sirolimus and Hyperlipidemias

Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Most LAM patients are at a high risk of losing lung function at an accelerated rate and developing progressive dyspnea. Recently, several studies have reported their experience with pharmacological treatments for LAM. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy and safety of these therapies.. PubMed (Medline), EMBASE, Cochrane Library, Web of Science and EBSCO Host were searched (until March 31, 2019) for eligible prospective studies regarding LAM patients treated with pharmacological treatments. Random effect models were used for quantitative analysis.. Fourteen prospective studies regarding five pharmacological treatments (including sirolimus, everolimus, doxycycline, triptorelin, and a combination therapy of sirolimus and hydroxychloroquine) were enrolled in our systematic review, and ten of them were used for the meta-analysis. Seven prospective studies reported that sirolimus was effective at improving or stabilizing lung function and alleviating renal angiomyolipoma (AML) in LAM patients. Subsequent quantitative analyses showed that during sirolimus treatment, the pooled values of lung function and 6-min walk distance (6MWD) were not significantly changed (P > 0.05), with the pooled response rate of AML being 0.62 (95% confidence intervals [CIs]: 0.43 to 0.82, I. Overall, sirolimus and everolimus were recommended for the treatment of LAM because they could stabilize lung function and alleviate renal AML. Doxycycline and triptorelin were not recommended for the treatment of LAM because no beneficial outcomes were consistently observed. The efficacy and safety of combination therapy remain to be further explored.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Drug Therapy, Combination; Enzyme Inhibitors; Everolimus; Humans; Hydroxychloroquine; Hyperlipidemias; Lymphangioleiomyomatosis; Prospective Studies; Sirolimus; Stomatitis; Treatment Outcome

The study was designed to compare the outcomes of sirolimus (SRL) combined with tacrolimus (TAC) and mycophenolate mofetil (MMF) combined with TAC in kidney transplantation recipients.. A literature search of PubMed, Embase, and Web of Science was performed to identify relevant studies, and the last update was on February 1, 2018. All studies with appropriate data comparing the SRL group with the MMF group were included. SRL and MMF were used in sufficient doses. Relevant information was recorded and analyzed. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the effects of SRL and MMF. Relevant outcomes, including delayed graft function, acute rejection, graft survival, seroma, anemia, lymphocele, and hyperlipidemia, were compared.. Ten studies with a total of 2357 patients (n = 1256 receiving SRL vs n = 1101 receiving MMF) were ultimately included. Our results indicated that the SRL group experienced a higher rate of hyperlipidemia (OR: 1.864; 95% CI, 1.494-2.325) and lymphocele (OR: 2.58; 95% CI, 1.49-4.47). However, no significant differences were detected regarding the rates of delayed graft function, acute rejection, graft survival, infectious complications, anemia, or seroma.. This meta-analysis suggested that SRL combined with TAC and MMF combined with TAC were equally safe and effective for the kidney transplantation recipients. However, the MMF group exhibited a marginally significant advantage of lower incidence of hyperlipidemia and lymphocele.

Topics: Adult; Delayed Graft Function; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lymphocele; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus

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

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

Sirolimus and its derivate everolimus are two immunosuppressive drugs with similar chemical structure that inhibit the proliferation of T cells by interfering with a serine-threonine kinase, called mTOR. Apart from their immunosuppressive effects, these agents may also inhibit endothelial intimal proliferation, the replication of cytomegalovirus, and the development of certain cancers. The main dose-dependent adverse events of mTOR inhibitors are hyperlipidemia, thrombocytopenia, mucositis, edema, and proteinuria. The use of mTOR inhibitors in renal transplantation may allow to reduce the doses of calcineurin inhibitors. Withdrawal of calcineurin inhibitors is also possible and may improve renal function, but some patients do not tolerate this regimen because of side effects. Further studies are needed to assess the role of mTOR inhibitors in the long-term.

Topics: Animals; Calcineurin; Everolimus; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Thrombocytopenia; TOR Serine-Threonine Kinases

Everolimus is an orally available inhibitor of the mammalian target of rapamycin (mTOR), which has been approved in combination with exemestane for hormone receptor-positive (HR) breast cancer after failure of treatment with non-steroidal aromatase inhibitors. Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening. Given the efficacy of everolimus in HR-positive metastatic breast cancer, it is crucial for physicians to recognize toxicities related to everolimus and start timely interventions. This review will focus on the adverse events reported with everolimus in breast cancer trials and will provide practical guidelines for the management of these adverse events.

Topics: Antineoplastic Agents; Breast Neoplasms; Everolimus; Fatigue; Female; Humans; Hyperglycemia; Hyperlipidemias; Pneumonia; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

SRL, an mTOR inhibitor that inhibits cell cycle progression, represents an important alternative to CNIs, which are still the cornerstones of pediatric solid organ tx. Because there are still limited data on SRL use among pediatric solid organ recipients, further studies are needed to verify the efficacy and safety of SRL. It has unique pharmacokinetic characteristics concerning dosing intervals and reduction of the dose in combination with other immunosuppressants. SRL also has antineoplastic, antiviral, and antiatherogenic advantages over other immunosuppressive agents. The adverse effects of SRL including thrombocytopenia, hyperlipidemia, proteinuria, impaired wound healing, mouth ulcers, edema, male hypogonadism, TMA, and interstitial pneumonitis must be considered carefully in pediatric population. This article reviews the most recent data on SRL application in the field of pediatric renal tx.

Topics: Child; Drug Therapy, Combination; Female; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Pediatrics; Pneumonia; Proteinuria; Sirolimus; Thrombocytopenia; Time Factors; TOR Serine-Threonine Kinases; Wound Healing

Sirolimus is a potent immunosuppressive medication that acts by inhibiting T-cell proliferation. It has been used in kidney transplantation because of its lack of nephrotoxicity. It is now being investigated in liver transplantation, but there are concerns about safety and long-term side effects such as dyslipidaemia. Hypertriglyceridaemia is a common adverse event seen with sirolimus use, and often does not respond to dose reduction or anti-lipemic drugs.. We report six patients who have developed significant hyperlipidaemia while receiving sirolimus, in spite of therapeutic trough levels.. All six patients showed either resolution or improvement in lipid levels with discontinuation of sirolimus.

