sirolimus and Renal-Insufficiency--Chronic

Nutrients such as glucose, amino acids and lipids are fundamental sources for the maintenance of essential cellular processes and homeostasis in all organisms. The nutrient-sensing kinases mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) are expressed in many cell types and have key roles in the control of cell growth, proliferation, differentiation, metabolism and survival, ultimately contributing to the physiological development and functions of various organs, including the kidney. Dysregulation of these kinases leads to many human health problems, including cancer, neurodegenerative diseases, metabolic disorders and kidney diseases. In the kidney, physiological levels of mTOR and AMPK activity are required to support kidney cell growth and differentiation and to maintain kidney cell integrity and normal nephron function, including transport of electrolytes, water and glucose. mTOR forms two functional multi-protein kinase complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Hyperactivation of mTORC1 leads to podocyte and tubular cell dysfunction and vulnerability to injury, thereby contributing to the development of chronic kidney diseases, including diabetic kidney disease, obesity-related kidney disease and polycystic kidney disease. Emerging evidence suggests that targeting mTOR and/or AMPK could be an effective therapeutic approach to controlling or preventing these diseases.

Topics: AMP-Activated Protein Kinases; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes; Nutrients; Polycystic Kidney Diseases; Renal Insufficiency, Chronic; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Chronic kidney disease (CKD) patients have worse adverse cardiovascular outcomes after percutaneous coronary intervention (PCI). Clinical outcomes comparing a limus-eluting stent (LES) to a paclitaxel-eluting stent (PES) in patients with CKD remain controversial.A systematic search was conducted using PubMed, EMBASE, and Cochrane Library. A pooled odds ratio (OR) and 95% confidence interval (CI) were used to calculate original data. We conducted heterogeneity, quality assessment, and publication bias analyses.A total of 17 trials involving 10,724 patients were included. No significant differences were found regarding target vessel revascularization, target lesion revascularization (TLR), stent thrombosis (ST), myocardial infarction (MI), all-cause mortality, and major adverse cardiac events (MACE) between first-generation LES implantation and PES implantation. Second-generation LES implantation was associated with lower rates of all-cause mortality (OR, 0.56; 95% CI, 0.39-0.82; P = 0.003), MACE (OR, 0.61; 95% CI, 0.38-0.97; P = 0.04), and ST (OR, 0.45; 95% CI, 0.26-0.77; P = 0.004) compared with PES implantation. In all, the long-term all-cause mortality rate was significantly lower after LES implantation than after PES implantation in patients with CKD (OR, 0.78; 95% CI, 0.66-0.93; P = 0.004). However, second-generation LES implantation resulted in a higher rate of TLR (OR, 2.23; 95% CI, 1.53-3.25; P < 0.001) than PES implantation in dialysis patients.In patients with CKD, first-generation LES and PES implantation had comparable mortality and morbidity. Second-generation LES implantation was superior to PES in reducing long-term mortality, MACE, and ST. However, PES may be more effective than LES in dialysis patients.

Topics: Antineoplastic Agents; Coronary Occlusion; Drug-Eluting Stents; Humans; Odds Ratio; Paclitaxel; Percutaneous Coronary Intervention; Renal Insufficiency, Chronic; Sirolimus; Treatment Outcome

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

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Pancreas-kidney transplant is an effective treatment for patients with insulin-dependent dabetes and chronic renal failure. Reduction in technical failure loss and early acute rejection rates contributed to prolong pancreas graft survival. However, drug toxicity affects negatively both short- and long-term follow-ups.. This article reviews the existing literature and knowledge of the immunosuppressive drugs that are frequently used in pancreas transplant, including calcineurin inhibitors, sirolimus, corticosteroids, and mycophenolate. The article also discusses the short- and long-term adverse effects of these drugs. The article also reports and discusses the most relevant in vitro studies, providing additional information to in vivo findings. Some clinically relevant drug interactions with immunosuppressive drugs are also highlighted. Over- and underimmunosuppression effects will not be addressed.. Immunosuppressive regimen after pancreas transplant is very effective and contributed to pancreas allograft survival. However, they present several side effects that are potentiated when drugs are combined. Modifiable and non-modifiable risk factors can aggravate metabolic and toxicological effects of immunosuppressive drugs. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

Topics: Adrenal Cortex Hormones; Bone Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Hematologic Diseases; Humans; Hyperkalemia; Hyperuricemia; Immunosuppressive Agents; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Pneumonia; Renal Insufficiency, Chronic; Sirolimus

The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC.

Topics: Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Liver Transplantation; Renal Insufficiency, Chronic; Sirolimus; Tacrolimus

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; 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Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; 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STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency.. In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria ≤0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline.. At the 1-year preplanned interim analysis, GFR fell from 26.7±5.8 to 21.3±6.3 ml/min per 1.73 m(2) (P<0.001) and from 29.6±5.6 to 24.9±6.2 ml/min per 1.73 m(2) (P<0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8±81.8 versus 154.9±152.9 μg/min; P=0.02) and proteinuria (0.3±0.2 versus 06±0.4 g/24 h; P<0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P<0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrast-enhanced computed tomography imaging) increased by 9.0% from 2857.7±1447.3 to 3094.6±1519.5 ml on sirolimus and 4.3% from 3123.4±1695.3 to 3222.6±1651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively.. Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.

Topics: Adult; Albuminuria; Disease Progression; Early Termination of Clinical Trials; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Sirolimus

Percutaneous coronary interventions in patients with chronic kidney disease have shown suboptimal results. Drug-eluting stents (DES) might reduce the rate of target vessel revascularization in comparison with bare-metal stents (BMS) in patients with chronic kidney disease. However, given the multiple concomitant individual variables present in such patients, the comparison of neointimal growth after percutaneous coronary intervention is complex and difficult to assess.. Randomized Comparison of Xience V and Multi-Link Vision Coronary Stents in the Same Multivessel Patient with Chronic Kidney Disease (RENAL-DES) was a prospective, randomized, multicenter study to directly compare the efficacy in the prevention of clinical restenosis of everolimus-eluting stent (Xience V) and BMS with an identical design (Multi-Link Vision), both implanted in the same patient with multivessel coronary artery disease and chronic kidney disease (estimated glomerular filtration rate <60 mL/min). The primary end point of the study was the ischemia-driven target vessel revascularization as detected with myocardial scintigraphy at 12 months. In 215 patients, 512 coronary vessels were successfully treated with the randomly assigned DES (n=257) or BMS (n=255). At 1 year, the rate of ischemia-driven target vessel revascularization for DES and BMS groups was 2.7% (95% confidence interval, 1.1%-5.6%) and 11.4% (95% confidence interval, 7.8% to 16%), respectively, P<0.001. For the multivariate analysis, independent predictors of the ischemia-driven target vessel revascularization were BMS implantation (odds ratio, 4.95; 95% confidence interval, 2.1-11.6; P<0.001) and vessel size (odds ratio, 0.32; 95% confidence interval, 0.1-0.7; P=0.006).. This is the first randomized trial showing a reduction of clinical restenosis with a new-generation DES in comparison with a BMS of equal design, in patients who have chronic kidney disease with multivessel coronary artery disease.. http://clinicaltrials.gov. Unique identifier: NCT00818792.

