sirolimus and Hypertension

When subjected to pressure overload, the ventricular myocardium shifts from fatty acids to glucose as its main source for energy provision and frequently increases its mass. Here, we review the evidence in support of the concept that metabolic remodeling, measured as an increased myocardial glucose uptake using dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG), precedes the onset of left ventricular hypertrophy (LVH) and heart failure. Consistent with this, early intervention with propranolol, which attenuates glucose uptake, prevents the maladaptive metabolic response and preserves cardiac function in vivo. We also review ex vivo studies suggesting a link between dysregulated myocardial glucose metabolism, intracellular accumulation of glucose 6-phosphate (G6P) and contractile dysfunction of the heart. G6P levels correlate with activation of mTOR (mechanistic target of rapamycin) and endoplasmic reticulum stress. This sequence of events could be prevented by pretreatment with rapamycin (mTOR inhibition) or metformin (enzyme 5'-AMP-activated protein kinase activation). In conclusion, we propose that metabolic imaging with FDG PET may provide a novel approach to guide the treatment of patients with hypertension-induced LVH.

Topics: 3-O-Methylglucose; Animals; Disease Models, Animal; Endoplasmic Reticulum Stress; Fatty Acids; Glucose-6-Phosphate; Heart Failure; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Hypoglycemic Agents; Metformin; Mice; Myocardium; Positron-Emission Tomography; Rats; Sirolimus; TOR Serine-Threonine Kinases; Ventricular Function, Left

In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high-risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy.

Topics: Albuminuria; Child; Cyclosporine; Diabetes Mellitus; Diabetic Retinopathy; Glucocorticoids; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Insulin; Liver Failure; Liver Transplantation; Metformin; Pediatrics; Risk Factors; Sirolimus; Tacrolimus

Since 2006, new treatments as targeted therapies (anti angiogenic and mTOR inhibitors) are prescribed in renal cell cancer. Toxicity of these treatments is well known by clinicians. Occurrence of these side effects has been associated with anti tumoral efficacy. High blood pressure, hypothyroïdie and hand foot syndrome were reported to be predictive of anti tumoral response. Fatigue and hyponatremia are still largely discussed. Moreover, non infectious pneumonia, which frequently occurs with mTOR inhibitors, is associated with clinical benefit. The main objective of treatment of advanced kidney cancer, specially renal cell cancer, is obtaining clinical benefit (stabilization and response) with a chronic evolution of the disease. This prolong exposure to drugs, according to their toxicity profile, often contributes to dose reduction, moreover interruption of treatment, potentially associated with a loss of control of disease. Thus, the adverse effects, described hereby, may be considered as « positive events », predicting efficacy, and thus looked for… Moreover, the sequential approach, with new drugs, emphasizes the need of defining the optimal sequence. Thus, because of the lack of molecular biomarkers to date, this predictives secondary effects may help for selecting the therapeutic strategy.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Asthenia; Carcinoma, Renal Cell; Everolimus; Hand-Foot Syndrome; Humans; Hypertension; Hypothyroidism; Kidney Neoplasms; Molecular Targeted Therapy; Prognosis; Sirolimus; Treatment Outcome

The review will examine clinically relevant advances in the area of polycystic kidney disease (PKD), mainly focusing on autosomal dominant polycystic kidney disease (ADPKD). Discussion will focus on predicting the course of ADPKD, clinical trials and new research endeavors.. During the past several years PKD research has been one of the most prolific areas in investigative nephrology. Research endeavors have focused on decreasing cyst proliferation and cyst fluid formation based on an understanding of the pathophysiology of these processes. If cysts can be prevented from growing, kidney function can be better preserved.. Progression of this most common inherited kidney disorder can be altered by understanding that cysts are the disease in ADPKD. Assessing total kidney volume and noting its relationship to glomerular filtration rate is key in predicting the course of the disease and will aid in the evaluation of the new research initiatives that are designed to stop cyst proliferation and fluid secretion into the kidney cysts. The role of biomarkers is an advancement in predicting PKD progression and can potentially be used in evaluation of treatments for this disease. Complications of PKD alter the course and prognosis; hence management approaches will be addressed.

Topics: Antineoplastic Agents; Benzazepines; Curcumin; Everolimus; Gastrointestinal Agents; Glomerular Filtration Rate; Humans; Hypertension; Hypoglycemic Agents; Immunosuppressive Agents; Indazoles; Kidney; Metformin; Octreotide; Organ Size; Polycystic Kidney, Autosomal Dominant; Sirolimus; Sodium; Tolvaptan

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Administration Schedule; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Neoplasms; Postoperative Complications; Sirolimus

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function, however, it also carries risk of acute rejection. We conducted a systematic review of randomized trials that involved CNI withdrawal from a sirolimus-based immunosuppressive regimen. The search strategy yielded six trials (n = 1047 patients) reported in eight publications. CNI withdrawal from sirolimus-based therapy, was associated with an increased risk of acute rejection (risk difference, 6%; 95% CI 2-10%, p = 0.002) but a higher creatinine clearance (mean difference, 7.49 mL/min; 95% CI 5.08-9.89 mL/min, p < 0.00001) at 1 year compared to continued CNI and sirolimus therapy. Graft loss (relative risk, 0.87; 95% CI 0.46-1.64, p = 0.66) and death (relative risk, 0.88; CI 0.40-1.96, p = 0.76) were similar in both groups at 1 year. Hypertension was significantly reduced in the CNI withdrawal group (relative risk, 0.56; 95% CI 0.40-0.78, p = 0.0006). CNI withdrawal from sirolimus-based therapy is associated with an increased risk of acute rejection in the short term with a significant improvement in renal function and a reduction in hypertension. Longer follow-up is needed to determine if these changes will result in a significant improvement in patient and graft survival.

Topics: Acute Disease; Calcineurin Inhibitors; Drug Administration Schedule; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Transplantation; Randomized Controlled Trials as Topic; Risk; Sirolimus

Topics: Adrenal Cortex Hormones; Azathioprine; Blood Pressure; Cyclosporine; Diabetes Mellitus; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lipid Metabolism; Sirolimus; Substance Withdrawal Syndrome; Transplantation Immunology

Cyclosporine microemulsion (CyA) and tacrolimus (Tac) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. In the majority of patients, these calcineurin inhibitors have been used in combination with other immunosuppressive drugs, such as azathioprine or mycophenolate mofetil (MMF). In this review we will address the question of what calcineurin inhibitor we should use in an individual pediatric renal transplant patient. Well-designed randomized studies in children showed no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However Tac is significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population when used in conjunction with azathioprine and corticosteroids. This difference disappears when calcineurin inhibitors are used in combination with MMF as both Tac and CyA produce similar rejection rates and graft survival. However, Tac is associated with improved graft function at 1 and 2 yr post-transplant. Adverse events of hypomagnesaemia and diarrhea seem to be higher in Tac group whereas hypertrichosis, flu syndrome and gum hyperplasia occurs more frequently in the CyA group. The incidence of post-transplant diabetes mellitus was almost identical between Tac and CyA treated patients. The recommendation drawn from the available data is that both CyA and Tac can be used safely and effectively in children. However Tac may be preferable to CyA because of steroid sparing effect and less hirsutism. We recommend that cyclosporine should be chosen when patients experience Tac-related adverse events. Nevertheless, the best calcineurin inhibitor should be decided on individual patients according to variable risk factors, such as risk of rejection in sensitized patient or delayed graft function. The possibility of adverse events should also be considered.

Topics: Azathioprine; Calcineurin Inhibitors; Child; Clinical Trials as Topic; Cyclosporine; Growth and Development; Hematologic Neoplasms; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Care; Sirolimus; Tacrolimus

Cardiovascular disease is one of the major causes of morbidity and mortality following solid organ transplantation. Many of the current immunosuppressive drugs are associated with an increase of one or more risk factors for the development of atherosclerosis. This review compares the mechanism by which individual immunosuppressive agents may impact on these risk factors and the differential contribution of cyclosporine, tacrolimus, mycophenolate, azathioprine, and Rapamycin to these individual risk factors. Attention to the potential cardiovascular toxicities of individual immunosuppressive agents may help design strategies for maintenance of immunosuppression tailored to individual patients.

Topics: Adrenal Cortex Hormones; Animals; Cardiovascular System; Coronary Artery Disease; Cyclosporine; Diabetes Mellitus; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Sirolimus; Tacrolimus

Arterial hypertension is highly prevalent after renal transplantation and may contribute to the risk of cardiovascular disease. Also, arterial hypertension has been reported to be an independent risk factor for graft failure. Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may be important contributing factors to post-transplant hypertension. Recent data from multicenter trials and from conversion studies (cyclosporine to tacrolimus) suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive drugs, including mycophenolate mofetil and rapamycin, are not nephrotoxic and they do not have any hypertensive effect. New immunosuppressive combinations including mycophenolate mofetil in a triple therapy regimen (associated with corticosteroids and cyclosporine) can reduce blood pressure so that corticosteroids can be stopped or cyclosporine reduced or even eliminated. Non-nephrotoxic regimens using rapamycin (sirolimus) as basic immunosuppression, associated with azathioprine or mycophenolate mofetil, could reduce the incidence of post-transplant arterial hypertension. Also, in renal transplant patients initially immunosuppressed with rapamycin, cyclosporine and corticosteroids, after the elimination of CSA, a lower blood pressure is achieved. In summary, new protocols with mycophenolate mofetil and/or rapamycin may permit several combinations that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation.

Topics: Adrenal Cortex Hormones; Blood Pressure; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Sirolimus; Tacrolimus; Time Factors

Cyclosporin and tacrolimus have improved survival figures in organ transplantation. However, both drugs are potentially nephrotoxic. The immunosuppressive and nephrotoxic effects of both drugs appear to depend on the inhibition of calcineurin. Cyclosporin and tacrolimus cause acute (functional changes) and chronic nephrotoxicity (structural lesions in the kidney). These last important lesions include arteriolar hyalinosis, stripped interstitial fibrosis and tubular atrophy. It is possible that repeated episodes of renal ischaemia contribute to the development of chronic nephrotoxicity and then chronic allograft nephropathy. Cyclosporin and tacrolimus also induce arterial hypertension. Therefore, the beneficial effects of immunosuppression have been limited due to nephrotoxicity and arterial hypertension. Rapamycin, a novel immunosuppressive agent, that does not inhibit calcineurin, provides immunosuppression without nephrotoxicity. In fact, in the trials performed in Europe, sirolimus-treated immunosuppression patients exhibited a much better renal function than cyclosporin-treated patients. However, sirolimus can potentiate the nephrotoxic effect of cyclosporin. Therefore, when cyclosporin and sirolimus are used in combination, a reduction of the cyclosporin dose is desirable.