Topics: Adult; Aged; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sirolimus; Tacrolimus

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

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

Sirolimus therapy has been used in orthotopic liver transplant (OLT) recipients diagnosed with a variety of diseases; chronic graft rejection (CR), calcineurin associated renal toxicity, preemptive immune suppression, calcineurin related neurotoxicity, preemptive therapy in transplant recipients with history of hepatocellular carcinoma, and steroid resistant allograft rejection.. A search for the medical literature and experiences involving sirolimus was done.. Several animal and human reports evaluating the use sirolimus in liver transplant recipients are found and discussed.. Sirolimus has been used for multitude of indications, primarily based on anecdotal experiences. However, reports of sirolimus related side effects have decreased the transplant communities' enthusiasm towards promoting this agent as a safe immune suppression agent.

Topics: Creatinine; Graft Rejection; Humans; Hyperlipidemias; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Safety; Sirolimus; Skin; Tacrolimus; Time Factors; Wound Healing

After transplantation, immunosuppressive drugs induce frequently lipid changes and glucose intolerance which result in worsening of the patient's prognosis. The mechanisms of the metabolic changes of corticosteroid hormones, cyclosporine, tacrolimus, sirolimus and mycophelonate are shortly reviewed but are not fully understood. Controlling serum lipids is critical in the management of the patients after transplantation. Statins seem to be the best choice but it remains some concerns about drug interactions and risk of rhabdomyolysis. Fibrates except gemfibrozil are not recommended because potential renal side effects.

Topics: Anticholesteremic Agents; Cyclosporine; Diabetes Mellitus; Heart Transplantation; Humans; Hyperlipidemias; Immunosuppressive Agents; Insulin Resistance; Liver Transplantation; Lung Transplantation; Mycophenolic Acid; Prednisone; Prognosis; Sirolimus; Tacrolimus; Transplantation Immunology

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

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

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

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

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

Topics: Adrenal Cortex Hormones; Cyclosporine; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipids; Lipoprotein(a); Sirolimus; Tacrolimus

Cixutumumab (a humanized monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]) and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus were combined in a phase I study of patients with advanced cancer. We investigated the prevalence of metabolic toxicities, their management, and impact on outcome.. The temsirolimus dose was 25 mg or 37.5 mg i.v. weekly with escalating doses of cixutumumab (3, 5, or 6 mg/kg i.v. weekly). No patients with diabetes or hyperlipidemia at baseline were eligible until the expansion cohort. We assessed metabolic derangements in our patient cohort, their management, and their association with tumor shrinkage, time to progression (TTP) and overall survival (OS).. Of the 57 patients analyzed, hyperglycemia was seen in 36 (63%) (grade 1-2: 33 [58%]; grade 3-4: 3 [5%]). The median blood sugar level (fasting and nonfasting) across cohorts was 149 mg/dL (upper limit of normal: 110 mg/dL). No patient developed diabetic ketoacidosis or nonketotic hyperosmolar coma or pancreatitis during treatment. Median maximum triglyceride, cholesterol, and low-density lipoprotein levels achieved were 247 mg/dL (range: 65-702 mg/dL), 243 mg/dL (range: 103-424 mg/dL), and 153 mg/dL (range 50-375 mg/dL), respectively. Higher glucose levels were associated with more RECIST tumor shrinkage (r = -.30 [95% confidence interval: -.52, -.03; p = .03]). There was no association between metabolic toxicities of the mTOR and IGF-1R combination and TTP or OS.. The combination of temsirolimus and cixutumumab was safe and resulted in manageable metabolic toxicities. More tumor shrinkage was seen in patients who developed these adverse events. Although perhaps limited by the small number of patients, no significant association was discerned between hyperglycemia, hypertriglyceridemia, or hypercholesterolemia and TTP or OS.. Results of this study show that the combination of temsirolimus and cixutumumab is safe. The most common side effects, hyperglycemia and hyperlipidemia, are tolerable and manageable. This combination of therapies should not be withheld from diabetic patients and patients with high cholesterol levels. Collaboration between oncologist and endocrinologist allows for individualized treatment and better control of these adverse events, with few dose interruptions and reductions. Supportive care and close monitoring is needed. Those patients who develop hyperglycemia or hypercholesterolemia may benefit more from the drug.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Hypercholesterolemia; Hyperglycemia; Hyperlipidemias; Male; Middle Aged; Neoplasms; Receptor, IGF Type 1; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

The metabolic syndrome (MS) is an important risk factor for graft dysfunction and patient death after renal transplantation. The aim of this sub-analysis of the Symphony study was to assess the progression of the laboratory parameters associated with MS in the first year after transplantation.. Data collected from the Symphony study were used; 1645 patients were randomized to receive standard-dose cyclosporine (Stand-CsA), low-dose cyclosporine (Low-CsA), tacrolimus (Low-Tac) or sirolimus (Low-SRL), in addition to mycophenolate mofetil (MMF) and corticosteroids. Data were collected for levels and progression over the first year post-transplantation of systolic and diastolic blood pressure, uric acid, triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and fasting glucose levels by treatment arm.. The low-SRL group had significantly higher levels of triglycerides and LDL. The two CsA arms were associated with the highest uric acid levels at each time point. There were no significant differences in overall levels or changes in glucose or HDL. Patients in the standard-CsA arm had significantly higher diastolic blood pressure than those in the Low-SRL and Low-Tac arms. Systolic blood pressure was higher in the Low-CsA arm than in the Low-Tac arm. The use of antihypertensive and antidiabetic agents was similar between the treatment arms. In the Low-SRL arm, more patients were treated with lipid-lowering therapy. Mean daily steroid doses were the highest in the Low-SRL arm.. This sub-analysis demonstrates that there is a difference in metabolic parameters between immunosuppressive groups. CsA therapy was associated with the highest values of uric acid and systolic and diastolic blood pressure. Patients on SRL therapy had the worst lipaemic control. A possible effect of Tac on new-onset diabetes could not be excluded.

