sirolimus and Postoperative-Complications

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.

Topics: Adaptive Immunity; Antiviral Agents; Betacoronavirus; Calcineurin Inhibitors; Contraindications, Drug; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Disease Susceptibility; Drug Interactions; Everolimus; Glucocorticoids; Humans; Immunity, Innate; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Pandemics; Pneumonia, Viral; Postoperative Complications; SARS-CoV-2; Sirolimus; TOR Serine-Threonine Kinases

Heterotopic ossification (HO) is associated with inflammation. The goal of this review is to examine recent findings on the roles of inflammation and the immune system in HO. We examine how inflammation changes in fibrodysplasia ossificans progressiva, in traumatic HO, and in other clinical conditions of HO. We also discuss how inflammation may be a target for treating HO.. Both genetic and acquired forms of HO show similarities in their inflammatory cell types and signaling pathways. These include macrophages, mast cells, and adaptive immune cells, along with hypoxia signaling pathways, mesenchymal stem cell differentiation signaling pathways, vascular signaling pathways, and inflammatory cytokines. Because there are common inflammatory mediators across various types of HO, these mediators may serve as common targets for blocking HO. Future research may focus on identifying new inflammatory targets and testing combinatorial therapies based on these results.

Topics: Adaptive Immunity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthroplasty, Replacement, Hip; Blast Injuries; Brain Injuries, Traumatic; Burns; Cell Differentiation; Cytokines; Humans; Hypoxia; Immunosuppressive Agents; Inflammation; Janus Kinase Inhibitors; Macrophages; Mast Cells; Mesenchymal Stem Cells; Myositis Ossificans; Ossification, Heterotopic; Postoperative Complications; Pyrazoles; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Signal Transduction; Sirolimus; Spinal Cord Injuries; Stilbenes; Wounds and Injuries

Previous studies have indicated that sirolimus (SRL) may be effective for HCC patients undergoing liver transplantation (LT). However, the following results are still contradictory and do not have a clear conclusion. Therefore, we conducted an updated meta-analysis by retrieving published data in EMBASE, PubMed, and the Cochrane Library up to October 2017. Both efficiency and safety of SRL were analyzed using pooled odds ratio (ORs) with 95% confidence interval (CIs). A total of 11 studies involving 7,695 HCC patients were included. Compared with control group, SRL prolonged 1-year (OR = 2.44; CI = 1.66-3.59), 3 year (OR = 1.67; CI = 1.08-2.58) and 5-year (OR = 1.68; CI = 1.21-2.33) overall survival, as well as 1-year (OR = 2.13; CI = 1.19-3.81) disease-free survival. Pooled results found that SRL-treated patients had lower recurrence (OR = 0.60; CI = 0.37-0.98), lower recurrence-related mortality (OR = 0.58; CI = 0.42-0.81) and lower overall mortality (OR = 0.62; CI = 0.44-0.89). Moreover, fewer SRL-treated patients suffered from portal vein thrombosis (OR = 0.29; CI, 0.09-0.91) and diabetes (OR = 0.23; CI = 0.12-0.47), while SRL-treated patients were more vulnerable to acne compared with the control group (OR = 4.44; CI = 1.56-12.60). No significant differences in other adverse effects were found between two groups. Taken together, SRL-based immunosuppression is safe and effective in improving survival, as well as reducing recurrence and mortality for HCC patients following LT.

Topics: Carcinoma, Hepatocellular; Diabetes Mellitus; Disease-Free Survival; Graft Rejection; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Neoplasm Recurrence, Local; Portal Vein; Postoperative Complications; Sirolimus; Venous Thrombosis

This brief overview discusses recent data on the use of mammalian target of rapamycin (mTOR) inhibitors in heart transplantation. Trials on de novo use have shown good efficacy of mTOR inhibitors; however, adverse events are often seen. Conversion protocols in long-term patients are mainly used in patients with renal insufficiency. Calcineurin inhibitor minimization and conversion to calcineurin inhibitor-free protocols have proven to stabilize renal function in recent trials. Lastly, beneficial effects of mTORs against the development of graft vasculopathy, cytomeglovirus infection and malignancy have been shown. Nevertheless, lower tolerability of the drug has affected the long-term use in patients. Future consideration of using mTORs will be individualized protocols in special subpopulation after heart transplantation.

Topics: Calcineurin Inhibitors; Drug Therapy, Combination; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Postoperative Complications; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Viruses are the leading cause of infections after solid organ transplant. The antiviral properties of mammalian target of rapamycin inhibitors (mTORis) have been ascribed to a variety of mechanisms and historical data have supported their use over other immunosuppressants for a myriad of viruses. Herein, we summarize the most current data to highlight the role of mTORis in the management of viral infections after solid organ transplant. The mTORis play a clear role in the management of cytomegalovirus, and have data supporting their potential use for BK virus and human herpesvirus 8-related Kaposi sarcoma. No data definitively supports mTORis for use in Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder or hepatitis C virus viral replication. Although theoretically an advantageous therapy for hepatitis C virus-related liver allograft fibrosis and human immunodeficiency virus, mTORi use specifically for these indications is less attractive with modern treatments currently available. Data surrounding mTORi efficacy in preventing rejection, and their toxicity profile must be balanced with their potential antiviral effects in combination with patient-specific factors.

Topics: Everolimus; Humans; Organ Transplantation; Postoperative Complications; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Virus Diseases

Although first-generation drug-eluting stents (DES) have significantly reduced the risk of in-stent restenosis, they have also increased the long-term risk of stent thrombosis. This safety concern directly triggered the development of new generation DES, with innovations in stent platforms, polymers, and anti-proliferative drugs. Stent platform materials have evolved from stainless steel to cobalt or platinum-chromium alloys with an improved strut design. Drug-carrying polymers have become biocompatible or biodegradable and even polymer-free DES were introduced. New limus-family drugs (such as everolimus, zotarolimus or biolimus) were adopted to enhance stent performances. As a result, these new DES demonstrated superior vascular healing responses on intracoronary imaging studies and lower stent thrombotic events in actual patients. Recently, fully-bioresorbable stents (scaffolds) have been introduced, and expanding their applications. In this article, the important concepts and clinical results of new generation DES and bioresorbable scaffolds are described.

Topics: Absorbable Implants; Coated Materials, Biocompatible; Coronary Restenosis; Drug-Eluting Stents; Humans; Immunosuppressive Agents; Inventions; Percutaneous Coronary Intervention; Polymers; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; Thrombosis

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly used in cardiothoracic transplantation. Several recent clinical trials have demonstrated their efficacy in combination with reduced cyclosporine dosing in de novo heart transplant recipients, in particular with everolimus. A number of other studies have demonstrated their efficacy for improving renal function and reducing calcineurin inhibitor use, attenuating cardiac allograft vasculopathy progression and reducing cytomegalovirus infections in maintenance heart transplant populations. A growing body of literature, including a small number of clinical trials, now describes the use mTOR inhibitors in lung transplant recipients. The benefits in this population include improved lung and renal function in limited studies. Considerably less evidence is available in pediatric heart transplantation, though similar indications in the maintenance therapy population have been described. The benefits of mTOR inhibitors must be weighed against the increased risk of adverse events and drug intolerance compared with other primary immunosuppressants, and discontinuation rates are particularly high in lung transplant recipients. The risks of surgical wound healing complications in transplant recipients receiving mTOR inhibitors previously or actively supported by mechanical circulatory support devices remains poorly described in the current literature. The current role and recent evidence for mTOR inhibitor use in heart and lung transplantation is examined in this review.

Topics: Allografts; Antineoplastic Agents; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Cytomegalovirus Infections; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Lung Transplantation; Postoperative Complications; Sirolimus; TOR Serine-Threonine Kinases; Transplant Recipients; Wound Healing

Topics: Animals; Cardiovascular Diseases; CD18 Antigens; Cell Adhesion; Coronary Vessels; Cytokines; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Inflammation Mediators; Neutrophils; Postoperative Complications; Sirolimus; TOR Serine-Threonine Kinases

Post-transplant diabetes mellitus is a significant risk factor for cardiovascular disease in solid organ transplantation. The main underlying pathophysiological mechanism of PTDM is pancreatic beta cell dysfunction in the context of insulin resistance, but the relative importance of each of these important components of glycemic metabolism is under intense debate.. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials to January 15, 2015. We selected systematic reviews and meta-analyses and randomized clinical trials. When no such reports were found for a given topic or drug, observational studies were included in the assessment.. There are agents with known diabetogenic effects: corticosteroids, calcineurin inhibitors including tacrolimus and cyclosporine, as well as the mammalian target of rapamycin inhibitors (sirolimus and everolimus). The association between the use of induction agents and PTDM is very scarce. No diabetogenic effects have been found with the use of azathioprine, mycophenolate mofetil and its derivatives.. Immunosuppression is the major modifiable risk factor for development of PTDM but risk versus benefit analysis is required to balance risk of developing PTDM versus rejection. Caution is advisable in immunosuppressant adjustments in the event that PTDM develops based on current evidence. Physicians should choose and use immunosuppression regimens shown to have the best outcome for patient and graft survival, irrespective of PTDM risk.

Topics: Adrenal Cortex Hormones; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Everolimus; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Transplantation

Although new-generation drug-eluting stents represent the standard of care among patients undergoing percutaneous coronary intervention, there remains debate about differences in efficacy and the risk of stent thrombosis between the Resolute zotarolimus-eluting stent (R-ZES) and the everolimus-eluting stent (EES). The aim of this study was to evaluate the safety and efficacy of the R-ZES compared with EES in patients undergoing percutaneous coronary intervention.. A systematic literature search of electronic resources was performed using specific search terms until September 2014. Random-effects meta-analysis was performed comparing clinical outcomes between patients treated with R-ZES and EES up to maximum available follow-up. The primary efficacy end point was target-vessel revascularization. The primary safety end point was definite or probable stent thrombosis. Secondary safety end points were cardiac death and target-vessel myocardial infarction. Five trials were identified, including a total of 9899 patients. Compared with EES, R-ZES had similar risks of target-vessel revascularization (risk ratio [RR], 1.06; 95% confidence interval [CI], 0.90-1.24; P=0.50), definite or probable stent thrombosis (RR, 1.26; 95% CI, 0.86-1.85; P=0.24), cardiac death (RR, 1.01; 95% CI, 0.79-1.30; P=0.91), and target-vessel myocardial infarction (RR, 1.10; 95% CI, 0.89-1.36; P=0.39). Moreover, R-ZES and EES had similar risks of late definite or probable very late stent thrombosis (RR, 1.06; 95% CI, 0.53-2.11; P=0.87). No evidence of significant heterogeneity was observed across trials.. R-ZES and EES provide similar safety and efficacy among patients undergoing percutaneous coronary intervention.

Topics: Drug-Eluting Stents; Everolimus; Humans; Immunosuppressive Agents; Percutaneous Coronary Intervention; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; Survival Analysis; Thrombosis; Treatment Outcome

Cardiac allograft vasculopathy (CAV) is a common complication following heart transplantation (HT), resulting in diminished graft survival. The preferred strategy for preventing CAV is optimal medical management; however, for patients who develop CAV, delaying disease progression through effective medication management is equally important. A review of the literature regarding medication management of CAV was conducted via a search of the MEDLINE database. Studies were included if they were published in English, conducted in humans ≥ 18 years of age or older, and used noninvestigational medications. Immunosuppressive medications such as the antiproliferative mycophenolate, the calcineurin inhibitor tacrolimus, and the proliferation signal inhibitors sirolimus and everolimus have been shown to prevent the development of CAV. Certain cardiovascular medications, such as HMG-CoA reductase inhibitors (statins), gemfibrozil, calcium channel blockers, and angiotensin-converting enzyme inhibitors, have also demonstrated efficacy in preventing this disease process. Prevention of CAV has also been observed with prophylaxis against cytomegalovirus infection and antioxidant medications. Despite being commonly used in HT patients, neither antiplatelet agents nor glycemic control have proved effective at preventing CAV. Only sirolimus has been shown to arrest the progress of existing CAV.

Topics: Allografts; Antioxidants; Calcineurin Inhibitors; Cardiovascular Agents; Cytomegalovirus Infections; Everolimus; Graft Occlusion, Vascular; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus

In-stent restenosis (ISR) remains a difficult problem in interventional cardiology. The relative efficacy and safety of available interventions is not clear. We aimed to perform a network meta-analysis using both direct evidence and indirect evidence to compare all available interventions.. We systematically searched electronic databases for randomized trials comparing ≥2 treatments for ISR. A network meta-analysis was performed using a Bayesian approach. Eleven treatments were compared in 31 studies with 8157 patient-years follow-up. Compared with balloon angioplasty, everolimus-eluting stent (hazard ratio [95% credibility interval], 0.13 [0.048-0.35]), paclitaxel-eluting balloon (0.32 [0.20-0.49]), paclitaxel-eluting cutting balloon (0.054 [0.0017-0.5]), paclitaxel-eluting stent (0.39 [0.24-0.62]), and sirolimus-eluting stent (0.32 [0.18-0.50]) are associated with lower target vessel revascularization. Balloon angioplasty is not different from cutting balloon (0.73 [0.31-1.5]), excimer laser (0.89 [0.29-2.7]), rotational atherectomy (0.96 [0.53-1.7]), and vascular brachytherapy (0.60 [0.35-1.0]). In drug-eluting stent ISR, balloon angioplasty was inferior to everolimus-eluting stent (0.19 [0.049-0.76]), paclitaxel-eluting balloon (0.43 [0.18-0.80]), paclitaxel-eluting stent (0.35 [0.13-0.76]), and sirolimus-eluting stent (0.36 [0.11-0.86]) for target vessel revascularization. There was no difference between treatments in probable or definitive stent thrombosis. The results of binary restenosis and target lesion revascularization were similar. Paclitaxel-eluting cutting balloon, everolimus-eluting stent, and paclitaxel-eluting balloon have the highest probability of being in the top 3 treatments based on low target lesion revascularization, but there was no statistical significant difference between them.. Balloon angioplasty is inferior to all drug-eluting treatments for ISR, including drug-eluting stent ISR. Drug-eluting stent, particularly everolimus-eluting stent, or paclitaxel-eluting cutting balloon and paclitaxel-eluting balloon should be preferred for treating ISR.

Topics: Angioplasty, Balloon; Blood Vessel Prosthesis Implantation; Coronary Restenosis; Drug-Eluting Stents; Everolimus; Humans; Paclitaxel; Percutaneous Coronary Intervention; Postoperative Complications; Proportional Hazards Models; Randomized Controlled Trials as Topic; Sirolimus

Organ transplant recipients are prone to the development of non-melanoma skin cancer. Organ transplant recipients often develop multiple non-melanoma skin cancers and the tumors show an aggressive growth pattern, therefore surgical therapy can be difficult. Switch of the immunosuppressive regimen to mTOR-inhibitors such as everolimus or sirolimus can have an antitumor effect.. In a monocentric retrospective study we evaluated organ transplant recipients who presented with non-melanoma skin cancer in the years 2008-2010. Experience with patients who were switched to an mTOR-inhibitor due to non-melanoma skin cancer are reported in detail, and recent clinical studies are reviewed.. 60 organ transplant recipients with non-melanoma skin cancer were evaluated. Due to the development of multiple non-melanoma skin cancer within a few years, the immunosuppressive regimen was switched to everolimus in 7 patients and to sirolimus in 5 patients. Eight patients were evaluable for the effect of mTOR-inhibitors on the development of non-melanoma skin cancer; 4 patients had to discontinue the medication with mTOR-inhibitors early due to various side effects. In the year before the switch to mTOR-inhibitors, 8 patients developed 16 squamous cell carcinomas, 3 Basal cell carcinomas and 22 cases of Bowen's disease. All tumors were histologically confirmed. In the year after switch of immunosuppression, the rate of squamous cell carcinomas (n = 2) and Bowen's disease (n = 3), but not of basal cell carcinomas (n = 2) was significantly reduced. Moreover, 5 prospective randomized trials recently have demonstrated a reduced number of non-melanoma skin cancers in organ transplant recipients after switch of the immunosuppressive regimen to mTOR-inhibitors.. Switch of the immunosuppressive regimen to mTOR-inhibitors should be considered for organ transplant recipients suffering from multiple non-melanoma skin cancers.

Topics: Aged; Bowen's Disease; Carcinoma, Basal Cell; Drug Substitution; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Postoperative Complications; Randomized Controlled Trials as Topic; Retrospective Studies; Sirolimus; Skin Neoplasms

Coronary artery bypass graft surgery (CABG) compared with percutaneous coronary intervention (PCI) reduces mortality in patients with diabetes mellitus. However, prior trials compared CABG with balloon angioplasty or older generation stents, and it is not known if the gap between CABG and PCI can be reduced by newer generation drug-eluting stents.. PUBMED/EMBASE/CENTRAL search for randomized trials comparing mode of revascularization in patients with diabetes mellitus. Primary outcome was all-cause mortality. Secondary outcomes were myocardial infarction, repeat revascularization, and stroke. Mixed treatment comparison analyses were performed using a random-effects Poisson regression model. Sixty-eight randomized trials that enrolled 24 015 diabetic patients with a total of 71 595 patient-years of follow-up satisfied our inclusion criteria. When compared with CABG (reference rate ratio [RR]=1.0), PCI with paclitaxel-eluting stent (RR=1.57 [1.15-2.19]) or sirolimus-eluting stent (RR=1.43 [1.06-1.97]) was associated with an increase in mortality. However, PCI with cobalt-chromium everolimus-eluting stent (RR=1.11 [0.67-1.84]) was not associated with a statistically significant increase in mortality. When compared with CABG, there was excess repeat revascularization with PCI, which progressively declined from plain old balloon angioplasty (341% increase) to bare metal stent (218% increase) to paclitaxel-eluting stent (81% increase) and to sirolimus-eluting stent (47% increase). However, for PCI with cobalt-chromium everolimus-eluting stent (RR=1.31 [0.74-2.29]), the excess repeat revascularization was not statistically significant although the point estimate favored CABG. CABG was associated with numerically higher stroke.. In patients with diabetes mellitus, evidence from indirect comparison shows similar mortality between CABG and PCI using cobalt-chromium everolimus-eluting stent. CABG was associated with numerically excess stroke and PCI with cobalt-chromium everolimus-eluting stent with numerically increased repeat revascularization. This hypothesis needs to be tested in future trials.

Topics: Coronary Artery Bypass; Diabetes Complications; Diabetes Mellitus; Drug-Eluting Stents; Everolimus; Humans; Intention to Treat Analysis; Myocardial Infarction; Paclitaxel; Percutaneous Coronary Intervention; Postoperative Complications; Randomized Controlled Trials as Topic; Reoperation; Sirolimus; Stroke; Survival Analysis; Treatment Outcome

Drug-eluting stents (DES) have transformed interventional cardiology over the past decade. Whilst their efficacy has rarely been called into question, there have been concerns over the safety of the early devices, which has prompted the development of new coronary stents. Many of these new devices have entered clinical practice, however questions remain as to whether they offer the improvements in clinical outcomes that were originally anticipated. In addition, there is a debate whether the reported high efficacy of these devices enables percutaneous coronary intervention (PCI) to be performed in patient and lesion sub-groups previous entirely the domain of the cardiac surgeon. This review paper addresses these outstanding questions.

Topics: Biocompatible Materials; Clinical Trials as Topic; Combined Modality Therapy; Comorbidity; Coronary Restenosis; Coronary Stenosis; Coronary Thrombosis; Diabetes Complications; Disease-Free Survival; Drug-Eluting Stents; Humans; Meta-Analysis as Topic; Multicenter Studies as Topic; Myocardial Infarction; Paclitaxel; Percutaneous Coronary Intervention; Polymers; Postoperative Complications; Sirolimus; Thrombolytic Therapy; Treatment Outcome

The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium.

Topics: Everolimus; Evidence-Based Medicine; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Postoperative Complications; Risk Factors; Sirolimus

Successful transplantation should lead to improvements in sexual function and sex hormone disturbances in both men and women, but immunosuppressive drugs may interfere with hormone metabolism. In this regard, several studies have showed a potential negative effect of mTOR inhibitors (mTORi) on male gonadal function, while their role in the female patients is not well documented in the literature. Successful pregnancy is possible after solid organ transplantation. The fetal effects of mTORi are still poorly defined but they seem not to represent an absolute contraindication for pregnancy. The aim of our study would be to review the impact of mTORi on fertility and pregnancy in order to have a clearer picture about their possible use after organ transplantation.

Topics: Animals; Cell Cycle; Female; Fertility; Graft Rejection; Humans; Immunosuppressive Agents; Male; Organ Transplantation; Postoperative Complications; Pregnancy; Pregnancy Complications; Quality of Life; Sirolimus; TOR Serine-Threonine Kinases

Controlled trials of mTOR inhibitors in children following solid organ transplantation are scarce, although evidence from prospective single-arm studies is growing. Everolimus with reduced CNI therapy has been shown to be efficacious and safe in de novo pediatric kidney transplant patients in prospective trials. Prospective and retrospective data in children converted from CNI therapy to mTOR inhibition following kidney, liver, or heart transplantation suggest preservation of immunosuppressive efficacy. Good renal function has been maintained when mTOR inhibitors are used de novo in children following kidney transplantation or after conversion to mTOR inhibition with CNI minimization. mTOR inhibition with reduced CNI exposure is associated with a low risk for developing infection in children. Growth and development do not appear to be impaired during low-dose mTOR inhibition, but more studies are required. No firm conclusions can be drawn as to whether mTOR inhibitors should be discontinued in children requiring surgical intervention or whether mTOR inhibition delays progression of hepatic fibrosis after pediatric liver transplantation. In conclusion, current evidence suggests that use of mTOR inhibitors in children undergoing solid organ transplantation is efficacious and safe, but a number of issues remain unresolved and further studies are required.

Topics: Calcineurin Inhibitors; Child; Everolimus; Fibrosis; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Risk; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Wound Healing

To investigate the safety and efficacy of durable polymer drug eluting stents (DES) and biodegradable polymer biolimus eluting stents (biolimus-ES).. Network meta-analysis of randomised controlled trials.. Medline, Google Scholar, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) database search for randomised controlled trials comparing at least two of durable polymer sirolimus eluting stents (sirolimus-ES) and paclitaxel eluting stents (paclitaxel-ES), newer durable polymer everolimus eluting stents (everolimus-ES), Endeavor and Resolute zotarolimus eluting stents (zotarolimus-ES), and biodegradable polymer biolimus-ES.. Safety (death, myocardial infarction, definite or probable stent thrombosis) and efficacy (target lesion and target vessel revascularisation) assessed at up to one year and beyond.. 60 randomised controlled trials were compared involving 63,242 patients with stable coronary artery disease or acute coronary syndrome treated with a DES. At one year, there were no differences in mortality among devices. Resolute and Endeavor zotarolimus-ES, everolimus-ES, and sirolimus-ES, but not biodegradable polymer biolimus-ES, were associated with significantly reduced odds of myocardial infarction (by 29-34%) compared with paclitaxel-ES. Compared with everolimus-ES, biodegradable polymer biolimus-ES were associated with significantly increased odds of myocardial infarction (by 29%), while Endeavor zotarolimus-ES and paclitaxel-ES were associated with significantly increased odds of stent thrombosis. All investigated DES were similar with regards to efficacy endpoints, except for Endeavor zotarolimus-ES and paclitaxel-ES, which were associated with significantly increased the odds of target lesion and target vessel revascularisations compared with other devices. Direction of results beyond one year did not diverge from the findings for up to one year follow-up. Bayesian probability curves showed a gradient in the magnitude of effect, with everolimus-ES and Resolute zotarolimus-ES offering the highest safety profiles.. The newer durable polymer everolimus-ES and Resolute zotarolimus-ES and the biodegradable polymer biolimus-ES maintain the efficacy of sirolimus-ES; however, for safety endpoints, differences become apparent, with everolimus-ES and Resolute zotarolimus-ES emerging as the safest stents to date.

Topics: Absorbable Implants; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Female; Humans; Male; Myocardial Infarction; Polymers; Postoperative Complications; Sirolimus; Thrombosis; Treatment Outcome

Cytomegalovirus (CMV) infection and disease are major complications in the renal transplant recipient. The occurrence of CMV is associated with acute rejection, allograft dysfunction, significant end-organ disease, and mortality. Several clinical studies have indicated that the use of certain immunosuppressive drugs can delay the reconstitution of CMV-specific cell-mediated immune responses, thereby leading to uncontrolled CMV replication. Accumulating evidence indicates, however, that the use of the mammalian target of rapamycin (mTOR) inhibitors, sirolimus, and everolimus, may decrease the incidence and severity of CMV infection in renal transplant recipients. The purpose of this article is to review CMV infection data from randomized clinical trials that investigated the use of sirolimus- and everolimus-based treatment regimens in de novo renal transplantation. The mTOR inhibitor clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors' discretion. This review will summarize these studies to discuss whether mTOR inhibitor-based immunosuppressive therapy can reduce the magnitude of CMV-related complications in the de novo renal transplantation setting.

Topics: Cytomegalovirus; Cytomegalovirus Infections; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Sirolimus

Surgical complications, including events such as lymphocele and urological complications that affect wound healing, are reported with an incidence of 15% to 32% after kidney transplantation. The experience of the surgeon and comorbidities play an important role in determining the risk of such complications occurring. Since the introduction of the inosine 5'-monophosphate dehydrogenase inhibitors (mycophenolate mofetil) to the immunosuppressive armamentarium, replacing the antimetabolite prodrug azathioprine, reports have associated certain forms of wound healing complications (wound dehiscence, impaired healing, lymphocele, and incisional hernia) with the use of these agents. When mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) became available, these findings were observed increasingly, particularly in direct comparisons with inosine 5'-monophosphate dehydrogenase inhibitors. The purpose of this article was to review the reported incidence of wound healing complications from randomized clinical trials that investigated the use of sirolimus- and everolimus-based treatment regimens in de novo kidney transplantation and the information available from the U.S. Food and Drug Administration database. The clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors' discretion. This review summarizes these studies to consider whether modern mTOR inhibitor-based immunosuppressive regimens exert and affect wound healing after kidney transplantation.

Topics: Drug Therapy, Combination; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Protein Kinase Inhibitors; Risk Assessment; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Wound Healing

Topics: Abatacept; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Desensitization, Immunologic; Graft Rejection; Hand Disinfection; Heart Failure; HLA Antigens; Humans; Immunoconjugates; Immunomodulation; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Mesenchymal Stem Cell Transplantation; Opportunistic Infections; Peritoneal Dialysis; Plasmapheresis; Postoperative Complications; Prognosis; Renal Dialysis; Renal Insufficiency; Sirolimus; Skin Neoplasms

Evidence supporting the use of drug-eluting stents (DES) in saphenous vein graft (SVG) disease is uncertain. Previous studies have suggested that DES might reduce the re-intervention rate in SVG disease, with conflicting data on mortality. Thus, a meta-analysis was performed to compare outcomes of DES vs. bare metal stent (BMS) in SVG disease.. Medline and Web databases were searched for studies comparing DES and BMS for SVG disease, reporting rates of overall mortality, target vessel revascularization (TVR) and myocardial infarction (MI) with a follow-up of ≥6 months. The meta-analysis included 23 studies (7,090 patients). Compared with BMS, DES-treated patients had lower rates of TVR (odds ratio (OR), 0.53; confidence interval (CI), 0.39-0.72; P<0.0001) and overall mortality (OR, 0.63; CI, 0.40-0.99; P=0.05), but similar rates of MI (OR, 0.92; CI, 0.64-1.33; P=0.7). Subgroup analysis highlighted differences between non-randomized studies, in which DES improved mortality rates, and randomized trials, in which benefit from DES was not evident. Meta-regression analysis showed that DES were more effective in the presence of older grafts and type 2 diabetes.. The present meta-analysis showed that, in SVG disease, DES significantly reduced TVR, but did not provide clear benefits on mortality and MI, with an opposite direction of results in mortality observed from randomized and observational data.

Topics: Aged; Aged, 80 and over; Angioplasty; Bias; Clinical Trials as Topic; Coronary Artery Bypass; Coronary Disease; Coronary Restenosis; Diabetic Angiopathies; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Paclitaxel; Postoperative Complications; Randomized Controlled Trials as Topic; Regression Analysis; Saphenous Vein; Sirolimus; Stents; Treatment Outcome

Calcineurin inhibitor drugs (CNI) are the mainstay of modern immunosuppression in renal transplantation. However, they contribute significantly to the chronic loss of renal grafts and the high morbidity and mortality in this population due to their deleterious effects on the renal graft, cardiovascular profile and tumour pathology. Anti-mTOR drugs, sirolimus (SRL) and everolimus (EVE) are potent immunosuppressants with antiproliferative and anti-migratory capacities. These properties mean that they have a potential protective role in graft dysfunction, in renal function optimisation and the appearance of malignant tumours. Indeed, clinical trials and observational studies have demonstrated that conversion from CNI to anti-mTOR-based maintenance therapy has beneficial effects on transplant outcomes in terms of renal function, without significant increase in acute rejection rates. This review article examines the evidence of the use of anti-mTOR in the following clinical situations following renal transplantation: 1) prevention of immune dysfunction and renal function preservation in de novo renal transplantation and after early or late CNI withdrawal; 2) chronic dysfunction of the renal graft; 3) cardiovascular effects; 4) de novo post-transplant diabetes, and 5) de novo tumour pathology.

Topics: Animals; Calcineurin Inhibitors; Diabetes Mellitus, Type 2; Dyslipidemias; Everolimus; Evidence-Based Medicine; Graft Rejection; Graft vs Host Disease; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney; Kidney Transplantation; Models, Animal; Multicenter Studies as Topic; Neoplasms; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases

mTOR inhibitors have been associated with wound complications and lymphoceles. We systematically reviewed randomized controlled trials (RCTs) to compare these outcomes for solid organ transplant recipients. Relevant medical databases were searched to identify RCTs in solid organ transplantation comparing mTOR inhibitors with an alternative therapy reporting on wound complications and/or lymphoceles. Methodological quality of RCTs was assessed. Pooled analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Thirty-seven RCTs in kidney, heart, simultaneous pancreas-kidney and liver transplantation were included. Pooled analyses showed a higher incidence of wound complications (OR 1.77, CI 1.31-2.37) and lymphoceles (OR 2.07, CI 1.62-2.65) for kidney transplant recipients on mTOR inhibitors together with calcineurin inhibitors (CNIs). There was also a higher incidence of wound complications (OR 3.00, CI 1.61-5.59) and lymphoceles (OR 2.13, CI 1.57-2.90) for kidney transplant recipients on mTOR inhibitors together with antimetabolites. Heart transplant patients receiving mTOR inhibitors together with CNIs also reported more wound complications (OR 1.82, CI 1.15-2.87). We found a higher incidence of wound complications and lymphoceles after kidney transplantation and a higher incidence of wound complications after heart transplantation for immunosuppressive regimens that included mTOR inhibitors from the time of transplantation.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Everolimus; Humans; Immunosuppressive Agents; Lymphocele; Organ Transplantation; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases

Prognosis after cardiac transplantation continues to improve with long-term outcomes limited by malignancy and coronary allograft vasculopathy (CAV). Everolimus may potentially reduce these late term complications, while maintaining the low cellular rejection rates seen with standard therapy.. Multiple studies have demonstrated the efficacy of everolimus in reducing acute rejection in heart transplant patients, progression and development of CAV, and the prevention and treatment of common malignancies, including skin cancer and Kaposi sarcoma. This review re-examines these studies with a focus on patient tolerability and safety.. Tolerability and safety of everolimus remain a concern with pneumonitis, effusions, mouth ulcers, edema and impaired wound healing associated with morbidity and mortality. Studies have repeatedly demonstrated renal function deterioration with concomitant everolimus and a standard dose calcineurin inhibitor (CNI). This impact can be partly reduced with CNI dose reduction without an increase in the rate of rejection.. If future studies confirm reduced CAV and malignancy rates, everolimus will become an important agent in de novo and maintenance immunotherapy in cardiac transplantation. Patient centered immunotherapy is preferred to protocol-based immunotherapy as it allows tailoring of immune therapy to each individual patient's rejection risk and side profile.

Topics: Animals; Disease Susceptibility; Dyslipidemias; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Lung Diseases; Mice; Multicenter Studies as Topic; Neoplasms; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases; Vascular Diseases; Wound Healing

Topics: Angioplasty; Animals; Clinical Trials as Topic; Coated Materials, Biocompatible; Constriction, Pathologic; Drug-Eluting Stents; Endothelium, Vascular; Humans; Lactic Acid; Metals; Polyesters; Polymers; Postoperative Complications; Sirolimus

Cancer morbidity and mortality are increasingly apparent risks in transplant recipients, thus reducing life quality and overall survival. These risks have largely been attributed to long-term immunosuppressive drug therapy, which remains necessary to prevent organ allograft rejection. Interestingly, however, recent studies challenge the premise that all immunosuppressive drugs necessarily promote cancer. A particular class of immunosuppressants, referred to as mammalian target of rapamycin (mTOR) inhibitors, has been shown to have potent anti-cancer effects that are presently being tested in clinical studies. The focus of this review is to present current evidence that allows us to understand better the dual immunosuppressive and anti-cancer functions of this class of drugs used to prevent allograft rejection. We will concentrate on the different functions of mTOR that allow it to simultaneously control the immune system and tumor development. We will also discuss results from current clinical studies that either support or refute this potential dualistic role.

Topics: Animals; Antibiotics, Antineoplastic; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Neoplasms; Postoperative Complications; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Transplantation Immunology

Topics: Acute Disease; Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Humans; Kidney Transplantation; Leukemia; Neoplasms; Postoperative Complications; Sarcoma, Kaposi; Sirolimus

Topics: Calcineurin Inhibitors; Chronic Disease; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Proteinuria; Sirolimus; Treatment Outcome

Topics: Acute Disease; Chronic Disease; Clinical Trials as Topic; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Diseases; Postoperative Complications; Sirolimus; Tacrolimus

Everolimus is a proliferation signal inhibitor (PSI)/mammalian target of rapamycin inhibitor that is structurally similar to sirolimus, but with a number of important pharmacokinetic differences, including a shorter half-life and time to steady state. In clinical trials, the efficacy of everolimus 1.5 mg/day and 3.0 mg/day combined with ciclosporin (CsA) and steroids in de novo renal transplant recipients is similar to that of mycophenolate mofetil, with one study showing a significantly lower risk of antibody-treated acute rejection with everolimus. When combined with reduced-dose CsA, everolimus is associated with improved renal function compared with full-dose CsA, with no decrease in efficacy. Thus, everolimus may play an important role in calcineurin inhibitor (CNI)-sparing regimens for renal transplant recipients. Studies with sirolimus have shown that CNI withdrawal is associated with a significant improvement in renal function, although there may be an increase in the risk of acute rejection. however, patient and graft survival are not adversely affected by CNI withdrawal. Notably, proteinuria <800 mg/day before conversion is a strong predictor of successful response to sirolimus treatment, and hypertensive therapy and serum lactate dehydrogenase levels may also predict response. Adverse events commonly associated with the PSIs include dyslipidaemia, proteinuria and anaemia, although these can usually be managed without difficulty. Data are also available to suggest that the PSIs are associated with a lower risk of malignancy than other immunosuppressive agents. In conclusion, everolimus may permit reduced exposure to CNIs in renal transplant recipients, with the potential to improve tolerability and renal function.

Topics: Acute Disease; Calcineurin; Calcineurin Inhibitors; Cell Proliferation; Clinical Trials as Topic; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Practice Guidelines as Topic; Signal Transduction; Sirolimus

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Atherosclerosis; Bone Marrow Diseases; Cell Division; Clinical Trials as Topic; Cyclosporine; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Lymphocyte Subsets; Mice; Multicenter Studies as Topic; Muscle, Smooth, Vascular; Neoplasms; Postoperative Complications; Sirolimus; TOR Serine-Threonine Kinases; Wound Healing

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

Immunosuppression remains the cause of most morbidity following organ transplantation. However, its use is also responsible for the outstanding graft and patient survival rates commonplace in modern transplantation. Thus, the predominant challenge for transplant clinicians is to provide a level of immunosuppression that prevents graft rejection while preserving immunocompetence against environmental pathogens. This review will outline several strategies for minimizing or tailoring the use of immunosuppressive drugs. The arguments for various strategies will be based on clinical trial data rather than animal studies. A distinction will be made between conventional immunosuppressive drug reduction based on over-immunosuppression, and newer induction methods specifically designed to lessen the need for chronic immunosuppression. Based on the available data we suggest that most patients can be transplanted with less immunosuppression than is currently standard.

Topics: Dose-Response Relationship, Drug; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Sirolimus

We compared the risk of stent thrombosis (ST) after drug-eluting stents (DES) versus bare-metal stents (BMS), and tested the hypothesis that the risk of DES thrombosis is related to stent length.. Whether DES increase the risk of ST remains unclear. Given the very low restenosis rate after drug-eluting stenting, longer stents are frequently implanted for the same lesion length in comparison to BMS.. We included in a meta-analysis 10 randomized studies comparing DES and BMS. Overall, 5,030 patients were included (2,602 were allocated to DES and 2,428 to BMS). The risk of thrombosis after DES versus BMS was compared, and the relationship between the rate of DES thrombosis and stent length was evaluated.. Incidence of ST was not increased in patients receiving DES (0.58% vs. 0.54% for BMS; odds ratio: 1.05; 95% confidence interval [CI]: 0.51 to 2.15; p = 1.000). The overall rate of ST did not differ significantly between patients receiving sirolimus- or paclitaxel-eluting stents (0.57% vs. 0.58%; p = 1.000). We found a significant relation between the rate of ST and the stented length (Y = -1.455 + 0.121 X; 95% CI for beta: 0.014 to 0.227; R = 0.716; p = 0.031). In patients with DES, mean stented length was longer in those suffering ST (23.4 +/- 8.1 mm vs. 21.3 +/- 4.1 mm, p = 0.025).. Drug-eluting stents do not increase the risk of ST, at least under appropriate anti-platelet therapy. The risk of ST after DES implantation is related to stent length.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Artery Disease; Coronary Thrombosis; Equipment Design; Follow-Up Studies; Humans; Paclitaxel; Postoperative Complications; Risk Factors; Sirolimus; Statistics as Topic; Stents; Treatment Outcome

We conducted a meta-analysis on 6 studies in 2,963 patients who had coronary artery disease and received a sirolimus-eluting stent or a bare metal stent for revascularization. Compared with bare metal stents, sirolimus-eluting stents did not appear to increase the risk for thrombosis up to 13.5 months after coronary intervention (risk ratio 0.49, 95% confidence interval 0.22 to 1.12, p = 0.09).

Topics: Angioplasty, Balloon, Coronary; Coated Materials, Biocompatible; Coronary Disease; Coronary Stenosis; Coronary Thrombosis; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Postoperative Complications; Radiography; Randomized Controlled Trials as Topic; Registries; Retrospective Studies; Risk Factors; Sirolimus; Stents; Time Factors; Treatment Outcome

Neurotoxicity associated with calcineurin inhibitors cyclosporin A and tacrolimus is established. Sirolimus is a new agent related to tacrolimus, but its mechanism of action differs. The authors reviewed 202 transplant recipients treated with sirolimus from 2001 to 2004. They found no evidence of neurotoxicity with sirolimus therapy for up to 18 months (range, 15 days to 3 years). Sirolimus could be considered a substitute immunosuppressant for patients with cyclosporin A or tacrolimus neurotoxicity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Calcineurin; Child; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Postoperative Complications; Prednisolone; Retrospective Studies; Sirolimus

Target of rapamycin (TOR) functions within the cell as a transducer of information from various sources, including growth factors, energy sensors, and hypoxia sensors, as well as components of the cell regulating growth and division. Blocking TOR function mimics amino acid, and to some extent, growth factor deprivation and has a cytostatic effect on proliferating cells in vivo. Inhibition of TOR in vivo, utilising its namesake rapamycin, leads to immunosuppression. This property has been exploited successfully with the use of rapamycin and its derivatives as a therapeutic agent in the prevention of organ rejection after transplantation with relatively mild side effects when compared to other immunosuppressive agents. The cytostatic effect of TOR on vascular smooth muscle cell proliferation has also recently been exploited in the therapeutic application of rapamycin to drug eluting stents for angioplasty. These stents significantly reduce the amount of arterial reblockage that results from proliferating vascular smooth muscle cells. In cancer, the effect of blocking TOR function on tumour growth and disease progression is currently of major interest and is the basis for a number of ongoing clinical trials. However, different cell types and tumours respond differently to TOR inhibition, and TOR is clearly not cytostatic for all types of cancer cells in vitro or in vivo. As the molecular details of how TOR functions and the targets of TOR activity are further elucidated, tumour and tissue specific functions are being identified that implicate TOR in angiogenesis, apoptosis, and the reversal of some forms of cellular transformation. This review will describe our current understanding of TOR function, describe the current strategies for employing TOR inhibitors in clinical and preclinical development, and outline future strategies for appropriate targets of TOR inhibitors in the treatment of disease.

Topics: Antineoplastic Agents; Apoptosis; Arterial Occlusive Diseases; Cell Division; Clinical Trials as Topic; Energy Metabolism; Gene Expression Regulation; Growth Substances; Heart Transplantation; Humans; Immunosuppressive Agents; Models, Biological; Muscle, Smooth, Vascular; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Postoperative Complications; Protein Kinase Inhibitors; Protein Kinases; Protein Structure, Tertiary; Signal Transduction; Sirolimus; Stents; TOR Serine-Threonine Kinases; Wound Healing

Rapamycin powerfully inhibits the progression of antigen-activated T cells through the cell cycle. In animal heart transplantation models, rapamycin therapy has been associated with profound immunosuppressive effects on host humoral and cellular responses. In consequence, further studies have been conducted to evaluate the efficiency of rapamycin in preventing acute heart allograft rejection, treating refractory acute heart allograft rejection, inducing transplantation tolerance, and preventing and treating transplant coronary artery disease. The results of these studies indicated that rapamycin can effectively prevent acute graft rejection and inhibit refractory acute graft rejection in heart transplant recipients by exerting potent immunosuppressive and antiproliferative effects without adversely affecting renal function. This supports the use of rapamycin therapy in heart transplant recipients, especially in those with renal dysfunction, for whom treatment with calcineurin inhibitors is contraindicated. Rapamycin may also halt and even reverse the progression of cardiac allograft vasculopathy, which warrants further clinical trials in humans. Finally, rapamycin may be able to induce transplantation tolerance, thus making it one of the most promising modalities for improving the long-term survival of heart transplant recipients.

Topics: Cell Cycle; Communicable Disease Control; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Infections; Postoperative Complications; Sirolimus; T-Lymphocytes

This study evaluated the early outcomes of patients with acute coronary syndromes (ACS) treated with sirolimus-eluting stents (SES).. The safety of SES implantation in patients with a high risk for early thrombotic complications is currently unknown.. Sirolimus-eluting stents have been utilized as the device of choice for all percutaneous procedures in our institution, as part of the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. After four months of enrollment, 198 patients with ACS had been treated exclusively with SES (64% of those treated in the period) and were compared with a control group composed of 301 consecutive patients treated with bare stents in the same time period immediately before this study. The incidence of major adverse cardiac events (MACE) during the first month was evaluated (death, nonfatal myocardial infarction [MI], or re-intervention).. Compared with control patients, patients treated with SES had more primary angioplasty (95% vs. 77%; p < 0.01), more bifurcation stenting (13% vs. 5%; p < 0.01), less previous MI (28% vs. 45%; p < 0.01), and less glycoprotein IIb/IIIa inhibitor utilization (27% vs. 42%; p < 0.01). The 30-day MACE rate was similar between both groups (SES 6.1% vs. control patients 6.6%; p = 0.8), with most complications occurring during the first week. Stent thrombosis occurred in 0.5% of SES patients and in 1.7% of control patients (p = 0.4). In multivariate analysis, SES utilization did not influence the incidence of MACE (odds ratio 1.0 [95% confidence interval: 0.4 to 2.2]; p = 0.97).. Sirolimus-eluting stent implantation for patients with ACS is safe, with early outcomes comparable with bare metal stents.

Topics: Acute Disease; Aged; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Combined Modality Therapy; Coronary Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Multivariate Analysis; Netherlands; Postoperative Complications; Predictive Value of Tests; Risk Factors; Sirolimus; Stents; Syndrome; Time Factors; Treatment Outcome

There have been only five reported cases of primary posttransplant T-cell lymphoma. We report the first case associated with the use of sirolimus (Rapamycin, Wyeth-Ayerst, Philadelphia, PA). The patient, receiving prednisone, cyclosporine, and sirolimus treatment, developed ascites, diarrhea, and weight loss 7 months after his second renal transplant. Tissue obtained at laparotomy established the diagnosis of primary T-cell lymphoma. Latent membrane protein-1 for Epstein-Barr virus was negative, but in-site hybridization test for Epstein-Barr-encoded RNA was positive. Despite aggressive chemotherapy, the patient died 8 months posttransplant. This is the sixth reported case of primary intestinal posttransplant T-cell lymphoma, but it is the first case associated with the use of sirolimus. The incidence of posttransplant lymphoproliferative disease in patients receiving sirolimus should be studied.

Topics: Fatal Outcome; Humans; Immunosuppressive Agents; Intestinal Neoplasms; Kidney Transplantation; Lymphoma, T-Cell; Male; Middle Aged; Postoperative Complications; Sirolimus

Topics: Calcineurin Inhibitors; Enzyme Inhibitors; Humans; Hyperlipidemias; Immunosuppression Therapy; Immunosuppressive Agents; Postoperative Complications; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Transplantation Immunology

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Postoperative Complications; Sirolimus; Tacrolimus; Transplantation Immunology

Topics: Clinical Trials as Topic; Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Postoperative Complications; Sirolimus

Topics: Coronary Disease; Cyclosporine; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppression Therapy; Immunosuppressive Agents; Isoxazoles; Leflunomide; Mycophenolic Acid; Polyenes; Postoperative Complications; Sirolimus; Tacrolimus

This study evaluated the 5-year clinical outcomes of the Genoss DES, the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer.We previously conducted the first-in-patient prospective, multicenter, randomized trial with a 1:1 ratio of patients using the Genoss DES and Promus Element stents; the angiographic and clinical outcomes of the Genoss DES stent were comparable to those of the Promus Element stent. The primary endpoint was major adverse cardiac events (MACE), which was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR) at 5 years.We enrolled 38 patients in the Genoss DES group and 39 in the Promus Element group. Thirty-eight patients (100%) from the Genoss DES group and 38 (97.4%) from the Promus Element group were followed up at 5 years. The rates of MACE (5.3% vs 12.8%, P = .431), death (5.3% vs 10.3%, P = .675), TLR (2.6% vs 2.6%, P = 1.000), and target vessel revascularization (TVR) (7.9% vs 2.6%, P = .358) at 5 years did not differ significantly between the groups. No TLR or target vessel revascularization was reported from years 1 to 5 after the index procedure, and no MI or stent thrombosis occurred in either group during 5 years.The biodegradable polymer Genoss DES and durable polymer Promus Element stents showed comparable low rates of MACE at the 5-year clinical follow-up.

Topics: Absorbable Implants; Adult; Aged; Aged, 80 and over; Cardiovascular Agents; Coronary Artery Disease; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Percutaneous Coronary Intervention; Polymers; Postoperative Complications; Prospective Studies; Republic of Korea; Sirolimus; Treatment Outcome

We compared 10-year clinical outcomes in diabetes and nondiabetes patients treated with Endeavor zotarolimus-eluting (ZES) or Cypher sirolimus-eluting coronary stents (SES). A total of 1,162 patients were randomized to ZES (169 with diabetes) and 1,170 patients were randomized to SES (168 with diabetes). Patients were further stratified by diabetes status at the time of inclusion. A subgroup of patients with diabetes (n = 88) underwent angiographic re-evaluation 10 months after stent implantation. End points included a combined end point of death or myocardial infarction, and the individual end points of death, myocardial infarction, and revascularization. In patients with diabetes, we found no difference in the combined end point (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.53 to 1.24), death (OR 0.80, 95% CI 0.51 to 1.25), or in MI (OR 1.07, 95% CI 0.60 to 1.91). However, diabetics with ZES more frequently underwent coronary revascularization compared with SES patients (OR 1.93, 95% CI 1.05 to 3.66). In patients without diabetes, ZES and SES had similar 10-year rates of all end points (death: OR 1.13, 95% CI 0.93 to 1.39; MI: OR 0.80, 95% CI 0.61 to 1.05; revascularization: OR 0.81, 95% CI 0.61 to 1.09). Landmark analysis from 5 to 10 years showed no difference in outcomes between SES and ZES in either subgroup. In conclusion, at 10 years, SES and ZES performed similarly in patients with and without diabetes. Although coronary revascularization was more prevalent in diabetes patients with ZES, this may, in part, have been related to the angiographic follow-up that was offered to a subgroup of diabetes patients.

Topics: Cause of Death; Coronary Angiography; Coronary Artery Disease; Denmark; Diabetes Mellitus; Drug-Eluting Stents; Follow-Up Studies; Forecasting; Humans; Immunosuppressive Agents; Incidence; Postoperative Complications; Retrospective Studies; Risk Assessment; Sirolimus; Survival Rate

Patients aged ≥80 years are often treated with new-generation drug-eluting stents (DES), but data from randomized studies are scarce owing to underrepresentation in most trials. We assessed 1-year clinical outcome of octogenarians treated with new-generation DES versus younger patients.. We pooled patient-level data of 9,204 participants in the TWENTE, DUTCH PEERS, BIO-RESORT, and BIONYX (TWENTE I-IV) randomized trials. The main clinical end point was target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction (MI), or clinically indicated target vessel revascularization.. The 671 octogenarian trial participants had significantly more comorbidities. TVF was higher in octogenarians than in 8,533 patients <80 years (7.3% vs 5.3%, hazard ratio [HR]: 1.36, 95% CI: 1.0-1.83, P = .04). The cardiac death rate was higher in octogenarians (3.9% vs 0.8%, P < .001). There was no significant between-group difference in target vessel MI (2.3% vs 2.3%, P = .88) and repeat target vessel revascularization (1.9% vs 2.8%, P = .16). In multivariate analyses, age ≥ 80 years showed no independent association with TVF (adjusted HR: 1.04, 95% CI: 0.76-1.42), whereas the risk of cardiac death remained higher in octogenarians (adjusted HR: 3.38, 95% CI: 2.07-5.52, P < .001). In 6,002 trial participants, in whom data on major bleeding were recorded, octogenarians (n = 459) showed a higher major bleeding risk (5.9% vs 1.9%; HR: 3.08, 95% CI: 2.01-4.74, P < .001).. Octogenarian participants in 4 large-scale randomized DES trials had more comorbidities and a higher incidence of the main end point TVF. Cardiac mortality was higher in octogenarians, whereas there was no increase in MI or target vessel revascularization rates. Treatment of octogenarian patients with new-generation DES appears to be safe and effective.

Topics: Aged, 80 and over; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Complications; Reoperation; Risk Adjustment; Risk Factors; Sirolimus; Treatment Outcome

The mechanistic target of rapamycin (mTOR) integrates environmental inputs to regulate cellular growth and metabolism in tumors. However, mTOR also regulates T-cell differentiation and activation, rendering applications of mTOR inhibitors toward treating cancer complex. Preclinical data support distinct biphasic effects of rapamycin, with higher doses directly suppressing tumor cell growth and lower doses enhancing T-cell immunity. To address the translational relevance of these findings, the effects of the mTOR complex 1 (mTORC1) inhibitor, rapamycin, on tumor and T cells were monitored in patients undergoing cystectomy for bladder cancer. MB49 syngeneic murine bladder cancer models were tested to gain mechanistic insights. Surgery-induced T-cell exhaustion in humans and mice and was associated with increased pulmonary metastasis and decreased PD-L1 antibody efficacy in mouse bladder cancer. At 3 mg orally daily, rapamycin concentrations were 2-fold higher in bladder tissues than in blood. Rapamycin significantly inhibited tumor mTORC1, shown by decreased rpS6 phosphorylation in treated versus control patients (

Topics: Aged; Animals; B7-H1 Antigen; Cell Proliferation; Cystectomy; Disease Models, Animal; Female; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Phosphorylation; Postoperative Complications; Programmed Cell Death 1 Receptor; Ribosomal Protein S6; Sirolimus; T-Lymphocytes; Urinary Bladder; Urinary Bladder Neoplasms

Ovarian cysts are a common finding in reproductive-aged females. Most of them are functional cysts that typically resolve spontaneously and require no treatment. However, ovarian cysts may also be adverse events associated with inhibitors of the mammalian target of rapamycin (mTOR). Both approved mTOR inhibitors everolimus and sirolimus are widely used as immunosuppressive agents after organ transplantation. The aim of this study was to compare the effect of mTOR inhibitors vs. non-mTOR inhibitor immunosuppression on the incidence, size and complication rate of ovarian cysts in renal transplant recipients.. We retrospectively analysed 571 consecutive female kidney transplant patients in our centre between 2000 and 2008. The follow-up period was extended through December 31st, 2012.. 102 (17.8%) patients received mTOR inhibitors for at least one month after transplantation. We identified 44 women (7.7%) with new ovarian cysts. Ovarian cysts were significantly more frequent among patients receiving mTOR inhibitors (20.5%) than in the control group (4.9%; p < 0.001). Also the hospitalization rate was higher (p = 0.05) in the mTOR group and ten patients (47.6%) requiring surgery.. Future prospective studies are required to determine the underlying cause of ovarian toxicity and treatment strategies have to be developed in order to avoid severe complications.

Topics: Adolescent; Adult; Child; Everolimus; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Middle Aged; Ovarian Cysts; Postoperative Complications; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Transplant Recipients; Treatment Outcome; Young Adult

Graft survival following pancreas transplant alone (PTA) is inferior to other pancreas transplants. Steroid elimination is appealing, but a two-drug maintenance strategy may be inadequate. Additionally, recipients tend to have diabetic nephropathy and do not tolerate nephrotoxic medications. A three-drug maintenance strategy permits immunosuppression through different mechanisms as well as an opportunity to use lower doses of the individual medications. Induction consisted of five doses of rabbit antithymocyte globulin (1 mg/kg/dose). As of October 2007, a single dose of rituximab (150 mg/m

Topics: Adult; Animals; Antilymphocyte Serum; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prognosis; Rabbits; Retrospective Studies; Risk Factors; Rituximab; Sirolimus; Tacrolimus

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.

Topics: Australia; Cyclosporine; Everolimus; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Sirolimus; Skin Neoplasms; Transplant Recipients

Polymer coatings of drug-eluting stents (DES) may induce allergic reactions and inflammation, resulting in late-acquired stent malapposition (LASM) with the risk of stent thrombosis. This study evaluated, if biodegradable polymer (BP) reduces the incidence of LASM compared to permanent polymer (PP) after treatment with newer generation DES.. Fifty patients with 59 lesions were randomized (2:1) to elective treatment with second generation PP-DES (n = 32, 39 stents), either Everolimus-eluting or Zotarolimus-eluting stents, or with BP-DES (Biolimus-eluting stents [BES]; n = 18, 20 stents) and underwent optical coherence tomography directly after implantation and after 1 year. After implantation acute stent malappositions (ASM) were documented in 30 stents (51%) distributed to 22 stents treated with PP-DES (56%) and 8 with BP-DES (40%; n.s.). After 1 year, late stent malappositions (LSM) were detected in 14 stents (24 %); ASM persisted (APSM) in 9 stents after one year (7 PP-DES-18%, 2 BES-10%), whereas ASM resolved in 21 stents. In addition, LASM was documented in nine stents including five stents without and four stents with additional APSM. All LASM were located in PP-DES (n = 9; 23%), none in BP-DES (P = 0.022). Compared to the reference lumen area, in-stent lumen area of stents without LASM was smaller due to neointimal hyperplasia (P = 0.021), whereas in-stent lumen area at maximum LASM of stents with LASM was larger due to positive remodeling (P = 0.002).. In conclusion the use of BP-DES reduced the occurrence of LASM due to positive remodeling compared to second generation PP-DES.

Topics: Absorbable Implants; Aged; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Neointima; Percutaneous Coronary Intervention; Polymers; Postoperative Complications; Prospective Studies; Prosthesis Design; Prosthesis Failure; Sirolimus; Tomography, Optical Coherence; Treatment Outcome

Head to head trials of clinical outcomes of sirolimus eluting polymer free vs. biodegradable polymer stents are lacking.. Single centre prospective open labeled randomised controlled clinical trial. Basis for sample size calculation was the rate of MACE from the ISAR TEST 3 trial in which the absolute difference was 10.25% with a standard deviation of 0.24. Assuming null hypothesis, 80% power and 5% alpha error, to detect a 10% difference, adjusting for 10% loss of follow up, sample size was 204.. Patients with stable coronary artery disease or recent acute coronary syndrome ( >1 week from the date of STEMI), being taken up for elective angioplasty.. Primary end point was MACE at 1 year and secondary end points at the end of 1 year were cardiac death, urgent target lesion revascularization, acute coronary syndrome, stroke and in-stent re-stenosis.. 204 patients were enrolled between January 2013 to July 2014, 91 in the polymer-free group and 113 in the biodegradable polymer group. Baseline characteristics were comparable between both groups. 21 patients (10.29%), were lost to follow up. MACE at 1 year were comparable in both the groups 3 of 85(3.52%) in the polymer-free group and 3 of 98(3.06%) in the biodegradable polymer group, p = 0.859. The secondary end points were also comparable between the two groups- Death- 1 of 85(1.17%) vs. 2 of 98(2.04%), p = 0.646, Stroke 0 of 85 vs. 2 of 98(2.04%), p = 0.185 and acute coronary syndrome - 2 of 85(2.35%) vs. 1 of 98(1.02%), p = 0.204. There were no instances of urgent target lesion re-vascularisation or definite stent thrombosis in either groups. In stent re-stenosis was found in 7 of 85(8.2%) in the polymer-free group vs. 6 of 98(6.12%) in the biodegradable polymer group.. The 1 year MACE rates are comparable in patients who underwent elective coronary revascularization using sirolimus eluting polymer-free and biodegradable polymer stents.

Topics: Absorbable Implants; Adolescent; Adult; Aged; Aged, 80 and over; Coronary Artery Disease; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Percutaneous Coronary Intervention; Polymers; Postoperative Complications; Prospective Studies; Prosthesis Design; Sirolimus; Time Factors; Treatment Outcome; Young Adult

Long-term follow-up after a clinical trial of 2 often-used, newer-generation drug-eluting stents (DESs) in a broad patient population is of interest. Comprehensive long-term outcome of eligible nonenrolled patients has never been reported.. To assess 5-year safety and efficacy of 2 newer-generation DESs in randomized participants with non-ST-elevation acute coronary syndromes or stable angina and to evaluate long-term outcomes of nonenrolled eligible patients treated with the same DESs.. The TWENTE (Real-World Endeavor Resolute vs Xience V Drug-Eluting Stent Study in Twente) trial is an investigator-initiated, patient-blinded, randomized, comparative DES trial that enrolled patients from June 18, 2008, to August 26, 2010. Most patients had non-ST-elevation acute coronary syndromes and complex lesions. Of all 1709 eligible patients, 1391 (81.4%) were treated in the TWENTE trial with zotarolimus-eluting (ZES, n = 697) or everolimus-eluting (EES, n = 694) cobalt-chromium stents. The remaining 318 eligible patients (18.6%) were not enrolled but underwent nonrandomized treatment with the same DESs. Data were analyzed from August 26, 2015, to October 11, 2016. Event rates (percentages) were derived from log-rank analysis and may differ from straightforward calculation (nominator/denominator). The 5-year follow-up of the TWENTE participants was prespecified in the trial protocol; that of the nonenrolled participants was ad hoc.. Target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction, or target vessel revascularization.. Of 1709 eligible participants, 1233 (72.1%) were men, 476 (27.9%) were women, and mean (SD) age was 64.6 (10.6) years. Among the 1370 of 1391 TWENTE trial participants (98.5% follow-up), TVF was similar between those in the ZES (16.1%) and EES (18.1%) groups (P = .36). Stent thrombosis rates were low: definite (7 of 697 [1.0%] vs 4 of 694 [0.6%]; P = .37) and occurred after more than 1 year in 3 (0.4%) with ZES vs 4 (0.6%) with EES (P = .69). The 318 nonenrolled eligible patients (308 patients [96.9%] of whom were followed up) were older and had more advanced disease than trial participants. Their TVF rate was higher than that of trial participants (71 of 318 [23.3%] vs 233 of 1391 [17.1%]; P = .02), which partly reflects a difference in cardiac mortality (23 of 318 [7.7%] vs 60 of 1391 [4.5%]; P = .03). Similar 5-year rates were found for myocardial infarction (91 of 1391 [6.7%] vs 22 of 318 [7.2%]; P = .80) and target vessel revascularization (129 of 1391 [9.7%] vs 34 of 318 [11.4%]; P = .36) between trial participants and nonenrolled eligible patients. In all eligible patients (ie, trial participants plus nonenrolled eligible patients), the TVF rate was only slightly higher than in trial participants only (18.3% vs 17.1%).. Long-term outcome data from nonenrolled eligible patients support the validity of the TWENTE trial findings and present, with the trial, a strong case for the long-term safety and efficacy of the newer-generation DESs used.. clinicaltrials.gov Identifier: NCT01066650.

Topics: Coronary Angiography; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Myocardial Infarction; Patient Selection; Percutaneous Coronary Intervention; Postoperative Complications; Prosthesis Design; Sirolimus; Survival Rate; Time Factors; Treatment Outcome; United States

Several concerns have emerged about the higher risk of very late stent thrombosis (ST) with first generation drug-eluting stent (DES), especially in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). New generation DES have demonstrated reduction in ST at mid-term follow-up, however no data are available on long-term follow-up. Therefore, the aim of this study was to report long-term results of the RACES-MI trial conducted to compare Everolimus-Eluting Stent (EES) vs Sirolimus-Eluting Stent (SES) in patients undergoing primary PCI.. The RACES-MI trial enrolled consecutive STEMI patients admitted within 12h of symptom onset, undergoing primary PCI with stent implantation at a tertiary center with 24-hour primary PCI capability, who were randomly assigned to SES or EES. Primary endpoint of this analysis is major adverse cardiac events (MACE) at long-term follow-up. Secondary endpoints are 1) death; 2) reinfarction; 3) definite or probable ST; 4) target-vessel revascularization (TVR) at long-term follow-up.. From April 2007 to May 2009 500 patients with STEMI were randomized to EES (n=250) or SES (n=250). No difference was observed between the groups either in baseline clinical characteristics, in the number of implanted stent or total stent length per patient. However, a larger reference diameter was observed with SES (3.35±0.51 mm vs 3.25±0.51 mm, p=0.001), whereas patients randomized to EES received Gp IIb-IIIa inhibitors more often (54.4% vs 42.4%, p=0.006). At long-term follow-up (2132±528 days), EES was associated with a significant reduction in MACE (23.8 vs 34.1%, adjusted p=0.028), ST (2.5% vs 7.7%, adjusted p=0.009), without any difference in death (8.7% vs 11.4%, adjusted p=0.47), reMI (9.3% vs 13.1%; adjusted p=0.18) and TVR (8.6% vs 12.3%, adjusted p=0.31).. This study shows that among STEMI patients undergoing primary PCI EES, as compared to SES, is associated with significant reduction in MACE and ST at long-term follow-up.