Topics: Antihypertensive Agents; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Sirolimus; Tacrolimus

The immunosuppressive benefits of cyclosporine and tacrolimus in short-term and medium-term renal allograft survival are well documented. It is becoming increasingly clear that the basis of this immunosuppression, the inhibition of calcineurin, may be linked with nephrotoxicity, hypertension, hyperlipidemia, and new-onset diabetes mellitus, side effects that may lead to CRAD, death due to CVD, and late renal allograft loss. This clinical picture presents a clear need for new strategies that produce adequate immunosuppression to prevent acute rejection while simultaneously reducing the side effects associated with CNI-related therapies. Sirolimus combined with cyclosporine and tacrolimus has demonstrated an ability to reduce incidences of early acute rejection and, used as base therapy, has provided protection against acute rejection equivalent to that of cyclosporine, without the consequent nephrotoxicity associated with CNIs. In preliminary results from an ongoing clinical trial, sirolimus has been used to eliminate cyclosporine during maintenance immunosuppression, with subsequent improvements in measures of blood pressure and renal function. In addition, the antiproliferative properties of sirolimus and its ability to prevent graft vascular disease in animal studies make sirolimus a promising agent to decrease incidences of CRAD and improve long-term renal allograft survival. These findings point to a clear need to further explore both the efficacy of sirolimus immunotherapy and its long-term effects.

Topics: Calcineurin Inhibitors; Chronic Disease; Graft Rejection; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Sirolimus

Nephrotoxicity from immunosuppressive drugs can complicate otherwise successful therapy. This paper reviews the clinical and pathophysiologic aspects of nephrotoxicity. The chronic progressive nephropathy is emphasized based on a recently developed animal model. Experimental and clinical data regarding FK506, new cyclosporine analogs, and Rapamycin are also discussed.

Topics: Animals; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Polyenes; Rats; Sirolimus; Tacrolimus

Acute and chronic nephrotoxicity frequently limits the therapeutic benefits of immunosuppressive therapy for transplant and autoimmune indications. The clinical aspects, pathophysiology, and relevant pharmacology of current and future immunosuppressive drugs are reviewed in this paper. Insights gained from experimental models of chronic nephrotoxicity associated with tubulointerstitial fibrosis are presented.

Topics: Acute Kidney Injury; Animals; Cyclosporins; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Polyenes; Sirolimus; Tacrolimus

Bevacizumab and temsirolimus are active agents in gynecologic tumors. Temsirolimus attenuates upregulation of HIF-1α levels, a resistance mechanism for antiangiogenics, and targets the PI3-kinase/AKT/mTOR axis, commonly aberrant in these tumors.. We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus.. Median age of the 41 women was 60 years (range, 33-80 years); median number of prior systemic therapies was 4 (1-11). Grade 3 or 4 treatment-related toxicities included: thrombocytopenia (10%), mucositis (2%), hypertension (2%), hypercholesterolemia (2%), fatigue (7%), elevated aspartate aminotransferase (2%), and neutropenia (2%). Twenty-nine patients (71%) experienced no treatment-related toxicity greater than grade 2. Full FDA-approved doses of both drugs (bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25mg IV weekly) were administered without dose-limiting toxicity. Eight patients (20%) achieved stable disease (SD) > 6 months and 7 patients (17%), a partial response (PR) [total = 15/41 patients (37%)]. Eight of 13 patients (62%) with high-grade serous histology (ovarian or primary peritoneal) achieved SD > 6 months/PR.. Bevacizumab and temsirolimus was well tolerated. Thirty-seven percent of heavily-pretreated patients achieved SD > 6 months/PR, suggesting that this combination warrants further study.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bevacizumab; Carcinoma; Fatigue; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Mucositis; Neutropenia; Ovarian Neoplasms; Sirolimus; Thrombocytopenia; Uterine Cervical Neoplasms

Telmisartan is a peroxisome proliferator-activated receptor-γ activator with potent anti-inflammatory and antiatherogenic effects. The authors compared the effects of telmisartan and valsartan on neointima volume, atherosclerosis progression and brachial-ankle pulse wave velocity (baPWV) after stenting in hypertensive type 2 diabetes.. This was a prospective, randomised, 8-month follow-up study that included patients with significant coronary stenosis who received telmisartan (n=36) or valsartan (n=37).. University hospital.. Neointima volume and atherosclerosis progression 10 mm proximal and distal to the stented segment were analysed using repeat intravascular ultrasonography. baPWV and inflammatory markers such as interleukin 6, tumour necrosis factor α, C-reactive protein and adiponectin were compared.. Neointima volume at 8 months was significantly lower in the telmisartan group than the valsartan group (1.9±1.0 vs 2.6±1.4 mm(3)/1 mm, p=0.007, respectively). Total plaque volumes 10 mm proximal (7.1±1.5 vs 7.8±1.6 mm(3)/1 mm, p=0.032, respectively) and distal (3.5±1.4 vs 4.1±1.3 mm(3)/1 mm, p=0.028, respectively) to the stent were significantly lower in the telmisartan group than the valsartan group at 8 months. The decrease from baseline in baPWV was significantly greater in the telmisartan group than the valsartan group (-52±104 vs 30±113 cm/s, p=0.002, respectively). The increase from baseline in adiponectin levels and the decreases from baseline in interleukin 6 and tumour necrosis factor α levels were significantly greater in the telmisartan group at 8 months. Retinol-binding protein-4, homeostasis model of assessment index, hemoglobin A(1c) and low-density lipoprotein cholesterol levels decreased significantly in both groups without differences in changes from baseline between the two groups.. Telmisartan reduced neointima volume; atherosclerosis progression 10 mm proximal and distal to the stented segment and baPWV independent of blood pressure, glucose and lipid control in hypertensive type 2 diabetes. Clinical trial no NCT00599885 (clinicaltrials.gov.).

Topics: Adiponectin; Aged; Ankle Brachial Index; Anti-Inflammatory Agents; Benzimidazoles; Benzoates; C-Reactive Protein; Coronary Stenosis; Diabetes Mellitus, Type 2; Disease Progression; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Hypertension; Interleukin-6; Male; Middle Aged; Neointima; Prospective Studies; Single-Blind Method; Sirolimus; Telmisartan; Tetrazoles; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Ultrasonography, Interventional; Valine; Valsartan

Overlapping drug-eluting stents might be associated with an adverse vessel response because of increased drug/polymer toxicity and lesion rigidity.. Lesions treated with overlapping everolimus- (EES=36) or paclitaxel-eluting stents (PES=38) were analyzed for 8-9-months by 3-dimensional intravascular ultrasound. EES were associated with significantly greater neointimal suppression in the single-strut regions than PES, with a similar trend in the overlap region. PES had significant vessel expansion in all regions, whereas there were no changes with EES. Neither stent fracture nor late incomplete stent apposition (LISA) in the overlap region was observed.. Overlapping EES appears to be effective without vessel expansion, stent fracture or LISA for up to 8-9 months.

Topics: Aged; Antineoplastic Agents, Phytogenic; Diabetes Mellitus; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Retrospective Studies; Sirolimus; Ultrasonography, Interventional

Chronic kidney disease (CKD) has emerged as a significant cause of morbidity and a risk factor for mortality after orthotopic liver transplantation (OLT). The use of calcineurin inhibitor (CNI)-based immunosuppression is an important etiologic factor for developing CKD. CNI discontinuation or minimization protocols with replacement of the CNI with non-nephrotoxic drugs, such as mycophenolate mofetil (MMF) or sirolimus (SRL), may have the potential to preserve or recover renal function.. In this prospective, randomized, single-center study with CNI discontinuation, OLT recipients with CKD (measured glomerular filtration rate [GFRm] 15-45 mL/min/1.73 m(2)) were randomized to either SRL or MMF-based immunosuppression. The main objective was to study the effect of CNI discontinuation on renal function. Secondary aims were to assess the frequency of biopsy-proven acute rejection episodes (BPAR) and adverse events (AE). Renal function was followed with GFRm using 51-Chromium EDTA clearance at baseline, 3 months, and 1 year. Patients were stratified according to baseline GFRm > versus <30 mL/min/1.73 m(2). The 25 patients were enrolled for MMF (n = 13) or SRL (n = 12). The median age at inclusion was 59 years (range, 25-66) and the median number of years after OLT was 4.4 (range, 1-13). Twenty-two patients were followed up for a year; MMF (n = 12) and SRL (n = 10).. Mean GFRm for the whole cohort (n = 25) was 31+/-8 mL/min/1.73 m(2) at baseline. After 3 months the GFRm (n = 23) increased to 40+/-10 mL/min/1.73 m(2) (P = .0001) and at 1 year 42 +/- 11 mL/min/1.73 m(2) (n = 22). There was not significant difference between the MMF and the SRL study arms. The cohort (n = 8) with baseline GFRm <30 mL showed a 63% (P = .003) increased filtration after 1 year. There was no significant difference in the frequency or severity of AE between the study arms with the exception of oral ulcerations and persistent hypertriglyceridemia in the SRL group. Two deaths occurred, 1 in each study arm, both probably unrelated to the change in immunosuppression. There were no BPAR episodes.. CNI discontinuation and replacement with either MMF or SRL resulted in a significant improvement in renal function even in those patients with severe CKD. The protocol was effective with no acute rejection episodes. The SRL arm showed a higher frequency of oral apthous ulcerations and hypertriglyceridemia. Future studies addressing long-term renal function after CNI discontinuation are needed.

Topics: Adult; Antihypertensive Agents; Calcineurin Inhibitors; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Liver Transplantation; Mycophenolic Acid; Prospective Studies; Sirolimus

To evaluate the patency of sirolimus-eluting stents (SES) compared to bare-metal stents (BMS) in the treatment of atherosclerotic renal artery stenosis (RAS).. Between November 2001 to June 2003, 105 consecutive symptomatic patients (53 men; mean age 65.7 years) with RAS were treated with either a bare-metal (n=52) or a drug-eluting (n=53) low-profile Palmaz-Genesis peripheral stent at 11 centers in a prospective nonrandomized trial. The primary endpoint was the angiographic result at 6 months measured with quantitative vessel analysis by an independent core laboratory. Secondary endpoints were technical and procedural success, clinical patency [no target lesion revascularization (TLR)], blood pressure and antihypertensive drug use, worsening of renal function, and no major adverse events at 1, 6, 12, and 24 months.. At 6 months, the overall in-stent diameter stenosis for BMS was 23.9%+/-22.9% versus 18.7%+/-15.6% for SES (p=0.39). The binary restenosis rate was 6.7% for SES versus 14.6% for the BMS (p=0.30). After 6 months and 1 year, TLR rate was 7.7% and 11.5%, respectively, in the BMS group versus 1.9% at both time points in the SES group (p=0.21). This rate remained stable up to the 2-year follow-up but did not reach significance due to the small sample. Even as early as 6 months, both types of stents significantly improved blood pressure and reduced antihypertensive medication compared to baseline (p<0.01). After 6 months, renal function worsened in 4.6% of the BMS patients and in 6.9% of the SES group. The rate of major adverse events was 23.7% for the BMS group and 26.8% for the SES at 2 years (p=0.80).. The angiographic outcome at 6 months did not show a significant difference between BMS and SES. Renal artery stenting with both stents significantly improved blood pressure. Future studies with a larger patient population and longer angiographic follow-up are warranted to determine if there is a significant benefit of drug-eluting stents in treating ostial renal artery stenosis.