Topics: Adrenal Cortex Hormones; Adult; Blood Chemical Analysis; Blood Pressure Determination; Body Mass Index; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Metabolic Syndrome; Middle Aged; Monitoring, Physiologic; Mycophenolic Acid; Prognosis; Reference Values; Risk Assessment; Sirolimus; Tacrolimus; Transplantation Immunology

Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models.. Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. In addition, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined.. Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3,810 ng-h/mL was achieved at sirolimus doses of 90, 16, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma.. Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogs.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Citrus paradisi; Female; Humans; Hyperglycemia; Hyperlipidemias; Ketoconazole; Lymphopenia; Male; Middle Aged; Neoplasm Staging; Neoplasms; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases

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

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

De novo sirolimus in calcineurin inhibitor-free regimens, although potentially useful to improve early renal function, are complicated by various drug-related side effects.. We report a prospective open-label, multicenter, randomized trial to evaluate early conversion from a CsA-based to a sirolimus (SRL)-based regimen 10 to 24 days after renal transplantation. Of the 196 patients, 141 patients with a low-to-moderate immunological risk were eligible to be converted to SRL or to continue CsA. All patients received antithymocyte globulin-F single-bolus induction, mycophenolate mofetil, and steroids.. The primary endpoint, renal function determined by S-creatinine and estimated glomerular filtration rate calculated by Nankivell formula at 12 months was significantly better in the SRL group (1.51+/-0.59 vs. 1.87+/-0.98 mg/dL or 64.5+/-25.2 vs. 53.4+/-18.0 mL/min/1.73 m). Patient survival, graft survival, and incidence of biopsy-proven acute rejection after conversion were not statistically different. Drug discontinuations were significantly higher in the SRL group (36.2% vs. 19.7%). Significantly, more patients in the SRL group reported acne, aphtous, and temporary hyperlipidemia, whereas cytomegalovirus viremia was significantly decreased (7.3% vs. 28.2%).. Early conversion to a calcineurin inhibitor-free regimen with SRL in combination with mycophenolate mofetil may be a useful strategy to improve renal function. The identification of appropriate candidates and safe management of SRL-related adverse events will be a key to avoid the high rate of dropouts, which currently limit the broad applicability of this protocol.

Topics: Acne Vulgaris; Adrenal Cortex Hormones; Adult; Antilymphocyte Serum; Calcineurin Inhibitors; Creatinine; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Survival; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Patient Selection; Prospective Studies; Safety; Sirolimus; Time Factors; Tissue Donors

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid-resistant cGVHD. Thirty-five patients who developed GVHD after day 100 post-transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count > or = 100 x 10(9)/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD-free survival are warranted.

Topics: Adult; Aged; Chronic Disease; Drug Therapy, Combination; Female; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hyperlipidemias; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Proportional Hazards Models; Sirolimus; Tacrolimus

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

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

This report describes the effects of sirolimus on plasma lipids, and uses the Framingham risk model to assess the clinical importance of these effects. Lipid data from two large controlled studies of 1295 renal transplant patients were analyzed retrospectively. Sirolimus 2 mg/day and 5 mg/day were compared with placebo or azathioprine, and administered concomitantly with steroids and cyclosporine over 12 months. Hypercholesterolemia and hypertriglyceridemia occurred in all treatment groups and were maximal at 2-3 months. The sirolimus groups evidenced higher lipid levels than the controls, but the elevations diminished over time. At 1 year, the patients given sirolimus 2 mg/day had a mean cholesterol level 17 mg/dL greater and a mean triglyceride level 59 mg/dL greater than the controls. Among the patients given sirolimus 5 mg/day, mean cholesterol was 30 mg/dL greater and mean triglycerides were 103 mg/dL greater than the controls. Treatment with statins and fibrates was effective in reducing cholesterol and triglyceride levels, respectively, in the sirolimus-treated patients. The Framingham risk model predicted that the 17 mg/dL elevation in cholesterol would increase the incidence of coronary heart disease (CHD) by 1.5 new cases per 1000 persons per year and CHD death by 0.7 events per 1000 persons per year. Lipid elevations observed in the sirolimus-treated patients were manageable, improved over time, and responded to lipid-lowering therapy. Based on the Framingham risk model, the CHD risks associated with these cholesterol elevations are small compared with the baseline risks of the transplant population.

Topics: Cholesterol; Coronary Disease; Humans; Hyperlipidemias; Hypolipidemic Agents; Immunosuppressive Agents; Kidney Transplantation; Lipid Metabolism; Risk Assessment; Sirolimus; Triglycerides

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

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

Patients with tuberous sclerosis complex (TSC) demonstrate disrupted lipid homeostasis before and during treatment with mammalian target of rapamycin (mTOR) inhibitor. However, few previous reports focused on if the serum lipid status at baseline would influence lipid metabolic side-effects of mTOR inhibitors for TSC associated renal angiomyolipomas (TSC-AML). The present study was designed to evaluate the predictive function of serum lipid status at baseline for hyperlipidaemia by mTOR inhibitor treatment in TSC-AML patients.. The clinical data of TSC-AML patients who took mTOR inhibitors in Department of Urology of Peking Union Medical College Hospital (PUMCH) from 1 January 2014 to 1 January 2021, were retrospectively analysed. The record of lipid parameters at baseline and the highest levels of total cholesterol (TC) and triglyceride (TG) after treatment at least ≥3 months were collected. The correlation of serum lipid parameters at baseline with incidence of hyperlipidaemia during mTOR inhibitor treatment was analysed. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the ability of the serum lipid parameters in predicting hyperlipidaemia.. 19 patients experienced hyperlipidaemia and 13 patients still had normal TC and TG levels during mTOR inhibitor treatment. The levels of high-density lipoprotein cholesterol (HDL-C) (0.98 ± 0.30 mmol/L vs. 1.23 ± 0.31 mmol/L, p = 0.030), low-density lipoprotein cholesterol (LDL-C) (2.47 ± 0.69 mmol/L vs. 1.95 ± 0.53 mmol/L, p = 0.029) and apolipoprotein B (ApoB) (0.82 ± 0.21 g/L vs. 0.65 ± 0.16 g/L, p = 0.019) are higher in the patients who experienced hyperlipidaemia during mTOR inhibition therapy. TC, TG, LDL-C, ApoB and high-sensitivity C-reactive protein (hsCRP) at baseline had positive correlation with TC after treatment; ApoB at baseline had positive correlation, while HDL-C and free fat acid (FFA) at baseline had negative correlation with TG after treatment. Therefore, ApoB concentration at baseline has statistically significant correlation with both TC (p < 0.001) and TG (p = 0.012) levels after mTOR inhibitor treatment. ROC curve and AUC revealed that ApoB with a cut-off value of 0.640g/L may be the best parameter for predicting hyperlipidaemia during mTOR inhibitor treatment in TSC-AML patients. The incidence rates of hyperlipidaemia were 27.3% and 76.2% among the patients with ApoB level ≤0.640 g/L and >0.640 g/L respectively.. Some baseline serum lipid parameters could be used for predicting incidence of hyperlipidaemia during mTOR inhibition therapy in TSC-AML patients, and ApoB with 0.640 g/L as a cut-off value may be a potentially optimal indicator, which could help for diagnosis and treatment decision-making.

