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

Nephrotoxicity caused by calcineurin inhibitors can lead to either delayed graft function or long-term decline of renal function after kidney transplantation. Therefore, recipients of renal transplants from marginal donors require non-nephrotoxic immunosuppression. Eighteen patients received kidney transplants from marginal donors, with a calcineurin inhibitor-free immunosuppressive regimen, based on basiliximab, mycophenolate mofetil, steroids, and sirolimus. Renal graft biopsy was performed in all cases before surgery. Mean follow-up was 11.8 months. We report immediate renal function in 9 patients, delayed graft function in 5 and acute tubular necrosis in 4 patients. One patient was successfully treated for biopsy-proven acute rejection. Hypercholesterolemia and hypertriglyceridemia were the most common adverse effects (n = 13) associated with arthralgia (n = 2) and thrombocytopenia (n = 2). Five patients underwent a switch to tacrolimus, due to sirolimus-induced side effects. Immunosuppression without the use of calcineurin inhibitors is a safe and effective regimen in kidney transplantation, although sirolimus-related side effects still represent a morbidity factor in these patients.
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PMID:Sirolimus in kidney transplantation from marginal donors. 1511 May 69

Sirolimus (SRL) has been used for most islet recipients over the past 5 years. It provides balanced immunosuppression in combination with low-dose calcineurin inhibitors, while avoiding corticosteroids. This regimen decreases the risk of nephrotoxicity, neurotoxicity and diabetogenicity. SRL has also been used selectively in clinical liver and kidney transplantation. A number of common side effects including anemia, leucopenia, thrombocytopenia, hypercholesterolemia, mouth ulceration, joint pain, extremity edema and impaired wound healing have been associated with the use of SRL. As SRL is used more frequently, evidence has been gathered on its rare but severe side effects. We report 2 patients who underwent islet transplantation and developed symptomatic small bowel ulceration that resolved after complete withdrawal of SRL. Although small bowel ulceration is rare, it can potentially progress to more serious complications if not treated adequately. Our experience highlights an uncommon but potentially serious adverse effect of high-dose SRL in islet recipients.
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PMID:Sirolimus-induced ulceration of the small bowel in islet transplant recipients: report of two cases. 1621 44

The mTOR inhibitor sirolimus improves renal transplant function compared with the nephrotoxic calcineurin inhibitors. We evaluated retrospectively the adverse events in 119 of 134 patients getting sirolimus which seemed to be caused by sirolimus. Patients were converted to sirolimus because of malignancies (n = 47), a creeping creatinine (n = 33), or hypertension (n = 26). One cohort had started sirolimus from the time of transplantation (n = 28). A rise in serum lipids and a decrease in hemoglobin were seen relatively regularly, while arthralgia, peripheral edema, gastrointestinal complaints, skin disorders, electrolyte disturbances, and infections occurred only occasionally. Interestingly, 31% of patients developed doubling or more proteinuria. Among renal biopsies, 9/13 showed a glomerulopathy which in 6 cases was de novo and in 3 cases, a presumed recurrence of the primary kidney disease. Thus, we think that caution is required, particularly in connection with preexisting glomerular disease.
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PMID:Side effects of sirolimus. 1664 52

Sirolimus (SRL) has been proposed to replace calcineurin inhibitors (CNI) in case of CNI-induced toxicity. The aim of this study was to evaluate the efficacy and safety of conversion from CNI to SRL in maintenance liver transplantation (LT) patients. Between 2002 and 2006, conversion was performed in 48 patients (17 female, 31 male; mean age 57 +/- 10 yr) after a median delay of 19.4 months (range 0.2-173 months) after LT. Indication for conversion was renal impairment (RI) (78%), CNI neurotoxicity (13%), or post-LT cancer (9%). Median follow-up was 22.6 +/- 11 months. Median SRL dosage and trough levels were 2.4 +/- 1.3 mg and 8.1 +/- 2.7 microg/L. Immunosuppression consisted of SRL alone (33%), or SRL + mycophenolate mofetil (MMF) (39%), SRL + prednisone (15%), SRL + CNI (4%), or SRL + MMF + prednisone (8%). Mean glomerular filtration rate (GFR) improved from 33 to 48 mL/minute in patients with severe RI (P = 0.022) and from 56 to 74 mL/minute in patients with moderate RI (P = 0.0001). After conversion, main complications were albuminuria (36%), hyperlipidemia (49%), dermatitis (14%), edema (14%), oral ulcers (12%), joint pain (4%), infection (2%), and pneumonia (2%). Acute rejection (AR) occurred in 17% of the patients. SRL was withdrawn in 17% of the patients. In conclusion, conversion from CNI to SRL is safe and is associated with significant renal function improvement.
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PMID:Conversion to sirolimus-based immunosuppression in maintenance liver transplantation patients. 1745 87