Topics: Aged; Angioplasty, Balloon; Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Europe; Female; Follow-Up Studies; Humans; Hypertension; Kidney Function Tests; Male; Metals; Middle Aged; Prospective Studies; Prosthesis Design; Radiography; Recurrence; Renal Artery; Renal Artery Obstruction; Renal Insufficiency; Research Design; Sirolimus; Stents; Time Factors; Treatment Outcome; Vascular Patency

We compared the effects of telmisartan and valsartan on late lumen loss and inflammatory markers after sirolimus-eluting stent implantation in hypertensive patients. This was a prospective, randomized, single-blinded, 8-month follow-up study that included hypertensive patients with significant coronary artery stenosis treated with telmisartan (n=79) or valsartan (n=80). Risk factors such as diabetes, hyperlipidemia, smoking, and obesity were similar between groups. After 8 months of follow-up, only the telmisartan group showed significant decreases in interleukin-6 and tumor necrosis factor-alpha. The decreases from baseline level in total cholesterol and low-density lipoprotein cholesterol concentrations were significantly greater in the telmisartan group. The increase in adiponectin concentrations from baseline measurements was significantly greater in the telmisartan group than in the valsartan group (1.9+/-2.7 vs 0.4+/-2.0 microg/ml, respectively, p<0.05). Moreover, late lumen loss was significantly lower in the telmisartan group than in the valsartan group (0.1+/-0.4 vs 0.3+/-0.5 mm, respectively, p=0.001). Major adverse cardiac events were similar between groups. In conclusion, compared with valsartan, telmisartan was associated with a significant decrease in late lumen loss and inflammatory markers after sirolimus-eluting stent implantation in hypertensive patients with significant coronary narrowing.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Biomarkers; Cholesterol; Cholesterol, LDL; Coronary Stenosis; Drug-Eluting Stents; Female; Humans; Hypertension; Immunosuppressive Agents; Interleukin-6; Male; Middle Aged; Single-Blind Method; Sirolimus; Telmisartan; Tetrazoles; Tumor Necrosis Factor-alpha; Valine; Valsartan

Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation.. In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored.. Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P = 0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P = 0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy.. Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.

Topics: Acute Disease; Adult; Biopsy; Body Mass Index; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hypertension; Kidney Transplantation; Lipids; Lymphocele; Male; Middle Aged; Monitoring, Immunologic; Mycophenolic Acid; Sirolimus; Steroids; Tacrolimus; Wound Healing

Randomized clinical trials have shown that a sirolimus-eluting stent significantly reduces restenosis after percutaneous coronary revascularization. Diabetic patients are known to have a higher risk of restenosis compared with nondiabetic patients. The purpose of this analysis was to determine the impact of sirolimus-eluting stents on outcomes of diabetic compared with nondiabetic patients.. The SIRIUS (SIRolImUS-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions) trial is a randomized, double-blind study that compared sirolimus-eluting and bare metal stent implantation in 1058 patients with de novo native coronary artery lesions. Diabetes mellitus was present in 279 (26%) patients (diabetes mellitus group, 131 patients received sirolimus-eluting stents and 148 patients received bare metal stents) and was absent in 778 patients (no-diabetes mellitus group, 402 patients received sirolimus-eluting stents and 376 patients received bare metal stents). At 270 days, target lesion revascularization was reduced in diabetic patients from 22.3% with bare metal stents to 6.9% with sirolimus-eluting stents (P<0.001) and in nondiabetic patients from 14.1% to 2.99% (P<0.001), respectively. Major adverse cardiac events were reduced in diabetic patients from 25% with bare metal stents to 9.2% with sirolimus-eluting stents (P<0.001) and from 16.5% to 6.5% (P<0.001) in nondiabetic patients, respectively.. Implantation of sirolimus-eluting stents compared with bare metal stents in de novo coronary lesions reduces major adverse cardiac events in patients with and without diabetes mellitus. However, among patients receiving sirolimus-eluting stents, there remains a trend toward a higher frequency of repeat intervention in diabetic patients compared with nondiabetic patients, particularly in the insulin-requiring patients.

Topics: Aged; Anticoagulants; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Diabetes Complications; Diabetes Mellitus; Disease-Free Survival; Double-Blind Method; Drug Implants; Female; Follow-Up Studies; Growth Inhibitors; Humans; Hypertension; Immunosuppressive Agents; Incidence; Insulin; Male; Middle Aged; Mortality; Myocardial Infarction; Sirolimus; Stents; Treatment Outcome

Despite recent advances in interventional cardiology, including the introduction of drug-eluting stents for de novo coronary lesions, the treatment of in-stent restenosis (ISR) remains a challenging clinical issue. Given the efficacy of systemic sirolimus administration to prevent neointimal hyperplasia in animal models and to halt and even reverse the progression of allograft vasculopathy, the aim of the present double-blind, placebo-controlled study was to evaluate the efficacy of a 10-day oral sirolimus treatment with 2 different loading regimens for the prevention of recurrent restenosis in patients with ISR.. Three hundred symptomatic patients with ISR were randomly assigned to 1 of 3 treatment arms: placebo or usual-dose or high-dose sirolimus. Patients received a cumulative loading dose of 0, 8, or 24 mg of sirolimus 2 days before and the day of repeat intervention followed by maintenance therapy of 2 mg/d for 7 days. Angiographic restenosis at 6-month angiography was the primary end point of the study. Restenosis was significantly reduced from 42.2% to 38.6% and to 22.1% in the placebo, usual-dose, and high-dose sirolimus groups, respectively (P=0.005). Similarly, the need for target vessel revascularization was reduced from 25.5% to 24.2% and to 15.2% in the placebo, usual-dose, and high-dose groups, respectively (P=0.08). The sirolimus blood concentration on the day of the procedure correlated significantly with the late lumen loss at follow-up (P<0.001).. In patients with ISR, an oral adjunctive sirolimus treatment with an intensified loading regimen before coronary intervention resulted in a significant improvement in the angiographic parameters of restenosis.

Topics: Administration, Oral; Aged; Angioplasty, Balloon, Coronary; Biomarkers; Comorbidity; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Coronary Vessels; Creatine Kinase; Creatine Kinase, MB Form; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypertension; Isoenzymes; Male; Middle Aged; Myocardial Infarction; Retreatment; Sirolimus; Stents; Treatment Outcome; Tunica Intima

This is the first report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Results at 6 months of follow-up are presented.. Before transplantation, patients were randomized to receive tacrolimus plus corticosteroids with sirolimus (n=185) or MMF (n=176). The primary endpoint of the study was the incidence of biopsy-confirmed acute rejection. Patient and graft survival, renal function, and composite endpoints also were evaluated. Safety was assessed by monitoring laboratory parameters and adverse events.. By 6 months of follow-up, the incidence of biopsy-confirmed acute rejection was similar in both treatment groups (13.0% tacrolimus+sirolimus vs. 11.4% tacrolimus+MMF; P=0.64 log-rank). Patient survival (97.3% tacrolimus+sirolimus vs. 97.7% tacrolimus+MMF) and graft survival (93.0% tacrolimus+sirolimus vs. 95.5% tacrolimus+MMF) were equivalent (P=0.53, overall survival log-rank). There was a significantly higher incidence of study drug discontinuation in patients receiving sirolimus (21.1% vs. 10.8%; P=0.008). Renal function was significantly better in the MMF-treatment group (serum creatinine 1.44+/-0.45 mg/dL vs. 1.77+/-1.42 mg/dL; P=0.018). Hyperlipidemia was significantly more prevalent in the sirolimus-treatment group. Diastolic blood pressure was significantly higher in sirolimus-treated patients. There were significantly more leukopenia and gastrointestinal adverse events in the MMF-treatment group. The incidence of posttransplant diabetes mellitus was 7.6% in the sirolimus group and 7.7% in the MMF group.. Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.

Topics: Acute Disease; Adult; Cardiovascular Diseases; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Sirolimus; Survival Analysis; Tacrolimus; Time Factors

FIM STUDY: We investigated the 2-year safety and efficacy of sirolimus-eluting stents. Thirty patients had a single 18-mm sirolimus-eluting coronary stent implanted. Twenty-eight patients underwent angiographic and intravascular ultrasound follow-up at 2 years. No death occurred during the study period. No patient developed in-stent restenosis. One patient had a 52% in-lesion stenosis that required repeated revascularization and another patient underwent target vessel revascularization. Neointimal hyperplasia volume was minimal at 2 years in both groups. This study demonstrates the 2-year safety and efficacy of sirolimus-eluting stenting. The slow release formulation showed slight superiority over the fast-release formulation in preventing late lumen loss, which was minimal in both groups.. This-study was a randomized, double-blind study that included 238 patients at 19 medical centers (15 in Europe, 3 in Brazil, and 1 in Mexico). Patients were eligible for the study if they were between 18 and 85 years of age, and had been given a diagnosis of stable or unstable angina or silent ischemia. Additional eligibility criteria were presence of a single primary target lesion in a native coronary artery that was 2.5 to 3.5 mm in diameter and that could be covered by an 18-mm stent stenosis of 51% to 99% of the luminal diameter and a flow rate of grade 1 or higher according to the Thrombolysis in Myocardial Infarction.. One hundred twenty patients were randomly assigned to receive the sirolimus-eluting stent, and 118 were assigned to receive the standard stent. At 6 months, the degree of neointimal proliferation, manifested as the mean (+/-SD) late luminal loss, was significantly lower in the sirolimus-stent group (-0.01 +/- 0.33 mm) than in the standard-stent group (0.80 +/- 0.53 mm, P <.001). None of the patients in the sirolimus-stent group, as compared with 26.6% of those in the standard-stent group, had restenosis of >/=50% of the luminal diameter (P <.001). There were no episodes of stent thrombosis. During a follow-up period of up to 1 year, the overall rate of major cardiac events was 5.8% in the sirolimus-stent group and 28.8% in the standard-stent group (P <.001). The difference was due entirely to the higher rate of revascularization of the target vessel in the standard-stent group.. Patients with angina who received sirolimus-eluting stents for the treatment of single, primary lesions in native coronary arteries had no angiographic evidence of late luminal loss or in-stent restenosis at 6 months, no episodes of thrombosis, and a very low rate of cardiac events at 1 year.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Coronary Angiography; Coronary Disease; Coronary Restenosis; Coronary Vessels; Female; Follow-Up Studies; Humans; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Risk Factors; Sirolimus; Smoking; Stents; Time Factors; Treatment Outcome

The present study aimed to explore the contribution of mammalian target of rapamycin (mTOR) in deoxycorticosterone acetate (DOCA) salt-induced hypertension and related pathophysiological changes in cardiovascular and renal tissues. DOCA salt loading resulted in an increase in systolic blood pressure, diastolic blood pressure, and mean blood pressure along with the activity of ribosomal protein S6, the effector protein of mTOR. Treatment with rapamycin, the selective inhibitor of mTOR, initiated at the fourth week of DOCA- salt administration normalized the systolic blood pressure and attenuated ribosomal protein S6 activity in the heart, aorta, and kidney. Cardiac and vascular hypertrophy, oxidative stress, and infiltration of macrophages (CD68+), the marker of inflammation, were also reduced in rapamycin-treated, DOCA-salt, hypertensive rats. In addition, renal hypertrophy and dysfunction were also reduced with rapamycin-treated hypertensive rats. Moreover, these pathophysiological changes in DOCA-salt hypertensive rats were associated with increased NADPH oxidase (NOX) activity, gp91phox (formerly NOX2) expression, ERK1/2, and p38 MAPK activities in the heart, aorta, and kidney were minimized by rapamycin. These data indicate that mTOR plays an important role in regulating blood pressure and the development of cardiovascular and renal pathophysiological changes, most likely due to increased NOX expression/activity, ERK1/2, and p38 MAPK activity with macrophages infiltration in the heart, kidney, and aorta. Pharmacological inhibition of mTOR and related signaling pathways could serve as a novel target for the treatment of hypertension.

