (0.819, 0.928); rater B: 0.921 (0.632, 0.969)).
CONCLUSION
We observed a weaker correlation in the measurements of volume flow rates in arteriovenous fistulas when obtained using earlybird compared to dilution technique, unlike the comparison between duplex ultrasound and the dilution technique. However, inter-rater reliability for the arteriovenous fistula was excellent with earlybird and good with duplex ultrasound, indicating the potential of earlybird as a tool for frequent measurements, enabling trend surveillance and predicting adverse outcomes.
PubMed: 38708835
DOI: 10.1177/11297298241250379 -
International Journal of Nanomedicine 2024Dihydroartemisinin (DHA) has emerged as a promising candidate for anticancer therapy. However, the application of DHA in clinics has been hampered by several limitations...
Acidic Environment-Responsive Metal Organic Framework-Mediated Dihydroartemisinin Delivery for Triggering Production of Reactive Oxygen Species in Drug-Resistant Lung Cancer.
BACKGROUND
Dihydroartemisinin (DHA) has emerged as a promising candidate for anticancer therapy. However, the application of DHA in clinics has been hampered by several limitations including poor bioavailability, short circulation life, and low solubility, significantly restricting its therapeutic efficacy and leading to notable side effects during the treatment.
PURPOSE
We present DHA-loaded zeolitic imidazolate framework-8 (D-ZIF) with controllable and targeted DHA release properties, leading to enhanced antitumor effects while reducing potential side effects.
METHODS
D-ZIF was prepared by one-pot synthesis method using methylimidazole (MIM), Zn(NO)•6HO and DHA. We characterized the physical and chemical properties of D-ZIF by TEM, DLS, XRD, FT-IR, and TG. We measured the drug loading efficiency and the cumulative release of DHA in different pH conditions. We evaluated the cytotoxicity of D-ZIF on renal cell carcinoma (RCC786-O), glioma cells (U251), TAX-resistant human lung adenocarcinoma (A549-TAX) cells by CCK8 in vitro. We explored the possible antitumor mechanism of D-ZIF by Western blot. We evaluated the biocompatibility and hemolysis of D-ZIF and explored the in vivo antitumor efficiency in mice model by TUNEL testing and blood biomarker evaluations.
RESULTS
D-ZIF showed rhombic dodecahedral morphology with size of 129±7.2 nm and possessed a noticeable DHA encapsulation efficiency (72.9%). After 48 hours, D-ZIF released a cumulative 70.0% of the loaded DHA at pH 6.5, and only 42.1% at pH 7.4. The pH-triggered programmed release behavior of D-ZIF could enhance anticancer effect of DHA while minimizing side effects under normal physiological conditions. Compared with the free DHA group with 31.75% of A549-TAX cell apoptosis, the percentage of apoptotic cells was approximately 76.67% in the D-ZIF group. D-ZIF inhibited tumor growth by inducing tumor cell apoptosis through the mechanism of ROS production and regulation of Nrf2/HO-1 and P38 MAPK signaling pathways. D-ZIF showed potent effects in treating tumors with high safety in vivo.
CONCLUSION
This pH-responsive release mechanism enhanced the targeting efficiency of DHA towards tumor cells, thereby increasing drug concentration in tumor sites with negligible side effects. Herein, D-ZIF holds great promise for curing cancers with minimal adverse effects.
Topics: Artemisinins; Animals; Humans; Reactive Oxygen Species; Metal-Organic Frameworks; Lung Neoplasms; Mice; Drug Resistance, Neoplasm; Cell Line, Tumor; Antineoplastic Agents; Hydrogen-Ion Concentration; A549 Cells; Drug Liberation; Mice, Nude; Apoptosis; Mice, Inbred BALB C; Xenograft Model Antitumor Assays; Drug Carriers; Hemolysis; Imidazoles
PubMed: 38708182
DOI: 10.2147/IJN.S451042 -
Frontiers in Cardiovascular Medicine 2024Postoperative acute kidney injury (PO-AKI) is a prevalent complication among patients with acute type A aortic dissection (aTAAD) for which unrecognized trajectories of...
BACKGROUND
Postoperative acute kidney injury (PO-AKI) is a prevalent complication among patients with acute type A aortic dissection (aTAAD) for which unrecognized trajectories of renal function recovery, and their heterogeneity, may underpin poor success in identifying effective therapies.
METHODS
This was a retrospective, single-center cohort study in a regional Great Vessel Center including patients undergoing aortic dissection surgery. Estimated glomerular filtration rate (eGFR) recovery trajectories of PO-AKI were defined through the unsupervised latent class mixture modeling (LCMM), with an assessment of patient and procedural characteristics, complications, and early-term survival. Internal validation was performed by resampling.
RESULTS
A total of 1,295 aTAAD patients underwent surgery and 645 (49.8%) developed PO-AKI. Among the PO-AKI cohort, the LCMM identified two distinct eGFR trajectories: early recovery (ER-AKI, 51.8% of patients) and late or no recovery (LNR-AKI, 48.2% of patients). Binary logistic regression identified five critical determinants regarding poor renal recovery, including chronic kidney disease (CKD) history, renal hypoperfusion, circulation arrest time, intraoperative urine, and myoglobin. LNR-AKI was associated with increased mortality, continuous renal replacement therapies, mechanical ventilation, ICU stay, and hospital stay. The assessment of the predictive model was good, with an area under the curve (AUC) of 0.73 (95% CI: 0.69-0.76), sensitivity of 61.74%, and specificity of 75.15%. The internal validation derived a consistent average AUC of 0.73. The nomogram was constructed for clinicians' convenience.
CONCLUSION
Our study explored the PO-AKI recovery patterns among surgical aTAAD patients and identified critical determinants that help to predict individuals at risk of poor recovery of renal function.
PubMed: 38707890
DOI: 10.3389/fcvm.2024.1364332