Topics: Aged; Aged, 80 and over; Comorbidity; Coronary Angiography; Coronary Artery Disease; Drug-Eluting Stents; Endpoint Determination; Everolimus; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Multivariate Analysis; Percutaneous Coronary Intervention; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors; Sirolimus; Stents; Treatment Outcome

Chronic kidney disease (CKD) is a frequent complication after liver transplantation (LT) and is associated with increased mortality. Strategies to reduce calcineurin inhibitor (CNI) dose or conversion to either mycophenolate mofetil and/or rapamycin resulted in variable results and side-effect profiles.. We evaluated the effectiveness of CNI conversion to long-term anti-CD25 monoclonal antibody (mAb)-based immunosuppression in 15 adult LT patients with CKD at 7.6±4 years posttransplant (intervention group). Three patients had been previously switched to rapamycin, and 12 patients were on CNI. The control group included 15 LT patients on CNI with stable renal function over a similar posttransplant follow-up period.. Anti-CD25 mAb were given over a period of 26±15 months (range, 2-51 months) and were well tolerated. The slope of calculated creatinine clearance was -0.66 mL/min/month over 6 months before conversion and -0.05 mL/min/month after conversion to anti-CD25 mAb (P=0.16 and P=0.86 vs. controls). Three acute rejection episodes occurred in the intervention group. Acute rejection was reversible in two patients. However, one patient died of chronic rejection 1 year after having been switched to tacrolimus. Anti-CD25 mAb were replaced with either CNI or rapamycin in six patients (acute rejection [n=2], progression to end-stage renal disease [n=2], poor venous status [n=1], increased liver enzymes [n=1]).. The use of long-term anti-CD25 mAb therapy as a replacement to CNI and rapamycin-based immunosuppression may be feasible. It is crucial that rejection surveillance is intensified. A randomized controlled trial is required to confirm the benefits of this strategy.

Topics: Aged; Antibodies, Monoclonal; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Interleukin-2 Receptor alpha Subunit; Liver Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation; Treatment Outcome

To determine which drug-eluting stents are more effective in acute myocardial infarction (MI) patients with chronic kidney disease (CKD).. This study included a total of 3,566 acute MI survivors with CKD from the Korea Acute Myocardial Infarction Registry who were treated with stenting and followed up for 12 months: 1,845 patients who received sirolimus-eluting stents (SES), 1,356 who received paclitaxel-eluting stents (PES), and 365 who received zotarolimus-eluting stents (ZES). CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) calculated by the modification of diet in renal disease method.. At the 12-month follow-up, patients receiving ZES demonstrated a higher incidence (14.8%) of major adverse cardiac events (MACEs) compared to those receiving SES (10.1%) and PES (12%, p = 0.019). The ZES patients also had a higher incidence (3.9%) of target lesion revascularization (TLR) compared to those receiving SES (1.5%) and PES (2.4%, p = 0.011). After adjusting for confounding factors, ZES was associated with a higher incidence of MACE and TLR than SES (adjusted hazard ratio [HR], 0.623; 95% confidence interval [CI], 0.442 to 0.879; p = 0.007; adjusted HR, 0.350; 95% CI, 0.165 to 0.743; p = 0.006, respectively), and with a higher rate of TLR than PES (adjusted HR, 0.471; 95% CI, 0.223 to 0.997; p = 0.049).. Our findings suggest that ZES is less effective than SES and PES in terms of 12-month TLR, and has a higher incidence of MACE due to a higher TLR rate compared with SES, in acute MI patients with CKD.

Topics: Aged; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Prospective Studies; Registries; Renal Insufficiency, Chronic; Republic of Korea; Sirolimus

This prospective study assesses over a period of 6 months, the variations in glomerular filtration rate (GFR) and safety parameters within a cohort of 44 cadaveric renal-transplant (RT) patients presenting with moderate renal insufficiency. They were progressively switched from calcineurin inhibitors (CNIs) based- to sirolimus (SRL) based-therapies aiming SRL troughs at levels approximately 8 ng/ml (range 6-10). All the patients were receiving in addition mycophenolate mofetil. The intent-to-treat (ITT) patient and graft survivals were 100%. Thirty-four patients, i.e. 77.3% completed the study. Overall, there was a significant improvement in the calculated GFR (Nankivell formula) from day 0 to month 6, i.e. from 45.98 (+/-16.3) to 53.07 (+/-12.68) ml/mn (P=0.03). However, renal function improved in only 20 cases (group I), and deteriorated in the others (group II). Groups I and II did not significantly differ with respect to time between transplantation and drug switch, GFR, serum creatinine, and proteinuria at baseline. There was only one case of steroid-sensitive acute rejection. Overall, there was a significant increase in proteinuria from 0 (0-3.15) to 0.57 (0-4.85) g/day (P=0.002). Finally, the conversion was associated with a significant increase in lipids, and a significant decrease in hemoglobin levels.

Topics: Adult; Calcineurin Inhibitors; Female; Glomerular Filtration Rate; Graft Rejection; Hematologic Tests; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Sirolimus

Declining kidney function in tuberous sclerosis complex (TSC) is often attributed to large lesions, including angiomyolipomas (AMLs) and cysts, that encroach on the normal parenchyma or that require intervention and loss of parenchyma from surgical debulking or embolization. Consequently, research on inhibitors of the mammalian target of rapamycin (mTOR), a protein complex implicated in TSC pathophysiology for its role in promoting cell growth and proliferation, has largely focused on their ability to reduce AML size. Clinical guidelines distilled from this research limit mTOR inhibition as a first-line treatment to patients with large AMLs. However, chronic kidney disease (CKD) occurs in patients without large AMLs or a history of renal intervention. Alternate mechanisms postulated for CKD in TSC may suggest a role for mTOR inhibition in this population. In this report, we present 2 cases of a microscopic variant of TSC kidney disease causing declining kidney function, as well as anecdotal evidence for the use of mTOR inhibition to improve kidney function in the absence of large AMLs. We highlight the importance of annual kidney function assessment in patients with TSC and suggest a low threshold for kidney biopsy in patients with declining glomerular filtration rate without a clear etiology clinically or radiographically.