Topics: Acetates; Animals; Blood Pressure; Desoxycorticosterone Acetate; Hypertension; Hypertrophy; Inflammation; Male; Mammals; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Rats; Ribosomal Protein S6; Sirolimus; TOR Serine-Threonine Kinases

Hypertension is a common chronic cardiovascular disease reported among both men and women. Hypertension in males affects the testis and reproduction function; however, the pathogenesis is poorly understood. Rapamycin has been reported to have a variety of beneficial pharmacological effects; however, high-doses rapamycin does have side effects such as immunosuppression. The present study investigates whether low-dose rapamycin can reduce the damage caused by hypertension to the testis of spontaneously hypertensive rats (SHRs) and further examines molecular mechanism of low-dose rapamycin in preventing testicular toxicity induced by angiotensin II (Ang II). Low rapamycin dose restores the testicle size, histological alterations, 3β-hydroxysteroid dehydrogenase (3β-HSD) expression, and prevents apoptosis in SHR rats. Ang II downregulates angiotensin-converting enzyme-2 (ACE2) expression through AT1R, p-ERK, and MAS receptor in LC-540 Leydig cells in a dose-dependent manner. Low doses of rapamycin effectively upregulate steroidogenic enzymes, steroidogenic acute regulatory protein and 3β-HSD expression in Leydig cells. Rapamycin upregulates ACE2 expression through p-PKAc and p-PI3k in Ang II-treated cells. Further, rapamycin curbs mitochondrial superoxide generation and depleted mitochondrial membrane potential induced by Ang II through activation of Nrf2-mediated Gpx4 and superoxide dismutase 2 expression. Our results revealed the involvement of ACE2, AT1R, AT2R, PKAc, and oxidative stress in Ang-II-induced testicular toxicity, suggesting low-dose rapamycin could be a potential therapeutic candidate to attenuate testicular toxicity.

Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Female; Humans; Hydroxysteroid Dehydrogenases; Hypertension; Leydig Cells; Male; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Rats; Rats, Inbred SHR; Sirolimus; Superoxides

The rapid fall in blood pressure following unclipping of the stenotic renal artery in the Goldblatt two-kidney one-clip (2K1C) model of renovascular hypertension is proposed to be due to release of renomedullary vasodepressor lipids, but the mechanism has remained unclear. In this study, we hypothesized that the hypotensive response to unclipping is mediated by exosomes released from the renal medulla. In male C57BL6/J mice made hypertensive by the 2K1C surgery, unclipping of the renal artery after 10 days decreased mean arterial pressure (MAP) by 23 mmHg one hr after unclipping. This effect was accompanied by a 556% increase in the concentration of exosomes in plasma as observed by nanoparticle tracking analysis. Immunohistochemical analysis of exosome markers, CD63 and AnnexinII, showed increased staining in interstitial cells of the inner medulla of stenotic but not contralateral control kidney of clipped 2K1C mice. Treatment with rapamycin, an inducer of exosome release, blunted the hypertensive response to clipping, whereas GW-4869, an exosome biosynthesis inhibitor, prevented both the clipping-induced increase in inner medullary exosome marker staining and the unclipping-induced fall in MAP. Plasma exosomes isolated from unclipped 2K1C mice showed elevated neutral lipid content compared to sham mouse exosomes by flow cytometric analysis after Nile red staining. Exosomes from 2K1C but not sham control mice exerted potent MAP-lowering and diuretic-natriuretic effects in both 2K1C and angiotensin II-infused hypertensive mice. These results are consistent with increased renomedullary synthesis and release of exosomes with elevated antihypertensive neutral lipids in response to increased renal perfusion pressure.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Diuretics; Exosomes; Hypertension; Kidney; Lipids; Male; Mice; Natriuretic Agents; Sirolimus

Topics: Angiotensin II; Animals; Autophagy; DNA, Mitochondrial; Heart Diseases; Heart Injuries; Hypertension; Mice; Microglia; Nucleotidyltransferases; Paraventricular Hypothalamic Nucleus; Sirolimus

Congenital hepatic hemangioma (CHH) is a common benign vascular tumor of the liver, seen in infancy. The clinical manifestations vary from incidental findings to life-threatening complications. The authors present here a case of an infant with massive CHH who developed systemic hypertension because of compression of the right renal artery by the CHH and did not respond to other lines of treatment. After sirolimus therapy, the CHH size decreased and antihypertensive drugs were no longer necessary. In a critical situation, if the embolization and/or steroids do not seem to control the situation, then adding sirolimus may be considered as secondary therapy with good additive effects.

Topics: Embolization, Therapeutic; Hemangioma; Humans; Hypertension; Infant; Liver Neoplasms; Sirolimus

The FLEX-LONG study assessed the safety and clinical outcomes of ultra-long (44 mm/48 mm) biodegradable polymer-coated Supraflex (Sahajanand Medical Technology Pvt. Ltd., Surat, India) sirolimus-eluting stents (SES) in real-world patients with complex, long coronary artery lesions.. It was an investigator-initiated, retrospective, non-randomized, observational and single-center study, which evaluated one-year results of 141 patients who had undergone implantation of at least one ultra-long (44 mm/48 mm) Supraflex SES. The incidence of major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction (MI) and target lesion revascularization (TLR), at one-year follow-up was considered as primary outcome. Stent thrombosis was analyzed as a safety outcome.. The mean age of the study population was 56.2±9.6 years and 78.0% (110/141) patients were male. The study analyzed high risk patients, including 62 (44.0%) hypertensive and 60 (42.6%) diabetic patients. Total 147 target lesions were treated, including 25 (17.0%) total occlusions. Total 51 (34.7%) and 96 (65.3%) Supraflex SES of 44 mm and 48 mm were implanted, respectively. Average stent length and diameter were 46.6±1.9 mm and 3.4±0.2 mm, respectively. One-year follow-up was obtained in 100% of patients. There was one probable stent thrombosis after three weeks. At one-year follow-up, 99.3% of patients remained event free.. The results of the FLEX-LONG study support the use of ultra-long (44 mm/48 mm) Supraflex SES, in the treatment of high-risk real-world patients. The stent appeared to be safe and effective at one-year with low clinical events in complex, long coronary artery lesions.

Topics: Absorbable Implants; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Female; Humans; Hypercholesterolemia; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Prosthesis Design; Retrospective Studies; Sirolimus; Smokers; Thrombosis; Treatment Outcome

mTOR (mammalian target of rapamycin) signaling has emerged as a key regulator in a wide range of cellular processes ranging from cell proliferation, immune responses, and electrolyte homeostasis. mTOR consists of 2 distinct protein complexes, mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) with distinct downstream signaling events. mTORC1 has been implicated in pathological conditions, such as cancer and type 2 diabetes mellitus in humans, and inhibition of this pathway with rapamycin has been shown to attenuate salt-induced hypertension in Dahl salt-sensitive rats. Several studies have found that the mTORC2 pathway is involved in the regulation of renal tubular sodium and potassium transport, but its role in hypertension has remained largely unexplored. In the present study, we, therefore, determined the effect of mTORC2 inhibition with compound PP242 on salt-induced hypertension and renal injury in salt-sensitive rats. We found that PP242 not only completely prevented but also reversed salt-induced hypertension and kidney injury in salt-sensitive rats. PP242 exhibited potent natriuretic actions, and chronic administration tended to produce a negative Na

Topics: Acute Kidney Injury; Animals; Blood Pressure; Cell Proliferation; Disease Models, Animal; Hypertension; Immunosuppressive Agents; Male; Rats; Rats, Inbred Dahl; Signal Transduction; Sirolimus; Sodium Chloride, Dietary; TOR Serine-Threonine Kinases

Drug-induced nephrotic syndrome (NS) can be resolved by eliminating the causative agents. However, patients with metastatic cancer have not been previously reported to achieve complete recovery from anticancer drug-induced NS after discontinuation of treatment, because many patients die of cancer progression before NS is restored.. A 67-year-old man presented with edema of both lower extremities. He received pazopanib therapy for recurrent metastatic renal cell carcinoma (mRCC) for 17 months. Laboratory examinations revealed 7484.58 mg/day of 24-h urine protein, 434 mg/dL of serum cholesterol, and 2.9 g/dL of serum albumin. He was diagnosed with NS, and pazopanib treatment was discontinued. Four months later, he completely recovered from NS. He was then treated with temsirolimus and nivolumab sequentially for > 26 months. Pazopanib was re-introduced following disease progression, and demonstrated antitumor effects for 7 months without NS recurrence.. Pazopanib-induced NS can occur late in patients with mRCC, and its subsequent discontinuation can enable patients to completely recover from its adverse effects. Moreover, pazopanib treatment may be re-introduced without the recurrence of NS.

