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)

Sirolimus (SRL) provides effective immunosuppression for kidney transplantation and may be useful in patients with delayed allograft function after kidney transplantation. We review our experience with SRL in liver transplant recipients for whom calcineurin inhibitors are undesirable. Fourteen patients with renal insufficiency or acute mental status impairment were administered SRL after liver transplantation (5- to 10-mg load, 1 to 4 mg/d). Immunosuppression also consisted of mycophenolate mofetil and corticosteroids. On resolution of neurological or renal dysfunction (return to baseline mental status or serum creatinine level), tacrolimus (TAC) therapy was initiated. Twelve patients received primary transplants, 1 patient received a combined liver-kidney transplant, and 1 patient received a third transplant. Follow-up was 2 to 7 months. Calcineurin inhibitors were initially withheld in 9 patients, and therapy was aborted because of toxicity in the remaining 5 patients. Mean times to the initiation of SRL and TAC therapy were 5.4 +/- 4.6 and 26.8 +/- 24.4 days, respectively. Serum trough levels of SRL did not correlate with dose or other patient variables. Two patients died after prolonged pretransplantation hospital courses in the intensive care unit. Six patients experienced acute rejection, but only 1 patient required antilymphocyte therapy. Serum creatinine levels at the start of SRL therapy were 2.2 +/- 1.1 and 1.2 +/- 0.6 mg/dL at 3 months. All 3 patients with neurological indications for SRL had a return to their baseline mental status. All patients had improved liver function chemistry test results and prothrombin times. No patients developed leukopenia or thrombocytopenia. SRL is safe after liver transplantation in patients with acute neurological or renal impairment. SRL is an attractive alternative when calcineurin inhibitors are undesirable, but serum trough levels of SRL should be monitored. A prospective randomized study of an SRL-based calcineurin inhibitor-avoiding regimen compared with standard therapy in patients with renal insufficiency will further evaluate the role for SRL in liver transplantation.
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PMID:Experience with the use of sirolimus in liver transplantation--use in patients for whom calcineurin inhibitors are contraindicated. 1108 60

Renal transplants may undergo changes secondary to the decrease of the renal mass, the effects of rejection, and various other risk factors that contribute to the progression of renal insufficiency. We have performed a prospective study of 285 cadaveric renal transplants recipients, that were receiving various maintenance immunosuppressives regimens, to study the evolution of their renal function and to evaluate the influence of various factors in the progression of renal insufficiency. All variables were analysed in a regression model of multivariate analysis. We found a progressive increase of the serum creatinine in the studied population. The mean initial creatinine was 1.70 +/- 0.84 mg/dl and final creatinine in the study 2.17 +/- 2.06 mg/dl, difference statistically significant (p = 0.000). We calculated the increase of creatinine in each patient. We observed that 113 patients (42.2%), had stable serum creatinine but the remaining 155 patients (57.8%) had a mean increase of 0.04 +/- 0.8 mg/dl/month. We analysed the patients according to various variables. Although in most the final creatinine is significantly greater than the initial, this increase of creatinine level was not present in patients with delayed graft function, in patients with no acute rejection, in the extreme age groups, in the grafts from younger donors and in those patients without initial proteinuria. The patients transplanted from younger donor had the best renal function, without any decrease in their function during the study. The advanced age of the donor has a great negative impact in the evolution of the renal transplant. According to our study, proteinuria and its quantity is a major predictor of progressive renal insufficiency. The multivariate analysis confirms that the age of the donor and initial proteinuria predict decrease of renal function. It is important to identify the factors that they could predict a greater progression to the failure of the graft. We have the possibility of acting on them, establishing immunosuppressive strategies that reduce the deleterious effects of the calcineurin inhibitors in the recipients of grafts from older donors' and to encourage the use of drugs which reduce proteinuria.
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PMID:[Changes in renal function in renal transplantation. Predictive factors for functional deterioration]. 1147 10