Topics: Angiomyolipoma; Humans; Kidney; Kidney Neoplasms; Renal Insufficiency, Chronic; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease and have a worse prognosis after percutaneous coronary interventions (PCI). The BioFreedom polymer-free biolimus-A9-eluting stent (PF-BES) has shown promising results in patients at high bleeding risk; however, its performance in CKD patients has yet to be analyzed.. The all-comers RUDI-FREE registry documented patients undergoing PCI with PF-BES in routine clinical practice. Patients were stratified into three groups according to their estimated glomerular filtration rate (eGFR): preserved renal function, mild renal insufficiency (RI), and with moderate to severe RI (eGFR ≥ 90, between 90 and 45, and <45 ml/min/1.73 m2, respectively). The primary safety end point was a patient-oriented composite end point of cardiovascular death, myocardial infarction (MI), and definite or probable stent thrombosis (ST). The primary efficacy end point was target lesion revascularization (TLR).. The registry documented 1,104 consecutive patients treated with PF-BES: 258 (23.4%) with preserved renal function, whereas 712 (64.7%) and 131 (11.9%) had mild and moderate to severe RI, respectively. At 1 year, the primary safety end point was significantly higher in patients with moderate to severe RI (3.5% vs. 2.8% vs. 11.5%; P < 0.001). Conversely, TLR proved similar among groups (0.4% vs. 1.8% vs. 0.8%; P = 0.235).. Patients with worse renal function had increased risk of the composite of cardiovascular deaths, MI, and definite or probable ST. However, the PF-BES showed similar efficacy despite differences in renal function. These findings need to be confirmed in large-scale randomized trials.

Topics: Aged; Cardiovascular Diseases; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Prospective Studies; Registries; Renal Insufficiency, Chronic; Sirolimus; Thrombosis

The global burden of chronic kidney disease is increasing, and the majority of these diseases are progressive. Special site-targeted drugs are emerging as alternatives to traditional drugs. Oligonucleotides (ODNs) have been proposed as effective therapeutic tools in specific molecular target therapies for several diseases. We designed ring-type non-coding RNAs (ncRNAs), also called mTOR ODNs to suppress mammalian target rapamycin (mTOR) translation. mTOR signaling is associated with excessive cell proliferation and fibrogenesis. In this study, we examined the effects of mTOR suppression on chronic renal injury. To explore the regulation of fibrosis and inflammation in unilateral ureteral obstruction (UUO)-induced injury, we injected synthesized ODNs via the tail vein of mice. The expression of inflammatory-related markers (interleukin-1β, tumor necrosis factor-α), and that of fibrosis (α-smooth muscle actin, fibronectin), was decreased by synthetic ODNs. Additionally, ODN administration inhibited the expression of autophagy-related markers, microtubule-associated protein light chain 3, Beclin1, and autophagy-related gene 5-12. We confirmed that ring-type ODNs inhibited fibrosis, inflammation, and autophagy in a UUO mouse model. These results suggest that mTOR may be involved in the regulation of autophagy and fibrosis and that regulating mTOR signaling may be a therapeutic strategy against chronic renal injury.

Topics: Actins; Animals; Autophagy; Beclin-1; Disease Models, Animal; Fibronectins; Fibrosis; Inflammation; Interleukin-1beta; Kidney; Mammals; Mice; Microtubule-Associated Proteins; Oligonucleotides; Renal Insufficiency, Chronic; RNA, Untranslated; Sirolimus; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha; Ureteral Obstruction

Atherosclerosis arising from the pro-inflammatory conditions associated with chronic kidney disease (CKD) increases major cardiovascular morbidity and mortality. Rapamycin (RAPA) is known to inhibit atherosclerosis under CKD and non-CKD conditions, but it can cause dyslipidemia; thus, the co-application of lipid-lowering agents is recommended. Atorvastatin (ATV) has been widely used to reduce serum lipids levels, but its synergistic effect with RAPA in CKD remains unclear. Here, we analyzed the effect of their combined treatment on atherosclerosis stimulated by CKD in apolipoprotein E-deficient (ApoE-/-) mice. Oil Red O staining revealed that treatment with RAPA and RAPA＋ ATV, but not ATV alone, significantly decreased the atherosclerotic lesions in the aorta and aortic sinus, compared to those seen in the control (CKD) group. The co-administration of RAPA and ATV improved the serum lipid profile and raised the expression levels of proteins involved in reverse cholesterol transport (LXRα, CYP7A1, ABCG1, PPARγ, ApoA1) in the liver. The CKD group showed increased levels of various genes encoding atherosclerosispromoting cytokines in the spleen (Tnf-α, Il-6 and Il-1β) and aorta (Tnf-α and Il-4), and these increases were attenuated by RAPA treatment. ATV and RAPA＋ATV decreased the levels of Tnf-α and Il-1β in the spleen, but not in the aorta. Together, these results indicate that, in CKD-induced ApoE-/- mice, RAPA significantly reduces the development of atherosclerosis by regulating the expression of inflammatory cytokines and the co-application of ATV improves lipid metabolism. [BMB Reports 2021; 54(3): 170-175].

Topics: Animals; Apolipoproteins E; Atherosclerosis; Atorvastatin; Cytokines; Disease Models, Animal; Female; Lipid Metabolism; Mice; Mice, Knockout; Renal Insufficiency, Chronic; Sirolimus

The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular degradation procedures. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood.. To investigate the role of the UPS in podocytes, mice were generated that had deletion of. Impairment of proteasome function in podocytes led to CKD, and antioxidants and autophagy activators can be therapeutic agents for age-dependent CKD.

Topics: Aging; Animals; Apoptosis; Autophagy; Bortezomib; Cells, Cultured; Glomerulosclerosis, Focal Segmental; Lysosomes; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Podocytes; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Aggregates; Renal Insufficiency, Chronic; Sirolimus; Ubiquitination

Despite optimal anticoagulation and blood pressure control, patients with antiphospholipid syndrome (APS) nephropathy frequently progress to kidney failure, and recurrence after transplantation is common. The mTORC (mechanistic target of rapamycin complex) pathway was recently identified as a potential intermediate and a therapeutic target in vascular lesions associated with APS nephropathy. However, these results were derived from the retrospective analysis of a small cohort of patients receiving sirolimus after kidney transplantation. Therefore, they warranted external validation and the demonstration of the potential benefit of sirolimus in native kidney APS nephropathy. We report a patient with active APS nephropathy lesions occurring on native kidneys, in which endothelial mTORC activation was substantiated at the molecular level. Treatment with sirolimus was shown on a repeat kidney biopsy to successfully inhibit the AKT/mTORC pathway and was associated with significant improvement in kidney function and lesions of vasculopathy. Drug tolerance was excellent during the entire follow-up. This case validates and extends previous observations in kidney transplant recipients and demonstrates that endothelial activation of the AKT/mTORC pathway occurs in the damaged renal vasculature of native kidneys in APS nephropathy. These findings further support the potential of precision medicine and the use of mTORC activation as a biomarker of disease activity and as therapeutic target in patients with APS nephropathy.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Antiphospholipid Syndrome; Female; Humans; Immunosuppressive Agents; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Microscopy, Confocal; Proto-Oncogene Proteins c-akt; Ramipril; Renal Insufficiency, Chronic; Ribosomal Protein S6; Signal Transduction; Sirolimus; Thrombotic Microangiopathies; TOR Serine-Threonine Kinases; Treatment Outcome

