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)

Despite recent advances in the prolongation of patient and graft survival, transplant patients continue to die prematurely of accelerated cardiovascular disease. Arterial hypertension is a well-known risk factor for cardiovascular disease morbidity and mortality in the general population and a frequent complication following transplantation. The pathogenesis of posttransplant hypertension in renal transplant recipients is multifactorial and includes pretransplant hypertension in the recipient, donor hypertension, uncontrolled renin secretion from the remaining native kidney, hypertension as a consequence of graft dysfunction, recurrent or de novo renal disease, and, nowadays more rarely, transplant artery stenosis. The strong impact of an immunosuppressive regimen consisting of calcineurin inhibitors and steroids must also be considered. Calcineurin inhibitors and corticosteroids induce hypertension in renal, cardiac, liver, bone marrow, and lung transplant recipients. Posttransplant hypertension appears to be a major risk factor for graft and patient survival. Recent controlled studies support the opinion that posttransplant hypertension must be treated as strictly as in a population with essential hypertension, diabetes mellitus, or chronic renal failure.
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PMID:Management strategies for posttransplant hypertension. 1115 34

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.
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PMID:Exploring treatment options in renal transplantation: the problems of chronic allograft dysfunction and drug-related nephrotoxicity. 1158 88

Cardiovascular disease is now the leading cause of death in transplant recipients. This is due, in part, to the vulnerability of these patients to a complicated set of conditions including hypertension, diabetes mellitus, and post-transplant hyperlipidaemia (PTHL). PTHL is characterised by persistent elevations in total serum cholesterol, low density lipoprotein cholesterol and triglyceride levels. The causes of PTHL are complex and not fully understood, however several classes of immunosuppressants including the corticosteroids, rapamycins and calcineurin inhibitors, appear to play a role. PTHL has been observed in most studies in which patients received calcineurin inhibitor-based regimens, and has been observed with both tacrolimus and cyclosporin. Comparing these calcineurin inhibitors with regard to the relative incidence or severity of PTHL occurring during treatment is difficult because of the use of higher doses of corticosteroids in cyclosporin-based regimens, as compared with tacrolimus-based regimens. However, current expert opinion suggests that the discrepancies in the relative incidence and severity of PTHL are largely accounted for by this difference in corticosteroid dose. At this point in time, evidence for potential differences is scant and inconclusive. Further study is needed, not only to investigate differences in lipid profile, but also of the relative effects of these immunosuppressants on long term graft function as well as on cardiovascular morbidity and mortality. PTHL can be successfully managed with a combination of dietary management, reduction and, if appropriate, withdrawal of corticosteroids, and the administration of lipid-lowering drugs. With this combination of therapeutic options, the threats to long term health posed by PTHL may be effectively addressed.
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PMID:Calcineurin inhibitors and post-transplant hyperlipidaemias. 1167 3

Hypertension (HTN) contributes to the high incidence of cardiovascular disease mortality as well as chronic allograft nephropathy (CAN) and late graft failure in renal transplant recipients. The mechanisms are complex and may involve pathogenic factors attributable to the host, allograft, and immunosuppressive drugs. Calcium channel blockers should be used to ameliorate the nephrotoxicity of calcineurin inhibitors in the early years after transplantation. Angiotensin-converting enzyme inhibitors and angiotensin-2 type-1 receptor blockers are safe and effective, have antiproteinuric effects, slow the progression of CAN, and may provide survival benefits. Diuretics and/or beta-adrenergic receptor blockers are frequently added in combination regimen. Appropriate adjustment of the immunosuppressive drugs should also be considered for the long-term care of kidney recipients with HTN.
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PMID:Hypertension after kidney transplantation: impact, pathogenesis and therapy. 1269 25