Topics: Coronary Angiography; Drug-Eluting Stents; Electrocardiography; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Italy; Male; Middle Aged; Myocardial Infarction; Postoperative Complications; Prospective Studies; Recurrence; Sirolimus; Survival Rate; Time Factors

Our aim was to evaluate the incidence and clinical outcomes of late-acquired incomplete stent apposition (LAISA) after implantation of first- and second-generation drug-eluting stents in patients with acute myocardial infarction (AMI).. Late-Acquired incomplete stent aPPOsition after everolimus-eluting stent versus sirolimus-eluting Stent ImplanTatION in pAtients with non ST-segment elevation Myocardial Infarction and ST-segment elevation myocardial infarction (APPOSITION-AMI) was a prospective, randomised study comparing LAISA after everolimus-eluting stent (EES) and sirolimus-eluting stent (SES) implantation in AMI patients. Intravascular ultrasound examination was serially performed post-procedurally and at eight-month follow-up in 195 AMI patients (205 native coronary lesions: 100 EES; 105 SES). LAISA was observed in 6.0% and 16.2% of EES- vs. SES-treated lesions (p=0.021), respectively. In 64.7% of SES-treated lesions, LAISA was caused by positive remodelling, whereas thrombus dissolution or plaque reduction was observed in 66.7% of EES-treated lesions. Among patients with LAISA, MACE developed in one (4.5%) in the SES group with no ST in either group up to one year.. The incidence of LAISA was lower in AMI patients treated with EES as compared to SES, mainly secondary to positive remodelling in SES- but not EES-treated lesions. Patients with LAISA in both groups showed a very low MACE incidence at one-year follow-up.

Topics: Aged; Antineoplastic Agents; Drug-Eluting Stents; Everolimus; Female; Humans; Male; Middle Aged; Non-ST Elevated Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Complications; Prosthesis Failure; Sirolimus; ST Elevation Myocardial Infarction; Ultrasonography, Interventional

To assess performance of new, bioresorbable polymer sirolimus-eluting stent (BP-SES), in patients with long coronary lesions (LL) and to compare it to permanent polymer everolimus-eluting stent (PP-EES).. LL have been associated with worse clinical outcomes in percutaneous coronary interventions (PCI). The impact of lesion length on the outcomes of drug eluting stent (DES) implantations is not as clear.. In the frame of a randomized, multicentre CENTURY II study, out of 1119 patients enrolled, 182 patients had LL (defined as ≥25 mm), and were assigned randomly to treatment with BP-SES (101) or PP-EES (81). Primary endpoint was target lesion failure (TLF, composite of cardiac death, target vessel related myocardial infarction [MI], and target lesion revascularization [TLR]) at 9 months. All data were 100% monitored and adverse events were adjudicated by an independent clinical event committee.. The baseline patient and lesion characteristics were similar in the 2 study arms. At 9-months, the rates of cardiac death (2.0% vs 1.2%; P = 0.70), MI (3.0% vs 4.9%; P = 0.49) and clinically driven TLR (2.0% vs 3.7%; P = 0.48) and TLF (6.9% vs 8.6%; P = 0.67) were similar for BP-SES and PP-EES, respectively. There was no stent thrombosis (ST) in BP-SES group up to 9 months, while 1 case (1.2%) of ST was recorded in PP-EES group (P = 0.44).. Patients with LL showed similar clinical outcomes when treated with Ultimaster BP-SES and Xience PP-EES.

Topics: Absorbable Implants; Aged; Antineoplastic Agents; Coronary Stenosis; Drug-Eluting Stents; Everolimus; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Polymers; Postoperative Complications; Prosthesis Design; Risk Factors; Severity of Illness Index; Sirolimus; Treatment Outcome

Long-term safety and efficacy for everolimus-eluting stents (EES) versus those of sirolimus-eluting stents (SES) are unknown.. This study compared 5-year outcomes for EES with those for SES from the SORT OUT IV (Scandinavian Organization for Randomized Trials with Clinical Outcome) trial.. Five-year follow-up was completed for 2,771 patients (99.9%). Primary endpoint was a composite of major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), and definite stent thrombosis.. At 5-years, MACE occurred in 14.0% and 17.4% in the EES and SES groups, respectively (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.66 to 0.97; p = 0.02). The MACE rate did not differ significantly within the first year (HR: 0.96, 95% CI: 0.71 to 1.19; p = 0.79), but from years 1 through 5, the MACE rate was lower with EES (HR: 0.71, 95% CI: 0.55 to 0.90; p = 0.006; p interaction = 0.12). Definite stent thrombosis was lower with EES (0.4%) than with SES (2.0%; HR: 0.18, 95% CI: 0.07 to 0.46), with a lower risk of very late definite stent thrombosis in the EES group (0.2% vs. 1.4%, respectively; HR: 0.16, 95% CI: 0.05 to 0.53). When censoring the patients at the time of stent thrombosis, we found no significant differences between the 2 stent groups for MACE rates (HR: 0.89, 95% CI: 0.73 to 1.08; p = 0.23), target lesion revascularization (HR: 0.90, 95% CI: 0.64 to 1.27; p = 0.55), and MI (HR: 0.93, 95% CI: 0.64 to 1.36; p = 0.72).. At 5-year follow-up, MACE rate was significantly lower with EES- than with SES-treated patients, due largely due to a lower risk of very late definite stent thrombosis. (Randomized Clinical Comparison of the Xience V and the Cypher Coronary Stents in Non-selected Patients With Coronary Heart Disease [SORT OUT IV]; NCT00552877).

Topics: Coronary Artery Disease; Denmark; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Percutaneous Coronary Intervention; Postoperative Complications; Prosthesis Design; Retrospective Studies; Single-Blind Method; Sirolimus; Survival Rate; Time Factors; Treatment Outcome

There is a lack of conclusive evidence to suggest if calcineurin inhibitor (CNI) withdrawal or minimization with sirolimus is the best strategy for African Americans.. This was a randomized, prospective, open-label, pilot study comparing the two mammalian target of rapamycin (mTOR) transition strategies in adult African Americans between six and 24 wk post-transplant. The primary outcome was a comparison of the eGFR at one yr after conversion.. Forty patients were randomized and analyzed in an intent-to-treat fashion. Median day of transition was day 96 (withdrawal) and 68 (minimization). Patients in the CNI-withdrawal group (n = 23) had significantly higher eGFR at one yr compared to the CNI-minimization group (n = 17, 73 vs. 56 mL/min, p = 0.03), as well as a significantly larger increase in eGFR from baseline (12 vs. 5 mL/min, p = 0.03). There were no differences in infections, acute rejection, death, or graft loss. Both regimens were constrained by disproportionately high discontinuation rates despite modest toxicity profiles.. In spite of considerable withdrawal rate across both study arms, African American kidney transplant recipients who underwent early transition to a sirolimus-based CNI-withdrawal regimen had significantly better graft function at one yr compared to those transitioned to a sirolimus-based CNI-minimization regimen. Clinicaltrials.gov identifier: NCT01005706.

Topics: Black or African American; Calcineurin Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Sirolimus; Transplant Recipients; United States; Withholding Treatment

The biodegradable polymer drug-eluting stents (DES) were developed to improve vascular healing. However, further data and longer-term follow-up are needed to confirm safety and efficacy of these stents. This randomized clinical trial aimed to compare safety and efficacy of 2 sirolimus-eluting stents (SES): Cordimax-a novel abluminal biodegradable polymer SES and Cypher Select-a durable polymer SES, at 9 months angiographic and 5-year clinical follow-up.. We randomized 402 patients with coronary artery disease to percutaneous coronary intervention with Cordimax (n = 202) or Cypher select (n = 200). Angiographic follow-up was performed at 9 months after the index procedure and clinical follow-up annually up to 5 years. The primary endpoint was angiographic in-stent late luminal loss (LLL). Secondary endpoints included angiographic restenosis rate, target vessel revascularization (TVR), and major adverse cardiac events (MACEs; defined as cardiac death, myocardial infarction, or TVR) at 5-year follow-up.. Cordimax was noninferior to Cypher select for in-stent LLL (0.25 ± 0.47 vs 0.18 ± 0.49 mm; P = 0.587) and in-stent mean diameter stenosis (22.19 ± 12.21% vs 19.89 ± 10.79%; P = 0.064) at 9 months angiographic follow-up. The MACE rates were not different at 1 year (5.9% vs 4.0%, P = 0.376); however, MACE rates from 2 to 5 years were lower in the Cordimax group (6.8% vs 13.1%; P = 0.039).. Abluminal biodegradable polymer SES is noninferior to durable polymer SES at 9-month angiographic and 1-year clinical follow-up. However, MACE rates from 2 to 5 years were less in the abluminal biodegradable polymer group.

Topics: Absorbable Implants; Aged; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Durable Medical Equipment; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Percutaneous Coronary Intervention; Polymers; Postoperative Complications; Prosthesis Design; Sirolimus; Time Factors; Treatment Outcome

Chronic lung allograft dysfunction (CLAD), predominantly manifest as bronchiolitis obliterans syndrome (BOS), is the primary cause of morbidity and death after lung transplantation. We assessed the efficacy and safety of 2 de novo immunosuppression protocols to prevent BOS.. This was a multicenter, prospective, international, randomized (1:1) open-label superiority study of de novo enteric-coated mycophenolate sodium (MPS) vs delayed-onset everolimus (RAD), both arms in combination with cyclosporine (CsA) monitored by 2-hour post-dose (C2) levels, and corticosteroids. Target C2 levels were lower in the RAD group because RAD is known to potentiate CsA nephrotoxicity. Cytolytic induction therapy was not used. Patients were stratified at entry for cystic fibrosis. Confirmation of anastomotic healing was required for randomization. Primary efficacy was freedom from BOS Grade 1 on intention-to-treat (ITT) analysis. Secondary efficacy parameters were patient and graft survival and severity of rejection. Treatment failure was defined by graft loss, patient death, drug cessation, or need for other therapy.. The 3-year freedom from BOS Grade 1 was 70% for MPS (n = 80) vs 71% for RAD (n = 84; p = 0.95 by log-rank) in ITT but was lower in the RAD arm of the per-protocol population (p = 0.03). The 3-year survival was 84% (MPS) vs 76% (RAD; p = 0.19 by log-rank). Thirteen patients switched from MPS vs 31 from RAD (p < 0.01). Days on MPS were greater than days on RAD (p < 0.01). Rejection events proven by biopsy specimen were more common on MPS (p = 0.02), as were leucopenia (p < 0.01), diarrhea (p < 0.01), and cytomegalovirus infection (p = 0.04). Venous thromboembolism was more frequent on RAD (p = 0.02). Creatinine at 3 years was 160 ± 112 μmol/1iter in MPS patients vs 152 ± 98 μmol/1iter in RAD patients (p = 0.67).. This 3-year ITT analysis found no significant difference between arms but was underpowered to accept the null hypothesis that RAD and MPS have equivalent efficacy in preventing BOS or death after lung transplantation.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Bronchiolitis Obliterans; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Sirolimus; Time Factors; Treatment Outcome; Young Adult

The currently recommended duration of dual antiplatelet therapy (DAPT) in drug-eluting stent (DES) recipients is 12 months to reduce the risk of late stent thrombosis, particularly in those with acute coronary syndrome (ACS).. This study hypothesized that antiplatelet treatment with DAPT for 6 months may be noninferior to 24-month DAPT in aspirin-sensitive patients.. A multicenter, randomized study assigned patients undergoing implantation of everolimus-eluting stents with confirmed nonresistance to aspirin to receive 6- or 24-month DAPT. The primary endpoint was a composite of death, myocardial infarction, urgent target vessel revascularization, stroke, and major bleeding at 12 months post-stenting.. A total of 2,031 patients were enrolled in 70 European and Middle Eastern centers. The trial was prematurely terminated due to recruitment problems, leaving 941 patients randomized to 24-month DAPT and 953 to 6-month DAPT. The 2 treatment groups had similar baseline and procedural characteristics. There was no significant difference in the primary endpoint (24-month: 1.5% vs. 6-month: 1.6%; p = 0.85). Noninferiority was demonstrated for 6- versus 24-month DAPT, with an absolute risk difference of 0.11% (95% confidence interval: -1.04% to 1.26%; p for noninferiority = 0.0002). There were no significant differences in stent thrombosis or bleeding complications. In the 792 (44%) high-risk patients with ACS, primary and secondary endpoints did not significantly differ (hazard ratio: 1.7 [95% confidence interval: 0.519 to 6.057; p = 0.361]).. Rates of bleeding and thrombotic events were not significantly different according to 6- versus 24-month DAPT after PCI with new-generation DES in good aspirin responders. (Is There A LIfe for DES After Discontinuation of Clopidogrel [ITALICplus]; NCT01476020).

Topics: Aged; Aspirin; Clopidogrel; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Early Termination of Clinical Trials; Europe; Everolimus; Female; Hemorrhage; Humans; Immunosuppressive Agents; Male; Middle Aged; Middle East; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; Ticlopidine; Time Factors; Treatment Outcome

ZEUS study was an open-label, 12-month, multicenter study in which 300 de novo kidney transplant recipients were randomized to continue receiving cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant. Five-year follow-up data were available for 245/269 patients (91.1%) who completed the core 12-month study (123 everolimus, 109 CsA). At 5 years, adjusted estimated GFR was 66.2 mL/min/1.73 m(2) with everolimus versus 60.9 mL/min/1.73 m(2) with CsA; the mean difference was 5.3 mL/min/1.73 m(2) in favor of everolimus (95% CI 2.4, 8.3; p < 0.001 [intent-to-treat population]). In a post hoc analysis of patients remaining on study drug at 5 years (everolimus 77, CsA 86), mean difference was 8.2 mL/min/1.73 m(2) (95% CI 4.3, 12.1; p < 0.001) in favor of everolimus. The cumulative incidence of biopsy-proven acute rejection postrandomization was 13.6% with everolimus versus 7.5% with CsA (p = 0.095), largely accounted for by grade I rejection (16/21 patients and 7/11 patients, respectively). Postrandomization, graft loss, mortality, serious adverse events and neoplasms were similar in both arms. In conclusion, conversion of kidney transplant patients to everolimus at 4.5 months posttransplant is associated with a significant improvement in renal function that is maintained to at least 5 years. The increase in early mild acute rejection did not affect long-term graft function.

Topics: Adolescent; Adult; Aged; Cyclosporine; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Research Design; Risk Factors; Sirolimus; Transplant Recipients; Young Adult

The aim of this study was to analyze the incidence of drug-eluting stent thrombosis (sirolimus or everolimus) in patients with chronic total coronary occlusions (CTO) and to determine its clinical implications and related factors.. Data from the 12-month follow-up of the 207 patients included in the CIBELES trial with CTO were analyzed.. Stent thrombosis occurred in three patients, two definite and one probable (overall thrombosis rate: 1.4%). However, there were no cases of death or Q-wave myocardial infarction. In univariate analysis, patients with a higher incidence of stent thrombosis were those in whom the target vessel was the left anterior descending, who had single-vessel disease, were assigned to treatment with sirolimus-eluting stents, and those with smaller minimum luminal diameter immediately after the procedure. In multivariate analysis, the only independent predictor of stent thrombosis was minimal luminal diameter immediately after the procedure.. The rate of drug-eluting stent thrombosis in patients with CTO is relatively low (1.4%). The only independent predictor of stent thrombosis in this context was minimal luminal diameter after the procedure and the clinical presentation was in all cases relatively benign.

Topics: Aged; Chronic Disease; Coronary Occlusion; Drug-Eluting Stents; Everolimus; Female; Humans; Incidence; Male; Middle Aged; Postoperative Complications; Sirolimus; Thrombosis

The first CE-approved bioresorbable vascular scaffold (BVS) is effective at treating simple lesions and stable coronary artery disease, but it has yet to be assessed versus the best-in-class drug-eluting stents (DES).. This study sought to compare the performance of a BVS with that of everolimus-eluting stents (EES) and biolimus-eluting stents (BES) in all-comer patients.. The EVERBIO II (Comparison of Everolimus- and Biolimus-Eluting Stents With Everolimus-Eluting Bioresorbable Vascular Scaffold Stents II) trial was a single-center, assessor-blinded study of 240 patients randomly assigned in a 1:1:1 ratio to EES, BES, or BVS. The only exclusion criterion was a reference vessel diameter >4.0 mm, which precluded treatment with BVS. The primary endpoint was angiographic late lumen loss (LLL) at 9 months. Secondary endpoints included patient-oriented major acute coronary events (MACE) (death, myocardial infarction [MI], and any revascularization), device-oriented MACE (cardiac death, MI, and target lesion revascularization), and stent thrombosis at the 9-month clinical follow-up.. Follow-up angiography was performed in 216 patients (90.7%) at 9 months. In-stent LLL was similar between patients treated with BVS (0.28 ± 0.39 mm) and those treated with EES/BES (0.25 ± 0.36 mm; p = 0.30). Clinical outcomes were similar at 9 months: the patient-oriented MACE rate was 27% in BVS and 26% in the EES/BES group (p = 0.83) and the device-oriented MACE rate was 12% in BVS and 9% in the EES/BES group (p = 0.6).. New-generation metallic DES (EES/BES) were not superior to BVS in terms of angiographic LLL and clinical outcomes. (Comparison of Everolimus- and Biolimus-Eluting Stents With Everolimus-Eluting Bioresorbable Vascular Scaffold Stents [EVERBIO II]; NCT01711931).

Topics: Absorbable Implants; Aged; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Materials Testing; Middle Aged; Percutaneous Coronary Intervention; Postoperative Complications; Sirolimus; Tissue Scaffolds; Treatment Outcome

The use of drug-eluting stents (DES) in patients at high risk of bleeding or thrombosis has not been prospectively studied; limited data are available in patients who have a low restenosis risk.. This study sought to compare a hydrophilic polymer-based, second-generation zotarolimus-eluting stent (ZES) with a unique drug fast-release profile versus bare-metal stents (BMS) under similar durations of dual-antiplatelet therapy (DAPT).. We randomly assigned 1,606 patients with stable or unstable symptoms, and who on the basis of thrombotic bleeding or restenosis risk criteria, qualified as uncertain candidates for DES, to receive ZES or BMS. DAPT duration was on the basis of patient characteristics, rather than stent characteristics, and allowed for a personalized 1-month dual antiplatelet regimen. The primary endpoint was the risk of 1-year major adverse cardiovascular events (MACE), which included death, myocardial infarction (MI), or target vessel revascularization (TVR).. Median DAPT duration was 32 days (interquartile range [IQR]: 30 to 180 days) and did not differ between the groups. In the ZES group, 140 patients (17.5%) reached the primary endpoint, compared with 178 patients (22.1%) in the BMS group (hazard ratio: 0.76; 95% confidence interval: 0.61 to 0.95; p = 0.011) as a result of lower MI (2.9% vs. 8.1%; p < 0.001) and TVR rates (5.9% vs.10.7%; p = 0.001) in the ZES group. Definite or probable stent thrombosis was also significantly reduced in ZES recipients (2.0% vs. 4.1%; p = 0.019).. Compared with BMS, DES implantation using a stent with a biocompatible polymer and fast drug-eluting characteristics, combined with an abbreviated, tailored DAPT regimen, resulted in a lower risk of 1-year MACE in uncertain candidates for DES implantation. (Zotarolimus-eluting Endeavor Sprint Stent in Uncertain DES Candidates [ZEUS] Study; NCT01385319).

Topics: Aged; Aged, 80 and over; Aspirin; Biocompatible Materials; Clopidogrel; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Hemorrhage; Humans; Immunosuppressive Agents; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Risk Assessment; Risk Factors; Sirolimus; Ticlopidine; Treatment Outcome

Most trials comparing percutaneous coronary intervention (PCI) with coronary-artery bypass grafting (CABG) have not made use of second-generation drug-eluting stents.. We conducted a randomized noninferiority trial at 27 centers in East Asia. We planned to randomly assign 1776 patients with multivessel coronary artery disease to PCI with everolimus-eluting stents or to CABG. The primary end point was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years after randomization. Event rates during longer-term follow-up were also compared between groups.. After the enrollment of 880 patients (438 patients randomly assigned to the PCI group and 442 randomly assigned to the CABG group), the study was terminated early owing to slow enrollment. At 2 years, the primary end point had occurred in 11.0% of the patients in the PCI group and in 7.9% of those in the CABG group (absolute risk difference, 3.1 percentage points; 95% confidence interval [CI], -0.8 to 6.9; P=0.32 for noninferiority). At longer-term follow-up (median, 4.6 years), the primary end point had occurred in 15.3% of the patients in the PCI group and in 10.6% of those in the CABG group (hazard ratio, 1.47; 95% CI, 1.01 to 2.13; P=0.04). No significant differences were seen between the two groups in the occurrence of a composite safety end point of death, myocardial infarction, or stroke. However, the rates of any repeat revascularization and spontaneous myocardial infarction were significantly higher after PCI than after CABG.. Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG. (Funded by CardioVascular Research Foundation and others; BEST ClinicalTrials.gov number, NCT00997828.).

Topics: Aged; Coronary Artery Bypass; Coronary Artery Disease; Coronary Restenosis; Diabetes Complications; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Complications; Prospective Studies; Sirolimus; Stroke

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

Topics: Adult; Allografts; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Sirolimus; Transplant Recipients; Vascular Diseases

To describe the long-term results of a previously developed a sirolimus-based sequential immunosuppression protocol for kidney transplant comprising 2 phases: sirolimus + cyclosporine + prednisolone for 3 months followed by sirolimus + prednisolone + mycophenolate mofetil with steroid minimization the first year. Two-year outcomes of patients on this protocol (group A) showed equivalent patient and graft survival, yet with significantly better function, compared with those on cyclosporine + mycophenolate mofetil + prednisolone (group B).. We report the 8-year outcomes in the same cohort (76 patients in group A and 37 in group B).. 42% switched from group A to B versus 43% switching from B to A. Intent-to-treat patient survivals at 5 and 8 years were 88% and 85.5% for group A, and 78% and 73% for group B. Death-censored graft survivals were 93% for group A and 95% for group B. Graft function was significantly better at 8 years, with 91% of group A patients compared with 50% in group B having estimated glomerular filtration rates > 45 mL/min/1.73 m2, and a significantly lower incidence of chronic allograft nephropathy in the former. Secondary parameters including blood pressure control, new onset diabetes mellitus, proteinuria and other drug-related adverse events showed no significant differences between the groups.. The sirolimus-based sequential immunosuppression protocol was well tolerated in 58% of patients. The intent-to-treat and patients-ontherapy analyses revealed that it was equivalent to the widely used cyclosporine + mycophenolate mofetil + prednisolone protocol regarding patient and graft survival. It is associated with better graft function and lower incidence of chronic allograft nephropathy in 8 years' follow-up. The incidence of drug-related adverse reactions was not statistically different from those in the comparator.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Drug Administration Schedule; Drug Substitution; Drug Therapy, Combination; Egypt; Female; Glucocorticoids; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisolone; Risk Factors; Sirolimus; Time Factors; Treatment Outcome

This study compared the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate and no CMV pharmacological prophylaxis. We randomized 288 patients to receive a single 3 mg/kg dose of antithymocyte globulin, tacrolimus, everolimus, and prednisone (r-ATG/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (BAS/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (BAS/MPS, n = 101). The primary end-point was the incidence of first CMV infection/disease in the intention-to-treat population at 12 months. Patients treated with r-ATG/EVR showed a 90% proportional reduction (4.7% vs. 37.6%, HR 0.10, 95% CI 0.037-0.29; p < 0.001), while those treated with BAS/EVR showed a 75% proportional reduction (10.8% vs. 37.6%, HR 0.25, 95% CI 0.13-0.48; p < 0.001) in the incidence of CMV infection/disease compared to BAS/MPS. There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 15.8%, p = 0.403), wound-healing complications, delayed graft function, and proteinuria. Mean estimated glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p = 0.021). In de novo kidney transplant recipients receiving no pharmacological CMV prophylaxis, reduced-dose tacrolimus and everolimus was associated with a significant reduction in the incidence of CMV infection/disease compared to standard tacrolimus dose and mycophenolate (ClinicalTrials.gov NCT01354301).

Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Treatment Outcome

Objective of this study was to assess the clinical performance of bioresorbable vascular scaffold (BVS) compared to everolimus-eluting stent (EES) in subjects with ST-segment elevation myocardial infarction (STEMI). We included all consecutive patients with STEMI who underwent percutaneous coronary intervention (PCI) with BVS implantation in centers participating to the Italian ABSORB Prospective Registry (BVS-RAI) and PCI with EES in the same centers during the same period. The 2 groups were compared. The primary end point was patient-oriented composite end point (POCE) including cardiac death, myocardial infarction, and target lesion revascularization (TLR) at the longest available follow-up. BVS or EES thrombosis at follow-up was also evaluated. Of the 563 patients with STEMI included, 122 received BVS and 441 EES. Procedural success was obtained in 549 (97.5%) cases without significant differences between the 2 groups (BVS 99.3% vs EES 97.0%, p = 0.2). At a median of 220-day (interquartile range 178 to 369) follow-up, no significant differences were observed in terms of POCE (BVS 4.9% vs EES 7.0%, p = 0.4); death (BVS 0.8%, EES 2.0%, p = 0.4), MI (BVS 4.1%, EES 2.0%, p = 0.2), TLR (BVS 4.1%, EES 4.5%, p = 0.8), device thrombosis (BVS 2.5%, EES 1.4%, p = 0.4). All TLR cases were successfully managed with re-PCI in both groups. A propensity matching of the study populations showed no significant differences regarding POCE at the longest available follow-up (odds ratio 0.53, 0.1 to 4.3). In conclusion, in this direct prospective comparison, BVS was associated with similar clinical results compared to EES in the STEMI setting. Larger and adequately powered randomized trials are needed to fully assess the potential clinical benefit of BVS versus the current standard of care in patients with STEMI.

Topics: Absorbable Implants; Aged; Antineoplastic Agents; Coronary Angiography; Drug-Eluting Stents; Electrocardiography; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Italy; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Complications; Prospective Studies; Prosthesis Design; Sirolimus; Time Factors; Tissue Scaffolds; Treatment Outcome

This prospective, randomized, double-blind, placebo-controlled study evaluated the effects of ramipril on urinary protein excretion in renal transplant patients treated with sirolimus following conversion from a calcineurin inhibitor. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks thereafter. Doses were increased if patients developed proteinuria (urinary protein/creatinine ratio ≥0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, 138; placebo, 126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%) (p < 0.001). No significant differences were observed between ramipril and placebo for change in glomerular filtration rate from baseline (p = 0.148) or in the number of patients with biopsy-confirmed acute rejection (13 vs. 5, respectively; p = 0.073). One patient in the placebo group died due to cerebrovascular accident. Treatment-emergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril co-administration. Ramipril was effective in reducing the incidence of proteinuria for up to 1 year following conversion to sirolimus in maintenance renal transplant patients.

Topics: Antihypertensive Agents; Calcineurin Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Proteinuria; Ramipril; Risk Factors; Sirolimus; Tacrolimus

There is a paucity of data reporting the clinical outcomes of biodegradable polymer biolimus-eluting stent (BP-BES) compared with durable polymer everolimus-eluting stent (DP-EES) beyond 1 year after stent implantation when the polymer is fully degraded.. The NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial (NEXT) is a prospective, multicenter, randomized, open-label, noninferiority trial comparing BP-BES with DP-EES in patients scheduled for percutaneous coronary intervention using drug-eluting stent (DES) without any exclusion criteria among 98 participating centers in Japan. The trial was designed to evaluate noninferiority of BP-BES relative to DP-EES in terms of any target-lesion revascularization at 1 year and death or myocardial infarction at 3 years. Between May and October 2011, 3235 patients were randomly assigned to receive either BP-BES (1617 patients) or DP-EES (1618 patients). Complete 3-year follow-up was achieved in 97.6% of patients. At 3 years, the primary safety end point of death or myocardial infarction occurred in 159 patients (9.9%) in the BP-BES group and in 166 patients (10.3%) in the DP-EES group, demonstrating noninferiority of BP-BES relative to DP-EES (P noninferiority<0.0001 and P superiority=0.7). Cumulative incidence of target-lesion revascularization was not significantly different between the 2 groups (7.4% versus 7.1%; P=0.8). By a landmark analysis at 1 year, the cumulative incidences of death or myocardial infarction and target-lesion revascularization were also not significantly different between the 2 groups (4.6% versus 5.2%; P=0.46 and 3.3% versus 2.7%; P=0.39, respectively).. Safety and efficacy outcomes of BP-BES were non inferior to those of DP-EES 3 years after stent implantation.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01303640.

Topics: Absorbable Implants; Aged; Blood Vessel Prosthesis Implantation; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Japan; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Complications; Prospective Studies; Sirolimus; Survival Analysis; Treatment Outcome

Kidney transplantation remains limited by toxicities of calcineurin inhibitors (CNIs) and steroids. Belatacept is a less toxic CNI alternative, but existing regimens rely on steroids and have higher rejection rates. Experimentally, donor bone marrow and sirolimus promote belatacept's efficacy. To investigate a belatacept-based regimen without CNIs or steroids, we transplanted recipients of live donor kidneys using alemtuzumab induction, monthly belatacept and daily sirolimus. Patients were randomized 1:1 to receive unfractionated donor bone marrow. After 1 year, patients were allowed to wean from sirolimus. Patients were followed clinically and with surveillance biopsies. Twenty patients were transplanted, all successfully. Mean creatinine (estimated GFR) was 1.10 ± 0.07 mg/dL (89 ± 3.56 mL/min) and 1.13 ± 0.07 mg/dL (and 88 ± 3.48 mL/min) at 12 and 36 months, respectively. Excellent results were achieved irrespective of bone marrow infusion. Ten patients elected oral immunosuppressant weaning, seven of whom were maintained rejection-free on monotherapy belatacept. Those failing to wean were successfully maintained on belatacept-based regimens supplemented by oral immunosuppression. Seven patients declined immunosuppressant weaning and three patients were denied weaning for associated medical conditions; all remained rejection-free. Belatacept and sirolimus effectively prevent kidney allograft rejection without CNIs or steroids when used following alemtuzumab induction. Selected, immunologically low-risk patients can be maintained solely on once monthly intravenous belatacept.

Topics: Abatacept; Adrenal Cortex Hormones; Adult; Aged; Calcineurin Inhibitors; Disease Management; Female; Flow Cytometry; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Sirolimus; Young Adult

De novo malignancies are a main cause for late death after liver transplantation (LT). Everolimus (ERL) is an immunosuppressive agent with antitumoral properties. The aim of the present retrospective study was to identify prognostic factors, including conversion to ERL, for patients presenting non-cutaneous de novo solid organ malignancy after LT for alcoholic cirrhosis. The study population consisted of 83 patients (presenting 100 tumors, including 75% of upper aerodigestive tract cancers), among the 398 patients who underwent LT for alcoholic cirrhosis in our center. After diagnosis, ERL was introduced in 38 patients and calcineurin-inhibitor was discontinued in 64.1% of them. Tumor stage was a significant prognostic factor with a one-yr survival at 82.6% for early stages, 63.4% for intermediate stages (N+) and 27.4% for disseminated diseases (p < 0.001). Associated relative risk factor was 2.202 (95% CI 1.044-4.644) for intermediate stages and 5.743 (95% CI 2.436-13.541) for metastatic stages. One- and five-yr survival was 77.4% and 35.2% in ERL group vs. 47.2% and 19.4% in the non-ERL group, respectively (p = 0.003). The relative risk factor for ERL was 0.447 (95%CI 0.257-0.778). Our results strongly suggest that conversion to ERL improves the prognosis of de novo malignancies after LT for alcoholic cirrhosis. Prospective studies are needed to confirm this benefit.

Topics: Adult; Aged; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Neoplasms; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Sirolimus; Survival Rate

Compromised quality of life (QoL) is a frequent consequence of treatment-refractory chronic graft-versus-host disease (cGvHD). Here, we report on the assessment of QoL in a subgroup of 22 patients with a median age of 54 (17-70) yr receiving an everolimus-based salvage therapy at a single center for their steroid-refractory cGvHD. Five patients suffered from mild, 13 from moderate, and four from severe cGvHD according to NIH consensus criteria when everolimus was introduced. Median treatment duration was 390 d ranging from 86 to 814 d. We performed actual and retrospective assessments of QoL (EuroQol EQ-5D questionnaire) and degree of bother experienced by cGvHD symptoms (Lee cGvHD Symptom Scale). Seventeen of 22 patients showed an improved QoL according to the EQ-5D visual analog scale (37.5% vs. 70.0%; p < 0.001), and a decline in the median Lee cGvHD Symptom Scale was noted in 20 of 22 patients (28 vs. 17; p < 0.001). Furthermore, an improvement was noted in each of the five dimensions of the EQ-5D descriptive system. These data even when limited by their retrospective nature suggest that beyond physical responses everolimus may have contributed to the rebuilding of patients' QoL.

Topics: Adolescent; Adult; Aged; Chronic Disease; Everolimus; Female; Follow-Up Studies; Glucocorticoids; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prognosis; Quality of Life; Retrospective Studies; Risk Factors; Salvage Therapy; Severity of Illness Index; Sirolimus; Surveys and Questionnaires; TOR Serine-Threonine Kinases; Transplantation, Homologous; Young Adult

Patients with coronary total occlusions are at especially high risk for restenosis and new revascularizations. Sirolimus-eluting stents dramatically improved the clinical outcome of this subset of patients in randomized trials, but other drug-eluting stents, mainly the everolimus-eluting stent (currently the most frequently used stent), have not yet been evaluated in patients with coronary total occlusions. The objective was to compare the second-generation everolimus-eluting stent with the first-generation sirolimus-eluting stent in patients with coronary total occlusions.. A total of 207 patients with coronary total occlusions and estimated time since occlusion >2 weeks were randomized to everolimus- or sirolimus-eluting stent. The primary end point was in-stent late loss at 9-month angiographic follow-up (noninferiority trial). Clinical follow-up was performed at 1 and 12 months. In-stent late loss at 9 months was 0.29±0.60 versus 0.13±0.69 mm in patients allocated to sirolimus- and everolimus-eluting stent, respectively. The observed difference in in-stent late loss between both groups was -0.16 mm (95% confidence interval, 0.04 to -0.36 mm; P for noninferiority <0.01). The rate of binary angiographic restenosis was 10.8% and 9.1% in patients allocated to sirolimus- and everolimus-eluting stent, respectively (P=0.709), whereas the rate of vessel reocclusion was 3.2% and 1.1%, respectively (P=0.339). At 12 months, the rate of major adverse events was 15.9% versus 11.1% with sirolimus- and everolimus-eluting stent, respectively (P=0.335), and probable or definitive stent thrombosis occurred in 3.0% and 0.0% of patients, respectively (P=0.075).. In patients with coronary total occlusions, everolimus-eluting stent is as effective as sirolimus-eluting stent.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00793221.

Topics: Aged; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Postoperative Complications; Risk; Sirolimus; Survival Analysis; Treatment Outcome

Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n=440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n=151); high-level tacrolimus (TAC, 8-12 μg/L) and low-level sirolimus (SIR, 3-7 μg/L) (TACH/SIRL, n=149) or low-level TAC (3-7 μg/L) and high-level SIR (8-12 μg/L) (TACL/SIR(H) , n=140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p=0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p=0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.

Topics: Adult; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies; Sirolimus; Steroids; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database.. The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution.. The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis.. These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.

Topics: Cytomegalovirus Infections; Female; Humans; Immunosuppressive Agents; Incidence; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Prospective Studies; Sirolimus

Traditionally, chronic calcineurin inhibitor (CNI) nephrotoxicity has been considered to be one of the main nonimmune mechanisms causing chronic renal allograft dysfunction. CNI minimization and withdrawal strategies have yielded inconsistent results. Few studies address the feasibility of CNI elimination in a prednisone-free regimen. We report a prospective, randomized trial in 200 patients evaluating the impact on renal function and incidence of acute rejection after conversion from tacrolimus (Tac) to sirolimus (SRL). Patients with recent (<3 months) acute rejection episodes or with >0.5 g/day of proteinuria were excluded. All were induced with alemtuzumab, underwent rapid steroid elimination and were maintained on mycophenolate mofetil and Tac. At 12 months posttransplant, patients were randomized 2:1 to SRL (n = 123) or maintained on Tac (n = 64). Mean follow-up was 41.1 ± 15.8 months in the SRL group and 40.7 ± 14.4 months in the Tac group. Biopsy-proven acute rejection at 24 months postrandomization was similar between the groups. Patient survival, graft survival and estimated GFR were also not statistically different. Our study demonstrates that in a prednisone-free immunosuppressive regimen, conversion from Tac to SRL at 12 months posttransplantation is not associated with increased rates of acute rejection and graft loss. However, despite CNI elimination, renal allograft function is equally maintained in both groups.

Topics: Adult; Allografts; Anti-Inflammatory Agents; Calcineurin Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisone; Prognosis; Prospective Studies; Sirolimus; Survival Rate; Tacrolimus; TOR Serine-Threonine Kinases

A pre-planned substudy of a larger multicenter randomized trial was undertaken to compare the efficacy of everolimus with reduced-dose cyclosporine in the prevention of cardiac allograft vasculopathy (CAV) after heart transplantation to that of mycophenolate mofetil (MMF) with standard-dose cyclosporine.. CAV is a major cause of long-term mortality following heart transplantation. Everolimus has been shown to reduce the severity and incidence of CAV as measured by first year intravascular ultrasound (IVUS). MMF, in combination with cyclosporine, has also been shown to have a beneficial effect in slowing the progression of CAV.. Study patients were a pre-specified subgroup of the 553-patient Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial who underwent heart transplantation and were randomized to everolimus 1.5 mg or MMF 3 g/day. IVUS was performed at baseline and at 12 months. Evaluable IVUS data were available in 189 patients (34.6%).. Increase in average maximal intimal thickness (MIT) from baseline to month 12 was significantly smaller in the everolimus 1.5 mg group compared with the MMF group (0.03 mm vs. 0.07 mm, p < 0.001). The incidence of CAV, defined as an increase in MIT from baseline to month 12 of greater than 0.5 mm, was 12.5% with everolimus versus 26.7% with MMF (p = 0.018). These findings remained irrespective of sex, age, diabetic status, donor disease, and across lipid categories.. Everolimus was significantly more efficacious than MMF in preventing CAV as measured by IVUS among heart-transplant recipients after 1 year, a finding, which was maintained in a range of patient subpopulations. CV surgery: transplantation, ventricular assistance, cardiomyopathy.

Topics: Coronary Artery Disease; Everolimus; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sirolimus; Ultrasonography, Interventional

Cytomegalovirus (CMV) causes several complications following cardiac transplantation including cardiac allograft vasculopathy. Previous studies suggested that immunosuppressive treatment based on everolimus might reduce CMV infection. Aiming to better characterize the action of everolimus on CMV and its interplay with patient/recipient serology and anti-CMV prophylaxis, we analyzed data from 3 large randomized studies comparing various everolimus regimens with azathioprine (AZA)- and mycophenolate mofetil (MMF)-based regimens.. CMV data were analyzed from 1009 patients in 3 trials of de novo cardiac transplant recipients who were randomized to everolimus 1.5 mg/day, everolimus 3 mg/day, or AZA 1-3 mg/kg/day, plus standard-dose (SD) cyclosporine (CsA; study B253, n = 634); everolimus 1.5 mg/day plus SD- or reduced-dose (RD)-CsA (study A2403, n = 199); and everolimus 1.5 mg/day plus RD-CsA or MMF plus SD-CsA (study A2411, n = 176).. In study B253, patients allocated to everolimus experienced almost a 70% reduction in odds of experiencing CMV infection compared with AZA (P < 0.001). In study A2403, CMV infection was low in both everolimus arms, irrespective of CsA dosing, and in study A2411, patients allocated to everolimus experienced an 80% reduction in odds of experiencing CMV infection, compared with MMF (P < 0.001). CMV syndrome/disease was rare and less frequent in everolimus-treated patients. Subgroup analyses showed that the benefit everolimus provides, in terms of CMV events, is retained in CMV-naïve recipients and is independent of anti-CMV prophylaxis or preemptive approaches.. Everolimus is associated with a lower incidence of CMV infection compared with AZA and MMF, which combined with its immunosuppressive efficacy and antiproliferative effects may positively impact long-term outcomes.

Topics: Adolescent; Adult; Aged; Azathioprine; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Drug Therapy, Combination; Everolimus; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Postoperative Complications; Sirolimus; Statistics as Topic

The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure.. This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance.. In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p < 0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period.. Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.

Topics: Adaptor Proteins, Signal Transducing; Aged; Cyclosporine; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Scandinavian and Nordic Countries; Sirolimus; Tacrolimus; Time Factors

A consensus definition for periprocedural myocardial infarction (MI) in coronary stent trials has not been established. Differences between a historic definition, based on modified World Health Organization (WHO) criteria, and a proposed universal definition have not been compared in a prospective clinical trial.. We randomly assigned 3687 patients with stable coronary artery disease to undergo stenting with either everolimus-eluting stents (2458 patients) or paclitaxel-eluting stents (1229 patients). Serial creatine kinase (CK) and CKMB or troponin measurements were obtained before and after stenting. MI was classified by protocol according to the WHO definition (total CK >2× normal with elevated CKMB) and post hoc according to the Universal/Academic Research Consortium (ARC) definition (CKMB or troponin >3× normal). Protocol MI was determined in 58 (1.6%) and universal/ARC MI in 287 (7.8%) patients within 48 hours post index procedure. There were substantial differences in frequency of universal/ARC MI if only CKMB (5.4%) or troponin (18.7%) data were included for evaluation. Total stent length was a strong predictor of both protocol and universal/ARC MI. Mortality at 2 years was low (2.3%) and was not different for either MI definition. The mortality rates did not increase with elevations of CKMB or troponin to >10× normal.. There was a marked difference in periprocedural MI rates according to protocol or universal/ARC MI definitions. No association was present between periprocedural MI and mortality up to 2 years by either definition.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00307047.

Topics: Aged; Biomarkers; Blood Vessel Prosthesis Implantation; Creatine Kinase; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Postoperative Complications; Practice Guidelines as Topic; Prognosis; Prospective Studies; Reference Standards; Sensitivity and Specificity; Sirolimus; Survival Analysis; Troponin; United States; United States Food and Drug Administration; World Health Organization

The long-term outcome and compliance of dual-antiplatelet therapy after implantation of drug-eluting stent in the "real world" setting in Japan has not been well investigated. The purpose of this study was to provide information on the introduction and outcomes including status and compliance of dual-antiplatelet therapy of sirolimus-eluting stent (SES). Five-year follow-up was achieved in 1937 of 2050 patients (94.5%). Off-label use was 87.3% in this study. The incidence of MACE was 23.2%, including death (13.4%), MI (3.4%), and target lesion revascularization (TLR, 9.6%). Multivariate analysis for TLR predicted dialysis [hazard ratio (HR) 3.5, 95% confidence interval (CI) 2.13-5.93], lesion length >30 mm (HR 1.89, 95% CI 1.24-2.84), vessel diameter <2.5 mm (HR 1.55, 95% CI 1.10-2.18), ostial lesion (HR 1.59, 95% CI 1.10-2.31), and previous PCI (HR 1.42, 95% CI 1.00-2.00). There were 25 events of definite/probable thrombosis. Very late thrombosis was identified in 17 cases, and the slope of the linear portion of the cumulative incidence curve of stent thrombosis was 0.28% per year. Seven of the 17 events (41.2%) occurred under dual anti-platelet therapy. Five-year outcomes after SES implantation in the "real world" in Japanese showed that dialysis, previous PCI, small vessel <2.5 mm, long lesion >30 mm, and ostial lesions were the predictors of TLR at 5-years. Stent thrombosis rate was lower than previous reports.

Topics: Aged; Aged, 80 and over; Coronary Vessels; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Incidence; Japan; Male; Patient Compliance; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; Treatment Outcome

The mammalian target of rapamycin inhibitor sirolimus has been associated with an increased incidence of wound-healing complications after de novo heart transplantation. To evaluate the possibility of a similar association for everolimus, we performed a risk-factor analysis to compare the incidence of incision-related wound complications for everolimus with that of other adjunctive drugs.. Safety data from 1009 heart transplant recipients (n=214, receiving azathioprine; n=84, mycophenolate mofetil (MMF); n=711, everolimus) were reviewed in a post hoc analysis from three randomized, multicenter studies-B253 (n=634), A2403 (n=199), and A2411 (n=176)-in which de novo patients received fixed-dose or concentration-controlled everolimus (target trough, 3-8 ng/mL), azathioprine, or MMF with standard- or reduced-exposure cyclosporine A. Incisional complications were analyzed for incidence, type, and severity up to day 90 posttransplant.. Incisional-complication events occurred in 25 (11.7%) azathioprine, six (7.2%) MMF, and 87 (12.3%) everolimus patients. Serious incisional complications were more frequent with everolimus (6.9%) compared with azathioprine (4.2%; P=0.197) or MMF (1.2%; P=0.051). In a univariate analysis, patient sex, body mass index (BMI), and diabetes were associated with incisional complications. Only BMI was significantly associated with incisional complications in the subsequent multivariate analysis, with the odds of an incisional-complication event increasing by 12.9% for every 1 kg/m increase in BMI (P<0.001).. The incidence of incisional complications with everolimus was generally low, although numerically higher compared with MMF. Our analyses provided no strong evidence that everolimus is an independent risk factor for incisional complications. After de novo heart transplantation, patients with a high BMI are at higher risk of incision-related wound complications.

Topics: Adult; Azathioprine; Cyclosporine; Everolimus; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Postoperative Complications; Risk Factors; Sirolimus

The use of sirolimus (SRL) in orthotopic liver transplantation (OLT) has been controversial after experimental data suggested an increased risk of hepatic artery thrombosis (HAT). To assess the safety and efficacy of SRL as de novo immunosuppression in OLT recipients. Outcomes of 252 OLT patients who received SRL were compared with outcomes of 291 OLT recipients who received calcineurin inhibitor in a retrospective study. Primary outcomes of this study were: patient- and graft survivals, vascular, biliary, wound complications and rejection rates. Secondary outcomes were: postoperative infection rate, bone marrow and renal function and changes of lipid levels. Patient- and graft survivals, rejection and infection rates were similar. In the SRL group, HAT occurred in 1.2%, biliary complications in 19.4%, and incisional hernias in 9.1%. In the control group the incidence of HAT was 5.8% (P = 0.004), biliary complications 18.5% (P = NS) and incisional hernias 7.2% (P = NS). Patients on SRL experienced significantly higher levels of serum triglycerides but fewer acute cellular rejections. Bone marrow and renal functions were similar in both the groups. Our findings would suggest that SRL is safe and effective for very selected OLT recipients. Randomized controlled trials are necessary to confirm our results.

Topics: Adult; Bile Duct Diseases; Bone Marrow; Calcineurin Inhibitors; Cohort Studies; Female; Graft Rejection; Graft Survival; Hepatic Artery; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney; Lipids; Liver Transplantation; Male; Middle Aged; Opportunistic Infections; Postoperative Complications; Retrospective Studies; Sirolimus; Surgical Wound Infection; Thrombosis; Treatment Outcome

To establish the efficacy of oral rapamycin at a dose of 2 mg for 1 month at reducing the 6-month restenosis rate after the implantation of bare metal stents.. A prospective, 1:1 randomized, single-blind, placebo-controlled study was conducted in 108 consecutive patients assigned immediately after stent implantation to oral rapamycin (4 mg loading dose followed by 2 mg daily for 30 days) or a placebo.. Rapamycin was maintained in 98% of patients. Angiographic in-stent binary restenosis was 14.3% in the rapamycin group versus 32.1% in the placebo group, with a relative risk (RR) of 0.45 (95% CI 0.24-0.84, p = 0.015). The rapamycin blood concentration at 15 days correlated with binary restenosis (p = 0.044). The volume obstructions found by intravascular ultrasound for the rapamycin and the placebo groups were 18.1+/-10.7 and 27.1+/-15.7% (p = 0.002), respectively. Major adverse cardiac events at a 5-year follow-up were 31.5% for the rapamycin group and 50.0% for the placebo group (RR 0.63, 95% CI 0.39-1.01, p = 0.078).. Oral rapamycin significantly reduces the incidence of restenosis at follow-up compared to a placebo.We believe these findings deserve further testing in larger trials.

Topics: Administration, Oral; Aged; Antibiotics, Antineoplastic; Blood Vessel Prosthesis Implantation; Coronary Angiography; Coronary Restenosis; Female; Follow-Up Studies; Humans; Male; Middle Aged; Postoperative Complications; Prospective Studies; Single-Blind Method; Sirolimus; Stents; Ultrasonography, Interventional

Whether drug-eluting stents are effective and safe in patients with moderate renal insufficiency (RI) is unknown. We performed a pooled analysis of data from 3 blinded randomized trials of sirolimus-eluting stents (SESs) versus bare metal stents (BMSs; SIRIUS, C-SIRIUS, E-SIRIUS) that included 1,510 patients. Clinical and angiographic outcomes were stratified by the presence of RI defined by creatinine clearance calculated by the Cockcroft-Gault formula (normal ≥ 90, mild 60 to 89, moderate < 60 ml/min). Patients with baseline creatinine > 3.0 mg/dl were excluded from these trials. Baseline mild RI was present in 517 patients (34.7%, mean creatinine clearance 75.7 ml/min) and moderate RI in 228 patients (15.3%, mean creatinine clearance 47.2 ml/min). Treatment with SESs resulted in lower rates of 8-month angiographic restenosis rates in patients with RI (mild RI 6.7% vs 42.6%, p < 0.001; moderate RI 9.7% vs 39.7%, p < 0.001) and without baseline RI (7.7% vs 37.2%, p < 0.001). One-year target vessel revascularization rates were similarly decreased with SESs in patients with (mild RI 4.7% vs 24.2%, p < 0.001; moderate RI 5.5% vs 26.9%, p < 0.001) and without (8.1% vs 22.4%, p < 0.001) RI, and this benefit was maintained at 5 years. Compared to patients with normal or mild RI, patients with moderate RI had higher rates of overall mortality and cardiac death at 1 year and 5 years (death 2.6% vs 0.6%, p <0.01, and 17.5% vs 6.3%, p < 0.01, at 1 year and 5 years, respectively; cardiac death 1.3% vs 0.2%, p = 0.05, and 6.6% vs 3.4%, p = 0.04, at 1 year and 5 years, respectively). However, there was no differential effect of SESs versus BMSs on any safety end point. In conclusion, patients with moderate RI have a nearly threefold increase in 5-year mortality after percutaneous coronary intervention compared to patients without RI. The effectiveness of SESs in decreasing restenosis compared to BMSs in patients with moderate RI was preserved and rates of death and myocardial infarction were not adversely affected.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Restenosis; Double-Blind Method; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Severity of Illness Index; Sirolimus; Stents

We compared 1-year outcomes in patients treated with paclitaxel-eluting stents (PESs) or sirolimus-eluting stents (SESs) in "real-world" clinical practice. Clinical outcomes were evaluated in 1,558 consecutive, unselected, retrospectively collected patients treated with drug-eluting stents (DESs; PES = 816, SES = 742) at 19 United States centers. The primary end point was 1-year target vessel revascularization (TVR). The study included a prespecified diabetic cohort (PES = 289, SES = 247), for which efficacy comparisons between DESs were analyzed according to vessel diameter and presence of chronic kidney disease. Baseline demographic, angiographic, and procedural characteristics were similar between patients treated with PESs and those treated with SESs. At 1 year, there were no overall statistical differences in death, myocardial infarction, TVR, or stent thrombosis. In the diabetic cohort, however, the cumulative incidence of TVR was significantly lower for patients treated with PESs (3%) compared with SESs (9%, p <0.01), which persisted after adjustment for baseline differences (hazard ratio 0.29, 95% confidence interval 0.12 to 0.67). This decrease in TVR with PES was similar in insulin- and noninsulin-requiring diabetic patients. In multivariate analysis, independent predictors of TVR included diabetes, bifurcation stenting, and overlapping stents; in the diabetic cohort, treatment with SESs was also a multivariate predictor of TVR. In conclusion, in this observational, retrospective analysis of DES-treated patients, PESs and SESs demonstrated similar overall safety and efficacy, but PESs were associated with a significant decrease in 1-year TVR rates in diabetic patients.

Topics: Antineoplastic Agents, Phytogenic; Coronary Angiography; Coronary Stenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Myocardial Revascularization; Paclitaxel; Postoperative Complications; Prosthesis Design; Retrospective Studies; Sirolimus; Time Factors; Treatment Outcome; United States

We sought to assess the long-term effectiveness and safety of sirolimus-eluting stents (SES) in patients with in-stent restenosis (ISR).. Treatment of patients with ISR remains a challenge. The long-term outcome of patients with ISR treated with SES remains unknown.. The RIBS-II (Restenosis Intra-stent: Balloon angioplasty vs. elective sirolimus-eluting Stenting) study was a randomized trial conducted in 150 patients with ISR (76 SES, 74 balloon angioplasty [BA]). The long-term (>1 year) clinical outcome and pre-specified subgroup analyses were pre-defined secondary study end points.. At 1 year, the event-free survival (death, myocardial infarction, target vessel revascularization [TVR]) was better in the SES group (88% vs. 69%, p < 0.005). Additional long-term (>3 years) clinical follow-up was obtained in 97% of patients (median 3.3 years). After the first year, 3 patients died (1 SES, 2 BA), 5 suffered myocardial infarction (4 SES, 1 BA), and 7 required TVR (4 SES, 3 BA). At last follow-up, definitive/probable/possible stent thrombosis was similar in both groups (2/2/1 SES vs. 1/0/3 BA, p = NS). At 4 years, the event-free survival was 76% in the SES arm and 65% in the BA arm (p = 0.019). On multivariate analysis, SES implantation was an independent predictor of event-free survival. Subgroup analyses were consistent with the main outcome measure.. In patients with ISR, SES implantation remains effective and safe at very long-term clinical follow-up.

Topics: Aged; Angioplasty, Balloon, Coronary; Antibiotics, Antineoplastic; Clopidogrel; Coronary Restenosis; Coronary Thrombosis; Drug-Eluting Stents; Follow-Up Studies; Humans; Platelet Aggregation Inhibitors; Postoperative Complications; Prospective Studies; Sirolimus; Ticlopidine

One year survival of islet cell grafts has been reproducibly achieved under combination immune therapy including tacrolimus (TAC). However, the use of TAC causes beta-cell and renal toxicity. Because sirolimus (SIR) monotherapy was successful in kidney transplantation under antithymocyte globulin (ATG), we undertook a pilot study comparing SIR monotherapy with SIR-TAC combination therapy.. Nonuremic type 1 diabetics received a cultured beta-cell graft under ATG and were randomly assigned to SIR or SIR-TAC-maintenance therapy; a second graft was implanted during posttransplantation month 3 without ATG. The planned number of patients per group (n=10) was reduced to five in view of the observed side effects.. At posttransplant month 6, three SIR-patients had lost graft function and two presented marginal function; among SIR-TAC-patients, there were two early graft failures but three became insulin-independent. These three patients maintained metabolically relevant function (C-peptide >1 ng/ml and coefficient of variation fasting glycemia <25%) for more than 2 years but low-dose insulin therapy was needed from 8, 18, and 26 months posttransplant; this was still the case in two of them after reducing and stopping TAC dose. In both groups, incapacitating adverse events were attributed to sirolimus requiring its discontinuation in 4 of 10 patients; in the 3 patients with pretransplant microalbuminuria, macroalbuminuria developed which resolved when sirolimus was stopped.. SIR monotherapy is not sufficient to suppress rejection after transplantation under ATG, but it can maintain survival of established beta-cell grafts. However, the risk for a SIR-induced proteinuria remains a concern.

Topics: Adult; Albuminuria; Autoantibodies; C-Peptide; Cell Transplantation; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Lymphocyte Count; Male; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus

Pediatric renal transplant recipients were enrolled in a multicenter, randomized, double-blind trial of steroid withdrawal. Subjects received basiliximab, calcineurin inhibitor, sirolimus and steroids. Of 274 subjects enrolled, 19 (6.9%) subjects developed posttransplant lymphoproliferative disorder (PTLD). The relative hazard (RH) for PTLD was 5.3-fold higher in children aged < or =5 versus those >12 years (p = 0.0017). EBV seronegative subjects had a 4.7-fold higher RH compared to EBV positive subjects (p = 0.02). Among EBV donor+/recipient- (D+/R-) subjects, the RH increased by 6.1-fold (p = 0.0001). In a multivariate model, risk factors included recipient age < or =5 years (RH 3.2, 95% CI: 1.1-9.6, p = 0.034) and EBV D+/R- status (RH 7.7, 95% CI: 1.6-35.9, p = 0.010). Of 19 patients with PTLD, 17 are alive with functioning grafts and 2 lost their grafts, 1 of whom subsequently died of recurrent PTLD. This 'robust' immunosuppression protocol was associated with low rejection rates but an unacceptably high incidence of PTLD. The combination of basiliximab, calcineurin inhibitor, sirolimus and steroids resulted in over-immunosuppression in a high-risk pediatric population and we do not recommend its use. Future studies must include routine viral monitoring to permit early identification of viral activity and a protocol driven reduction of immunosuppression aimed at avoiding complications.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Child; Child, Preschool; Cyclosporine; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Lymphoproliferative Disorders; Male; Multivariate Analysis; Postoperative Complications; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

Despite encouraging results from randomized trials, concerns exist about long-term results of sirolimus-eluting stent implantation. We sought to determine whether in-stent restenosis occurring >1 year ("late") after sirolimus-eluting stent implantation is a real clinical entity. We analyzed data on all sirolimus-eluting stents implanted in our institution before March 2003. During the study period 928 lesions in 433 patients were treated. Angiographic follow-up was performed in 306 patients (70.6%) with 679 lesions (73.2%). Angiography after 1 year was performed only in symptomatic patients. We considered restenosis "early" if it occurred during the first year and late if after 1 year. Late restenosis required demonstration of a widely patent stent at 6 to 9 months, with repeat angiography after 1 year demonstrating restenosis. Restenosis occurred in 160 lesions overall (23.5%). Of the 31 (4.6%) that were documented after 1 year, 13 were excluded from analysis due to absence of 6- to 9-month angiography; the remaining 18 (2.6%, 1.7 to 4.2) fulfilled our criteria for late restenosis (median time of documentation 607 days, interquartile range 511 to 923). In conclusion, late restenosis is an infrequent but real entity; its existence implies we should not discount the possibility of restenosis as the cause of symptoms that develop >1 year after sirolimus-eluting stent implantation.

Topics: Aged; Blood Vessel Prosthesis Implantation; Coronary Angiography; Coronary Restenosis; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Sirolimus; Stents; Time Factors

Calcineurin inhibitors (CNIs) have been associated with the development of posttransplant malignancies, especially lymphoma and solid organ tumors. Sirolimus (SRL) has been shown to inhibit the growth of tumor cell lines in vitro and in vivo and has proven effective in clinical practice for the treatment of Kaposi's sarcoma. Organ transplant patients treated with CNIs who develop a tumor may thus benefit from conversion to SRL.. From December 2001 to May 2006, 25 patients who developed a tumor were converted from a CNI-based immunosuppressive regimen to SRL. We analyzed the evolution of the tumor, renal function, and the adverse effects resulting from the change of immunosuppression.. The mean follow-up was 19 months. Creatinine clearance (Cockcroft-Gault) increased from 59.5 +/- 21.7 to 66.0 +/- 24.2 mL/min at 12 months (P = .4) and serum cholesterol from 176.7 +/- 46.8 to 216.4 +/- 40.3 mg/dL (P = .01). Proteinuria rose from 0.3 +/- 0.1 to 1.3 +/- 0.9 g/24 hours (P = .004). Adverse events included anemia, thrombocytopenia, and oral ulcers in 20% of cases, cutaneous eruption and gastrointestinal alterations in 12%, and edema in 24%. Four (16%) patients had improved blood pressure readings. Six (24%) patients died and one experienced an acute rejection episode after conversion to SRL. Nineteen (76%) patients displayed a favorable evolution with no evidence of tumor progression.. Conversion to SRL stabilized tumor progression in 76% of long-term renal transplant patients who developed a neoplasm over a mean follow-up of 19 months. Moreover, renal function improved. The most important adverse effects were increased cholesterol and proteinuria.

Topics: Antineoplastic Agents; Calcineurin Inhibitors; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Neoplasms; Postoperative Complications; Sirolimus; Time Factors

Although the increased utilization of drug-eluting stents is well supported by multiple studies with clinical trial data for many patient and lesion subsets, their use to treat diseased saphenous vein graft (SVG) lesions is much less well substantiated. We sought to ascertain and compare 12-month target vessel revascularization (TVR) rates for sirolimus-eluting Cyphertrade mark stents and bare-metal stents (BMS) when utilized to treat stenoses in diseased SVGs.. Therefore, we conducted a multicenter matched-control study in patients treated for de novo SVG lesions with Cypher or BMS, matching for reference vessel diameter, stent length, diabetes and number of stents utilized. The primary study endpoint was TVR at 12 months.. Three hundred and fifty patients were matched, with patient age = 69 +/- 9 years, 77% male, 39% diabetics, SVG age = 119 +/- 75 months, reference vessel diameter = 3.3 +/- 0.4 mm, target lesion length = 17.4 +/- 8.4 mm (p = NS for all between-group comparisons). Twelve-month TVR was modestly reduced with Cypher stenting (6.8% vs. 11.8%; p = 0.14) due to a trend toward a reduction in binary restenosis (7.4% vs. 13.6%; p = 0.08). Twelve-month survival was 95.3% and 96.4% in the Cypher and BMS groups, respectively (p = 0.79).. Cypher stents appear to modestly reduce TVR without apparent safety risk compared with BMS when applied to the treatment of diseased SVGs. In conjunction with other available studies, these data support Cypher stent use in this setting.

Topics: Aged; Angioplasty, Balloon, Coronary; Case-Control Studies; Coronary Artery Bypass; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Saphenous Vein; Sirolimus; Treatment Outcome

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.