Topics: Apolipoproteins B; Cholesterol, HDL; Cholesterol, LDL; Humans; Hyperlipidemias; Leukemia, Myeloid, Acute; Lipids; MTOR Inhibitors; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Triglycerides; Tuberous Sclerosis

Topics: Adolescent; Anemia, Sickle Cell; Child; Child, Preschool; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hyperlipidemias; Immunosuppressive Agents; Male; Retrospective Studies; Sirolimus

To evaluate the efficacy and safety of conversion from calcineurin inhibitors to sirolimus among liver transplant recipients with calcineurin inhibitor-induced complications.. After receiving liver transplants, 25 patients with calcineurin inhibitor-induced complications (22 renal dysfunction and 3 new-onset diabetes mellitus) were converted from sirolimus to tacrolimus. The serum creatinine, sirolimus trough level, liver function, acute rejection episodes, and drug-related adverse effects were monitored.. The patients were followed for 12 to 50 months (median, 25 months). The renal function of the 22 patients with renal dysfunction improved after sirolimus conversion. The serum creatinine levels were significantly lower at 3 months after conversion versus before conversion (113.2 ± 21.8 μmol/L vs 163.2 ± 45.3 μmol/L; P < .05). At the end of the follow-up, the average serum creatinine level was 101.9 ± 23.4 μmol/L among the 20 living recipients. Diabetes also was under control in 3 diabetic recipients after the conversion. Four patients experienced episodes of acute rejection, and intravenous steroid bolus therapy was administered in 2 of them. No graft was lost because of acute rejection. The adverse effects of sirolimus included hyperlipidemia (7/25), anemia (8/25), and mouth ulcers (9/25). All these adverse effects were relieved after a short-term symptomatic therapy, and no patient was withdrawn from the conversion trial.. Sirolimus monotherapy is effective and safe in liver transplant recipients. Conversion to sirolimus was associated with a sustained improvement in renal function and diabetes mellitus without an increased incidence of acute rejection episodes.

Topics: Acute Disease; Anemia; Calcineurin Inhibitors; Creatinine; Diabetes Mellitus, Type 2; Follow-Up Studies; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Oral Ulcer; Retrospective Studies; Sirolimus; Tacrolimus

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

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

Life expectancy after pediatric renal transplantation remains lower than that of the normal population largely due to cardiovascular morbidity and mortality. Hyperlipidemia is a potentially modifiable risk factor for cardiovascular morbidity. Retrospective chart review of all available pediatric renal transplant patients (26) in a single center with assessment of anthropometry, renal function, steroid, calcineurin or mTOR inhibitor exposure and Ω3 FA supplementation. Eighteen transplant recipients without Ω3 FA supplementation served as control. Nutrition and supplement surveys were conducted with standardized questionnaires. Fasting cholesterol values were compared using the latest value prior to start of Ω3 FA and at last follow-up. Eight patients (five receiving mTOR inhibitor) started Ω3 FA supplementation at a mean dose of 29.2 ± 12 mg of EPA/kg and 16.1 ± 7.4 mg DHA/kg body weight. Median duration of treatment was 2.5 yr (range 0.8-5.9 yr) and their total fasting cholesterol at last follow-up dropped significantly from 5.08 ± 0.97 (control group 3.77 ± 0.81, p = 0.0084) to 4.17 ± 0.54 mm (p = 0.0158). High-density lipoprotein cholesterol increased not significantly from 1.74 ± 0.49 to 2.02 ± 0.93 mm. No patient had increased bleeding. Supplementation of omega-3 FAs may reduce hyperlipidaemia after pediatric renal transplantation.

Topics: Adolescent; Calcineurin Inhibitors; Child; Cholesterol; Diet; Fatty Acids, Omega-3; Female; Humans; Hyperlipidemias; Kidney Transplantation; Male; Prevalence; Renal Insufficiency; Retrospective Studies; Risk Factors; Sirolimus; Steroids

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

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

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Case-Control Studies; Cell Proliferation; Cytochrome P-450 CYP3A; Everolimus; Haplotypes; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Proteinuria; Retrospective Studies; Signal Transduction; Sirolimus; Treatment Outcome

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor, which provides an immunosuppressive effect by inhibiting cell cycle progression. The encouraging results of combined SRL-cyclosporine therapy paved the way to further immunosuppressant combinations. Although SRL is relatively non-nephrotoxic when administered as monotherapy, it pharmacodynamically enhances the toxicity of calcineurin inhibitors. Other side effects may include hyperlipidemia and myelosuppression and less commonly wound healing impairment, proteinuria, edema and pneumonitis. Surprisingly, SRL also showed encouraging properties as an antiatherogenic and antineoplastic, opening a large spectrum of new potential applications. Whether SRL can be used safely over the long term with low doses of calcineurin inhibitors requires further study. The use of SRL as a corticosteroid-sparing agent also remains to be proven in controlled trials.

Topics: Cell Cycle; Graft Rejection; Humans; Hyperlipidemias; Immunosuppression Therapy; Organ Transplantation; Sirolimus; Wound Healing

The mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) pathway is a critical signaling component in the development of obesity-linked insulin resistance and operates a nutrient-sensing negative feedback loop toward the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) inhibitor rapamycin prevents nutrient-induced insulin resistance, the chronic effect of rapamycin on insulin sensitivity and glucose metabolism in vivo remains elusive.. To assess the metabolic effects of chronic inhibition of the mTORC1/S6K1 pathway, rats were treated with rapamycin (2 mg/kg/day) or vehicle for 15 days before metabolic phenotyping.. Chronic rapamycin treatment reduced adiposity and fat cell number, which was associated with a coordinated downregulation of genes involved in both lipid uptake and output. Rapamycin treatment also promoted insulin resistance, severe glucose intolerance, and increased gluconeogenesis. The latter was associated with elevated expression of hepatic gluconeogenic master genes, PEPCK and G6Pase, and increased expression of the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) as well as enhanced nuclear recruitment of FoxO1, CRTC2, and CREB. These changes were observed despite normal activation of the insulin receptor substrate/PI 3-kinase/Akt axis in liver of rapamycin-treated rats, as expected from the blockade of the mTORC1/S6K1 negative feedback loop.. These findings unravel a novel mechanism by which mTORC1/S6K1 controls gluconeogenesis through modulation of several key transcriptional factors. The robust induction of the gluconeogenic program in liver of rapamycin-treated rats underlies the development of severe glucose intolerance even in the face of preserved hepatic insulin signaling to Akt and despite a modest reduction in adiposity.

Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; C-Peptide; Down-Regulation; Fatty Acids, Nonesterified; Glucagon; Glucose Intolerance; Hyperlipidemias; Immunosuppressive Agents; Insulin; Liver; Male; Mice; Muscle, Skeletal; Polymerase Chain Reaction; Pyruvates; Rats; Rats, Sprague-Dawley; RNA; Sirolimus; Triglycerides

The present study was designed to investigate the effect of low-dose calcineurin inhibitor (CNI) tacrolimus combined with a mammalian target of rapamycin (mTOR) inhibitor on renal function in transplant recipients without allograft nephropathy.. Twelve patients including seven men (58.3%) of overall mean age of 34.8 ± 14.1 years underwent renal transplantation and were switched to a new second-line treatment of low-dose CNI combined with an mTOR inhibitor, either sirolimus or everolimus.. The underlying cause of renal failure was not clear in half of the cases; for the others it was chronic glomerulonephritis, diabetic nephropathy, polycystic kidney disease, or hypovolemia. After 6 months of the new therapy, there was a significant increase in calculated creatinine clearance levels compared to baseline (75.5 ± 21.9 vs 89.6 ± 19.1 mL/min; P < .001), but no significant change in serum creatinine (1.3 ± 0.4 vs 1.2 ± 0.3 mg/dL) or urinary protein excretion (187.5 ± 142.0 vs 394.0 ± 326.4 mg/g). For almost all patients, proteinuria remained stable, but in two patients, it developed but responded to enalapril treatment. Dose decrement was required for four patients with hyperlipidemia (50%); one patient experienced new-onset hyperlipidemia that responded to treatment. One patient developed a urinary tract infection that responded to antibiotic treatment. None of the patients developed an acute rejection episode.. Low-dose CNI combined with an mTOR inhibitor, as a replacement for mycophenolate mofetil or enteric-coated mycophenolate sodium, seemed to prevent renal dysfunction for at least 6 months among renal transplant patients without allograft nephropathy.

Topics: Adult; Biomarkers; Calcineurin Inhibitors; Creatinine; Drug Substitution; Drug Therapy, Combination; Everolimus; Female; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Proteinuria; Sirolimus; Tacrolimus; Time Factors; TOR Serine-Threonine Kinases; Transplantation, Homologous; Treatment Outcome; Turkey; Urinary Tract Infections; Young Adult

Cardiovascular disease (CVD) accounts for 35% to 50% of deaths among renal transplant recipients. Beside the atherogenic risk factors related to hemodialysis, renal function, and use of immunosuppressive agents, other relevant risk factors for CVD include acute rejection episodes, microalbuminuria (muAlb), diabetes, arterial hypertension, lipid disorders, inflammatory triggers, hyperhomocysteinemia, anemia, erythrocytosis, obesity, and hyperuricemia. We studied the prevalence of risk factors and the impact of various drugs on CVD among 103 renal transplant recipients with measured glomerular filtration rates showing values >45 mL/min. We measured uric acid, triglycerides (TG), low-density lipoprotein (LDL)/high-density lipoprotein (HDL) LDL/HDL ratio, homocysteine (HOMO), insulin resistance, muAlb, C-reactive protein (CRP), and fibrinogen. Subsequently, patients were divided into 8 groups based on the immunosuppressive protocol to evaluate its impact on CVD risk factors. Insulin resistance and hyperhomocysteinemia were present in >2/3 of patients. Considering the impact of protocols, the combination of cyclosporine (CsA) + everolimus (EVL) resulted in the most favorable profile in terms of reduction of hyperuricemia, hyperlipidemia, and hyperhomocysteinemia. Insulin resistance tended to be more frequent among patients treated with protocols including calcineurin inhibitors (CNI) and steroids. The prevalence of hyperhomocyteinemia was similar among patients on CsA and on tacrolimus (Tac). Sirolimus (SRL) was associated with higher levels of HOMO. The combination of CNI and proliferative signal inhibitors (PSI) seemed to be the most promising one to reduce the impact of CVD risk factors. The reduction in CVD morbidity can improve expectancy and quality of life, as well as graft function and survival among renal transplant patients.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Humans; Hyperhomocysteinemia; Hyperlipidemias; Hyperuricemia; Immunosuppressive Agents; Kidney Transplantation; Lipoproteins, HDL; Middle Aged; Risk Factors; Sirolimus; Tacrolimus; Transplant Recipients

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

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

Proliferation signal inhibitors (PSI) could help to lower the calcineurine inhibitors level to minimize their toxicity and improve long-term graft survival. Side effects of this drugs are specific and must been known. Hyperlipidemia and cutaneous side-effects are the most frequent, angioedema and interstital pneumonitis the most serious. In majority of cases, early and adapted management could limit the impact of these side effects.

Topics: Angioedema; Calcineurin Inhibitors; Cicatrix; Cyclosporine; Graft Rejection; Graft Survival; Hematologic Diseases; Humans; Hyperlipidemias; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney Diseases; Lymphocele; Pneumonia; Protein Serine-Threonine Kinases; Sirolimus; Skin Diseases; TOR Serine-Threonine Kinases

Accelerated atherosclerosis is a major risk for long-term survivors receiving hemodialysis (HD), with coronary events being the leading cause of mortality.. A total of 88 consecutive patients on HD (121 lesions) who underwent percutaneous coronary intervention (PCI) with sirolimus-eluting stents (SES) were compared with 78 patients on HD (95 lesions) who received bare metal stents (BMS) in the preceding 1 year. The primary endpoint was angiographic restenosis defined as > or =50% diameter stenosis at 6-8 months follow-up after PCI. The angiographic restenosis rate at follow-up was 22.2% in the SES group and 24.4% in the BMS group. No difference was detected in the restenosis rate between the 2 groups (p=0.73). When including both HD and non-HD patients, the independent predictors for restenosis after SES implantation were treatment with HD (hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.23-7.95; p=0.016), incidence of hyperlipidemia (HR 3.93; 95%CI 1.12-13.7; p=0.032), coronary calcification (HR 2.78; 95%CI 1.12-6.91; p=0.027), and implantation of multi-stents (HR 4.14; 95%CI 1.70-10.1; p=0.0017).. Even if treated with SES, patients with end-stage renal failure on HD are at high risk of restenosis after PCI.