Sirolimus, being nonnephrotoxic, is a viable alternative in patients who develop renal insufficiency caused by calcineurin inhibitors (CIs). The aim of this study is to determine whether there is improvement in renal function in liver transplant recipients after switching to sirolimus-based immunosuppression. In this retrospective review, patients who were more than 3 years posttransplantation were selected. Patients who had proteinuria (protein > 300 mg/24 hr), those administered any other nephrotoxic agents, and those with a creatinine clearance (CCr) less than 20 mL/min were excluded. Renal insufficiency was defined as mild (CCr > 70 mL/min), moderate (CCr, 40 to 70 mL/min), or severe (CCr, 20 to 40 mL/min). In the 16 patients studied; there was significant improvement in serum blood urea nitrogen (36 mg/dL; range, 19 to 53 mg/dL; to 25 mg/dL; range, 10 to 37 mg/dL; P =.002) and serum creatinine levels (median, 1.95 mg/dL; range, 1.3 to 2.8 mg/dL; to 1.5 mg/dL; range, 1.0 to 2.4 mg/dL; P =.001) 6 months after switching to sirolimus therapy. There also was a trend in improvement in CCr from 43 mL min (range, 24 to 68 mL/min) to 49 mL/min (range, 22 to 152 mL/min). Among 9 patients with moderate renal insufficiency, 2 patients improved to mild renal insufficiency, 4 patients remained unchanged, and 3 patients deteriorated to severe renal insufficiency. Among 7 patients with severe renal insufficiency, 1 patient improved to mild renal insufficiency, 4 patients improved to moderate renal insufficiency, and 2 patients remained unchanged. No patient developed cellular rejection or other graft-related complications. In liver transplant recipients with chronic renal insufficiency, conversion to sirolimus-based immunosuppression allows complete withdrawal of CIs, leading to some improvement in renal function.
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PMID:Sirolimus monotherapy in nephrotoxicity due to calcineurin inhibitors in liver transplant recipients. 1254 5

Since its introduction in renal transplantation in 1999, sirolimus is being used by an increasing number of liver transplant centers. Compared to the calcineurin inhibitors, sirolimus acts through a separate signal transduction pathway and has a myriad of important biologic effects including: inhibition of lymphocyte proliferation, inhibition of fibrosis and fibroblast proliferation, and antineoplastic effects. The clinical side-effect profile of this drug is also different than calcineurin inhibitors. Most important, sirolimus does not cause glucose intolerance, hypertension, or renal insufficiency. As a result, this drug offers significant potential advantages over conventional immunosuppressive agents. However, sirolimus may cause hyperlipidemia and has also been associated with hepatic artery thrombosis in liver transplant recipients. This review will summarize the published data on sirolimus in liver transplantation, focusing on the potential advantages and disadvantage of the use of this drug in liver transplant recipients. Finally, the potential benefits of antifibrosis and antineoplastic effects of sirolimus in liver transplant recipients will be discussed.
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PMID:Sirolimus in liver transplantation. 1274 96

Sirolimus (Rapamune; Wyeth-Ayerst, Philadelphia, PA) is a newer immunosuppressive drug with no known acute or chronic nephrotoxic effects; however, limited data are available in liver transplant recipients. We prospectively evaluated changes in renal function in liver transplant recipients after conversion from a calcineurin inhibitor to sirolimus monotherapy. We measured serial serum creatinine levels in liver transplant recipients with chronic nephrotoxicity caused by calcineurin inhibitors before and after conversion to sirolimus therapy. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease formula. Change in eGFR over time, incidence of acute hepatocellular rejection, and adverse events while being administered sirolimus monotherapy were recorded. Mean interval between liver transplantation and initiation of sirolimus therapy was 310 weeks (range, 9 to 780 weeks). Of 21 patients included in our study, 18 patients were converted to sirolimus monotherapy and 3 patients were switched to sirolimus and low-dose steroid therapy. Patients were followed up for a mean of 66.8 +/- 38.9 (SD) weeks after conversion. Renal function improved in 71% of patients (15 of 21 patients). Median eGFR improved significantly from 34 mL/min/1.73 m2 at the time of conversion to 43 mL/min/1.73 m2 at the last follow-up (27% increase in eGFR; P = 001). Median monthly change in eGFR was from -0.25 mL/min/1.73 m2 pre-sirolimus therapy to +1.28 mL/min/1.73 m2 post-sirolimus therapy (P =.09). Adverse events were mostly mild and self-limited. Only 1 patient developed biopsy-proven acute cellular rejection, which was treated with sirolimus and mycophenolate mofetil. Two patients discontinued sirolimus therapy because of toxicity (oral ulceration, 1 patient; interstitial pneumonitis, 1 patient). Renal function improved significantly in the majority of liver transplant recipients with renal insufficiency caused by calcineurin inhibitors when converted to sirolimus therapy. Sirolimus monotherapy provided adequate immunosuppression with a low incidence of acute cellular rejection and minimal adverse events.
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PMID:Renal function improves in liver transplant recipients when switched from a calcineurin inhibitor to sirolimus. 1452 3

Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiac failure. Techniques have evolved to reduce surgical mortality to under 5%. Immediate and subsequent long-term survival is more dependent on acute and chronic rejection and the complications of immunosuppressive therapy. Ten-year survival is greater than 50%.The success of transplantation over the last 20 years has been largely due to the advances in immunosuppression. The most notable and dramatic milestone was the introduction of cyclosporine in the early 1980s, which resulted in a significant improvement in allograft and patient survival. Cyclosporine is a peptide that inhibits the immune system by suppressing T-helper cell activation via inhibition of calcineurin, a critical intracellular enzyme. Tacrolimus has a similar (but not identical) mechanism of action, and was introduced in the 1990s. Drugs such as cyclosporine and tacrolimus, generically referred to as calcineurin inhibitors, have become the cornerstones of immunosuppressive protocols. As a group, calcineurin inhibitors have adverse effects, including neurotoxicity, hypertension, and nephrotoxicity, which complicate their use. Early renal insufficiency manifests as postoperative oliguria (<50 mL/h urine output) or rising serum creatinine levels. There are a variety of postulated causes for calcineurin inhibitor-associated early renal insufficiency including direct calcineurin inhibitor-mediated renal arteriolar vasoconstriction, increased levels of endothelin-1 (a potent vasoconstrictor), as well as decreased nitric oxide production and alterations in the kidney's ability to adjust to changes in serum tonicity. Once early renal insufficiency occurs, no single treatment has been shown to be effective. Approaches discussed in this paper include reduction in calcineurin inhibitor dosages, as well as various drugs to promote increased renal perfusion such as misoprostol and dopamine. In addition, the paper emphasizes the importance of ruling out other causes of renal insufficiency in the early postoperative period, including volume depletion, depressed cardiac output, and mechanical obstruction to urine flow. Given that there is no highly efficacious treatment for this syndrome, ways to avoid its occurrence are desirable. One paper is referenced that suggests that avoidance of rapid changes in tacrolimus level during the first three days of therapy is associated with a low occurrence of early renal insufficiency.
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PMID:Calcineurin inhibitor-associated early renal insufficiency in cardiac transplant recipients: risk factors and strategies for prevention and treatment. 1496 63

The long-term use of calcineurin inhibitors (CIs) is associated with significant morbidity in liver transplant recipients. Although mycophenolate mofetil (MMF) is well tolerated, two small studies reported an unacceptable rate of acute allograft rejection in liver transplant recipients receiving MMF monotherapy. In this study, we retrospectively investigated the safety and efficacy of MMF monotherapy in liver transplant recipients. We reviewed the medical records of all patients who underwent liver transplant at our institution. Sixteen patients were identified who received MMF either as monotherapy (n = 13) or with corticosteroids (n = 3; 2 of them for other comorbid conditions), and these patients were studied to determine the efficacy and complications. Fifteen (15/16) patients were converted from a CI to MMF because of renal insufficiency. Patients were converted to MMF monotherapy after a median of 2,056 days (range, 606-5,893) after liver transplantation. The median postconversion follow-up was 668 days (range, 60-1,509). Four patients required dialysis despite conversion; of those patients not requiring dialysis, serum creatinine stabilized and showed a trend toward improvement (2.51 +/- 1.12 mg/dL to 1.85 +/- .58 mg/dL, P = .1). However, there were 3 episodes (47, 107, and 1,203 days after conversion) of severe, irreversible allograft rejection after conversion resulting in death in 2 patients and necessitating retransplantation in 1 patient. There were no patient characteristics, except perhaps African-American race, that predicted the development of rejection. In conclusion, MMF monotherapy was associated with a significant risk (19%) of unpredictable, severe, and irreversible allograft rejection even among long-term transplant survivors. Caution should be exercised before converting patients to MMF monotherapy.
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PMID:Mycophenolate mofetil monotherapy in liver transplant recipients: a single center experience. 1535 13