Topics: Adult; Antiviral Agents; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Heart-Lung Transplantation; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Patient Selection; Postoperative Complications; Sirolimus; Treatment Outcome; United States

Everolimus is a potent immunosuppressive agent that has anti-proliferative activity. The benefits of everolimus vs azathioprine in de novo heart transplant recipients were assessed in a randomized, double-blind study. Patients (n = 634) were randomized to receive everolimus (1.5 mg/day or 3.0 mg/day) or azathioprine; all patients received steroids and full-dose ciclosporin (CsA). The primary endpoint was the incidence of efficacy failure [biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up]. The incidence of cardiac allograft vasculopathy (CAV) was assessed by intravascular ultrasound. The incidence and hospitalization costs of major adverse cardiac events (MACE) were assessed after 4 years. The incidence of efficacy failure was significantly reduced with everolimus compared with azathioprine at 12, 24 and 48 months (P < 0.05), largely because of a lower incidence of BPAR. An increase in serum creatinine levels was seen with everolimus compared with azathioprine, likely attributed to CsA nephrotoxicity. There was a significantly larger increase in vascular intimal thickness with azathioprine than with everolimus (P

Topics: Azathioprine; Cardiovascular Diseases; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Everolimus; Glucocorticoids; Graft Rejection; Heart Transplantation; Hospital Costs; Humans; Immunocompromised Host; Immunosuppressive Agents; Pennsylvania; Postoperative Complications; Risk Factors; Sirolimus; Tunica Intima; Ultrasonography

We assessed predictive factors and characteristics of patients with late-onset invasive aspergillosis in the current era of novel immunosuppressive agents. Forty transplant recipients with invasive aspergillosis were included in this prospective, observational study initiated in 2003 at our institutions. In 50% (20/40) of these patients, the infections were late-occurring. Receipt of sirolimus in conjunction with tacrolimus for refractory rejection or cardiac allograft vasculopathy (P=0.047) was significantly associated with late-onset infection. The use of depleting or non-depleting T or B-cell antibodies, either as induction or as antirejection therapy did not correlate with time to onset of invasive aspergillosis. Mortality at 90 days was 20% (4/20) for the patients with early-onset infection and 45% (9/20) for those with late-onset infection (P=0.17). Thus, nearly one-half of the Aspergillus infections in transplant recipients in the current era are late-occurring. These data have implications relevant for prophylactic strategies and guiding clinical management of transplant recipients presenting with pulmonary infiltrates.

Topics: Adult; Age of Onset; Aged; Antibodies; Antifungal Agents; Aspergillosis; B-Lymphocytes; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Postoperative Complications; Prospective Studies; Risk Factors; Sirolimus; Spain; T-Lymphocytes; Tacrolimus; Treatment Outcome; United States

A prospective study was performed to evaluate low dose Anti-Thymocyte Globulin (ATG) and Rituximab along with high dose Sirolimus as induction agents for reducing the incidence of acute rejection in renal transplantation. 66 patients who were to undergo live renal transplantation were divided into the low risk Group I (GpI, n=41) and the high risk Group II (GpII, n=25) recipients. Induction therapy included single dose Rituximab (200 mg), ATG (2 mg/kg) and Sirolimus 12 mg/d administered minus 3 days pretransplant. All patients underwent splenic radiation and Double Filtration Plasmapheresis (DFPP). Post-operatively, all recipients received MMF, prednisolone 5-10 mg/d and Tacrolimus started when serum creatinine (Scr) fell below 2.5 mg/dl on the first Post Operative Day (POD). If creatinine still remained high second dose ATG and Sirolimus continued. Once serum creatinine fell below 1.5 mg/dl Tacrolimus initiated at 0.1 mg per kg per day dose stopping ATG.. Acute rejection at 6 months for GpI was nil and for GpII it was 8%. Mean Scr on 1st POD was 1.8+/-0.6 mg/dl in GpI and 2.6+/-0.9 mg/dl in GpII. After 6 months the creatinine level in high risk was similar to that of low risk group (1.1+/-0.6 mg/dl in GpI and 1.2+/-0.8 mg/dl in GpII). No patient or graft loss was observed. Infections requiring hospitalization were observed in six patients and wound related complications requiring surgical intervention were observed in 4 of the 66 recipients.. Low dose ATG with Rituximab and high dose Sirolimus can be used as induction agents in immune-conditioned recipients with better apparent results than using high dose induction ATG. This combinational regimen also helps in individualizing post-operative immunosuppressive drugs based upon the post-operative renal function.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antilymphocyte Serum; Creatinine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunologic Factors; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prospective Studies; Rituximab; Sirolimus; Transplantation Conditioning; Treatment Outcome

Optimal treatment for patients with chronic allograft nephropathy (CAN) is not known. Early intervention is preferred. We examined the benefit of adding sirolimus (SRL; C(0) 5-12 ng/mL: HPLC) on the rate of progression of early CAN. We identified patients with biopsy-confirmed Banff grade 1 CAN. After biopsy, patients were switched to SRL + CsA + prednisolone (SRL), MMF + CsA + prednisolone (MMF), or CsA + AZA + prednisolone (AZA). GFR was estimated by Cockcroft-Gault and MDRD formulae. The rate of GFR decline (delta GFR) was determined by calculating the slope of the regression line of estimated GFR (MDRD and Cockcroft-Gault method) at different times. Statistical analysis was performed by the Wilcoxon test. The 41 patients with CAN grade 1 were assigned to SRL: MMF: AZA = 12: 20: 9. Before biopsy; the graft age for SRL: MMF: AZA were 56 +/- 27: 70 +/- 48: 51 +/- 36 months; and the GFR (MDRD method), 38 +/- 8: 42 +/- 15: 36 +/- 14 mL/min; GFR (C-G method) 45 +/- 13, 42 +/- 12, 41 +/- 15 mL/min; trough CsA levels 152 +/- 36: 145 +/- 46: 177 +/- 61 ng/dL; delta GFR (MDRD method) -0.18 +/- 0.20: -0.15 +/- 0.59: -0.20 +/- 1.08; delta GFR (C-G method) -0.13 +/- 0.37: -0.19 +/- 0.24: -0.65 +/- 0.99. Follow-up time for SRL: MMF: AZA was 19 +/- 4: 35 +/- 32: 59 +/- 54 months. At last follow-up; GFR (MDRD method) for SRL: MMF: AZA were 39 +/- 13: 35 +/- 21: 40 +/- 24 mL/min; GFR (C-G method) 46 +/- 17, 37 +/- 18, 46 +/- 25 mL/min; BP 128 +/- 11/79 +/- 7: 131 +/- 22/80 +/- 14: 132 +/- 20/82 +/- 11 mm Hg; and CsA level 52 +/- 25: 122 +/- 41: 155 +/- 49. After biopsy, statin was prescribed in nine SRL, 10 MMF, and three AZA. ACEI was prescribed in two SRL, three MMF, and two AZA. Compared with the prebiopsy values, the delta GFR (MDRD method) changed to -0.04 +/- 0.31 (SRL; P = .04), -0.17 +/- 0.40 (MMF; P = .60), and -0.97 +/- 1.52 (AZA: P = .16). Delta GFR (C-G method) was also significantly improved in the SRL group (-0.02 +/- 0.47; P = .05) but not in the MMF (-0.13 +/- 0.51; P = .53) or AZA (-0.54 +/- 1.78; P = .44). We concluded that patients with early CAN who are switched to SRL and low-dose CsA have a significant attenuation of the rate of GFR declination when compared with patients who receive MMF or AZA addition.

Topics: Adult; Azathioprine; Biopsy; Blood Pressure; Chronic Disease; Creatinine; Cyclosporine; Disease Progression; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sirolimus; Transplantation, Homologous; Treatment Outcome

We explored relationships between blood levels of fingolimod (FTY720) and everolimus versus treated biopsy-proven acute rejection (BPAR) in an open-label trial in de novo kidney transplant recipients.. Patients (n = 52) who fulfilled predefined criteria placing them at increased risk of delayed graft function received fingolimod 2.5 mg/d, everolimus 2 mg twice daily with trough blood levels (C0) adjusted to 4 to 8 ng/mL, and corticosteroids. Everolimus and fingolimod C0 were collected over 1 year; efficacy readout was at 3 months.. Fingolimod C0 accumulated over the first 3 months with a time-averaged level (C0avg) of 5.7 +/- 3.5 ng/mL. At steady state in months 3 to 12, C0 was 7.0 +/- 4.4 ng/mL. Overall, 30 patients (58%) were free from BPAR to month 3. Patients were divided into four groups based on whether their fingolimod C0avg and everolimus C0avg were above or below the population medians. Freedom from BPAR was 53% and 57% for low fingolimod combined with low and high everolimus, whereas the percentages were improved to 83% and 85% for high fingolimod combined with low and high everolimus.. This pilot study with an everolimus-fingolimod regimen demonstrated trends in freedom from rejection that were drug concentration-related and that underscored, in particular, a strong contribution to efficacy from fingolimod.

Topics: Drug Therapy, Combination; Everolimus; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Lymphocyte Count; Postoperative Complications; Propylene Glycols; Sirolimus; Sphingosine

We sought to determine the real-world incidence of angiographically confirmed and possible stent thrombosis (ST) in an unrestricted population during the first 30 days after bare-metal stent (BMS), sirolimus-eluting stent (SES), and paclitaxel-eluting stent (PES) implantation.. Current data on ST in drug-eluting stents (DES) have come from randomized trials with strict entry criteria, which limits their generalizability to daily practice.. The study population comprised three sequential cohorts of 506 consecutive patients with BMS, 1,017 consecutive patients with SES, and 989 consecutive patients treated with PES.. In the first 30 days after stent implantation, 6 BMS (1.2%, 95% confidence interval [CI] 0.5% to 2.6%; p = 0.9), 10 SES (1.0%, 95% CI 0.5% to 1.8%), and 10 PES (1.0%, 95% CI 0.6% to 1.9%) patients developed angiographically proven ST. Multiple potential risk factors were identified in most patients with ST. Bifurcation stenting in the setting of acute myocardial infarction was an independent risk factor for angiographic ST in the entire population (odds ratio [OR] 12.9, 95% CI 4.7 to 35.8, p < 0.001). In patients with DES who had angiographic ST, 30-day mortality was 15%, whereas another 60% suffered a nonfatal myocardial infarction; no further deaths occurred during six months of follow-up. Including possible cases, 7 BMS (1.4%, 95% CI 0.7% to 2.8%), 15 SES (1.5%, 95% CI 0.9% to 2.4%), and 16 PES (1.6%, 95% CI 1.0% to 2.6%) patients had ST.. The unrestricted use of SES or PES is associated with ST rates in the range expected for BMS. Stent thrombosis was associated with a high morbidity and mortality. Bifurcation stenting, when performed in patients with acute myocardial infarction, was associated with an increased risk of ST.

Topics: Aged; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Cohort Studies; Coronary Angiography; Coronary Artery Disease; Coronary Thrombosis; Equipment Design; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Paclitaxel; Postoperative Complications; Sirolimus; Stents; Survival Analysis; Time Factors; Treatment Outcome

We compared the risk of stent thrombosis (ST) after drug-eluting stents (DES) versus bare-metal stents (BMS), and tested the hypothesis that the risk of DES thrombosis is related to stent length.. Whether DES increase the risk of ST remains unclear. Given the very low restenosis rate after drug-eluting stenting, longer stents are frequently implanted for the same lesion length in comparison to BMS.. We included in a meta-analysis 10 randomized studies comparing DES and BMS. Overall, 5,030 patients were included (2,602 were allocated to DES and 2,428 to BMS). The risk of thrombosis after DES versus BMS was compared, and the relationship between the rate of DES thrombosis and stent length was evaluated.. Incidence of ST was not increased in patients receiving DES (0.58% vs. 0.54% for BMS; odds ratio: 1.05; 95% confidence interval [CI]: 0.51 to 2.15; p = 1.000). The overall rate of ST did not differ significantly between patients receiving sirolimus- or paclitaxel-eluting stents (0.57% vs. 0.58%; p = 1.000). We found a significant relation between the rate of ST and the stented length (Y = -1.455 + 0.121 X; 95% CI for beta: 0.014 to 0.227; R = 0.716; p = 0.031). In patients with DES, mean stented length was longer in those suffering ST (23.4 +/- 8.1 mm vs. 21.3 +/- 4.1 mm, p = 0.025).. Drug-eluting stents do not increase the risk of ST, at least under appropriate anti-platelet therapy. The risk of ST after DES implantation is related to stent length.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Artery Disease; Coronary Thrombosis; Equipment Design; Follow-Up Studies; Humans; Paclitaxel; Postoperative Complications; Risk Factors; Sirolimus; Statistics as Topic; Stents; Treatment Outcome

Renal failure induced by calcineurin-inhibitor agents is a common complication of lung transplantation. Sirolimus, a macrolide immunosuppressant with a distinct mechanism of action, may prevent renal failure but was found to have a high infectious and toxicity rate in the only relevant study conducted so far. The aim of the present prospective pilot study was to assess the benefit of sirolimus combined with low-dose calcineurin inhibitors in this patient population.. Sixteen lung transplant recipients with post-transplantation renal dysfunction were allocated to receive the standard immunosuppression regimen or a combination sirolimus/low-dose calcineurin-inhibitor regimen. Target trough levels of sirolimus were 4 to 8 ng/mL. Tacrolimus was tapered down to target trough levels of 4 to 8 ng/mL and cyclosporine to 80 to 120 ng/mL. Duration of follow-up was 18 months.. At the end of follow-up, the sirolimus group showed a significant improvement in creatinine clearance (42.6 mL/min vs. 32.5 mL/min, P= 0.05), whereas the control group showed a significant reduction (32.3 mL/min vs. 40.3 mL/min, P= 0.02). The difference between the groups was statistically significant (P < 0.0001). Acute rejection episodes occurred in 2 patients in the sirolimus group and 1 patient in the control group (P= NS). Pneumonia developed in 6 study patients and 4 controls; all responded to antibiotics.. Sirolimus combined with low-dose calcineurin inhibitors appears to be a safe and effective alternative immunosuppressive therapy to sirolimus alone in lung transplant recipients with renal failure. Graft function is preserved, and infection and drug toxicity rates are low.

Topics: Aged; Creatinine; Drug Therapy, Combination; Emphysema; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Lung Transplantation; Male; Middle Aged; Pilot Projects; Postoperative Complications; Sirolimus

Our objective was to determine the impact of thymoglobulin-sirolimus-cyclosporine immunosuppression on the alloimmune response of pancreas-kidney transplant recipients.. Thirty-six pancreas transplant recipients received an induction protocol of thymoglobulin, sirolimus, reduced-dose cyclosporine, and corticosteroids. A subset of 10 recipients were also enrolled in a study to measure immune responsiveness. Flow PRA-determined HLA antibody, donor-specific flow cytometry crossmatching (FCXM), T-cell subset, and suppressor cell assays were performed at various timepoints during the first posttransplant year.. One-year patient, kidney, and pancreas survivals were 97%, 94%, and 92%, respectively. There was 1 death due to sepsis, and 1 kidney and 2 pancreas graft losses. There were no acute rejection episodes. Recipients in the immune-monitoring study displayed depression of CD3, CD4, and CD8 counts (<80%) until 3 months posttransplant. At transplantation, 9 of 10 patients displayed <10% class I HLA antibody. By 3 months, 7 of 10 showed a transient elevation in class I HLA antibodies, with 2 patients expressing >80% flow PRA. At transplant 1 patient was FCXM-positive, whereas, by 3 months posttransplant, 2 of 10 patients demonstrated a positive FCXM. There were no clinical consequences to either the presence of HLA antibody or the positive FCXMs. By 6 months, 7 of 9 patients expressed immunoregulatory suppressor cell activity.. The absence of acute rejection events was likely due to inhibition of donor-specific immunity. Seventy percent of patients demonstrated an early non-donor-directed HLA antibody response that had no adverse effect on graft function and 78% of the patients displayed immunoregulatory suppressor cell function, probably contributing to the successful clinical outcome.

Topics: Anti-Bacterial Agents; Antilymphocyte Serum; Communicable Disease Control; Cyclosporine; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Count; Monitoring, Immunologic; Pancreas Transplantation; Postoperative Complications; Sirolimus; T-Lymphocytes; Transplantation Conditioning; Transplantation, Homologous

A prospective, randomized trial evaluated the combination of everolimus of 1.5 or 3 mg/d with steroids, basiliximab, and low-dose cyclosporine (CsA) adjusted by C2 monitoring in 256 renal transplant recipients. CsA C2 target levels, initially set at 600 ng/mL, were tapered over time posttransplant. The median serum creatinine concentrations were 130 mumol/L in both sirolimus groups (1.5 and 3 mg/d) at 6 months. Biopsy-proven acute rejection (BPAR) occurred in 13.7% and 15.1% of patients in the 1.5 and 3 mg/d groups, respectively. The incidence of BPAR was significantly higher among patients with everolimus trough levels < 3 ng/mL. Posttransplant diabetes mellitus occurred rarely, and blood pressure control appeared favorable; however, serum cholesterol levels were increased by approximately 50%, and serum triglycerides by approximately 100%. Serum testosterone concentrations increased after renal transplantation in both everolimus groups. Concentration-controlled everolimus therapy combined with low-dose CsA provides effective protection against rejection with good renal function and safety profiles.

Topics: Antibodies, Monoclonal; Basiliximab; Blood Pressure; Cardiovascular Diseases; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Gonadal Steroid Hormones; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Kidney Function Tests; Kidney Transplantation; Male; Postoperative Complications; Recombinant Fusion Proteins; Risk Factors; Sirolimus

Everolimus has recently shown promise in terms of short- and long-term clinical lung transplant outcomes. This study aims to determine the altered lung allograft cellular and cytokine mileau when everolimus is substituted for azathioprine (AZA). Twenty-three stable lung transplantation (LTx) recipients were randomized in a double-blinded study to receive everolimus (13) or AZA (10) plus standard cyclosporine/prednisolone. Bronchoalveolar lavage (BAL) and endobronchial biopsies (EBB) were performed on three occasions (T(0)-T(2)) to elucidate cellular and cytokine profiles via immunocytochemistry, immunohistology and enzyme-linked immunosorbent assay (ELISA) techniques. There were no group differences for demographics or clinical events throughout the study nor baseline cellular/cytokine differences. BAL lymphocyte percentage fell in the AZA group by T(2) (p = 0.05). BAL and EBB CD4 measures significantly declined in the everolimus group by T(2) (p < 0.05). EBB neutrophils rose significantly in the AZA group, with a fall in the everolimus group resulting in a significant difference at T(2) (p = 0.01). In conclusion, everolimus has contributed to potentially important differences in BAL and EBB cellular profiles.

Topics: Anti-Inflammatory Agents; Azathioprine; Bronchoalveolar Lavage; Bronchoscopy; Cytokines; Double-Blind Method; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Lymphocyte Count; Male; Middle Aged; Placebos; Postoperative Complications; Prospective Studies; Sirolimus

Limited data exist regarding the safety and efficacy of sirolimus in combination with a calcineurin inhibitor in heart transplant recipients.. From January 2001 to June 2002, 31 de novo heart transplant recipients (treatment group) received a combination of sirolimus, tacrolimus, low-dose rabbit antithymocyte globulin, and glucocorticoids. Outcomes, such as actuarial survival, rate of rejection, incidence of infection, probability of developing diabetes mellitus, renal function, platelet and white blood cell counts, and incidence of coronary artery disease at 1 year, were compared with a cohort of 25 patients (control group) who underwent transplantation primarily in 2000 and in early 2002 treated with cyclosporine, mycophenolate mofetil, and glucocorticoids. All patients were followed up for at least 12 months.. Kaplan-Meier actuarial 1-year survival rates were equivalent between groups (97% for the treatment group and 88% for the control group), as was freedom from allograft rejection (48% and 42% for treatment and control groups, respectively). No cases of transplant arteriopathy were noted within the first posttransplantation year. Renal function was not significantly affected in either group. There was a striking increased incidence of mediastinitis in the treatment group (19%) versus 0% in the control group (P = .02). Tacrolimus-sirolimus therapy was associated with a nearly 11-fold increased incidence of new-onset diabetes mellitus as well (P = .004).. Tacrolimus, sirolimus, and steroids (following low-dose rabbit antithymocyte globulin) were associated with an increased incidence of mediastinitis and posttransplantation diabetes mellitus. No obvious long-term benefit on survival, arteriopathy, or renal function was noted.

Topics: Adrenal Cortex Hormones; Cyclosporine; Diabetes Mellitus; Follow-Up Studies; Glucocorticoids; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Sirolimus; Survival Analysis; Tacrolimus; Time Factors

The effect of lesion characteristics on neointimal hyperplasia after sirolimus-eluting stent implantation was examined in 45 patients who underwent successful preinterventional intravascular ultrasound. There were no differences in neointimal hyperplasia between the moderate/severe calcified lesion group (calcium arc >120 degrees ) and the non/mild calcified lesion group or between the positive vessel remodeling group (external elastic membrane area at the minimal lumen area site larger than that at the proximal reference site) and negative vessel remodeling group. No correlation between preinterventional plaque burden and neointimal hyperplasia was found. In patients who have coronary artery disease, sirolimus-eluting stents continue to demonstrate striking suppression of neointimal proliferation, irrespective of lesion characteristics previously associated with greater restenotic risk.

Topics: Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Restenosis; Coronary Stenosis; Coronary Vessels; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Humans; Hyperplasia; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prospective Studies; Prosthesis Failure; Risk Factors; Severity of Illness Index; Sirolimus; Stents; Tunica Intima; Ultrasonography, Interventional

Randomized clinical trials have shown that sirolimus-eluting stents (SESs) decrease restenosis rates compared with bare metal stents (BMSs), but their efficacy among patients who have diabetes mellitus remains to be established. This study investigated the effect of SES implantation in a high-risk population (i.e., patients who had diabetes and small coronary vessel disease). For this purpose, we analyzed outcomes of the subset of patients who had diabetes and were enrolled in the SES-SMART, a randomized trial that compared the results of implantation of SESs and BMSs in small coronary arteries. Twenty-nine patients who had diabetes were originally randomized to receive SESs and 45 patients received BMSs. The use of SESs was associated with approximately 60% decreases in the relative incidence of in-segment angiographic restenosis (63% vs 25%, p = 0.003) and in-segment late loss (0.76 vs 0.28 mm, p <0.002). Angiographic patterns of restenosis were more favorable in the SES group. SES implantation was associated with a 15% absolute decrease in adverse clinical events. In patients who had insulin-dependent diabetes mellitus, SESs showed a high in-segment restenosis rate (40%) that was principally due to persistent restenosis. In conclusion, in diabetics with small coronary arteries, SES implantation significantly reduces the incidence of the 8-month angiographic restenosis rate compared with BMSs.

Topics: Aged; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Single-Blind Method; Sirolimus; Stents; Survival Rate; Treatment Outcome

To assess whether asymmetric stent expansion affects suppression of neointimal hyperplasia after sirolimus-eluting stent implantation, 64 patients in the SIRolImUS-coated Bx Velocity stent trial who underwent single 18-mm stent implantation and 3-dimensional intravascular ultrasonography at 8-month follow-up were enrolled. To assess the longitudinal stent asymmetric expansion, 2 cross sections with a maximal/minimal stent area were chosen in each patient. To assess for tomographic stent asymmetric expansion, stent eccentricity was determined by dividing the minimum stent diameter by the maximum stent diameter. At the 2 cross sections with a maximal/minimal stent area, a sirolimus-eluting stent reduced neointimal hyperplasia significantly with no interaction between the treatment and stent areas. A sirolimus-eluting stent also significantly reduced neointimal hyperplasia in the concentric and eccentric stent groups.

Topics: Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Stenosis; Double-Blind Method; Follow-Up Studies; Humans; Hyperplasia; Immunosuppressive Agents; Postoperative Complications; Prospective Studies; Sirolimus; Stents; Treatment Outcome; Tunica Intima; Ultrasonography, Interventional

Delayed graft function (DGF) has long been identified as one of the main correlates of poor graft survival in cadaveric renal transplantation, but the factors that affect its onset and duration are not fully elucidated. The impact of two immunosuppressive protocols on the incidence and length of DGF among kidney transplant recipients of a suboptimal organ was evaluated. Patients were randomly treated with corticosteroids (CS); low-dose cyclosporine (CsA) and sirolimus (SRL; group 1; n = 42); or CS, full-dose CsA, and mycophenolate mofetil (group 2; n = 48). All recipients received immunoprophylaxis with basiliximab. After 3 mo, group 1 discontinued CsA and continued with SRL, whereas group 2 continued the same treatment. The incidence of DGF was similar in the two groups (group 1 = 52.4%; group 2 = 58.3%), whereas its duration was significantly higher in the group 1 (19.0 +/- 6.0 versus 10.3 +/- 3.2 d; P = 0.001). Both groups showed 100% actuarial graft and patient survival at 1-yr. Among DGF patients, serum creatinine (sCr) at discharge was significantly worse in group 1 (sCr, 3.0 +/- 1.0 versus 1.5 +/- 0.2 mg/dl; calculated creatinine clearance, 31.2 +/- 9.3 versus 61.1 +/- 10 ml/min; P = 0.001). During the first year, the former group displayed a significant improvement of graft function, such that at 1-yr, no difference could be measured between groups (sCr, 1.8 +/- 0.5 versus 1.7 +/- 0.4 mg/dl; calculated creatinine clearance, 51.5 +/- 10.2 versus 53.3 +/- 9.4 ml/min). In conclusion, in de novo renal transplanted patients, the administration of SRL, in combination with low-dose CsA, is associated with a delayed recovery from DGF but does not worsen 1-yr graft function.

Topics: Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Postoperative Complications; Recovery of Function; Sirolimus; Time Factors

In an attempt to reduce chronic calcineurin inhibitor induced allograft nephropathy in first cadaver and human leukocyte antigen non-identical living-donor renal transplantation, sirolimus (Siro) or mycophenolate mofetil (MMF) was tested as adjunctive therapy, with planned dose reductions of tacrolimus (Tacro) over the first year postoperatively. Adjunctive Siro therapy with a similar dose reduction algorithm for Neoral (Neo) was included for comparison.. The detailed dose reduction plan (Tacro and Siro, group A; Tacro and MMF, group B; Neo and Siro, group C) is described in our companion report in this issue of Transplantation. The present report documents function, patient and graft survival, protocol compliance, and adverse events.. As mentioned (in companion report), group demographics were similar. The present study shows no significant differences in 1-year patient and graft survival but does show a trend that points to more difficulties in group C by way of a rising slope of serum creatinine concentration (P=0.02) and decreasing creatinine clearance (P=0.04). There were more patients who discontinued the protocol plan in group C. Thus far, no posttransplant lymphomas have appeared, and infectious complications have not differed among the groups. However, a greater percentage of patients in group C were placed on antihyperlipidemia therapy, with an (unexpected) trend toward a higher incidence of posttransplant diabetes mellitus in this group. Group A required fewer, and group B the fewest, antihyperlipidemia therapeutic interventions (P<0.00001).. This 1-year interim analysis of a long-term, prospective, randomized renal-transplant study indicates that decreasing maintenance dosage of Tacro with adjunctive Siro or MMF appears to point to improved long-term function, with reasonably few adverse events.

Topics: Creatinine; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Kidney Function Tests; Kidney Transplantation; Lymphocele; Mycophenolic Acid; Patient Compliance; Postoperative Complications; Sirolimus; Surgical Wound Infection; Tacrolimus; Time Factors

A sirolimus-eluting stent (Cypher, Cordis Corp) has been reported to markedly decrease restenosis in selected lesions; higher-risk lesions, including coronary bifurcations, have not been studied.. This prospective study evaluated the safety and efficacy of sirolimus-eluting stents for treatment of coronary bifurcation lesions. Patients were randomly assigned to either stenting of both branches (group A) or stenting of the main branch with provisional stenting of the side branch (SB) (group B). Eighty-five patients (86 lesions) were enrolled. There was 1 case of unsuccessful delivery of any device at the bifurcation site. Given the high crossover, more lesions were treated with 2 stents (n=63) than with stent/balloon (n=22). Clinical follow-up at 6 months was completed in all patients and angiographic follow-up in 53 patients in group A (85.5%) and 21 in group B (95.4%). One patient died suddenly 4.5 months after the procedure. There were 3 cases of stent thrombosis (3.5%). The total restenosis rate at 6 months was 25.7%, and it was not significantly different between the double-stenting (28.0%) and the provisional SB-stenting (18.7%) groups. Fourteen of the restenosis cases occurred at the ostium of the SB and were focal. Target lesion revascularization was performed in 7 cases; target vessel failure occurred in 15 cases (17.6%).. These results are an improvement compared with historical controls using bare metal stents. Restenosis at the SB remains a problem. At this time, no statement can be made regarding the most appropriate technique to use when treating bifurcations with the Cypher stent.

Topics: Aged; Anticoagulants; Aspirin; Catheterization; Clopidogrel; Combined Modality Therapy; Comorbidity; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Coronary Thrombosis; Coronary Vessels; Death, Sudden; Diabetes Mellitus; Disease-Free Survival; Drug Implants; Female; Follow-Up Studies; Humans; Life Tables; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prospective Studies; Safety; Sirolimus; Stents; Survival Analysis; Ticlopidine; Treatment Outcome

Calcineurin inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this prospective study was to evaluate the safety and efficacy of a completely CNI-free immunosuppressive regimen [mycophenolate mofetil (MMF) and sirolimus (Sir)] in HTx-recipients with late post-transplant renal impairment.. Since 2001, 30 HTx-patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine >1.9 mg/dl were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Conversion was started with 6 mg Sir or 500 mg MMF according to the pre-existing regimen and was continued with the dose adjusted to achieve target trough levels between 8 and 14 ng/ml (Sir) or 1.5 and 4 microg/ml (mycophenolate). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up included endomyocardial biopsies, echocardiography and laboratory studies. Additionally, every HTx-patient treated at our centre between 1996 and 2001 due to chronic renal failure without immunosuppressive conversion and fulfilling the inclusion criteria were retrospectively analysed and acted as control group.. Patient demographics and 1-year survival [93 (conversion) vs 90% (control)] were compared. No acute rejection episode was detected in either group. Renal function improved significantly in the conversion group (creatinine: 3.18+/-0.71 vs 2.22+/-0.79 mg/dl, P=0.001; cystatin pre- vs post-conversion: 2.95+/-1.06 vs 2.02+/-1.1 mg/l, P=0.01). In three patients haemodialysis therapy was stopped completely after conversion. In the control group renal impairment was deteriorating, creatinine increased from 2.44+/-0.8 to 3.28+/-1 mg/dl (P=0.01). In 10 out of 33 patients chronic haemodialysis had to be initiated within 1 year. Although side effects of CNI-free immunosuppression were common (76%), no patient had to be excluded due to adverse effects.. Conversion from CNI-based immunosuppression to MMF and Sir in HTx-patients with chronic renal failure was safe, preserved graft function and improved renal function.

Topics: Blood Pressure; Calcineurin Inhibitors; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Sirolimus

Sirolimus is a new immunosuppressive agent increasingly being used in liver transplant recipients. There is concern that sirolimus may be associated with wound complications and hepatic artery thrombosis (HAT). We have used sirolimus as primary immunosuppression in 170 liver transplant recipients and therefore reviewed our experience with wound complications and HAT in our cohort of patients. Records of all 170 patients administered sirolimus as primary immunosuppression and 180 historic controls were reviewed. Numbers of wound and hepatic artery complications were recorded, as well as the prevalence of obesity, reoperation, diabetes, and OKT3 use, all of which are risk factors for wound complications. The prevalence of wound complications was 12.4% in sirolimus-treated patients compared with 13.9% in historic controls (P = not significant [NS]). The prevalence of hepatic artery complications was 5.3% in sirolimus-treated patients compared with 8.3% in historic controls (P = NS). The prevalence of obesity and OKT3 administration was significantly lower in sirolimus-treated patients. Multivariate analysis failed to show an association between sirolimus therapy and hepatic artery or wound complications. The prevalence of wound and hepatic artery complications is not different in liver transplant recipients administered sirolimus as part of a primary immunosuppressive regimen compared with historic controls.

Topics: Cohort Studies; Diabetes Mellitus; Female; Graft Rejection; Hepatic Artery; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Muromonab-CD3; Obesity; Postoperative Complications; Prevalence; Reoperation; Risk Factors; Sirolimus

We describe the clinical and morphological patterns of restenosis after sirolimus-eluting stent (SES) implantation.. From 121 patients with coronary angiography obtained >30 days after SES implantation, restenosis (diameter stenosis >50%) was identified in 19 patients and 20 lesions (located at the proximal 5-mm segment in 30% or within the stent in 70%). Residual dissection after the procedure or balloon trauma outside the stent was identified in 83% of the proximal edge lesions. Lesions within the stent were focal, and stent discontinuity was identified in some lesions evaluated by intravascular ultrasound.. Sirolimus-eluting stent edge restenosis is frequently associated with local trauma outside the stent. In-stent restenosis occurs as a localized lesion, commonly associated with a discontinuity in stent coverage. Local conditions instead of intrinsic drug-resistance to sirolimus are likely to play a major role in post-SES restenosis.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coronary Angiography; Coronary Restenosis; Drug Implants; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Registries; Sirolimus; Stents; Treatment Outcome; Ultrasonography, Interventional

The present study reports on the clinical outcome of 31 consecutive patients with left main coronary artery disease treated with a sirolimus-eluting stent. The implantation of this stent was associated with abolition of post-discharge fatal events and percutaneous reintervention.

Topics: Aged; Blood Vessel Prosthesis Implantation; Coronary Artery Disease; Drug Implants; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Postoperative Complications; Reoperation; Sirolimus; Stents; Survival Analysis; Treatment Outcome

The aim of this study was to describe the National Institutes of Health's experience initiating an islet isolation and transplantation center, including descriptions of our first six recipients, and lessons learned.. Six females with chronic type 1 diabetes, hypoglycemia unawareness, and no endogenous insulin secretion (undetectable serum C-peptide) were transplanted with allogenic islets procured from brain dead donors. To prevent islet rejection, patients received daclizumab, sirolimus, and tacrolimus.. All patients noted less frequent and less severe hypoglycemia, and one-half were insulin independent at 1 year. Serum C-peptide persists in all but one patient (follow-up 17-22 months), indicating continued islet function. Two major procedure-related complications occurred: partial portal vein thrombosis and intra-abdominal hemorrhage. While we observed no cytomegalovirus infection or malignancy, recipients frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, myelosuppression, and other symptoms. Three patients discontinued immunosuppressive therapy: two because of intolerable toxicity (deteriorating kidney function and sirolimus-induced pneumonitis) while having evidence for continued islet function (one was insulin independent) and one because of gradually disappearing islet function.. We established an islet isolation and transplantation program and achieved a 50% insulin-independence rate after at most two islet infusions. Our experience demonstrates that centers not previously engaged in islet transplantation can initiate a program, and our data and literature analysis support not only the promise of islet transplantation but also its remaining hurdles, which include the limited islet supply, procedure-associated complications, imperfect immunosuppressive regimens, suboptimal glycemia control, and loss of function over time.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Glucose; Daclizumab; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoglycemia; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Islets of Langerhans Transplantation; Middle Aged; Postoperative Complications; Reproducibility of Results; Sirolimus; Tacrolimus; Time Factors

Topics: Adrenal Cortex Hormones; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Pilot Projects; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adolescent; Blood Glucose; Child; Child, Preschool; Cholesterol; Diabetes Mellitus; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Survival; Humans; Hyperlipidemias; Kidney Transplantation; Lipids; Male; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Triglycerides

Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients.. We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL.. Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine.. Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.

Topics: Adolescent; Adult; Aged; Calcineurin; Calcineurin Inhibitors; CD4-CD8 Ratio; Cyclosporine; Drug Interactions; Enzyme Inhibitors; Female; Follow-Up Studies; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Platelet Count; Postoperative Complications; Prospective Studies; Sirolimus

Topics: Anticholesteremic Agents; Bacterial Infections; Cholesterol; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Patient Selection; Postoperative Complications; Prednisone; Sirolimus; Time Factors; Transplantation, Homologous; Treatment Failure; Treatment Outcome; Triglycerides

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Cadaver; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Graft Survival; Humans; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Opportunistic Infections; Placebos; Postoperative Complications; Risk Factors; Sirolimus; Survival Rate; Thrombocytopenia; Time Factors; Tissue Donors; Transplantation, Homologous; Triglycerides

Our study assessed the factors that predispose renal transplant recipients to the occurrence of thrombocytopenia and leukopenia, as well as the severity and the time- and concentration-dependence of these side-effects, after administration of sirolimus (SRL) in combination with a cyclosporine (CsA) and prednisone (Pred) regimen.. The clinical courses of two cohorts of renal transplant recipients were compared over 1 year: 119 patients received SRL in addition to CsA and Pred, and 65 demographically similar, concurrent patients received only CsA and Pred. Using an analysis of variance, pretransplant laboratory values and SRL trough concentrations (C0) were correlated with the occurrence, severity, and persistence of drug-induced thrombocytopenia (platelet count <150x10(3) cell/mm3) and/or leukopenia (white blood cell count <5,000/mm3).. Neither the ethnic background nor the pretransplant cytomegalovirus serological status was associated with the occurrence of hematological complications. Thrombocytopenia was usually observed during the first 4 weeks of treatment (P=0.004). The occurrence, but not the severity or the persistence, of both thrombocytopenia and leukopenia correlated significantly with SRL trough concentrations > or =16 ng/ml (P=0.001 and 0.0001, respectively). A significant correlation is evident between the occurrence of the two adverse effects (P=0.001). In 89% of patients, the first episode of either type of cytopenia resolved spontaneously. Among the remaining 11%, 7% responded to SRL dose reduction, and 4% to temporary suspension. No patient required permanent cessation of SRL therapy. Most patients experienced repeated, but self-limited, episodes of toxicity.. Thrombocytopenia and leukopenia are not infrequent occurrences with SRL treatment, and they generally resolve spontaneously.

Topics: Adolescent; Adult; Aged; Cadaver; Cohort Studies; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Living Donors; Male; Middle Aged; Postoperative Complications; Prednisone; Sirolimus; Thrombocytopenia; Tissue Donors

The novel agent sirolimus (SRL; Rapamune; rapamycin) inhibits the immune response by a mechanism distinct from those of calcineurin antagonists or antimetabolites. This randomized, controlled, multicenter, single blind, phase II trial examined the combination of SRL, steroids, and full versus reduced doses of cyclosporine (CsA) for prophylaxis of acute renal allograft rejection.. A total of 149 recipients of mismatched cadaveric- or living-donor primary renal allografts were randomized into six groups. Three groups received placebo or 1 or 3 mg/m2/day SRL, as well as steroids and full-dose CsA (Sandimmune). Three groups received steroids, reduced-dose CsA (target trough level 50% of full-dose range), and 1, 3, or 5 mg/m2/day SRL.. The incidence of biopsy-proven acute rejection episodes within the first 6 months after transplant was reduced from 32.0% in the control group to 8.5% in patients receiving SRL (1 or 3 mg/m2/day) and full-dose Sandimmune CsA (P=0.018). Similar low rates of acute rejection episodes were observed among non-African-Americans, but not African-Americans, treated with SRL and reduced-dose Sandimmune CsA. Despite the augmented immunosuppression, 1-year patient and graft survival rates did not differ significantly across groups. Adverse effects attributable to CsA, including hypertension and new-onset diabetes mellitus, were not exacerbated by SRL. Except for an increased incidence of pneumonia among patients receiving full-dose CsA and 3 mg/m2/day SRL, the incidences of opportunistic infections were similar in all treatment groups. Although SRL produced more frequent, but reversible, hematological and lipid abnormalities, it had no apparent nephrotoxic effects to exacerbate CsA-induced renal dysfunction.. SRL in combination with CsA and steroids not only lowers the incidence of biopsy-proven acute renal allograft rejection episodes, but also may permit CsA sparing, at least among Caucasian patients, without an increased risk of rejection.

Topics: Adult; Aged; Black People; Cyclosporine; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Single-Blind Method; Sirolimus; White People

Sirolimus is an interesting immunosuppressive drug that does not seem to cause nephrotoxicity, neurotoxicity, or diabetogenicity, as commonly seen in patients treated with cyclosporine or tacrolimus. In this report, we describe a possible association between sirolimus and observed hyperlipidemia.. Serum levels of triglycerides and cholesterol were analyzed in 11 patients who participated in a pilot study evaluating the effect of oral sirolimus or placebo combined with cyclosporine and corticosteroids on the occurrence of acute renal transplant rejection.. In four of nine patients given sirolimus, significantly increased serum triglyceride levels were seen, with peak levels occurring 2-4 months after transplantation and ranging between 11.7 and 42.0 mmol/L (reference value <2.2 mmol/L). In two patients given placebo, the serum triglyceride levels remained below 5.0 mmol/L. After reduction or discontinuation of sirolimus, the serum triglyceride levels decreased within 1-2 months and after 1-8 months levels had returned to their pretransplant values. A significant increase in serum cholesterol levels was seen in one of nine patients given sirolimus.. It seems that long-term treatment with sirolimus in combination with cyclosporine and corticosteroids may increase the risk of hypertriglyceridemia.

Topics: Adrenal Cortex Hormones; Adult; Cyclosporine; Drug Combinations; Female; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Pilot Projects; Polyenes; Postoperative Complications; Sirolimus

Sirolimus, a novel immunosuppressant that inhibits cytokine-driven cell proliferation and maturation, prolongs allograft survival in animal models. After a phase I trial in stable renal transplant recipients documented that cyclosporine and sirolimus have few overlapping toxicities, we conducted an open-label, single-center, phase I/II dose-escalation trial to examine the safety and efficacy of this drug combination.. Forty mismatched living-donor renal transplant recipients were sequentially assigned to receive escalating initial doses of sirolimus (0.5-7.0 mg/m2/day), in addition to courses of prednisone and a concentration-controlled regimen of cyclosporine. We conducted surveillance for drug-induced side effects among sirolimus-treated patients and compared their incidence of acute rejection episodes as well as mean laboratory values with those of a historical cohort of 65 consecutive, immediately precedent, demographically similar recipients treated with the same concentration-controlled regimen of cyclosporine and tapering doses of prednisone.. The addition of sirolimus reduced the overall incidence of acute allograft rejection episodes to 7.5% from 32% in the immediately precedent cyclosporine/prednisone-treated patients. At 18- to 47-month follow-up periods, both treatment groups displayed similar rates of patient and graft survival, as well as morbid complications. Although sirolimus-treated patients displayed comparatively lower platelet and white blood cell counts and higher levels of serum cholesterol and triglycerides, sirolimus did not augment the nephrotoxic or hypertensive proclivities of cyclosporine. The degree of change in the laboratory values was more directly associated with whole blood trough drug concentrations than with doses of sirolimus.. Sirolimus potentiates the immunosuppressive effects of a cyclosporine-based regimen by reducing the rate of acute rejection episodes.

Topics: Adult; Aged; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infections; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisone; Sirolimus

Sirolimus has demonstrated effectiveness as a treatment option for several types of vascular anomalies; however, it has a potential side effect of delayed surgical wound healing. The purpose of this study was to evaluate the association of sirolimus with postoperative complications in the pediatric vascular anomaly population.. A retrospective cohort study was performed for children with a vascular anomaly who underwent excision or debulking of the anomaly from 2015 to 2020. Patient demographics, vascular anomaly characteristics, operative variables, sirolimus dosing information, and perioperative outcomes were collected. Univariate analysis was performed to compare outcomes based on the administration of sirolimus.. Forty-seven patients with vascular anomalies underwent 57 surgical procedures (36 without perioperative sirolimus, 21 with perioperative sirolimus). The median age at the time of surgery was seven years (IQR 1.7-14.0). The most common anomalies were lymphatic and venolymphatic malformations. Of the patients administered perioperative sirolimus, the median preoperative and postoperative sirolimus levels were comparable (preoperative 6.9 ng/mL (IQR 4.9-10.1), postoperative 6.5 ng/mL (IQR 4.7-9.4)). The rate of postoperative complications (sirolimus 19%, without sirolimus 11%; p = 0.45) and wound complications (sirolimus 14%, without sirolimus 6%; p = 0.26) were comparable between the cohorts.. Our results suggest sirolimus may not significantly increase perioperative complication rates in pediatric patients undergoing resection of their vascular anomaly.. Level III.

Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Postoperative Complications; Retrospective Studies; Sirolimus; Treatment Outcome; Vascular Malformations

Peritoneal adhesion formation is a challenging postoperative complication. We aim to evaluate the effect of orally administered sirolimus, prednisolone, and their combination to prevent this entity.. Eighty female albino underwent intraperitoneal injection of 3 mL of 10% sterile talc solution to induce peritoneal adhesion, and were subsequently and randomly divided into four groups (each n = 20); including a control group; 1 mg/kg oral prednisolone daily in the morning; 0.1 mg/kg oral sirolimus daily; and a combination group which received both drugs, with the same dosage. On the 29th day, abdominal cavities were explored, and classification was done based on Nair classification.. All rats were healthy on the 29th day, in which exploration was performed. The rats in the control group had extensive intra-abdominal adhesions, while 17 (85%) rats in the control group had substantial adhesion; however, the prednisolone, sirolimus, and combination group had lesser adhesion formation. Also, 14 (70%) rats of prednisolone group, 13 (65%) of sirolimus group, and 16 (80%) of combination group had insubstantial adhesion. The decrease in the grade of peritoneal adhesion bands was highly significant in the combination group (P > 0.001).. The combination of sirolimus and prednisolone was effective for preventing peritoneal adhesions in rats.

Topics: Abdominal Cavity; Animals; Disease Models, Animal; Female; Peritoneal Diseases; Postoperative Complications; Prednisolone; Rats; Sirolimus; Tissue Adhesions

Less is known about the risk factors and outcomes associated with stroke in the current era of increasing heart transplantation (HT) being performed in older patients. The impact of immunosuppression on risk of stroke has not yet been previously studied. We aimed to determine the incidence, risk factors and outcomes of stroke after HT.. We retrospectively analyzed the incidence of ischemic and hemorrhagic strokes and associated outcomes in all consecutive HT recipients transplanted between 1994 and 2016 at a single institution.. Of 529 patients who underwent HT, 57 (10.7%) developed stroke, 8.1% had an ischemic events and (2.6%) had a hemorrhagic stroke. Age at HT (adjusted hazard ratio [HR] 1.33; P=0.03) and diabetes (HR, 2.60; P=0.02) were associated with increased risk of ischemic events. Patients with stroke (any type) were more likely to have worse kidney function (HR, 1.81; P=0.02) whereas patients with ischemic events were more likely to undergo combined organ transplantation (HR, 2.01; P=0.05). Cytomegalovirus infection was found to be associated with increased risk of any stroke (HR, 2.09; P=0.02).Conversion from calcineurin inhibitor to sirolimus-based immunosuppression was not found to be associated with a significant change in stroke risk (HR, 1.39; P=0. 45) compared with calcineurin inhibitor maintenance therapy. Stroke of any type and ischemic events were independently associated with increased risk of death (HR, 1.90; P=0.001 and HR, 2.14; P<0.001, respectively).. Stroke after HT is associated with increased mortality. Older age at HT, diabetes, renal dysfunction, and CMV infection were associated with greater risk of stroke.

Topics: Adult; Aged; Calcineurin Inhibitors; Female; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Sirolimus; Stroke

To compare the efficacy and safety of CD34+ selected ex vivo T-cell depletion (TCD) vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil (PTCy-Sir-MMF) as graft-vs-host disease (GVHD) prophylaxis.. We retrospectively included patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either TCD (n = 38) or PTCy-Sir-MMF (n = 91).. Cumulative incidence of neutrophil and platelet recovery was 92% vs 99% (P = .06) and 89% vs 97% (P = .3) in TCD and PTCy-Sir-MMF, respectively. Cumulative incidences of aGHVD grade II-IV, III-IV, and moderate to severe cGVHD were 11% vs 19% (P = .2), 3% vs 2% (P = .9), and 3% vs 36% (P < .001) in TCD and PTCy-Sir-MMF, respectively. The 2-year non-relapse mortality, relapse, disease-free and overall survival were 25% vs 8% (P = .01), 20% vs 16% (P = .2), 55% vs 76% (P = .004), 57% vs 83% (P = .004) for TCD and PTCy-Sir-MMF, respectively. Cumulative incidence of cytomegalovirus and Epstein-Barr infection requiring therapy was 76% vs 40% (P < .001) and 32% vs 0% (P < .001) in TCD and PTCy-Sir-MMF, respectively. PTCy-Sir-MMF platform showed faster T-cell reconstitution.. PTCy-Sir-MMF provides better survival outcomes but is associated with higher risk of cGVHD compared to TCD.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Cyclophosphamide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immune Reconstitution; Leukemia, Myeloid, Acute; Leukocyte Count; Lymphocyte Depletion; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Prognosis; Recurrence; Severity of Illness Index; Sirolimus; T-Lymphocytes; Transplantation, Homologous; Treatment Outcome; Young Adult

Recent improvements in coronary stent design have focussed on thinner struts, different alloys and architecture, more biocompatible polymers, and shorter drug absorption times. This study evaluates safety and efficacy of a newer generation thin-strut cobalt chromium sirolimus-eluting coronary stent (SES, Ultimaster) in comparison with a second-generation thicker strut stainless steel biolimus-eluting stent (BES, Nobori) in percutaneous coronary intervention (PCI) practice.. A propensity score analysis was performed to adjust for differences in baseline characteristics of 8137 SES patients and 2738 BES patients of two PCI registries (e-Ultimaster and NOBORI 2). An independent clinical event committee adjudicated all endpoint-related adverse events.. The use of SES, as compared with BES was associated with a significantly lower rate of myocardial infarction (MI) (1.2% vs 2.2%; P = 0.0006) and target vessel-related MI (1.1% vs 1.8%; P = 0.002) at 1 year. One-year composite endpoints of all predefined endpoints were lower in patients undergoing SES implantation (target lesion failure: 3.2% vs 4.1%; P = 0.03, target vessel failure: 3.7% vs 5.0%; P = 0.003, patient-oriented composite endpoint 5.7% vs 6.8%; P = 0.03). No significant differences between SES and BES were observed in all-cause death (2.0% vs 1.6%; P = 0.19), cardiac death (1.2% vs 1.2%; P = 0.76) or stent thrombosis (0.6% vs 0.8%; P = 0.43).. These findings suggest an improved clinical safety and efficacy of a newer generation thin-strut SES as compared with a second-generation thicker strut BES.

Topics: Aged; Biocompatible Materials; Chromium Alloys; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Equipment Failure Analysis; Female; Humans; Immunosuppressive Agents; Male; Percutaneous Coronary Intervention; Postoperative Complications; Prosthesis Design; Registries; Sirolimus; Survival Analysis

To assess the long-term outcomes of patients treated with sirolimus-eluting Stentys stent in a real-life setting.. Few data regarding the safety and effectiveness of self-apposing sirolimus-eluting Stentys stent are available.. 278 patients (30% stable coronary artery disease, 70% acute coronary syndromes, and 54% on unprotected left main) treated with sirolimus eluting Stentys stent were retrospectively included in the self-aPposing, bAlloon-delivered, siRolimus-eluting stent for the Treatment of the coronary Artery disease multicenter registry. Major adverse cardiovascular events (MACE, a composite of cardiac death, myocardial infarction, target lesion revascularization, stent thrombosis) were the primary end-point, single components of MACE were the secondary ones.. After 13 months (interquartile range 5-32), MACE was 14%. Stent thrombosis occurred in 3.9% of the patients (2.5% definite stent thrombosis and 1.4% probable stent thrombosis), 66% of them presenting with ST-segment elevation myocardial infarction (STEMI) at admission. Cardiovascular death, target lesion revascularization and myocardial infarction was 4.7%, 8.3%, and 7.2%, respectively. At multivariate analysis, risk of MACE was increased by diabetes (hazard ratios 4.76; P = 0.002) but was not affected by the indication leading to sirolimus-eluting Stentys stent implantation (marked vessel tapering vs. coronary ecstasies, hazard ratios 0.74, P = 0.71).. Sirolimus-eluting Stentys stent may represent a potential solution for specific coronary anatomies such as bifurcation, ectasic, or tapered vessels. Risk of stent thrombosis appears related to clinical presentation with STEMI and to anatomic features, stressing the importance of the use of intracoronary imaging for self-expandable stents implantation.

Topics: Acute Coronary Syndrome; Aged; Antibiotics, Antineoplastic; Cardiovascular Diseases; Coronary Artery Disease; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Percutaneous Coronary Intervention; Postoperative Complications; Registries; Retrospective Studies; Sirolimus; ST Elevation Myocardial Infarction; Thrombosis; Treatment Outcome

Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking.. This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab.. We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018.. Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died.. The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.

Topics: Antibodies, Monoclonal, Humanized; B-Lymphocytes; Child; Combined Modality Therapy; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Incidence; Male; Postoperative Complications; Primary Immunodeficiency Diseases; Retrospective Studies; Rituximab; Sirolimus; Transplantation Conditioning; Treatment Outcome; United Kingdom

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Calcineurin Inhibitors; Child; Drug Substitution; Female; Humans; Immunosuppressive Agents; Incidence; Ireland; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Young Adult

There is little evidence about whether mammalian target of rapamycin (mTOR) inhibitor could prevent post-kidney transplant (KT) urothelial carcinoma (UC) or not. The aim of this study is to analyze the role of mTOR inhibitor add-on in tacrolimus-based kidney transplant recipients.. The data were obtained from the Kaohsiung Chang Gung Memorial Hospital using the Chang Gung Research Database and retrospectively reviewed from January 2000 to December 2015. Patients then were categorized into 2 groups: group FK (more than 2-year tacrolimus [FK] prescription) and group FK + mTOR inhibitor (more than 2-year tacrolimus plus at least 6-month continued sirolimus prescription). The primary end point is post-KT UC development. The secondary end point is mTOR inhibitor add-on effect on renal function deterioration episode.. There were 140 patients with tacrolimus-based immunosuppressant (group FK) and 82 patients with tacrolimus-based and add-on mTOR inhibitor regimen (group FK + mTOR inhibitor). The follow-up duration, sex distribution, and combined mycophenolate mofetil rate are similar in both groups. Younger age, lower tacrolimus trough level, lower UC incidence, and longer KT-to-UC interval were observed. Short- to intermediate-term results revealed noninferior graft outcome by creatinine level or creatinine deterioration.. In our preliminary result, mTOR inhibitor add-on in patients with tacrolimus-based regimen revealed less post-KT UC occurrence. In addition, noninferior graft outcome was also observed. In Taiwan, a high UC prevalence area, mTOR inhibitor add-on strategy can be considered as a preventive strategy for UC after KT.

Topics: Adult; Carcinoma, Transitional Cell; Female; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Taiwan; TOR Serine-Threonine Kinases

Although incidence rates of postoperative neurocognitive disorder (PND) in aged individuals following noncardiac major surgery are rising as individuals are living longer, the mechanism of PND remains poorly understood. We wondered if mammalian target of rapamycin (mTOR) signaling might be associated with PND since mTOR controls some essential intracellular events.. To investigate whether surgery activates the mTOR signaling pathway in aged rats, leading to PND, and whether the mTOR inhibitor, rapamycin, can be used to alleviate PND.. We randomly assigned aged rats to four groups: normal control (C), isoflurane (I), surgery (S), and rapamycin (R). Then, we anesthetized Groups I, S, and R, following which, Groups S and R underwent a splenectomy. After surgery, Group R was administered rapamycin. We used the Morris water maze to test the rats' spatial learning and memory after surgery.. In Group S, escape latency (ie, the time to find the platform) was markedly higher, and the ratio of swimming time in the target quadrant was lower, compared to the other groups. In Group R, escape latency was markedly lower as compared with Group S, and the ratio of swimming time in the target quadrant was higher.. Our results indicate that an altered mTOR signaling pathway after a splenectomy causes PND in aged rats, which can be alleviated by rapamycin.

Topics: Age Factors; Animals; Humans; Male; Neurocognitive Disorders; Postoperative Complications; Random Allocation; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; Splenectomy; TOR Serine-Threonine Kinases

Topics: Allografts; Animals; B-Lymphocytes; Epstein-Barr Virus Infections; Female; Graft Rejection; Graft Survival; Heart Transplantation; Heterocyclic Compounds, 3-Ring; Humans; Inhibitory Concentration 50; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Organ Transplantation; Phosphoinositide-3 Kinase Inhibitors; Postoperative Complications; Proto-Oncogene Proteins c-akt; Purines; Quinazolinones; Sirolimus; TOR Serine-Threonine Kinases

Some literature exists potentially linking proliferation signal inhibitors (PSIs) to venous thromboembolism (VTE). We sought to determine the impact of PSIs on development of VTE in heart transplant (HT) patients while controlling for other risk factors.. The incidence and predisposing factors of VTE were analyzed in this retrospective review of patients >18 years who underwent HT January 2000 to October 2016. Re-transplants, multiorgan transplants, or patients that expired within 30 days post-HT were excluded. VTE incidence rates are reported as number of events per 100 person-years. Cox proportional hazards models were used to assess the relationship between PSI exposure (time-varying covariate) and VTE.. Of 561 HT recipients, 112 received PSIs, started a median of 1.5 years post-HT. There were 102 total VTE events: 78 in PSI-naive patients during 2,547 patient-years (3.0 events per 100 person-years) vs 24 in PSI-exposed patients during 544 patient-years (4.4 events per 100 person-years). Cox proportional hazards models with PSI exposure as a time-varying covariate indicated the increased risk was statistically significant (unadjusted hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.31 to 3.49, p = 0.002). A VTE history was significantly associated with increased risk of VTE post-HT (HR 1.58, 95% CI 1.07 to 2.35, p = 0.022); however, the risk remained significant when adjusting for potential confounders, including previous VTE (HR 2.0, 95% CI 1.18 to 3.38, p = 0.010).. Exposure to PSIs is associated with a significant increase in risk for VTE even when controlling for other risk factors. When considering the use of PSI-based immunosuppression after HT, the risk of VTE over time should be weighed against the potential benefit.

Topics: Adult; Aged; Cell Proliferation; Everolimus; Female; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Sirolimus; Venous Thromboembolism; Young Adult

Use of the everolimus-eluting stent (EES) instead of the sirolimus-eluting stent (SES) has been shown to improve clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) out to 3 years. However, it is not known whether the differences in efficacy and safety outcomes remain constant throughout 5 years.. This was a retrospective, non-randomized, observational study. We followed 1460 consecutive patients undergoing PCI in our institutions from April 2005 to March 2012. There were 718 cases in patients with SES (SES group) and 742 with EES (EES group). Ten-month angiographic follow-up results and 5-year clinical follow-up outcomes were compared between the EES and SES groups. The primary outcome of this study was major adverse cardiac events (MACE), defined as the composite of cardiac death, recurrent myocardial infarction (MI), target vessel revascularization (TVR), and stent thrombosis (ST).. At 5 years, the rates of target lesion revascularization (TLR), TVR, recurrent MI and ST were significantly lower in the EES group compared to the SES group (TLR: 4.6% vs. 8.2%, p<0.05; TVR: 5.0% vs. 9.0%, p<0.05; recurrent MI: 1.5% vs. 4.4%, p<0.05; ST: 1.2% vs. 3.9%, p<0.05). Thus, MACE were significantly lesser in the EES group compared to the SES group (8.8% vs. 12.8%, p=0.006).. EES improved clinical outcomes compared to SES, and specifically, was associated with reductions in TVR, ST, and recurrent MI out to 5 years.

Topics: Aged; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Postoperative Complications; Retrospective Studies; Sirolimus; Thrombosis; Time Factors; Treatment Outcome

Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a potent immunosuppressant that is increasingly used in prevention and treatment of graft-vs-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) patients. However, data regarding its adverse effects in HSCT patients remain limited. We describe an 18-year-old HSCT patient with a history of invasive fungal infection, who developed pericardial effusion with cardiac tamponade and interstitial pneumonitis while receiving sirolimus for GVHD prophylaxis. Our case illustrates potentially life-threatening complications of sirolimus use in allogeneic HSCT patients.

Topics: Adolescent; Cardiac Tamponade; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Mycoses; Pericardial Effusion; Postoperative Complications; Recurrence; Siblings; Sirolimus

The aim of this study was to investigate the incidence of binary restenosis and its predictors in patients with ostial lesions of the right coronary artery (RCAos) who underwent percutaneous coronary intervention (PCI). RCAos are associated with a high incidence of restenosis, and the implantations of drug-eluting stents for RCAos have not been fully elucidated. The study participants included 75 patients (72.3 ± 9.5 years, 72% men) who underwent PCI for RCAos at our institution between November 2001 and May 2017. The angle between the greater curvature of the aortic wall and the right coronary artery take-off in the diastolic and systolic phases in the left anterior oblique position view was investigated. Clinical outcome was defined as binary restenosis at follow-up coronary angiography. We also evaluated target lesion failure (TLF) defined as a composite of cardiac mortality, target vessel myocardial infarction, and target lesion revascularization (TLR). The incidence of binary restenosis was 48.0% (n = 36) of the entire cohort. The incidence of TLF was 49.3% (n = 37) of the entire cohort, which was mainly driven by TLR (36.0%, n = 27). The area under the curve of the gap-angle ratio [(difference between the maximum and minimum angles)/(minimum angle); GAR] for binary restenosis was 0.73, and the cutoff value was 0.306 (sensitivity 67%, specificity 82%). The patients were divided into two groups: a low-GAR (< 0.306; n = 30) and high-GAR group (> 0.306; n = 45). Binary restenosis was more frequent in the high-GAR group than in the low-GAR group (76.7% vs. 28.9%, p = 0.007). The cumulative rate of TLF was significantly higher in the high-GAR group when compared with the low-GAR group (53.3% vs. 40.0%, p = 0.01), which was mainly driven by TLR (56.7% vs. 22.2%, p = 0.01). High-GAR (> 0.306) [OR 2.66 (1.34-5.31), p = 0.005] and stent under expansion [OR 2.37 (1.10-5.11), p = 0.03] were found to be independent predictors of binary restenosis after adjustment for multiple confounders. Multivariable analysis also revealed that high-GAR (> 0.306) [OR 2.06 (1.02-4.14), p = 0.03] and stent under expansion [OR 2.82 (1.28-6.19), p = 0.01] were independent predictors of TLF. We suggest that GAR (> 0.306) predicts binary restenosis and TLF in patients undergoing PCI for RCAos.

Topics: Aged; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Japan; Male; Percutaneous Coronary Intervention; Postoperative Complications; Prosthesis Design; Registries; Risk Factors; Sirolimus; Time Factors; Treatment Outcome

To report the genotype-phenotype characteristics, demographic features and clinical outcome of Omani patients with congenital hyperinsulinism (CHI). Methods: We retrospectively analyzed the clinical, biochemical, genotypical, phenotypical characteristics and outcomes of  children with CHI who were presented to the pediatric endocrine team in the Royal Hospital, Muscat, Oman between January 2007 and December 2016. Results: Analysis of 25 patients with CHI genetically revealed homozygous mutation in ABCC8 in 23 (92%) patients and 2 patients (8%) with compound heterozygous mutation in ABCC8. Fifteen (60%) patients underwent subtotal pancreatectomy as medical therapy failed and 2 (8%) patients showed response to medical therapy. Three patients expired during the neonatal period, 2 had cardiomyopathy and sepsis, and one had sepsis and severe metabolic acidosis. Out of the 15 patients who underwent pancreatectomy, 6 developed diabetes mellitus, 6 continued to have hypoglycemia and required medical therapy and one had pancreatic exocrine dysfunction post-pancreatectomy, following up with gastroenterology clinic and was placed on pancreatic enzyme supplements, while 2 patients continued to have hypoglycemia and both had abdominal MRI and 18-F-fluoro-L-DOPA positron emission tomography scan (PET-scan), that showed  persistent of the disease and started on medical therapy. Conclusion:  Mutation in ABCC8 is the most common cause of CHI and reflects the early age of presentation. There is a need for early diagnosis and appropriate therapeutic strategy.