It is very difficult to treat patients with aplastic anemia accompanied by chronic kidney disease. The nephrotoxicity of cyclosporine limits its use in these patients. Most of these patients also lack suitable sibling donors. Sirolimus, as a new type of immunosuppressive agent, has good therapeutic effect, lower toxicity, especially lower nephrotoxicity, thus attracting the attention of hematologists.. This 55-year-old Chinese male patient suffered from pancytopenia and renal insufficiency and has a poor quality of life.. The patient was diagnosed as severe aplastic anemia with chronic kidney disease-G3a.. We started the sirolimus therapy with the initial dose of 1 mg per day. Based on the good tolerability and clinical effect, we increased the dose of sirolimus to 2 mg per day after 2 weeks.. By taking sirolimus, the patient's peripheral blood cell count gradually increased, and he achieved blood transfusion independent, and eventually the blood cell count was completely normal.. We consider that sirolimus is a safe, effective, and well-tolerated oral drug that can be used as a treatment for aplastic anemia patients with chronic kidney disease.

Topics: Administration, Oral; Anemia, Aplastic; Humans; Immunosuppressive Agents; Male; Middle Aged; Renal Insufficiency, Chronic; Sirolimus

An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys, which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

Topics: Animals; Capillary Permeability; Cell Adhesion Molecules; Cell Hypoxia; Diabetic Nephropathies; Disease Progression; Glomerular Filtration Rate; Kidney Glomerulus; Kidney Tubules; Male; Mitochondria; Oxidative Stress; Oxygen Consumption; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Elevated serum phosphorus level is an important risk factor for cardiovascular death in general patients on hemodialysis (HD). However, the effect of serum phosphorus levels on outcomes after drug-eluting stent (DES) implantation in HD patients is unknown.Methods and Results:This was a post-hoc study of the OUCH study series, a series of prospective multicenter registries of HD patients who underwent DES implantation comprising 359 patients from 31 centers in Japan. Patients were categorized into 3 groups according to their preprocedural serum phosphorus levels. The 1-year clinical outcomes of the 336 patients treated for de novo lesions were evaluated. Compared with patients with high (>5.5 mg/dL; n=65) or normal (3.5-5.5 mg/dL; n=219) serum phosphorus levels, those with low serum phosphorus levels (<3.5 mg/dL; n=52) had significantly fewer target lesion revascularization events (13.9% vs. 16.9% vs. 1.9%; P=0.0090) and major adverse cardiac and cerebrovascular events (29.2% vs. 31.1% vs. 13.5%; P=0.032). Multivariate logistic regression analysis revealed that low serum phosphorus level was an independent negative predictor for major adverse cardiac and cerebrovascular events (adjusted odds ratio, 0.31; 95% confidence interval, 0.12-0.70; P=0.0036).. Lowering of serum phosphorus levels beyond the current recommended range may be considered in HD patients who undergo DES implantation.

Topics: Aged; Antineoplastic Agents; Cardiovascular Diseases; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Paclitaxel; Phosphorus; Registries; Renal Dialysis; Renal Insufficiency, Chronic; Sirolimus; Treatment Outcome

Podocytes are highly differentiated epithelial cells wrapping glomerular capillaries to form the filtration barrier in kidneys. As such, podocyte injury or dysfunction is a critical pathogenic event in glomerular disease. Autophagy plays an important role in the maintenance of the homeostasis and function of podocytes. However, it is less clear whether and how autophagy contributes to podocyte injury in glomerular disease. Here, we have examined the role of autophagy in adriamycin-induced nephropathy, a classic model of glomerular disease. We show that autophagy was induced by adriamycin in cultured podocytes in vitro and in podocytes in mice. In cultured podocytes, activation of autophagy with rapamycin led to the suppression of adriamycin-induced apoptosis, whereas inhibition of autophagy with chloroquine enhanced podocyte apoptosis during adriamycin treatment. To determine the role of autophagy in vivo, we established an inducible podocyte-specific autophagy-related gene 7 knockout mouse model (Podo-Atg7-KO). Compared with wild-type littermates, Podo-Atg7-KO mice showed higher levels of podocyte injury, glomerulopathy, and proteinuria during adriamycin treatment. Together, these observations support an important role of autophagy in protecting podocytes under the pathological conditions of glomerular disease, suggesting the therapeutic potential of autophagy induction.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Autophagy; Autophagy-Related Protein 7; Cells, Cultured; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Male; Mice, Inbred C57BL; Mice, Knockout; Podocytes; Proteinuria; Renal Insufficiency, Chronic; Signal Transduction; Sirolimus; Time Factors

Chronic kidney disease is a significant complication after liver transplantation (LT), but the role of pre-existing renal insufficiency and proteinuria remains unclear among LT recipients receiving sirolimus.. We assessed the effects of proteinuria and baseline renal function on long-term renal and survival outcomes among 576 LT recipients who received SRL in a medical center between 2005 and 2014. Renal outcomes were the incidences of >50% reduction in their baseline estimated glomerular filtration rate and end stage kidney disease requiring renal replacement therapy. Proteinuria was identified using morning dipstick results (≥30 mg/dL) at baseline and within the first year after the initiation of SRL therapy. A Kaplan-Meier analysis was performed to estimate time to event. Factors associated with the outcomes were determined using the Cox proportional hazards model with a significance level set at P <0.05.. During the study period, renal function deteriorated in 135 (25.3%) patients and 68 (11.8%) patients died. Persistent and new onset proteinuria contributed to a high rate of mortality and the deterioration of renal function (both log-rank tests, P <0.0001). After adjustments, new onset proteinuria within the first year after the initiation of SRL therapy increased the risk of deteriorating renal function, regardless of baseline estimated glomerular filtration rate. Moreover, pre-existing (hazard ratio = 1.91; P <0.001) and new onset diabetes (hazard ratio = 2.34; P <0.0001) were significantly associated with new onset proteinuria among SRL users.. These findings support the effective monitoring and early management of the predictable risks for proteinuria among new SRL users in order to delay the progression of renal disease.