Topics: Aged; Calcinosis; Coronary Angiography; Coronary Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Hyperlipidemias; Japan; Kidney Failure, Chronic; Male; Middle Aged; Recurrence; Renal Dialysis; Sirolimus; Stents

The influence of drug concentrations on the development of persistent posttransplant hyperlipidemia was investigated in 82 patients who received cyclosporin A (CsA) and prednisone plus sirolimus (SRL) (52) or azathioprine (AZA) (30) during the first year after transplantation. Blood levels of CsA and SRL, daily doses of AZA and prednisone, and cholesterol, triglyceride, and glucose concentrations were determined during each visit (pretransplant and 30, 60, 90, 120, 180, and 360 days posttransplant). Persistent hyperlipidemia was defined as one-year average steady-state cholesterol (CavCHOL) or triglyceride (CavTG) concentrations above 240 and 200 mg/dL, respectively. Mean cholesterol and triglyceride concentrations increased after transplantation (P < 0.01) and were higher in patients receiving SRL compared to AZA (P < 0.001). Patients receiving SRL showed a significantly higher number of cholesterol (> 229 or > 274 mg/dL) and triglyceride (> 198 or > 282 mg/dL) determinations in the upper interquartile ranges. CsA and SRL interquartile ranges correlated with cholesterol concentrations (P = 0.001) whereas only SRL interquartile ranges correlated with triglyceride concentrations (P < 0.0001). Only pretransplant cholesterol concentration > 205 mg/dL was independently associated with development of persistent hypercholesterolemia (CavCHOL > 240 mg/dL, relative risk (RR) = 20, CI 3.8-104.6, P = 0.0004) whereas pretransplant triglyceride concentration > 150 mg/dL (RR = 7.2, CI 1.6-32.4, P = 0.01) or > 211 mg/dL (RR = 19.8, CI 3.6-107.9, P = 0.0006) and use of SRL (RR = 3, CI 1.0-8.8, P = 0.0049) were independently associated with development of persistent hypertriglyceridemia (CavTG > 200 mg/dL). Persistent hypercholesterolemia was more frequent among patients with higher pretransplant cholesterol concentrations and was dependent on both CsA and SRL concentrations. Persistent hypertriglyceridemia was more frequent among patients with higher pretransplant triglyceride concentrations and was dependent on SRL concentrations.

Topics: Adult; Azathioprine; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hyperlipidemias; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lipid Metabolism; Male; Prednisone; Severity of Illness Index; Sirolimus; Time Factors

The primary aim of this study was to assess the safety and efficacy in lung transplantation of an immunosuppressive regimen aimed at achieving sirolimus and tacrolimus concentrations of 6 to 10 microg/ml and 5 to 7 ng/ml, respectively.. We retrospectively identified 49 lung transplant recipients who were converted to an immunosuppressive regimen consisting of tacrolimus, sirolimus, and prednisone. Data collected included demographic information, laboratory work, episodes of rejection, bronchiolitis obliterans syndrome (BOS) grade, and adverse effects.. The most common reason for conversion to a sirolimus and tacrolimus regimen was BOS. The most common adverse effects were increased triglycerides (10%), leukopenia (8%), and skin rash (6%). Four patients (8%) experienced acute allograft rejection during the study period. We followed BOS grade for 1 year in 23 patients. Of these, BOS grade improved in 8, 13 patients remained unchanged, and 2 worsened. Eleven patients (22%) discontinued sirolimus because of adverse events.. An immunosuppressive regimen consisting of sirolimus and tacrolimus that aims to keep the trough drug concentrations at 6 to 10 microg/ml and 5 to 7 ng/ml, respectively, provides effective lung allograft protection while maintaining an acceptable side-effect profile. The use of this immunosuppressive combination may have a benefit with regard to BOS.

Topics: Biopsy; Bronchiolitis Obliterans; Bronchoscopy; Drug Therapy, Combination; Female; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Lipids; Lung; Lung Transplantation; Male; Middle Aged; Retrospective Studies; Safety; Sirolimus; Tacrolimus; Treatment Outcome

We analyzed the effect of oral administration of cyclosporine-methylprednisone (CsA-MP) and sirolimus (SRL) on the lipid pattern of kidney-transplanted rats after a 7-day survival. A significant increase in plasma cholesterol in CsA-MP group (control: 26 +/- 3 mg/dl vs. 59 +/- 8 mg/dl, P < 0.05) and in triglyceride levels in SRL group (control: 53 +/- 4 mg/dl vs. 114 +/- 3 mg/dl, P < 0.05), was shown. Kidney microsomal membranes from both treated groups showed that cholesterol and triglyceride values and the relative percentage of arachidonic acid in the total amount of n-6 fatty acids decreased. A diminution of linoleic acid occurred in testis (control: 9.4 +/- 0.1 mg/dl vs. CsA-MP: 6.0 +/- 0.3 mg/dl and vs. SRL: 6.8 +/- 0.2 mg/dl, P < 0.05), liver (control: 17.7 +/- 0.6 mg/dl vs. CsA-MP: 15.1 +/- 0.6 mg/dl and SRL: 13.5 +/- 0.8 mg/dl, P < 0.05) and erythrocyte membranes (control:11.7 +/- 0.1% vs. CsA-MP: 10.6 +/- 0.2% and SRL: 10.0 +/- 0.4%, P < 0.01). The immunosuppressive therapies improved the rejection rate of the graft, fact that was remarkable in the SRL-treated group. However, lipid abnormalities still remain in spite of immunosuppressive therapies (150).

Topics: Animals; Cholesterol; Creatinine; Cyclosporine; Erythrocyte Membrane; Hyperlipidemias; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lipid Metabolism; Lipids; Male; Membrane Lipids; Methylprednisolone; Microsomes, Liver; Rats; Rats, Wistar; Sirolimus; Testis; Triglycerides; Urea

Hypercholesterolemia (HCHL) and hypertriglyceridemia (HTRG) have emerged as the most significant metabolic consequences of therapy with sirolimus. Lipid status can be exacerbated by a variety of factors in the posttransplant setting, including genetic factors. Apoliprotein E (Apo E) polymorphism is an established genetic risk factor for hyperlipidemia. We studied the association between Apo E gene polymorphisms and lipids after kidney transplantation in patients undergoing sirolimus treatment.. We studied 98 kidney transplant patients (KTP) with stable renal allograft undergoing sirolimus treatment: 39 with HCHL and HTRG within 90 days postsirolimus treatment (PST) and 59 without hyperlipidemia PST. Apo E genotyping was performed using INNO-LiPA-ApoE.. The cholesterol and the triglyceride values between the groups were 323.3+/-71.6 vs. 180.9+/-31.2 mg/dL (P<0.001) and 318.9+/-97.2 vs. 159.7+/-38.7 mg/dL (P<0.001). There was a significant difference in the genotype distribution of the hyperlipidemia and normal groups (P=0.009) with the percentages in each group as follows: E2/2 and E3/2: 12.8 vs. 5.1%; E3/3: 69.2% vs. 86.4%; and E4/3 and E4/4: 18.0% vs. 8.5%. We observed a higher number of patients with the genotype E3/3 in the group without hyperlipidemia PST (P=0.039). E3/2 and E4/4 genotype frequencies were higher in patients with hyperlipidemia PST. LDL levels in the hyperlipidemia PST group was statistical significant higher (P<0.001) and we observed an association between Apo E allelic distribution and LDL (P=0.005).. Genetic factors, as Apo E genotypes, could allow the early identification of patients who are at a high risk for developing hyperlipidemia PST.