Topics: Apnea; Child, Preschool; Congenital Hyperinsulinism; Diabetes Mellitus; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Female; Gastrointestinal Agents; Heterozygote; Homozygote; Humans; Hypoglycemia; Infant; Infant, Newborn; Lethargy; Male; Mutation; Octreotide; Oman; Pancreatectomy; Peptides, Cyclic; Postoperative Complications; Retrospective Studies; Seizures; Sirolimus; Somatostatin; Sulfonylurea Receptors; Treatment Outcome

Sirolimus is an important immunosuppressive drug in renal transplantation but contains numerous side effects. In this study, we describe a case of renal transplant recipient treated with sirolimus who developed pericardial effusion associated with interstitial pneumonia. An extensive search for alternative causes were all negative, and all symptoms disappeared after sirolimus interruption. Therefore, this case demonstrates that sirolimus can cause pericardial effusion possibly through a proinflammatory mechanism.

Topics: Diagnosis, Differential; Drug Substitution; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Pericardial Effusion; Postoperative Complications; Sirolimus; Transplant Recipients; Treatment Outcome

In the distal left main (LM) atherosclerosis mainly develops within bifurcation or trifur-cation. The aim of this study was to analyze the strategy of distal LM stenosis treatment and associated clinical outcomes in a large hospital in Northern Poland.. The study population consisted of consecutive patients with stable coronary artery disease or acute coronary syndrome (ACS) and distal LM stenosis who were hospitalized between June 2012 and June 2013. Patients were treated with regular drug-eluting stents (rDES), including bioresorbable vascular scaffolds, or dedicated bifurcation stents (BiOSS LIM®). Clinical outcomes were analyzed at 12, 24 and 36 months. Primary endpoint was cumulative major adverse cardiovascular events (MACE) inducing rate of cardiac death, myocardial infarction, and target lesion revascularization (TLR) after 36 months.. One hundred and two patients were identified, 90 of whom were treated with percutaneous coronary intervention (56 rDES, including 9 Absorb, and 34 BiOSS) with no stent implantation fail-ure. In 15 (16.7%) patients rDES was required within side branch (SB). After 36 months MACE rate was 19.0% (BiOSS: 18.8% vs. rDES 19.2%), whereas TLR rate was 10.7% (BiOSS 12.5% vs. rDES 9.6%). In logistic regression for 36-month TLR rate proximal optimization technique (OR 0.311, 95% CI 0.211-0.644) was a prognostic factor of better clinical outcome, whereas non-ST-elevation ACS (OR 2.211, 95% CI 1.642-5.110), ST-elevation myocardial infarction (OR 2.771, 95% CI 1.325-7.209) and SB stenting (OR 1.141, 95% CI 1.002-1.881) were risk factors of poor outcome.. Regular drug-eluting stents as well as dedicated bifurcation BiOSS LIM® stents enabled a simple and fast distal LM treatment option with a single stent. Both resulted in comparable MACE and TLR rates.

Topics: Aged; Antineoplastic Agents, Phytogenic; Coronary Angiography; Coronary Stenosis; Coronary Vessels; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Paclitaxel; Percutaneous Coronary Intervention; Poland; Postoperative Complications; Prosthesis Design; Retrospective Studies; Sirolimus; Survival Rate; Tissue Scaffolds; Treatment Outcome

The objective of this study was to compare the safety and efficacy of a polymer-free sirolimus coated, ultrathin strut drug eluting stent (PF-SES) to its uncoated bare-metal stent (BMS) platform of identical stent architecture.. Recently published randomized trials comparing BMS to DES with a focus on shortened dual-antiplatelet therapy reported incidences of stent thrombosis (ST) and bleeding complications (LEADERS FREE) in favor of drug eluting stents (DES).. Data of previously published large-sale, international, single-armed, multicenter, observational studies of ultra-thin PF-SES, and BMS were propensity score (PS) matched for selected lesion morphological and cardiovascular risk factors to compare target lesion revascularization (TLR), myocardial infarction, cardiac death, major adverse cardiac events (MACE), bleeding complications and ST rates. Primary endpoint in both studies was TLR at 9 months.. At 9 months the rates of TLR was significantly lower in the PF-SES group as compared with patients treated with the BMS analogue of identical stent design (1.4% vs. 4.6%, P = 0.005). Likewise the 9-month MACE rates were lower in the PF-SES group (3.2% vs. 8.7%, P = 0.001) whereas there were no differences in the accumulated ST rates (0.5% vs. 1.5%, P = 0.109). Overall accumulated bleeding incidences (BARC 1-5) were not significantly different between PF-SES and BMS patients (1.8% vs. 2.7%, p = 0.388).. PF-SES are superior over analogue BMS of identical stent architecture in daily clinical routine with lower rates of TLR and MACE in a PS-matched, unselected patient population without differences in accumulated ST rates and bleeding frequencies given the currently favored postprocedural comedication (ClinicalTrials.gov Identifier NCT02629575).

Topics: Aged; Aged, 80 and over; Asia; Cardiovascular Agents; Coronary Artery Disease; Drug-Eluting Stents; Europe; Female; Humans; Male; Metals; Middle Aged; Percutaneous Coronary Intervention; Postoperative Complications; Probucol; Propensity Score; Prospective Studies; Prosthesis Design; Registries; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome

Topics: Aged; Antibodies; Antigens, CD34; Coronary Artery Disease; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Postoperative Complications; Prosthesis Design; Prosthesis Failure; Randomized Controlled Trials as Topic; Registries; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome

We describe an unclassified overgrowth syndrome characterised by unregulated growth of dermal fibroblasts in the lower limbs of a 35-year-old woman. A

Topics: Adult; Amputation Stumps; Amputation, Surgical; Class I Phosphatidylinositol 3-Kinases; Female; Gigantism; Humans; Immunosuppressive Agents; Lower Extremity; Postoperative Complications; Sirolimus

Topics: Energy Metabolism; Everolimus; Graft Rejection; Humans; Immune System; Immunosuppressive Agents; Organ Transplantation; Postoperative Complications; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases

Topics: Coronary Angiography; Coronary Thrombosis; Diagnosis, Differential; Drug-Eluting Stents; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; Survivors; Video Recording

Drug-induced angioedema has been reported as an adverse effect of many different drugs. But small bowel angioedema associated with sirolimus (SRL) used was barely understood. It must be necessary to report a case suffering from small bowel angioedema with detailed discussion and literature review.. A 38-year-old Chinese woman presented with generalized gastric pain in the following day after renal transplantation. The patient began to crampy abdominal pain accompanied by nausea, vomiting, and diarrhea on postoperative day 6 (POD).. We strongly suspected the angioedema was an adverse reaction to SRL.. The immunosuppressive regimen was switched from tacrolimus (TAC), SRL, and prednisone to TAC, mycophenolate and prednisone.. The symptoms were relieved within next 48 hours after withdrawing the SRL. One more CT scan showed complete resolution of bowel wall thickening and ascites.. This was the first report of small bowel angioedema associated with SRL. Drug-induced-angioedema is a relatively common presentation and is potentially fatal. It must be aware of potential adverse effects.

Topics: Adult; Angioedema; Female; Humans; Immunosuppressive Agents; Intestinal Diseases; Intestine, Small; Kidney Transplantation; Postoperative Complications; Sirolimus

BACKGROUND Atypical hemolytic uremic syndrome (aHUS), a rare thrombotic microangiopathy, is characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Caused by genetic mutations in the alternative complement cascade, aHUS often will culminate in end-stage renal disease and occasionally death. Renal transplantation in aHUS patients has been contraindicated in the past due to the recurrence risk, with certain immunosuppressive regimens being commonly attributed. In this study, we analyzed the association between aHUS and immunosuppressive agents so as to offer evidence for the use of certain immunosuppressive regimens in renal transplant recipients. MATERIAL AND METHODS Our study is a retrospective analysis using data from the United States Renal Data System from 2004 to 2012. A cohort of renal transplantation patients diagnosed with aHUS were identified to include in the study. The primary endpoint was the determination of aHUS incidence in renal transplant recipients due to various immunosuppressive agents. The secondary endpoints were to check the relationship between the drug type as well as the demographic variables that increase the risk for aHUS. RESULTS It was found that there was a higher usage of sirolimus (P=0.015) and corticosteroids (P=0.030) in the aHUS patients compared to patients in other diagnoses group. CONCLUSIONS There was a higher usage of sirolimus and corticosteroids in renal transplantation patients diagnosed with aHUS. Unfortunately, due to the rarity of this disease, the sample size was small (n=14). Despite the small sample size, this data analysis throws light on the relationship between aHUS and immunosuppressive agents in renal transplant recipients, although we still have much to learn.

Topics: Adrenal Cortex Hormones; Adult; Atypical Hemolytic Uremic Syndrome; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus; Transplant Recipients

To study the anti- scarring effect of rapamycin in rabbits receiving glaucoma filtering surgery.. Ninety-six Chinchilla rabbits were randomized equally into 3 rapamycin treatment groups and one control group. All the rabbits underwent trabeculectomy, after which the rabbits in the 3 rapamycin groups were treated with eye drops containing 1%, 3%, or 5% rapamycin in the operated eyes, and those in the control groups were given castor oil 4 times a day. The intraocular pressure (IOP) and inflammatory reaction in the treated eyes were observed, and the PCNA-positive cells in the filtering bleb were detected using immunohistochemistry. RTFs isolated from the Tenon's capsule of the rabbits were cultured. The IOP was significantly lower in rapamycin-treated group than in the control group after the surgery (. Rapamycin can inhibit excessive proliferation of the fibroblasts in the filtering bleb to reduce scar formation after glaucoma filtration surgery in rabbits. Rapamycin also increases the expressions of caspase-3 and caspase-9 to induce apoptosis of the RTFs.

Topics: Animals; Caspase 3; Caspase 9; Cell Proliferation; Cicatrix; Filtering Surgery; Glaucoma; Intraocular Pressure; Postoperative Complications; Proliferating Cell Nuclear Antigen; Rabbits; Random Allocation; Sirolimus; Trabeculectomy

Coronary allograft vasculopathy (CAV) is the leading cause of death after pediatric heart transplantation from 1 year postoperation. Anecdotal evidence suggests a difference in the severity of disease between UK and North America. We performed a comparative study using intravascular ultrasound (IVUS).. Consecutive IVUS procedures from a single year were included from each center. Using standardized techniques, measurement of the vessel area, lumen area, and maximal intimamedial thickening (IMT) were performed with calculation of intimal index (II) for each slice. Mean II, mean IMT, and absolute maximum IMT were calculated along the left coronary artery for each patient. Transplant demographics and treatment details were included in the analysis.. One hundred four patients were included between the 2 centers. Interobserver variability for IVUS analysis was excellent. Patients were aged mean 14.2 (SD 3.3) years at the time of the study and 9.2 (SD 6.0) years earlier post-transplant procedure. UK patients were older, at transplant for a shorter time, and demonstrated more severe CAV. Multiple regression analysis demonstrated the detrimental effect of donor age and time from transplant on CAV severity and benefits of sirolimus use.. The data show more severe CAV in the UK cohort despite significantly shorter time post-transplant. Donor age and time post-transplant were associated with more severe CAV and sirolimus use was associated with a reduction in IMT. This study demonstrates a marked difference in the prevalence of CAV in children between UK and North America. The causes are likely to be multifactorial; however, younger donors and recipients have significantly less disease.

Topics: Adolescent; Allografts; Child; Coronary Angiography; Coronary Artery Disease; Cross-Sectional Studies; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; North America; Postoperative Complications; Prevalence; Risk Factors; Sirolimus; Ultrasonography, Interventional; United Kingdom

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

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

The incidence and long-term clinical impact of stent fracture (SF) occurred beyond 1 year after sirolimus-eluting stent (SES) implantation remains unclear. From April 2004 to March 2008, 985 consecutive patients with 1,307 lesions were treated only with SES. Of these, 868 patients (88.1%) with 1,140 lesions underwent follow-up angiography within 1 year after the index procedure, and 646 patients (65.6%) with 872 lesions underwent it both within and beyond 1 year after the index procedure. According to the diagnosed timing of SF, we divided the patients into the 2 groups: early SF (<1 year after the index procedure) and late-acquired SF (>1 year after the index procedure). Early- and late-acquired SFs were observed in 64 of 868 patients (7.4%) and 66 of 1,140 lesions (5.8%); 12 of 646 patients (1.9%) and 12 of 872 lesions (1.4%), respectively. Cumulative 10-year incidence of clinically driven target lesion revascularization and definite stent thrombosis were numerically higher in the early- and late-acquired SF groups than in the non-SF group (41.6% vs 45.5% vs 19.0%; 8.0% vs 8.3% vs 2.0%, respectively). In conclusion, late-acquired SF after SES implantation occurred in 1.4% of lesions, which was lower than that of early SF. However, both early- and late-acquired SFs appeared to be associated with clinically driven target lesion revascularization and stent thrombosis during the long-term follow-up.

Topics: Aged; Coronary Angiography; Coronary Stenosis; Coronary Vessels; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Japan; Male; Postoperative Complications; Prosthesis Failure; Retrospective Studies; Sirolimus; Time Factors

Despite its rarity (1%-2%), acute graft-versus-host disease after liver transplantation (LT-aGVHD) has a high mortality rate (85%). A gradual decrease in regulatory T cells (Tregs) correlates with disease progression in a rat LT-GVHD model, and treatments which increase Tregs exert therapeutic effects on LT-aGVHD. In this study, LT-aGVHD model rats were treated with rapamycin (RAPA), OSI-027, or an equal quantity of vehicle. Rats treated with OSI-027 survived longer (>100 days) than those in the RAPA (70 ± 8 days) or control (24 ± 3 days) groups. Flow cytometric analysis showed that the Treg ratios in peripheral blood mononuclear cells in the OSI-027 group were higher than those in the RAPA or control groups. The proportions of donor-derived lymphocytes in the OSI-027 group were lower than those in the RAPA or control groups. Hematoxylin-eosin staining of skin tissue demonstrated less severe lymphocyte infiltration in the OSI-027 group than that in the RAPA or control groups. In vitro, OSI-027 induced differentiation of CD4

Topics: Acute Disease; Allografts; Animals; Cell Differentiation; Disease Models, Animal; Disease Progression; Female; Forkhead Transcription Factors; Graft vs Host Disease; Humans; Imidazoles; Immunosuppressive Agents; Leukocyte Count; Leukocytes, Mononuclear; Liver Transplantation; Postoperative Complications; Rats; Rats, Inbred Lew; Sirolimus; Specific Pathogen-Free Organisms; T-Lymphocytes, Regulatory; Triazines

Success after solid organ transplantation is dependent on the proper balance of immunosuppression to prevent rejection of the allograft while limiting the risk of developing infections and malignancy. We present a 9-year-old girl, remote from transplant, who presented with airway plaque after a change in immunosuppression to include the mTOR inhibitor sirolimus. Differential diagnosis included direct medication side effect, infection, and neoplasia.

Topics: Child; Epstein-Barr Virus Infections; Female; Graft Rejection; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Lymphoproliferative Disorders; Postoperative Complications; Sirolimus

We conducted a retrospective examination of the very long-term outcomes of placing sirolimus (SES) and paclitaxel (PES)-eluting stents in patients with ST-elevation myocardial infarction (STEMI). This was a nonrandomized, retrospective, single-center study that included 872 first STEMI patients who underwent successful placement of either SES (n = 547) or PES from November 2004 to April 2012. The primary end point was the incidence of severe cardiac events comprising cardiac death, nonfatal recurrent myocardial infarction, and definite stent thrombosis (ST). The frequency of target lesion revascularization (TLR) was also compared. A propensity score-matched analysis was used to adjust the 29 baseline variables. In the baseline-adjusted cohorts in 231 STEMI patients in each arm, the frequency of the primary end point in the SES group (5.6 %) during the follow-up duration of 2583 ± 806 days was not significantly different from that in the PES group (6.1 %, follow-up: 1866 ± 699 days). The cumulative primary end point-free ratio in the SES group was not significantly different from that in the PES group (p = 0.503). The frequency of TLR in the SES group (7.5 %) was significantly lower than that in the PES group (16.9 %, p = 0.005), with and the significantly higher cumulative TLR-free ratio in the SES group than that in the PES group (p < 0.001). The very long-term clinical outcomes after SES or PES placement for STEMI patients were statistically equivalent. SES showed the better angiographic outcomes for STEMI compared to PES.

Topics: Aged; Coronary Angiography; Drug-Eluting Stents; Female; Follow-Up Studies; Forecasting; Humans; Immunosuppressive Agents; Incidence; Japan; Kaplan-Meier Estimate; Male; Paclitaxel; Postoperative Complications; Propensity Score; Retrospective Studies; Sirolimus; ST Elevation Myocardial Infarction; Survival Rate

Late decapsulation with fluid collection is a rare complication of renal transplantation with deleterious effects on kidney function. Its physiopathology is unclear but there might be an association with mammalian target of rapamycin (m-TOR) inhibitors, especially in patients with chronic hepatitis C. We report a case of late spontaneous decapsulation 12 years after kidney transplant in a patient infected with hepatitis C under treatment with sirolimus. He underwent marsupialisation of the collection, sirolimus was converted to cyclosporine and hepatitis C treatment was performed with success. This is the first successful case report of late spontaneous decapsulation of the kidney graft in a patient with hepatitis C.

Topics: Antiviral Agents; Cyclosporine; Drug Substitution; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisolone; Risk Factors; Sirolimus; Tomography, X-Ray Computed

Diabetes mellitus has worse outcome after percutaneous coronary intervention.. We assessed stent thrombosis (ST), major adverse cardiac events (MACE), and major bleeding rates at 1 year after implantation of sirolimus-eluting stents (SES) in patients with diabetes mellitus in a large multicenter registry.. From May 2006 to April 2008, 15,147 unselected consecutive patients were enrolled at 320 centers in 56 countries in a prospective, observational registry after implantation of ≥ 1 SES. Source data were verified in 20% randomly chosen patients at > 100 sites. Adverse events were adjudicated by an independent Clinical Event Committee.. Complete follow-up at 1 year was obtained in 13,693 (92%) patients, 4,577 (30%) of whom were diabetics. Within diabetics, 1,238 (9%) were insulin-treated diabetics (ITD). Diabetics were older (64 vs. 62 years, P < 0.001), with higher incidence of major coronary risk factors, co-morbidities, and triple-vessel coronary artery disease. Coronary lesions had smaller reference vessel diameter (2.88 ± 0.46 vs. 2.93 ± 0.45 mm, P < 0.001) and were more often heavily calcified (26.1% vs. 22.6%, P < 0.001). At 1 year, diabetics had higher MACE rate (6.8% vs. 3.9%, P < 0.001) driven by ITD (10.6% vs. 5.5%, P < 0.001). Finally, diabetics had significant increase in ST (1.7% vs. 0.7%, P < 0.001), principally owing to ITD (3.4% vs. 1.1%, P < 0.001). There was an overall low risk of major bleeding during follow-up, without significant difference among subgroups.. In the e-SELECT registry, diabetics represented 30% of patients undergoing SES implantation and had significantly more co-morbidities and complex coronary lesions. Although 1-year follow-up documented good overall outcome in diabetics, higher ST and MACE rates were observed, mainly driven by ITD. © 2015 Wiley Periodicals, Inc.

Topics: Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Female; Follow-Up Studies; Global Health; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Percutaneous Coronary Intervention; Postoperative Complications; Prospective Studies; Registries; Retrospective Studies; Sirolimus; Time Factors

Biolimus-eluting stents (BES) have similar efficacy and safety compared with cobalt chromium everolimus-eluting stents (CoCr-EES), whereas it is unclear whether the same applies to small vessel disease. We sought compare clinical outcomes between BES and CoCr-EES in patients with small vessel disease.. A total of 1,132 patients treated only with BES (612 patients) or EES (520 patients) in small vessel disease (stent size 2.5-mm) were retrospectively analyzed. We assessed the cumulative 2-year incidence of major adverse cardiovascular events (MACE), defined as a composite of cardiac death, myocardial infarction (MI), definite stent thrombosis (ST), and clinically driven target lesion revascularization (CD-TLR). The cumulative 2-year incidence of MACE was similar between the two groups (12.1% vs. 11.8%, P = 0.77). The cumulative incidence of cardiac death, CD-TLR, and definite ST were also not significantly different between both groups (3.2% vs. 3.6%, P = 0.78; 8.3% vs. 8.4%, P = 1.00; 0.33% vs. 0.21%, P = 0.66, respectively). After multivariate adjusting, the adjusted risk of BES group relative to CoCr-EES group for MACE was not significantly different (hazard ratio [HR]: 0.78, 95% confidential interval [CI]: 0.53-1.15, P = 0.20). Similarly, no significant difference in the adjusted risks for cardiac death and CD-TLR were observed between the two groups (HR: 0.62, 95% CI: 0.28-1.37, P = 0.24; HR: 0.81, 95% CI: 0.51-1.29, P = 0.38).. Two-year clinical outcomes of BES are similar to those of CoCr-EES in patients with small vessel disease. The use of BES is acceptable for small coronary artery disease. © 2015 Wiley Periodicals, Inc.

Topics: Aged; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Japan; Male; Percutaneous Coronary Intervention; Postoperative Complications; Retrospective Studies; Risk Factors; Sirolimus; Survival Rate; Time Factors

Polyomavirus BK (BKV) reactivation causes allograft dysfunction in some kidney transplant recipients. The use of mammalian target of rapamycin (mTOR) inhibitor-based immunotherapy is associated with a lower incidence of polyomavirus-associated nephropathy compared with other immunosuppressants. This retrospective study assessed whether conversion to mTOR inhibitor-based immunotherapy directly reduced urinary BKV load.. A total of 63 kidney recipients were divided into mTOR inhibitor-conversion (21 patients) and nonconversion (42 patients) groups. Urinary BKV loads were determined before and at least 6 months after the conversion.. The results demonstrated that urinary BKV titer was significantly reduced in the conversion group (3.94 ± 0.43 copies (log)/mL to 2.49 ± 0.19 copies (log)/mL) and remained unaltered in the nonconversion group (3.19 ± 0.20 copies (log)/mL to 2.90 ± 0.20 copies (log)/mL). In addition, the percentage of patients with reduced urinary BKV load was significantly higher in the conversion group (76.2% vs. 42.9%). The estimated glomerular filtration rate after 24 months mTOR inhibitor conversion was significantly increased compared with that in the nonconversion group. Conversion to mTOR-inhibitor-based immunotherapy was the only factor associated with an increase in estimated glomerular filtration rate.. This study reveals an association of conversion to mTOR-inhibitor-based immunotherapy with the reduction of urinary BKV load.

Topics: Adult; BK Virus; Creatinine; Everolimus; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Immunotherapy; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged; Polyomavirus Infections; Postoperative Complications; Retrospective Studies; Sirolimus; Taiwan; TOR Serine-Threonine Kinases; Viral Load

Although some clinical studies have revealed adverse clinical and angiographic outcomes of early-generation overlapping drug-eluting stents (DES), the safety and efficacy of overlapping newer-generation DES for long narrowings have not been well established. This study aimed to compare angiographic and 1-year clinical outcomes between a long single stent (LSS) and overlapping double stents (ODS) in patients treated with newer-generation DES for similarly long narrowings. We analyzed 8 to 10 months angiographic and 1-year clinical outcomes of 112 lesions of 105 patients with long (30 to 38 mm) narrowings treated with everolimus-eluting stent, a newer-generation DES, using LSS or ODS. We divided our patients into LSS group (46 patients with 49 lesions) and ODS group (59 patients with 63 lesions). As a result, the rates of freedom from major adverse cardiac events (92.9% vs 93.1%, p = 0.91) and target lesion revascularization (94.5% vs 95.1%, p = 0.79) during 1-year follow-up were similar between the 2 groups. There was no stent thrombosis observed between the 2 groups. In conclusion, everolimus-eluting stent provided similar angiographic and 1-year clinical outcomes regardless of overlap status in long narrowings.

Topics: Aged; Antineoplastic Agents, Phytogenic; Coronary Angiography; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Paclitaxel; Percutaneous Coronary Intervention; Postoperative Complications; Prosthesis Design; Retrospective Studies; Sirolimus; Survival Rate; Time Factors; Treatment Outcome

Kidney transplant recipients are at higher risk of developing pulmonary complications related to immunosuppression, and inhibitor of the mammalian target of rapamycin (mTORi) has been reported as a potential cause.. Five hundred kidney-transplanted patients were retrospectively analyzed for pulmonary complications on the basis of clinical and instrumental data (chest radiography, high-resolution computed tomography, broncho-alveolar lavage, oximetry).. We found 26 interstitial lung diseases (ILD) (16%): 12 cases (46.2%) were from infections (42.8% by Pneumocystis jirovecii) and 14 cases of ILD (53.8%) resulted as drug-induced ILD (DI-ILD). According to anti-rejection protocols, DI-ILD occurred in 8 patients (57%) while on triple regimen including steroids, everolimus (EVL), and cyclosporine (CyA) and in 6 patients on double regimen with steroids and mTORi: EVL or sirolimus (43%). In ILD+ patients, everolimus trough-concentration (EVL(TLC)) and cyclosporine (2nd-hour concentration: CyA(C2)) levels were higher than in patients in the same regimen but with ILD- (EVL(TLC) [ng/mL] 9.84 versus 6.85; CyA(C2) [ng/mL] 303.97 versus 298.56). The formula that used the combined blood levels of both drugs (EVL(TLC) + CyA(C2)/100) resulted in a significant difference between groups of patients (12.88 ± 1.61 versus 9.83 ± 1.91). Applying receiver operator characteristic curve (ROC) analysis to detect risk of developing ILD when on combined protocol with EVL and CyA, we obtained an area under the curve of 0.8622 (P = .0081) and 0.9082 (P = .0028), respectively, when using EVL(TLC) or the combination formula with both drugs.. In renal transplant patients, we obtained a relationship of ILD to specific drug concentration. On the basis of ROC analysis, patients on EVL and CyA combined protocol are at risk of ILD when EVL(TLC) is >9.03 ng/mL or >11.41 when a formula with summation of EVL(TLC) and CyA(C2) is used.

Topics: Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung Diseases, Interstitial; Male; Postoperative Complications; Predictive Value of Tests; Retrospective Studies; ROC Curve; Sirolimus

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

Anemia is a very common occurrence in post-renal transplant patients. Post-transplantation anemia (PTA) is associated with significant graft loss or cardiovascular morbidity. The objective of this study is to identify clinical risk factors associated with anemia after kidney transplantation.. Our retrospective cohort study included a total of 570 renal transplant recipients. For the definition of anemia, we adopted "the lower limit of normal for Hgb concentration of blood" proposed by Beutler E and Waalen J [14], which has adjustments for age, gender and ethnicity. Post-transplant anemia (PTA) was defined as anemia that arose between 30 and 180days after transplantation. Based on this definition, of the 570 renal transplant recipients, 344 patients (62.1%) experienced PTA. The patients were divided into anemic and non-anemic groups, and a total of 20 clinical factors were compared between the two groups.. In the univariate analysis, age, race, multiple transplants, delayed graft function (DGF), and use of tacrolimus, sirolimus, thymoglobulin, ganciclovir, ACE inhibitors, and ARBs were associated with PTA. In the multivariate analysis, age (>60years old, OR=2.62, p=0.001), race (OR=2.54, p=0.001), and use of sirolimus (OR=2.01, p=0.019), antiviral agents (OR=1.96, p=0.015), thymoglobulin (OR=1.86, p=0.011), and DGF (OR=2.78, p=0.001) remained significant.. The current results show that undergoing a transplant at age 60 or older, use of sirolimus, antiviral agents, and thymoglobulin are independent clinical risk factors associated with PTA. In terms of ethnicity, AA, MEA, or PI is higher risk for PTA and Hispanic is significantly lower risk for PTA compared to Caucasians.

Topics: Adolescent; Adult; Age Factors; Anemia; Antilymphocyte Serum; Antiviral Agents; Cohort Studies; Delayed Graft Function; Ethnicity; Female; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Young Adult

A 70-year-old man underwent percutaneous coronary intervention (PCI) using sirolimus-eluting stent (SES) at the just proximal site of left anterior descending coronary artery. Six months after SES implantation, he suffered from late stent thrombosis. Intravascular ultrasound (IVUS) images demonstrated positive remodeling of the vessel, indicating late-acquired incomplete stent apposition (ISA). An angioplasty with a bigger balloon was performed to obtain sufficient stent struts apposition. Twenty-six months after the second PCI, he developed ST-elevation myocardial infarction and his CAG showed re-occlusion of the SES. Optical coherence tomography showed ISA and IVUS revealed further enlargement of the coronary artery around the SES.

Topics: Aged; Chronic Disease; Coronary Occlusion; Coronary Thrombosis; Coronary Vessels; Drug-Eluting Stents; Humans; Male; Percutaneous Coronary Intervention; Postoperative Complications; Prosthesis Failure; Radiography; Sirolimus; Tomography, Optical Coherence; Ultrasonography, Interventional

Very late stent thrombosis (VLST) is a catastrophic complication after implantation of a drug-eluting stent (DES). It has been reported that VLST is associated with pathological changes, which often include late acquired incomplete stent apposition (LAISA) with thrombus formation. In addition, the vascular response to the stent (evaginations, neointimal growth, and thrombosis) and the incidence of LAISA are reported to vary among the different types of DES. We experienced a patient with cardiogenic shock induced by simultaneous VLST of both the left anterior descending artery (LAD) and the left circumflex artery (LCX) at 3 years after implantation of two sirolimus-eluting stents. Intravascular ultrasound (IVUS) showed LAISA of both arteries. A paclitaxel-eluting stent, which had been implanted in the right coronary artery 3 years earlier, did not show such a finding. IVUS revealed "different vascular reactions" to "different types of DES" in this patient.

Topics: Coronary Angiography; Coronary Thrombosis; Coronary Vessels; Drug-Eluting Stents; Humans; Male; Middle Aged; Paclitaxel; Postoperative Complications; Shock, Cardiogenic; Sirolimus; Treatment Outcome; Ultrasonography, Interventional

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cyclophosphamide; Doxorubicin; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Neoplasms, Multiple Primary; Postoperative Complications; Prednisone; Remission Induction; Rituximab; Sirolimus; Skin Diseases; Skin Neoplasms; Vincristine; Warts

Bullous pemphigoid (BP) is an acquired autoimmune disease, with typical histology and immune pathological findings, which might be associated with drug therapy. The list of responsible drugs increases every year, but a current literature revision do not include the mammalian target of rapamycin (mTOR) inhibitors. By converse, bullous pemghigoid cases have been described in renal transplant recipients and associated with the allogenic graft itself, causing a cross reaction against the skin, or unbalancing the immune response, through a chronic cell-mediated suppression, non-specifically favouring the autoantibody production.. Two cases of BP occurred, respectively, 10 days to 2 months after the addition to their current regimen of everolimus in a 35-year-old woman and sirolimus in a 65-year-old man. The graft functionality was within normal range. General corticosteroids therapy resistance, immediate improvement after drug discontinuation (dechallenge) and relapse after re-exposure (rechallenge) were striking criteria supporting a causative role of the drugs, grouped in the mTOR inhibitors class.. The diagnosis of drug-induced events is crucial for early management, and particularly bullous eruptions affect patients' health and quality of life. Additional research is necessary to confirm the m-TOR inhibitors association, which exploit the possible mechanisms and eventually point out preventive measures.

Topics: Adult; Aged; Drug Eruptions; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pemphigoid, Bullous; Postoperative Complications; Sirolimus; TOR Serine-Threonine Kinases

Previous studies reporting long-term (≥5 year) clinical outcome in patients with unprotected left main coronary artery (LMCA) disease undergoing drug-eluting stent (DES) implantation are currently limited, although late adverse events beyond 1 year are one of the major concerns of DES. We evaluated long-term clinical outcomes in 134 consecutive patients who underwent sirolimus-eluting stents (SES) for unprotected LMCA lesion in a single center from 2004 to 2009. The median follow-up duration was 3.8 (range: 0.5-7.9) years. Eight patients suffered from serious cardiovascular events potentially related to LMCA lesion (primary outcome measure) (sudden cardiac death: N = 5, emergent coronary revascularization for the LMCA lesion: N = 2, and acute congestive heart failure related to LMCA lesion: N = 1) with the cumulative 5-year incidence of only 4.4 %. The cumulative 5-year incidence of all-cause death, cardiac death, target vessel myocardial infarction, definite stent thrombosis, and target-lesion revascularization was 26.5, 8.1, 0, 0, and 12.9 %, respectively. In a subgroup analysis, the cumulative incidence of the primary outcome measure was significantly higher in patients with 2-stenting (N = 27) than in patients with 1-stenting (N = 107) (14.0 and 2.2 %, P < 0.001). All 8 patients with serious adverse events had a true bifurcation lesion and 5 patients received 2-stenting for the LMCA lesion. SES implantation in patients with unprotected LMCA lesion was associated with a favorable long-term outcome with acceptably low rate of serious adverse event potentially related to LMCA lesion. However, complex LMCA lesions necessitating 2-stenting strategy might be associated with higher risk for serious adverse events.

Topics: Aged; Aged, 80 and over; Coronary Artery Disease; Coronary Thrombosis; Death, Sudden, Cardiac; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Myocardial Infarction; Postoperative Complications; Prognosis; Prosthesis Implantation; Sirolimus; Treatment Outcome

This study evaluated the safety and efficacy of the RESOLUTE(TM)zotarolimus-eluting stent (R-ZES; Medtronic, Inc, Santa Rosa, CA, USA) in Japanese patients for the treatment of de novo native coronary lesions.. Both RESOLUTE Japan (R-Japan) and RESOLUTE Japan Small Vessel Study (R-Japan SVS) were prospective, multicenter, single-arm observational studies. R-Japan enrolled 100 patients (reference vessel diameter, 2.5-3.5 mm) and R-Japan SVS enrolled 65 patients (at least 1 lesion suitable for 2.25-mm stent) treated with R-ZES. In R-Japan, in-stent late lumen loss (LLL; the primary endpoint) at 8 months was 0.12 ± 0.22 mm and volume obstruction on intravascular ultrasound was 2.33 ± 3.51%. At 4 years, there were no cases of clinically driven target lesion revascularization (TLR); the target lesion failure (TLF; composite of cardiac death, target vessel myocardial infarction, and clinically driven TLR) was 5.6% (5/90). In R-Japan SVS, in-stent LLL at 9 months was 0.27 ± 0.33 mm, TLF (primary endpoint) was 4.6% (3/65), without incidence of TLR. At 3 years, TLF was 7.9% (5/63) and clinically driven TLR, 3.2% (2/63).. R-Japan and R-Japan SVS demonstrate substantial suppression of neointimal hyperplasia, low LLL, and excellent and sustained long-term clinical outcome with R-ZES in Japanese patients.

Topics: Combined Modality Therapy; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Heart Diseases; Humans; Incidence; Japan; Myocardial Infarction; Myocardial Revascularization; Neointima; Platelet Aggregation Inhibitors; Postoperative Complications; Prospective Studies; Risk Factors; Sirolimus; Treatment Outcome; Ultrasonography, Interventional

The angiographic features of restenosis contain prognostic information. However, restenosis patterns of the new generation drug-eluting stents (DES), everolimus-(EES) and resolute zotarolimus-eluting stent (ZES) have not been described.A total of 210 consecutive patients with DES restenosis were enrolled from 2003 to 2012. We analyzed 217 restenotic lesions after DES implantation, and compared the morphologic characteristics of the 2nd generation DES restenosis to those of restenosis with 2 first generation DES, sirolimus-(SES) and paclitaxel-eluting stent (PES).Baseline characteristics were comparable between the different stent groups. The incidence of focal restenosis was significantly lower for PES than the other stents (49.5% versus 87.0%, 76.2%, and 82.1% for PES versus SES, EES, and ZES, respectively, P < 0.001). When considering the pattern of restenosis solely within the stent margins, a further clear distinction between PES and other stents was observed (40.0% versus 92.9%, 88.9%, and 81.2% in PES versus SES, EES, and ZES, respectively, P < 0.001). There were no significant differences in restenosis patterns among SES, EES, and ZES. In multivariate analysis, PES implantation, hypertension, and age were associated with non-focal type of restenosis after DES implantation. After the introduction of EES and ZES into routine clinical practice in 2008, focal restenosis significantly increased from 63.9% to 76.7% and diffuse restenosis significantly decreased from 26.4% to 11.0% (P = 0.045).Focal restenosis was the most common pattern of restenosis in the new generation DES and the incidence of diffuse restenosis significantly decreased with the introduction of the 2nd generation DES.

Topics: Aged; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Everolimus; Female; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Paclitaxel; Percutaneous Coronary Intervention; Postoperative Complications; Registries; Republic of Korea; Sirolimus; Treatment Outcome; Vascular Patency

To date, it remains unknown whether different types of new-generation drug-eluting stents have a differential impact on long-term outcomes in diabetic patients.. In this historical cohort study (two Italian centers), we analyzed 400 diabetic patients with 553 coronary lesions treated with new-generation CoCr zotarolimus-eluting stents (R-ZES: 136 patients, 196 lesions) or everolimus-eluting stents (EES: 264 patients, 357 lesions) between October 2006 and August 2012. Primary endpoint was the occurrence of major adverse cardiac events (MACE) over a 2-year follow-up period. MACE was defined as all-cause mortality, any myocardial infarction (MI) and/or target lesion revascularization (TLR). Multivessel revascularization, intervention for restenotic lesion and use of intravascular ultrasound were significantly higher in the R-ZES group, whereas small stent (≤2.5 mm) deployment was significantly higher in the EES group. At 2-year follow-up, there was no significant difference in occurrence of MACE (R-ZES vs EES: 22.8% vs 18.9%, P = 0.39). Similarly, no significant differences were observed in the composite endpoint of all-cause mortality/MI (10.0% vs 10.3%, P = 0.86) or TLR (12.4% vs 7.4%, P = 0.11). Adjustment for confounders and baseline propensity-score matching did not alter the aforementioned associations.. After 2 years of follow up similar outcomes (MACE, all-cause mortality/MI, TLR) were observed in real-world diabetic patients, including those with complex lesions and patient characteristics, treated with R-ZES and EES.

Topics: Aged; Chromium Alloys; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Japan; Male; Percutaneous Coronary Intervention; Postoperative Complications; Prosthesis Design; Retrospective Studies; Sirolimus; Time Factors; Treatment Outcome

Topics: Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Everolimus; Female; Humans; Male; Percutaneous Coronary Intervention; Postoperative Complications; Sirolimus

Topics: Clopidogrel; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Hemorrhage; Humans; Male; Percutaneous Coronary Intervention; Postoperative Complications; Sirolimus; Ticlopidine

Sirolimus (SRL) is an immunosuppressant often used in liver transplantation (LT) to mitigate renal insufficiency associated with calcineurin inhibitors. Sirolimus can cause hyperlipidemia, but its association with coronary artery disease (CAD) and cerebrovascular accidents (CVAs) is unclear. The purpose of this study was to assess the risk of CAD and CVAs with the use of SRL in LT recipients.. We retrospectively reviewed all of our LT recipients from 2000 to 2011. Patients with multiorgan transplant, multiple liver transplants, everolimus therapy, or survival <3 months were excluded. The 803 remaining patients were divided into 3 groups: 1) 134 patients who received and tolerated SRL; 2) 604 patients who never received SRL; and 3) 65 patients who started but discontinued SRL. The primary outcome was the development of CAD or CVA beyond 4 months after transplantation with the use of time-dependent Kaplan-Meier analysis.. In group 1, there were 6 CAD and 2 CVA events; in group 2, 27 CAD and 16 CVA events; and in group 3, 10 CAD and 2 CVA events. The event-free survival for CAD/CVA at 1, 3, and 5 years was 100%, 98.1%, and 97.2% respectively for group 1; 99.7%, 98.4%, and 96.1% for group 2; and 92.3%, 92.3%, and 85.6% for group 3. On an unadjusted basis, compared with group 2, there was no difference in CAD/CVA rates in group 1 (hazard ratio [HR] 0.92; not significant), but there was an increase in group 3 (HR 2.94; P = .0019). However, on multivariate analysis, only age at transplantation (HR 1.06; P = .001) and diabetes before transplantation (P = .011) were associated with increased CAD/CVA risk.. Our analysis showed that patients receiving SRL after LT had no increased risk of CAD/CVA events compared with patients maintained on a calcineurin inhibitor. The risk of CAD/CVA should not be a factor in avoiding SRL.

Topics: Adult; Aged; Calcineurin Inhibitors; Coronary Artery Disease; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Liver Transplantation; Male; Middle Aged; Outcome Assessment, Health Care; Postoperative Complications; Retrospective Studies; Sirolimus; Stroke

Results of trials and registry studies have shown lower long-term mortality after coronary-artery bypass grafting (CABG) than after percutaneous coronary intervention (PCI) among patients with multivessel disease. These previous analyses did not evaluate PCI with second-generation drug-eluting stents.. In an observational registry study, we compared the outcomes in patients with multivessel disease who underwent CABG with the outcomes in those who underwent PCI with the use of everolimus-eluting stents. The primary outcome was all-cause mortality. Secondary outcomes were the rates of myocardial infarction, stroke, and repeat revascularization. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics.. Among 34,819 eligible patients, 9223 patients who underwent PCI with everolimus-eluting stents and 9223 who underwent CABG had similar propensity scores and were included in the analyses. At a mean follow-up of 2.9 years, PCI with everolimus-eluting stents, as compared with CABG, was associated with a similar risk of death (3.1% per year and 2.9% per year, respectively; hazard ratio, 1.04; 95% confidence interval [CI], 0.93 to 1.17; P=0.50), higher risks of myocardial infarction (1.9% per year vs. 1.1% per year; hazard ratio, 1.51; 95% CI, 1.29 to 1.77; P<0.001) and repeat revascularization (7.2% per year vs. 3.1% per year; hazard ratio, 2.35; 95% CI, 2.14 to 2.58; P<0.001), and a lower risk of stroke (0.7% per year vs. 1.0% per year; hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). The higher risk of myocardial infarction with PCI than with CABG was not significant among patients with complete revascularization but was significant among those with incomplete revascularization (P=0.02 for interaction).. In a contemporary clinical-practice registry study, the risk of death associated with PCI with everolimus-eluting stents was similar to that associated with CABG. PCI was associated with a higher risk of myocardial infarction (among patients with incomplete revascularization) and repeat revascularization but a lower risk of stroke. (Funded by Abbott Vascular.).

Topics: Aged; Coronary Artery Bypass; Coronary Artery Disease; Coronary Restenosis; Diabetes Complications; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Complications; Propensity Score; Registries; Sirolimus; Stroke

Full-dose sirolimus (SRL) therapy without a calcineurin inhibitor (CNI) reduces the incidence of malignancy after renal transplantation, but with significant side effects. We hypothesized that de novo therapy with low-dose SRL combined with a CNI could still prevent cancer in renal transplant recipients.. A retrospective case-control study was performed to assess the cancer incidence among renal transplant patients who had undergone surgery in our transplant centers between January 2000 and June 2012. Patients who received low-dose SRL and a CNI (SRL group, n = 189) were compared with patients receiving conventional CNI-based therapy in the same hospitals (Conventional group, n = 271).. The 5-year graft and patient survival rates were comparable between the two groups. Seven patients in the SRL group and 24 patients in the Conventional group developed malignancies during mean follow-up periods of 68.2 ± 37.5 months and 81.7 ± 51.4 months, respectively. The cancer incidence at 5 years was significantly lower in the SRL group (1.9%), than that in the Conventional group (6.7%; p = 0.04). By multivariate analyses, SRL therapy (p = 0.04), male sex (p = 0.04), and younger age (p = 0.01) were significantly associated with a lower risk of malignancy after kidney transplantation.. De novo therapy with low-dose SRL combined with a CNI was associated with reduced risk of post-transplant cancer in renal transplant recipients. De novo cancer prevention using a low-dose proliferation signal inhibitor such as SRL could be effective for renal transplant recipients.

Topics: Adult; Calcineurin Inhibitors; Case-Control Studies; Cyclosporine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Neoplasms; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sirolimus; Survival Rate; Tacrolimus; Taiwan; Treatment Outcome

The aim of this study was to assess the efficacy of sirolimus-based immunosuppression vs. conventional prophylaxis therapy in preventing cytomegalovirus (CMV) infection or disease in liver transplantation recipients.. One hundred and twenty-seven consecutive liver transplant recipients, with a minimum of one-yr follow-up from 2008 to 2013 in the first affiliated hospital of Nanchang University, were retrospectively divided into the sirolimus-treated (n = 51) and ganciclovir-treated (n = 76) groups. The CMV incidence, rejection events, and survival rate were compared.. The overall incidences of CMV events were decreased but did not reach statistical significance in the sirolimus arm compared with the ganciclovir arm (p > 0.05) at one yr after liver transplantation. There was no significant difference in the rejection incidence and survival rates between the two groups.. Sirolimus-based immunosuppression had a lower incidence of CMV infection compared with conventional prophylaxis therapy and did not increase rejection risks and mortality after liver transplantation, indicating that with the use of an mammalian target-of-rapamycin (mTOR)-inhibitor, CMV prophylaxis may be dispensable.

Topics: Adult; Aged; Antiviral Agents; Cytomegalovirus Infections; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus; Treatment Outcome

Cancer in transplant recipients represents a therapeutic challenge even when the patient is already under mTOR inhibitors. A 78-year-old man received a deceased donor kidney transplant in 1993. After 6 months, he developed a multifocal cutaneous and nonvisceral Kaposi's Sarcoma while on cyclosporine immunosuppressant therapy. The patient was converted to sirolimus monotherapy in 2001 with subsequent complete recovery within 2 years. In 2007, the patient was diagnosed with an esophageal adenocarcinoma stage IIA. An esophagectomy was performed without requirement of further treatment. He has continued on sirolimus monotherapy ever since, with no other incidents and no recurrences of either tumor. In this report, we describe an interesting case of a second cancer while on immunosuppressive therapy with anticancer activity. Moreover, the present knowledge of the matter is discussed.

Topics: Adenocarcinoma; Aged; Azathioprine; Biomarkers; Cyclosporine; Drug Substitution; Esophageal Neoplasms; Esophagectomy; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Neoplasm Proteins; Neoplasms, Second Primary; Phosphorylation; Postoperative Complications; Prednisone; Protein Processing, Post-Translational; Sarcoma, Kaposi; Signal Transduction; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

A 25-year-old woman, a never smoker with a history of heart-lung transplantation for World Health Organization group 1 pulmonary arterial hypertension performed 20 months prior to presentation, was evaluated for shortness of breath. Following transplantation, she was initiated on standard therapy of prednisone, tacrolimus, and azathioprine, along with routine antimicrobial prophylaxis. Her posttransplant course was complicated by persistent acute cellular rejection, as determined from a transbronchial biopsy specimen, without evidence of rejection in an endomyocardial biopsy specimen. The immunosuppressive medications were supplemented with pulse-dosed steroids, and the patient was transitioned from azathioprine to mycophenolate mofetil. Sirolimus was added 9 months prior to presentation. Three months prior to presentation, she was admitted for increasing oxygen requirements, shortness of breath, and bilateral infiltrates on the CT scans of the chest.

Topics: Adult; Female; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Postoperative Complications; Pulmonary Alveolar Proteinosis; Respiratory Insufficiency; Sirolimus

Topics: Antiviral Agents; Cytomegalovirus Infections; Female; Ganciclovir; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Postoperative Complications; Sirolimus

There are no established prognostic factors or standardized therapies for hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT). The aim of this study was to investigate impact of underlying patient condition on treatment and outcomes of recurrence of HCC after LT. The medical records of 268 LT patients with HCC were evaluated. Potential prognostic factors for survival after recurrence were evaluated, including recurrent tumor characteristics, medical/radiological/surgical therapies for recurrence, and an inflammatory marker (neutrophil/lymphocyte ratio). Laboratory tests at recurrence, including albumin, absolute lymphocyte count (ALC), prognostic nutritional index (PNI: ALC(/μL) × 0.005 + Albumin(g/dL) × 10), were evaluated as surrogate markers for underlying patient conditions. A total of 51 (19%) patients developed HCC recurrence. The use of sirolimus and sorafenib significantly improved outcome (p = 0.007 and 0.04), and better nutritional status (PNI ≥ 40) enhanced their efficacy. On multivariate analysis, low ALC (<500/μL) and albumin (<2.8 g/L) remained independent prognostic factors (p = 0.03 and 0.02; hazard ratio = 3.61 [Ref. >1000/μL] and 4.97 [Ref. >3.5 g/dL], respectively). Low PNI (<40) showed significantly lower survival rate after adjusting the risk (p = 0.006, hazard ratio = 3.29). Underlying patient conditions and nutritional status, represented by ALC and albumin, are important to successful cancer treatment and strong prognostic markers for survival after HCC recurrence.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Combined Modality Therapy; Follow-Up Studies; Graft Survival; Humans; Liver Neoplasms; Liver Transplantation; Lymphocytes; Multivariate Analysis; Neoplasm Recurrence, Local; Neutrophils; Niacinamide; Phenylurea Compounds; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Sirolimus; Sorafenib; Survival Rate

It has been shown that triple antiplatelet therapy with cilostazol results in better clinical outcomes than dual therapy in patients treated with a first-generation drug-eluting stent (DES); however, it is unclear whether triple antiplatelet therapy has a similar efficacy after the implantation of second-generation DES.In the COACT (Cath Olic medical center percutAneous Coronary in Tervention) registry, 1248 study subjects who underwent percutaneous coronary intervention with an everolimus- or zotarolimus-eluting stent (Endeavor, Xience V, or Promus) were analyzed. The patients were divided into 2 groups after propensity score matching (n = 724; M = 422 [58.3%]; mean age = 66.1 ± 11.0 years): Group 1: patients treated with dual antiplatelet drugs (aspirin and clopidogrel; n = 362; M = 213 [58.8%]; mean age = 65.6 ± 11.7 years); Group 2: patients treated with triple antiplatelet drugs (aspirin, clopidogrel, and cilostazol; n = 362; M = 209 [57.7%]; mean age = 65.6 ± 11.7 years). The mean follow-up duration was 13 ± 10 months, and the cumulative incidence of major cardiovascular events (MACE) was 6.3% in Group 1 and 7.7% in Group 2. There were no significant differences in MACE (death, nonfatal myocardial infarction, and stroke) between the 2 groups (OR, 1.210; 95% CI: 0.772-1.898; P = 0.406). Kaplan-Meier curves for MACE did not show any survival benefit for triple antiplatelet therapy, even in patients with acute coronary syndrome.In patients treated with a second-generation DES implantation, there is no added clinical benefit to using triple rather than dual antiplatelet therapy.

Topics: Adult; Aged; Aspirin; Cilostazol; Clopidogrel; Drug Therapy, Combination; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Care; Postoperative Complications; Registries; Sirolimus; Tetrazoles; Thrombosis; Ticlopidine; Treatment Outcome

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Restenosis; Delayed Diagnosis; Diagnosis, Differential; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Postoperative Complications; Sirolimus; Tomography, Optical Coherence; Ultrasonography, Interventional

This study aimed to examine clinical efficacy, safety, and intermediate clinical outcomes with everolimus-eluting stents (EESs) in patients with transplant coronary artery disease (TCAD).. TCAD is a major cause of mortality in patients following orthotopic heart transplantation (OHT). Systemic everolimus in OHT patients has been shown to reduce TCAD. The safety and efficacy of an EES, the Xience V, have not been evaluated in this population.. Patients post-OHT with hemodynamically significant CAD who underwent percutaneous coronary intervention (PCI) with EES were included. Participants were maintained on dual antiplatelet therapy for 1-year post-PCI. We examined procedural success, in-hospital and 1-year mortality, stent thrombosis, angiographic restenosis, and myocardial infarction rates. All patients had follow-up angiography 1-year after PCI. Target vessel revascularization (TVR), target lesion revascularization (TLR), in-segment restenosis, target vessel failure (TVF), and lumen late loss were noted.. PCI was performed in 34 de novo lesions in 21 patients, and 40 EES were placed. Procedural success rate was 100%. Average stent was 16.5 ± 5.1 mm long and 3.0 ± 0.6 mm in diameter. All patients had angiographic follow-up (409 ± 201 days). There was no stent thrombosis, deaths, or myocardial infarctions during follow-up. Two patients had focal in-stent restenosis. TLR rate was 5.9% (2/34), and TVR rate was 11.1% (3/27). Quantitative coronary angiography (QCA) showed stenosis diameter to be 19.98 ± 17.57%.. Use of an EES is associated with a low incidence of TVR and TLR in patients with TCAD. Further studies are needed to determine whether PCI with EES changes long-term outcomes.

Topics: Allografts; Coronary Angiography; Coronary Disease; Drug-Eluting Stents; Everolimus; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Percutaneous Coronary Intervention; Postoperative Complications; Retrospective Studies; Sirolimus; Treatment Outcome

Sirolimus (SIR) has been shown to stabilize the lung function in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). However, there is no long-term data on the prophylactic use of SIR in lung transplant recipients. This retrospective study examines the effects of SIR in the prevention of BOS.. From 1999 to 2009, 24 lung transplant recipients whose maintenance immunosuppression regimen consisted of tacrolimus (Tac), mycophenolate mofetil (MMF) or azathioprine (AZA), and prednisone (Pred), were switched to Tac, SIR, and Pred at 1 year after transplantation. From these 24 patients, 5 developed side effects that necessitated the cessation of SIR within 1 year, while 19 patients tolerated long-term use of SIR. The clinical outcomes of these 19 patients (SIR group) were compared with 22 lung transplant recipients whose immunosuppression regimen consisted of Tac, MMF or AZA, and Pred from the time of transplant (MMF group). Survival rates and freedom from BOS were calculated by the Kaplan-Meier method.. The SIR group had a lower incidence of BOS and viral infection (p = 0.05), and higher survival rates (p = 0.004). The SIR group had lower levels of Tac and received less Pred. The incidences of acute rejection, carcinoma, hypertension, and diabetes were similar between both groups.. Results from this study suggest that conversion to SIR 1 year after lung transplantation improves survival and decreases the development of BOS. Randomized studies with higher number of patients are needed to determine the prophylactic efficacy of sirolimus in preventing the development of BOS.

Topics: Adult; Bronchiolitis Obliterans; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Primary Prevention; Retrospective Studies; Sirolimus; Survival Rate; Syndrome; Treatment Outcome

We sought to determine the morphologic predictors of major adverse cardiac events (MACEs) after successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES), using integrated backscatter intravascular ultrasound (IB-IVUS). Conventional IVUS and IB-IVUS were performed in 260 consecutive patients who underwent PCI with DES. Three-dimensional analyses were performed to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcification). Patients were divided into two groups according to the median lipid volume (LV) in the target lesion. MACEs were defined as death, nonfatal myocardial infarction, and any repeat revascularization. The median follow-up interval was 1285 days. MACEs were observed in 64 patients (24.6 %). Patients having a larger LV compared with their counterparts had worse long-term clinical outcomes regarding mortality (3.8 vs. 0 %, P = 0.02) and MACEs (31.5 vs. 17.7 %, P = 0.008) by log-rank test. After adjustment for confounders, large LV (odds ratio 1.95, 95 % confidence interval 1.14-3.33, P = 0.02) was significantly and independently associated with MACEs. The assessment of coronary plaque characteristics in the target lesion may be useful to predict long-term outcome following successful coronary intervention.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Artery Disease; Drug-Eluting Stents; Follow-Up Studies; Humans; Japan; Lipids; Male; Middle Aged; Plaque, Atherosclerotic; Postoperative Complications; Predictive Value of Tests; Prognosis; Risk Factors; Sirolimus; Treatment Outcome; Ultrasonography, Interventional

Lymphangiomas of the tongue are rare, and their treatment is problematic. A 10 year-old patient with tongue lymphangioma who was previously treated with surgery and propranolol with no response was treated with sirolimus in our department. We used sirolimus with a dose of 1.6 mg/m(2)/day. After 3 months of treatment, the mass had decreased by more than 60%. We continued the treatment for 1 year with a maximum response of 70% decrease in mass. Disease remained stable 6 months after stopping therapy, the latest time of follow-up. Sirolimus appears to be effective in lymphangioma but requires further study.

Topics: Adrenergic beta-Antagonists; Antibiotics, Antineoplastic; Child; Combined Modality Therapy; Humans; Lymphangioma; Male; Postoperative Complications; Propranolol; Sirolimus; Tongue Neoplasms; Treatment Outcome

Topics: Anti-Infective Agents; Coated Materials, Biocompatible; Coronary Artery Disease; Coronary Thrombosis; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Male; Myocardial Infarction; Myocardial Revascularization; Postoperative Complications; Sirolimus; Stents; Thrombosis

A 67-year-old man with a more than 15-year-old history of hypertension, dyslipidemia, and glucose intolerance presented at our hospital with exertional angina. Coronary angiography showed considerable stenosis of 3 vessels. A diffuse calcified lesion in the left anterior descending coronary artery was pre-treated using rotational atherectomy followed by sirolimus-eluting stent (SES) implantation. A lesion in the proximal right coronary artery was treated by bare-metal stent (BMS) implantation, and the tandem lesion in the left circumflex artery was treated using paclitaxel-eluting stent (PES) implantation. All the procedures were performed within 1 month of the initial presentation and yielded good angiographic results. 3 months after the final stenting, the patient was re-admitted because of congestive heart failure (CHF). While recovering from CHF, he suddenly developed cardiopulmonary arrest and died during hospitalization. Autopsy examination of the coronary arteries showed that both drug-eluting stents (DESs: SES and PES) and the BMS had characteristic histopathological features. Inflammatory responses in the neointima were greater in both the DESs than in the BMS. SES and PES showed different inflammatory infiltration pattern or fibrin deposition status; these histopathological differences observed in the DES environments have implication to cause adverse clinical events such as late stent thrombosis or late catch-up phenomena.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Autopsy; Coronary Angiography; Coronary Vessels; Drug-Eluting Stents; Fatal Outcome; Humans; Male; Paclitaxel; Postoperative Complications; Sirolimus; Thrombosis; Treatment Outcome

The RESOLUTE China Registry is a prospective, multicenter, all-comers, observational study of patients in China implanted with the Resolute zotarolimus-eluting stent (R-ZES). R-ZES was commercially available before the enrollment began. All patients suitable for R-ZES implantation according to applicable guidelines were candidates for enrollment at 30 centers and were treated per standard hospital practice. Dual antiplatelet therapy (DAPT) was prescribed for a minimum of 6 months per current European Society of Cardiology guidelines and the device instructions for use. There were 1,800 patients enrolled with a mean age of 61.3 ± 10.9 years, 76% of patients were men, and 61% had complex disease. DAPT use was 94% at 1 year. Target lesion failure (cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization) at 1 year was 3.5% (95% confidence interval 2.7% to 4.5%). The rate of cardiac death was 0.6%, target vessel myocardial infarction 2.3%, and clinically driven target lesion revascularization 0.9%. The 1-year rate of definite or probable stent thrombosis was 0.5% (8 of 1,750); 0.4% (7 of 1,750) occurred early (0 to 30 days) and 1 event occurred late (1 to 12 months). One stent thrombosis occurred in a patient who had an interruption of DAPT within the first month; all other stent thromboses occurred while on DAPT. Outcomes did not differ significantly between monitored and unmonitored patients (difference in target lesion failure, p = 0.264). In conclusion, the RESOLUTE China Registry confirms the safety and effectiveness of R-ZES in a large real-world Chinese population.

Topics: Aged; Anti-Bacterial Agents; China; Coronary Artery Disease; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Prospective Studies; Registries; Sirolimus; Survival Rate; Treatment Outcome

The German Sirolimus Study Group has established a database among 10 transplant centers throughout Germany to study the outcomes in 726 renal transplant patients being converted to a sirolimus-containing therapy between 2000 and 2008 with a total of more than 1500 recorded patient years on therapy. In this study, we present a detailed description of the cohort, of characteristic changes over the observation period, proteinuria and graft survival, and new-onset proteinuria after conversion. Over the study period, age, graft function at the time of conversion, and the proportion of patients switched to sirolimus because of malignancy increased, whereas the proportion of patients with significant proteinuria at conversion decreased. Already modest proteinuria (151-268 mg/L) at conversion and new-onset proteinuria (>500 mg/L) after conversion were associated with inferior graft survival. Even mild proteinuria (>71 mg/L) at conversion was associated with new-onset proteinuria (>500 mg/L) post-conversion. Serum creatinine and urinary protein excretion at conversion together with age at transplantation had a significant impact on patient and graft survival. This large data set confirms and extends previous observations that proteinuria is an important indicator for graft outcome after conversion to sirolimus. We conclude that patients without any proteinuria have the greatest benefit from conversion to sirolimus.

Topics: Adult; Creatinine; Databases, Factual; Female; Follow-Up Studies; Germany; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Proteinuria; Retrospective Studies; Sirolimus; Survival Rate

Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD) that carries a high morbidity and mortality. The 'two hit theory' suggests that long term deterioration of the peritoneum combined with intraperitoneal inflammation is needed in the pathogenesis of EPS. For unclear reasons, post transplantation EPS is being increasingly reported in patients previously on PD. To date, there is no proven effective therapy with an absence of randomised controlled trials. Individual case reports and small case series have reported on the use of tamoxifen and corticosteroids for medical management of EPS. The use of everolimus has been reported in a single case, and never in the setting of renal transplantation. Here, we present the first case of post-transplant encapsulating peritoneal sclerosis treated successfully with a combination of everolimus, tamoxifen, low dose corticosteroid and surgery.

Topics: Adult; Combined Modality Therapy; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Peritoneal Fibrosis; Postoperative Complications; Sirolimus

mTOR inhibitors avoid calcineurin nephrotoxicity, but sirolimus de novo is associated with unacceptable side effects and higher rejection rates. We have investigated a modified strategy: alemtuzumab induction with tacrolimus and mycophenolate maintenance, switching from tacrolimus to sirolimus at 6 months and stopping mycophenolate at 12 months. Here, we report the 6-year follow-up of 30 patients prospectively recruited to this single-arm pilot study and compare outcomes to a matched contemporaneous control group of 30 patients who received standard induction and calcineurin-inhibitor-based immunosuppression.Six-year patient and graft survival were 83% and 80%(alemtuzumab) versus 77% and 70% (control). Rejection rates in the first 6 months were similar in alemtuzumab (6.6%) and control groups (10%). A higher than expected incidence of rejection in the alemtuzumab group following cessation of mycophenolate at 1 year (17%) was mitigated in later patients by retaining low dose mycophenolate. Mean eGFR was higher in the alemtuzumab group at all time points but not significantly (p¼0.16). Tacrolimus levels in the first 6 months were significantly higher in the contemporaneous control group (p<0.001). Alemtuzumab induction with initial treatment with tacrolimus enables conversion to sirolimus without the side effects and incidence of acute rejection seen in earlier protocols.