Vascular disease and chronic allograft nephropathy have prompted re-evaluation of steroids and calcineurin inhibitors (CNIs) in renal transplantation. Sirolimus (SRL) can facilitate early CNI withdrawal. We report on the Early CNI and Steroid Elimination in Leeds (ECSEL) study, which was terminated early due to poor tolerability of SRL. Basiliximab/methylprednisolone induction was used, then 2 months of tacrolimus (TAC) and mycophenolate mofetil (MMF) treatment. A total of 51 patients were randomized to continue TAC/MMF or switch to SRL/MMF. In ECSEL1, patients were switched at 2 months (n=10). In ECSEL2, SRL was introduced at months 4-6 and TAC was tapered (n=13). Median overall follow up was 701 days. All 10 ECSEL1 and 10 of 13 (77%) ECSEL2 patients discontinued SRL due to adverse events, including leucopenia, rash, mucosal ulceration, arthralgia, and possible pneumonitis. Mean end-of-study creatinine was comparable in all groups. Sirolimus should be used with caution in complete CNI and steroid withdrawal, due to the resultant intolerable adverse event profile.
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PMID:Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation. 1834 44

Sirolimus (SRL) is an mTOR inhibitor that has been shown, in contrast to calcineurin inhibitors (CNI), to inhibit cancers in experimental models. Since February 2005, we introduced SRL in liver transplant patients in group a, in whom the primary disease was hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic or autoimmune liver cirrhosis, and group b, HCC-negative patients who developed posttransplantation cancers de novo. Of 18 patients in group a, 11 received SRL ab initio (subgroup a1), starting for 10 patients at 66.1+/-29.2 days after surgical healing and after 10 days in 1 case; the remaining 7 patients (subgroup a2) received SRL at 31.2+/-24.2 months. Three patients in group b, included 1 with Kaposi's sarcoma, 1 with bladder cancer, and 1 with thyroid cancer. In this group, SRL was introduced at 80.8+/-40.4 months. In all patients but one, who received a single 5 mg loading dose, SRL was started at 2 mg/d and adjusted to 6 to 8 ng/mL blood levels. CNI drugs, present as primary therapy, were gradually tapered to low levels and eventually stopped. The following observations were drawn from this initial experience: (1) 4/21 (19.0%) patients had to discontinue SRL because of early and late side effects: thrombocytopenia (n=2) and headache with leukopenia and leg edema associated with knee joint arthralgia (n=2); (2) 14 patients (11 in group a and 3 in group b) are still on SRL monotherapy; (3) 1 HCC recurrence and 1 de novo pancreatic adenocarcinoma were observed at 14 and 16 months, respectively (at the time of transplantation, both patients were beyond the MIlan HCC criteria), and (4) 1 patient, from subgroup a1, died after 99 days due to pneumonitis and possible relation to SRL lung toxicity. In conclusion, SRL appeared to be an effective immunosuppressant that could be used as monotherapy in liver transplant patients. Any conclusion on SRL anticancer effects can only come from randomized large studies after long follow-up.
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PMID:Sirolimus therapy in liver transplant patients: an initial experience at a single center. 1867 98

Chronic graft-versus-host disease (cGVHD) is one of the main late complications of allogeneic hematopoietic stem cell transplant and a major contributor to the mortality and morbidity in surviving recipients. Skin is the most common involved organ in cGVHD and may mimic a wide spectrum of dermatological conditions in its clinical and histopathologic manifestations. Some of the commonly simulated diseases are scleroderma, morphea, and lichen sclerosus. Chronic GVHD simulating eosinophilic fasciitis (EF) is relatively rare, frequently presenting with skin induration, a typical "peau d'orange" appearance, peripheral blood eosinophilia, myalgia, arthralgia, and arthritis leading to joint contractures in severe cases.Diagnosis is based on clinical manifestations and histopathology. Treatment is challenging because most cases are refractory to first-line therapy of glucocorticoids and calcineurin inhibitors (CNIs), and there is no standard second-line therapy.We report a comprehensive review of literature on all reported cases of CGVHD presenting as EF. We also describe an additional interesting case of cGVHD presenting as EF that was resistant to traditional therapy of high-dose glucocorticoids and cyclosporin A, but showed complete resolution of skin manifestations after addition of imatinib.Chronic GVHD presenting as EF is a rare variant of sclerodermatous cGVHD. Diagnosis is difficult, and treatment of cGVHD mimicking EF remains a therapeutic challenge because of obscure pathogenesis and poor response to traditional immunosuppressive medications. Emerging insights into the pathogenesis of cGVHD have resulted in the development of novel targeted therapies, which may improve outcomes and should be attempted in this subset of the disease. Larger studies are warranted to substantiate these preliminary findings.
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PMID:Chronic graft-versus-host disease presenting as eosinophilic fasciitis: therapeutic challenges and an additional case. 2571 Aug 60

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