Topics: Aged; Amlodipine; Angiogenesis Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Diabetic Nephropathies; Dihydropyridines; Drug Substitution; Edema; Everolimus; Humans; Hypertension; Indazoles; Kidney Failure, Chronic; Lung Neoplasms; Male; Nephrotic Syndrome; Nivolumab; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Obesity is a major risk for hypertension. Endothelial dysfunction contributes to increased peripheral vascular resistance and subsequent hypertension. Autophagy regulates endothelial function, however, whether autophagy is related to hypertension in obesity remains largely unclear. We wished to ascertain: (i) the role of autophagy in obesity-induced hypertension and the underlying mechanisms; (ii) if tetrahydroxystilbene glycoside (TSG) influences endothelial dysfunction and obesity-associated hypertension.. (TSG-treated) male Zucker diabetic fatty (ZDF) rats and cultured human umbilical vein endothelial cells (HUVECs) were used. Blood pressure was measured non-invasively with a tail-cuff system. Westernblotting was performed to determine the expression of autophagy-associated proteins. Autophagy flux was assessed by transfection HUVECs with the Ad-mGFP-RFP-LC3.. Compared with their lean counterparts, obese ZDF rats exhibited hypertension and endothelial dysfunction, along with impaired Akt/mTOR signaling and upregulated expression of autophagy-associated proteins beclin1, microtubule-associated protein 1 light chain 3 II/I, autophagy protein (ATG)5 and ATG7. Two-week TSG administration restored blood pressure and endothelial function, reactivated Akt/mTOR pathway and decreased endothelial autophagy in ZDF rats. Rapamycin pretreatment blocked the hypotensive effect of TSG in ZDF rats. Suppression of Akt/mTOR expression with siRNA significantly blunted the anti-autophagic effect of TSG in HUVECs as evidenced by abnormal autophagic flux and increased expression of autophagy-associated proteins.. Endothelial dysfunction in ZDF rats is partially attributable to excessive autophagy. TSG improves endothelial function and exerts hypotensive effects via regulation of endothelial autophagy.

Topics: Animals; Apoptosis; Autophagy; Blood Pressure; Glycosides; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Male; Microtubule-Associated Proteins; Obesity; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; RNA Interference; Signal Transduction; Sirolimus; Stilbenes; TOR Serine-Threonine Kinases; Up-Regulation; Vasodilation

In transplant patients receiving de novo anticalcineurin-free sirolimus (SRL)-based immunosuppression, we determined the influence of cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette, sub-family B (MDR/TAP), member (ABCB1) genotypes on SRL blood levels and medium-term relevant clinical outcomes, in order to improve effectiveness of immunosuppression strategies when anti-mammalian target of rapamycin (anti-mTOR) inhibitor is indicated for clinical reasons.. Forty-eight renal transplant recipients (suffered 48% diabetes mellitus, 91% hypertension, and 47% dyslipidemia) were genotyped for CYP3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Sirolimus blood levels were determined using microparticle enzyme immunoassay technique. Relationships between genotypes and pharmacokinetics, graft function, and patient-graft survival were determined by univariate analysis.. CYP3A5*1/*3 showed lower SRL levels than CYP3A5*3/*3 (4.13±1.54 vs. 8.49±4.18 ng/mL; p=0.003) and level/dose ratio (LDR) (92.74±37.47 vs. 178.62±116.45; p=0.019) in early post-transplant period. In ABCB1 polymorphisms, CT genotypes showed higher SRL levels than CC and TT (8.93±2.22 vs. 7.28±2.47 vs. 7.35±1.15 ng/mL; p=0.038) in the late period; LDR in CC and CT were 171.29±36.24 vs. 335.66±138.71 (p=0.003), despite receiving lower doses (p=0.018). Acute rejection rate was 14% vs. 42% for *3/*3 and 14% (TT), 48% (CT), and 31% (CC). Median patient survival was 45 months, significantly lower than that of *3/*3 patients (69 months). Death-censored graft survival during 5-year follow-up was similar for both CYP3A5 genotypes and significantly lower in TT than CT and CC groups, without survival differences.. CYP3A5 and ABCB1 polymorphisms influenced SRL levels; preliminary data suggest this may affect patient and graft survival. Genotyping renal transplant patients could help select candidates for SRL (genotype*3/*3 for CYP3A5 and CT for ABCB1), when anti-mTOR immunosuppression is indicated.

Topics: ATP Binding Cassette Transporter, Subfamily B; Cytochrome P-450 CYP3A; Diabetes Mellitus; Dyslipidemias; Female; Graft Survival; Humans; Hypertension; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Sirolimus; Treatment Outcome

Cardiovascular disease (CVD) is the second major cause of death in kidney-transplanted children. Cardiovascular risk factors (CVRF) prevalence after transplant may increase. The effect of immunosuppressive therapy has not been fully studied in children. The objective of the study was to measure and compare CVRF prevalence in kidney-transplanted children, depending of immunosuppressive therapy.. The study was an observational, transversal, retrospective, comparative study of pediatric patients transplanted at UMAE Hospital General Centro Medico La Raza. All patients were treated with prednisone and mycophenolic acid and any of cyclosporine, tacrolimus, or sirolimus. Demographic, clinical, and biochemical variables and immunosuppressive therapy were evaluated. We used analysis of variance, χ(2), and Fisher tests with the SPSS 18.0 statistical program.. One hundred fifteen patients were studied. Sixty-five (56.5%) were male, and median age was 18.5 ± 2.3 years. Seventy-eight (67.2%) were transplanted from a living related donor. Prevalence of anemia and nephrotic proteinuria was significantly less in patients treated with tacrolimus. Those treated with cyclosporine had a significantly greater prevalence of increased LDL-cholesterol, increased serum phosphorus, and increased calcium-phosphorus. Those treated with tacrolimus had lower, not significant, prevalence of hypertension, hyperuricemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and low serum HDL-cholesterol than those treated with sirolimus and cyclosporine. In multivariate analysis, patients treated with cyclosporine had significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75-41.16, P = .001) and calcium-phosphorus (OR, 37.94; 95% CI, 3.45-416.17, P = .003) than those treated with tacrolimus.. Patients treated with tacrolimus had less prevalence of CVRF than those treated with cyclosporine or sirolimus. Tacrolimus is the best immunosuppressive option to diminish CVRF in children after kidney transplantation.

Topics: Adolescent; Adult; Cardiovascular Diseases; Child; Cyclosporine; Female; Humans; Hypertension; Hypertriglyceridemia; Hyperuricemia; Immunosuppressive Agents; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Young Adult

It has not been established whether the achievement of optimal medical therapy (OMT) before implantation of a drug-eluting stent has a clinical benefit for patients with stable coronary artery disease (CAD). This study included 3,004 patients with CAD treated with drug-eluting stent from 123 Japanese participating centers. The achievement of OMT was defined as control of blood pressure <130/80 mm Hg, hemoglobin A1c <7.0%, and low-density lipoprotein cholesterol <100 mg/dl. The primary end point was target vessel failure, a composite of death related to the target vessel, myocardial infarction, or clinically driven revascularization at 24 months after stent implantation. Immediately before the procedure, only 548 patients (18.2%) had achieved all 3 target criteria (the achieved OMT group), whereas the remaining 2,456 patients failed to achieve one or more criteria (the non-OMT group). At 24 months, the incidence of target vessel failure was 7.0% in the achieved OMT group versus 10.0% in the non-OMT group (hazard ratio 0.68, 95% CI 0.48 to 0.96, p = 0.03). The incidence of non-Q-wave myocardial infarction was also lower in the achieved OMT group than in the non-OMT group (0.5% vs 1.5%, p = 0.08). Multivariate logistic regression analysis identified that hemoglobin A1c <7.0% was the only protective predictor of 24-month target vessel failure (odds ratio 0.56, 95% CI 0.43 to 0.73, p <0.01). In conclusion, this study demonstrated that in patients with stable CAD scheduled for stent implantation, achievement of OMT before percutaneous coronary intervention significantly reduced subsequent cardiac events. Achievement of OMT is still insufficient in modern clinical practice.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Blood Pressure; Cholesterol, LDL; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Dyslipidemias; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypoglycemic Agents; Japan; Male; Middle Aged; Paclitaxel; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; Risk Reduction Behavior; Sirolimus

Mammalian hearts undergo hypertrophy upon pressure overload to support increased workload. Sustained hypertrophy results in cardiac decompensation and subsequently heart failure. The mechanism that prevents the development of cardiac hypertrophy is still not fully understood. Here we elucidate the anti-hypertrophic role of the histone demethylase PHF8.. PHF8 protein and mRNA levels were down-regulated in human failing hearts, mouse hypertrophic hearts and neonatal rat ventricle myocytes that underwent hypertrophy. Then we generated a cardiac-specific PHF8 transgenic mice, and found that PHF8 overexpression reversed cardiac dysfunction, hypertrophy and fibrosis upon pressure overload. In vivo evidence showed that PHF8 blocked protein synthesis and hypertrophic fetal genes expression. Furthermore, we found that PHF8 inhibited Akt-mTOR pathway in hypertrophic hearts and neonatal rat ventricle myocytes, and rapamycin treatment rescues the effects of PHF8 loss.. These results indicate that PHF8 serves as an endogenous factor that the host uses to attenuate cardiac hypertrophy upon cardiac overload. Strategies based on its enhancement might be of benefit in the treatment of hypertrophic cardiomyopathy.

Topics: Animals; Cardiomegaly; Cells, Cultured; Down-Regulation; Histone Demethylases; Humans; Hypertension; Male; Mice; Mice, Transgenic; Myocytes, Cardiac; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

Hypertension is an independent risk factor for heart disease and is responsible for the increased cardiac morbidity and mortality. Oxidative stress plays a key role in hypertensive heart diseases although the precise mechanism remains unclear. This study was designed to examine the effect of cardiac-specific overexpression of metallothionein, a cysteine-rich antioxidant, on myocardial contractile and intracellular Ca(2+) anomalies in N(G)-nitro-l-arginine methyl ester (l-NAME)-induced experimental hypertension and the mechanism involved with a focus on autophagy. Our results revealed that l-NAME treatment (14 days) led to hypertension and myocardial anomalies evidenced by interstitial fibrosis, cardiomyocyte hypertrophy, increased LV end systolic and diastolic diameters (LVESD and LVEDD) along with suppressed fractional shortening. l-NAME compromised cardiomyocyte contractile and intracellular Ca(2+) properties manifested as depressed peak shortening, maximal velocity of shortening/relengthening, electrically-stimulated rise in intracellular Ca(2+), elevated baseline and peak intracellular Ca(2+). These l-NAME-induced histological and mechanical changes were attenuated or reconciled by metallothionein. Protein levels of autophagy markers LC3B and p62 were decreased and increased, respectively. Autophagy signaling molecules AMPK, TSC2 and ULK1 were inactivated while those of mTOR and p70s6K were activated by l-NAME, the effects of which were ablated by metallothionein. Autophagy induction mimicked whereas autophagy inhibition nullified the beneficial effect of metallothionein against l-NAME. These findings suggested that metallothionein protects against l-NAME-induced myocardial anomalies possibly through restoration of autophagy.