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Sirolimus; Survival Rate

This study aimed to assess the long-term safety and clinical effectiveness of the Xience V everolimus-eluting stent (EES) compared to both Taxus paclitaxel-eluting stent (PES) and Cypher sirolimus-eluting stent (SES) in an unselected patient population.. There are limited long-term data comparing Xience V EES vs the first-generation Cypher SES.. This retrospective analysis included 6069 patients treated with Cypher SES, Taxus PES, or Xience V EES from 2003-2009 at our institution. Patients were followed by telephone contact or office visit up to 2 years after the index procedure.. Baseline characteristics were generally comparable, with the exception of a significantly higher prevalence of diabetes mellitus, systemic hypertension, history of angioplasty, and coronary bypass surgery among Xience V EES patients. At 2 years, the incidence of major adverse cardiovascular events was 13.3% (Xience V EES) vs 17.8% (Cypher SES) vs 22% (Taxus PES) (P<.001). The main drivers for the differences in event rates were lower mortality, the need for target vessel revascularization, and Q-wave myocardial infarction. Stent thrombosis was lowest in Xience V EES patients (0.2% vs 1.2% SES vs 0.7% PES, respectively; P=.01). A landmark analysis after 1 year showed that the benefits of Xience V EES continued in long-term follow-up.. In a contemporary clinical United States practice with an unselected patient population, Xience V EES use was associated with improved safety profile and reduction of all-cause mortality and stent thrombosis when compared to both first-generation drug-eluting stents. This superiority continues to widen from 1 to 2 years.

Topics: Aged; Coronary Artery Disease; Coronary Stenosis; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Percutaneous Coronary Intervention; Postoperative Complications; Retrospective Studies; Sirolimus; Treatment Outcome

Chronic kidney disease (CKD) is a common complication of calcineurin inhibitors (CNIs) in solid organ transplantation. Previous data suggest that the use of everolimus as an immunosuppressant drug leads to improvement in renal function. The aim of our study was to establish the effect of everolimus in combination with lower doses of CNIs on renal function among lung transplant recipients. Data regarding renal function and pulmonary function were collected from 41 lung transplanted patients in whom treatment was converted to a combination of everolimus with lower doses of CNIs. Patients transferred to everolimus and low dose CNIs showed an improvement in renal function. Patients who continued treatment with everolimus showed improvement in renal function, as opposed to patients who discontinued the treatment. Subjects without proteinuria at baseline showed a better improvement compared with subjects with proteinuria. The incidence of graft rejection did not increase. We concluded that a protocol that includes everolimus and lower doses of CNIs is effective for preserving renal function in lung transplant recipients with CKD. We also believe that an early implementation of everolimus, before proteinuria occurs or creatinine clearance is reduced, could lead to better outcomes.

Topics: Adult; Aged; Calcineurin Inhibitors; Drug Therapy, Combination; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Function Tests; Lung Diseases; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Renal Insufficiency; Retrospective Studies; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases

The consequences of acute strut malapposition in everolimus-eluting stents (EES) are unknown. This study investigated the impact of strut-vessel (S-V) distance and plaque type underneath acute strut malapposition on the mid-term vessel response in EES. Twenty-nine patients (35 EES) underwent optical coherence tomography (OCT) immediately after percutaneous coronary intervention and at 8-month follow-up. S-V distance and plaque type (lipid, calcified, or fibrous) underneath acute strut malapposition were evaluated. Follow-up OCT classified acute strut malapposition as persistent or resolved. The S-V cutoff value for predicting resolved strut malapposition and the incidence of intra-stent thrombi were determined. Among 569 cases of acute strut malapposition, involving 29,168 struts, 139 (24.4 %) were persistent. Mean S-V distance was significantly longer in persistent than in resolved strut malapposition (600 ± 294 vs. 231 ± 95 μm; P < 0.0001). S-V distance ≤380 μm was the best cutoff value for predicting resolved strut malapposition (sensitivity 93.5 %, specificity 69.8 %, area under curve 0.878). Acute strut malapposition with S-V distance ≤380 μm remained persistent more frequently over lipid/calcified than over fibrous plaques (lipid: 13.4 %, calcified: 18.2 %, fibrous: 4.2 %; lipid vs. fibrous, P = 0.001; calcified vs. fibrous, P = 0.02). Intra-stent thrombi were more frequent in stents with ≥1 persistent strut malapposition than in those without [4/11 stents (36.3 %) vs. 0/24 (0 %); P = 0.006]. Lipid and calcified plaque, together with S-V distance, affect the resolution of acute strut malapposition in EES. Persistent strut malapposition is associated with the presence of thrombi at follow-up, which could be the substrate for late stent thrombosis.

Topics: Aged; Coronary Disease; Drug-Eluting Stents; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Postoperative Complications; Prosthesis Failure; Sensitivity and Specificity; Sirolimus; Tomography, Optical Coherence

Posterior capsule opacification (PCO) is a common complication after cataract surgery. The purpose of this study was to determine the effects of three administering ways of rapamycin (RAPA) on the formation of PCO in rabbit eyes for 12 weeks.. Eighty rabbits were divided into four groups, according to the different administrations of RAPA which they received. These were: (1) the control group, (2) the irrigation-treated group - 5 ng/ml intraoperative RAPA irrigation solution, (3) the eye-drop-treated group - 2 mg/ml RAPA eye drops, and (4) the IOL-treated group - RAPA-poly(lactic-co-glycolic) acid (PLGA) loaded on the surface of intraocular lens (IOLs) (RAPA-PLGA-IOLs). All right eyes were treated with lens extraction plus IOL implantation, receiving relative administrations of RAPA. RAPA concentrations in the aqueous humour were determined by high performance of liquid chromatography (HPLC). The anterior chamber (AC) response was observed through slit-lamp biomicroscopy. After 12 weeks, the degree of PCO was determined by clinical evaluation. The histological sections, immunohistochemistry expression of proliferating cell nuclear antigen (PCNA) in the lens capsule were conducted.. In the early period, AC response for both experimental and control eyes were similar. In the IOL-treated group, RAPA reached its peak at 25.68 ± 0.74 μg/ml on the 4th day, and it was detectable until 8 weeks afterwards. However, in the other groups, RAPA could not be detected all the time. Compared with other groups, in the IOL-treated group, PCO was greatly alleviated; only a few layers of the lens epithelial cells (LECs) and a little proliferative material around the posterior capsules, and a significantly weak expression of PCNA in the nuclei of LECs. By contrast, there was no significant statistical difference in eye-drop-treated or irrigation-treated eyes and control eyes respectively.. Intraocular RAPA-PLGA-IOL was a promising, effective, and safe administration to prevent PCO compared with other methods in the rabbit PCO model.

Topics: Animals; Aqueous Humor; Biomarkers; Capsule Opacification; Immunoenzyme Techniques; Immunosuppressive Agents; Lens Implantation, Intraocular; Ophthalmic Solutions; Phacoemulsification; Posterior Capsule of the Lens; Postoperative Complications; Proliferating Cell Nuclear Antigen; Rabbits; Sirolimus

Topics: Adult; Chronic Disease; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphedema; Male; Postoperative Complications; Sirolimus

Second-generation drug eluting stent (DES) implantation gradually replaced the first-generation DES in clinical practice. Whether the new DESs in use differ from one another, in terms of clinical outcomes, is still not known. We explored potential differences among DESs.. We followed 9584 consecutive patients undergoing percutaneous coronary intervention at our institution (2004-2012; mean follow-up, 2.8 years). Patients treated with bare-metal stent (BMS; n = 5599; 58.4%) were compared to 3985 DES counterparts (41.5%). The sirolimus-eluting stent (SES) served as the prototype for comparison to other DES types, using propensity matching. The primary outcome was a composite endpoint of total mortality, myocardial infarction, and clinically driven target vessel revascularization or coronary artery bypass graft. At 3 years, the composite endpoint was significantly lower in the DES vs. BMS group (17.9% vs. 25.3%; P<.001). Comparisons between SES and each of the five other stent types yielded no significant differences for the primary composite endpoint: SES vs. paclitaxel-eluting stent (n = 350 pairs; 18.1% vs. 17.7%; P=.70); vs. zotarolimus-eluting stent (n = 474 pairs; 21.8% vs. 23.2%; P=.35); vs. Resolute zotarolimus-eluting stent (n = 434 pairs; 16.9% vs. 11.7%; P=.70); vs. everolimus-eluting stent (n = 824 pairs; 14.2% vs. 14.1%; P=.60); and vs. biolimus-eluting stent (n = 117 pairs 13.7% vs. 13.4%; P=.60).. Cardiac prognosis did not differ between sirolimus and other DES types. The use of DES was associated with better clinical outcomes compared to BMS.

Topics: Aged; Comparative Effectiveness Research; Coronary Artery Disease; Coronary Restenosis; Coronary Thrombosis; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Long Term Adverse Effects; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Complications; Prognosis; Prosthesis Design; Sirolimus; Time Factors; Treatment Outcome

Human CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) prevent allogeneic graft rejection by inhibiting T cell activation, as has been shown in mouse models. Recently, low-dose IL-2 administration was shown to specifically activate Tregs but not pathogenic conventional T cells, leading to resolution of type 1 diabetes in nonobese diabetic mice. We therefore tested the ability of low-dose IL-2 to prevent allogeneic skin graft rejection. We found that while IL-2 alone was inefficient in preventing rejection, combined with rapamycin, IL-2 treatment promoted skin graft survival both in minor disparate and semi-allogeneic skin graft combinations. Tregs are activated by this combined treatment while conventional CD4(+) cell expansion and activation are markedly inhibited. Co-administration of anti-CD25 antibodies dramatically reduces the effect of the IL-2/rapamycin treatment, strongly supporting a central role for Treg activation. Thus, we provide the first preclinical data showing that low-dose IL-2 combined with rapamycin can significantly delay transplant rejection in mice. These findings may form the rational for clinical evaluation of this novel approach for the prevention of transplant rejection.

Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Combinations; Flow Cytometry; Graft Rejection; Graft Survival; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Interleukin-2; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Postoperative Complications; Sirolimus; Skin Transplantation; T-Lymphocytes, Regulatory; Transplantation Tolerance; Transplantation, Homologous

We included into this study 112 patients with ischemic heart disease (IHD) and concomitant type 2 diabetes mellitus (DM) subjected to percutaneous coronary interventions with stenting. Everolimus and sirolimus eluting stents (EES and SES) were implanted in 54 (group 1) and 58 (group 2) patients, respectively. After 12 months in groups 1 and 2 rates of repeat target lesion revascularizations (TLR) were 5.5 and 8.6% (odds ratio - OR - 0.62, 95% confidence interval - CI - 0.14- 2.74, p = 0.72); acute myocardial infarctions (MI) - 3.7 and 5.2% (OR 0.71, 95% CI 0.11- 4.4, p = 0.94); deaths - 1.85 and 1.7% (OR 1.1, 95% CI 0.1- 17.6, p = 1.0), respectively. There was no significant difference between groups by rate of unfavorable cardiac events (composite of cardiac death, nonfatal MI, and clinically indicated TLR) - 11.1 and 15.5% in groups 1 and 2, respectively (OR 0.68, 95% CI 0.225- 2.059, p = 0.69). Rates of stent thrombosis also did not differ (1.85 and 3.4% in groups 1 and 2, respectively; OR 0.53, 95% CI 0.05- 6.0; p = 0.94). Thus the use of EES and SES in patients with IHD and type-2 DM was equally effective.

Topics: Aged; Coronary Restenosis; Diabetes Mellitus, Type 2; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Heart Function Tests; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Moscow; Myocardial Ischemia; Percutaneous Coronary Intervention; Postoperative Complications; Severity of Illness Index; Sirolimus; Treatment Outcome

Coronary artery aneurysm after coronary interventions are rare but variable (0.2%-1.7%) clinicopathological entity depending on whether a incidental or a routine 6 monthly angiographic follow up finding and is seen more common with drug eluting stents (DES) rather than bare metal stents (BMS). It is of three types and depending on the type and patient clinical response further strategy (conservative, covered stents or coronary artery bypass surgery) is decided. We report a patient with large type 2 coronary artery aneurysms post percutaneous coronary intervention (PCI) to the right coronary artery (RCA) and the Left anterior descending (LAD) coronary artery and presenting four months later.

Topics: Angioplasty, Balloon, Coronary; Coronary Aneurysm; Coronary Angiography; Drug-Eluting Stents; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Sirolimus

Topics: Everolimus; Female; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Optic Nerve Diseases; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Sirolimus; Vision, Ocular

Previous intravascular ultrasound studies have shown that echolucent neointimal hyperplasia occasionally appears after bare-metal stent (BMS) or sirolimus-eluting stent (SES) implantation. Optical coherence tomography (OCT) studies have also demonstrated that paclitaxel-eluting stent (PES) restenosis exhibited similar images showing low signal intensity areas (LSIA) surrounding stent struts and three-layer appearance (TLA). The aim of the present study was to investigate the clinical significance of LSIA on OCT images in various types of stents. Fifty nine consecutive patients who underwent scheduled follow-up coronary angiography and OCT were enrolled. There was no significant difference in the prevalence of LSIA among the 3 stent groups (BMS 30%, SES 19%, PES 28%, P = 0.70). LSIA thickness was larger in the PES group than in the other stent groups (BMS 0.51 ± 0.21 mm, SES 0.35 ± 0.06 mm, PES 0.87 ± 0.19 mm, P < 0.01). The ratio of LSIA thickness to the neointimal thickness was also larger in PES compared with other stents (BMS 53 ± 9 %, SES 57 ± 8 %, PES 77 ± 5 %, P < 0.01). Also, LSIA thickness in patients with in-stent restenosis (ISR) was significantly larger than in those without ISR (0.37 ± 0.37 mm versus 0.12 ± 0.26 mm, P = 0.048). Our results suggest that LSIA might be involved in excessive neointimal formation, and that the healing response after PES implantation might be different from BMS or SES.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Disease; Coronary Restenosis; Female; Humans; Hyperplasia; Immunosuppressive Agents; Japan; Male; Middle Aged; Neointima; Outcome Assessment, Health Care; Paclitaxel; Postoperative Complications; Prospective Studies; Sirolimus; Stents; Tomography, Optical Coherence; Tubulin Modulators

The BASE-ACS trial demonstrated an outcome of titanium-nitride-oxide-coated bioactive stents (BAS) that was statistically non-inferior to that of everolimus-eluting stents (EES) at 12-month follow-up, in patients presenting with acute coronary syndrome (ACS) who underwent early percutaneous coronary intervention (PCI). We explored a post-hoc analysis of the 12-month outcome of the BASE-ACS trial in the subgroup of patients with ST-elevation myocardial infarction (STEMI) versus non-ST-elevation ACS (non-STEACS).. A total of 827 patients with ACS (321 STEMI) were randomly assigned to receive either BAS or EES. The primary endpoint was a composite of cardiac death, non-fatal myocardial infarction (MI) and ischemia-driven target lesion revascularization (TLR) at 12-month follow-up.. The 12-month cumulative incidence of the primary endpoint was similar between the two subgroups (9% versus 9.5%, in STEMI versus non-STEACS patients respectively, P=0.90). The 12-month rate of cardiac death was significantly higher in the STEMI subgroup as compared with the non-STEACS subgroup (2.8 versus 0.6%, respectively, P=0.01). However, the rates of non-fatal MI, ischemia-driven TLR, definite stent thrombosis, and non-cardiac death were all statistically matched between the two subgroups (P>0.05 for all).. In the current post-hoc analysis of the BASE-ACS trial based on the infarction type, the 12-month outcome of patients who underwent early PCI for ACS was slightly worse in the setting of STEMI as compared with non-STEACS, as reflected by a significantly higher rate of cardiac death.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Coated Materials, Biocompatible; Combined Modality Therapy; Coronary Restenosis; Disease-Free Survival; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Heart Diseases; Humans; Incidence; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Myocardial Ischemia; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; Titanium; Treatment Outcome

Topics: Biopsy; Creatinine; Cyclosporine; Female; Humans; Hyperoxaluria, Primary; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Oxalates; Postoperative Complications; Renal Dialysis; Renal Insufficiency; Sirolimus; Transplantation, Homologous; Treatment Outcome

Saphenous vein grafts (SVGs) are prone to an aggressive atherosclerotic process, and the efficacy of drug-eluting stents (DES) in treating this is still debated. In recent years, second-generation DES have been increasingly used in SVG intervention. The main objective of this study was to compare midterm clinical outcomes between first- and second-generation DES in SVGs because data regarding the use of second-generation DES in SVG are lacking. Patients treated with first-generation DES (127 patients with 143 lesions) and those treated with second-generation DES (84 patients with 100 lesions) were included in the study. Major adverse cardiac events, defined as the composite of all-cause death, myocardial infarction, and target vessel revascularization, as well as target vessel revascularization and target lesion revascularization separately, were evaluated at 30-day, 12-month, and 18-month follow-up. Baseline characteristics were similar between the 2 groups. Older grafts were treated with second-generation DES (11.6 ± 5.3 vs 14.3 ± 6.0 years, p = 0.001). Stent length was longer in the first-generation group (34.1 ± 25.1 vs 30.5 ± 19.4 mm, p = 0.006), and maximum balloon diameter was smaller in the second-generation group (3.42 ± 0.42 vs 3.30 ± 0.41 mm, p = 0.003). Embolic protection device use was higher in the second-generation DES group (55.2% vs 72.0%, p = 0.012). At 18-month follow-up, rates of major adverse cardiac events, target vessel revascularization, and target lesion revascularization for the first- and second-generation groups were 24.4% versus 20.2% (p = 0.479), 18.1% versus 14.2% (p = 0.465), and 15.0% versus 10.7% (p = 0.373), respectively. In conclusion, second-generation DES are at least comparable with first-generation DES with regard to clinical outcomes at midterm follow-up.

Topics: Aged; Antineoplastic Agents; Cause of Death; Coronary Artery Bypass; Coronary Restenosis; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Male; Middle Aged; Paclitaxel; Postoperative Complications; Prosthesis Design; Reoperation; Sirolimus; Veins

The safety and efficacy outcomes of stent overlap with second-generation drug-eluting stents (DES) have not been well established. This study aimed to compare the 1-year clinical outcomes of overlapping everolimus-eluting stents (EES) with those of overlapping first-generation DES. This retrospective analysis included 350 patients treated with overlapping EES (169 patients with 237 lesions), sirolimus-eluting stents (SES, 102 patients with 252 lesions), or paclitaxel-eluting stents (PES, 79 patients with 182 lesions). End points were major adverse cardiovascular events (MACE: defined as the composite of death, myocardial infarction, or target lesion revascularization), target vessel revascularization, and definite stent thrombosis at 1 year. During a follow-up of 1 year, overall MACE occurred in 6.5% of EES-, 16.8% of SES-, and 10.1% of PES-treated patients (p = 0.026). Myocardial infarction was lowest in the EES group versus SES and PES groups (0 vs 1.0% vs 2.5%, respectively; p = 0.080), and mortality was similar (3.6% vs 9.0% vs 5.1%, p = 0.162). The EES patients showed a trend toward lower rates of 1-year target lesion revascularization (3.1% vs 8.2% vs 6.5%, p = 0.181) and target vessel revascularization (3.7% vs 9.1% vs 11.7%, p = 0.051) compared with the SES- and PES-treated patients. The cumulative incidence of definite stent thrombosis was lowest in the EES group (0 for EES vs 3.9% for SES vs 2.5% for PES, p = 0.014). In conclusion, stent overlap with EES versus first-generation DES was associated with lower rates of MACE and stent thrombosis. Our results suggest that the use of EES when deploying overlapping stents is effective and safe.

Topics: Aged; Antineoplastic Agents, Phytogenic; Coronary Artery Disease; District of Columbia; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Paclitaxel; Postoperative Complications; Prosthesis Design; Retrospective Studies; Sirolimus; Treatment Outcome

Posttransplant lymphoproliferative disorder (PTLD) continues to be a devastating and potentially life-threatening complication in organ transplant recipients. PTLD is associated with EBV infection and can result in malignant B cell lymphomas. Here we demonstrate that the PI3K/Akt/mTOR pathway is highly activated in EBV+ B cell lymphoma lines derived from patients with PTLD. Treatment with the mTORC1 inhibitor Rapamycin (RAPA) partially inhibited the proliferation of EBV+ B cell lines. Resistance to RAPA treatment correlated with high levels of Akt phosphorylation. An mTORC1/2 inhibitor and a PI3K/mTOR dual inhibitor suppressed Akt phosphorylation and showed a greater anti-proliferative effect on EBV+ B lymphoma lines compared to RAPA. EBV+ B cell lymphoma lines expressed high levels of PI3Kδ. We demonstrate that PI3Kδ is responsible for Akt activation in EBV+ B cell lymphomas, and that selective inhibition of PI3Kδ by either siRNA, or a small molecule inhibitor, augmented the anti-proliferative effect of RAPA on EBV+ B cell lymphomas. These results suggest that PI3Kδ is a novel, potential therapeutic target for the treatment of EBV-associated PTLD and that combined blockade of PI3Kδ and mTOR provides increased efficacy in inhibiting proliferation of EBV+ B cell lymphomas.

Topics: Blotting, Western; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Imidazoles; Lymphoma, B-Cell; Lymphoproliferative Disorders; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes; Organ Transplantation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Postoperative Complications; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinolines; Sirolimus; TOR Serine-Threonine Kinases

Several lines of evidence have indicated that rapamycin acts as an inhibitor of mammalian target of rapamycin (mTOR) and this produces therapeutic benefits as a treatment for Alzheimer's disease (AD) by activating an autophagic pathway. Similarly, postoperative cognitive dysfunction (POCD) is a decline in cognitive function for weeks or months after surgery. POCD and AD are both characterized by cognitive dysfunction, and more importantly, are both related to aging. We therefore hypothesized that rapamycin may have a therapeutic effect to relieve POCD. Inhibition of mTOR induces autophagic effect, thereby leading to a slower aging process, so this would be a novel target for the prevention and treatment of POCD.

Topics: Aging; Cognition Disorders; Humans; Models, Biological; Postoperative Complications; Sirolimus; TOR Serine-Threonine Kinases

Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by clopidogrel has an influence on the formation of obliterative bronchiolitis, the histopathological correlate to bronchiolitis obliterans syndrome, present in the majority of patients suffering from CLAD. C57Bl/6(H2(b) ) donor tracheas were orthotopically transplanted into CBA.J(H2(k) ). Mice received different doses of clopidogrel alone or in combination with tacrolimus or everolimus. Grafts were analyzed by histology and immunofluorescence method on postoperative days 15, 30 or 60. Cytokines were analyzed by real-time polymerase chain reaction on postoperative day 21 and alloantibodies by FACS. Mice treated with 20 mg/kg/day clopidogrel for 30 days showed reduced obliteration [34.40 ± 3.76% (20 mg/kg/day clopidogrel) vs. 49.92 ± 2.11% (control), n = 5, P < 0.05]. Platelet inhibition resulted in significant lower infiltration of T cells and macrophages, and we also found significantly lower expression of IL-12, IL-4, IL-6, TNF-α, TGF-β, PDGFβ, MCP1, P-/E-selectin, ICAM1 and CD40L after treatment with clopidogrel. Combination of 1 mg/kg/day clopidogrel and 0.05 mg/kg/day everolimus or 12 mg/kg/day tacrolimus revealed a synergistic effect. Humoral immunity as manifested by donor-specific alloantibody secretion was also impaired after treatment with clopidogrel. Here, we can show that platelet inhibition by clopidogrel as a single treatment and in combination with tacrolimus or everolimus reduced the development of fibrosis and obliteration in tracheal allografts.

Topics: Animals; Blood Platelets; Bronchiolitis Obliterans; Calcineurin Inhibitors; Clopidogrel; Cytokines; Everolimus; Gene Expression Regulation; Immunohistochemistry; Isoantibodies; Lung Diseases; Lung Transplantation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Microscopy, Fluorescence; Models, Animal; Platelet Aggregation; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; T-Lymphocytes; Tacrolimus; Ticlopidine; Time Factors; TOR Serine-Threonine Kinases; Trachea

Recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT) is a rare but challenging condition. In most cases, the recurrent tumor is presented with extrahepatic spread. Therefore, systemic treatment with sorafenib has to be assessed. Because of a plethora of possible drug interactions, e.g., with immunosuppressant or anti-infective therapy, safety and feasibility of sorafenib treatment requires special attention.. We retrospectively analyzed 18 patients who suffered from recurrent advanced HCC after LT between January 2002 and December 2010 at the University Hospital Heidelberg regarding safety of sorafenib treatment and survival.. Results showed that 8 patients were eligible for treatment with sorafenib showing a median time to progression (TTP) of 4.5 months and an overall survival of 9 months. Most common side effects were grades I and II diarrhea and hand-foot syndrome (HFS) which could be managed by sorafenib dose reduction. No grade III or IV adverse events (AEs) were noticed. No patient had to discontinue treatment due to AEs. The ten patients not amenable for sorafenib treatment, due to initial poor performance status or its deterioration after first line treatment, were treated with surgical resection (n = 3), locoregional therapies (n = 1), or palliative radiation therapy (n = 1). They showed a median overall survival of 2.3 months.. Sorafenib may represent a therapeutic option for recurrent HCC after LT with manageable side effects. The clinical benefit of sorafenib in this setting is promising but needs to be confirmed in a prospective randomized trial.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Female; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Niacinamide; Phenylurea Compounds; Postoperative Complications; Retrospective Studies; Sirolimus; Sorafenib; Survival Rate; Treatment Outcome

Few studies examined the clinicopathologic features of PTLD arising in pediatric SBT patients. Particularly, the association between ATG and PTLD in this population has not been described. Retrospective review of 81 pediatric patient charts with SBT--isolated or in combination with other organs--showed a PTLD incidence of 11%, occurring more frequently in females (median age of four yr) and with clinically advanced disease. Monomorphic PTLD was the most common histological subtype. There was a significant difference in the use of ATG between patients who developed PTLD and those who did not (p < 0.01); a similar difference was seen with the use of sirolimus (p < 0.001). These results suggested a link between the combination of ATG and sirolimus and development of more clinically and histologically advanced PTLD; however, the risk of ATG by itself was not clear. EBV viral loads were higher in patients with PTLD, and median time between detection of EBV to PTLD diagnosis was three months. However, viral loads at the time of PTLD diagnosis were most often lower than at EBV detection, thereby raising questions on the correlation between decreasing viral genomes and risk of PTLD.

Topics: Adolescent; Antilymphocyte Serum; Child; Child, Preschool; Female; Gene Rearrangement; Genome, Viral; Humans; Immunosuppressive Agents; In Situ Hybridization; Infant; Intestinal Diseases; Intestine, Small; Lymphoma; Lymphoproliferative Disorders; Male; Postoperative Complications; Retrospective Studies; Risk; Sirolimus; VDJ Recombinases; Viral Load; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Delayed Diagnosis; Dermatitis; Diagnostic Errors; Drug Substitution; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Postoperative Period; Prednisone; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Tacrolimus; Vinblastine

To investigate the pathogenesis of ischemic-type biliary lesions (ITBLs) in post-liver transplant patients and the possible therapeutic mechanisms of sirolimus.. The clinic data of 32 post-liver transplant patients with ITBLs from May 2004 to December 2010 was analyzed. There were including 25 male and 7 female patients with a median age of 46 years (ranging from 19 to 61 years). Patients were divided into those who received sirolimus (sirolimus group) and those who did not (control group). The expression of IL-2, FoxP3, and IL-10 in the portal area, liver function indexes, and bile duct injury score were assessed pre-ITBL, when ITBLs were identified, and after 6 months of sirolimus treatment.. Compared with pre-ITBL optical density (OD) values, there was a significantly increase in IL-2 OD(0.138 ± 0.050 in control group and 0.141 ± 0.052 in sirolimus group), but not FoxP3 and IL-10 OD in both groups at the time ITBLs were diagnosed. After 6 months of treatment, the IL-2, FoxP3, and IL-10 OD values in the control group were not different from those when ITBLs were diagnosed. There was a significant reduction in post-therapy IL-2 OD(0.107 ± 0.043, t = 2.087, P = 0.044), and a significant elevation in FoxP3(0.213 ± 0.039) and IL-10 OD(0.187 ± 0.048) in sirolimus group as compared with those when ITBLs were diagnosed(t = -3.822 and -4.350, both P < 0.01). There was a significant increase in serum levels of ALT, AST, total bilirubin, γ-glutamyl transpeptidase and ALP at the time ITBLs were diagnosed compared with pre-ITBL levels in both groups. After 6 months of treatment, the above indexes had not changed in the control group, but significantly improved in the sirolimus group, and the bile duct injury score in the sirolimus group had significantly decreased(4.4 ± 2.4, Z = -2.568, P = 0.010). The 1-year and 3-year graft survival rates in the control group were 6/13 and 5/13, respectively, and 17/19 and 13/19, respectively, in the sirolimus group (χ(2) = 7.166, P = 0.007; χ(2) = 5.398, P = 0.020, respectively).. Sirolimus can downregulate IL-2 expression and upregulate FoxP3 and IL-10 expression, thereby stimulating FoxP3+ Treg cells, suppressing immunopathological damage, and promoting epithelial repair in bile ducts.

Topics: Adult; Bile Duct Diseases; Female; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Interleukin-10; Interleukin-2; Ischemia; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Sirolimus; Young Adult

In experiments involving tracheal wall defects in rabbits, metallic coil stents inevitably induce granulation formation in the defects. We examined the involvement of the mammalian target of rapamycin (mTOR) signaling pathway in granulation formation and examined the effects of rapamycin.. The anterior half of the tracheal wall was removed for a longitudinal length of six tracheal rings. Metallic coils were placed into the tracheal lumen through a wall defect. The rabbits were sacrificed two months after undergoing an endoscopic examination, and the granulation tissue in the tracheal defects was removed for a Western blot analysis and immunohistochemical analysis. Rapamycin (0.5 mg kg(-1) day(-1)) was administered three times per week intramuscularly. The data were expressed as the relative expression versus the expression of actin.. The level of mTOR phosphorylation in the resected trachea was 0.72±0.45, and it significantly increased in the granulation tissue to 11.6±5.2, with concomitant increases in the phosphorylation levels of p70S6K and S6RP in all five rabbits. Although the systemic administration of rapamycin significantly decreased the levels of phosphorylated mTOR to 4.0±2.4 in the five treated rabbits, the clinical outcomes were unsatisfactory. Three of the five treated rabbits exhibited signs of wound complications, and wet granulation tissue that caused respiratory symptoms was found inside and outside of the coils in four rabbits.. Although rapamycin effectively reduced the mTOR activity in the granulation tissue, the granulation formation process seemed to be disturbed, most likely owing to the immunosuppressive effects of rapamycin.

Topics: Animals; Biomarkers; Blotting, Western; Drug Administration Schedule; Foreign-Body Reaction; Granulation Tissue; Immunohistochemistry; Immunosuppressive Agents; Injections, Intramuscular; Male; Phosphorylation; Postoperative Complications; Rabbits; Sirolimus; Stents; TOR Serine-Threonine Kinases; Trachea; Treatment Outcome

Topics: Aged; Anticoagulants; Antitubercular Agents; Comorbidity; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Pericarditis; Phenindione; Polypharmacy; Postoperative Complications; Rifampin; Sirolimus; Venous Thrombosis; Vitamin K

HVEM/BTLA/CD160/LIGHT pathway is a very special costimulatory molecule system which can regulate T-cell immune responses by activating both inflammatory and inhibitory signalings. The regulatory effect of Sirolimus on HVME costimulatory system in allo-renal recipients has not been reported. In this study, we analyzed the expression of HVEM, BTLA, CD160 and LIGHT on circulating T cell subgroups and the expression of HVEM on CD4+ Tregs by flow cytometry and also the pre-dose concentration of Sirolimus by automatic analyzer. Both the allo-renal recipients receiving Sirolimus immunosuppressive regimen and health volunteers were included. The expression of both BTLA and CD160 on T cells increased significantly while the expression of LIGHT on T cells decreased significantly in allo-renal recipients receiving Sirolimus regimen (p<0.05). The expression of HVEM on T cells and CD4+ T-cell subgroup decreased (p<0.05) while that on CD8+ T-cell subgroup remained roughly normal (p>0.05).The expression of HVEM on CD4+ Tregs increased significantly (p<0.05) in allo-renal recipients receiving Sirolimus regimen (p<0.05). Though regulating the expression of HVEM/BTLA/CD160/LIGHT costimulatory system, Sirolimus-based regimen promotes inhibitory costimulatory signal in T cells and enhances the function of CD4+ Tregs in allo-renal recipients, which are in benefit of the control of transplant rejection as well as the induction and maintenance of transplant tolerance.

Topics: Adult; Antigens, CD; CD4-Positive T-Lymphocytes; Female; GPI-Linked Proteins; Graft Rejection; Humans; Kidney Transplantation; Male; Postoperative Complications; Receptor Cross-Talk; Receptors, Immunologic; Receptors, Tumor Necrosis Factor, Member 14; Signal Transduction; Sirolimus; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Tumor Necrosis Factor Ligand Superfamily Member 14

To investigate the characteristics and one-year outcomes following sirolimus-eluting CYPHER Select Plus stent (SES) implantation in small (SmVD) and non-small vessel disease (NSmVD) in the international e-SELECT registry.. Large-scale registry data are lacking on DES outcomes in SmVD treatment.. There were 4,700 SmVD (at least one vessel with estimated reference vessel diameter [RVD] < 2.5 mm, excluding 283 patients with unknown RVD vessels) and 10,139 NSmVD only patients.. The SmVD population was older, with more women, diabetics, and vessels treated, higher mean Charlson Comorbidity Index score (CCI), shorter lesions, and less STEMI presentation. The 1-year stent thrombosis (ST) rate (primary end-point), was significantly higher (1.3% vs. 0.7%) in SmVD versus NSmVD, mainly driven by early events. One-year major adverse cardiac event (MACE), myocardial infarction (MI), and clinically indicated target-lesion revascularization (TLR) rates were significantly higher in SmVD although death and major bleeding rates were similar in both groups. Complication rates were similar between pure (3,188 patients; only RVD < 2.5 mm) and mixed (1,795 patients; some RVD < 2.5 mm or unknown RVD) SmVD. Multivariate predictors for 1-year MACE in SmVD included saphenous vein graft or bifurcation lesions, major bleeding, any antiplatelet therapy discontinuation within 1 month, age, number of stents implanted, CCI, acute coronary syndrome, and insulin-dependent diabetes mellitus.. SES implantation for SmVD occurs more frequently in women, diabetics, and those with multivessel disease and comorbidities. One-year ST, MACE, MI, and clinically indicated TLR rates are higher, although low overall, in SmVD or mixed SmVD patients while death rates are similar to NSmVD.

Topics: Aged; Cohort Studies; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Postoperative Complications; Registries; Sirolimus; Survival Analysis; Treatment Outcome

We performed this study to clarify natural consequences of abnormal structures (stent malapposition, thrombus, tissue prolapse, and stent edge dissection) after percutaneous coronary intervention (PCI).. Thirty-five patients treated with 40 drug-eluting stents underwent serial optical coherence tomography (OCT) imaging immediately after PCI and at the 8-month follow-up. Among a total of 73 929 struts in every frame, 431 struts (26 stents) showed malapposition immediately after PCI. Among these, 49 remained malapposed at the follow-up examination. The mean distance between the strut and vessel wall (S-V distance) of persistent malapposed struts on post-stenting OCT images was significantly longer than that of resolved malapposed struts (342 ± 99 vs. 210 ± 49 μm; P <0.01). Based on receiver-operating characteristic curve analysis, an S-V distance ≤260 µm on post-stenting OCT images was the corresponding cut-off point for resolved malapposed struts (sensitivity: 89.3%, specificity: 83.7%, area under the curve = 0.884). Additionally, 108 newly appearing malapposed struts were observed on follow-up OCT, probably due to thrombus dissolution or plaque regression. Thrombus was observed in 15 stents post-PCI. Serial OCT analysis revealed persistent thrombus in 1 stent, resolved thrombus in 14 stents, and late-acquired thrombus in 8 stents. Tissue prolapse observed in 38 stents had disappeared at the follow-up. All eight stent edge dissections were repaired at the follow-up.. Most cases of stent malapposition with a short S-V distance, thrombus, tissue prolapse, or minor stent edge dissection improved during the follow-up. These OCT-detected minor abnormalities may not require additional treatment.

Topics: Aged; Angina Pectoris; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Paclitaxel; Percutaneous Coronary Intervention; Postoperative Complications; Prolapse; Prosthesis Failure; Retrospective Studies; Sensitivity and Specificity; Sirolimus; Thrombosis; Tomography, Optical Coherence

Posterior reversible encephalopathy syndrome (PRES) is a small vessel microangiopathy of the cerebral vasculature that occurs in 0.5-5% of solid organ transplant recipients, most commonly associated with tacrolimus (Tac). Clinical manifestations include hypertension and neurologic symptoms. We report an adult multivisceral transplant recipient who experienced recurrent PRES initially associated with Tac and subsequently with sirolimus. A 49-year-old woman with short bowel syndrome underwent multivisceral transplantation due to total parenteral nutrition-related liver disease. She was initially maintained on Tac, mycophenalate mofetil (MMF) and prednisone. Three months after transplantation, she developed renal dysfunction, leading to a reduction in Tac and the addition of sirolimus. Eight months after transplantation, she developed PRES. Tac was discontinued and PRES resolved. Sirolimus was increased to maintain trough levels of 12-15 ng/mL. Fourteen months after transplant, she experienced recurrent PRES which resolved after discontinuing sirolimus. Currently 3 years posttransplant, she is maintained on cyclosporine, MMF and prednisone with no PRES recurrence. In addition to calcineurin inhibitors, sirolimus may also be associated with PRES after solid organ transplantation. Ours is the first report of sirolimus-associated PRES in the setting of multivisceral transplantation. Identifying a safe alternative immunosuppression regimen was challenging but ultimately successful.

Topics: Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Middle Aged; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Prognosis; Recurrence; Sirolimus; Tacrolimus

Sirolimus-eluting stent (SES) has shown a significant efficacy in reducing restenosis after percutaneous coronary interventions. However, an increase in total number of SES use along with targeting more complex lesions generated a large number of SES restenosis. This study aimed to investigate the clinical and angiographic outcomes of different revascularization strategies for SES restenosis.. A total of 176 lesions in 149 patients were included in the study. Fifteen patients underwent coronary artery bypass graft surgery (CABG group) and the remaining patients were treated with percutaneous coronary intervention (PCI). Stent reimplantation was performed in 88 patients (Stent group), whereas 46 patients received balloon therapy (Balloon group). Among 176 lesions, major cardiac adverse event (MACE) occurred in 41 lesions (23.3%) during a median follow-up of 310 days (interquartile range: 146-517 days). The Kaplan-Meier method with a log-rank test revealed no significant difference in MACE rates between the three groups (6%, 25%, 26%, p = 0.13; CABG group, Stent group, Balloon group, respectively). However, when the Balloon group and Stent group were combined together as a PCI group, PCI group had a significantly higher rate of MACE compared with the CABG group (p = 0.04). In addition, angiographic restenosis was significantly less prevalent in the CABG group when compared with the other two groups (8%, 57%, 46%, p = 0.006; CABG group, Stent group, Balloon group, respectively).. CABG surgery for patients with SES restenosis is associated with the better clinical outcomes as well as better angiographic outcomes when compared with that of PCI.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Artery Bypass; Coronary Restenosis; Death; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Complications; Radiography; Retrospective Studies; Sirolimus; Treatment Outcome

Sirolimus, a potent inhibitor of B- and T-cell activation. is a commonly used immunosuppressant after renal transplantation. Withdrawal of sirolimus from the immunosuppression regimen may reduce B-cell surveillance. We present a case of rapidly progressive central nervous system (CNS) polymorphic Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder following the withdrawal of sirolimus.

Topics: Adult; Biopsy; Disease Progression; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Sirolimus; Tomography, X-Ray Computed

Reperfusion injury remains one of the major problems in transplantation. Repair from ischaemic acute renal failure (ARF) involves stimulation of tubular epithelial cell proliferation. The aim of this exploratory study was to evaluate the effects of preconditioning donor animals with rapamycin and tacrolimus to prevent ischaemia-reperfusion (I/R) injury. Twelve hours before nephrectomy, the donor animals received immunosuppressive drugs. The animals were divided into four groups, as follows: group 1 control: no treatment; group 2: rapamycin (2 mg/kg); group 3 FK506 (0, 3 mg/kg); and group 4: FK506 (0, 3 mg/kg) plus rapamycin (2 mg/kg). The left kidney was removed and after 3 h of cold ischaemia, the graft was transplanted. Twenty-four hours after transplant, the kidney was recovered for histological analysis and cytokine expression. Preconditioning treatment with rapamycin or tacrolimus significantly reduced blood urea nitrogen and creatinine compared with control [blood urea nitrogen (BUN): P < 0·001 versus control and creatinine: P < 0·001 versus control]. A further decrease was observed when rapamycin was combined with tacrolimus. Acute tubular necrosis was decreased significantly in donors treated with immunosuppressants compared with the control group (P < 0·001 versus control). Moreover, the number of apoptotic nuclei in the control group was higher compared with the treated groups (P < 0·001 versus control). Surprisingly, only rapamycin preconditioning treatment increased anti-apoptotic Bcl2 levels (P < 0·001). Finally, inflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, showed lower levels in the graft of those animals that had been pretreated with rapamycin or tacrolimus. This exploratory study demonstrates that preconditioning donor animals with rapamycin or tacrolimus improves clinical outcomes and reduce necrosis and apoptosis in kidney I/R injury.

Topics: Animals; Apoptosis; Blood Urea Nitrogen; Complement C3; Creatinine; Cytokines; Drug Evaluation; Drug Synergism; Drug Therapy, Combination; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Male; Postoperative Complications; Premedication; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sirolimus; Tacrolimus

Impaired endothelial recovery after the implantation of drug-eluting stents is a major concern because of the increased risk for late stent thrombosis. The disruption of the chemokine axis CXCL12/CXCR4 inhibits neointima formation by blocking the recruitment of smooth muscle progenitor cells. To directly compare a CXCR4-targeting treatment strategy with drugs that are currently used for stent coating, we studied the effects of the CXCR4 antagonist POL5551 and the drug sirolimus on neointima formation. Apolipoprotein E-deficient mice were treated with POL5551 or sirolimus continuously for 28 days after a carotid wire injury. POL5551 inhibited neointima formation by 63% (for a dosage of 2 mg/kg/day) and by 70% (for a dosage of 20 mg/kg/day). In comparison, sirolimus reduced the neointimal area by 69%. In contrast to treatment with POL5551 during the first three days after injury, injection of POL5551 (20 mg/kg) once per day for 28 days diminished neointimal hyperplasia by 53%. An analysis of the cellular composition of the neointima showed a reduction in the relative smooth muscle cell (SMC) and macrophage content in mice that had been treated with a high dose of POL5551. In contrast, the diminished SMC content after sirolimus treatment was associated with a neointimal enrichment of macrophages. Furthermore, endothelial recovery was impaired by sirolimus, but not by POL5551. Therefore, the inhibition of CXCR4 by POL5551 is equally effective in preventing neointima formation as sirolimus, but POL5551 might be more beneficial because treatment with it results in a more stable lesion phenotype and because it does not impair re-endothelialisation.

Topics: Angioplasty; Animals; Apolipoproteins E; Blood Vessel Prosthesis Implantation; Carotid Arteries; Cell Movement; Coronary Restenosis; Disease Models, Animal; Drug-Eluting Stents; Endothelium, Vascular; Humans; Lysophospholipids; Macrophages; Mice; Mice, Knockout; Myocytes, Smooth Muscle; Neointima; Postoperative Complications; Proteins; Receptors, CXCR4; Sirolimus

This retrospective case series reviews our center's experience with sirolimus and a CNI as alternative therapy for the treatment of PTAH. It also characterizes regulatory T cells (Tregs) in PTAH. LT recipients with PTAH who had received or were receiving treatment with sirolimus were retrospectively identified (n = 12). Liver enzymes, immunohistochemistry, and histology were compared in all 12 patients. Immunophenotyping for Tregs in peripheral blood mononuclear cells was performed on LT recipients with PTAH on conventional therapy with CNI, azathioprine ± prednisone (CT) (n = 11), recipients with PTAH on sirolimus, CNI ± prednisone (n = 8), recipients without PTAH (n = 25), and pre-transplant patients (n = 5). Severity of necro-inflammatory changes markedly improved with sirolimus. Treg frequency and number were significantly lower in recipients with PTAH on CT compared to (i) those on sirolimus (p = 0.002 and p = 0.01, respectively), and (ii) recipients without PTAH (p = 0.07 and p = 0.009, respectively). Treg frequency was significantly higher in recipients with PTAH on sirolimus compared to recipients without PTAH under CNI therapy (p = 0.027). Sirolimus in addition to a CNI is successful in reversing inflammation in LT recipients with PTAH. This is associated with significantly higher circulating Tregs.

Topics: Azathioprine; CD4 Lymphocyte Count; Child; Child, Preschool; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis; Humans; Immunosuppressive Agents; Infant; Liver; Liver Transplantation; Male; Postoperative Complications; Prednisone; Retrospective Studies; Single-Blind Method; Sirolimus; T-Lymphocytes, Regulatory; Tacrolimus; Treatment Outcome

The paclitaxel-eluting stent (PES) and sirolimus-eluting stent (SES) are first-generation drug-eluting stents (DES) that have been the most widely used; however, it is unclear whether there are differences in the long-term safety and efficacy between the 2 stents. The long-term effectiveness of DES in unselected people with diabetes is also currently unclear. Moreover, the possibility of late catch-up is suggested in the DES population.. This study is an 8-center collaborative network analysis of all comers who received SES and PES. All patients who received SES and PES from February 2003 to October 2006 were enrolled. We analyzed 9315 patients (33.3% with diabetes) treated with SES or PES in the major 8 centers representing whole area of Korea. The primary end point was a major adverse cardiac event (MACE) composite of overall death, myocardial infarction, and target lesion revascularization. All analyses were performed using multivariable, adjusted models and propensity score-matching methods. Long-term MACE for 5 years were significantly lower in the SES than the PES group (13.3% versus 15.6%; hazard ratio, 0.82; 95% confidence interval, 0.71 to 0.96; P=0.01), which was mainly driven by the difference of MACE within the first year (hazard ratio, 0.73; 95% CI, 0.59 to 0.90; P=0.003), but the rate of MACE between 1 and 5 years in the landmark analysis was not different between the 2 stents (1.9 versus 2.0%/yr). In the subpopulation of people with diabetes, in contrast to the whole population, PES was comparable to SES in terms of any clinical outcome, both within the first year and from 1 to 5 years (MACE for 5 years, 20.3 versus 17.9%; MACE within the first year, 9.6 versus 8.2%; MACE 1 to 5 years, 2.9 versus 2.6%/yr).. The PES was inferior to the SES in the clinical follow-up of more than 9000 patients' cohort for 5 years, which was mainly driven by the difference in the first year. In the subpopulation of people with diabetes that showed higher MACE than people without diabetes, however, PES was comparable to SES in any clinical outcome for 5 years. Although these 2 stents are not frequently used as before, the data would be useful to expect the long-term clinical course of the current DES.

Topics: Aged; Blood Vessel Prosthesis Implantation; Coronary Artery Disease; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Korea; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Paclitaxel; Postoperative Complications; Sirolimus; Survival Analysis; Treatment Outcome

Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9-/- mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy.

Topics: Animals; Gene Expression Regulation; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 4; Hyperinsulinism; Insulin; Insulin Resistance; Liver; Liver Transplantation; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Multiprotein Complexes; Postoperative Complications; Proprotein Convertase 9; Proprotein Convertases; Proteins; Proto-Oncogene Proteins c-akt; Receptor, Insulin; Receptors, LDL; RNA Interference; RNA, Small Interfering; Serine Endopeptidases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

This retrospective single-center study evaluated long-term renal function after conversion from calcineurin inhibitors to sirolimus-based immunosuppression in kidney transplant recipients.. From 2001 to 2009, one hundred fifty kidney transplant recipients were converted from calcineurin inhibitors to sirolimus at least 3 months after transplant.. After a mean follow-up of 171 weeks, 56.7% of converted patients remained on sirolimus. The 5-year survival rate of the patients (including intent-to-treat) and grafts was 85.5% and 83.6%. Patients on sirolimus showed significant improvement in renal function with a creatinine clearance of 50.9 ± 20.7 and 52.9 ± 20.8 mL/minute at month 0 and month 24. Independent predictive factors associated with a stable estimated glomerular filtration rate at the last follow-up of sirolimus patients were (1) having a living donor, (2) absence of anti-HLA alloantibodies at month 0, and (3) cyclosporine versus tacrolimus used before conversion. Adverse effects were reported in 134 patients (89.3%). They included (1) hospitalization for infection (n=52), (2) de novo proteinuria (n=40), and (3) eight patients with biopsy-proven acute rejection. Sirolimus was stopped and replaced by calcineurin inhibitors in 37 patients after a mean of 16 months treatment. After stopping sirolimus, renal-allograft function remained stable at 2 years.. Conversion of calcineurin inhibitors to sirolimus in kidney transplant recipients was associated with improved renal function. The reintroduction of calcineurin inhibitors was safe in patients who were withdrawn from sirolimus owing to adverse effects.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neoplasms; Opportunistic Infections; Postoperative Complications; Proteinuria; Retrospective Studies; Sirolimus; Tacrolimus

Topics: Blood Vessel Prosthesis Implantation; Drug-Eluting Stents; Everolimus; Female; Humans; Male; Myocardial Infarction; Paclitaxel; Postoperative Complications; Practice Guidelines as Topic; Sirolimus

Encapsulating peritoneal sclerosis (EPS) is a serious complication of long-term peritoneal dialysis (PD), but only a few cases have been described in the pediatric patient population. There is no established medical treatment, and surgery has been reported with variable success. The number of reports of EPS being successfully treated with tamoxifen, based on its anti-fibrotic effects, are increasing. The role of sirolimus, an mTOR inhibitor with immunomodulatory and anti-proliferative properties, has been less well-defined.. A 17-year-old kidney transplant recipient, with a previous cumulative time on PD of 8 years and 3 months, developed severe bowel obstruction 8 months after undergoing a second kidney graft. Her immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and prednisolone. The patient underwent laparotomy, which revealed multiple thick leathery adhesions with an encapsulated small bowel. Enterolysis was performed, and total parenteral nutrition was commenced after surgery to provide an adequate food intake. Treatment with tamoxifen was initiated, but the patient developed significant liver toxicity 2 weeks later, and the drug was withdrawn. The immunosuppressive regimen was changed to an increased dose of prednisolone, and tacrolimus was replaced with sirolimos. At 20 months of follow-up, the patient remains symptom-free, with a functioning kidney transplant.. Although EPS is a very rare condition in the pediatric population, it should be considered when a child or adolescent with a long-term history of PD presents with nonspecific gastrointestinal symptoms or with signs of bowel obstruction. There is an urgent need for alternative immunosuppressive protocols. The use of sirolimus in this group of patients remains controversial.

Topics: Adolescent; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Peritoneal Dialysis; Peritoneal Fibrosis; Postoperative Complications; Prednisolone; Sirolimus; Tacrolimus

Malignancy is not uncommon with immunosuppressive therapy, but pancreatic cancer is infrequently complicated in recipients of heart transplantation. Here we report a transplant case diagnosed with pancreatic cancer 4 years and 8 months after the heart transplantation. We changed the immunosuppressive regimen after the malignancy was detected, and administered everolimus along with chemotherapy using S-1, an oral fluoropyrimidine prodrug. The patient lived for 8 months after the diagnosis, and received metallic stenting for the biliary and duodenal obstruction. Also, to the best of our knowledge, this is the first report about chemotherapy and endoscopic intervention for pancreatic cancer in a heart transplantation patient.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Cholestasis, Extrahepatic; Combined Modality Therapy; Drug Combinations; Drug Therapy, Combination; Duodenal Obstruction; Everolimus; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Ischemia; Neoplasm Staging; Oxonic Acid; Pancreatic Neoplasms; Postoperative Complications; Sirolimus; Stents; Tegafur

While, theoretically, a drug-eluting stent (DES) with a biodegradable polymer should reduce the incidence of late in-stent thrombosis, this has not been experimentally tested.. This study compared long-term manifestations of the Excel DES, with a biodegradable polymer, to the Endeavor DES, with a biocompatible polymer, in the same individuals.. Forty-eight patients underwent simultaneous implantation of 1 or more Endeavor stents and 1 or more Excel stents, during the same procedure, and were evaluated with coronary angiography and intravascular ultrasound (IVUS) at least 1 year postprocedure. Within-patient comparisons were made between the Excel- and Endeavor-stented segments for efficacy and safety.. A total of 131 stents (69 Endeavor stents and 62 Excel stents) were implanted in 98 lesions among 48 patients. Baseline characteristics of the lesions in the two stented segments groups were comparable. Average follow-up duration was 14.3 ± 2.5 months. In-stent late luminal loss and luminal stenosis were higher in Endeavor-stented segments than in Excel-stented segments (P<.01). The binary restenosis rate was slightly higher in Endeavor-stented segments (4.3% vs. 1.6%; P=.379). In-stent thrombosis, late incomplete stent apposition, and uncovered stent struts were higher in Excel-stented segments than in Endeavor-stented segments (P<.01). There was 1 case of an in-stent coronary aneurysm with an Excel-stented segment. Four segments, in 4 cases (2 in each stent group), required target lesion revascularization.. This study suggested that, compared to DESs with a biocompatible polymer, DESs with biodegradable polymer do not appear to present an advantage for long-term safety.

Topics: Aged; Antibiotics, Antineoplastic; Biocompatible Materials; Comparative Effectiveness Research; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Polymers; Postoperative Complications; Sirolimus; Treatment Outcome; Ultrasonography, Interventional

The goal of this study was to compare the outcomes of patients treated with everolimus-eluting stents (EES) with outcomes of patients treated with first-generation paclitaxel-eluting stents (PES) for unprotected left main disease (ULMD).. No data exist about the comparison of these 2 types of stents in ULMD.. The primary endpoint of the study was a 1-year composite of cardiac death, nonfatal myocardial infarction, target vessel revascularization, and stroke (MACE). Secondary endpoints were 1-year target vessel failure (TVF) and 9-month angiographic in-segment restenosis >50%.. From 2004 to 2010, a total of 390 patients underwent ULMD percutaneous coronary intervention (224 received PES and 166 EES). The 1-year MACE rate was 21.9% in the PES group and 10.2% in the EES group (p = 0.002). TVF rate was 20.5% in the PES group and 7.8% in the EES group (p < 0.001). The in-segment restenosis rate was 5.2% in the EES group and 15.6% in the PES group (p = 0.002). EES and EuroSCORE were the only variables related to the risk of MACE. EES (odds ratio: 0.32; p = 0.007) was also independently related to the risk of restenosis.. EES implantation for ULMD is associated with a reduced incidence of 1-year MACE, TVF, and restenosis as compared with PES implantation.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Death; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Paclitaxel; Percutaneous Coronary Intervention; Postoperative Complications; Registries; Sirolimus; Treatment Outcome

Everolimus is a derivative of sirolimus, and is considered to be free of the latter's pulmonary toxicity. Recently, a few cases of everolimus-induced lung injury have been reported. Early recognition of drug-induced lung disease is important because it can be reversed if appropriate therapy is instituted soon after the onset of symptoms.. We present the case of an everolimus-induced pneumonitis in a renal transplant recipient, which occurred as early as on the 5th day after everolimus introduction. Shortly after the transplant procedure, the patient presented with typical symptoms of pulmonary infection. Chest radiography and computed tomography showed bilateral patchy lung infiltrates with peribronchial distribution that were suggestive of bacterial pneumonia. However, there was no improvement with empiric antibiotic treatment. Repeated cultures from the blood, sputum, and broncho-alveolar lavage (BAL) also were negative. Tuberculosis, Pneumocystis jiroveci, and Cytomegalovirus infections were excluded. A transbronchial lung biopsy performed 9 days after the onset of symptoms revealed mild nonspecific inflammation with a fibrotic component in the bronchial walls. Withdrawal of everolimus on the third day of hospitalization and after 8 days of its usage resulted in quick clinical recovery and resolution of radiological abnormalities within 1 month.. Diagnosis of drug-induced pulmonary toxicity is difficult because it is essentially a diagnosis of exclusion. Lack of response to empiric antibiotic treatment and an imaging pattern of organizing pneumonia should raise suspicion of everolimus-induced pneumonitis in patients undergoing therapy with this drug.

Topics: Adult; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Pneumonia; Postoperative Complications; Sirolimus

Topics: Aged, 80 and over; Constriction, Pathologic; Coronary Angiography; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Mammary Arteries; Postoperative Complications; Saphenous Vein; Sirolimus; Tomography, X-Ray Computed; Vascular Diseases; Vascular Grafting

Topics: Angioplasty; Clinical Trials as Topic; Coronary Artery Bypass; Coronary Disease; Coronary Restenosis; Drug-Eluting Stents; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Meta-Analysis as Topic; Paclitaxel; Postoperative Complications; Randomized Controlled Trials as Topic; Saphenous Vein; Sirolimus; Stents; Treatment Outcome

Our purpose was to investigate the clinical outcomes of Zotarolimus- and Paclitaxel-eluting stents in Turkish patients with coronary artery disease (CAD). In general, the outcome of drug-eluting stent (DES) placement has a proven efficacy in randomized trials. However, the difference in efficacy between the Zotarolimus and Paclitaxel-eluting stents in unselected Turkish patients is controversial. Therefore, we investigated the clinical outcomes of these two drug-eluting stents in the real-world.. We created a registry and prospectively analyzed data on a consecutive series of all patients who presented to our institution with symptomatic coronary artery disease between February 2005 and March 2007 and who were treated with the zotarolimus- or the paclitaxel-eluting stent. The follow-up period was approximately two years. The primary end-point was major cardiac events, and the secondary end-point was definite stent thrombosis. Informed consent was obtained from all subjects, and the study protocol was approved by the local ethical committee.. In total, 217 patients were treated with either the zotarolimus-eluting stent (n = 116) or the paclitaxel-eluting stent (n = 101). The lesions in the 2 arms of the study were treated similarly by conventional technique. At 24-month follow-up the paclitaxel-eluting stent group showed significantly higher non-Q wave myocardial infarction (2.6% vs 5.9%, p: 0.02), Q wave myocardial infarction (1.7% vs 5.9%, p: 0.049), coronary artery binding graft surgery (2.6% vs 6.9%, p: 0.002), and late stent thrombosis (1.7% vs 3.9%, p: 0.046).. Zotarolimus-eluting stents demonstrated better clinical outcomes than Paclitaxel-eluting stents in a daily routine practice of coronary intervention in an unselected Turkish population.

Topics: Aged; Cardiovascular Agents; Coronary Artery Disease; Drug-Eluting Stents; Follow-Up Studies; Humans; Middle Aged; Paclitaxel; Patient Selection; Postoperative Complications; Prospective Studies; Random Allocation; Registries; Retrospective Studies; Sirolimus; Thrombosis; Time Factors; Treatment Outcome; Turkey

Post-transplant haemolytic uraemic syndrome (HUS) is a rare but serious disease with a high mortality rate, when left untreated. Immunosuppressive drugs like calcineurin inhibitors as well as mammalian target of rapamycin inhibitors have been reported as causative agents for post-transplant HUS.. A retrospective observational study was performed in lung transplant recipients, who took part in an interventional study, in two centres. Haemoglobin, platelets, creatinine and lactate dehydrogenase levels were monitored during routine follow-up and patients with deteriorating kidney function were screened for post-transplant HUS. All cases of post-transplant HUS were identified by clinical and laboratory findings. Outcome was recorded until 6 months after diagnosis.. A total of 2188 visits in 512 lung transplant recipients (outpatients) were analysed. Out of those, 126 patients took part in an interventional study. In this study, 67 were switched to everolimus in combination with calcineurin inhibitors 4 weeks after transplantation, 59 patients remained on standard immunosuppression (calcineurin inhibitors, mycophenolate mofetil and prednisolone). Five cases of post-transplant HUS were identified in the everolimus group. None of the patients had evidence of gastrointestinal infection or preexisting renal disease. Post-transplant HUS was treated with therapeutic plasma exchange and methylprednisolone pulse therapy. Everolimus was discontinued in all five patients. This treatment regimen led to normalization of haemoglobin, platelets and improved renal function. Two patients developed end-stage renal failure and were maintained on haemodialysis. One patient died due to multiorgan failure. Improvement of renal function was seen in two patients. No further cases were recorded in patients without everolimus during the study period.. Our data should raise the awareness of post-transplant HUS in lung transplant recipients. Post-transplant HUS is a rare disease, but it is a serious cause of acute renal failure in lung transplant recipients treated with a combination of everolimus and calcineurin inhibitors.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Everolimus; Female; Follow-Up Studies; Graft Rejection; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Lung Diseases; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Retrospective Studies; Sirolimus; Survival Rate

Malignancies and opportunistic infections are frequently observed after solid-organ transplantation. Their occurrence strongly affects recipient survival. We report the case of a 29-year-old Tunisian kidney-recipient who was diagnosed simultaneously with post-transplant lymphoproliferative disease (PTLD) and visceral leishmaniasis (VL). Withdrawal of immunosuppressive therapy together with antiparasitic treatment using liposomal amphotericin B, and anti-CD20 antibodies medication resulted in cure of leishmaniasis and remission from PTLD. This case is of clinical interest because of the uncommon association of VL with PTLD after solid organ transplantation. It is also original by the favourable outcome of VL and PTLD, both known as life-threatening diseases. Also, it illustrates the predisposing role of immunosuppressive therapy in occurrence of opportunistic infections and malignancies after solid organ transplantation.