Topics: Disease Progression; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Proteinuria; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Sirolimus

Long-term clinical outcomes of new-generation drug-eluting stents in complex anatomic and clinical settings are not well defined. This study assessed the impact of patient and lesion complexity on 2-year outcomes after coronary revascularization with ultrathin strut biodegradable-polymer (BP) sirolimus-eluting stents (SES) versus durable-polymer (DP) everolimus-eluting stents (EES). In a prespecified analysis of the BIOSCIENCE randomized trial (NCT01443104), complex patients (911 of 2,119; 43%) were defined by the presence of acute ST-elevation myocardial infarction (MI); left ventricular ejection fraction ≤30%; renal dysfunction; insulin-treated diabetes; treatment of ostial lesion, bypass graft, unprotected left main lesion; or 3-vessel intervention. The primary end point was target lesion failure (TLF), a composite of cardiac death, target vessel MI, and clinically indicated target lesion revascularization. At 2 years, complex compared with simple patients had a greater risk of TLF (14.5% vs 7.4%, risk ratio 2.05, 95% confidence interval 1.56 to 2.69; p <0.001). The difference was sustained beyond 1 year on landmark analysis. Complex patients had higher rates of the patient-oriented composite end point of death, any MI, or any revascularization (23% vs 14.4%; p <0.001) as well as definite stent thrombosis (1.6% vs 0.4%, p = 0.006). There were no differences in TLF and patient-oriented composite end point between the BP-SES versus DP-EES, consistently among simple and complex patients. In conclusion, patient and lesion complexity had a durable adverse impact on clinical outcomes throughout 2 years of follow-up in this all-comers randomized trial. Safety and efficacy of new-generation BP-SES and DP-EES were comparable, irrespective of complexity status.

Topics: Absorbable Implants; Aged; Antibiotics, Antineoplastic; Comorbidity; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Percutaneous Coronary Intervention; Polymers; Prognosis; Prospective Studies; Prosthesis Design; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Severity of Illness Index; Sirolimus; ST Elevation Myocardial Infarction; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

Chronic kidney disease (CKD) is an important risk factor for coronary artery disease (CAD) and cardiovascular events. Cystatin C (CysC) has been proposed as a sensitive marker for CKD. However, the predictive value of CysC for cardiovascular events in CAD patients with preserved estimated glomerular filtration rate (eGFR) is unclear. We enrolled 277 consecutive patients undergoing elective percutaneous coronary intervention with sirolimus-eluting stents (SES). Patients with an eGFR ≤60 ml/min/1.73 m(2) were excluded. Serum CysC levels were measured immediately before SES implantation. Major adverse cardiac and cerebrovascular events (MACCE) were defined as cardiovascular death, acute coronary syndrome, stroke, and hospitalization because of congestive heart failure. After a median follow-up of 63 months, 29 patients had MACCE. The subjects were divided into 2 groups based on median serum CysC levels and eGFR (0.637 mg/L and 72.43 ml/min/1.73 m(2), respectively). Kaplan-Meier curves showed that the high CysC group had a significantly higher occurrence of MACCE than the low CysC group (p = 0.006), although a low level of eGFR was not significantly associated with an increased risk for occurrence of MACCE. Multivariate analysis revealed that serum CysC levels were an independent predictor of MACCE [hazards ratio: 1.30 per 0.1 mg/L (1.01-1.63), p = 0.038]. These data suggested that serum CysC level is an independent predictor of MACCE, even in patients with preserved eGFR after elective SES implantation.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Cardiovascular Agents; Chi-Square Distribution; Coronary Artery Disease; Cystatin C; Drug-Eluting Stents; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kaplan-Meier Estimate; Kidney; Male; Middle Aged; Multivariate Analysis; Percutaneous Coronary Intervention; Proportional Hazards Models; Renal Insufficiency, Chronic; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Stroke; Time Factors; Treatment Outcome; Up-Regulation

Developmental changes (ontogeny) of drug disposition of Mycophenolate mofetil (MMF) have been understudied.. The charts of 37 pediatric renal transplant recipients (median age 7.3 years, median follow-up 7.8 (IQR 6.6, 14.3 years) who had regular mycophenolic acid (MPA) trough level monitoring in combination with tacrolimus (n = 31) or sirolimus (n = 6) therapy were analyzed retrospectively for their dose-normalized MPA exposure, steroid dose, albumin, hematocrit, and cystatin C estimated glomerular filtration rate (eGFR). Using appropriate univariate and multivariate methods, we determined whether MPA exposure was age dependent when controlling for the confounders.. Dose-normalized MPA trough levels could be calculated in 2,128 (median 45/patient) instances. Spearman rank correlation analysis revealed that age correlated with dose-normalized MPA trough level for both body weight and body surface area, as well as serum albumin, hematocrit, steroid dose, and eGFR. In the multivariate analysis, serum albumin and steroid dose were not significant, and hematocrit only being significant when the youngest group of patients < 6 years of age was compared. eGFR was the most important confounder, but age dependency remained significant when controlling for all confounders.. Small children are at a significantly greater risk for low MPA trough levels than adolescents, highlighting the need for pharmacokinetic monitoring of MPA.

Topics: Adolescent; Adult; Age Factors; Child; Child Development; Child, Preschool; Drug Monitoring; Drug Therapy, Combination; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Male; Mycophenolic Acid; Renal Insufficiency, Chronic; Retrospective Studies; Sirolimus; Tacrolimus; Young Adult

Hyperphosphatemia-induced endothelial dysfunction has been shown to play a pathogenic role in the development of atherosclerosis in chronic kidney disease (CKD) through unclear mechanisms. Emerging evidence indicates that autophagy is involved in the maintenance of normal cardiovascular function. However, it is unclear whether autophagy participates in the molecular mechanism underlying high phosphate (Pi)-induced endothelial dysfunction.. The autophagy activity was determined by the immunofluorescence staining of the expression of endothelial microtubule-associated protein 1 light chain 3 (LC3) in the 5/6 nephrectomy rat model of CKD and sham-operated control rats. The LC3-II/LC3-I ratio and the activation of the Akt/mammalian target of rapamycin (mTOR) signaling pathway were determined in cultured human microvascular endothelial cell (HMEC-1) endothelial cells that were exposed to a high concentration of Pi with or without the Pi influx blocker phosphonoformic acid, the autophagy inhibitor 3-methyladenine, and the autophagy inducer rapamycin. The impacts of autophagy on Pi-induced apoptotic damage were assessed by flow cytometry.. The in vivo rat model of CKD revealed that hyperphosphatemia is associated with increased endothelial LC3 staining. The exposure of HMEC-1 cells to high Pi induced both dose-dependent and time-dependent increases in the LC3-II/LC3-I expression ratio accompanied by the inhibition of the Akt/mTOR signaling pathway. In HMEC-1 cells, high Pi-induced autophagy and the inhibition of Akt/mTOR signaling were reversed by phosphonoformic acid through the blockage of Pi influx. Apoptosis, characterized by the levels of cleaved caspase 3 and poly(ADP-ribose) polymerase, along with autophagy was induced by high Pi, and the inhibition of autophagy by 3-methyladenine significantly aggravated high Pi-induced apoptosis. The flow cytometry results confirmed that the blockage of autophagy promoted the apoptosis of endothelial cells.. Hyperphosphatemia induces endothelial autophagy, possibly through the inhibition of the Akt/mTOR signaling pathway, which may play a protective role against high Pi-induced apoptosis.