In eligible patients, cardiac transplantation has become the definitive treatment for end-stage heart failure. The initial posttransplantation course is marked by many potential difficulties, including renal insufficiency, hemodynamic instability, and perioperative bleeding. It is important to prevent early rejection; calcineurin inhibitors, such as tacrolimus or cyclosporine, are integral parts of such management. However, these drugs are associated with renal toxicity in some patients. Previous work suggests that limiting the increase in tacrolimus levels is associated with less renal insufficiency. The hypothesis of the current study was that a combination of clinical or laboratory variables could identify patients at risk for rapid changes in tacrolimus target levels. No single variable was strongly associated with high resultant trough levels following a standard 1-mg oral "test dose" of tacrolimus. However, the combination of 2 indices of liver metabolism (alanine aminotransferase and total bilirubin) along with serum creatinine did identify patients who tended toward elevated levels of tacrolimus (> or =4.5 ng/dL). Other variables, such as demographics, and even functional variables, such as right ventricular function by echocardiography, did not enhance the predictive value of this simple scoring system.
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PMID:Can initial tacrolimus trough levels be predicted from clinical variables? 1562 Nov 57

Cardiovascular diseases are more common in renal transplant recipients than in the general population, and a number of 'traditional' risk factors, such as smoking, diabetes mellitus and dyslipidaemia, are known to be associated with an increased risk. However, concentrating solely on these risk factors can lead to an underestimation of the true risk in this patient population, because other factors such as C-reactive protein and homocysteine levels are also associated with cardiovascular morbidity and mortality. Renal insufficiency also appears to be a key cardiovascular risk factor in the general population, with increasing proteinuria and decreasing glomerular filtration rate related to increased risk. In renal transplant recipients, a high proportion of whom have some renal insufficiency, the role of graft dysfunction in cardiovascular risk is controversial. While some studies have shown no correlation between graft dysfunction and congestive heart failure or ischaemic heart disease, registry data suggest that increased post-transplant serum creatinine levels are strongly associated with cardiovascular risk. This is believed to be the result of cardiovascular disease developing in the pre-transplantation period, as renal transplantation has been shown significantly to improve cardiovascular risk. As such, renal transplant recipients should be routinely screened for cardiovascular disease pre-transplantation, and immunosuppressive therapy should be tailored to minimize further risk. Different immunosuppressive agents, such as corticosteroids and calcineurin inhibitors, are associated with different exposure to cardiovascular risk, and studies involving withdrawal of these agents have generally shown improvement in parameters such as blood pressure and dyslipidaemia. However, these benefits are often associated with an increased incidence of acute rejection, although overall graft loss and mortality rates are not affected. Further studies are required to determine optimal regimens for minimizing cardiovascular risk in renal transplant recipients.
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PMID:Cardiovascular risk factors in renal transplantation--current controversies. 1681 54

Transplantation-associated microangiopathy (TAM) or renal insufficiency (RI) after allogeneic hematopoietic stem cell transplantation is associated with a high mortality. As calcineurin inhibitors (CI) may contribute to TAM or RI, we evaluated the efficacy of replacing CI by daclizumab in patients with graft-versus-host disease (GVHD). Thirteen patients with GVHD-associated TAM and five patients with RI were treated with daclizumab 1 mg/kg intravenous (i.v.)/week, discontinuation of the CI and continuation of the remaining GVHD treatment. All patients had acute GVHD (steroid-sensitive (n=4), steroid-refractory (n=10)) or chronic GVHD (n=4) and were treated with CI before the start of daclizumab. Nine of 13 patients with TAM treated with daclizumab and discontinuation of CI achieved complete remission of TAM, two had stable disease, and one patient did not respond. Patients receiving daclizumab for RI without TAM showed stabilization (2/5) or improvement (3/5) of renal function. Four of 14 patients with acute GVHD achieved CR, two partial remission, eight patients did not respond and 11/14 died at a median of 39 days after start of the daclizumab. Our data demonstrate that replacement of CI by daclizumab can improve TAM and RI. However, mortality remains high in patients with acute GVHD.
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PMID:Replacement of calcineurin inhibitors with daclizumab in patients with transplantation-associated microangiopathy or renal insufficiency associated with graft-versus-host disease. 1695 92


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