Topics: Animals; Autophagy; Calcium; Hypertension; Male; Metallothionein; Mice; Myocardial Contraction; Myocardium; NG-Nitroarginine Methyl Ester; Oxidative Stress; Reactive Oxygen Species; Sirolimus

Neointimal hyperplasia causes a high rate of hemodialysis synthetic graft failure. Thus, therapies that inhibit neointimal hyperplasia are urgently needed. The Coll-R is a sirolimus-eluting collagen matrix designed for intra-operative perivascular implantation around the graft-venous anastomosis. Sirolimus is an anti-proliferative drug that has proven clinical utility in suppressing neointimal tissue growth in coronary artery disease when delivered locally to the vascular wall by an endovascular drug eluting stent.. A cohort of 12 chronic hemodialysis patients underwent surgical placement of 13 polytetrafluoroethylene grafts + Coll-R and were followed for up to 24 months. The primary endpoint was safety (freedom from device related adverse events). Secondary endpoints were pharmacokinetics of sirolimus release, success of Coll-R implantation and primary unassisted graft patency.. There were no technical failures, infections, vascular anastomotic or wound-healing problems. Whole blood sirolimus levels rose to a mean peak of 4.8 ng/mL at 6 h and fell to <1 ng/mL at 1 week (n = 5). Twelve and 24-month primary unassisted patencies were 76 and 38%, respectively, and the thrombosis rate was 0.37/patient-year.. Perivascular implantation of the Coll-R during graft surgery safely delivered sirolimus to the vascular wall. Systemic sirolimus levels were sub-therapeutic for immunosuppression. This small first-in-human study supports the concept that the Coll-R can safely deliver sirolimus to the graft-venous anastomosis. Safety and patency in this small study were sufficiently encouraging to justify randomized controlled trials to further test the efficacy of the Coll-R.

Topics: Adolescent; Adult; Aged; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Collagen; Drug Delivery Systems; Female; Follow-Up Studies; Humans; Hypertension; Male; Microscopy, Electron, Scanning; Middle Aged; Polytetrafluoroethylene; Renal Dialysis; Safety; Sirolimus; Survival Rate; Thrombosis; Vascular Patency; Young Adult

Topics: Blood Vessel Prosthesis Implantation; Drug Delivery Systems; Female; Humans; Hypertension; Male; Polytetrafluoroethylene; Renal Dialysis; Sirolimus; Vascular Patency

Tacrolimus (Tac) in combination with mycophenolate mofetil is widely used after heart transplantation (HT). Everolimus (EVR), a new potent proliferation signal inhibitor can be used with a carcineurin inhibitor to reduce the occurrence of rejection. The purpose of this study was to evaluate the efficacy and safety of Tac combined with EVR in de novo HT.. From January 2009 to April 2011, 33/62 patients who underwent HT were prescribed Tac and EVR as de novo immunosuppression. The main exclusion criteria were poor kidney function (serum creatinine > 2.8 mg/dL), panel-reactive antibodies > 25%, donors > 60 years old, or cold ischemia time > 6 hours. All patients received Tac (C0 blood level 5-10 ng/mL during the first 6 months, then 3-5 ng/mL), EVR (C0 target 3-8 ng/mL), and corticosteroids. After transplantation, routine examinations included echocardiogram and protocol endomyocardial biopsy.. There was no operative mortality. The 1- and 3-year actuarial survivals were 95.74% ± 3.49%. One patient who had undergone coronary artery bypass grafting previously and received intra-aortic balloon pumping and extracorporeal membrane oxygenator-assisted cardiopulmonary resuscitation before HT died of Aspergillus septicemia 58 days after HT. No biopsy-proven acute rejection > grade 2R or acute rejection associated with hemodynamic compromise was observed. Hyperlipemia was noted in 16 cases (48.5%), hypertension in 11 (33.3% 5%), and diabetes mellitus in 12 (36.4%). No other severe adverse events were noted.. Concentration-controlled EVR (C0 target 3-8 ng/mL) in combination with Tac achieved good efficacy and safety. The 1- and 3-year actuarial survivals were 95.74% ± 3.49%.

Topics: Adolescent; Adult; Aged; Child; Diabetes Mellitus; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Sirolimus; Survival Analysis; Tacrolimus; Taiwan; Time Factors; Treatment Outcome; Young Adult

Maintenance therapy with calcineurin inhibitors (CNIs) increases cardiovascular risk. Use of the m-TOR inhibitors everolimus or sirolimus to minimize CNI exposure is usually undertaken to preserve renal function following kidney transplantation, but may also improve cardiovascular risk status. Recent studies of early conversion from CNI to m-TOR inhibitors have shown a numerical improvement in the incidence of hypertension, but results are not clear-cut. Dyslipidaemia, in contrast, is more frequent under m-TORs than with CNI-based immunosuppression. New-onset diabetes is rare (≤ 5%) using modern m-TOR regimens, for example, everolimus and reduced-exposure CNI. Renal function improvement with m-TOR inhibitor regimens versus CNIs would also be expected to improve cardiovascular risk. Moreover, m-TOR-based CNI-minimization regimens are not associated with proteinuria, a known cardiovascular risk factor, with the possible exception of late conversion in patients with poor renal function. Interestingly, m-TOR inhibitors may also exert cardioprotective effects. Animal data suggest that m-TORs may restrict the pathogenesis of atherosclerosis, consistent with preliminary clinical data that conversion from CNIs to everolimus can stabilize markers for arterial stiffness. In conclusion, use of m-TORs has the potential to lessen the toll of cardiovascular disease following kidney transplantation - an opportunity that merits further exploration.

Topics: Animals; Blood Pressure; Calcineurin Inhibitors; Cardiovascular Diseases; Diabetes Mellitus; Everolimus; Glomerular Filtration Rate; Humans; Hyperlipidemias; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Risk; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

A 70-year-old man with metastatic renal cell carcinoma developed progressive liver metastases after 8 weeks of treatment with the multitargeted tyrosine kinase inhibitor (TKI) sunitinib. He then participated in the phase III placebo-controlled clinical trial of the oral mammalian target of rapamycin (mTOR) inhibitor everolimus, initially randomized to placebo (but had disease progression after 3 months) and crossed over to everolimus at time of unblinding. The patient had stable disease after 8 weeks (two cycles) of everolimus that was maintained until 28 months of therapy, at which time the patient had achieved a partial response. This case illustrates the potential for patients with metastatic renal cell carcinoma, a malignancy with historically poor prognosis, to derive long-term benefit from everolimus when used in a manner consistent with its approved indication (after TKI therapy with sunitinib or sorafenib).

Topics: Aged; Antineoplastic Agents; Arthritis, Rheumatoid; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Everolimus; Humans; Hypercholesterolemia; Hypertension; Indoles; Kidney Neoplasms; Lung Neoplasms; Male; Pyrroles; Randomized Controlled Trials as Topic; Salvage Therapy; Sirolimus; Sunitinib

Topics: Antihypertensive Agents; Antineoplastic Agents; Aortic Aneurysm; Aortic Dissection; Carcinoma, Renal Cell; Combined Modality Therapy; Humans; Hypertension; Indoles; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Nephrectomy; Pyrroles; Sirolimus; Sunitinib

The transjugular intrahepatic portosystemic shunt (TIPS) is an acceptable procedure that has proven benefits in the treatment of patients who have complications from portal hypertension due to liver cirrhosis. In the literature few reports have described complications after TIPS placement. Initial surgery and local hemostasis have been needed to manage abdominal bleeding: if this treatment is insufficient, it may be necessary to perform a liver transplantation. This report describes the role of liver transplantation to manage dangerous complications in 2 patients after TIPS placement, when surgical procedures and hemostasis were unable to stop the bleeding.

Topics: Adult; Alcoholism; Antibiotic Prophylaxis; Female; Hepatic Veins; Humans; Hypertension; Hypertension, Portal; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Portacaval Shunt, Surgical; Sirolimus; Treatment Outcome

Short-term studies have demonstrated that rapamycin or everolimus treatment decreases cyst formation and improves renal function in animal models of polycystic kidney disease (PKD). Autosomal dominant polycystic kidney disease (ADPKD) patients would likely require life-long treatment with rapamycin.. Male Han:SPRD rats with PKD (Cy/+) were treated with rapamycin (0.2 mg/kg/day IP) or vehicle from 1 to 12 months of age. Mean trough levels of rapamycin (ng/mL) were 6.6 +/- 0.1 at 8 weeks of age. Twelve-month-old littermates (+/+) were used as normal controls.. Twelve-month-old male Cy/+ rats treated with the vehicle had a more than doubling of kidney volume, severe chronic renal failure, severe hypertension and increased heart weight compared to normal littermate controls (+/+). After rapamycin treatment, 12-month-old Cy/+ rats had markedly improved kidney volume, renal function, blood pressure and heart weight not statistically different from controls. Rapamycin reduced the cyst volume density (CVD) by 72%. Mammalian target of rapamycin (mTOR) activation in the heart, as evidenced by a marked increase in the phospho-S6 protein that was inhibited by rapamycin, was demonstrated in 12-month-old Cy/+ rats.. In conclusion, long-term rapamycin treatment in Cy/+ rats results in a normalization of kidney volume, renal function, blood pressure and heart weight. The novel finding that rapamycin decreases hypertension, heart enlargement and mTOR signalling in the heart in PKD rats is reported. The only side effect of rapamycin treatment was an 11% decrease in body weight.

Topics: Animals; Blood Pressure; Body Weight; Disease Models, Animal; Heart; Hypertension; Immunoblotting; Immunosuppressive Agents; Kidney Function Tests; Male; Organ Size; Polycystic Kidney Diseases; Rats; Rats, Sprague-Dawley; Sirolimus; Time Factors

The purpose of this study was to compare the effects of sirolimus (SRL) vs cyclosporine (CsA) concerning the cardiovascular mechanisms hypothetically contributing to hypertension development. Three rat groups were studied: control (vehicle), CsA (5 mg/kg/d), and SRL (1 mg/kg/d). The following parameters were evaluated after 7 weeks of treatment: blood pressured (BP) and heart rate (HR; tail cuff), lipid profile, hematology, plasma and platelet 5-HT and catecholamines (HPLC-ECD), and oxidative equilibrium (serum malondialdehyde [MDA] and total antioxidant status [TAS]). Systolic (SBP) and diastolic blood pressure (DBP) values were higher (P < .001) in both the CsA (146.2 +/- 4.5 and 124.9 +/- 4.5 mm Hg) and SRL (148.9 +/- 4.8 and 126.4 +/- 6.0 mm Hg) groups vs the controls (115.9 +/- 3.3 and 99.1 +/- 2.0 mm Hg). However, HR values were elevated in CsA but not SRL animals. The dyslipidemic pattern of CsA was even more enhanced in the SRL group, with significantly higher low-density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels vs CsA (P < .05); red blood cells, hematocrit, hemoglobin concentration, mean platelet volume, and platelet distribution width were significantly (P < .05) higher in the SRL vs CsA group. The pro-oxidative profile (increased MDA/TAS) in the CsA group was not reproduced in the SRL cohort. While plasma and platelet 5-HT were elevated in SRL rats, catecholamine content was higher in CsA animals. In conclusion, this study demonstrated that CsA and SRL produce identical hypertensive effects. However, while CsA promotes oxidative stress and sympathetic activation, SRL mainly interferes with lipid profile and hematological parameters. Thus, the hypertensive effects of CsA, a calcineurin inhibitor, and of SRL, an mTOR inhibitor, are associated with impairment of distinct cardiovascular pathways.