Posttransplantation hypertension has been identified as an independent risk factor for chronic allograft dysfunction and loss. Based on available morbidity and mortality data, posttransplantation hypertension must be identified and managed appropriately. During the past decade, calcium channel blockers have been recommended by some as the antihypertensive agents of choice in this population, because it was theorized that their vasodilatory effects would counteract the vasoconstrictive effects of the calcineurin inhibitors. With increasing data becoming available, reexamining the use of traditional antihypertensive agents, including diuretics and beta-blockers, or the newer agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, may be beneficial. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit, from both a renal and a cardiovascular perspective. Beta-blockers, diuretics, and ACE inhibitors have all demonstrated significant benefit on morbidity and mortality in patients with cardiovascular disease. Calcium channel blockers have been shown to possess the ability to counteract cyclosporine-induced nephrotoxicity. When compared with beta-blockers, diuretics, and ACE inhibitors, however, the relative risk of cardiovascular events is increased with calcium channel blockers. With the long-term benefits of calcium channel blockers on the kidney unknown and a negative cardiovascular profile, these agents are best reserved as adjunctive therapy to beta-blockers, diuretics, and ACE inhibitors.
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PMID:Calcium channel blockers as the treatment of choice for hypertension in renal transplant recipients: fact or fiction. 1282 Aug 20

The incidence of diabetes in kidney transplant recipients is between 4 and 20% in patients previously not affected by this pathology. This difference is partially due to the immunosuppressive therapy administered. The incidence of diabetes is very high during the first quarter after the transplant, and it becomes stable during the following quarters. The presence of diabetes - evaluated by postprandial glycemia and glycated hemoglobin - should be checked quarterly during the first year after the transplant, every six months during the second year, and yearly starting from the third year. The immunosuppressive therapy (calcineurin inhibitors and steroids), familial history, age, race, and weight (BMI) are among the risk factors of diabetes post-transplant. An increased risk of rejection seems to be among the principal consequences of diabetes in transplant recipients. Moreover, these patients are more prone to infections, cardiovascular disease, and the degenerative complications of diabetes. These facts increase the risk of organ insufficiency, morbidity, and mortality. To manage diabetes in transplant recipients it is necessary to identify at-risk patients before the transplantation, thus avoiding complicated and hazardous examinations after the transplant. After the transplantation, the modifiable risk factors, such as the immunosuppressant drugs used and the control of body weight, must be checked. The control of hypertension is important as well.
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PMID:[The incidence, clinical implications, and risk factors of diabetes mellitus]. 1452 6

Cardiovascular disease is the leading cause of mortality and morbidity within the industrialized nations of the world, with coronary heart disease (CHD) accounting for as much as 66% of these deaths. Acute myocardial infarction is a typical sequelae associated with long-standing coronary heart disease resulting in large scale loss of ventricular myocardium through both apoptotic and necrotic cell death. In this study, we investigated the role that the calcium calmodulin-activated protein phosphatase calcineurin (PP2B) plays in modulating cardiac apoptosis after acute ischemia-reperfusion injury to the heart. Calcineurin Abeta gene-targeted mice showed a greater loss of viable myocardium, enhanced DNA laddering and TUNEL, and a greater loss in functional performance compared with strain-matched wild-type control mice after ischemia-reperfusion injury. RNA expression profiling was performed to uncover potential mechanisms associated with this loss of cardioprotection. Interestingly, calcineurin Abeta-/- hearts were characterized by a generalized downregulation in gene expression representing approximately 6% of all genes surveyed. Consistent with this observation, nuclear factor of activated T cells (NFAT)-luciferase reporter transgenic mice showed reduced expression in calcineurin Abeta-/- hearts at baseline and after ischemia-reperfusion injury. Finally, expression of an activated NFAT mutant protected cardiac myocytes from apoptotic stimuli, whereas directed inhibition of NFAT augmented cell death. These results represent the first genetic loss-of-function data showing a prosurvival role for calcineurin-NFAT signaling in the heart.
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PMID:Calcineurin Abeta gene targeting predisposes the myocardium to acute ischemia-induced apoptosis and dysfunction. 1461 91