Topics: Adenine; Animals; Autophagy; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Activation; Foscarnet; Humans; Hyperphosphatemia; Male; Microtubule-Associated Proteins; Phosphates; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats, Wistar; Renal Insufficiency, Chronic; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Transfection

Septic kidney injury is one of the most common complications in critically ill patients with a high risk of developing chronic kidney disease (CKD). Emerging data indicate that mammalian target of rapamyci (mTOR) signaling plays a major role in septic inflammation by regulating the immune response of macrophage. This study was designed to evaluate the role of mTOR signaling in kidney macrophages during endotoxemia-induced chronic kidney injury and subsequent fibrogenesis.. Male C57BL/6 mice were used for all animal studies (n=9 for each group). Lipopolysaccharide (LPS) was injected intraperitoneally (1 mg/kg) every 2 days to induce persistent endotoxemia. Rapamycin (1 mg/kg·day) was administered to a subgroup of mice 1 day prior to LPS treatment and continued to termination of the experiment. In ex-vivo experiment, RAW264.7 cells were cultured and treated with LPS (2 µg/ml) for 48 h while a subgroup of cells were incubated in the presence of rapamycin (50 nmol) for 2 h.. Continuous administration of LPS resulted in progressive macrophage infiltration, tubular injury and collagen deposition in mice kidneys. Rapamycin markedly ameliorated LPS-induced kidney pathological changes. Expression of pS6K was rarely observed in normal kidney macrophages, but significantly increased with time by LPS treatment. In ex-vivo study, LPS induced prominent production of IL-1β and MCP-1 in cultured RAW264.7 cells, which was significantly suppressed by rapamycin.. Taken together, our findings show that endotoxemia results in activation of mTOR signaling in macrophages, leading to progressive kidney inflammatory injuries and subsequent fibrosis. Our study may reveal a mechanism involved in the development of sepsis-associated CKD and kidney fibrosis.

Topics: Animals; Blotting, Western; Cell Line; Chemokine CCL2; Collagen; Endotoxemia; Fibrosis; Fluorescent Antibody Technique; Immunohistochemistry; Immunosuppressive Agents; Injections, Intraperitoneal; Interleukin-1beta; Kidney; Kidney Tubules; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Renal Insufficiency, Chronic; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Remarkable basic and translational advances have elucidated the role of the mammalian target of rapamycin (mTOR) signaling network in the pathogenesis of renal disease. Many of these advances originated from studies of the genetic disease tuberous sclerosis complex (TSC), leading to one of the clearest therapeutic opportunities to target mTOR with rapamycin and its analogs ("rapalogs"), which effectively inhibit mTOR complex 1 (mTORC1) by an allosteric mechanism. Clinical trials based on these discoveries have provided strongly positive therapeutic results in TSC (Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. N Engl J Med 358: 140-151, 2008; Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN. N Engl J Med 363: 1801-1811, 2010; McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC. N Engl J Med 364: 1595-1606, 2011). In June 2013, the National Institute of Diabetes and Digestive and Kidney Diseases convened a small panel of physicians and scientists working in the field to identify key unknowns and define possible "next steps" in advancing understanding of TSC- and mTOR-dependent renal phenotypes. TSC-associated renal disease, which affects >85% of TSC patients, and was a major topic of discussion, focused on angiomyolipomas and epithelial cysts. The third major topic was the role of mTOR and mTOR inhibition in the pathogenesis and therapy of chronic renal disease. Renal cell carcinoma, while recognized as a manifestation of TSC that occurs in a small fraction of patients, was not the primary focus of this workshop and thus was omitted from panel discussions and from this report.

Topics: Angiomyolipoma; Biomedical Research; Humans; Kidney Diseases, Cystic; Renal Insufficiency, Chronic; Sirolimus; TOR Serine-Threonine Kinases; Translational Research, Biomedical; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Chronic kidney disease (CKD) is associated with poor outcomes after percutaneous coronary intervention (PCI). The aim of the study was to compare zotarolimus- and everolimus-eluting stents used during primary PCI in patients with acute myocardial infarction (AMI) and CKD.. We selected 854 consecutive ST-elevation MI patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m(2)) undergoing primary PCI who were followed up for 12 months. They were divided into two groups based on type of stents implanted: (1) zotarolimus-eluting stent (ZES) and (2) everolimus-eluting stent (EES). The study end point was the 12-month major adverse cardiac events (MACE) which included all-cause death, non-fatal MI, target lesion revascularization (TLR), and target vessel revascularization (TVR).. The average number of stents used per vessel was 1.4 ± 0.7. A total of 433 patients received ZES and 421 patients received EES. There was no significant difference in the incidence of 12-month MI, TLR, or TVR. All-cause death was found to be borderline significant between two groups (2.8% in ZES vs 0.9% in EES, p=0.05). The incidence of 12-month MACE in ZES and EES was 5.7% and 2.6% respectively, p=0.022. Stent thrombosis did not differ between groups (p=0.677). Kaplan-Meier analysis did not show significant difference for 12-month MACE-free survival between groups (log-rank p=0.158). It remained the same even after propensity adjustment for multiple confounders in Cox model (p=0.326).. Implantation of ZES or EES provided comparable clinical outcomes with similar risk of 12-month MACE and death in STEMI patients with CKD undergoing primary PCI.

Topics: Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Registries; Renal Insufficiency, Chronic; Retrospective Studies; Sirolimus

The efficacy in renal protection of Everolimus (Evr)-based regimens compared to standard dosages of Tacrolimus (Tac) has recently become known. The purpose of this study was to retrospectively compare the renal function in the first year after LT, with a case-control approach, in patients treated with Tac monotherapy at sub-standard dose vs. an immunosuppressive regimen with Tac and Evr.. Following a 2: 1 case-control approach, 37 patients with an immunosuppression regimen based on Tac only (Tac Group) were retrospectively compared with 74 patients utilizing a combination of Evr and Tac (Evr-Tac Group), based on the following preoperative parameters: sex, age, MELD score (±3), and pre-LT chronic kidney disease (CKD) stage.. After a mean follow-up of 82.8 ± 24 vs. 42.4 ± 16.6 months (p < 0.001), overall survival in 1, 3, and 5 years was 97.3, 91.9, and 86.5% vs. 95.9, 81.1, and 69.5% (p = 0.10) for the Tac Group vs. the Evr-Tac Group, respectively. The trend of the estimated glomerular filtration rate (e-GFR) during the first year post-LT was similar between the 2 study groups (80.1 ± 21 vs. 73.3 ± 16 mL/min/1.73 m^2, for the Tac Group vs. the Evr-Tac Group, respectively, p = 0.23). The incidence of acute rejection histologically proven was 32.4% vs. 20% (p = 0.71) for the Tac Group vs. the Tac-Evr Group, respectively. The rate of CKD was also similar in the 2 study groups.. The early combination of Evr and Tac is an efficient immunosuppressant regimen and provided similar renal function at 1 year post-LT, compared to a minimization of the monotherapy dose of Tac. The combination therapy of Evr-Tac is subject to a higher rate of drugs discontinuation due to adverse effects of 1 of the 2 drugs.