Topics: Adult; Amphotericin B; Antibodies, Monoclonal, Murine-Derived; Antiprotozoal Agents; Antiviral Agents; Epstein-Barr Virus Infections; Ganciclovir; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Leishmaniasis, Visceral; Lymphoproliferative Disorders; Male; Meglumine; Meglumine Antimoniate; Opportunistic Infections; Organometallic Compounds; Postoperative Complications; Remission Induction; Rituximab; Sirolimus

To investigate the safety and efficacy of everolimus-eluting stents (EES) in a real world population, including those with high-risk characteristics and complex lesions.. In this report, we analyze 2-year outcomes in 500 consecutive unselected patients treated with EES between April 2007 and March 2008. All patients were followed for 2 years for adverse events.. There were 995 EES deployed in 792 lesions. The indication for the coronary procedure was acute coronary syndrome in 94.2% of patients. Bifurcations were involved in 21% of lesions, 3.5% degenerated vein grafts, 2.7% left main stem stenoses, 33% multivessel disease, 4.5% in-stent restenosis, and 79.1% AHA/ACC classification B2/C lesions. The major adverse cardiac event rate (composite of cardiovascular death, acute myocardial infarction, target lesion revascularization) was 10.6%. Target lesion revascularization was required in 4.0% patients, 1.4% for in-stent thrombosis. These event rates are comparable with studies involving lower risk patients and less complex coronary lesions.. The use of EES, even in this real world, high-risk population, continues to demonstrate safety and efficacy rates comparable with current studies in more selected patient groups and, therefore, may justify current practice to utilize EES in "off label" situations.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Drug-Eluting Stents; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Medical Audit; Middle Aged; New Zealand; Postoperative Complications; Sirolimus; Treatment Outcome

Topics: Bile Duct Diseases; Biopsy; Constriction, Pathologic; Cyclosporine; Humans; Liver; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Sarcoidosis; Sarcoidosis, Pulmonary; Sirolimus; Time Factors; Treatment Outcome

Drug-eluting stents (DES) reduce the need for repeat target revascularization (TVR) compared with bare metal stents (BMS) but are more costly. The objective was to evaluate the cost-effectiveness of DES versus BMS.. We evaluated clinical outcomes and costs of care over 3 years in 1147 undergoing BMS before the availability of DES and 1247 DES patients at Wake Forest University Baptist Medical Center from 2002 to 2005. Costs for index stenting, TVR, and clopidogrel use were assessed. The 2 groups were well matched for baseline characteristics. Index stenting costs were $1846 higher per patient for DES versus BMS ($1737 more to $1950 more). At 3 years, absolute TVR rates were 15.2 per 100 DES patients and 24.1 per 100 BMS patients, and as a result, cumulative TVR-related costs were $2065 less per patient for DES versus BMS ($3001 less to $1134 less). Including the cost of clopidogrel, the incremental cost-effectiveness ratio per TVR avoided with DES was $4731 through 1 year, $4703 through 2 years, and $6379 through 3 years.. At 3 years, the higher index cost of DES versus BMS was completely offset by lower TVR-related costs. However, because of extended clopidogrel use for DES, the incremental cost-effectiveness ratio per TVR avoided ranged from $4703 to $6379 over 3 years. These unadjusted observational findings provide support for the continued use of DES in routine practice but highlight the important impact of prolonged dual antiplatelet use on the cost-effectiveness of this technology.

Topics: Acute Coronary Syndrome; Aged; Blood Vessel Prosthesis Implantation; Coronary Restenosis; Cost-Benefit Analysis; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Paclitaxel; Postoperative Complications; Sirolimus

Although stent fracture (SF) after sirolimus-eluting stent (SES) implantation has been recognized as one of the predisposing factors of in-stent restenosis, it remains uncertain whether SF can increase the risk of major adverse cardiac events (MACE), especially beyond 1 year after SES implantation. The aim of this study was to assess the impact of SF relative to non-SF on 4-year clinical outcomes after treatment with SES of comparable unselected lesions.. A total of 874 lesions in 793 patients undergoing SES implantation and subsequent angiography 6 to 9 months after index procedure were analyzed. At 6- to 9-month angiographic follow-up, SF was identified in 70 of 874 lesions (8.0%). In-stent late loss was significantly higher in SF lesions versus non-SF lesions (0.42±0.59 mm versus 0.13±0.49 mm, P<0.001), resulting in a significantly higher in-stent restenosis rate (21.4% versus 4.1%, P<0.001). At 4 years, SF versus non-SF was associated with a significantly higher MACE rate (23.2% versus 12.6%, P=0.014), mainly driven by significantly higher target-lesion revascularization (18.8% versus 10.2%, P=0.029) rate. Adverse effects of SF on clinical outcomes occurred mostly within the first year (17.4% versus 6.6%, P=0.001), with similar MACE rate between 1 and 4 years (5.8% versus 5.9%, P=0.611). No significant differences between SF versus non-SF patients were observed in the cumulative frequency of very late stent thrombosis (2.9% versus 1.4%, P=0.281), death (0% versus 2.1%, P=0.252), or myocardial infarction (5.8% versus 2.9%, P=0.165).. SF of SES was associated with higher MACE rate up to 1 year, mainly driven by higher target-lesion revascularization, whereas no significant association was evident between years 1 and 4.

Topics: Aged; Blood Vessel Prosthesis Implantation; Coronary Restenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Postoperative Complications; Prosthesis Failure; Risk Factors; Sirolimus; Treatment Outcome

Dermatological complications, especially skin infections, are very common following organ transplantation, and result in a lot of distress in the recipient. Herpes zoster, herpes simplex, and human papillomavirus infections are common infections in kidney transplant recipients, and therapeutic management is usually disappointing in immunosuppression state. We report here 2 cases of kidney transplant recipients who developed diffuse human papillomavirus-induced cutaneous warts with no response to conventional treatments. According to similar reports in organ transplant recipients, we modified the immunosuppressive regimen by converting to sirolimus, which led to a rapid relief from cutaneous warts in both patients. This evidence along with other case reports suggest that conversion to sirolimus may be considered as an effective strategy in cases of giant or multiple viral warts in kidney and perhaps other transplant recipients.

Topics: Adolescent; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Sirolimus; Skin Diseases; Warts; Young Adult

Drug-coated balloons are rapidly emerging as a therapeutic alternative for the interventional treatment of peripheral vascular disease. The purpose of this study was to test the hypothesis that an angioplasty balloon coated with the mTOR inhibitor zotarolimus (ZCB) would inhibit neointimal hyperplasia in a novel injury-based superficial femoral artery model in the familial hypercholesterolemic swine.. A total of 44 familial hypercholesterolemic swine were included (12 designated to study tissue pharmacokinetics and 32 to study safety and efficacy). Fogarty balloon denudation was performed in all superficial femoral artery segments, followed by balloon angioplasty. In the pharmacokinetic study, a total of 24 ZCBs (300 μg/cm(2)) were used. Zotarolimus was detected in arterial tissue at 5 minutes (162 ng/mg of tissue), 24 hours (5.9 ng/mg of tissue), and 28 days (0.007 ng/mg of tissue) after ZCB inflation. In the safety and efficacy study, superficial femoral artery segments were randomized to either high-dose (600 μg/cm(2), n=16), low-dose (300 μg/cm(2), n=16), or paired uncoated balloons (high-dose ZCB control, n=16; low-dose ZCB control, n=16). At 28 days, the percentage of angiographic stenosis was similar among all tested groups. Histological analysis demonstrated a reduction in neointimal formation in both ZCB groups compared with controls (high-dose ZCB 44% reduction, P=0.007; low-dose ZCB 22% reduction, P=0.08). There was no evidence of delayed arterial healing or vascular toxicity in any of the ZCB groups.. The single delivery of zotarolimus via coated balloon is feasible, and therapeutic levels are maintained up to 28 days. The ZCB technology appears to be effective in the reduction of neointimal proliferation in the superficial femoral artery of the familial hypercholesterolemic swine.

Topics: Angioplasty, Balloon; Animals; Catheterization; Clinical Protocols; Femoral Artery; Humans; Hyperlipoproteinemia Type II; Infusion Pumps, Implantable; Models, Animal; Neointima; Postoperative Complications; Radiography; Sirolimus; Swine; TOR Serine-Threonine Kinases

Many studies collect multiple outcomes to characterize treatment effectiveness or evaluate risk factors. These outcomes tend to be correlated because they are measuring related quantities in the same individuals, but the common approach used by researchers is to ignore this correlation and analyze each outcome separately. There may be advantages to consider the simultaneous analysis of the outcomes using multivariate methods. Although the joint analysis of outcomes measured in the same scale (commensurate outcomes) can be undertaken with standard statistical methods, outcomes measured in different scales (noncommensurate outcomes), such as mixed binary and continuous outcomes, present more difficult challenges. In this article, we contrast some statistical approaches to analyze noncommensurate multiple outcomes. We discuss the advantages of a multivariate method for the analysis of noncommensurate outcomes, including situations of missing data. A real data example from a clinical trial, comparing bare-metal with sirolimus-eluting stents, is used to illustrate the differences between the statistical approaches.

Topics: Adult; Aged; Biometry; Blood Vessel Prosthesis Implantation; Cardiovascular Diseases; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; Treatment Outcome

Topics: Everolimus; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Pneumonia; Postoperative Complications; Sirolimus

Topics: Antibiotics, Antineoplastic; Blood Vessel Prosthesis Implantation; Coronary Restenosis; Humans; Postoperative Complications; Sirolimus

We describe a 66-year-old woman with aortitis syndrome, successfully treated with percutaneous coronary intervention using sirolimus-eluting stent (SES) for ostial stenosis of left main coronary artery after Bentall operation. At one-year follow-up, she had no evidence of restenosis and no clinical events. Stent implantation with SES may be useful for ostial left main coronary stenosis after Bentall operation in selected patients with aortitis syndrome.

Topics: Aged; Coronary Angiography; Coronary Stenosis; Drug-Eluting Stents; Female; Humans; Postoperative Complications; Prosthesis Implantation; Sirolimus; Takayasu Arteritis

The ability of supplemental islet infusions (SII) to restore insulin independence in islet transplant recipients with graft dysfunction has been attributed to the coadministration of exenatide. However, improving islet transplant outcomes could explain the success of SII. We aimed to determine the effect on islet graft function and insulin independence of SII using these new protocols, without the use of exenatide.. Seventeen islet transplant recipients underwent SIIs after developing graft dysfunction requiring insulin use. For induction therapy, four subjects received daclizumab induction therapy, whereas 13 subjects received thymoglobulin and etanercept. Maintenance immunosuppression consisted of sirolimus+tacrolimus or tacrolimus+cellcept.. SII was performed 49.3+/-4.8 months (mean+/-SEM) after the preceding islet transplant. Subjects received significantly lower islet mass with their SII compared with initial transplant(s) (6076+/-492 vs. 9071+/-796 IEQ/kg; P=0.003). Fifteen of the 17 subjects (88.2%) became insulin independent 2.4+/-0.5 months after SII. Insulin-independent duration after SII exceeded that of the initial transplant(s) (24.8+/-2.2 vs. 14.2+/-2.6 months by Kaplan-Meier analysis, P=0.009). Subjects show improved glycemic control after SII (HbA1c 7.0%+/-0.2% pre-SII vs. 6.1%+/-0.2% post-SII, P=0.005) and did not become immunosensitized.. Using current protocols, SII in the absence of exenatide results in impressive insulin-independence rates and the durability of insulin independence seems to be promising. However, a beneficial effect of exenatide should not be discounted until tested in randomized controlled studies.

Topics: Antilymphocyte Serum; Blood Glucose; C-Peptide; Drug Therapy, Combination; Etanercept; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Immunoglobulin G; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Male; Postoperative Complications; Receptors, Tumor Necrosis Factor; Sirolimus; Tacrolimus

Posttransplant diabetes mellitus (PTDM) is considered to be a serious complication of kidney transplantation that may reduce patient and graft survival. The immunosuppressant tacrolimus (TAC) increases the risk of developing PTDM.. We sought to estimate the risk of PTDM among renal transplant recipients treated with TAC, to identify other risk factors for PTDM, and to describe its consequences.. We retrospectively analyzed 413 recipients of ages >or=18 years who were free of diabetes before kidney transplantation. They were treated with TAC, cyclosporine (CyA), or sirolimus (SIR) plus steroid therapy with a minimum follow-up posttransplant of 6 months. PTDM was diagnosed according to American Diabetes Association guidelines.. The mean age was 42.3 years and 230 (55.7%) were male. The initial immunosuppression for 171 (41.4%) patients was TAC; 221 (53.5%), CyA; and 21 (5.1%), SIR. PTDM occurred in 85/413 (20.6%) of patients. The median time to PTDM development was 54 days posttransplant. The cumulative incidence of PTDM was 24.6% and 17.2% for TAC and CyA treatment groups, respectively. In the intention-to-treat analysis, the proportion of patients receiving TAC who developed PTDM was significantly higher than that of CyA (HR = 1.6 [1.01-2.42]; P = .04). The Kaplan-Meier method showed that 78.5% patients taking TAC were free of PTDM at 6 months compared with 88.8% taking CyA (P = .003). The other independent risk factors were body mass index (BMI; P < .0001); recipient age (P < .0001) and acute rejection episodes (AE; P = .01). Three-year actuarial graft survivals were 85.5% for PTDM patients compared with 93.3% for those without diabetes (P = .021); patient survivals, 88.9% and 96.7%, respectively (P = .017).. The incidence of PTDM is associated with TAC use, recipient age, BMI, and ARE. Therefore, PTDM is an important risk factor for graft loss and mortality.

Topics: Adolescent; Adult; Body Mass Index; Cyclosporine; Diabetes Mellitus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Living Donors; Male; Postoperative Complications; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Tissue Donors

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Bronchoalveolar Lavage Fluid; Diagnosis, Differential; Diarrhea; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Metronidazole; Mycophenolic Acid; Pneumonia; Pneumonia, Bacterial; Pneumonia, Viral; Postoperative Complications; Sirolimus; Tacrolimus; Tomography, X-Ray Computed

Hepatotoxicity, including cholestasis, is a rare but significant complication of treatment with calcineurin inhibitors. Timely life-saving therapy with revision of immunosuppression is mandatory. A 43-year-old woman with pulmonary hypertension was found to have severe cholestasis (serum bilirubin up to 35 mg/dL) after a living-donor lobar lung transplantation. Calcineurin-inhibitor cholestasis markedly improved after withdrawal of the calcineurin inhibitor, initiation of sirolimus, and interleukin-2 receptor blockade. Awareness of the diagnostic criteria of this rare posttransplant complication is important to initiate timely therapy.

Topics: Adult; Calcineurin; Calcineurin Inhibitors; Cholestasis; Disease Progression; Fatal Outcome; Female; Graft Rejection; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Living Donors; Lung Transplantation; Methylprednisolone; Pneumonia, Bacterial; Postoperative Complications; Pseudomonas Infections; Risk Assessment; Sirolimus; Tacrolimus; Transplantation Immunology

Cardiovascular disease (CVD) is the main cause of morbidity and mortality in renal transplant recipients. The incidence of CVD in this setting is approximately 5-fold greater than in age- and and gender-matched subjects. This excess cardiovascular risk is not completely explained by traditional cardiac risk factors. It has been well documented that these patients show greatly increased prevalence of both fasting and postmethionine-loading hyperhomocysteinemia (hHcy) compared with the general population. An immunosuppressive therapy based on everolimus has been demonstrated to reduce the incidence major adverse coronary events at 4 years compared with azathioprine among heart transplant recipients. In contrast, scarce data are available on the impact of everolimus on emerging risk factors, such as homocysteine (Hcy), in renal transplant recipients. The aim of this study was to evaluate the possible impact of everolimus compared with other immunosuppressive regimes among 132 stable recipients, including 91 men and 41 women who were at least 1 year after transplant with stable renal function and no clinical evidence of acute or chronic renal graft rejections. We compared 31 subjects on everolimus immunosuppressive therapy (group A) versus 101 on immunosuppressive therapy based on cyclosporine, steroids, and mycophenolate. The Hcy levels were significantly lower among group A patients compared with group B: 16.5 +/- 5 micromol/L vs 21.2 +/- 11 micromol/L; P < .005. Hyper-Hcy, defined as Hcy levels >15 micromol/L, was diagnosed in 18 out of 31 patients (51%) of group A and in 82 out of 101 patients (81%) of group B. This preliminary study demonstrates a favorable impact of everolimus on a marker of atherothrombosis which is associated with a worse vascular prognosis.

Topics: Cardiovascular Diseases; Drug Therapy, Combination; Everolimus; Female; Homocysteine; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Sirolimus

A 70-year-old male underwent the implantation of sirolimus-eluting stent at our hospital for total occlusion of the right coronary artery, which had caused acute myocardial infarction. Off-pump coronary artery bypass grafting (OPCAB) was performed for residual stenosis of the left anterior descending artery and the diagonal branch 10 days later. Though the operation was successfully performed, acute myocardial infarction recurred in the early postoperative period. Emergency coronary angiography showed subacute thrombotic occulusion of the drug eluting stent (DES). Percutaneous catheter intervention restored the stent patency. Attention should be paid to subacute thrombosis (SAT) in cases with the history of DES implantation.

Topics: Aged; Coronary Artery Bypass, Off-Pump; Coronary Thrombosis; Drug-Eluting Stents; Humans; Male; Myocardial Infarction; Postoperative Complications; Sirolimus

Reactivation of latent BK polyomavirus (BKV) infection is relatively common following renal transplantation and BKV-associated nephropathy has emerged as a significant complication. JC polyomavirus (JCV) reactivation is less well studied. The aim of the study was to determine reactivation patterns for these polyomaviruses in renal transplant recipients using an in-house quantitative real-time multiplex PCR assay and IgG serological assays using recombinant BK and JC virus-like particles.. Retrospective analysis of urine and plasma samples collected from 30 renal transplant patients from February 2004 to May 2005 at Leeds Teaching Hospitals NHS Trust. Samples were collected at 5 days and thereafter at 1, 3, 6 and 12 months post-transplantation.. Eight patients (26.7%) were positive for BK viruria; three of these patients submitted plasma samples and two had BK viraemia. Five patients (16.7%) were positive for JC viruria. A corresponding rise in BKV and JCV antibody titres was seen in association with high levels of viruria.. Different patterns of reactivation were observed: BK viruria was detected after 3-6 months, and JC viruria was observed as early as 5 days post-transplantation. One patient had biopsy-proven BKV nephropathy. No dual infections were seen. In order to ensure better graft survival, early diagnosis of these polyomaviruses is desirable.

Topics: Adult; Aged; Antibodies, Viral; BK Virus; Female; Humans; Immunosuppressive Agents; JC Virus; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polymerase Chain Reaction; Polyomavirus Infections; Postoperative Care; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Tumor Virus Infections; Viral Load; Virus Activation

To review our experience with SRL as a second-line therapy in our series of 45 SBTx recipients (1997-2009). Retrospective review of five children converted to SRL: 3 M/2 F; median of three yr old (range 20 months-18 yr); rescue indications, adverse events with SRL, resolution of tacrolimus-related side effects, incidence of rejection, PTLD, or GVHD were summarized. Tacrolimus was discontinued (average 13 months after transplant) because of refractory hemolytic anemia in four patients with decreased renal function and because of advanced renal failure and unclear neutropenia in one. PTLD and GVHD had been previously diagnosed in two. Tacrolimus-related side effects disappeared in all five although other immunosuppressants and splenectomy were used simultaneously or later in most of them. Adverse events reported after the conversion were infections (tuberculosis and Pneumocystis carinii in two) and mild hypertriglyceridemia. No rejection, GVHD, or PTLD episode was observed. Four patients are alive with excellent quality of life (median follow-up 18 months). Sirolimus is a safe rescue therapy in SBTx children when tacrolimus is not well tolerated. Renal function and hematologic disorders seem to improve, although other simultaneous strategies could be also involved. Further studies could demonstrate its efficacy as a first-line treatment.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Intestines; Male; Organ Transplantation; Pediatrics; Postoperative Complications; Sirolimus; Treatment Outcome

Topics: Graft Rejection; Humans; Immunosuppressive Agents; Organ Transplantation; Postoperative Complications; Risk Factors; Sirolimus; Skin Neoplasms

Posterior capsular opacification (PCO) is caused by the proliferation and migration of residual lens epithelium cells (LECs) after extracapsular cataract extraction (ECCE). Rapamcin (RAPA) is known to be a potent immunosuppressive drug with anti-inflammatory and anti-proliferative effects. The aim of this study was to investigate the safety and efficacy of rapamycin sustained release from modified intraocular lens (IOLs) in the prevention of PCO in rabbits.. Three types of IOLs were used, including the original IOL without modification, IOL with polylactide-glycoli acid (PLGA) coating (PLGA-IOL), and RAPA-loaded PLGA-IOL (RAPA-PLGA-IOL). Sixty New Zealand albino rabbits undergoing phacoemulsification in left eyes were randomly and equally divided into three groups. Group A was implanted with the original IOLs, group B was implanted with the PLGA-IOLs, and group C was implanted with the RAPA-PLGA-IOLs. All of the 60 treated left eyes were examined by a slit-lamp microscope. The concentrations of RAPA in the aqueous humor and blood were determined by high-performance liquid chromatography (HPLC), indicating an vivo release of drug from the polymer carrier. Anterior segment tissue was histologically examined, and wet posterior capsules were weighed. Six months after intervention the PCO was graded.. The mean concentrations of RAPA in the aqueous humor from group C at 2 h, 1 days, 3 days, and 7 days after operation were 12.81 +/- 1.27 microg/ml, 14.57 +/- 0.99 microg/ml, 6.39 +/- 0.95 microg/ml, and 1.10 +/- 0.32 microg /ml respectively. The concentrations of RAPA in blood were undetectable. During the early days after the operation, the reactions of the anterior chamber from groups A and B were more severe than from group C. Our findings showed that the initial appearance of PCO in group C was much later than in the other two groups. The wet posterior capsules were weighed to be 0.3735 +/- 0.0943 g (group A), 0.3754 +/- 0.1093 g (group B), and 0.0432 +/- 0.0089 g (group C). Histological observation showed a similar phenomenon, that there was remarkably less accumulation of lens materials on the posterior capsules in group C than in the other two groups.. Our findings suggest that the designed RAPA-PLGA-IOL effectively prevented formation and development of PCO for a relatively long duration.

Topics: Animals; Aqueous Humor; Cataract; Cell Proliferation; Chromatography, High Pressure Liquid; Coated Materials, Biocompatible; Drug Carriers; Epithelial Cells; Immunosuppressive Agents; Lactic Acid; Lens Capsule, Crystalline; Lens Implantation, Intraocular; Lenses, Intraocular; Phacoemulsification; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Postoperative Complications; Rabbits; Sirolimus

Pulmonary lymphangioleiomyomatosis is a rare disease that generally progresses to respiratory failure. We experienced a patient who had recurring lymphangioleiomyomatosis in the transplanted lungs. A chest computed tomographic scan showed a progressing emphysematous change. The patient had a subclinical extent of pan-circumferential stricture at the distal site of the left bronchial anastomosis. We treated the patient with sirolimus for three years. Chest computed tomography showed no sign of exacerbation during the late 3 years, whereas pulmonary function test revealed a slight increase after the use of sirolimus. Bronchial stricture also disappeared almost completely. This is the first reported case with sirolimus treatment for post-transplant recurrent lymphangioleiomyomatosis.

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Living Donors; Long-Term Care; Lung Neoplasms; Lung Transplantation; Lymphangioleiomyomatosis; Postoperative Complications; Recurrence; Respiratory Function Tests; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

De novo posttransplant thrombotic microangiopathy (TMA) is a complication of solid organ transplantation, which remains difficult to treat. In many cases, immunosuppressants and particularly calcineurin inhibitors, trigger TMA. Although withdrawing the offending drug may lead to resolution of TMA, graft and patient outcomes are poor. Specific treatments, including plasma exchange, have not gained widespread acceptance in those with fulminant disease and new approaches to the condition are urgently needed. We report a case of posttransplant de novo TMA presenting serially in association with ciclosporin, tacrolimus and sirolimus in a young recipient of a living donor kidney transplant. We describe a patient treated with belatacept, a novel CTLA4 Ig fusion protein, as ongoing maintenance immunosuppression to allow avoidance of conventional agents once associated with TMA. We report excellent early graft outcome, with no adverse events using this strategy. We suggest that belatacept may have a role in this traditionally difficult-to-treat group of patients.

Topics: Abatacept; Adult; Cyclosporine; Female; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Sirolimus; Tacrolimus; Thrombosis; Tumor Necrosis Factor-alpha

The aim of this study was to analyze, in heart transplant patients, if renal function improvement after cyclosporine replacement by everolimus persists at the middle term and its predictors. We studied prospectively 56 patients in whom conversion was consecutively made. Forty-five patients completed the follow-up period. Significant improvement was observed at 6 and 12 months in plasma creatinine levels (1.92+/-0.7 vs. 1.67+/-0.6 and 1.69+/-0.6 mg/dL; P=0.047) and glomerular filtration rate (43.9+/-17 vs. 52.5+/-23 and 51.3+/-22.3 mL/min; P=0.004). Glomerular filtration rate increased in 32 patients (71%). Baseline characteristics comparison showed a lower percentage of patients with smoking history and new onset diabetes in responders group, but only previous smoking was shown as independent factor (Exp B: 0.083; 95% confidence interval: 0.010-0.793; P=0.024). No differences regarding age, gender, body mass index, disease leading to transplantation, time between transplantation and replacement, cardiovascular risk factors, lipid levels, and hematologic parameters were found.

Topics: Diabetes Mellitus; Disease Progression; Everolimus; Follow-Up Studies; Glomerular Filtration Rate; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Postoperative Complications; Sirolimus; Smoking

To determine whether sirolimus therapy is associated with neurologic complications, including stroke, among heart transplant recipients.. We retrospectively studied patients who underwent heart transplant at Mayo Clinic's site in Rochester, MN, from January 1, 1988, through June 30, 2006.. Of 313 patients in the cohort, the medical regimen in 116 patients (37%) was switched from cyclosporine-based therapy to sirolimus. The hazard ratio of sirolimus for any neurologic or psychiatric event was 1.94 (95% confidence interval, 0.67-4.29). This hazard ratio was driven mainly by the association between sirolimus and the development of tremor and depression. Cerebrovascular events occurred with a cumulative incidence of 14% but did not occur in any of the patients who received sirolimus therapy. There were no cases of posterior reversible encephalopathy syndrome with sirolimus use.. No early or late episodes of major neurotoxicity occurred in heart transplant recipients using sirolimus immunosuppression. The absence of stroke and transient ischemic attacks in these high-risk transplant recipients treated with sirolimus is notable but needs confirmation in future studies.

Topics: Adolescent; Adult; Child; Heart Transplantation; Humans; Immunosuppressive Agents; Middle Aged; Nervous System Diseases; Postoperative Complications; Psychoses, Substance-Induced; Retrospective Studies; Sirolimus

Liver transplantation (OLT) in children has seen significant improvements in recent years. Long-term immunosuppressive strategies have focused on avoiding the risks of long-term immunosuppression, particularly nephrotoxicity, de novo malignancy and late infections. Since its introduction in renal transplantation in 1999, sirolimus (SRL) has been used by an increasing number of liver transplant centers. The aim of this study was to review the experience using SRL in pediatric liver transplant recipients at a single center.. Between 1989 and 2006, 318 children underwent OLT including 13 who were converted to SRL therapy because of tacrolimus-related side effects. The indications were posttransplant lymphoproliferative disease (PTLD; n = 11), nephrotoxicity (n = 1), and de novo autoimmune hepatitis (n = 1). One patient with PTLD previously concurrently displayed chronic rejection. SRL dosages ranged between 0.4 and 5 mg/d. The median duration of follow-up was 18 months.. PTLD recurred in 1 patient. There were no episodes of acute rejection. One child developed hyperlipidemia that resolved with diet and medication.. Conversion from tacrolimus to SRL in selected pediatric liver transplant recipients is safe. Children with PTLD may benefit from immunosuppression with SRL after liver transplantation.

Topics: Adolescent; Cadaver; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Lymphoproliferative Disorders; Male; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Tissue Donors

The new class of immunosuppressants--inhibitors of the mammalian target of rapamycin--has no nephrotoxicity and the capacity to inhibit vascular smooth cell proliferation. These characteristics may afford considerable clinical advantages in the transplantation of kidneys from expanded criteria donors (ECD). Six clinical experiences of the use of sirolimus (SRL) in ECD kidneys recipients have been reported in the literature. Although the results varied somewhat, probably due to differences in the types of deceased donor and in the immunosuppressive regimens used, it seems that a calcineurin inhibitor free, SRL-based protocol can assure a good immunosuppressive effect with less nephrotoxicity and a low incidence of cytomegalovirus infection. For recipients of ECD kidneys at low immunological risk, we would recommend a regimen based on antithymocyte globulin induction and SRL, mycophenolate mofetil, and steroids for maintenance. For strongly responding recipients, we recommend SRL combined with a reduced, 76% to 87% dose of calcineurin inhibitor.

Topics: Aged; Cadaver; Clinical Trials as Topic; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Kidney Transplantation; Medical History Taking; Patient Selection; Postoperative Complications; Sirolimus; Tissue Donors

Nowadays cancer represents the second main cause of death in renal transplant patients with normal function of the graft. The incidence is 10 to 20 times higher than normal population. Calcineurin inhibitor therapy contributes to the increase in the development of neoplasia. Important evidence could bring a preventive effect of mammalian target of rapamycin in skin cancer, Kaposi's sarcoma, and renal cell carcinoma.

Topics: Aged; Calcineurin Inhibitors; Carcinoma, Renal Cell; Cause of Death; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Male; Middle Aged; Neoplasms; Postoperative Complications; Protein Kinases; Risk Factors; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

Immunosuppression favors the development of skin cancer. Experimental data suggest that sirolimus (SRL) has antitumoral and antiangiogenic properties. An investigation was undertaken into the effects of SRL on squamous cell carcinoma (SCC) developing in organ transplant recipients (OTR) receiving immunosuppressive treatments, with special emphasis on vascularization.. SCC that developed in eight OTR before and after conversion from calcineurin inhibitors (CNI) to SRL were compared for thickness, differentiation, ulceration, perineural invasion, density of peritumoral infiltrate, peritumoral vascularization, density of T-regulatory cells and of intratumoral Langerhans cells and growth fraction.. SCC developing under SRL showed lower peritumoral vascularization and thickness, and higher growth fraction and density of peritumoral T-regulatory cells.. Conversion from CNI to SRL at clinically relevant doses is associated in vivo with a reduced vascularization and thickness of post-transplant human cutaneous SCC. This effect could account for the beneficial effect of SRL on immunosuppression-induced skin carcinogenesis in humans.

Topics: Adult; Aged; Angiogenesis Inhibitors; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Cohort Studies; Cyclosporine; Female; Graft Rejection; Heart Transplantation; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neovascularization, Pathologic; Postoperative Complications; Sirolimus; Skin Neoplasms; Treatment Outcome

While conversion of stable renal transplant recipients (RTR) from calcineurin inhibitors (CNI) to sirolimus (SRL) is safe and effective, it is still under investigation for recent, high-risk cases. We studied the long-term effects of conversion of high-risk subjects maintained on a CNI, mycophenolate mofetil, plus steroid regimen to SRL, mycophenolate mofetil, plus steroid on graft and patient outcomes. We retrospectively reviewed the first 100 RTR converted to SRL treatment over approximately 5 years. The main indications for conversion were biopsy-proven acute rejection (BPAR), CNI toxicity, CNI elimination, and acute-tubular necrosis (ATN). Exclusion criteria were limited to bone marrow suppression. The overall mean +/- SD age was 38.5 +/- 15.6 years, including pediatric and geriatric age groups. Mean +/- SD body mass index (BMI) was 28.99 +/- 8.0 and 40% had a BMI > 30. There were 40% RTR from deceased donors and 60% showed 4 to 6 HLA mismatches. Preconversion total BPAR and steroid-resistant rejection incidences were 35% and 14%, respectively. Mean +/- SD time to start of SRL was 11.9 +/- 22.8 months posttransplantation. Proteinuria > 2 g/d, leukopenia, and hyperlipidemia increased significantly after conversion (P = .001, P = .0003, and P = .0001, respectively). Patient and graft survivals were 95% and 90%, respectively. There was significant improvement in graft function postconversion (P < .0001). There was a high incidence of side effects and cases of SRL discontinuation. Multivariate analysis demonstrated the influence of bone marrow suppression, obesity, hyperlipidemia, nutritional status, proteinuria, and graft function on graft and patient outcomes. We concluded that conversion from CNI to SRL was effective among high-risk RTR, but with a high incidence of adverse events during long-term follow-up.

Topics: Adult; Azathioprine; Calcineurin Inhibitors; Creatinine; Diabetes Mellitus; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Intracranial Hypertension; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Sirolimus; Survival Analysis; Young Adult

Post transplant lymphoproliferative disorder (PTLD) is the commonest form of post transplant malignancy in children. The incidence in renal transplant recipients varies between 2%-4%. They are characterized by uncontrolled B lymphocyte proliferation, in most cases driven by Epstein Barr virus (EBV). They are more common in younger children, EBV seronegative patients and those who receive aggressive immunosuppression. PTLD commonly presents in an unspecific form and it requires high suspicion rate for its diagnosis, especially in children with risk factors. We report a twelve year-old girl who developed fever, sore throat and lymph node enlargement, six months after receiving a renal allograft. Laboratory assessment and imaging studies were compatible with PTLD, which was confirmed by biopsy. Treatment was reduction of immunosuppression and surveillance. The patient had a favorable evolution.

Topics: Child; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Sirolimus

New-onset diabetes after transplantation (NODAT) is a frequent complication and has an impact on patient and graft survival. Hypomagnesemia is common in both renal transplant recipients and in diabetics. This study examines the relationship between hypomagnesemia, NODAT and the type of immunosuppression in renal transplant recipients. We conducted a retrospective single-center analysis (2002-2008) in order to assess NODAT the first year posttransplantation as defined by American Diabetes Association criteria. Serum magnesium (Mg) levels were defined as the median of all Mg levels registered during the first month posttransplantation. Patients with NODAT (N = 75; 29.5%) versus non-NODAT had lower Mg levels (p < 0.001). Patients with an Mg level < versus > or = 1.9 mg/dL showed a faster development of NODAT (log-rank p < 0.001). Mg levels were lower in patients on calcineurin inhibitors (CNI) versus no CNI patients (p < 0.001). Mg levels, albumin, BMI, triglycerides, posttransplantation hyperglycemia, tacrolimus levels and the use of sirolimus were predictors of NODAT in the multivariate analysis. Hypomagnesemia was an independent predictor of NODAT in renal transplant recipients. We confirm that the use of CNI is associated with NODAT, but, to a large extent, this effect seems attributable to the induction of hypomagnesemia. After adjustment for Mg, sirolimus was also associated with NODAT.

Topics: Aged; Body Mass Index; Calcineurin Inhibitors; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnesium; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Sirolimus; Tacrolimus; Triglycerides

Chronic kidney disease is common after heart transplantation, and is related to ciclosporin (CsA) therapy. We compared the safety and efficacy of two ciclosporin withdrawal regimens.. CsA was stopped and sirolimus (SRL) commenced immediately and the transfer was covered with prednisolone. Those on azathioprine (AZA) were transferred to MMF. In protocol A, the SRL target concentration was 16 (12-20) ng/ml; in protocol B, the target concentration was 7(5-10) ng/ml, but mycophenolate (MMF) and steroids were commenced prior to the transfer.. Baseline characteristics were similar in both groups except that group B were switched later after transplantation. Renal function improved significantly in both groups; this was maintained up to 1 year. Two patients in group A experienced acute rejection (ISHLT grade 3A or 2R); none was seen in group B. Six patients (46%) remained on protocol A and 22 (85%) remained on protocol B at 1 year.. MMF-SRL substitution resulted in a rapid but partial improvement in renal function; the lower dose SRL regimen was better tolerated.

Topics: Chronic Disease; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Sirolimus

Chronic allograft nephropathy and calcineurin inhibitor toxicity may cause graft loss. After kidney transplantation, especially among those patients with chronic allograft nephropathy, sirolimus may be a good alternative to calcineurin inhibitors. Unlike calcineurin inhibitors, sirolimus is devoid of significant nephrotoxicity, but approximately 30% to 50% of patients on sirolimus therapy display mild or severe adverse effects. We sought to report our experience with sirolimus conversion among patients with chronic allograft nephropathy as well as the mild versus severe adverse effects that limit the drug's use.. We analyzed the outcomes of 88 patients (64 men and 24 women) of overall mean age of 35.9 +/- 9.9 years (range, 21-59 years) who had undergone kidney transplantation. Immunosuppressive therapy had been converted from a calcineurin inhibitor to sirolimus because of biopsy-proven chronic allograft nephropathy, calcineurin inhibitor toxicity, or presence of malignancy. We excluded patients with prior acute rejection episodes. Subjects were divided into two groups with respect to their creatinine levels: Group A < 2 mg/dL and Group B >or= 2 mg/dL. After conversion to sirolimus, possible adverse effects of sirolimus were evaluated at the follow-up inset. Each patient underwent a physical examination, and estimation of serum lipid and electrolyte levels as well as hemoglobin concentration.. At the time of conversion of the 88 renal transplant patients, their mean duration after grafting was 48 +/- 15 months (range, 4-296). The prior treatment consisted of a calcineurin inhibitor, prednisolone, and mycophenolate mofetil. After conversion, the calcineurin inhibitor was stopped and sirolimus was begun. The 48 Group 2 patients (34 men, 14 women) of overall mean posttransplant time of 22.7 +/- 14.6 months who underwent conversion displayed a mean serum creatinine increase to 3.2 +/- 1.4 mg/dL, including 17 subjects who underwent rejection. The 40 Group 1 patients (30 men, 10 women) with a mean overall posttransplant period of 67.6 +/- 49.9 months showed an fall in serum creatinine level to 1.4 +/- 0.5 mg/dL among only 3 patients. While 5/88 patients showed no increase in proteinuria (5.6%); 83 (94.4%) did experience it. Proteinuria increased from a mean of 192 +/- 316 to 449 +/- 422 mg/d. Only three patients displayed heavy proteinuria (>3 g/d); sirolimus was discontinued for this reason. Proteinuria was well controlled in the other patients with angiotensin-converting enzyme and/or angiotensin II receptor inhibitor agents. After sirolimus conversion, serum cholesterol levels increased from 187 +/- 42 to 214 +/- 52 mg/dL, and serum triglyceride levels increased from 161 +/- 61 to 194 +/- 102 mg/dL. All but four patients responded to statin therapy, with serum lipid levels falling to acceptable levels. Another four patients developed unilateral lower extremity edema with sirolimus discontinued for this reason. One patient displayed generalized arthralgia.. Chronic allograft nephropathy or calcineurin inhibitor toxicity can lead to loss of graft kidney function. Calcineurin inhibitor toxicity can lead to chronic allograft nephropathy. Patients with a low baseline serum creatinine level who undergo sirolimus conversion showed stabilized kidney function. Late conversion of patients with a serum creatinine above 2 mg/dL face a risk of graft failure. Sirolimus displayed a limited incidence of serious adverse effects; mild or moderate adverse effects, such as hyperlipidemia and proteinuria, were easily controlled with countermeasure therapy.

Topics: Adult; Calcineurin Inhibitors; Creatinine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Patient Selection; Postoperative Complications; Sirolimus; Transplantation, Homologous; Young Adult

Sirolimus, a macrolide with immunosuppressive properties, was introduced into clinical practice a decade ago. The optimal use of this drug remains controversial: It displays a wide range of organ and tissue toxicities owing to the critical role of its therapeutic site- the kinase mammalian target of rapamycin-in the signal transduction pathways of numerous cytokines, growth factors, hormones, and nutrients. However, it displays unique, recognized benefits for renal transplant recipients: synergistic interactions with cyclosporine and possibly tacrolimus, allowing marked reduction in exposure to the calcineurin inhibitor; reduction in the frequency of posttransplant malignancies, particularly lymphomas, Kaposi sarcomas, and hypernephromas; and modest nephrotoxicity in comparison with calcineurin inhibitors. Because of its inhibitory effects on endothelial and smooth muscle cell proliferation, sirolimus may be a useful tool to dampen chronic vasculo-obliterative processes that attenuate graft survival. With increasing experience with the drug, the true potential of sirolimus will be realized to be a critical element in the immunosuppressive matrix.

Topics: Calcineurin Inhibitors; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Postoperative Complications; Sirolimus; Tacrolimus

Chronic renal dysfunction is a multifactorial and frequent event after organ transplantation. The measurement or the estimation of glomerular filtration rate is essential to detect early progressive renal dysfunction. Proliferation signal inhibitors are nonnephrotoxic immunosuppressive drugs which may be useful to minimize calcineurin inhibitors-related side effects through a conversion strategy. Most studies in the setting of kidney transplantation showed improvement in glomerular filtration rate as high than conversion was early. Proliferation signal inhibitors may be included quickly in new immunosuppressive regimen for liver transplanted patients with chronic renal dysfunction.

Topics: Calcineurin Inhibitors; Cyclosporine; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney Diseases; Kidney Transplantation; Liver Transplantation; Postoperative Complications; Protein Serine-Threonine Kinases; Proteinuria; Renal Insufficiency; Sirolimus; TOR Serine-Threonine Kinases

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

Despite several case reports of sirolimus-eluting stent (SES) fracture and concern regarding restenosis after successful SES implantation, the clinical characteristics of this problem are not well known.. Clinical records and angiographic films of patients who received follow-up coronary angiography between February 2005 and October 2006 were retrospectively analyzed.. Among the 686 SES implanted in 479 patients, 27 fractures were found in 22 (3.2%) stents in 18 patients. All stent fractures occurred in long stented segments, i.e. >/=28 mm (range, 28 mm to 83 mm). Of the 22 fractured stents, sixteen (72.7%) were identified in the right coronary artery (RCA) and fifteen (68.2%) were found to have a fracture site within 10 mm from areas with increased rigidity due to metal overlap. The significant multivariate predictors of stent fracture were the stented length (Odds ratio 1.06; 95% confidence interval 1.04-1.09; p=0.001) and the RCA location (Odds ratio 4.44; 95% confidence interval 1.66-11.86; p=0.003). The binary restenosis rate was 22.7% and target lesion revascularization was performed in two (9.1%) fractured stents.. SES fracture was associated with a long stented segment, RCA location and metal overlap. Stent fracture may be another potential risk factor for restenosis after successful SES implantation.

Topics: Aged; Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Postoperative Complications; Prosthesis Failure; Retrospective Studies; Risk Factors; Sirolimus

Posttransplant lymphoproliferative disorder (PTLD) remains one of the most important complications of intensive immunosuppressive therapy. A 65-year-old Caucasian woman received a primary en bloc kidney transplant from a deceased 2-year-old donor. After antithymocyte globulin induction she was treated with a maintenance regimen including cyclosporine and mycophenylate mofetil (MMF). She had a history of recurrent dermatomyositis, suggesting a flawed immune system. After a benign course for 9 months and after an increase in MMF from 2 to 3 g daily, she presented with pneumonia owing to Candida albicans, which was responsive to antibiotics, as was the PTLD. Persistent fever led to a diagnosis of PTLD. The immunosuppressive regimen was converted to sirolimus (SRL) and rituximab, with over 90% necrosis of the neoplasm at 1 month. However, owing to concern at exploration, the allografts were extirpated. This case documented the benefit of the rituximab-SRL combination to treat PTLD while maintaining dermatomyositis in remission.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Appendectomy; Child, Preschool; Dermatomyositis; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Lymphoproliferative Disorders; Ovariectomy; Postoperative Complications; Rituximab; Sirolimus

Ascites is a rare complication of renal transplantation. Ascites has been reported after kidney transplantation due to rejection, decapsulation of the graft, urinary or vascular leak, lymphocele, transudation, or infection. While technical complications of the procedure are the most frequent cause, portal hypertension and graft rejection are other causes. Ascites can occur after renal transplantation independent of kidney function. Usually, a time relation can be made between the surgical procedure and ascites development. Chylous ascites is still more uncommon; it is usually related to traumatic lymphatic injury. Drugs are rarely associated with the genesis of ascites. Sirolimus has been associated with a high rate of lymphoceles, lymphedema, and pulmonary alveolar proteinosis. The exact mechanisms remain unknown. The risk for lymphocele formation with sirolimus is 12% to 15%. Ascites is an adverse effect with an incidence between 3% and 20%, but no relation between sirolimus and chylous ascites was previously established. We present a clinical report of chylous ascites in a renal transplant patient under sirolimus therapy; our investigation pointed to sirolimus as the cause.

Topics: Adult; Chylous Ascites; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Nephritis, Hereditary; Postoperative Complications; Sirolimus

Post-transplant lymphoproliferative disease (PTLD) can occur in different sites, such as lymph nodes, allograft, and central nervous system. We report a 6-year-old girl with end-stage renal disease secondary to hypoplastic-dysplastic kidneys, who received a kidney transplant. Thirty months post transplant, she developed PTLD in the tongue, an area of muscular tissue only. At that time her peripheral blood Epstein-Barr viral (EBV) load was only 40 copies/10(5) lymphocytes, though the tumor was EB early RNA (EBER) positive. Immunosuppression was reduced with initial improvement in her symptoms. One month later, she returned with abdominal complaints and a contained cecal abscess. The excised cecal tissue revealed CD20 and EBER-positive lymphoid cells. At the same time, her peripheral blood EBV copy number rose to 400 copies/10(5) lymphocytes. She was successfully treated for the progressive PTLD by complete cessation of immunosuppression and a modified reduced-dose chemotherapy protocol plus rituximab. Partial immunosuppression was eventually re-introduced with sirolimus and prednisone. She remains in remission 60 months post transplant, and 30 months post PTLD, with serum creatinine value maintained at 1.3 mg/dL. Unusual localization of PTLD to areas in non-lymphoid tissue without regional lymphoid involvement may result in misleading low peripheral blood EBV viral loads.

Topics: Abscess; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cecum; Child; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Prednisone; Rituximab; Sirolimus; Tongue Neoplasms; Viral Load

In this study we describe 3 single lung transplant recipients who developed unilateral pulmonary edema in the setting of cardiac and renal dysfunction. All 3 patients responded to diuresis with clinical and radiographic improvement. Unilateral cardiogenic pulmonary edema should be considered in the differential diagnosis of dyspnea and unilateral radiographic infiltrates in single lung transplant recipients.

Topics: Angioplasty, Balloon, Coronary; Coronary Artery Disease; Echocardiography, Doppler; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Pulmonary Edema; Radiography, Thoracic; Sirolimus; Tacrolimus; Treatment Outcome; Tuberous Sclerosis

The efficacy of sirolimus is strictly dose-dependent; an inappropriate exposure may cause either rejection episodes or drug toxicity. The variability of sirolimus trough levels (C0) may also have an impact on renal allograft function. We prospectively evaluated the impact of the dose-normalized C0 of sirolimus and the intrapatient coefficient of variation (% CV) on renal allograft function at 6 months after the administration of sirolimus to kidney transplant recipients with chronic allograft nephropathy (CAN). We enrolled 51 recipients with CAN who were treated with sirolimus. The dose-normalized C0 of sirolimus was 3.8 +/- 1.9 ng/mL/mg. The intra- and interpatient variabilities of sirolimus C0 were 26.1% and 51.9%, respectively. Based on receiver operating characteristic analysis, patients were divided into 2 groups: group I, sirolimus % CV <22.9% (n = 36) versus group II, sirolimus % CV >22.9% (n = 15). Patients in group II experienced significantly greater risk for progressive deterioration of allograft function (group I vs group II: 11.1% vs 73.3%; P < .05). Multiple logistic regression analysis revealed that higher baseline serum creatinine, but not age, gender, or concomitant immunosuppressants, positively correlated with the sirolimus % CV. In conclusion, both higher baseline serum creatinine and higher intraindividual variability of sirolimus C0 impact the outcome of renal allograft function in CAN. Thus, we suggest that close monitoring of sirolimus C0 is necessary for recipients treated with sirolimus, especially for patients with CAN.

Topics: Adult; Aged; Analysis of Variance; Biopsy; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Sirolimus; Transplantation, Homologous

We sought to determine the risk of late stent thrombosis (ST) during long-term follow-up beyond 3 years, searched for predictors, and assessed the impact of ST on overall mortality.. Late ST was reported to occur at an annual rate of 0.6% up to 3 years after drug-eluting stent (DES) implantation.. A total of 8,146 patients underwent percutaneous coronary intervention with a sirolimus-eluting stent (SES) (n=3,823) or paclitaxel-eluting stent (PES) (n=4,323) and were followed up to 4 years after stent implantation. Dual antiplatelet treatment was prescribed for 6 to 12 months.. Definite ST occurred in 192 of 8,146 patients with an incidence density of 1.0/100 patient-years and a cumulative incidence of 3.3% at 4 years. The hazard of ST continued at a steady rate of 0.53% (95% confidence interval [CI]: 0.44 to 0.64) between 30 days and 4 years. Diabetes was an independent predictor of early ST (hazard ratio [HR]: 1.96; 95% CI: 1.18 to 3.28), and acute coronary syndrome (HR: 2.21; 95% CI: 1.39 to 3.51), younger age (HR: 0.97; 95% CI: 0.95 to 0.99), and use of PES (HR: 1.67; 95% CI: 1.08 to 2.56) were independent predictors of late ST. Rates of death and myocardial infarction at 4 years were 10.6% and 4.6%, respectively.. Late ST occurs steadily at an annual rate of 0.4% to 0.6% for up to 4 years. Diabetes is an independent predictor of early ST, whereas acute coronary syndrome, younger age, and PES implantation are associated with late ST.

Topics: Aged; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Coronary Thrombosis; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Netherlands; Paclitaxel; Postoperative Complications; Risk Factors; Sirolimus; Switzerland; Time Factors

Topics: Adult; Angiomyolipoma; Female; Humans; Immunosuppressive Agents; Lung Neoplasms; Lung Transplantation; Lymphangioleiomyomatosis; Postoperative Complications; Sirolimus

We report a successful case of sirolimus treatment for chylous pleural and peritoneal effusions of lymphangioleiomyomatosis after lung transplantation. A 32-year-old woman underwent living donor lung transplantation. Persistent chylous pleural and peritoneal effusions were seen postoperatively. Pleurodesis by intrathoracic injection of OK-432, minomycin, and somatostatine analog failed to control chylous effusions. However, sirolimus treatment reduced the amount of chylous drainage and improved both chylous pleural and peritoneal effusions.

Topics: Administration, Oral; Adult; Chylothorax; Chylous Ascites; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lung Neoplasms; Lung Transplantation; Lymphangioleiomyomatosis; Postoperative Complications; Risk Assessment; Sirolimus; Treatment Outcome

Statins are an established therapy after cardiac transplantation. Sirolimus (Srl) has been used successfully in cardiac transplant patients. However, potential side effects are hyperlipidemia and interactions with statins. The aim of the study was to evaluate the safety and efficacy of statin therapy after switch to a Srl-based immunosuppression.. Ninety-eight long-term patients were switched from Cyclosporine A to Srl. Also all patients received mycophenolate mofetil alone or mycophenolate mofetil plus steroid therapy. Reasons for switch were renal dysfunction, graftvasculopathy, or skin cancer. Patients were switched 7.8+/-4.7 years after transplant. Total observation period was 12 months before and after switch, respectively. Safety evaluation consisted of regular measurements of CPK and liver enzymes to evaluate the incidence myopathy and hepatoxicity. Efficacy analysis was performed by serial blood lipid assessments (low-density lipoprotein, high-density lipoprotein, total cholesterol, and triglycerides).. Forty-three percentage of patients received atorvastatin, 38% pravastatin, and 18% other drugs or therapy changes. Most lipid blood levels increased significantly after switch (cholesterol: 192.9+/-38.6 mg/dL vs. 221.8+/-49.2 mg/dL, P<0.0001; low-density lipoprotein: 108.0+/-35.6 mg/dL vs. 123.8+/-37.9 mg/dL, P<0.0001; and triglycerides: 178.3+/-88.2 mg/dL vs. 225.5+/-139.1 mg/dL, P<0.0001). Blood lipid levels after switch were not associated with statin type. Overall safety was acceptable, although incidence of myopathy doubled after switch (n=20 vs. 40; P<0.01). However, most cases were asymptomatic CPK elevations in the pravastatin group. Hepatotoxicity rate was 4% and only temporary.. Statin therapy after switch from cyclosporine A to Srl in long-term cardiac transplant patients is safe. However, regular testing of blood lipids and CPK should be mandatory.

Topics: Adrenal Cortex Hormones; Aged; Atorvastatin; Cholesterol; Cyclosporine; Dyslipidemias; Female; Heart Transplantation; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, LDL; Male; Middle Aged; Postoperative Complications; Pravastatin; Pyrroles; Safety; Sirolimus; Treatment Outcome; Triglycerides

The diabetic patient is at high risk of coronary heart disease. He/she can benefit of revascularisation procedures, even if he/she is exposed to a higher incidence of complications after a coronary artery bypass graft or a percutaneous transluminal coronary angioplasty. The use of drug-eluting stents--paclitaxel (PES) or sirolimus (SES)--dramatically reduces the risk of restenosis as compared to bare-metal stents; nevertheless, the rate of restenosis remains almost double in diabetic patients compared to that observed in non-diabetic subjects. However, the risk of (very) late thrombosis is higher with drug-eluting stents than with bare-metal stents, in the diabetic population as in the non-diabetic population. Altogether, among diabetic patients, the incidence of major cardiovascular events is significantly reduced with drug-eluting stents. This global clinical benefit essentially results from a diminution of revascularisation procedures rather than from a reduction of myocardial infarcts or cardiovascular deaths. Comparison between SES and PES gives discordant results. Indeed, while the loss of intra-stent lumen is more important with PES than with SES, PES are associated with a lower rate of major cardiovascular events than SES. Efficacious antiplatelet therapy in the long run is mandatory in all diabetic patients treated with drug-eluting stents.

Topics: Coronary Artery Disease; Coronary Restenosis; Diabetic Angiopathies; Drug-Eluting Stents; Humans; Incidence; Paclitaxel; Postoperative Complications; Risk Assessment; Sirolimus; Thrombosis

Sirolimus, a TOR (target of rapamycin)-binding immunosuppressant, has been associated with wound healing complications; however, its effects have not been documented in dermatologic surgery.. The objective was to determine the effect of sirolimus on wound healing in dermatologic surgery.. Databases at Mayo Clinic were queried for organ transplant recipients undergoing dermatologic surgery. Medical records were reviewed retrospectively, and telephone interviews were conducted. Patients receiving sirolimus were compared with patients not receiving sirolimus.. Postoperative infections occurred in 19.2% of the sirolimus group (n=26) and 5.4% of the controls (n=37; p=.11; odds ratio [OR], 4.2; 95% confidence interval [CI], 0.7-23.4). The incidence of wound dehiscence was greater in the sirolimus group (7.7% vs. 0%; p=.17; OR, 7.7; 95% CI, 0.4-166.3).. No significantly increased risk of wound complications was found in organ transplant recipients receiving sirolimus while undergoing dermatologic surgery. However, this study was retrospective and had a small sample size. A larger study is necessary for corroboration.

Topics: Adult; Aged; Aged, 80 and over; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Patient Satisfaction; Postoperative Complications; Retrospective Studies; Sirolimus; Skin Diseases; Surveys and Questionnaires; Treatment Outcome; Wound Healing

In this case report, we describe a rare patient who experienced complete fracture of a sirolimus-eluting stent that was implanted for a focally calcified lesion of the right coronary artery ostium. Although the fractured fragment migrated somewhere in the systemic circulation, fortunately there were no complications. Implantation for ostial lesions of the right coronary artery should be performed with great care.

Topics: Aged, 80 and over; Drug-Eluting Stents; Equipment Failure; Foreign-Body Migration; Humans; Male; Postoperative Complications; Sirolimus

Topics: Coronary Thrombosis; Drug-Eluting Stents; Humans; Immunosuppressive Agents; Paclitaxel; Postoperative Complications; Prosthesis Failure; Risk Factors; Sirolimus; Time Factors; Tubulin Modulators; Ultrasonography, Interventional

Sirolimus, an effective and non-nephrotoxic immunosuppressant, may have an antiproliferative effect on renal tubular cells and increase their apoptosis, thus hindering the recovery of an injured kidney. The aim of this study was to evaluate the impact of combined sirolimus and cyclosporine therapy on the incidence and duration of delayed graft function and long-term graft function.. The study group consisted of 23 renal transplant recipients treated with a sirolimus-cyclosporine-prednisone regimen (sirolimus group). The reference group was composed of 23 patients treated with azathioprine-cyclosporine-prednisone. Because of a long cold ischemia time, all the patients were at high risk of developing delayed graft function.. There was an equal frequency of delayed graft function in the sirolimus group compared with the reference group (39% vs 34.8%). The duration of delayed graft function was longer in sirolimus group compared with the reference group (21.2 +/- 12.2 days vs 6.8 +/- 2.5 days) (P < .004). The serum creatinine level at the 12th month was higher in patients with delayed graft function than it was in the remaining patients, independent of the immunosuppression protocol. One and 5-year graft survival rates were 100% and 87% in the sirolimus group, and 95% and 74% in the reference group. The 5-year patient survival rate was 100% in both groups.. Sirolimus significantly retards the recovery from posttransplant renal failure, but it does not increase the incidence of delayed graft function. Sirolimus therapy should be initiated after recovery from posttransplant renal failure. Sirolimus treatment is beneficial for long-term graft survival.

Topics: Adult; Cold Ischemia; Creatinine; Cyclosporine; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisolone; Renal Insufficiency; Sirolimus; Survival Rate; Time Factors; Transplantation, Homologous; Treatment Outcome

We report 13 cases of coronary stent patients, undergoing a non cardiac surgery. Despite an heterogenous perioperative management of antiplatelet agents, none of these patients developed any significant complications. Recently, several case reports of postoperative drug eluting stent thrombosis have been reported. However, the actual incidence of this dramatic event is not known. This confirms the need to perform prospective studies or registries of patients with coronary stents undergoing non cardiac surgery, in order to propose evidence-based recommendations on perioperative antiplatelet management in such patients.

Topics: Aged; Aged, 80 and over; Anesthesia, General; Coronary Restenosis; Coronary Stenosis; Drug Implants; Female; France; Hematoma; Humans; Incidence; Male; Middle Aged; Paclitaxel; Platelet Aggregation Inhibitors; Postoperative Complications; Prospective Studies; Registries; Sirolimus; Stents; Surgical Procedures, Operative; Thrombophilia; Thrombosis

Topics: Animals; Biological Transport; Cells, Cultured; Endocytosis; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules, Proximal; Models, Animal; Opossums; Postoperative Complications; Proteinuria; Serum Albumin; Sirolimus; Transplantation, Homologous

Renal ischemia followed by reperfusion leads to acute renal failure in both native kidneys and renal allografts. Cyclosporine has known nephrotoxic effects. Thus, cyclosporine therapy subsequent to ischemia/reperfusion (I/R) injury may further exacerbate graft dysfunction. Rapamycin is a newer agent that suppresses the immune system by a different mechanism. In the present study, the effects of Cyclosporine and rapamycin at low and higher concentrations were investigated in an I/R-induced injury model.. Cyclosporine (100 mg/kg or 50 mg/kg), rapamycin (3 mg/kg per day or 1.5 mg/kg), or both were administered to mice before being subjected to 45 minutes of ischemia. Blood and kidney samples were collected at 24, 48, and 120 hours after surgery. We quantified acute tubular necrosis and tubular regeneration.. Animals subjected to I/R showed impaired renal function that peaked at 24 hours (2.05 +/- 0.23 mg/dL), decreasing thereafter. Treatment with higher concentrations of cyclosporine or rapamycin caused even more renal dysfunction at 48 hours, which was sustained up to 120 hours after reperfusion (1.53 +/- 0.6 mg/dL), when compared to the low concentrations of cyclosporine or rapamycin (1.08 +/- 0.19 mg/dL; 0.99 +/- 0.14 mg/dL, P < .05, respectively). Cyclosporine delayed tubular regeneration, which was higher in controls at day 5 (67.0% vs 37.6%, P < .05).. These results demonstrated that cyclosporine or rapamycin might further aggravate ischemically injured organs, negatively affecting posttransplantation recovery in a concentration-dependent fashion.

Topics: Animals; Cyclosporine; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Mice; Mice, Inbred C57BL; Models, Animal; Postoperative Complications; Reperfusion Injury; Sirolimus; Transplantation, Isogeneic; Treatment Outcome

Chronic allograft nephropathy (CAN) is, among others, caused by nephrotoxic side effects of calcineurin inhibitors (CNI), which are to date still the mainstay of immunosuppressive therapy. Sirolimus (SIR), an immunosuppressive compound without effects on glomerular perfusion, has been used in CNI-sparing immunosuppressive protocols. We report the 5-year follow-up of a prospective, controlled conversion study from CNI to SIR in patients with moderately to severely impaired renal function.. Twelve renal transplant recipients with moderately to severely impaired renal function (estimated glomerular filtration rate of 17 to 35 mL/min according to the MDRD formula), enrolled in a prospective, controlled 1-year pilot study were followed for 5 years.. Three renal grafts (25%) were lost during the 5-year follow-up. Graft loss was due to noncompliance in one patient and to CAN in the other two patients. These two patients returned to dialysis 43 and 59 months after conversion, corresponding to 86 and 75 months after transplantation, respectively. Six of nine patients had a stable or even better renal function compared to the baseline. The lipid profile increased initially, but then remained stable over time.. Conversion of immunosuppressive therapy from CNI to SIR in patients with impaired renal function more than 1 year after transplantation is feasible and safe yielding improved renal function in the majority of patients, which was sustained at 5 years follow-up.

Topics: Calcineurin Inhibitors; Follow-Up Studies; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Sirolimus; Time Factors; Transplantation, Homologous

Most drug-associated angioedemas are induced by angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, or nonsteroidal anti-inflammatory drugs. Recently, the responsibility of immunosuppressive agents given to transplant recipients in the development of angioedema has been discussed.. To describe, in detail, angioedema episodes in renal transplant recipients (RTRs) on sirolimus.. A cross-sectional study in a university hospital. Eighty consecutive RTRs on sirolimus were studied.. Angioedema without urticaria occurred a mean of 5 times in 12/80 (15%) RTRs taking sirolimus. It was predominantly located on the face (83%), with mucous membrane involvement in 7 (58%) patients, and was life threatening in 1. Another putative cofactor for angioedema without urticaria was identified in 9 (75%) patients: drugs (n=8), food allergy or physical activity (n=3). Tacrolimus intake was significantly associated with sirolimus-associated angioedema.. Our results suggested a causal relationship between sirolimus and angioedema in RTRs.

Topics: Angioedema; Child, Preschool; Cross-Sectional Studies; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Sirolimus

The use of proliferative signal inhibitors (PSIs) in immunosuppression-related malignancies opens new roads for increasing the survival and quality of life in patients with solid organ transplantation. A 56-year-old female recipient of a living donor renal allograft (1990), who was immunosuppressed with cyclosporine (CsA; Neoral), azathioprine, and steroids, did initially well with acceptable renal function. During the last 5 years she required local therapy due to posterior vaginal lip human papillomavirus (HPV) lesions. In 2000, she discontinued azathioprine and the CsA doses were reduced to 100 mg daily. The local lesion showed a good response to reduced immunosuppression. In February 2005, the lesion reappeared and a biopsy showed malignancy. Local surgery was performed and CsA was replaced by everolimus (EVL; Certican). Two months after treatment initiation, the patient developed cough, dyspnea, and low-grade fever. Chest X-ray showed a lesion at the base of the left lung compatible with pneumonitis. After fiberbronchoscopy a diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP) was obtained. She was treated with increased doses of oral steroids. EVL was never discontinued. The radiological lesion disappeared and the malignancy is currently in remission. In summary, a case of gynecological cancer in a renal transplant recipient was treated by surgical removal. After 1 year of immunosuppression with EVL, no recurrence has been observed. The adverse event (BOOP) was probably related to the PSI treatment and was controlled with an increased dose of steroids without discontinuing EVL.