Results of renal transplantation have improved steadily over the years. This article reviews the current status of patient and graft survival and discusses major causes of mortality and renal allograft failure. Review of recent literature demonstrates that the traditional enemies of transplantation, acute rejection and opportunistic infections are no longer major problems facing transplantation. Chronic graft nephropathy and death with functioning graft due to cardiovascular disease are the main challenges in the current era. An impact of an early graft thrombosis, recurrent renal disease and post-transplant malignancies are also reviewed. Chronic graft nephropathy is examined in a context of differences between two calcineurin inhibitors, cyclosporin microemulsion and tacrolimus. Strategies of post-transplant surveillance are suggested.
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PMID:Strategies for ensuring effective surveillance in post-transplant patients: practical organization and clinical evaluation. 1473 Nov 50

Most of the experience acquired in our unit with cyclosporine (CsA) comes from randomized trials. A first trial demonstrated that CsA-treated patients had a better 10-year graft survival than azathioprine-treated patients. A second trial showed equivalence between double therapy with CsA plus steroids and triple therapy with CsA, steroids, and azatioprine. A third trial showed similar 2-year graft survival with CsA monotherapy and triple therapy. A larger multicenter study that compared three different CsA-based regimens showed similar long-term graft survival with monotherapy, double therapy, and triple therapy. However, patients given monotherapy had less frequent steroid-related side-effects. Finally a more recent multicenter international trial showed that the rate of acute rejection can be reduced without increasing side effects by adding the monoclonal antibody basiliximab to the triple therapy. By reviewing our cumulative experience with CsA we found a mean graft half-life of 18.7 years for cadaver renal transplant recipients and 31.9 for the living transplant recipients. No significant attrition of graft function was found for patients with grafts functioning at 15 years. Two important issues with the present immunosuppression concern the long-term nephrotoxicity of calcineurin inhibitors and the cardiovascular disease, which is at least in part related to the use of steroids. To face these problems, we are currently involved in two multicenter trials, one comparing sirolimus plus mycophenolate mofetil to sirolimus plus low-dose CsA, while the other trial compares certican plus CsA to certican plus CsA plus corticosteroids.
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PMID:From cyclosporine to the future. 1504 5

Cardiovascular disease post-transplant, particularly ischemic heart disease, is a significant problem for all transplant recipients. The major risk factors-smoking, obesity, diabetes, dyslipidemia and hypertension-are often more prevalent in heart transplant populations than in the general population. One of the main risk factors influencing graft loss and patient survival is cardiac allograft vasculopathy (CAV). Because CAV affects between 30% and 60% of cardiac transplant recipients within 5 years of surgery, prevention is a key focus for cardiac transplant teams today. CAV is caused by both immunologic mechanisms (e.g., acute rejection and anti-HLA antibodies) and non-immunologic mechanisms relating to the transplant itself or the recipient (e.g., donor age, hypertension, hyperlipidemia and pre-existing diabetes) or to the side effects often associated with immunosuppression with calcineurin inhibitors or corticosteroids (e.g., cytomegalovirus infection, nephrotoxicity and new-onset diabetes after transplantation). The calcineurin inhibitors, cyclosporine and tacrolimus, effectively prevent acute rejection, but do not prevent the development of CAV. CAV prevention will require a combined approach of new adjunct immunosuppressant agents (e.g., the proliferation signal inhibitors) and reduction in cardiovascular risk. Hypertension, hyperlipidemia and diabetes are also associated with the immunosuppression required to prevent organ rejection. Some studies have shown that hypertension is present more frequently in cyclosporine-treated patients than in tacrolimus-treated patients and that tacrolimus may be associated with a more favorable lipid profile. On the other hand, tacrolimus may be more diabetogenic than cyclosporine with current data suggesting a trend but no statistically significant supporting evidence. New-onset diabetes after transplantation is at times difficult to manage and may be an important determinant along with hypertension and hyperlipidemia of ischemic heart disease, cerebrovascular disease and peripheral vascular disease. The choice of calcineurin inhibitor for an immunosuppressive regimen in heart transplantation should consider the associated relative cardiovascular risks.
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PMID:Cardiac allograft vasculopathy after heart transplantation: risk factors and management. 1509 4


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