Topics: Adult; Aged; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney; Kidney Function Tests; Liver Transplantation; Male; Matched-Pair Analysis; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

Tremendous breakthrough in solid organ transplantation was made with the introduction of calcineurin inhibitors (CNI). At the same time, they are potentially nephrotoxic drugs with influence on onset and progression of renal graft failure. The aim of this study was to evaluate the outcome of a conversion from CNI-based immunosuppressive protocol to sirolimus (SRL) in recipients with graft in chronic kidney disease (CKD) grade III and proteinuria below 500 mg/day.. In the period 2003-2011 24 patients (6 famale and 18 male), mean age 41 +/- 12.2 years, on triple immunosuppressive therapy: steroids, antiproliferative drug [mycophenolate mofetil (MMF) or azathiopirine (AZA)] and CNI were switched from CNI to SRL and followe-up for 76 +/- 13 months. Nine patients (the group I) had early postransplant conversion after 4 +/- 3 months and 15 patients (the group II) late conversion after 46 +/- 29 months. During the regular outpatient controls we followed graft function through the serum creatinine and glomerular filtration rate (GFR), proteinuria, lipidemia and side effects.. Thirty days after conversion, in all the patients GFR, proteinuria and lipidemia were insignificantly increased. In the first two post-conversion months all the patients had at least one urinary or respiratory infection, and 10 patients reactivated cytomegalovirus (CMV) infection or disease, and they were successfully treated with standard therapy. After 21 +/- 11 months 15 patients from both groups discontinued SRL therapy due to reconversion to CNI (10 patients) and double immunosuppressive therapy (3 patients), return to hemodialysis (1 patient) and death (1 patient). Nine patients were still on SRL therapy. By the end of the follow-up they significantly improved GFR (from 53.2 +/- 12.7 to 69 +/- 15 mL/min), while the increase in proteinuria (from 265 +/- 239 to 530.6 +/- 416.7 mg/day) and lipidemia (cholesterol from 4.71 +/- 0.98 to 5.61 +/- 1.6 mmol/L and triglycerides from 2.04 +/- 1.18 to 2.1 +/- 0.72 mmol/L) were not significant. They were stable during the whole follow-up period. Ten patients were reconverted from SRL to CNI due to the abrupt increase of proteinuria (from 298 +/- 232 to 1639 +/- 1641/mg day in 7 patients), rapid growth of multiple ovarian cysts (2 patients) and operative treatment of persisted hematoma (1 patient). Thirty days after reconversion they were stable with an insignificant decrease in GFR (from 56.10 +/- 28.09 to 47 +/- 21 mL/min) and significantly improved proteinuria (from 1639 +/- 1641 to 529 +/- 688 mg/day). By the end of the follow-up these patients showed nonsignificant increase in the serum creatinine (from 172 +/- 88 to 202 +/- 91 mmol/L), decrease in GFR (from 56.10 +/- 28.09 to 47 +/- 21 mL/day) and increased proteinuria (from 528.9 +/- 688 to 850 +/- 1083 mg/min).. In this small descriptive study, conversion from CNI to SRL was followed by an increased incidence of infections and consecutive 25-50% dose reduction in the second antiproliferative agent (AZA, MMF), with a possible influence on the development of glomerulopathy in some patients, which was the major reason for discontinuation of SRL therapy in the 7 (29%) patients. Nine (37.5%) of the patients experienced the greatest benefit of CIN to SRL conversion without serious post-conversion complications.

Topics: Adult; Azathioprine; Biomarkers; Calcineurin Inhibitors; Creatinine; Cytomegalovirus Infections; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Renal Insufficiency, Chronic; Sirolimus; Time Factors; Treatment Outcome

Cyclosporin A (CsA) is associated with significant chronic nephrotoxicity, which typically manifests as renal fibrosis. In contrast, rapamycin (RAPA) has been shown to inhibit fibrosis. This study sought to determine the effect of CsA and RAPA on the expression of connective tissue growth factor (CTGF) and E-cadherin in a rat kidney model of chronic allograft nephropathy.. Left renal grafts from male Fisher (F344, RT1(1v1)) rats were orthotopically transplanted into Lewis (LEW, RT1(1)) rats. After transplantation, all recipients were given CsA 10 mg/kg(-1) d(-1) for 10 d and divided into three groups (n = 9/group): (1) vehicle, administered orally; (2) CsA, 6 mg/kg(-1) d(-1); (3) RAPA, 0.8 mg/kg(-1) d(-1). At 4, 8, and 12 wk posttransplantation, the kidney allografts were harvested and serum creatinine levels were measured. Connective tissue growth factor expression was determined using real-time polymerase chain reaction and Western blot. Kidney allografts sections also underwent hematoxylin-eosin and Masson trichrome staining, in addition to CTGF and E-cadherin immunostaining.. The serum creatinine levels were increased at 8 and 12 wk posttransplantation and were significantly lower in the RAPA group (P < 0.05). The Banff score also showed a significant decrease at 4, 8, and 12 wk (P < 0.05). CTGF messenger ribonucleic acid and protein levels were significantly lower in the RAPA group (P < 0.05), whereas E-cadherin expression was higher in the RAPA group at 4, 8, and 12 wk (P < 0.05). Masson's trichrome staining showed a significant decrease in collagen deposition at 8 and 12 wk after RAPA treatment.. RAPA can ameliorate fibrogenesis in kidney allografts by inhibiting epithelial-mesenchymal transition process, whereas CsA did not have this effect.