Topics: Adrenal Cortex Hormones; Azathioprine; Cryptogenic Organizing Pneumonia; Cyclosporine; Everolimus; Female; Humans; Kidney Transplantation; Methylprednisolone; Middle Aged; Papillomavirus Infections; Polycystic Kidney Diseases; Postoperative Complications; Sirolimus; Vaginal Neoplasms

Mammalian Target-of-Rapamycin inhibitors (mTOR inhibitors) can be used to replace the calcineurin inhibitors (CNIs) to prevent progression in chronic kidney disease (CKD) following organ transplantation. Discontinuation of tacrolimus in 136 recipients of kidney transplants with progressive renal dysfunction significantly decreased the rate of loss of estimated glomerular filtration rate (eGFR, mL/min/1.73 m(2)) (pre-intervention vs. post-intervention slopes, -0.013 vs. -0.002, p < 0.0001). Discontinuation of tacrolimus was associated with a sustained and significant improvement in graft function (pre-eGFR vs. post-eGFR; 26.0 +/- 1.1 vs. 47.4 +/- 2.1, p < 0.0001) in 74% of patients. This intervention was ineffective if the mean and (median) values of creatinine (mg/dL) and eGFR were 3.8 +/- 0.2 (3.4) and 18.4 +/- 1.9 (22.4), respectively, at the time of conversion therapy. During the follow-up (range, 1.5-34.6, months), a total of 13 patients had their first acute rejection following the conversion therapy, an annual incidence of less than 10% and none of these episodes resulted in graft loss. The salutary effects of sirolimus therapy following discontinuation of tacrolimus in patients with moderate to severe graft dysfunction due to allograft nephropathy even in high-risk patients improves kidney function and prevents acute rejection.

Topics: Biopsy; Calcineurin Inhibitors; Chronic Disease; Drug Administration Schedule; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sirolimus; Transplantation, Homologous

Heart transplant recipients treated with long-term calcineurin inhibitors (CNIs) experience significant nephrotoxicity and transplant vasculopathy. Signal proliferation inhibitors might prevent the development of transplant vasculopathy. In an open, prospective pilot study, 33 primary heart transplant recipients received tacrolimus (Tac) and sirolimus (rapamycin, Rapa) with steroids. To reduce both nephrotoxicity and transplant vasculopathy at the same time, both Tac and Rapa exposure was kept low (6 to 8 ng/ml). Steroids were withdrawn successfully from all patients within 6 months. Just one acute rejection occurred at 54 days post-transplant, resulting in 0.03 acute rejection episode per patient at 1-year (primary end-point) and 2-year follow-up. Transplant vasculopathy assessed by angiogram was absent at 2 years. Graft and patient survival were 100% at 1 and 2 years. Accordingly, the survival estimate for freedom from first acute rejection, transplant vasculopathy, graft loss or death was 0.97 at 1 and 2 years. The regimen was well tolerated with only 3 patients requiring a change of study medication. Mean serum creatinine increased during the first year but returned to baseline at 2 years.

Topics: Adrenal Cortex Hormones; Adult; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Infections; Male; Middle Aged; Postoperative Complications; Prospective Studies; Sirolimus; Tacrolimus; Time Factors

Randomised trials in a highly selected patient population have demonstrated a dramatic reduction in the incidence of in-stent restenosis (ISR) following implantation of sirolimus-eluting (S-E) Cypher coronary stents compared with bare metal stents (BMS). The clinical outcome following implantation of S-E stents for treatment of complex, unselected BMS ISR is less well defined. The aim of this study was to assess the safety and efficacy of S-E coronary stents in the treatment of an unselected population of BMS ISR. All patients who received S-E stents for treatment of BMS ISR from May 1 2002-November 30 2003 at a single institution were entered into a prospectively collected database. In-hospital and long-term outcomes were collected. Sixty patients were identified who received S-E stents for the treatment of ISR. Four patients (6%) had undergone previous brachytherapy and 22% were diabetic. The most common target vessel was the left anterior descending coronary artery (40%), and 6% of lesions were in saphenous vein grafts (SVGs). The mean reference diameter was 2.67+/-0.52 (range 1.75-4.0) mm and the mean lesion length was 16.22+/-11.46 (range 3-68) mm. There were no procedural or in-hospital major adverse cardiac events (MACE). Long-term follow-up was available in 59 patients (98%). The 12-month MACE rate (cardiac death, myocardial infarction or target lesion revascularisation) was 12% with a 7% percutaneous coronary intervention rate and a 7% coronary artery bypass graft rate. There were no cardiac deaths and two non-cardiac deaths. Of the seven patients who had clinical restenosis at 12 months, four had previously failed brachytherapy and three involved SVGs. In conclusion, the use of S-E stents appears safe and efficacious in the treatment of an unselected population of BMS ISR with results comparing favourably with historical controls. Further randomised studies are needed to delineate the optimal management of this high risk group of patients.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Postoperative Complications; Sirolimus; Time Factors; Treatment Outcome

Topics: Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Postoperative Complications; Sirolimus

Sirolimus has been associated with high-range proteinuria when used in replacement of calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy (CAN). Primary FSGS was demonstrated previously in some such patients, but the coexistence of CAN lesions made the interpretation uneasy. However, nephrotic syndrome and FSGS were observed recently in three patients who received sirolimus de novo, without medical history of primary FSGS or CAN. Markers of podocyte differentiation were studied in kidney biopsies of the three patients who received sirolimus de novo and of five patients who switched to sirolimus. All patients developed FSGS lesions of classic type (not otherwise specified), but only switched patients exhibited advanced sclerotic lesions. Immunohistochemistry showed that some podocytes in FSGS lesions had absent or diminished expression of the podocyte-specific epitopes synaptopodin and p57, reflecting dedifferentiation, and had acquired expression of cytokeratin and PAX2, reflecting a immature fetal phenotype. Such a pattern of epitope expression provides evidence for podocyte dysregulation. Moreover, a decrease in vascular endothelial growth factor expression was observed in some glomeruli. In conclusion, sirolimus induces FSGS that is responsible for proteinuria in some transplant patients.

Topics: Adult; Biopsy; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Sirolimus

Acute and long-term results after sirolimus-eluting stent (SES) implantation of proximal left anterior descending coronary artery (LAD) disease were evaluated.. Although SES has been used increasingly for the treatment of LAD disease, data regarding their safety and efficacy in a real-world population are limited.. We investigate the short- and long-term results in 966 patients who underwent SES implantation for stenosis of proximal LAD.. The procedural success rate was 97.6%, and procedural non-Q-wave myocardial infarction (MI) rate was 14.5%. In-hospital major complications occurred in five patients (0.5%), including three deaths and two Q-wave MIs. During follow-up (20.4 +/- 8.9 months), there were 16 deaths (1.7%; 10 cardiac, 6 noncardiac), 2 Q-wave MIs, and 22 target lesion revascularizations (2.3%). Late stent thrombosis occurred in two patients (0.2%), 14 and 23 months after the procedure. The event-free survival rates for cardiac death/Q-wave MI were 98.6% +/- 0.4% at 1 year and 97.8% +/- 0.6% at 2 years. The cumulative probabilities of survival without major adverse cardiac events (MACE) were 96.7% +/- 0.6% at 1 year and 95.4% +/- 0.8% at 2 years. In multivariate analysis, stented length (HR 1.04, 95%CI 1.01-1.07, P = 0.009) and infarct-related artery (HR 5.18, 95%CI 1.09-24.64, P = 0.039) were independently related to cardiac death/Q-wave MI. In addition, stented length (HR 1.04, 95%CI 1.02-1.06, P < 0.001) and left ventricular dysfunction (HR 2.66, 95%CI 1.07-6.63, P = 0.036) were significant independent predictors of MACE.. SES implantation for proximal LAD disease appears safe and effective in a real-world population, and the independent predictors of MACE included stented length and left ventricular dysfunction.

Topics: Adult; Aged; Aged, 80 and over; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Disease; Electrocardiography; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Revascularization; Postoperative Complications; Prognosis; Retrospective Studies; Sirolimus; Stents; Time Factors

mTOR inhibitors (imTOR) are immunosuppressive drugs that have a concentration-related effects on hematopoiesis, potentially resulting in anemia. The reason is uncertain, but a pathogenic link between sirolimus-induced anemia and the appearance of an inflammatory state was recently suggested. Because inflammation-related anemia is characterized by a functional iron deficiency, we studied whether everolimus influenced iron homeostasis.. We studied iron homeostasis in 43 patients after late introduction of everolimus into the immunosuppressive treatment. Thirty-seven patients (86%) were receiving mycophenolate. Hemoglobin concentration, red blood cell count, mean corpuscular volume, serum iron, ferritin, C-reactive protein levels, and transferrin saturation were evaluated 3 months before and 1, 3, and 6 months after the switch.. The percentage of anemic patients preconversion was 18.6% and it was 34.9% at 3 months and 18.6% at 6 months. We did not observe a significant reduction in hemoglobin, but there was increased red blood cell count after everolimus introduction, with a significant reduction in mean corpuscular volume. Serum iron and transferrin saturation levels were also markedly reduced after the switch, while ferritin serum concentrations remained stable. An improvement in renal function was observed.. The anemia caused by everolimus--microcytosis, low serum iron, despite high ferritinemia, and elevated C-reactive protein levels--was consistent with the anemia of a chronic inflammatory state. This alteration occurred within the first months postconversion and disappeared at 6 months. The combination of mycophenolate and everolimus seemed to be useful without significant secondary effects.

Topics: Anemia; C-Reactive Protein; Darbepoetin alfa; Erythrocyte Count; Erythropoietin; Everolimus; Ferritins; Hemoglobins; Hemostasis; Humans; Immunosuppressive Agents; Iron; Kidney Transplantation; Postoperative Complications; Sirolimus; Transferrin

During the last few years sirolimus has been introduced as an alternative to preserve renal function in transplant recipients receiving calcineurin inhibitors.. We reviewed our results on the use of sirolimus in cardiac transplant recipients.. Twenty-seven patients with an average age of 63 years received sirolimus. The average time after transplantation was 73.4 +/- 58.9 months and the average follow-up was 31.7 +/- 18.01 months. Sirolimus was prescribed in 37% of cases due to chronic renal failure (CRF), 14.8% because of cardiac allograft vasculopathy (CAV), 11.1% for tumors, 22.2% de novo, 7.4% for CRF and tumor, and 7.4% for CRF and CAV. Among the patients with CRF (n = 14), there were 5 (35%) on dialysis at the moment of starting the treatment and 1 was retired from dialysis. The other 4 (28.5%) patients had to be treated with dialysis after starting the treatment. In all, 42.8% of the patients with nephropathy maintained stable renal function or improved. Among the 17 (63%) patients who did not require dialysis, there was no significant change in renal function after 6 months or 1, 2, and 3 years follow-up.. The use of sirolimus in cardiac transplantation maintains stable renal function in the majority of patients in the medium term.

Topics: Aged; Creatinine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus

CAN is a common cause of late graft loss. Nephrotoxicity due to CNIs is known to contribute to CAN. We retrospectively evaluated the efficacy and safety of SRL in pediatric renal Tx recipients showing CAN in their allograft biopsy. Twenty-one patients aged 10.4 +/- 4.6 yr at Tx time receiving CNIs as primary immunosuppression were converted to SRL at 58.9 +/- 49.1 months after Tx, due to progressive decline of renal function and biopsy proven CAN. Mean follow-up after switch was 19.7 +/- 9.5 months. All patients received CsA as part of the immunosuppressive regimen, at a mean dose 4.4 +/- 1.2 mg/kg/day. Mean daily dose of SRL three month after conversion was 2.6 +/- 0.8 mg/body surface area/day and the mean through levels where 6.9 +/- 2.5 ng/mL. Graft biopsies showed Grade I CAN in 12 children and Grade II CAN in nine. After SRL introduction, there were neither acute rejection episodes nor graft losses. GFR improved at three months and was sustained thereafter only in children with Grade I CAN. Post-Tx time at conversion was the only significant variable between patients who had Grade I CAN and Grade II CAN (33.6 +/- 33.3 vs. 92.7 +/- 47.5 months, p = 0.003). Nine patients had no AEs, six patients had nine SAE: five diarrhea, one herpes zoster, one pancreatic pseudo cyst, one pneumonia, and one Influenza A infection; 11 patients had 13 AEs: six oral aphthous ulcers, three urinary tract infections, two herpes simplex, one lymphedema, and one nephrotic proteinuria. Significant improvement of GFR occurred in Grade I CAN group at three months from conversion and was sustained during follow-up. Those who had Grade II CAN experienced no change in GFR. The incidence of AEs and SAE is of concern and further studies are necessary to assess their relevance.

Topics: Biopsy; Child; Cholesterol; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Platelet Count; Postoperative Complications; Proteinuria; Retrospective Studies; Safety; Sirolimus; Transplantation, Homologous; Triglycerides

Incisional hernias occur in up to 17% of patients after liver transplantation. Laparoscopic ventral hernia repair is associated with fewer wound complications and a decreased incidence of recurrence when compared to open hernia repair in nontransplant patients. This is a retrospective review of 13 patients who underwent laparoscopic incisional hernia repair (LAP group) after liver transplantation compared to 14 patients who had open repairs (OP group; all but one with mesh). Primary immunosuppression in both groups at the time of transplantation was tacrolimus, but more patients in the LAP group were on sirolimus at the time of hernia, while more patients in the OP group were on prednisone at the time of hernia repair. All operations were completed with a laparoscopic approach; there were no conversions to open. Length of stay differed significantly between the 2 groups, with a mean of 5.4 days for the LAP group compared to 2.7 days in the OP group (0.0059). Complications occurred in 2 (15%) of the patients in the LAP group and 5 (36%) in the OP group. One patient in the LAP group required mesh removal to exclude causes of recurrent ascites, and 1 in the OP group for mesh infection. One (7.6%) of the patients in the LAP group developed a recurrence, compared to 29% (4) of the OP group (P =0.3259). In conclusion, laparoscopic incisional hernia repair is safe in patients after liver transplantation, with a low risk of infection or recurrence.

Topics: Aged; Female; Graft Rejection; Hernia, Ventral; Humans; Immunosuppressive Agents; Laparoscopy; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Recurrence; Retrospective Studies; Sirolimus; Surgical Mesh; Surgical Wound Infection; Tacrolimus

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Middle Aged; Neoplasms; Postoperative Complications; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Transplantation, Homologous

Sirolimus (SRL) has become an option in kidney transplantation, especially among patients who develop chronic allograft nephropathy (CAN). This study sought to evaluate the safety and efficacy of SRL in 103 kidney recipients of mean age 40 years, including 78 recipients of organs from deceased donors. The major reason for conversion was calcineurin inhibitor (CNI) nephrotoxicity (42.3%) followed by CAN (35.4%). A preconversion kidney biopsy was performed in 89 patients with CAN diagnosed in 51. Mean time to conversion was 40.5 months. The new therapy was: SRL/mycophenolate mofetil (MMF)/prednisone (Pred) in 79 patients; SRL/tacrolimus (TAC)/Pred in 15; and other SRL combinations in 9. The target SRL trough level was 5.0 to 8.0 ng/mL. To evaluate the impact of conversion on renal function, we compared the proteinuria and inverse serum creatinine at 3 months before conversion, at conversion, and at 1, 3, 6, 12, and 24 months postconversion. The overall mean follow-up time was 13.2 months. The analysis showed significant improvement in renal function at month 1 postconversion (P<.05) with stabilization thereafter. The SRL/MMF combination frequently induced anemia and/or leukopenia (n=23). Infections included pneumonia (n=10), herpes zoster (n=7), herpes simplex (n=3), cytomegalovirus (n=2), histoplasmosis (n=2), tuberculosis (n=2), and neurocryptococcosis (n=1). Reasons for SRL discontinuation were myelotoxicity (n=4), infection (n=3), nephrotoxicity (n=3), gastrointestinal intolerance (n=3), myopathy (n=1), pneumonitis (n=1), hyperlipidemia (n=1), and other reasons (n=3). Graft loss occurred in 29 patients due to CAN (n=21) followed by death (cardiovascular, n=2; infectious, n=2), acute rejection (n=3), and infection following immunosuppression withdrawal (n=1). We concluded that SRL represented an option but reducing associated immunosuppression should strongly be considered to minimize the frequent side effects, especially infections.

Topics: Azathioprine; Drug Therapy, Combination; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

The factors associated with recurrent restenosis after SES implantation for in-stent restenosis are unknown. This study aimed to assess the clinical outcome and to analyse predictive factors of cardiac events in patients with in-stent restenosis treated with Sirolimus-eluting stent (SES).. In 3 centers, consecutive patients (n = 100) with elective indication to percutaneous coronary intervention (PCI) for in-stent restenosis (n = 110) were treated with SES: 28 lesions were focal, 40 diffuse, 17 proliferative, and 15 showed total occlusion.. SES implantation was successful in all patients, without complication during the first hospital stay. The mean follow-up was 15 (10-24) months. A cardiac event related to the target vessel occurred in 24 (24%) patients, and was associated with dialysis status (p < 0.05), lower ejection fraction (p < 0.05) and revascularization without SES in another site (p < 0.0001). A cardiac event related to the SES occurred in 11 (11%) patients, secondary to an acute or sub-acute thrombosis of the SES (2%), to a late occlusion of the target vessel (4%) or to a non-occlusive restenosis of the SES (5%), and was associated with unstable angina (p < 0.01), multivessel disease (p < 0.03) and revascularization without SES in another site (p < 0.03). No cardiac event related to the SES occurred in patients with direct stenting. Target lesion revascularization for in-SES restenosis or occlusion of the target vessel was performed in 7 (7%) patients, and was associated with unstable angina (p < 0.01) and revascularization without SES in another site (p < 0.01). Target vessel revascularization was needed in 20 patients (20%), related to dialysis status (p < 0.01) and a revascularization without SES in another site (p < .0001).. SESs are effective in the treatment of high risk patients with complex in-stent restenosis. Most of cardiac events during follow-up are related to a revascularization without SES in another site.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Female; Follow-Up Studies; France; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Predictive Value of Tests; Reoperation; Risk Factors; Sirolimus; Stents; Treatment Outcome

The study was conducted in order to describe possible intraglomerular haemodynamic changes inducing proteinuria after 14 patients with chronic allograft dysfunction were converted from calcineurin inhibitors (CIs) to sirolimus without changing concomitant immunosuppression or antihypertensive treatment.. Creatinine, glomerular filtration rate (GFR), proteinuria, renal functional reserve (RFR) and effective renal plasma flow (ERPF) were determined before and 8 months after conversion. Intraglomerular pressure (P(G)), afferent arteriolar resistance (AAR) and efferent arteriolar resistance (EAR) were calculated using Gomez's formula.. Creatinine (1.97 vs 2.075 mg/dl; P = 0.270) and GFR (40 vs 43 ml/min; P = 0.505) remained unchanged, proteinuria increased (338 vs 1146 mg/24 h; P = 0.006), RFR decreased (34.84 vs 13.47%; P = 0.019), ERPF (248 vs 310.6 ml/min; P = 0.0625) and P(G) (42.72 vs 46.17 mmHg; P = 0.0625) tendentially increased and AAR tendentially decreased (14.12 vs 10.28 dyne/s/cm(5); P = 0.0625).. After conversion, P(G) shows a tendency to increase and RFR decreases significantly-characteristics of hyperfiltration, which could possibly partially explain the increase of proteinuria. Therefore, the application of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers seems promising. To avoid hyperfiltration, conversion should be performed early when renal insufficiency is still moderate.

Topics: Adult; Aged; Calcineurin Inhibitors; Chronic Disease; Female; Hemodynamics; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Proteinuria; Sirolimus

To determine whether pancreatic islet transplantation can control diabetes and prevent severe life-threatening hypoglycaemia.. A single-arm observation study of six patients undergoing islet transplantation. All patients had had type 1 diabetes mellitus for over 5 years and documented episodes of repeated severe hypoglycaemia. Islets were isolated from donor pancreases digested by Liberase. Separated islets were infused into the recipient's liver via the portal vein. Patients were immunosuppressed with daclizumab, sirolimus and tacrolimus. The transplants were performed at Westmead Hospital, NSW, between October 2002 and February 2005.. Normal blood glucose control without administration of exogenous insulin; demonstration of islet function and abolition of hypoglycaemia.. Five of the patients received two islet infusions, and the sixth was withdrawn after one infusion following a portal vein thrombosis. Three patients became insulin-independent, with excellent glycaemic control. Two had islet function with circulating C-peptide, improved glycaemic control, reduced insulin requirement and abolition of severe hypoglycaemia. However, over a 2-year period, graft function deteriorated. Recipients who were initially insulin free remained C-peptide positive but required supplemental insulin. Complications included one postoperative bleed, two portal vein thromboses (which resolved completely), presumed recurrence of tuberculosis in one patient, and deterioration in renal function in one patient.. Islet transplantation is effective at improving glycaemic control and hypoglycaemia unawareness in the short to medium term. However, problems with long-term safety of immunosuppression, islet-induced thrombosis and early detection of loss of islet function remain to be addressed.

Topics: Adult; Age Factors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Australia; Blood Glucose; Daclizumab; Diabetes Mellitus, Type 1; Follow-Up Studies; Graft Survival; Humans; Hypoglycemia; Immunoglobulin G; Immunosuppressive Agents; Islets of Langerhans Transplantation; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

The commonest cause of renal transplant loss is death with a functioning graft, usually from an excess of cardiovascular disease (CVD). Anaemia is becoming increasingly recognized as a reversible risk factor for the development of CVD. The purpose of this study was to estimate the prevalence of post-transplantation anaemia (PTA) in a large population of stable adult and paediatric renal transplants in one centre and to correlate the estimated glomerular filtration rate (eGFR), iron indices and the use of immunosuppressants with the prevalence of anaemia.. Every adult and paediatric patient with a functioning renal transplant and more than 3 months post-engraftment at Guy's hospital, London, as of 31 December 2004 and who had a valid creatinine and haemoglobin, in the period 1 September-31 December 2004 inclusive, was identified. A large database of clinical and biochemical indices was built up on the basis of medical notes and electronic patient records. Results were analysed for the prevalence of anaemia and risk factors for its development. Anaemia was defined according to the WHO criteria. All patients on treatment with an erythropoiesis stimulating agent were classified as anaemic, irrespective of haemoglobin.. A total of 878 adults and 73 children were identified. Mean haemoglobin in adults was 12.9 +/- 1.6 g/dl and 11.8 +/- 1.4 g/dl in the children. Mean eGFR was 49.3 +/- 20.1 ml/min in adults and 65.7 +/- 18.8 ml/min in the paediatric cohort. Haemoglobin correlated positively with the eGFR in both cohorts (R = 0.33 and 0.29 in adults and children, respectively (P < 0.0001 for both)). We identified anaemia in 45.3% of adults and 22% in children. Ferritin levels were lower in children than in adults (79 +/- 93 vs 204 +/- 353 mg/l), but were higher in both cohorts among the non-anaemic populations than in those with anaemia. 58% of adults taking mycophenolate mofetil (MMF) were anaemic compared with 22% of children. One child, and 68 adults, were on recombinant erythropoietin. Multiple regression analyses identified age, female gender, eGFR and serum ferritin levels as independent predictors of haemoglobin in adult subjects.. The prevalence of PTA was high in both adult and paediatric cohorts while comparatively few patients were being treated with erythropoiesis stimulating agents. The strongest predictors of haemoglobin in this cohort of patients were age, female sex and graft function. Immunosuppression including MMF or sirolimus was associated with a higher prevalence of anaemia, but this was likely to be the result of poorer graft function in these subjects. Iron deficiency did not seem to be a causative factor for anaemia in this population.

Topics: Adult; Anemia; Child; Cohort Studies; Female; Ferritins; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Regression Analysis; Sirolimus

Sirolimus was introduced in de novo immunosuppression at Stanford University in view of its favorable effects on reduced rejection and cardiac allograft vasculopathy. After an apparent increase in the incidence of post-surgical wound complications as well as symptomatic pleural and pericardial effusions, we reverted to a mycophenolate mofetil (MMF)-based regimen. This retrospective study compared the outcome in heart transplant recipients on sirolimus (48 patients) with those on MMF (46 patients) in de novo immunosuppressive regimen. The incidence of any post-surgical wound complication (52% vs. 28%, p=0.019) and deep surgical wound complication (35% vs. 13%, p=0.012) was significantly higher in patients on sirolimus than on MMF. More patients on sirolimus also had symptomatic pleural (p=0.035) and large pericardial effusions (p=0.033) requiring intervention. Logistic regression analysis showed sirolimus (p=0.027) and longer cardiac bypass time (OR=1.011; p=0.048) as risk factors for any wound complication. Sirolimus in de novo immunosuppression after cardiac transplantation was associated with a significant increase in the incidence of post-surgical wound healing complications as well as symptomatic pleural and pericardial effusions.

Topics: Female; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Racial Groups; Retrospective Studies; Sirolimus; Wound Healing; Wounds and Injuries

Sirolimus is increasingly used in transplantation for prevention and treatment of graft-versus-host disease and organ rejection. Voriconazole is contraindicated when used concomitantly with sirolimus because of a substantial increase in sirolimus drug exposure with unadjusted dosing, but voriconazole is also considered the best initial treatment of invasive aspergillosis and other fungal infections. Patients who received voriconazole and sirolimus concomitantly were identified by a review of the medical records of all allogeneic hematopoietic stem cell recipients at our institution from September 1, 2002, to June 1, 2005. Data including baseline characteristics, indications for both drugs, and potential adverse effects were evaluated. Eleven patients received voriconazole and sirolimus concomitantly for a median of 33 days (range, 3-100 days). In 8 patients whose sirolimus dose was initially reduced by 90%, trough sirolimus levels were similar to those obtained before the administration of voriconazole; no obvious significant toxicity from either drug was observed during coadministration. Serious adverse events were observed in 2 patients in whom sirolimus dosing was not adjusted during voriconazole administration. Sirolimus and voriconazole may be safely coadministered if there is an empiric initial 90% sirolimus dose reduction combined with systematic monitoring of trough levels.

Topics: Adult; Antifungal Agents; Cord Blood Stem Cell Transplantation; Creatinine; Dose-Response Relationship, Drug; Drug Evaluation; Drug Interactions; Female; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Leukemia; Lipids; Male; Middle Aged; Mycoses; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Pyrimidines; Retrospective Studies; Sirolimus; Transplantation, Homologous; Triazoles; Voriconazole

Sirolimus-induced pneumonitis usually requires the complete cessation of sirolimus. Herein we have reported five cases of recovery from sirolimus pneumonitis after conversion from sirolimus to everolimus.. All five cases were comparable with regard to their clinical conditions. The ages were between 46 and 64 years. They had received kidney transplants 3 to 18 years earlier. In four cases, the reason for sirolimus therapy was toxicity due to calcineurin inhibitors on a transplant biopsy; three of the patients also displayed malignant tumors: renal cell carcinoma, spinocellular carcinoma, or melanoma. Their serum creatinine levels were elevated between 150 and 350 micromol/L. In all five cases, bronchoscopy disclosed lymphocytic pneumonitis and bronchiolitis obliterans. The immunosuppressive co-medications were prednisolone in three, azathioprine in one, and mycophenolate mofetil in four cases. The previous sirolimus dose was 1 to 4 mg/day, with sirolimus trough levels between 5 and 12 ng/mL. The patients were switched to everolimus at doses between 1 x 0.25 and 2 x 0.75 mg/day to achieve trough concentrations between 3 and 8 ng/mL. Pulmonary symptoms and radiological findings resolved completely within 1 to 4 weeks.. Everolimus is more hydrophilic by virtue of differing from sirolimus by one hydroxyl group. Sirolimus-induced pneumonitis improved after conversion to everolimus.

Topics: Aged; Creatinine; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pneumonia; Postoperative Complications; Sirolimus; Treatment Outcome

The purpose of this study was to evaluate predictors of an adverse outcome after "crush" bifurcation stenting.. The "crush" technique is a recently introduced strategy with limited data regarding long-term outcomes.. We identified 231 consecutive patients treated with drug-eluting stent implantation with the "crush" technique for 241 de novo bifurcation lesions. Clinical follow-up was obtained in 99.6%.. The in-hospital major adverse cardiac event (MACE) rate was 5.2%. At 9 months, 10 (4.3%) patients had an event consistent with possible post-procedural stent thrombosis. Survival free of target lesion revascularization (TLR) was 90.3%; the only independent predictor of TLR was left main stem (LMS) therapy (odds ratio [OR] 4.97; 95% confidence interval [CI] 2.00 to 12.37, p = 0.001). Survival free of MACE was 83.5% and independent predictors of MACE were LMS therapy (OR 3.79; 95% CI 1.76 to 8.14, p = 0.001) and treatment of patients with multivessel disease (OR 4.21; 95% CI 0.95 to 18.56, p = 0.058). Angiographic follow-up was obtained in 77% of lesions at 8.3 +/- 3.7 months. The mean late loss of the main vessel and side branch were 0.30 +/- 0.64 mm and 0.41 +/- 0.67 mm, respectively, with binary restenosis rates of 9.1% and 25.3%. Kissing balloon post-dilation significantly reduced the side branch late lumen loss (0.24 +/- 0.50 mm vs. 0.58 +/- 0.77 mm, p < 0.001).. The crush technique of bifurcation stenting with drug-eluting stents is associated with favorable outcomes for most lesions; however, efficacy appears significantly reduced in LMS bifurcations, and further research is needed before the technique can be routinely recommended in this group. Furthermore, the incidence of possible stent thrombosis is of concern and requires further investigation. Kissing balloon post-dilatation is mandatory to reduce side branch restenosis.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Coronary Thrombosis; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Paclitaxel; Postoperative Complications; Prognosis; Sirolimus; Stents; Time Factors; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Postoperative Complications; Sirolimus; Stents; Ultrasonography, Interventional

Sirolimus (SRL) in combination with Cyclosporine A (CsA) and steroids has been shown to lower the incidence of acute renal allograft rejection episodes, allowing CsA sparing. We retrospectively compared the incidence of posttransplant diabetes mellitus (PTDM) among kidney transplant recipients (KTx) immunosuppressed with SRL + CsA versus CsA alone. Patients were divided into two groups: SRL + CsA (n = 38) versus CsA (n = 48). Mean follow-up was 53.9 +/- 17.1 months. Seventeen/86 subjects (19.8%) developed diabetes after transplantation (7 IFG, 8.1%; 10 PTDM, 11.6%). The incidence was significantly higher in SRL + CsA (12/38 patients, 31.6%) compared with CsA (5/43 patients, 10.4%) (P = .0144, odds ratio 3.97). More patients required treatment in the SRL + CsA compared to CsA alone cohort (13.2% vs 2.1%, P = .051): 4 pts (10.5%) became insulin- dependent among SRL+CsA, vs none in the CsA group. Use of OHD was similar in both groups (2.6% SRL + CsA vs 2.1% CsA). There were no significant differences between the two groups in terms of age, sex distribution, BMI, or serum creatinine at 1 to 3 and 5 years from transplantation. All PTDM patients are alive at follow-up, while two grafts were lost due to chronic renal allograft dysfunction. Within the limits of a small retrospective study, we observed that SRL in combination with CsA increased the diabetogenic potential of CsA. A possible explanation of our findings is that higher CsA doses were used in the early experience with SRL + CsA; therefore the higher incidence of PTDM that we observed in the SRL + CsA combination may be a sign of toxicity. Careful monitoring of blood levels is mandatory in the SRL + CsA combination to avoid pleiotropic toxicity.

Topics: Adult; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Incidence; Insulin; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus

Lymphocele is a complication of renal transplantation, representing a lymphatic collection around the grafted kidney. The use of the immunosuppressive agent sirolimus (SRL) has been associated with a significant increase in lymphocele formation. This complication has been related to the antiproliferative activity of SRL, which delays surgical wound repair and closure of injured lymphatic vessels. The aim of this study was to relate the incidence of lymphocele with immunosuppression among 158 renal transplant patients operated with routine closure of all the visible lymphatic vessels around the iliac vessels and at the renal hilum. The incidence of lymphocele was not significantly different among the various immunosuppressive regimens.

Topics: Drainage; Humans; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Lymphocele; Postoperative Complications; Renal Replacement Therapy; Sirolimus

This retrospective study aimed to evaluate the benefit of switching from calcineurin inhibitors (CnI) to sirolimus in posttransplant Kaposi's sarcoma (KS). Fourteen patients monitored in five French departments who had developed posttransplant KS were switched from CnI to sirolimus either abruptly (n=9) or progressively (n=5) with trough levels 5-12 ng/mL. Two patients had a complete remission, eight a partial response, and five no significant improvement of KS. The mean time to response was 3.9 months. After a mean follow-up of 16 months, 3 partial responders, with previous severe and refractory KS, suffered again from KS progression despite the lack of concomitant infectious or neoplastic event. These relapses occurred 5-9 months after switching. The tolerance of sirolimus has been excellent except for in one patient who developed severe interstitial pneumonitis. Sirolimus is usually useful in the management of posttransplant KS. It may be, however, ineffective or transiently effective in some patients with severe KS. Prospective studies with pharmacodynamic evaluation are important in order to better assess the duration of responses and the mechanisms of primary and acquired drug resistance.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Time Factors; Treatment Outcome

Over the last decade, there has been a decrease in acute graft rejection rates following renal transplantation; however, this has not corresponded with an improvement in long-term outcomes of transplantation. One of the major causes of long-term morbidity and mortality in renal transplant recipients is cardiovascular disease. Immunosuppressive regimens, especially those including steroids and calcineurin inhibitors, have a negative role in the induction of cardiovascular risk factors. The proliferation signal inhibitors (PSIs)/mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown considerable promise in reducing acute rejection in renal transplant recipients. Although PSIs are associated with an increase in hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia), which is a major risk factor for atherosclerosis and associated cardiovascular disease, recent studies with sirolimus have demonstrated protection from atheroma progression in hyperlipidaemic apolipoprotein E-deficient mice. Here, we summarize the results of pre-clinical and clinical studies with sirolimus and everolimus, with particular emphasis on the beneficial and adverse effects that these drugs exert on the cardiovascular system, and the underlying molecular mechanisms.

Topics: Atherosclerosis; Cell Proliferation; Everolimus; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Calcineurin inhibitors (CNIs) are associated with important side effects, such as nephrotoxicity, and thus there is an interest in developing CNI-sparing protocols using agents such as the proliferation signal inhibitor/mammalian target of rapamycin inhibitor everolimus. In a 3-month pilot study using an abrupt conversion protocol, ciclosporin (CsA) treatment was stopped after the morning dose and everolimus was started at 3.0 mg/day. Mycophenolic acid (MPA)-based therapy was continued, or prednisolone increased to 10 mg/day until target everolimus trough blood levels (3-8 ng/ml) were achieved. To date, seven patients have been enrolled, with three having completed at least 3 months of follow-up. Overall, conversion was effective and well-tolerated. Patients consistently achieved everolimus trough blood levels >3 ng/ml, and no episodes of acute rejection or proteinuria were reported after 3 months. In patients who completed the study, there were no major changes in the leucocyte or platelet counts during everolimus treatment. Serum creatinine levels were maintained or decreased slightly. One patient experienced a transient increase in serum creatinine during an episode of pneumonia, but levels decreased again after resolution of infection and temporary everolimus dose reduction. Serum cholesterol and triglyceride levels increased, but remained within acceptable limits. One patient receiving enteric-coated mycophenolate sodium 1440 mg/day experienced increasing everolimus trough blood levels and anaemia after conversion, and was therefore likely to have been over-immunosuppressed. Abrupt conversion to everolimus from CsA was effective and well-tolerated in renal transplant recipients. A reduction in MPA dosage at the time of conversion may be necessary to prevent over-immunosuppression.

Topics: Aged; Calcineurin Inhibitors; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Pilot Projects; Postoperative Complications; Prednisolone; Sirolimus; Withholding Treatment

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

The calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus are currently an important part of immunosuppressive regimens, but are associated with increased cardiovascular risk factors, including hyperlipidaemia, hypertension and diabetes mellitus. Conversion from CNI-based regimens to proliferation signal inhibitors or mammalian target of rapamycin inhibitors, such as everolimus and sirolimus, has been associated with an improvement in cardiovascular risk. This case study describes a 59-year-old renal transplant recipient who presented with angina pectoris while receiving immunosuppression with CsA, azathioprine and steroids. The patient developed angina pectoris 5 years after receiving a cadaveric renal transplant. At the time, the patient was obese, with hypertension controlled with diuretics and calcium channel blockers, and hyperlipidaemia controlled with statins. A scintigram revealed plurisegmental myocardial ischaemia, and a coronary angiogram showed the presence of occlusions in the left anterior descending artery and circumflex coronary artery. The patient also had 70% stenosis of the right coronary artery, which was corrected by angioplastic percutaneous intervention. The patient was converted from azathioprine to sirolimus 2 mg/day (trough blood level, 6-10 ng/ml), while the CsA dose was tapered and withdrawn. The angina pectoris subsequently resolved, no progression of coronary artery disease (CAD) has been observed during follow-up and stable renal function has been maintained throughout. Conversion to an immunosuppressive regimen of sirolimus with CsA withdrawal, along with angioplastic percutaneous correction of right coronary artery stenosis, therefore led to the complete resolution of angina pectoris and no progression of the CAD was noticed in this obese renal transplant patient with drug-controlled hypertension and hyperlipidaemia.

Topics: Angina Pectoris; Angioplasty; Azathioprine; Calcineurin Inhibitors; Cell Proliferation; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Postoperative Complications; Signal Transduction; Sirolimus; Treatment Outcome; Withholding Treatment

Cyclosporine (CyA) is associated with many side effects, including endothelial dysfunction and transplant vasculopathy (TxV). We previously demonstrated that CyA results in impairment of nitric oxide bioavailability and enhanced sensitivity to endothelin-1 (ET-1). In this study, we evaluated rapamycin (SRL) for its effects on the endothelium.. Lewis rats (n = 8) were injected with SRL (1.5 mg/kg), CyA (5 mg/Kg), or saline (Con) intraperitoneally daily for 2-weeks. Thoracic aortic segments were assessed for endothelial-dependent (Edep) and independent (Eind) relaxation after exposure to acetylcholine and sodium nitroprusside by deriving the percent maximum relaxation (Emax). ET-1 plasma levels were also measured. Thoracic aortic expression of endothelial nitric oxide synthase (eNOS), ET(A) and ET(B) receptors (Rc), were determined. Oxidative injury was assessed by changes in 8-isoprostane levels. CyA exposure resulted in lower Edep vasorelaxation compared with control and SRL (Emax: SRL, 58+/-4%; CyA, 24+/-7%; Con, 52+/-8%; P=0.001). No differences in Eind vasorelaxation were seen. CyA exposure also increased sensitivity to ET-1 (% maximum contraction [Cmax]: Con, 211+/-8%; SRL, 230+/-5%; CyA, 259+/-3%; P=0.04). Only SRL treatment reduced ET-1 plasma levels. CyA reduced eNOS expression by 30% and increased ETA Rc expression by 34% compared with both Con and SRL (P=0.02). CyA resulted in higher 8-isoprostane levels (CyA, 50+/-2%; SRL, 3+/-3%; Con, 2+/-5%; P=0.02).. CyA results in vascular dysfunction characterized by impairment of Edep vasorelaxation and enhanced sensitivity to vasospasm. SRL did not impair Edep vasorelaxation or increase sensitivity to vasospasm while lowering ET-1 levels and preserving eNOS protein expression. We conclude that SRL is less deleterious to the vasculature than CyA and may prevent TxV by these mechanisms.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Cyclosporine; Dinoprost; Endothelin-1; Endothelium, Vascular; Enzyme Induction; Gene Expression Regulation; Immunosuppressive Agents; Male; Models, Animal; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroprusside; Organ Transplantation; Oxidative Stress; Postoperative Complications; Rats; Rats, Inbred Lew; Receptor, Endothelin A; Receptor, Endothelin B; Sirolimus; Vasoconstriction; Vasodilation

We investigated the fate of postprocedural incomplete stent apposition (ISA) after sirolimus-eluting stent (SES) implantation by evaluating long-term intravascular ultrasound findings in 168 consecutive patients (182 de novo lesions). Postprocedural ISA was defined as > or = 1 stent strut that was clearly separated from the vessel wall with evidence of blood speckle behind the strut without overlapping a side branch. After SES implantation, there were 61 ISA sites in 46 stents in 31 patients (23 at the proximal edge, 7 at the distal edge, and 31 within the stent body). There were no clinical, procedural, or intravascular ultrasound measurement differences between patients and lesions with versus without ISA. At follow-up, 15 acute ISA sites (25%) in 11 patients completely resolved and 40 sites (75%) in 20 patients persisted, although 32 of 46 persisting ISA sites (70%) decreased. There was a greater decrease in effective lumen area and a greater increase in peristent plaque area in the complete-resolution group than in the persistent-ISA group. No lesion developed stent thrombosis or in-stent restenosis (angiographic diameter stenosis > 50%). Six acute ISA sites were also associated with new, late acquired ISA, only 1 of which resulted in aneurysm formation. Although most ISAs after SES implantation do not resolve completely, the incidence of restenosis or thrombosis is not affected.

Topics: Acute Disease; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Stenosis; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prosthesis Failure; Sirolimus; Stents; Ultrasonography, Interventional

Sirolimus-induced interstitial pneumonitis (SIP) has been reported mainly in renal transplant recipients. However, it has recently been reported with increasing frequency in heart transplantation (HT) patients switched from calcineurin inhibitors (CNIs) to sirolimus. We reviewed the medical records of 30 patients who were treated with sirolimus. Twenty-seven patients were switched from a CNI, 2 patients were initially treated with sirolimus and in 1 patient sirolimus was used to treat a persistent cellular acute rejection. Three patients developed SIP. Symptoms included dry cough, shortness of breath and hypoxemia. High-resolution computed tomography (HRCT) scans showed patchy pulmonary consolidation in a peribronchial distribution or diffuse interstitial pulmonary infiltrates. Before onset of SIP, 2 patients had previous heart failure. Sirolimus discontinuation resulted in a complete resolution of symptoms. SIP is a common and severe adverse event (10%) in HT recipients treated with sirolimus. Drug discontinuation can dramatically improve clinical status. Previous lung injury may play a role in SIP pathogenesis.

Topics: Aged; Diagnosis, Differential; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Lung Diseases, Interstitial; Male; Middle Aged; Postoperative Complications; Sirolimus; Tomography, X-Ray Computed

We present real world experience from a single center registry comparing the 6-month outcome of percutaneous coronary intervention (PCI) in unselected high-risk individuals using either sirolimus-eluting (SES) or paclitaxel-eluting stents (PES).. We compared clinical outcome at 6 months follow-up in two cohorts of 156 consecutive patients (total n = 312) who underwent SES (June 2002-February 2003) and PES (march 2003-July 2003) implantation. The primary endpoint was a composite of major adverse cardiac events (MACE). Baseline clinical characteristics were well matched. The 6-month target vessel revascularization (TVR) rates were 1.9% (SES) and 2.6% (PES) and MACE rates were similar in the two groups (SES 4.5% vs. PES 3.2%, P = NS). In the PES group, intervention for multivessel disease, bifurcation lesions and in small vessels was more common, and for in-stent restenosis less common, reflecting the impact of drug eluting stents on indications for PCI. The incidence of sub-acute stent thrombosis, related to inadequate antiplatelet therapy in 3 of the 6 cases, was 0.95% with no difference between the two groups.. This study confirms the safety and efficacy of SES and PES in unselected high risk patients undergoing PCI. Clinical outcomes of both stents are equivalent at 6 months with low rates of MACE and TVR. These data provide important complementary information to forthcoming randomized studies.

Topics: Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Coated Materials, Biocompatible; Coronary Artery Disease; Coronary Restenosis; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Paclitaxel; Postoperative Complications; Prospective Studies; Registries; Risk Factors; Sirolimus; Stents; Taxus; Treatment Outcome

To present a patient in whom severe external carotid artery (ECA) stenosis causing ocular ischemia was treated with a drug-eluting stent.. A 55-year-old woman with severe, diffuse atherosclerosis presented with impaired left ocular perfusion and amaurosis fugax. Duplex ultrasonography and angiography documented bilateral occlusion at the origin of the internal carotid arteries, bilateral subtotal ECA stenoses, and subtotal distal left common carotid artery (CCA) restenosis following endarterectomy. Percutaneous revascularization of the left ECA and CCA stenoses was performed using a short coronary balloon-expandable sirolimus-eluting stent and a self-expanding nitinol stent, respectively. The procedure was uneventful, and the ocular symptoms resolved. At 6 months, the patient remained asymptomatic, with angiographically patent stents.. Drug-eluting stenting may be a novel option to treat symptomatic ECA stenosis.

Topics: Alloys; Amaurosis Fugax; Angiography, Digital Subtraction; Blood Vessel Prosthesis Implantation; Carotid Artery, Common; Carotid Stenosis; Coated Materials, Biocompatible; Endarterectomy, Carotid; Eye; Female; Humans; Immunosuppressive Agents; Ischemia; Middle Aged; Postoperative Complications; Reoperation; Sirolimus; Stents; Vascular Patency

Conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) is an option for renal transplant patients who develop a tumor. This strategy, however, may be associated with an increased risk of rejection.. We sought to evaluate a series of renal transplant patients who underwent conversion from CNI to SRL because they developed a tumor during the posttransplant period.. This prospective study of 29 patients included 2 patients with skin cancer (1 melanoma and 1 squamous cell carcinoma) and 27 patients who developed other tumors: lung (n = 6), prostate (n = 4), lymphoma (n = 2), colon adenocarcinoma (n = 2), kidney (n = 2), Kaposi sarcoma (n = 2), urothelium (n = 1), parotid (n = 1), larynx (n = 1), gastric (n = 1), breast (n = 1), tongue (n = 1), liver (n = 1), xanthoastrocytoma (n = 1), and aggressive angiomyxoma of the perineum (n = 1).. CNI were withdrawn in 28 patients and reduced in the remaining patient. Renal function was better when CNI were rapidly or abruptly suspended, with maintenance of cyclosporine (CsA) + SRL for more than 3 months being especially detrimental. Proteinuria worsened in patients whose preconversion levels were >0.5 g/d, particularly those treated with CsA. There was no episode of rejection.. SRL is a promising option for the management of posttransplant tumors. The switch in immunosuppression should be undertaken quickly, especially in patients under treatment with CsA.

Topics: Creatinine; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Postoperative Complications; Sirolimus

Sirolimus is a potent, nonnephrotoxic immunosuppressant with antiproliferative activity in nonimmune cells. Recent data support the conversion in late renal failure secondary to calcineurin inhibitors (CNIs), with limited experience in de novo regimens in patients with predictive factors of postoperative renal impairment.. We evaluated our experience of sirolimus-based immunosuppression administered to 25 heart transplant recipients.. A retrospective analysis of 25 heart transplant recipients who received sirolimus included 17 conversions due to late CNI-related chronic renal dysfunction, six patients with a de novo regimen, and two patients who developed posttransplant pulmonary neoplasms. The conversion from CNI to sirolimus was started with 2 mg, with an average time after transplantation of 78 +/- 43 months and a mean baseline serum creatinine level of 2.1 +/- 0.45 mg/dL. The mean clinical follow-up was 17 +/- 9 months postconversion, and included echocardiography and laboratory studies. In the de novo group successive endomyocardial biopsies were performed during the first semester.. Serum creatinine fell from 2.1 +/- 0.45 mg/dL to 1.8 +/- 0.51 mg/dL (P = .012). Mean sirolimus levels were 15 +/- 9 ng/mL (doses 2.2 +/- 0.4 mg). This improvement continued until 3 months (creatinine 1.5 +/- 0.35 P < .01)/sirolimus levels 11.7 +/- 5 ng/mL [1.9 +/- 0.7 mg]), with maintenance at 6 months (1.58 +/- 0.3 mg/dL/14 +/- 4 ng/mL [1.85 +/- 0.7 mg]) and 1-year postconversion (1.53 +/- 0.39 mg/dL; P = .019/10.7 +/- 2.5 ng/mL [1.5 +/- 0.7 mg]). De novo, after a mean follow-up of 13 months (range 3 to 35), sirolimus appeared to increase the incidence of a moderate histological grade of rejection without hemodynamic compromise. Side effects were common (63%), including peripheral edema, skin eruptions, and pericardial effusion. Only one patient discontinued treatment, due to intestinal intolerance. Four patients died during follow-up: two because of lung neoplasms and two because of progressive graft vessel disease.. Sirolimus improved late CNI-related chronic renal dysfunction. Kidney function was preserved using a de novo CNI-free immunosuppressive regimen for recent cardiac transplant recipients.

Topics: Adult; Aged; Creatinine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus

Chronic allograft nephropathy (CAN) is the primary reason for late allograft loss in kidney transplantation. The use of calcineurin inhibitors is suggested to be a risk factor for the development of CAN. Thus, calcineurin-inhibitor-free immunosuppressive protocols are needed to improve long-term graft outcome. Sirolimus affects the immune response by interfering with postreceptor interleukin-2 signaling. Safety profile of sirolimus is different from that of calcineurin inhibitors. We investigated the long-term effects of sirolimus on kidney allografts and fibrogenic growth factor expression and compared it to cyclosporine A. Kidney transplantations were performed from DA to WF rats and syngenic controls were done between DA rats. Allograft recipients were immunosuppressed daily with sirolimus 2 p.o. or CsA 1.5 mg/kg s.c. In addition, sirolimus-treated animals were treated with cyclosporine 1.5 mg/kg s.c. for the first 7 days after transplantation. Serum creatinine levels were measured once a week. Grafts were harvested 90 days after transplantation for histology and immunohistochemistry. Histological changes were scored according to the chronic allograft damage index (CADI). No signs of CAN were seen in syngenic grafts, CADI 0.8 +/- 0.2 (mean +/- SEM). In cyclosporine-treated allografts moderate to intense chronic changes were seen; CADI 10.3 +/- 0.6. Sirolimus significantly ameliorated the development of CAN compared to cyclosporine, CADI 3.0 +/- 0.5 (P < .05). Creatinine values of sirolimus-treated allografts were lower compared to the cyclosporine-treated allografts and were nearly similar to the syngenic grafts. Our results demonstrate that sirolimus attenuates the development of CAN and restores kidney function. Based on our findings, sirolimus improves the long-term kidney graft outcome.

Topics: Animals; Chronic Disease; Disease Models, Animal; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Rats; Sirolimus; Transplantation, Homologous; Transplantation, Isogeneic

Topics: Aspirin; Clopidogrel; Coronary Restenosis; Coronary Vessels; Delayed-Action Preparations; Humans; Paclitaxel; Perioperative Care; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; Stents; Ticlopidine

Sirolimus (SRL) is a new, potent immunosuppressive agent. More recently, proteinuria has been reported as a consequence of sirolimus therapy, although the mechanism has remained unclear. We retrospectively examined the records of 25 renal transplant patients, who developed or displayed increased proteinuria after SRL conversion. The patient cohort (14 men, 11 women) was treated with SRL as conversion therapy, due to chronic allograft nephropathy (CAN) (n = 15) neoplasia (n = 8); Kaposi's sarcoma, Four skin cancers, One intestinal tumors, One renal cell carsinom) or BK virus nephropathy (n = 2). SRL was started at a mean of 78 +/- 42 (15 to 163) months after transplantation. Mean follow-up on SRL therapy was 20 +/- 12 (6 to 43) months. Proteinuria increased from 0.445 (0 to 1.5) g/d before conversion to 3.2 g/dL (0.2 to 12) after conversion (P = 0.001). Before conversion 8 (32%) patients had no proteinuria, whereas afterwards all patients had proteinuria. In 28% of patients proteinuria remained unchanged, whereas it increased in 68% of patients. In 40% it increased by more than 100%. Twenty-eight percent of patients showed increased proteinuria to the nephrotic range. Biopsies performed in five patients revealed new pathological changes: One membranoproliferative glomerulopathy and interstitial nephritis. These patients showed persistently good graft function. Serum creatinine values did not change significantly: 1.98 +/- 0.8 mg/dL before SRL therapy and 2.53 +/- 1.9 mg/dL at last follow-up (P = .14). Five grafts were lost and the patients returned to dialysis. Five patients displayed CAN and Kaposi's sarcoma. Mean urinary protein of patients who returned to dialysis was 1.26 (0.5 to 3.5) g/d before and 4.7 (3 to 12) g/d after conversion (P = .01). Mean serum creatinine level before conversion was 2.21 mg/dL and thereafter, 4.93 mg/dL (P = .02). Heavy proteinuria was common after the use of SRL as rescue therapy for renal transplantation. Therefore, conversion should be considered for patients who have not developed advanced CAN and proteinuria. The possibility of de novo glomerular pathology under SRL treatment requires further investigation by renal biopsy.

Topics: Adult; Cadaver; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Middle Aged; Neoplasms; Postoperative Complications; Proteinuria; Retrospective Studies; Sirolimus; Tissue Donors

Impaired surgical site healing occurs in 20% to 50% of sirolimus (SRL)-treated renal transplant (RT) recipients, with most patients having received concomitant corticosteroids. We determined the incidence of surgical site complications among RT recipients receiving SRL with mycophenolate mofetil (MMF), with most patients on a steroid-avoidance protocol. SRL/MMF patients with complications within 3 months of transplantation were compared with 1) SRL/MMF patients without them and 2) matched RT recipients receiving tacrolimus (FK)/MMF. Between January 2002 and March 2005, 44 of 300 (15%) RT recipients received SRL within 6 weeks of transplantation. Fourteen (31.8%) developed lymphocele, bladder leak, wound dehiscence, cellulitis, or an abscess. Obesity (BMI > or =30 kg/m2) was significantly associated with problems: the mean BMI of SRL cases with complications was 29.9 kg/m2 vs 25.4 kg/m2 for SRL patients without them (P = .047). Seventy-one percent of obese SRL patients experienced complications compared with 24.3% (P = .025) of non-obese SRL patients. Surgical treatment was required in 29% of patients. Rates of maintenance steroid use were similar in SRL complicated cases compared with SRL patients without them. The FK control group showed a lower rate of complications (14.3%; P = .163) despite similar BMI, rejection rates, and chronic steroid use as the SRL group. Obesity and graft rejection were independent predictors of complications. Thus, among a group of predominantly steroid-free recipients on SRL, the rates of wound complications were similar to those seen previously, but the highest risk for them was observed in obese recipients and in those with acute rejection episodes. Wound complications were associated with significant morbidity.

Topics: Adult; Antilymphocyte Serum; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Medical Records; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Risk Factors; Sirolimus; Wound Healing

Kidney transplantation (KTx) recipients are at a higher risk of oncogenesis when compared to the general population. Sirolimus (SRL), a potent immunosuppressant, has shown promising antineoplastic effects in vitro and in vivo. This study retrospectively analyzed the neoplasm occurrence and the efficiency of SRL on unresectable malignancies in South Chinese KTx recipients. Thirty-three (1.64%) of 2017 patients who received KTx from January 1984 to December 2004 developed neoplasms at 4 to 117 months posttransplant, mostly in digestive organs (33.3%), the hematologic system (15.2%), or the skin (12.1%). The most common type was liver cancer (24.2%), followed by skin cancer, lymphoma, and thyroid cancer (9.1%). The median survival times were 41.5 and 6.0 months for those who did (n = 10) receive radical surgery or did not (n = 23), respectively. The 20-month survival rates were 70.0% versus 13.0% (P < .01). For unresectable patients, the median survival time of those treated with SRL (n = 8) was 14.5 months compared to 3.0 months for those who did not (n = 15). The survival rates at 12(th) and 20(th) months were 75.0% and 37.5% in the SRL group and 6.7% and 0% in the non-SRL group (P < .05). In conclusion, when compared with Western studies, a lower incidence and unique location pattern (liver cancer-dominant) are characteristics of de novo posttransplant neoplasms in South Chinese KTx recipients. Early diagnosis and feasible radical surgery are favorable for prognosis, and SRL is a treatment of choice for KTx recipients with neoplasms.

Topics: China; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Neoplasms; Neoplasms; Postoperative Complications; Retrospective Studies; Sirolimus; Survival Analysis; Time Factors

Topics: Aged; Diagnosis, Differential; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Lung Volume Measurements; Male; Postoperative Complications; Sirolimus; Tomography, X-Ray Computed

Topics: Abnormalities, Drug-Induced; Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Interactions; Drug Therapy, Combination; Female; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Multicenter Studies as Topic; Organ Transplantation; Postoperative Complications; Pregnancy; Pregnancy Complications; Sirolimus

Avascular necrosis (AVN) after renal transplantation has been largely attributed to the use of corticosteroids. However, other risk factors such as microvascular thrombosis and hyperlipidemia have been well described and may be of increased importance in the era of early steroid cessation and avoidance. We hypothesized that maintenance immunosuppressive medications known to be associated with these risk factors for AVN would also be associated with a higher risk of AVN.. By using the U.S. Renal Data System database, we studied 27,772 primary patients on Medicare who received a solitary kidney transplant between January 1, 1996, and July 31, 2000. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (AHRs) for patient- and transplant-related factors (including allograft rejection) with Medicare claims for AVN. The intensity and duration of corticosteroid use could not be assessed.. Among patients who were prescribed sirolimus at discharge, 3.5% of patients who received the combination of sirolimus-cyclosporine A (CsA) demonstrated AVN, compared with 1.4% of patients who received the combination of sirolimus-tacrolimus (P=0.06 by chi). In Cox regression, CsA use (vs. tacrolimus) (AHR 1.36, 95% confidence interval, 1.09-1.71) was independently associated with an increased risk of AVN. Sirolimus use showed a trend toward significance (AHR 1.59, 95% confidence interval, 0.99-2.56), with no significant interaction with CsA.. Compared with other maintenance immunosuppression, AVN was significantly more common after use of CsA prescribed at the time of discharge for renal transplantation. Whether this increased risk of AVN was directly attributable to hyperlipidemia, microvascular thrombosis, or differences in corticosteroid dosing could not be determined.

Topics: Adult; Cyclosporine; Diabetes Mellitus; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Medicare; Middle Aged; Necrosis; Postoperative Complications; Regression Analysis; Sirolimus; Survival Analysis; United States

The purpose of the present report was to evaluate clinical and angiographic outcomes of drug-eluting stent (DES) implantation in saphenous vein graft (SVG) lesions.. The safety and efficacy of DES implantation for the treatment SVG lesions remains uncertain.. We evaluated in-hospital and six-month outcomes in 61 consecutive patients treated with DES in SVG lesions from March 2002 to March 2004 (DES group), as compared to 89 consecutive patients treated with bare-metal stents (BMS) in the 24 months immediately before the introduction of DES (BMS group). Major adverse cardiac events (MACE) including death, myocardial infarction, target lesion revascularization (TLR), and target vessel revascularization (TVR) were recorded in-hospital and at six-month follow-up.. The rate of in-hospital MACE was similar between the two groups (6.6% vs. 5.6%, p = 1.0). Cumulative MACE at six months was 11.5% in the DES group and 28.1% in the BMS group (p = 0.02). The DES group had a significantly lower incidence of in-segment restenosis (10.0% vs. 26.7%, p = 0.03), TLR (3.3% vs. 19.8%, p = 0.003), and TVR (4.9% vs. 23.1%, p = 0.003). By Cox regression analysis, diabetes (hazard ratio [HR]: 3.03; 95% confidence interval [CI]: 1.33 to 6.90; p = 0.008), usage of BMS (HR: 2.53; 95% CI: 1.07 to 5.97; p = 0.03), and age of SVG (HR: 1.10; 95% CI: 1.02 to 1.19; p = 0.02) were identified as predictors of MACE at six-month follow-up.. Compared to BMS implantation, DES implantation in SVG lesions appears safe with favorable and improved mid-term outcomes.

Topics: Aged; Angioplasty, Balloon, Coronary; Case-Control Studies; China; Coronary Angiography; Coronary Restenosis; Female; Follow-Up Studies; Graft Occlusion, Vascular; Hospitalization; Humans; Immunosuppressive Agents; Italy; Male; Paclitaxel; Postoperative Complications; Proportional Hazards Models; Registries; Retrospective Studies; Saphenous Vein; Sirolimus; Stents; Survival Analysis; Treatment Outcome

Rapamycin (Rapa), one of the newer immunosuppressants has been found to control and prevent autoimmune features in animal models. This is the first report describing the successful control of post-transplant autoimmune hepatitis (AIH) with Rapa. Post-transplant AIH is diagnosed in the presence of raised transaminases, elevated immunoglobulin G, presence of autoantibodies and histologic changes consistent with AIH on liver biopsy. It may represent a recurrence of the original AIH that led to transplantation or present as a de novo AIH after liver transplant. Post-transplant AIH has conventionally been treated with Prednisolone (Pred) and Azathioprine (AZA). In this report, tailoring of immunosuppression after diagnosis of post-transplant AIH is described with special emphasis on those treated successfully with Rapa. Fifteen of 21 patients responded to treatment with an increase in dose of Pred and addition of AZA or Mycophenolate Mofetil (MMF) to calcineurin inhibitor. Five non-responders and one other patient with post-transplant AIH were treated with addition of Rapa. All six responded to treatment but drug was withdrawn in one patient. Adverse events were minimal. Rapa may prove to be an important addition in the control of autoimmune liver disease.

Topics: Autoantibodies; Azathioprine; Biopsy; Calcineurin Inhibitors; Child; Child, Preschool; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Infant, Newborn; Liver; Liver Diseases; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Sirolimus; Time Factors; Transaminases; Treatment Outcome

Randomized controlled studies suggest an increased incidence of perioperative wound complications among sirolimus-treated renal transplant patients. The present study analyzed the effect of rabbit antithymocyte globulin (rATG) on these postoperative complications.. Four hundred and twelve renal transplants were performed and managed postoperatively at two University-affiliated hospitals between January 1, 2001, and December 31, 2003. The patients received corticosteroids and Sirolimus, with delayed introduction of cyclosporine when the serum creatinine had decreased below 2.5 mg/dL. Two groups of patients were discriminated: group 1 received Basiliximab 20 mg on day 0 and day 4 (n = 283); group 2 recipients with a high panel of reactive antibody (PRA > 20%) and retransplant patients received rATG for induction (n = 129) for a maximum of 2 weeks postoperatively. The incidence of rejection was 14.5% for group 1 vs. 8.5% for group 2 patients. To avoid confounding variable associated with the rejection treatment, any patient with rejection was excluded for statistical analysis, as were patients with follow- up less than 30 days. The final study group for analysis included 350 patients: 235 with Basiliximab induction (group 1) and 115 rATG induction (group 2). The mean follow-up was 21.8 +/- 11 months. Differences in the incidences of postoperative hernia, wound infections, or lymphoceles requiring any form of drainage were analyzed for statistical significance using the chi-square test.. The percentage of patients with wound complications was 26.0% versus 39.1% (P < .025) for group 1 versus group 2, respectively. Incisional hernias occurred in 10.6% versus 18.3% patients (P < .05), wound infections in 11.1% versus 16.5% (P = NS), and lymphoceles in 10.6% versus 15.9% (P = NS) for the two groups, respectively.. rATG-induced renal transplants recipients treated with sirolimus, cyclosporine, and steroids show a significantly increased incidence of postoperative incisional hernias and a trend toward a greater number of lymphocele and wound infection complications.