Topics: Adult; Aged; Apolipoproteins E; Cholesterol; Creatinine; Female; Gene Frequency; Genotype; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipoproteins, LDL; Male; Middle Aged; Retrospective Studies; Risk Factors; Sirolimus; Triglycerides; Virginia

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

Treatment options are limited for orthotopic liver transplant (OLT) recipients suffering from chronic rejection (CR). We performed a retrospective review of OLT recipients diagnosed with CR and treated with sirolimus. The medical records of all OLT recipients treated with sirolimus between October, 1998 and October, 2000 were retrospectively reviewed. The diagnosis of CR was made by both clinical and histologic criteria: bile duct to hepatic artery ratio less than 0.7, histologic activity index, hepatic arterial wall thickening, and chronic elevation of liver chemistries. Two groups were defined in regard to sirolimus response: sirolimus responders (SR) and sirolimus nonresponders (SNR). Response to treatment was granted only when patients were found to have resolution of abnormal liver transaminases and an improvement in hepatic artery to bile duct ratio. Serum collections for liver chemistries were collected on days 1, 30, 60, and 90. Liver biopsies were reviewed in blinded fashion from day 1 and at least 180 days on therapy by double-blinded pathologists. Sirolimus-related complications were recorded and include drug toxicity, anemia with and without treatment, hospitalizations, infections, immunosuppression complications, lipid profile disorders, edema, muscle aches, and gastrointestinal complaints. Twenty-one patients were diagnosed with CR. The SR group included 13 of 21, and 8 of 21 were in the SNR group. Anemia was diagnosed in 12 of 21 patients: SR, 7 of 13; SNR, 5 of 8; with 5 patients requiring red blood cell transfusions (2 SR, 3 SNR). Recombinant erythropoietin was started in 5 of 21 patients. Sirolimus serum levels were found to be greater than 20 ng/dL in 12 patients. Sirolimus was discontinued in 9 patients,

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Alkaline Phosphatase; Anemia; Bile Ducts; Bilirubin; Chronic Disease; Female; Graft Rejection; Graft Survival; Hepatic Artery; Humans; Hyperlipidemias; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Sirolimus; Triglycerides

Sirolimus (Rapammune, rapamycin, RAPA) is a strong immunosuppressive agent that reduces kidney transplant rejection. Hyperlipidemia is a significant side effect of sirolimus treatment and often leads to vascular disease. We have studied the repeatability, reversibility, and dose dependence of the plasma lipid and apoprotein changing effects of sirolimus and attempted to determine the mechanism by which sirolimus induces hypertriglyceridemia in some kidney transplant recipients.. Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short-term (14 days) sirolimus administration. For longer-term treatment, each patient was started on 10 mg/d sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia. Timed blood samples were analyzed for lipid, apoprotein, and sirolimus levels.. During sirolimus administration, mean total plasma cholesterol increased from 214 to 322 mg/dL (+50%); low density lipoprotein-cholesterol levels changed in a similar pattern. Mean triglyceride level rose from 227 to 432 mg/dL (+95%). ApoB-100 concentration rose from 124 to 160 mg/dL (+28%). ApoC-III level increased from 28.9 to 55.5 mg/dL (+92%). These lipid and apoprotein changes were found to be repeatable, reversible, and dose dependent. [(13)C(4)]-palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 42.3%). Incorporation of [(13)C(4)]-palmitate into triglycerides of very low density lipoprotien, intermediate density lipoprotein, low density lipoproteins was decreased 38.3%, 42.1%, and 38.4%, respectively, by sirolimus treatment of these patients.. These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity, decrease lipoprotein lipase activity, or both, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia.

Topics: Adult; Cadaver; Cholesterol; Cyclosporine; Female; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipids; Lipoproteins; Living Donors; Male; Middle Aged; Prednisone; Sirolimus; Tissue Donors; Transplantation, Homologous; Triglycerides

(1) Sirolimus, an immunosuppressant, is chemically related to tacrolimus but has a different mechanism of action. (2) In a double-blind trial in patients also treated with ciclosporin and a steroid, sirolimus was more effective than azathioprine at preventing acute rejection during the first three months, but caused more adverse effects (especially renal). (3) An unblinded trial compared ciclosporin + steroid + sirolimus with steroid + sirolimus for maintenance treatment. Ciclosporin was withdrawn gradually from the steroid + sirolimus group. Side effects from ciclosporin were therefore reduced (mainly nephrotoxicity and arterial hypertension), but rates of acute rejection, hepatotoxicity, and thrombocytopenia went up. (4) Sirolimus has numerous adverse effects, including hyperlipidemia, thrombocytopenia, hepatic disorders and opportunistic infections. The adverse effects of long term treatment are unknown. Sirolimus is metabolised by the cytochrome P450 isoenzyme CYP3A4, so may induce drug interactions. (5) In practice, sirolimus offers no advantage over existing immunosuppressive treatments for people with renal transplants.

Topics: Azathioprine; Clinical Trials as Topic; Cyclosporine; Drug Approval; Drug Therapy, Combination; Europe; Graft Rejection; Humans; Hyperlipidemias; Hypokalemia; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Thrombocytopenia; United States; United States Food and Drug Administration

