Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sirolimus is the first of a group of mammalian target of rapamycin inhibitors to be introduced for clinical use in the United States. At the University of Tennessee in Memphis, we have evolved strategies for the use of sirolimus in kidney transplant recipients; which utilize the drug as a primary immunosuppressant and exploit its potential for preserving renal function. Conversions from the calcineurins to sirolimusbased immunosuppression established the efficacy of calcineurin-free immunosuppressants in selected high-risk patients. The conversion experience stimulated the design of protocols for primary use of sirolimus. Posttransplant use of sirolimus was associated with low incidence of rejection whether sirolimus was used with low-dose Prograf or in calcineurin-free protocols. Primary use with full-dose Prograf was associated with a high incidence of calcineurin-related nephrotoxicity and was abandoned in our program. Hematologic and lipid side effects were manageable, as was an observed increase in wound-healing problems and lymphocele formation. Continuous modifications of the sirolimus protocols to increase our benefit-to-risk ratio are ongoing and indicate a continued role for the drug in posttransplant immune suppression.
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PMID:Observations on the use of sirolimus and tacrolimus in high-risk renal transplant recipients. 1274 77

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.
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PMID:Benefit-risk assessment of sirolimus in renal transplantation. 1569 Dec 25

Lymphocele formation is a common complication after kidney transplantation, and laparoscopic surgery has become a widely accepted treatment option. The aim of this retrospective study was to analyze the risk factors of lymphocele development and to assess the treatment outcome after laparoscopic fenestration. We analyzed 426 renal allograft recipients operated between 2002 and 2006 receiving triple immunosuppression with calcineurin inhibitors. The incidence of lymphocele was 9.9%, while 24 (5.6%) patients with symptomatic lymphoceles required laparoscopic surgery. Serum creatinine at diagnosis was significantly higher in patients with lymphoceles treated surgically (3.2 +/- 0.7 vs. 1.7 +/- 0.6 mg/dL; p < 0.001). After successful laparoscopic intervention, creatinine concentrations recovered until discharge and were comparable to other patients (1.6 +/- 0.5 vs. 1.5 +/- 0.5 mg/dL; p = NS). While we observed a significant association of lymphocele formation with diabetes, tacrolimus therapy, and acute rejection in univariate testing, only diabetes remained a significant factor after multivariate analysis. Laparoscopic fenestration proved to be a safe and efficient method without any associated mortality and a low recurrence rate of 8.3% (n = 2). We conclude that diabetes is an independent risk factor for lymphocele development, and laparoscopic fenestration should be the treatment of choice for larger and symptomatic lymphoceles, as it is safe and offers a low recurrence rate.
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PMID:Symptomatic lymphoceles after kidney transplantation - multivariate analysis of risk factors and outcome after laparoscopic fenestration. 1971 27

Mammalian target of rapamycin inhibitor (mTOR-I)/proliferation signal inhibitors (PSI) including sirolimus and everolimus represent a new class of drugs increasingly used in solid-organ transplantation as alternatives to calcineurin inhibitors for patients with renal dysfunction, transplant coronary arterial vasculopathy or malignancy. The most frequently occurring mTOR-I/PSI-related adverse events are similar to those associated with other immunosuppressive therapies, but some side effects are more characteristic of proliferation signal inhibitors (e.g. lymphocele, arthralgia, oedema and hyperlipidaemia). The present paper review incidence, clinical presentation and mechanism of oedema within the clinical experience of mTOR-I/PSI in solid organ transplantation.
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PMID:Oedema, solid organ transplantation and mammalian target of rapamycin inhibitor/proliferation signal inhibitors (mTOR-I/PSIs). 2585 58

Renal transplantation is the best treatment of choice for patient with chronic renal insufficiency because it provides better quality of life and longer survival. Survival rates for grafts and patients have improved over the recent decades because of significant evolution of surgical techniques and immunosuppressive treatment. However, renal transplantation is still associated with several complications, which may result in poor outcome. Cause of allograft dysfunction, which occurs in the early or late post-transplantation period, should be recognized immediately, so that it can be managed correctly. Surgical complications are rare and include renal artery stenosis, vascular thrombosis, hematoma, ureteral obstruction, urinary leak, hematoma, lymphocele, and perinephric fluid collections. Parenchymal complications, which are histopathologically categorized according to Banff classification, include antibody-mediated rejection, T-cell mediated rejection, interstitial fibrosis and tubular atrophy, calcineurin inhibitors, acute tubular injury, and others. Detection of changes in the allograft function is an important task in the appropriate management of complications. Although first-line imaging tool in the recognition of complications is ultrasonography, radionuclide imaging is a modality capable of assessing graft function qualitatively and quantitatively. Sequential renal scintigraphy is of particular importance in the differential diagnosis of complications, which need prompt and accurate management. Renal scintigraphy within 24-48 hours of transplantation surgery is recommended to serve as a baseline for comparison when functional impairment develops. In addition, studies have shown that early renal scintigraphy has a predictive value for the short-term and long-term graft outcomes. This article focuses in the main complications after renal transplantation, their imaging findings, and the role of renal scintigraphy.
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PMID:Peri- and Postsurgical Evaluations of Renal Transplant. 2896 63