Topics: Animals; Blood Pressure; Cyclosporine; Diastole; Heart Rate; Hypertension; Immunosuppressive Agents; Lipid Peroxidation; Male; Malondialdehyde; Rats; Rats, Wistar; Sirolimus; Systole

BACKGROUND.: Sirolimus (SRL) is an important component of clinical immunosuppression in renal transplantation, but few international studies have examined how this agent is used in routine practice. METHODS.: Within a large prospective pharmacoepidemiological study, 718 de novo renal graft recipients treated with SRL in 65 centers in 10 countries were monitored for up to 5 years posttransplant to compare the principal outcomes and adverse effects by treatment regimen. RESULTS.: Principal treatment regimens were SRL without a calcineurin inhibitor (33%), SRL+cyclosporine A (CsA) (33%), and SRL+tacrolimus (TAC) (34%); 18% of subjects discontinued SRL, 124/718 (17%) developed biopsy-confirmed acute rejection (BCAR), 64/718 (9%) lost their graft, and 50/718 (7%) died during follow-up. Calculated creatinine clearance was 66+/-26 mL/min at 2 years. The most common adverse events were hypertension, hyperlipidemia, anemia, urinary tract infections, and diabetes. BCAR was significantly lower in subjects receiving SRL+TAC (hazard ratio [HR] 0.46, P=0.009) but not significantly lower in those receiving SRL+CsA (HR 0.62, P=0.102) compared with SRL without a calcineurin inhibitor. Graft loss or death did not significantly differ between treatment groups but were associated, respectively, with deceased donor grafts (HR 3.33, P<0.001) and increased age (HR 1.04, P<0.001). No improvement was observed in patients receiving mycophenolate mofetil in any treatment combination (HR 0.80, P=0.438 for BCAR; HR 0.93, P=0.849 for graft loss; and HR 0.75, P=0.531 for death). CONCLUSIONS.: SRL is most commonly used in combination with mycophenolate mofetil, CsA, or TAC. BCAR was least common in subjects receiving SRL+TAC, but other outcomes seemed comparable between the treatment regimens in routine practice.

Topics: Algorithms; Anemia; Cohort Studies; Creatinine; Drug Therapy, Combination; Graft Rejection; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Longitudinal Studies; Observer Variation; Prospective Studies; Sirolimus; Tacrolimus; Urinary Tract Infections

Calcineurin inhibitors (CNI) have brought dramatic improvements in early renal allograft survival. However, CNI are associated with posttransplant hypertension (PTHTN), a risk factor for mortality from cardiovascular disease and graft failure. Sirolimus (SRL) is emerging as an alternative to CNI. SRL effects on blood pressure (BP) in humans are unclear. We compared the prevalence of PTHTN among patients receiving SRL as maintenance immunosuppression with a group receiving CNI by using 24-hour ambulatory BP (AMBP). AMBP has been shown to predict cardiovascular events and progression of kidney disease better than casual office BP measurements in chronic kidney disease (CKD) patients.. Renal transplant recipients with office hypertension (defined as BP > 130/80 or on antihypertensive medications), receiving stable immunosuppression and displaying consistent serum creatinine values for > or =6 months were eligible. We enrolled the first 40 patients to consent. Office BP was measured twice using a BP-Tru machine. AMBP was then analyzed for systolic BP (SBP), diastolic BP (DBP), and nocturnal blood pressure fall (NF; "dipping"). Patients were placed in the SRL group (n = 18) and the CNI group (n = 20) based on their maintenance immunosuppressive protocol. Two patients were excluded because of incomplete data. All patients received mycophenolate mofetil, and 14/38, maintenance steroids. We collected, demographics as well as type and date of renal allograft, medications, comorbidities, CKD stage, proteinuria, and plasma creatinine at the time of study enrollment.. Patients in the SRL group displayed lower 24-hour SBP than the CNI group (128.0 +/- 10.8 vs 137.7 +/- 14; P = .029). Nightime MAP, nightime SBP, and nighttime DBP were all lower in the SRL group. NF did not reach significance between the SRL and CNI groups (44% vs 15%; P = .074). Patient demographics and number of antihypertensive medications did not differ.. The lower 24-hour SBP seen in the SRL group by AMBP may lead to improved cardiovascular and renal outcomes over time. Long-term patient follow-up will be needed to clarify the effect of the lower 24-hour SBP.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Body Mass Index; Cadaver; Calcineurin; Cardiovascular Diseases; Diabetic Nephropathies; Female; Humans; Hypertension; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Monitoring, Ambulatory; Postoperative Complications; Postoperative Period; Sirolimus; Tissue Donors

A 69 year old man was admitted with unstable angina (Class IIB). He had a history of chronic renal impairment, diabetes mellitus, hypertension and coronary bypass surgery in 1997 (LIMA graft to the LAD anf diagonal branch, saphenous vein grafts to the RCA and first marginal branch of LCx.. Coronary angiography.. Unstable angina (Class IIB). Occlusion of the LCx and RCA. Functionally occluded LIMA on the LAD and diagonal branch. Diffuse disease of the LAD with two significant lesions at the LAD-first diagonal and mid-distal LAD.. Revascularisation.

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Chronic Disease; Coronary Angiography; Coronary Artery Bypass; Coronary Artery Disease; Diabetes Complications; Drug-Eluting Stents; Everolimus; Graft Occlusion, Vascular; Hemodynamics; Humans; Hypertension; Kidney Diseases; Male; Sirolimus; Treatment Outcome

One major cause of graft loss is chronic allograft nephropathy (CAN), which may relate to calcineurin inhibitors (CNIs). We converted CAN cases from CNIs to sirolimus and observed the outcomes.. From January 2004 to August 2007, there were 28 kidney recipients in our center with creeping creatinine levels compatible with CAN. We started sirolimus at 2 mg/d and reduced the CNIs gradually. Sirolimus trough levels were kept between 5 and 8 ng/mL. Mycophenolic acid was cut in half; there was no adjustment on prednisolone dose.. The mean switch time was 47.3 months after transplantation. One case discontinued sirolimus due to severe drug-induced pneumonitis. Twelve of the 27 (45%) patients showed improvements in graft function. The most frequent complications were anemia (13/28), hyperlipidemia (13/28), and pneumonitis (4/28). A baseline serum creatinine level less than 2.2 mg/dL seemed to forecast a response to sirolimus conversion. Most of the graft functional improvement occurred within 6 months after the switch. No graft or patient loss was encountered.. Our experience suggested that 45% of patients with sirolimus conversion showed improved graft function. Among patients within 1 year after transplantation, those with a creatinine level less than 2.2 mg/dL, no proteinuria, and no hyperlipidemia seemed to be better candidates for Sirolimus conversion.

Topics: Follow-Up Studies; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Proteinuria; Retrospective Studies; Sirolimus; Time Factors

Chronic treatment with the immunosuppressive drug rapamycin leads to hypertension; however, the mechanisms are unknown. Rapamycin binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and displaces them from intracellular Ca2+ release channels (ryanodine receptors) eliciting a Ca2+ leak from the endoplasmic/sarcoplasmic reticulum. We tested whether this Ca2+ leak promotes conventional protein kinase C-mediated endothelial NO synthase phosphorylation at Thr495, which reduces production of the vasodilator NO. Rapamycin treatment of control mice for 7 days, as well as genetic deletion of FKBP12.6, increased systolic arterial pressure significantly compared with controls. Untreated aortas from FKBP12.6-/- mice and in vitro rapamycin-treated control aortas had similarly decreased endothelium-dependent relaxation responses and NO production and increased endothelial NO synthase Thr495 phosphorylation and protein kinase C activity. Inhibition of either conventional protein kinase C or ryanodine receptor restored endothelial NO synthase Thr495 phosphorylation and endothelial function to control levels. Rapamycin induced a small increase in basal intracellular Ca2+ levels in isolated endothelial cells, and rapamycin or FKBP12.6 gene deletion decreased acetylcholine-induced intracellular Ca2+ release, all of which were reversed by ryanodine. These data demonstrate that displacement of FKBP12/12.6 from ryanodine receptors induces an endothelial intracellular Ca2+ leak and increases conventional protein kinase C-mediated endothelial NO synthase Thr495 phosphorylation leading to decreased NO production and endothelial dysfunction. This molecular mechanism may, in part, explain rapamycin-induced hypertension.

Topics: Animals; Blood Pressure; Calcium; Endothelium, Vascular; Hypertension; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type III; Phosphorylation; Protein Isoforms; Ryanodine Receptor Calcium Release Channel; Sirolimus; Tacrolimus Binding Proteins; Threonine

Topics: Adult; Antibiotics, Antineoplastic; Humans; Hypertension; Hypokalemia; Kidney Diseases; Male; Sirolimus

Everolimus (Certican; Novartis Pharma AG, Basel, Switzerland) represents the latest generation of proliferation signal inhibitors (PSIs). Everolimus is indicated for use as an immunosuppressive drug in renal and heart transplantation. This report reflects the recommendations of the second German-Austrian Certican Consensus Conference, held in January 2006, for the clinical use of everolimus.

Topics: Angioedema; Coronary Disease; Drug Interactions; Drug Monitoring; Everolimus; Heart Diseases; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Lipids; Lung Diseases, Interstitial; Renal Insufficiency; Sirolimus; Skin Diseases; Transplantation, Homologous; Wound Healing

FK506 Binding Protein 12 and its related isoform 12.6 (FKBP12/12.6) stabilize a closed state of intracellular Ca2+ release channels (ryanodine receptors [RyRs]), and in myocytes removal of FKBP12/12.6 from RyRs alters intracellular Ca2+ levels. The immunosuppressive drugs rapamycin and FK506 bind and displace FKBP12/12.6 from RyRs, and can also cause endothelial dysfunction and hypertension. We tested whether rapamycin and FK506 cause an intracellular Ca2+ leak in endothelial cells and whether this affects endothelial function and blood pressure regulation.. Rapamycin or FK506 concentration-dependently caused a Ca2+ leak in isolated endothelial cells, decreased aortic NO production and endothelium-dependent dilation, and increased systolic blood pressure in control mice. Rapamycin or FK506 at 10 micromol/L abolished aortic NO production and endothelium-dependent dilation. Similar results were obtained in isolated endothelial cells and aortas from FKBP12.6-/- mice after displacement of FKBP12 with 1 micromol/L rapamycin or FK506. In hypertensive FKBP12.6-/- mice, systolic blood pressures were further elevated after treatment with either rapamycin or FK506. Blockade of the Ca2+ leak with ryanodine normalized NO production and endothelium-dependent dilation.. Complete removal of FKBP12 and 12.6 from endothelial RyRs induces an intracellular Ca2+ leak which may contribute to the pathogenesis of endothelial dysfunction and hypertension caused by rapamycin or FK506.