Topics: Adult; Animals; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Body Mass Index; Cohort Studies; Creatinine; Cyclosporine; Drug Therapy, Combination; Ethnicity; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisone; Rabbits; Recombinant Fusion Proteins; Retrospective Studies; Risk Factors; Sirolimus

While bronchiolitis obliterans organizing pneumonia (BOOP) has been associated with the use of sirolimus (SIR), the incidence in a consecutive group of patients given SIR to replace a calcineurin-inhibitor (CI) is unknown. Twenty-nine consecutive cardiac transplant recipients were switched from a CI to SIR to ameliorate CI-associated nephropathy or coronary graft atherosclerosis. Seven patients (24%) developed BOOP. The clinical characteristics and biopsy results of these patients are presented. The clinical course and response to withdrawal of SIR in all and steroids in four of seven patients suggested the diagnosis of BOOP. Chest X-rays and CT scans showed typical findings of BOOP in all seven patients. Infection was excluded in all patients. Biopsy results were characteristic of BOOP in six of seven patients. Six patients recovered and one died. BOOP is a common and potentially serious adverse event in cardiac transplant patients switched from a CI to SIR, especially when SIR is started late post-transplantation.

Topics: Aged; Calcineurin Inhibitors; Cryptogenic Organizing Pneumonia; Female; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Sirolimus

Little is known about hearing impairment in patients after organ transplantation. Few cases of hearing loss associated with different immunosuppressants have been published. To evaluate severe hearing impairment in patients after liver transplantation (OLT), all living adult patients in need of a hearing aid were analyzed. Out of 521 transplanted patients, 25 (5%) were identified with hearing aids. Nine (36%) of these patients either suffered from hearing loss prior to OLT or experienced risk factors such as ototoxic drugs. Of the remaining 16 patients who developed severe hearing loss after OLT (64%), half were men. Mean age was 42 +/- 18 years at OLT, which took place 8 +/- 4 years ago. Main transplantation indication was virus-induced cirrhosis (44%). In 14/16 (88%) patients, the hearing aid was bilateral. In 50% of patients, the hearing aid was necessary within 2 years post-OLT. Additional tinnitus was present in 9/16 patients (56%), otalgia in three patients (19%). Four patients (25%) reported a history of sudden deafness. In three of them, an association with high levels of calcineurin inhibitors was found. The proportion of patients receiving tacrolimus (50%) was relatively higher than those receiving cyclosporine (50%) compared to control patients (28% respectively 64%, P < .05). In conclusion, a high incidence of severe hearing loss was found in patients after liver transplantation. In most patients, onset of hearing loss is early and bilateral, suggesting a dose-dependent toxicity. The pathogenetic role of different immunosuppressants remains to be evaluated.

Topics: Adult; Calcineurin Inhibitors; Deafness; Follow-Up Studies; Hearing Aids; Hearing Loss; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Postoperative Complications; Retrospective Studies; Sirolimus; Surveys and Questionnaires; Tacrolimus; Time Factors

Topics: Adult; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Sirolimus; Transplantation, Homologous

We describe two patients with in-stent thrombosis occurring 4 and 21 months after implantation of sirolimus-eluting stents. Both cases occurred following noncardiac surgery. In both cases, aspirin had been stopped prior to surgery. Both patient sustained a severe myocardial infarction; one died. The occurrence of late thrombosis of sirolimus-eluting stents is of concern.

Topics: Aged; Aged, 80 and over; Blood Vessel Prosthesis Implantation; Cardiac Surgical Procedures; Coated Materials, Biocompatible; Coronary Angiography; Coronary Stenosis; Coronary Thrombosis; Humans; Male; Myocardial Infarction; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; Stents; Time Factors

Sirolimus-eluting stents (SESs; Cypher) have demonstrated a significant reduction in restenosis rates when compared to bare metal stents (BMSs). The purpose of this study was to evaluate the strategy of exclusive use of two SESs versus the combination of one BMS and one SES for two-vessel coronary artery disease (CAD). It was found that the selective use of one SES combined with one BMS in patients undergoing percutaneous coronary intervention that requires more than one stent is safe, feasible, and associated with favorable procedural, 30-day, and 6-month clinical outcomes when compared to the exclusive use of SESs.

Topics: Aged; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Combined Modality Therapy; Coronary Angiography; Coronary Artery Disease; District of Columbia; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Sirolimus; Stents; Treatment Outcome

Drug-eluting stent usage has become commonplace for the percutaneous treatment of de novo coronary lesions, but the safety and efficacy profile for their evolving usage in restenotic lesions is largely unknown. We report three cases of angiographically confirmed drug-eluting stent thrombosis following treatment of restenotic lesions that occurred late (193, 237, and 535 days) and shortly after interruption of antiplatelet therapy. All three patients suffered ST elevation myocardial infarction, and there was one death. Further studies are necessary to better define the associated risk and ideal duration of antiplatelet therapy necessary in this cohort of patients with restenotic lesions.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Thrombosis; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; Stents; Time Factors

Sirolimus-eluting stents (SESs) are currently being used in patients undergoing percutaneous coronary intervention (PCI). SESs have not been evaluated in the treatment of acute myocardial infarction by primary angioplasty. We report our initial experience with SESs implanted during primary angioplasty. One hundred and three patients were treated within 12 hr after onset of acute myocardial infarction (AMI) with primary angioplasty and SES implantation. Those patients were compared to 504 patients treated with bare metal stents (BMSs). Angiographic success (TIMI flow grade 3 and residual stenosis < 50%) was completed in 98% of patients with SESs and no subacute stent thrombosis was reported. In-hospital outcomes were similar in the SES and BMS groups. At 6 months, major cardiac events were less frequent in the SES group than in the BMS group (9% vs. 24%, respectively; P < 0.001), driven by a lesser need for repeat revascularization with SESs (1% vs. 10.3% with BMSs; P = 0.014). Mortality at 6 months was 7% with SESs and 11% with BMSs (P = 0.14). SESs are safe and effective for the treatment of AMI by primary angioplasty. As compared to BMSs, SESs improve long-term outcome after AMI, mainly by reducing the need for repeat revascularization.

Topics: Aged; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Stenosis; District of Columbia; Female; Hospital Mortality; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Postoperative Complications; Retrospective Studies; Sirolimus; Stents; Treatment Outcome

Topics: Child; Humans; Immunosuppressive Agents; Organ Transplantation; Postoperative Complications; Sirolimus

We reported the late thrombosis of a drug-eluting coronary stent related to discontinuation of antiplatelet therapy for venous surgery of the right leg more than half and a year after its implantation. After this acute myocardial infarction, a cardiac assistance device has to be used as a bridge to transplantation because of end stage ischaemic cardiopathy. Antiplatelet therapy management must be revisited for eluting stents, which can clot lately after its implantation.

Topics: Acute Disease; Antineoplastic Agents, Phytogenic; Cardiomyopathy, Dilated; Heart Transplantation; Heart-Assist Devices; Humans; Leg; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Platelet Aggregation Inhibitors; Postoperative Complications; Sirolimus; Stents; Thrombosis; Vascular Surgical Procedures

We sought to identify the frequency of incomplete stent apposition (ISA) in sirolimus-eluting stents (SES) and clarify its findings and clinical sequelae.. Late-acquired ISA has been reported in bare-metal stents (BMS) and brachytherapy and recently in drug-eluting stents. However, the characteristics of late ISA in SES have not been clarified.. From the SIRIUS trial, a randomized, multicenter study comparing SES and BMS, serial qualitative intravascular ultrasound (IVUS; at stent implantation and eight-month follow-up) was available in 141 patients (BMS: n = 61; SES: n = 80). The IVUS images were reviewed for the presence of ISA.. Incomplete stent apposition at follow-up was observed in 19 patients (BMS: n = 6 [9.8%]; SES: n = 13 [16.3%]; p = NS). Among these, 12 had ISA after intervention and at follow-up (persistent ISA). Late-acquired ISA was seen in the remaining seven cases, all from the SES group (BMS: n = 0; SES: n = 7 [8.7%]; p < 0.05). In late-acquired ISA, there was an increase in external elastic membrane area (after intervention: 16.2 +/- 2.7 m2; follow-up: 18.9 +/- 3.6 mm2; p < 0.05). The location of stent-vessel wall separation was primarily at the stent edges in persistent ISA cases, whereas late-acquired ISA in SES occurred mostly in the mid portion of the stent. There were no negative clinical events reported for any ISA cases at 12-month clinical follow-up.. Late ISA was observed in 8.7% of patients after SES implantation. There were no negative clinical events associated with this IVUS finding at 12-month clinical follow-up; however, careful long-term follow-up will be necessary.

Topics: Combined Modality Therapy; Drug Delivery Systems; Female; Humans; Male; Middle Aged; Postoperative Complications; Sirolimus; Stents; Time Factors; Ultrasonography, Interventional

Restenosis rate is lower after sirolimus-eluting stent (SES) implantation than after bare metal stent (BS) implantation. We evaluated the impact of SES implantation on immediate and 12-month outcome in diabetic patients with multivessel coronary artery disease (MVD).. From April 2002 to September 2003, 100 consecutive diabetic patients with MVD without previous myocardial revascularization underwent successful elective percutaneous coronary intervention (PCI) with SES on native coronary arteries at our institutions. A group (n = 122) of consecutive diabetic patients with MVD treated with BS implantation (BS group) for de novo lesions was selected from our database and matched with the SES group. Major adverse cardiac events (MACEs) during hospital stay and at follow-up included nonfatal myocardial infarction, death, bypass surgery, and re-PCI.. At 12 +/- 4 months, MACEs occurred in 25% of patients in the SES group and in 44% of those in the BS group (P = .003, OR .72, 95% CI 0.57-0.91). Need for repeat intervention (re-PCI or bypass surgery) occurred in 17% of patients in the SES group and in 41% of those in the BS group (P < .001, OR .67, 95% CI 0.52-0.86). No significant difference in the rate of death and myocardial infarction was observed. In the SES group, the independent predictors of MACEs at follow-up were premature clopidogrel discontinuation (hazard ratio 20.62, 95% CI 1.60-264.97, P = .020) and chronic renal insufficiency (hazard ratio 4.73, 95% CI 1.99-11.25, P = .0004).. As compared with BS implantation, SES implantation favorably influences outcome in diabetic patients with MVD, mainly by reducing the need for new revascularization.

Topics: Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Carriers; Female; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Postoperative Complications; Sirolimus; Stents; Time Factors

To explore relationships between sirolimus dosing, concentration and clinical outcomes.. Data were collected from 25 kidney transplant recipients (14 M/11 F), median 278 days after transplantation. Outcomes of interest were white blood cell (WBC) count, platelet (PLT) count, and haematocrit (HCT). A naive pooled data analysis was performed with outcomes dichotomized (Mann-Whitney U-tests).. Several patients experienced at least one episode when WBC (n = 9), PLT (n = 12), or HCT (n = 21) fell below the lower limits of the normal range. WBC and HCT were significantly lower (P < 0.05) when sirolimus dose was greater than 10 mg day(-1), and sirolimus concentration greater than 12 microg l(-1). No relationship was shown for PLT and dichotomized sirolimus dose or concentration.. Given this relationship between sirolimus concentration and effect, linked population pharmacokinetic-pharmacodynamic modelling using data from more renal transplant recipients should now be used to quantify the time course of these relationships to optimize dosing and minimize risk of these adverse outcomes.

Topics: Adult; Dose-Response Relationship, Drug; Hematocrit; Hematologic Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukocyte Count; Platelet Count; Postoperative Complications; Prognosis; Retrospective Studies; Sirolimus

We examined our experience using the sirolimus eluting stents (Cypher) as an alternative to surgical revascularization in carefully selected cohort of patients undergoing multi-vessel percutaneous coronary intervention.. Fifty consecutive patients with multi-vessel disease who were good candidates for both surgical and percutaneous revascularization were included in the current analysis. All patients underwent a careful clinical evaluation prior to the intervention, and they were followed for procedural and clinical outcomes for nine months.. Mean age was 64+/-11 years (40 males, 30% diabetics) and 10 patients (20%) had three-vessel disease. Angina class was 2.7+/-0.6 at baseline. Overall, 116 lesions were treated using 122 stents (mean 2.4 stents per patient). Total mean stent length was 43+/-12 mm (range: 21-90 mm). Overall, one patient died during follow-up (2%), no patient had stroke or Q wave MI and one patient experienced non-Q myocardial infarction. There was no documented stent thrombosis and two patients (4%) underwent target-vessel revascularization. The hierarchical cumulative major adverse cardiac event rate was 8% and the cardiac event-free survival rate was thus 92%.. Multi-vessel stenting using Cypher stents is a viable treatment strategy in selected group of patients with multi-vessel coronary artery disease. It is associated with excellent intermediate-term clinical outcomes and thus it could serve as the primary revascularization strategy of choice in appropriate candidates.

Topics: Aged; Aged, 80 and over; Angina Pectoris; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Artery Disease; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Postoperative Complications; Retrospective Studies; Sirolimus; Stents; Survival Rate; Treatment Outcome

Anemia is common in patients with chronic kidney disease (CKD) and those who have received a kidney allograft. Anemia is most prevalent in kidney transplant recipients before and immediately after transplantation, but also can occur months after transplantation if the donor kidney begins to fail. Replacement therapy for CKD-related and posttransplantation anemia is effective through the administration of exogenous erythropoiesis-stimulating proteins. Darbepoetin alfa (Aranesp; Amgen Inc, Thousand Oaks, CA) is a unique erythropoiesis-stimulating protein that can be administered at an extended dosing interval relative to recombinant human erythropoietin because of its approximately 3-fold longer serum half-life. Although darbepoetin alfa has been shown to be an effective treatment for patients with anemia of CKD and anemia after kidney transplantation, limited data have been published showing efficacy in treating women with anemia of these conditions during pregnancy. We report a case of successful darbepoetin alfa treatment for severe anemia in a pregnant transplant recipient.

Topics: Adult; Anemia; Cesarean Section; Contraindications; Cyclosporine; Darbepoetin alfa; Erythropoietin; Female; Ferrous Compounds; Humans; Hydronephrosis; Immunosuppressive Agents; Kidney Transplantation; Nephrostomy, Percutaneous; Postoperative Complications; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy, High-Risk; Puerperal Disorders; Seizures; Sirolimus; Stents; Treatment Refusal

Conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) has become an option in patients with chronic allograft nephropathy or other conditions. However, in some cases an increase of proteinuria has been reported after such therapeutic intervention. The aim of this study was to characterize the clinical course of this so far unexplained proteinuria after conversion. We performed a retrospective analysis evaluating 94 renal transplant patients from various Spanish centers. Proteinuria (629 determinations) and clinical developments were analyzed between 6 months before and 6 months after conversion. Patients were divided into three groups according to mean proteinuria before conversion (group A: <300 mg/d; group B: 300 to 2000 mg/d; and group C: >2 g/d). The mean proteinuria level was 1.69 g/24 h (n = 312 determinations) before and 2.36 g/24 h after conversion (n = 317 determinations; P = .006), which corresponds to an overall increase of 25% (1.55 to 1.69 g/24 h considering only determinations of 1 month before and 1 month after conversion; P = NS). We could not detect any clear correlation between proteinuria and serum creatinine nor between changes of proteinuria and changes of serum creatinine. A variance analysis for repeated measures showed an increase in proteinuria compared to the preconversion values (P = .003), and when the three groups of preconversion proteinuria were evaluated separately it could be observed that this change in the evolution of proteinuria was almost completely dependent of an increase in the group C (preconversion proteinuria greater than 2 g/d; P = .03), whereas in the other two groups changes were almost irrelevant. Finally, the switch to SRL in renal transplant recipients is followed by an increase in the level of proteinuria predominantly dependent of an increase in patients with high levels of preconversion proteinuria, whereas it seems to be irrelevant in patients without or with light or moderate proteinuria. These results suggest that this might not be a direct effect of SRL.

Topics: Calcineurin Inhibitors; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Proteinuria; Sirolimus; Spain; Time Factors

Rapamycin (RAPA) is a powerful immunosuppressant that also acts as an antiproliferative, which, therefore, could be useful in the treatment and prevention of bronchiolitis obliterans (BOS) in lung transplant recipients. We sought to report our experiences with RAPA in lung transplant patients with BOS that has not responded to the administration of other drugs.. We performed a retrospective analysis of the clinical characteristics, pulmonary function, and complications among patients with BOS who received RAPA.. RAPA was administered to 11 patients, three single-lung transplant and eight bilateral lung transplant recipients, of whom five were women and six men, of mean age 48 years (26 to 65). The median posttransplant time to the initiation of RAPA for progressive BOS was 32 months (4 to 69) with a posttreatment follow-up of 15 months (3 to 34). RAPA was administered to all patients in association with a calcineurin inhibitor (tacrolimus in seven cases, and cyclosporine in four and steroids. Eight of the 11 patients (72%) with progressive deterioration of pulmonary function showed improved and/or stabilized FEV1 figures after introduction of RAPA. Eight patients developed adverse effects, which were possibly related to RAPA, leading to treatment withdrawal in two cases. The most frequent adverse effects were infections among 6 of the 12 cases, and myelosuppression in three.. RAPA may be useful to stabilize or improve pulmonary function in patients with BOS. Nevertheless, it was necessary for patients to be closely monitored so that possible adverse effects, and especially infections, may be detected early.

Topics: Bronchiolitis Obliterans; Forced Expiratory Volume; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Retrospective Studies; Sirolimus

Dysregulated fibroblast proliferation is thought to play an important role in the progression of bronchiolitis obliterans (BO) after lung transplantation. Augmented immunosuppression is often used to treat BO. We investigated the effect of methylprednisolone (mPRED), cyclosporine A (CsA), tacrolimus (FK506), azathioprine (AZA), mycophenolate mofetil (MMF), and everolimus (rapamycin derivative [RAD]) on the proliferative capacity of fibroblasts cultured from transbronchial biopsies of lung transplant recipients.. Primary cultures of human lung fibroblasts were obtained from 14 transbronchial biopsies of lung transplant recipients. Subconfluent cells were serum starved for 24 hr followed by growth stimulation in the presence or absence of the respective drug in six concentrations ranging as follows: 0.01 to 100 mg/L for mPRED; 0.01 to 50 mg/L for CsA and AZA; 0.001 to 5 mg/L for FK506 and MMF; and 0.00001 to 1 mg/L for RAD. Proliferation was quantified by [3H]thymidine incorporation and direct cell count. A toxic drug effect was excluded by trypan blue.. Drug concentrations (mg/L) causing a 50% inhibition of fibroblast proliferation were mPRED 4; CsA 20; FK506 0.3; AZA 7; MMF 0.3; and RAD 0.0006. Drug concentrations (mg/L) causing inhibition of fetal bovine serum-induced proliferation were mPRED 60; CsA 45; FK506 3; AZA 35; MMF 1; and RAD 0.003.. RAD and MMF were the most potent antifibroproliferative drugs and were effective at concentrations achieved clinically, supporting their use for the treatment of patients with early BO. Our method holds promise as an in vitro model to assess the likely in vivo responses of human lung fibroblasts to specific immunosuppressive drugs.

Topics: Adult; Aged; Azathioprine; Bronchi; Bronchiolitis Obliterans; Cell Division; Cells, Cultured; Cyclosporine; Everolimus; Female; Fibroblasts; Humans; Immunosuppressive Agents; Infections; Lung Diseases; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus

The increased incidence of Kaposi's sarcoma (KS) in organ transplantation has been related to the KS herpesvirus and the permissive effect of immunosuppressive therapy. Calcineurin inhibitors are the cornerstone of immunosuppression in organ transplantation, although they could promote tumor progression. In contrast, sirolimus, a new immunosuppressive agent, exhibits potent antitumor activity. We postulated that conversion from cyclosporine to sirolimus in patients with KS could favor regression of KS lesions without increasing the risk of graft rejection. Two renal transplant recipients with KS underwent conversion from cyclosporine to sirolimus. Both patients showed complete regression of KS lesions and excellent clinical and functional results. Sirolimus offers a new and promising approach to the management of posttransplantation KS and probably to other types of malignancies in organ transplant recipients.

Topics: Aged; Antibiotics, Antineoplastic; Cyclosporine; Diabetic Nephropathies; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Sarcoma, Kaposi; Sirolimus

This study evaluated clinical outcome after multivessel stenting with sirolimus-eluting stents (SES) in unselected lesions.. Safety and effectiveness of multivessel SES implantation is currently unknown.. Major adverse cardiac events (MACE) (death, myocardial infarction [MI], and repeat revascularization) were analyzed at 30 days and at 6 months after multivessel SES implantation.. In 155 consecutive patients, 573 SES were implanted in 3.3 +/- 1.3 lesions per patient. At 30 days, the cumulative MACE rate was 10.3%: 7.1% patients developed a non-Q-wave MI, 1.9% developed a Q-wave MI, 0.6% died for non-cardiac reasons, and 0.6% had a repeat revascularization. Clinical follow-up was obtained in all 112 eligible patients treated for 359 lesions at a mean time of 6.5 +/- 2.2 months. The cumulative MACE rate was 22.3%: 3 (2.7%) deaths (1 for cardiac reasons), 4 (3.6%) MIs, target lesion revascularization (TLR) in 16 (14.3%) patients with 24 (6.7%) lesions. Target vessel revascularization was required in 18 (16.1%) patients due to TLR of lesions treated with SES or to disease progression (1.8% of patients). Cox regression analysis revealed total stent length per patient as the most powerful independent predictor of MACE. Overall stent thrombosis occurred in three (1.9%) patients.. Multivessel SES implantation can be safely performed on patients with complex coronary artery disease. The need for revascularization increases because of the cumulative effect of TLR on patients with multiple lesions.

Topics: Aged; Angioplasty, Balloon, Coronary; Biomarkers; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Artery Disease; Creatine Kinase; Creatine Kinase, MB Form; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Isoenzymes; Italy; Male; Middle Aged; Postoperative Complications; Predictive Value of Tests; Reoperation; Sirolimus; Stents; Stroke Volume; Survival Analysis; Treatment Outcome

The purpose of this study was to assess the safety and effectiveness of sirolimus-eluting stent (SES) postdilatation with largely oversized balloons. We evaluated the clinical outcome of 68 consecutive patients enrolled in the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry who underwent percutaneous coronary intervention with SES implantation and further postdilatation with balloons > 1 mm larger than the stent nominal size. Angiographic follow-up was either scheduled for selected subgroups or clinically driven. Overall, 75 lesions were treated. The procedure was successful in 98.5% of the cases. One patient (1.5%) underwent emergency coronary bypass surgery for acute vessel occlusion. During 10.1 +/- 1.7 months of follow-up, three patients (4.5%) died, one (1.5%) had acute myocardial infarction, and four (6%) had target vessel revascularization. At angiographic follow-up, loss index was 0.13 +/- 0.34 and restenosis rate was 7.7%. Although not routinely recommended in every patient, SES postdilatation with largely oversized balloons appears a safe and effective strategy for selected patients.

Topics: Aged; Blood Vessel Prosthesis Implantation; Catheterization; Coated Materials, Biocompatible; Coronary Angiography; Coronary Disease; Coronary Restenosis; Equipment Design; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Netherlands; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Reoperation; Sirolimus; Stents; Treatment Outcome; Ultrasonography, Interventional

Restenosis has long remained the major limitation of intracoronary stenting, but several randomized trials have recently shown that the use of drug-eluting stents appear to reduce markedly the risk of recurrence following treatment of de novo lesions. To evaluate whether the results of randomized trials can be generalized to routine clinical practice, all patients receiving at least one sirolimus-eluting stent (SES) in two Swiss hospitals were entered into a prospective registry. Only target vessels with a reference diameter > 3.5 mm were excluded. Clinical follow-up was obtained after 6 months. A total of 183 patients were included. The procedural success was 97.8% and the incidence of in-hospital MACE was 2.2%. At 7 +/- 2 months, 95.6% of the patients were event-free, and target lesion revascularization was required in only three patients (1.6%). The excellent medium-term results obtained with the SES in randomized trials can be replicated in routine clinical practice.

Topics: Aged; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Disease; Coronary Restenosis; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Practice Patterns, Physicians'; Prospective Studies; Reoperation; Sirolimus; Stents; Switzerland; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Disease; Coronary Restenosis; Humans; Immunosuppressive Agents; Postoperative Complications; Practice Patterns, Physicians'; Sirolimus; Stents

A prospective, pilot trial was started to evaluate the effect of a sirolimus-based immunosuppressive regimen on acute and chronic rejection in de novo lung transplant patients. Primary lung transplant (LTx) recipients received a sirolimus- and tacrolimus-based immunosuppressive therapy immediately after transplantation. Both immunosuppressants were administered with trough level adjusted, while steroid administration was minimized. Four patients were enrolled (2 single-lung transplants, 1 double-lung transplant, 1 heart-lung transplant) in the study. Mean ischemia time was 387 +/- 92 minutes. Acute rejection (at least Grade A1 ISHLT) was detected in 1 patient. Incidence of infection was 0.6 infection per 100 patient-days (3 Aspergillus infections). Until hospital discharge mean sirolimus trough level was 6.2 +/- 1.2 ng/ml. Depending upon mean sirolimus trough levels of each patient, severe wound-healing complications were seen in 3 patients, resulting in bronchial airway dehiscence in 2 patients with lethal outcome in 1 patient. As a result of these complications, we revised the study design after inclusion of only 4 patients: Sirolimus administration is now started after completion of bronchial wound-healing. Sirolimus-based immunosuppressive therapy administered immediately after lung transplantation seems to be associated with severe wound-healing complications of the bronchial anastomosis.

Topics: Adrenal Cortex Hormones; Adult; Bronchial Diseases; Graft Rejection; Heart-Lung Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prospective Studies; Sirolimus; Tacrolimus; Wound Healing

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

The use of bare stents for the percutaneous intervention of saphenous vein bypass grafts (SVGs) is associated with a high subsequent rate of restenosis. To assess the impact of the sirolimus-eluting stent (SES), we studied 19 consecutive patients who underwent de novo SVG intervention treated solely with SES. Mean graft age was 10 years. Clinical presentation was an acute coronary syndrome in 68%. In total, twenty-two de novo lesions were treated with 35 SESs (mean=1.6 stents per lesion). Use of glycoprotein IIb/IIIa inhibitor therapy and distal embolization protection device were at operator discretion and were 42% and 32%, respectively. The rate of in-hospital major adverse cardiac events (MACE) was 11%, related to 2 patients with a creatine kinase rise consistent with peri-procedural acute myocardial infarction (AMI); a distal protection device was not utilized in either. Over a mean 12.5+/-2.6 month follow-up, one patient died from a non-cardiac cause, and there were no further AMIs. Target lesion revascularization was undertaken in 1 patient (5%); survival free of MACE was 84%. In conclusion, utilizing SESs for percutaneous intervention of degenerate SVGs is associated with a low rate of target vessel revascularization. Increased utilization of distal protection devices might reduce the peri-procedural rate of AMI.

Topics: Acute Disease; Aged; Anastomosis, Surgical; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Drug Delivery Systems; Female; Follow-Up Studies; Humans; Male; Postoperative Complications; Reoperation; Saphenous Vein; Sirolimus; Stents; Suture Techniques

Sirolimus is an immunosuppressive drug which has proved its effectivity to reduce the incidence of acute rejection in renal transplantation receptors. As this drug lacks nephrotoxic effects, its simultaneous use with other anticalcineurinic drugs allows the use of reduced doses. Thrombocytopenia and hyperlipidemia are the best known side-effects of sirolimus administration. Alterations in hepatic biochemistry results are also common. Some instances of interstitial pneumonitis associated to its use have been recently reported. In this paper we present a clinical case related to this rare but already confirmed adverse side-effect, which apart from the other more common nosologies occurring in immunosuppressed patients, should be taken into account in the differential diagnosis of interstitial pneumonitis in patients who are being administered this drug.

Topics: Aged; Antilymphocyte Serum; Azathioprine; Cyclosporine; Diagnosis, Differential; Diuretics; Doxazosin; Drug Therapy, Combination; Famotidine; Furosemide; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Male; Muscular Diseases; Mycophenolic Acid; Pneumonia, Bacterial; Postoperative Complications; Prednisone; Sirolimus

Among the numeruos adverse side effects of tacrolimus (TAC), de novo thrombotic microangiopathy stands out as an infrecuente but severe complication. Renal dysfunction is the only alteration that should lead to suspicion of thrombotic microangiopathy, because the clinical features of intravascular hemolysis are not always found. The definitive diagnosis can usually be made with kidney biopsy. Patientes with TAC induced thrombotic microangiopathy usually promptly recover after treatment withdrawal or reduction in the dose of TAC and a short course of plasma therapy, but the risk of rejection increases. Switching from TAC to cyclosporine has also been tried with resolution of the hemolysis but thrombotic microangiopathy has been noted with both and this condition may later recur. We present a 29-year-old man who received a kidney-pancreas transplant for end-stage diabetic nephropathy. After initial induction with basiliximab, the immunosuppression consisted of prednisone, tacrolimus and mycophenolate mofetil. Twenty four days posttransplantation his renal function declined with a peak creatine level of 2.35 mg/dl. Laboratory studies showed thrombocytopenia and features of intravascular hemolysis. TAC associated hemolytic uremic syndrome was suspected and drug was immediately stopped and converted to sirolimus. Also he was treated with plasma infusion. The allograft biopsy showed focal glomerular and arteriolar acute thrombosis without evidence of rejection. Our experience demostrate that switching from tacrolimus to sirolimus could be an adecuate strategy for patients who develop FK506-associated de novo thrombotic microangiopathy without increase risk of acute rejection.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Duodenostomy; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Jejunostomy; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Male; Mycophenolic Acid; Pancreas Transplantation; Pancreatic Fistula; Plasma; Postoperative Complications; Prednisone; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

A common clinical problem following organ transplantation is the development of renal failure due to calcineurin inhibitors. Sirolimus offers the potential of providing appropriate immunosuppression without nephrotoxicity. This study evaluates the impact of sirolimus monotherapy on renal function in patients late following heart transplantation and correlates trough sirolimus levels with area-under-the-concentration time curve measurements.. Six male patients with renal impairment late following heart transplantation (mean 8 years) were offered sirolimus therapy. Calcineurin inhibition was discontinued in all patients on commencing sirolimus. Patients started on sirolimus 2 to 5 mg/d orally. Venous blood samples for pharmacokinetic studies and repeat creatinine clearance were performed before and 6 weeks after commencement of sirolimus in all subjects.. Sirolimus trough levels accurately reflected sirolimus area-under-the-concentration time curve measurements. There was no change in renal function. Mean creatinine clearance prior to commencing sirolimus was 26.7 (12.2) mL/min and the post-sirolimus creatinine clearance performed 6 weeks later was 23.4 (11.7) mL/min (P = .64).. Trough levels of sirolimus correlate with drug exposure and may be used to monitor sirolimus therapy. No improvement in renal function following calcineurin inhibitor withdrawal occurred in this cohort.

Topics: Aged; Area Under Curve; Chronic Disease; Circadian Rhythm; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Postoperative Complications; Sirolimus; Time Factors

Sirolimus (SRL) is a powerful immunosuppressant used primarily in calcineurin inhibitors (CNI)-related nephrotoxicity. However, reports of drug-related side effects are increasing. The aim of our report is to review the frequency and timing of these complications within our transplant patient population.. We retrospectively reviewed the medical records of liver-transplanted patients treated with sirolimus between November 1998 and April 2002. The data collected included SRL serum levels, frequency of reported and documented SRL-related side effects, and survival outcomes. Statistical evaluation included Pearson chi-square and the Fisher's exact tests.. Overall, 205 patients were identified, with 30 patients removed from the analysis for different reasons. Of the remaining 175 patients, 91 (52%) patients developed a complication other than an increase in serum triglycerides and/or cholesterol. The most frequent complications were: bilateral lower extremity edema (57.1%), dermatitis (25.3%), oral ulcers (24.2%), joint pain (23.0%), pleural effusion (16.5%) and increase in abdominal girth (9.9%). Other complications included: generalized edema (5.5%), pericardial effusion (5.5%), facial edema (2.2%), and upper extremity edema (1.3%). In addition, we reported two cases of hepatic artery thrombosis, one case of wound dehiscence with evisceration that required surgical repair, and one case of skin cancer. Interestingly, we found that a previous history of myocardial ischemia correlates with the development of SRL side effects.. SRL is a powerful immunosuppressant but not devoid of side effects. These results have elevated our level of suspicion when instituting SRL and may help with early recognition and prevention of drug related complications.

Topics: Edema; Humans; Immunosuppressive Agents; Liver Transplantation; Oral Ulcer; Patient Selection; Postoperative Complications; Retrospective Studies; Sirolimus

We previously reported that the use of basiliximab together with sirolimus permits a window of recovery from delayed graft function before the introduction of reduced-dose cyclosporine. The present study reviews our experience with the substitution of thymoglobulin for basiliximab as induction therapy for recipients at increased risk for early acute rejection episodes.. We retrospectively reviewed 145 cadaveric renal allograft recipients who received either basiliximab (n=115) or thymoglobulin (n=30) in combination with sirolimus and prednisone, followed by delayed introduction of reduced doses of cyclosporine. Recipients were stratified as high immune responders if they were African American, a retransplant recipient, or a recipient with a panel-reactive antibody greater than 50%. All other recipients were considered low immune responders.. Basiliximab-treated high immune responders exhibited a higher incidence of acute rejection episodes (26%) than either basiliximab-treated low immune responders (10%, P=0.04) or thymoglobulin-treated high immune responders (3%, P=0.01). The median time to initiation of cyclosporine was 12 days; cyclosporine was initiated when the serum creatinine level was 2.5 mg/dL or less. Patients with early return of renal function displayed a lower incidence of acute rejection episodes than those with later recovery of function (P=0.003). High immune responders treated with basiliximab expressed a higher mean serum creatinine level at 3 months (P<0.01), 6 months (P=0.02) and 12 months (P=0.01) than either low immune responders treated with basiliximab or high immune responders treated with thymoglobulin.. A strategy combining sirolimus with basiliximab for low-immunologic risk recipients and thymoglobulin for high-risk recipients leads to prompt recovery of renal function with a low risk of acute rejection episodes.

Topics: Adult; Aged; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Racial Groups; Recombinant Fusion Proteins; Reoperation; Retrospective Studies; Sirolimus

Sirolimus-eluting stent (SES) implantation has been shown to reduce repeat revascularization in various randomized trials. The present study evaluated the outcomes after SES implantation in 46 octogenarian patients. SES implantation in octogenarians appears to be feasible and is associated with very small subsequent need for repeat target vessel revascularization at 1 year.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Combined Modality Therapy; Coronary Artery Disease; Female; Follow-Up Studies; Hospital Mortality; Humans; Immunosuppressive Agents; Male; Netherlands; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Sirolimus; Stents; Treatment Outcome

Sirolimus (SRL) is an immunosuppressive agent of potential benefit in clinical liver transplantation (LTX). One of the major side effects of SRL is hyperlipidemia, which is reported in up to 44% of patients. In this report, we describe the lipid profiles of 20 stable liver transplant recipients who received SRL for immunosuppression.. The study group received SRL in combination with tacrolimus and/or mycophenolate mofetil (MMF). The control group was administered calcineurin inhibitor (CI) and MMF. Fasting serum cholesterol level, high-density lipoproteins (HDL) and low-density lipoproteins (LDL) were measured regularly. Furthermore, the total cholesterol/HDL ratio and the LDL/HDL ratio were evaluated. Diabetes and hypertension were monitored as well.. In the SRL group, hypercholesterolemia was found in three patients (15%) and hypertriglyceridemia in two patients (10%). There was no marked difference from the control group, although a higher association of SRL with hyperlipidemia was described in the literature. Furthermore, HDL and LDL levels were similar in both groups, as well as total cholesterol/HDL ratio and LDL/HDL ratio. Diabetes and hypertension had a similar incidence in both the groups. Thus, there was no difference concerning the cardiovascular atherosclerosis risk between the immunosuppressive protocol with SRL or with CI.. The results of our retrospective study demonstrated that the immunosuppressive regimen can potentially influence the incidence of hyperlipidemia in patients after LTX. SRL in combination with tacrolimus and/or MMF had no higher incidence of hyperlipidemia than CI and MMF. The combination of immunosuppressive therapy with low dose and low levels of each immunosuppressive agent could decrease the risk of atherosclerosis and its complications in long-term survivors after LTX.

Topics: Adult; Aged; Female; Humans; Hyperlipidemias; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus

Voriconazole is currently contraindicated for use with sirolimus. We report our experience with voriconazole/sirolimus in two renal transplant recipients. To our knowledge, this is the first experience with voriconazole/sirolimus. An interaction requiring a 75% to 87.5% sirolimus dose reduction was noted, but goal trough levels and clinical tolerability were achieved.

Topics: Adult; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candidiasis; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Fungal; Male; Middle Aged; Postoperative Complications; Pyrimidines; Sirolimus; Triazoles; Voriconazole

Topics: Arterial Occlusive Diseases; Blood Vessel Prosthesis; Coated Materials, Biocompatible; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Postoperative Complications; Sirolimus; Stents

Topics: Creatinine; Cyclosporine; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Sirolimus

Sirolimus (SRL), a fermentation product of Streptomyces hygroscopicus, complexes with the FKBP12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G(1)-S phase cell cycle arrest. Safety and efficacy have been documented in clinical renal transplantation, but concerns were raised due to important biologically relevant side effects. Hyperlipidemia was identified, beginning with early clinical experiences, and the unexpected findings that SRL may exacerbate CsA associated nephrotoxicity was observed during the pivotal phase III studies. This report details results of our experience using SRL (target trough concentration, 10-15 ng/mL) with low dose CsA (target trough concentration, 50-100 ng/mL), seeking to determine whether this approach might provide effective immunosuppression while reducing associated nephrotoxicity. Among 121 renal transplant recipients, 62 received the SRL based regimen and 59 received MMF with all patients receiving CsA and prednisone. Similar to earlier clinical experiences, hematopoeitic abnormalities and hyperlipidemia were observed among patients who received SRL, and those abnormalities were readily controlled. However, unlike observations from the phase III SRL studies, renal function was not adversely affected. These findings support the growing body of evidence indicating that SRL based immunosuppression in combination low dose calcineurin inhibitors and corticosteroids is safe, efficacious, and without associated renal toxicity.

Topics: Blood Pressure; Creatinine; Cyclosporine; Dose-Response Relationship, Drug; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Reoperation; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins; Time Factors

A retrospective survey was performed to establish patient and graft outcome for all 41 patients at our centre receiving sirolimus (SRL) in combination with calcineurin inhibition (CNI) as primary therapy for the 6 years prior to March 2002. Patient mortality [12%; n = 5 (TTP, lymphoma, mucormycosis, and small bowel perforation] was significantly higher at 3 months compared with those not receiving SRL, but not thereafter. 12.8% had delayed graft function and 33% had one or more episodes of rejection in the first 6 months. Mean GFR at 12 months was significantly lower (47.3 mL/min) in the SRL group compared with those not receiving SRL (51.3 mL/min). Twenty-two patients had a 12-month protocol biopsy; CNI toxicity was present in 36%. SRL was associated with significant hyperlipidaemia (serum cholesterol, 5.2 +/- 1.4 at baseline vs 7.3 +/- 1.7 mmol/L at 3 months, P <.001; triglycerides, 2.3 +/- 1.4 at baseline vs 2.7 +/- 1.1 mmol/L at 3 months, P <.05). Mild thrombocytopenia occurred in 23% but was not associated with haemorrhagic events. LDH increased by 62%, remaining elevated out to 2 years post engraftment. Seven patients developed insulin requiring diabetes mellitus, similar to the rate observed in our general transplant population.Thus, in this early experience, SRL in combination with CNI was associated with significant mortality and morbidity including CNI toxicity, presumably a reflection of a heavy burden of immunosuppression. However, 1-year graft survival on SRL was similar to the mean Australia-wide graft survival regardless of immunosuppression. The future use of SRL may center around CNI sparing and avoidance type protocols.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Sirolimus; Survival Analysis; Time Factors; Treatment Outcome

At the Albany Medical Center, we have a long-term experience, mean follow-up of 61 months, in 31 renal transplant recipients treated with sirolimus, cyclosporine microemulsion formulation, and prednisone. In these patients the rate of acute rejection was 13%, actual patient and graft survival at 1 year was 100%, and the mean serum creatinine at 1 year was 1.3 mg/dL. Furthermore, long-term graft survival was 90%. The success of this regimen stimulated us to evaluate a subsequent sirolimus-based protocol, initiated in April, 2001, which decreased exposure to calcincurin inhibitors at 3 months posttransplant (n = 50). At a mean follow-up of 10 months, graft survival was 96%. The rate of acute rejection was only 10% and the mean serum creatinine was 1.5 mg/dL. Furthermore, no acute rejection episodes have developed subsequent to the reduction in calcineurin inhibitor dosing at 3 months. Sirolimus is an effective immunosuppressive agent that safely allows for a reduction in calcineurin-inhibitor dosing.

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sirolimus; Time Factors

Calcineurin inhibitors are associated with adverse events, including nephrotoxicity and diabetes that might reduce the benefits of long-term graft survival. We report our experience in converting kidney (K), kidney-pancreas (KP), pancreas (P), and (L) recipients from a calcineurin inhibitor/mycophenolate mofetil (MMF)/prednisone dose-induced nephrotoxicity (K = 9, KP = 5, P = 1, L = 5), hemolytic uremic syndrome (HUS) (K = 7, KP = 5), chronic allograft nephropathy (K = 12, L = 1), and glucose intolerance (K = 9, KP = 6, P = 2, L = 2).. The conversion protocol consisted of an abrupt discontinuation of the calcineurin inhibitor with sirolimus (8-12 mg, PO loading dose) initiated 24-72 hours after stopping the calcineurin inhibitor. Sirolimus was titrated to target trough levels of 12-16 ng/mL. Daclizumab 2 mg/kg IV was given to all KP and P recipients on days 0 and 14 postconversion.. Resolution of HUS occurred in 12 of 12 patients (100%) with a drop in serum creatinine from 3.3 +/- 1.5 to 1.8 +/- 0.9 mg/dL (P =.04). Sirolimus conversion due to nephrotoxicity, HUS, and chronic allograft nephropathy improved serum creatinine from 2.9 +/- 1.4 to 2.2 +/- 0.9 mg/dL (P =.01). Eleven of 19 patients (58%) resolved glucose intolerance. Two patients suffered rejection due to noncompliance. Increases in cholesterol (208 +/- 70 to 243 +/- 77 mg/dL, P <.05) and triglycerides (232 +/- 145 to 265 +/- 148 mg/dL, P = NS), and minimal reduction in platelet values (243 +/- 85 to 237 +/- 85, P = NS) occurred.. These data suggest that a calcineurin inhibitor-free immunosuppressive regimen with sirolimus, mycophenolate mofetil, and steroids preserves graft function in patients with clinical indications warranting calcineurin inhibitor discontinuation.

Topics: Adult; Calcineurin Inhibitors; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prednisone; Racial Groups; Retrospective Studies; Sirolimus; Time Factors

Rapamycin is an immunosuppressive drug with a distinct and unique mode of action and a specific side effect profile. We report here briefly on our personal clinical experience using this immunosuppressive drug in different combinations and settings. Rapamycin is without any doubt an efficient drug capable of preventing acute allograft rejection in a variety of immunosuppressive combinations. It is also a very potent drug that is not devoid of serious side effects. Infectious complications as a result of strong inhibition of the immune system are a frequent cause of hospitalization with severe morbidity and even mortality. Fungal infections and pneumonia are among the most devastating complications. As clinical experience with rapamycin grows and the therapeutic window of the drug can be further narrowed, these infectious complications will improve. Wound healing problems and lymphocoeles form another frequent surgical dilemma and are related to the antiproliferative properties of rapamycin. Last, hyperlipidemia warrants the use of statins in the majority of rapamycin-treated patients and whether this unfavorable side effect will offset the theoretically beneficial cardiovascular effects of the drug remains to be determined in controlled trials with long-term follow-up. Finally, the specific antiproliferative properties of rapamycin and the fact that it exerts no nephrotoxicity make this drug an alternative for calcineurin inhibitors and could make it an ideal candidate for treating chronic allograft dysfunction.

Topics: Female; Graft Rejection; Histocompatibility Testing; Hospitals, University; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Reoperation; Retrospective Studies; Sirolimus; Transplantation, Homologous; Wound Healing

Sirolimus was used as a single agent for maintenance immunosuppression in a pilot trial of 29 primary kidney transplant patients using lymphocyte depletion with Campath-1H as an induction strategy. This allowed sirolimus to be analyzed (dose, blood level, and side effect profile) in the absence of steroid and calcineurin inhibitors. A sirolimus dose of 4 mg/day resulted in blood levels in the 8 to 9 ng/mL range. Of the 29 patients, 8 patients (28%) had rejection. The sirolimus levels were not significantly different in patients with or without rejection. The cardiovascular risk profile in terms of lipid profile and hypertension control was favorable. Increase in cholesterol and triglyceride levels at one month (not statistically significant) necessitated treatment in 60% of patients with decline in levels by 6 and 12 months. Management of hypertension was also favorable with the majority of patients (55%) being on one hypertensive medication. Sirolimus monotherapy was well tolerated on the whole. Wound healing, leukopenia, and anemia were not significant problems. In conclusion, monotherapy has been well tolerated with a favorable side effect profile. However, a rejection rate of 28% was noted.

Topics: Follow-Up Studies; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Kidney Transplantation; Leukocyte Count; Leukopenia; Monitoring, Physiologic; Platelet Count; Postoperative Complications; Sirolimus; Time Factors

The goal of this study was to assess the efficacy of sirolimus in lung-transplant recipients.. The study was designed as a single center, consecutive case study of lung-transplant recipients treated with sirolimus, tacrolimus, and prednisone. All study subjects also received an HMG-CoA reductase inhibitor, and prophylaxis for cytomegalovirus and Pneumocystis carinii.. A total of 15 subjects were enrolled in the study. Within 6 months, significant airway complications occurred in four subjects, three of whom died. At that point, the investigators terminated enrollment in the study. The study population was compared retrospectively with a group of 83 consecutive lung recipients treated with cyclosporine (n=64) or tacrolimus (n=19), mycophenolate mofetil, and prednisone. This confirmed an increased incidence of airway dehiscence and reduced survival in the sirolimus-treated patients. Sirolimus-treated patients had a low incidence of acute rejection. No significant differences were noted in the incidence of bacterial or fungal bronchopulmonary infections.. We observed an unexpectedly high incidence of postoperative airway dehiscence in lung-transplant recipients treated with sirolimus, in combination with tacrolimus, prednisone, and an HMG-CoA inhibitor. Further studies will be needed to determine the safety and efficacy of using sirolimus after complete airway healing has occurred.

Topics: Adolescent; Adult; Aged; Bronchi; Female; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Sirolimus; Surgical Wound Dehiscence; Tacrolimus

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

Deep venous thrombosis (DVT) tends to occur in greater frequency among cyclosporine (CsA)-treated renal-transplant recipients. Because administration of sirolimus may increase the whole-blood concentrations of CsA, we sought to assess the impact of the combination regimen on the incidence, predisposing factors, and consequences of postoperative DVT, transplant renal-vein or artery thrombosis, and pulmonary embolus.. We retrospectively evaluated two cohorts of renal transplant recipients: CsA/prednisone (Pred)+/-azathioprine (n=136, group A) or sirolimus+CsA+Pred (n=354, group B) using Fisher's exact t and chi-square tests, as well as Kaplan-Meier analyses, odds ratios, and multiple logistic regression methods.. The 7 of 136 (5.1%) incidence of thrombotic events in group A was similar to the 20 of 354 (5.6%) incidence in group B (P=0.513; NS) and occurred no more frequently ipsilateral to the transplant. Although the occurrence of an acute-rejection episode was not associated with the DVT diagnosis, all affected patients displayed elevated serum creatinine (Scr) values, which remained slightly higher than baseline following recovery (group A 1.63+/-1.22-1.95+/-0.93 mg/dL; group B 1.70+/-1.11-2.01+/-0.88 mg/dL). Renal biopsies failed to show evidence of intrarenal coagulopathy. No patient lost a graft as a complication of DVT, nor did these events produce other lasting adverse effects. Patients in the sirolimus group showed a strong correlation between the occurrence of DVT and the previous existence of an ipsilateral or contralateral lymphocele.. Addition of sirolimus to a CsA+Pred regimen does not increase the incidence of postoperative thrombotic events among renal transplant recipients.

Topics: Adult; Anti-Inflammatory Agents; Cohort Studies; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Lymphocele; Male; Middle Aged; Postoperative Complications; Prednisone; Retrospective Studies; Risk Factors; Sirolimus; Thromboembolism

Mycophenolate mofetil (MMF) and sirolimus impair wound healing. We compared sirolimus vs. MMF to determine the relative impact on surgical complications and wound healing in adult kidney transplant recipients. This retrospective, single center study of 235 adult kidney transplants performed between 1 January 2000 and 31 January 2002 identified 158 adult, kidney-only recipients treated with tacrolimus and prednisone, from which two groups were defined: group 1 (n = 84) received MMF, group 2 (n = 74) received sirolimus. The incidence of fluid collections, wound problems, dehiscence, and urine leak were compared. A multivariate stepwise logistical regression analysis was performed to identify risk factors. The overall incidence of complications was 21.5%, with rates significantly lower in group 1 (2.4%) vs. group 2 (43.2%, p < 0.0001). Regression analysis showed only sirolimus (p < 0.001) and hypo-albuminemia (p = 0.006) to independently correlate with complication occurrence. In subanalyses, lymphoceles correlated only with sirolimus (p = 0.003), while other wound problems also correlated with higher body mass index (p = 0.067). The use of sirolimus, tacrolimus and prednisone was associated with a greater incidence of lymphoceles, non-lymphocele perinephric fluid collections and other consequences of poor wound healing, as compared to contemporary patients treated with MMF, tacrolimus and prednisone.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Postoperative Complications; Regression Analysis; Retrospective Studies; Sirolimus; Wound Healing

Chronic allograft nephropathy (CAN) is responsible for most cases of late kidney allograft loss. However, no effective treatment is available so far. Everolimus (RAD) (40-O [2-hydroxyethyl] rapamycin) is a new immunosuppressive agent with antiproliferative and apoptosis-enhancing effects. We asked whether everolimus can ameliorate CAN even at advanced stages, whether everolimus treatment affects the level of growth factor mRNA, and whether everolimus treatment affects the number of apoptotic cells in the graft.. We transplanted kidneys from Fisher rats into Lewis rats and treated recipients with everolimus over different time periods. Grafts were analyzed 20 or 28 weeks after transplantation.. Everolimus delayed the progression of CAN when started at an early stage. Surprisingly, everolimus even ameliorated CAN when initiated at an advanced stage. Interestingly, apoptosis was more prevalent in treated animals, particularly in those with delayed treatment as compared with controls.. Everolimus ameliorates CAN as a result of antiproliferative or apoptosis-enhancing effects.

Topics: Animals; Apoptosis; Chronic Disease; Everolimus; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Postoperative Complications; Rats; Rats, Inbred F344; Rats, Inbred Lew; Sirolimus; Transplantation, Homologous

To determine the effect of cyclosporine and rapamycin administration on renal function after ischemia/reperfusion injury (I/R). Cyclosporine A has known nephrotoxic effects. Thus, cyclosporine therapy subsequent to I/R injury may further exacerbate graft dysfunction. Rapamycin is a newer agent that suppresses the immune system by a different mechanism.. Male Wistar rats (250 g) were anesthetized, and the suprarenal aorta was clamped for 40 minutes. The right kidney was removed. After recovery, the rats were divided into four groups: group 1, controls, no ischemia and no treatment (n = 10); group 2, ischemia with no treatment (n = 8); group 3, ischemia plus rapamycin (0.17 mg/kg/day gavage, n = 8); and group 4, ischemia plus cyclosporine A (30 mg/kg/day intraperitoneally, n = 9). The glomerular filtration rate was measured 5 to 7 days after I/R injury using urinary iohexol clearance. Data are expressed as the mean +/- SEM, and intergroup comparisons were made using one-way analysis of variance.. The mean GFR value for the controls (no ischemia, no treatment) was 1.23 +/- 0.08 mL/min; for group 2 (ischemia, no treatment), it was 1.05 +/- 0.10 mL/min; for group 3 (ischemia plus rapamycin) 1.06 +/- 0.14 mL/min; and for group 4 (ischemia plus cyclosporine A) 0.44 +/- 0.06 mL/min (P <0.05 versus the other three groups). The mean arterial pressure was significantly lower in the ischemic rats treated with cyclosporine A (P <0.05 versus the other three groups).. After I/R injury, rapamycin may preserve renal function compared with cyclosporine treatment, because it does not have a direct vasoconstrictor effect on the renal microcirculation.

Topics: Animals; Calcineurin; Cyclosporine; Glomerular Filtration Rate; Immunosuppressive Agents; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Male; Nephrectomy; Postoperative Complications; Rats; Rats, Wistar; Reperfusion Injury; Sirolimus; Tissue and Organ Procurement

Topics: Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Lung Diseases, Interstitial; Middle Aged; Postoperative Complications; Sirolimus

The aim of this study was to determine whether there has been an increase in the incidence or severity of wound-healing complications that can be attributed to the introduction of newer immunosuppressive drugs.. Consecutive series of adult kidney-only transplant recipients were selected from our Unified Transplant Database backward from September 2002. There were 513 patients divided into groups on the basis of their maintenance immunosuppression given for at least the first 30 days posttransplant. Group I (152) was given sirolimus, mycophenolate mofetil, and prednisone (SRL/MMF/P) between March 2000 and September 2002; group II (168) was given cyclosporine A (CsA)/MMF/P between January 1999 and July 2002; and group III (193) was given azathioprine (AzA)/CsA/P between January 1993 and December 1997. A classification system for wound-healing problems was developed, and each of the three groups was analyzed by univariate and multivariate analysis.. From groups III to II to I, there was a significant increase in mean age (42.4 vs. 49 years), percent of patients diabetic (17% vs. 29%), mean body mass index (BMI) (24.2 vs. 27.1 kg/m2), and percent BMI greater than 30 (13.5% vs. 27%). The cumulative percentage of all wound-healing problems between group I (19.7%) vs. group II (16.1%) and group III (15.6%) was not significantly different. The most significant risk factor was a recipient BMI greater than 30 (P=0.0012) and delayed graft function (P=0.0041).. During a 10-year period marked by changing recipient demographics, the introduction of MMF and SRL did not result in a significant increase in transplant wound-healing complications. The most significant risk factor associated with transplant wound-healing complications remains body weight, which was the major influence for each of the immunosuppressive drug combinations described.

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Sirolimus; Time Factors; Wound Healing

Calcineurin inhibitor-related renal toxicity affects patient and graft survival in transplant recipients. Our clinical experience has revealed sirolimus to be an effective agent in treating renal insufficiency related to calcineurin inhibitor toxicity.. We performed a retrospective review of the medical records of OLT recipients suffering from chronic renal insufficiency and treated with sirolimus at the University of Miami.. Fourteen patients (nine men and five women) of mean age 57 years who had been treated with tacrolimus for at least 30 days were converted to sirolimus after developing nephrotoxicity. Mean creatinine clearances collected on day 0, 30, 60, and 90 after conversion were 40.1 mL/min, 49.6 mL/min, 53.9 mL/min, and 51.4 mL/min, respectively. Episodes of acute cellular rejection were not increased during the sirolimus conversion.. This retrospective review suggests that OLT patients suffering from tacrolimus-related renal insufficiency successfully converted to sirolimus may benefit from this therapy.

Topics: Creatinine; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Retrospective Studies; Sirolimus

Topics: Adult; Antilymphocyte Serum; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Plasmapheresis; Platelet Count; Polycystic Kidney, Autosomal Dominant; Postoperative Complications; Sirolimus; Thrombosis; Treatment Outcome

Topics: Calcineurin; Creatinine; Cytomegalovirus Infections; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Retrospective Studies; Sirolimus; Time Factors

Topics: Adult; Aged; Diabetes Mellitus; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Isoantibodies; Kidney Transplantation; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adult; Biopsy, Needle; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Humans; Male; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Antilymphocyte Serum; Child; Drug Administration Schedule; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Rituximab; Sirolimus

Topics: Adult; Child; Graft Rejection; Humans; Immunosuppressive Agents; Intestine, Small; Liver Transplantation; Postoperative Complications; Retrospective Studies; Sirolimus; Survival Rate; Transplantation, Homologous; Wound Healing

Topics: Antilymphocyte Serum; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Reoperation; Retrospective Studies; Risk Factors; Sirolimus; Steroids; Treatment Failure

Topics: Adult; Aged; Anti-Bacterial Agents; Erythromycin; Humans; Immunosuppressive Agents; Kidney Transplantation; Legionellosis; Male; Postoperative Complications; Sirolimus

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Epstein-Barr Virus Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Mice; Neoplasm Metastasis; Postoperative Complications; Sirolimus; Transplantation Immunology; Tumor Virus Infections; Virus Activation

Topics: Adult; Cardiovascular Diseases; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Reoperation; Retrospective Studies; Risk Factors; Sirolimus; Steroids; Tacrolimus

In our swine model of obliterative bronchiolitis preventing obliteration by the standard immunosuppression with cyclosporine, methylprednisolone, and azathioprine was not successful. The purpose of this study was to test the ability of a new immunosuppressive regimen to prevent alloimmune reaction and obliteration of the allografts. This regimen includes the novel macrolide SDZ RAD, i.e., 40-O-(2hydroxyethyl)-rapamycin.. Donor lung allografts of 1 cm3 were implanted sub-cutaneously into 11 random-bred non-related domestic pigs receiving daily oral cyclosporine (10 mg/kg) and methylprednisolone (20 mg). In addition, the animals received either oral azathioprine (2 mg/kg) (Group 1) or oral SDZ RAD (1.5 mg/kg) (Group 2). Histologic alterations were graded from 0 to 3 based on repeatedly removed implants during a follow-up period of 3 months.. Total epithelial destruction and permanent luminal obliteration occurred within 37 days in Group 1. After an initial grade of 2.3+/-0.3 destruction, epithelial recovery was evident in Group 2 (P < 0.01), and the bronchi stayed patent. Cartilaginous destruction was milder in Group 2 (P < 0.05) than in Group 1, but chondrocytic proliferation was more intense (P < 0.05). Alveolar tissue and native structures of the bronchial wall were destroyed in Group 1, but preserved in Group 2 with total recovery after a mild-grade initial necrosis.. Unlike the standard triple therapy, SDZ RAD combined with cyclosporine and methylprednisolone preserves the pulmonary allografts and prevents epithelial destruction and subsequent luminal obliteration. This suggests that this regimen might efficiently suppress obliterative bronchiolitis and improve long-term results in lung transplant recipients.

Topics: Animals; Azathioprine; Bronchi; Bronchiolitis Obliterans; Disease Models, Animal; Epithelium; Everolimus; Graft Rejection; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Sirolimus; Swine; Transplantation, Heterotopic; Transplantation, Homologous

Topics: Apolipoproteins; Cholesterol; Cholesterol, HDL; Cyclosporine; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipoprotein Lipase; Postoperative Complications; Sirolimus; Triglycerides

Topics: Adult; Apolipoprotein C-III; Apolipoproteins A; Apolipoproteins B; Apolipoproteins C; Azathioprine; Calcineurin Inhibitors; Cholesterol; Cyclosporine; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Postoperative Complications; Reference Values; Sirolimus; Tacrolimus; Triglycerides

Advances in surgical techniques, postoperative care, and experience have led to improved outcome in heart transplant patients. Specifically, the use of corticosteroid-free immunosuppression has reduced the risk of infection. The use of pravastatin early after transplantation has led to a decrease in clinically severe rejection episodes, improvement in survival, and reduction in transplant coronary artery disease. Reduction in natural-killer-cell cytotoxicity in the pravastatin-treated patients suggests an adjunct immunosuppressive effect of pravastatin in those patients on CyA-based immunosuppression. Quality of life has also improved in the heart transplant recipient with cardiac rehabilitation demonstrating a beneficial role in the improvement of exercise capacity. Newer immunosuppressive agents and strategies continue to demonstrate benefit in improving survival and the quality of life of the heart transplant recipient.

Topics: Acute Kidney Injury; Antibodies, Monoclonal; Denervation; Graft Rejection; Heart; Heart Transplantation; Humans; Immunosuppression Therapy; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Quality of Life; Sirolimus; Tacrolimus; Ventricular Dysfunction, Right

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Cyclosporine; Enzyme Induction; Immunosuppressive Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Polyenes; Postoperative Complications; Rats; Rats, Inbred ACI; Rats, Inbred WF; Sirolimus; Transplantation, Homologous; Transplantation, Isogeneic

Topics: Animals; Aorta, Abdominal; Arteriosclerosis; Everolimus; Immunosuppressive Agents; Ischemia; Male; Polyenes; Postoperative Complications; Rats; Rats, Inbred F344; Sirolimus; Transplantation, Isogeneic; Tunica Intima

Obliterative bronchiolitis is the major cause of long-term morbidity and mortality in heart-lung and lung transplant recipients. There is presently no completely effective therapy for the treatment of obliterative bronchiolitis. We have examined the effects of rapamycin (RPM) on the development of obliterative airway disease in murine recipients of heterotopically transplanted allograft tracheas. In this model, an untreated allograft develops almost complete occlusion of the airway lumen with fibroblastic tissue and collagen scar by day 28 after transplantation. RPM administered intraperitoneally at the time of transplantation or even as late as day 14 after transplantation markedly inhibited obliteration of the airway lumen by fibroblastic tissue. Also, RPM significantly inhibited infiltration of the graft by macrophages. In the RPM-treated animals, the airway was reconstituted with an attenuated squamous epithelium rather than a normal pseudostratified epithelium. No adverse side effects were observed with RPM doses up to 12 mg/kg/ day. These findings suggest a potential role for RPM, perhaps in combination with cyclosporine, in preventing and treating obliterative bronchiolitis in heart-lung and lung allograft recipients.

Topics: Animals; Bronchiolitis Obliterans; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Polyenes; Postoperative Complications; Sirolimus; Trachea; Transplantation, Homologous