Since its approval as an immunosuppressive agent in renal transplantation, sirolimus (RAPA) recently has been used in the primary immunosuppression regimen at several liver transplant centers. One of the major side effects of RAPA is hypercholesterolemia, which is reported in up to 44% of patients. We describe our experience in 57 primary liver transplant recipients treated with RAPA and either cyclosporine A (CSA) or tacrolimus (TAC). We report the incidence and severity of hypercholesterolemia using a prednisone-free immunosuppressive regimen. Between January 2000 and September 2000, a total of 57 patients underwent transplantation at the University of Colorado Health Sciences Center (Denver, CO) with RAPA and either CSA or TAC. The initial 10 patients who underwent transplantation under this protocol were not administered corticosteroids, and the subsequent 47 patients were administered only 3 doses of methylprednisolone days 0, 1, and 2 postoperatively (1, 0.5, and 0.5 g, respectively). Total fasting cholesterol, high-density cholesterol, low-density cholesterol, and triglyceride levels were measured at monthly intervals. Mean serum cholesterol level was significantly greater in CSA patients (200 mg/dL) compared with TAC patients (158 mg/dL; P =.0003). Serum triglyceride levels were more than 2-fold greater with CSA (292 mg/dL) compared with TAC (134 mg/dL; P =.002). Hypercholesterolemia (cholesterol > 240 mg/dL) was present in 10 of 57 patients (18%) and was significantly more common in CSA-treated patients (8 of 27 patients; 30%) compared with TAC-treated patients (2 of 30 patients; 6%; P <.05). Hypertriglyceridemia (serum triglyceride > 300 mg/dL) was present in 10 of 57 patients (18%) and was significantly more common in CSA-treated patients (9 of 27 patients; 33%) compared with TAC-treated patients (1 of 30 patients; 3%; P <.05). We conclude that (1) concomitant use of TAC with RAPA reduces the prevalence and severity of posttransplantation dyslipidemia, and (2) these findings have important implications in the prevention of complications of hypercholesterolemia in liver transplant recipients.

Topics: Adult; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hyperlipidemias; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome; Triglycerides

DE NOVO DIABETES AND CARDIOVASCULAR RISK: Certain kidney transplant recipients who develop de novo diabetes have an unfavorable cardiovascular risk profile, comparable to patients with type 2 diabetes mellitus, with advanced age, dyslipidemia, obesity and high blood pressure. MYOCARDIAL INFARCTION IN THE PERIOPERATIVE PERIOD: Among kidney transplant recipients, those whose risk factors include male gender diabetes, age over 50 years and prior revascularization procedure for coronary artery disease have a higher risk for myocardial infarction in the perioperative period. The usefulness of anticoagulant or beta-blockers as preventive treatment for these high-risk patients remains to be determined. HYPERLIPIDEMIA: A retrospective analysis of 530 kidney transplant recipients demonstrated that a very significant proportion of those with dyslipidemia are not receiving appropriate care although their lipid profile is indicative of a high or very high cardiovascular risk. MASSIVE PROTEINURIA: An angiotensin II inhibitor, losartan, has been found to be effective against massive proteinuria (> 3.5 g/l) occurring after kidney transplantation. CALCINEURIN-INHIBITOR-INDUCED HEMOLYTIC UREMIA SYNDROME: Five to ten percent of patients given calcineurin inhibitors develop a hemolytic uremia syndrome. Sirolimus appears to be a very interesting alternative for immunoprophylaxys against acute rejection.

Topics: Age Factors; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Losartan; Myocardial Infarction; Proteinuria; Risk Factors; Sirolimus

SIROLIMUS: The leading member of the mTOR inhibitor family, sirolimus or rapamycin, has dose-dependent side effects that can generally be well controlled. Sirolimus can be combined with tacrolimus at therapeutic doses; likewise for the sirolimus-cyclosporine combination at moderate dosage. Effective plasma concentrations of sirolimus vary from 5 to 20 ng/ml depending on the combination of immunosuppressant agents used. Sirolimus has been shown to inhibit metastatic diffusion of renal adenocarcinoma in the mouse. Its complex side effects on angiogenesis, fibrosis processes and chronic rejection are still being investigated. EVEROLIMUS: Everolimus, or RAD, has a very short half-life, but induces fewer hematologic effects. The therapeutic dose must reach at least 3 ng/ml to prevent rejection. Doses above 15 ng/ml increase the risk of thrombocytopenia. FTY 720: A new immunosuppressant agent, FTY 720, does not belong to any known family. It has a totally different mechanism of action compared with currently available immunosuppressants. FTY 720 increases the expression of chemokine receptors on the surface of T cells making them unavailable for the rejection reaction. FTY 720 has a very long half-life (108 hours). Due to its particular liver metabolism, there is a very low risk of drug interactions.

Topics: Cyclosporine; Drug Interactions; Drug Therapy, Combination; Everolimus; Fingolimod Hydrochloride; Hyperlipidemias; Immunosuppressive Agents; Kidney; Neoplasms; Propylene Glycols; Sirolimus; Sphingosine

Sirolimus (Rapamune, rapamycin, RAPA) is a potent immunosuppressive drug that has reduced the rate of acute rejection episodes by more than 40% in phase III trials when added to an immunosuppression regimen of cyclosporine (CsA) and prednisone. However, RAPA treatment tends to increase lipid levels, particularly among patients with pre-existing hyperlipidemia.. To identify the metabolic pathway(s) leading to RAPA-mediated hyperlipidemia, five patients with renal transplants maintained on CsA+/-prednisone+/- azathioprine (AZA) were studied before and after 6 weeks of treatment with RAPA (off RAPA and on RAPA, respectively). Each study patient was infused with a single bolus of [2H4]-lysine to derive metabolic parameters for apoB100-containing lipoproteins by using kinetic analysis based upon quantitation of isotopic enrichment by gas chromatography-mass spectrometry.. Serial lipid measurements revealed that four patients displayed increased plasma triglyceride levels after RAPA treatment, which coincided with significantly higher plasma VLDL-apoB100 concentrations (21.7+/-12.1 mg/dl off RAPA vs. 38.7+/-14.8 mg/dl on RAPA, mean+/-SD, P<0.05). Kinetic analysis showed that the RAPA-induced increase in VLDL-apoB100 concentrations was due to a significant reduction in the fractional catabolic rate (FCR) of very low-density lipoprotein (VLDL) apoB100 (0.83+/-0.65 off RAPA vs. 0.24+/-0.10 on RAPA, mean+/-SD, P<0.05), rather than an enhanced VLDL-apoB100 synthesis. In one patient, RAPA treatment induced hypercholesterolemia but not hypertriglyceridemia. This hypercholesterolemia was due to elevated low-density lipoprotein (LDL) cholesterol levels, which coincided with a decreased FCR of LDL-apoB100. Heparin-induced lipoprotein lipase activity was significantly lower in the immunosuppressed hyperlipidemic patients than in normolipidemic controls. However, RAPA treatment did not significantly alter basal lipoprotein lipase activity in renal transplant patients in this study.. This study indicates that for renal transplant patients in whom RAPA treatment induces hyperlipidemia, this effect is the result of reduced catabolism of apoB100-containing lipoproteins.

Topics: Apolipoprotein B-100; Apolipoproteins B; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipoproteins; Lipoproteins, VLDL; Models, Biological; Sirolimus

Topics: Clinical Trials as Topic; Fees, Pharmaceutical; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Leukopenia; Lymphocyte Activation; Sirolimus; T-Lymphocytes; Thrombocytopenia

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