Topics: Animals; Calcium Channels; Calcium Signaling; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Gene Deletion; Hypertension; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Nitric Oxide; Ryanodine Receptor Calcium Release Channel; Sensitivity and Specificity; Sirolimus; Tacrolimus; Tacrolimus Binding Protein 1A; Vasoconstriction; Vasodilation

Topics: Basilar Artery; Brain Infarction; Cerebellum; Cerebral Arteries; Disease Progression; Emphysema; Female; Headache; Hemianopsia; Humans; Hypertension; Immunosuppressive Agents; Intracranial Hemorrhage, Hypertensive; Kidney Neoplasms; Lung Transplantation; Magnetic Resonance Imaging; Middle Aged; Occipital Lobe; Posterior Cerebral Artery; Sirolimus

Topics: Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Restenosis; Cost-Benefit Analysis; Data Interpretation, Statistical; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Delivery Systems; Female; Humans; Hypertension; Immunosuppressive Agents; Incidence; Male; Meta-Analysis as Topic; Myocardial Infarction; Paclitaxel; Randomized Controlled Trials as Topic; Registries; Risk Factors; Sirolimus; Stents; Treatment Outcome

Calcineurin inhibitors (CNIs) are frequently associated with side effects such as nephrotoxicity and hypertension, so CNI withdrawal from immunosuppressive regimens is desirable in certain cases. The proliferation signal inhibitors/mammalian target of rapamycin inhibitors everolimus and sirolimus may play an important role in achieving CNI withdrawal. Studies on sirolimus have shown that conversion from CNIs is associated with improvements in renal function and hypertension. A case report is presented of a renal transplant recipient who experienced hypertension and recurrent cutaneous neoplasia while receiving a ciclosporin (CsA)-based immunosuppressive regimen. After transplantation, the patient received full-dose CsA and prednisolone. After 7 years, the patient's serum creatinine increased from 1.9 mg/dl to 2.5 mg/dl, and mycophenolate mofetil (MMF, 1000 mg/day) was introduced, enabling the CsA dose to be reduced to 100 mg b.i.d. The patient also required resection of five cutaneous neoplastic lesions; this led to the decision to stop CsA and start treatment with everolimus 1.5 mg/day, which was increased to 3.0 mg/day to achieve target trough blood levels of 3 ng/ml. To avoid over-immunosuppression, the MMF dose was reduced to 500 mg/day. After conversion, the patient experienced a substantial improvement in blood pressure, from 175/85 mmHg to 155/70 mmHg. Serum creatinine levels decreased to 1.6 mg/dl, and there has been no recurrence of cutaneous neoplasia in 9 months of follow-up. Therefore, conversion to everolimus from CsA in a renal transplant recipient led to improvements in blood pressure and resolution of recurrent cutaneous neoplasia, with no evidence of rejection or changes in renal function.

Topics: Blood Pressure; Calcineurin Inhibitors; Creatinine; Cyclosporine; Drug Therapy, Combination; Everolimus; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Postoperative Complications; Prednisolone; Sirolimus; Skin Neoplasms; Treatment Outcome; Withholding Treatment

Sirolimus-eluting stents (SESs) have been shown to decrease restenosis compared with bare metal stents (BMSs). Currently, there are limited data on the long-term efficacy of these devices in a real-world patient population. Furthermore, the potential of a late restenotic phenomenon has not yet been excluded. From April to October 2002, 508 consecutive patients with de novo lesions exclusively treated with SESs were enrolled and compared with 450 patients treated with BMSs in the preceding 6 months (control group). Patients in the SES group more frequently had multivessel disease and type C lesions, received more stents, and had more bifurcation stenting. After 3 years, the cumulative incidence of major adverse cardiac events (comprising death, myocardial infarction, and target vessel revascularization) was significantly lower in the SES group compared with the pre-SES group (18.9% vs 24.7%, hazards ratio 0.73, 95% confidence interval 0.56 to 0.96, p = 0.026). The 3-year risk of target lesion revascularization was 7.5% in the SES group versus 12.6% in the pre-SES group (hazards ratio 0.57, 95% confidence interval 0.38 to 0.87, p = 0.01). In conclusion, the unrestricted use of SESs is safe and superior to the use of BMSs. The beneficial effects, reported after 1 and 2 years in reducing major adverse cardiac events, persisted with no evidence of a clinical late restenotic "catch-up" phenomenon.

Topics: Age Factors; Angina, Unstable; Angioplasty, Balloon; Case-Control Studies; Coronary Restenosis; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Netherlands; Prosthesis Design; Registries; Regression Analysis; Shock, Cardiogenic; Sirolimus; Stents

Topics: Adolescent; Age of Onset; Cardiology; Child; Coronary Restenosis; Diastole; Drug Implants; Everolimus; Heart Failure; Humans; Hypertension; Hypolipidemic Agents; Immunosuppressive Agents; Postoperative Complications; Sirolimus; Stents; Treatment Outcome; United States

Recent studies with eluting stents showed encouraging results in preventing in-stent restenosis. We report a case of a patient in whom the implantation of carbon-coated and eluting stents in two different vessels was associated with different angiographic results. A diabetic hypertensive 67-year-old woman with an acute inferior myocardial infarction underwent direct coronary angioplasty on the right coronary artery with the implantation of two carbon-coated stents. In view of the severity of an additional lesion of the left anterior descending coronary artery and diabetes, coronary angioplasty and stenting with an eluting stent was performed in this vessel. Five months later the patient presented with acute pulmonary edema and an increase in troponin I levels. A new coronary angiography showed a long subtotal in-stent restenosis of the right coronary artery, whereas the left anterior descending coronary artery was normal. Our case report suggests that eluting stents should be considered a precious and effective tool in preventing in-stent restenosis.

Topics: Aged; Angioplasty; Carbon; Coated Materials, Biocompatible; Coronary Angiography; Coronary Stenosis; Diabetes Mellitus, Type 1; Female; Humans; Hypertension; Myocardial Infarction; Sirolimus; Stents

A rare but well-documented serious adverse reaction to the administration of the calcineurin inhibitors tacrolimus and cyclosporine in renal transplant recipients is the development of medication-induced thrombotic microangiopathy. The recently introduced immunosuppressive medication sirolimus has a very similar molecular structure to tacrolimus and also binds to the same intracellular proteins. Despite these similarities with tacrolimus, sirolimus has a different side-effect profile and reportedly lacks documented specific renal toxicity. This is a case report of the isolated administration of sirolimus without a concomitant calcineurin inhibitor being associated with the development of renal transplant biopsy-proven thrombotic microangiopathy. The patient is a 47-year-old African-American woman whose primary cause of renal failure was not thrombotic micrangiopathy, and she received a 5-antigen mismatched cadaveric renal transplant. Because of preexisting nephrosclerosis in the renal transplant, this patient was never administered a calcineurin inhibitor but was always maintained on sirolimus. With recent animal data showing that sirolmus can be nephrotoxic in a renal ischemic-reperfusion model (similar to what happens with a renal transplant), the authors speculate on a mechanism for this adverse reaction.

Topics: Adult; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Middle Aged; Nephrosclerosis; Postoperative Complications; Sirolimus; Smoking; Thrombosis; Tissue Donors; Transplantation; Vascular Diseases

Prevalence of arterial hypertension suddenly rose in patients after renal transplantation since cyclosporine A was introduced. Arterial hypertension is now diagnosed in 67-90% of patients after renal transplantation. It has not only negative effect on cardiovascular system but also shortens survival of renal graft. Ambulatory blood pressure monitoring (ABPM) enables evaluation of diumal profile of BP and efficacy of treatment. This diagnostic tool is very useful in the management of these patients. Nocturnal hypertension was 2.5 times more frequent than daytime elevation of BP in the group of 58 consecutive renal transplant patients treated with calcineurin inhibitors who were assessed by ABPM at our department. Lack of nocturnal dip of BP was observed in most of the patients. Conversion from calcineurin inhibitors (cyclosporine A, tacrolimus) to sirolimus or mycophenolate mofetil may improve BP profile in this group of patients.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Poland; Sirolimus; Tacrolimus

Inhibition of calcineurin-mediated signaling in T lymphocytes is a major mechanism of cyclosporine A (CsA)-induced immunosuppression, and previous rat studies have suggested that inhibition of calcineurin-mediated signaling in central neuronal pools involved in blood pressure regulation plays an important role in causing acute CsA-induced hypertension. However, a central neural mechanism is difficult to reconcile with other data suggesting that CsA-induced hypertension is due to activation of renal and other subdiaphragmtic visceral afferents that reflexively increase efferent sympathetic nerve activity. Accordingly, we now have revised our hypothesis to suggest that CsA stimulates renal afferents by a calcineurin-dependent process. To test this new hypothesis, in anesthetized rats we recorded arterial pressure and multifiber afferent renal nerve activity from the cut distal end of the renal nerve before, during, and after intravenous infusion of either CsA (5 mg/kg over 20 min, n = 8), FK506 (0.15 mg/kg, n = 7), another potent calcineurin inhibitor that is structurally unrelated to CsA, or rapamycin (0.15 mg/kg, n = 4), a structural analog of FK506 that has no effect on calcineurin. We found that renal afferent discharge was increased markedly by intravenous FK506, as well as CsA, but unaffected by rapamycin (or vehicle), indicating calcineurin mediation. After infusion of either calcineurin inhibitor, afferent renal nerve activity remained elevated for up to 2 h, paralleling the prolonged increase in blood pressure. Thus, the major new conclusion of this study is that, in contrast to what has been assumed previously, calcineurin inhibitors enhance sympathetic neurotransmission by a novel action localized to visceral sensory nerve endings rather than to nerve cell bodies or central synapses. In the rat, calcineurin-dependent activation of renal afferents appears to be the primary mechanism producing the large blood-pressure-raising effect of CsA. Because the data suggest that the major side-effect of CsA and FK506--hypertension--is inexorably linked to calcineurin inhibition in extralymphoid tissue, development of agents that selectively inhibit calcineurin only in T lymphocytes could eliminate this important secondary form of hypertension.

Topics: Animals; Blood Pressure; Calcineurin Inhibitors; Cyclosporine; Hypertension; Kidney; Male; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus; Time Factors

The effects of rapamycin (RAPA), administered at therapeutic doses, were investigated in the spontaneously hypertensive rat (SHR). Additionally, the reversibility of RAPA's renal effects was investigated at a supratherapeutic dose. At doses that were active in preventing heart and kidney allograft rejection in the rat (0.01-0.08 mg/kg i.v.), RAPA had no effect on kidney function or rat body weight gain. At higher doses (0.8 mg/kg), RAPA produced significant changes in kidney function parameters and caused a loss in body weight. Histopathologic changes, including necrotizing vasculopathy and tubular atrophy, were noted at therapeutic doses. The effects of RAPA on kidney function were completely reversible after a 2-week washout period, though the histopathologic changes were still evident. These studies demonstrate that RAPA does not impair kidney function at therapeutic doses when administered for 2 weeks but does appear to accelerate the naturally occurring renal lesions of the SHR.

Topics: Animals; Body Weight; Hypertension; Immunosuppressive Agents; Kidney; Male; Polyenes; Rats; Rats, Inbred SHR; Sirolimus