Topics: Animals; Cadherins; Connective Tissue Growth Factor; Creatinine; Cyclosporine; Epithelial-Mesenchymal Transition; Fibrosis; Graft Rejection; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Models, Animal; Rats; Rats, Inbred F344; Rats, Inbred Lew; Renal Insufficiency, Chronic; Sirolimus; Transplantation, Homologous

Recurrent in-stent restenosis remains an important clinical issue after a percutaneous coronary intervention even after treatment with a sirolimus-eluting stent (SES) especially in patients with chronic kidney disease. We evaluated the impact of renal insufficiency on the clinical and angiographic outcomes after treatment for SES restenosis.. A total of 74 patients with 76 lesions underwent subsequent revascularization with a drug-eluting stent for SES restenosis. Patients were classified into three groups: group 1 included 29 patients with an estimated glomerular filtration rate more than 60 ml/min/1.73 m(2); group 2 included 27 patients with lower estimated glomerular filtration rate (<60 ml/min/1.73 m(2)) without hemodialysis (HD) dependence; and group 3 included 18 patients on HD. Clinical and angiographic follow-up was carried out at 8 months. Late lumen loss at the 8-month follow-up angiography showed progressive increases from group 1 to 2 to 3 (group 1: 0.36 ± 0.39 mm, group 2: 1.11 ± 0.61 mm, group 3: 1.30 ± 0.85 mm, P<0.001). Similarly, compared with group 1, groups 2 and 3 had significantly higher rates of major adverse cardiac events (6.9, 37.0, and 38.9%, respectively, P=0.001), primarily because of a high frequency of target lesion revascularization (8.0, 34.8, and 33.3%, respectively, P=0.019).. Non-HD-dependent chronic kidney disease patients had increased neointimal growth in the follow-up phase after percutaneous coronary intervention, with a drug-eluting stent for SES restenosis almost equivalent to patients on HD, resulting in higher rates of recurrent restenosis than patients with preserved renal function.

Topics: Aged; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Incidence; Japan; Male; Middle Aged; Percutaneous Coronary Intervention; Prognosis; Prosthesis Failure; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus

Chronic renal insufficiency (CRI) is associated with an increased incidence of restenosis and stent thrombosis. Drug-eluting stents (DES), when compared to bare metal stents (BMS), reduce the incidence of restenosis in these patients. This study aimed to examine whether there are differences in clinical outcome after implantation of sirolimus-eluting stents (SES) versus paclitaxel-eluting stents (PES) in patients with CRI who are subjected to coronary intervention.. A cohort of 570 patients with CRI who underwent intervention with DES (346 with SES and 224 with PES) were followed clinically up to 1 year and the clinical events were recorded and compared between groups.. Baseline and procedural characteristics were similar, with a slightly higher number of diseased vessels in the SES group as compared to the PES group (2.3 +/- 0.9 vs 2.1 +/- 0.9, P = 0.06). The overall rates of major adverse cardiac events (MACE) and stent thrombosis were similar. The PES group had lower revascularization rates when compared to the SES group. After covariate adjustment, however, there was no difference seen in target vessel revascularization between stent types (hazard ratio [HR]: 2.3 [0.8-6.2], P = 0.110). The strongest predictor of death and MACE at 1 year was the number of diseased vessels.. Patients with CRI who undergo PCI with either SES or PES have similar repeat revascularization rates and acceptable stent thrombosis rates, although they continue to have high MACE and death rates.

Topics: Aged; Angioplasty, Balloon, Coronary; Antineoplastic Agents, Phytogenic; Coronary Restenosis; Coronary Thrombosis; Drug-Eluting Stents; Female; Glomerular Filtration Rate; Hospital Mortality; Humans; Immunosuppressive Agents; Incidence; Male; Multivariate Analysis; Myocardial Infarction; Paclitaxel; Proportional Hazards Models; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Sirolimus; Treatment Outcome; United States

Topics: Antimetabolites; Calcineurin Inhibitors; Creatinine; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Renal Insufficiency, Chronic; Renal Replacement Therapy; Sirolimus; Tacrolimus; Treatment Outcome

The purpose of this study is to review the clinical experience with sirolimus immunosuppression in liver transplant patients with calcineurin inhibitor-induced chronic renal insufficiency. The study design is a case-control retrospective series. Fifty-seven liver transplant patients with renal insufficiency that were started on sirolimus at greater than 90 days postoperatively and treated for more than 90 days were identified. A control group of 57 patients maintained on low-dose calcineurin inhibitors, matched for gender, year of transplant, and baseline creatinine clearance, was also identified. There were no significant differences in the absolute creatinine clearance values between the sirolimus and control groups from 6 months before sirolimus conversion to 12 months after sirolimus conversion. Patients exposed to calcineurin inhibitors for more than 5 years or those with an initial creatinine clearance of less than 30 mL/minute who were converted to sirolimus did worse than control patients maintained on low-dose calcineurin inhibitors. Progression to renal replacement therapy, episodes of acute and chronic rejection, and death were similar between the sirolimus and control groups. The overall prevalence of side effects was significantly higher in the sirolimus group compared with the control group, although these were generally tolerable in most patients. In conclusion, this study suggests that conversion to sirolimus in liver transplant patients with chronic renal insufficiency is associated with stabilization of renal function but confers no additional benefit to low-dose calcineurin inhibitor regimens and may in fact be disadvantageous in patients with a creatinine clearance of less than 30 mL/minute.

Topics: Adult; Aged; Antimetabolites; Calcineurin Inhibitors; Case-Control Studies; Creatinine; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Renal Replacement Therapy; Retrospective Studies; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor-based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (P < 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.

Topics: Animals; Immunosuppressive Agents; Kidney; Male; Protein Kinases; Proteinuria; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Patients with chronic renal insufficiency (CRI) have higher rates of target vessel revascularization and mortality. The efficacy of sirolimus-eluting stents (SESs) to improve the clinical outcomes of these patients is unknown. We investigated the effect of SESs versus bare metal stents (BMSs) on outcomes of patients with CRI. Among the first 1,522 patients treated with SESs, 76 were identified with CRI and 1,446 without CRI. In-hospital and 1- and 6-month clinical outcomes were compared with 153 patients with CRI who were treated with BMSs. Patients with CRI were older, hypertensive, and diabetic and had more previous myocardial infarctions, revascularizations, and decreased left ventricular function (p <0.001). These patients had more saphenous vein graft lesions, were treated with more debulking devices (p <0.003), and had higher rates of in-hospital complications and mortality (p <0.001) compared with those without CRI. Among patients with CRI, treatment with SESs did not affect clinical outcomes at 1 month and was associated with lower incidences of target vessel revascularization (7.1% vs 22.1%, p = 0.02) at 6 months but did not affect other events, including mortality (16.7% vs 14.7% p = 0.89), compared with BMSs. However, treatment with SESs in patients without CRI was associated with significantly lower rates of major adverse cardiac events at 6 months (p <0.001). In conclusion, percutaneous coronary intervention with SESs in patients with CRI is associated with low rates of repeat revascularization compared with BMSs but has no effect on mortality at 6 months.

Topics: Aged; Angioplasty, Balloon, Coronary; Anti-Bacterial Agents; Case-Control Studies; Coronary Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Prosthesis Design; Renal Insufficiency, Chronic; Retrospective Studies; Sirolimus; Stents; Survival Rate; Treatment Outcome