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)

Cyclosporin and tacrolimus have improved survival figures in organ transplantation. However, both drugs are potentially nephrotoxic. The immunosuppressive and nephrotoxic effects of both drugs appear to depend on the inhibition of calcineurin. Cyclosporin and tacrolimus cause acute (functional changes) and chronic nephrotoxicity (structural lesions in the kidney). These last important lesions include arteriolar hyalinosis, stripped interstitial fibrosis and tubular atrophy. It is possible that repeated episodes of renal ischaemia contribute to the development of chronic nephrotoxicity and then chronic allograft nephropathy. Cyclosporin and tacrolimus also induce arterial hypertension. Therefore, the beneficial effects of immunosuppression have been limited due to nephrotoxicity and arterial hypertension. Rapamycin, a novel immunosuppressive agent, that does not inhibit calcineurin, provides immunosuppression without nephrotoxicity. In fact, in the trials performed in Europe, sirolimus-treated immunosuppression patients exhibited a much better renal function than cyclosporin-treated patients. However, sirolimus can potentiate the nephrotoxic effect of cyclosporin. Therefore, when cyclosporin and sirolimus are used in combination, a reduction of the cyclosporin dose is desirable.
Nephrol Dial Transplant 2001
PMID:Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation. 1136 39

We have previously suggested that the in vitro donor-specific cytotoxic T-lymphocyte precursor (CTLp) assay can guide us to identify patients in which the immunosuppressive load can be tapered. In a clinical trial we had observed that a low (<10/10(6) PBMC) frequency of these CTLp was predictive for an uneventful rejection-free clinical course in patients that were converted from calcineurin inhibitors to mycophenolate mofetil or azathiopine. In the present prospective study in 81 stable kidney transplant recipients, already converted from calcineurin inhibitors, we measured CTLp frequencies and reduced the immunosuppressive load on a routine basis when CTLp were <10/10(6) PBMC. Donor-specific cytotoxicity could not be measured in 50/81 patients, while their reactivity against third-party lymphocytes was not impaired. These 50 patients were tapered in their immunosuppression. Only in one patient, who had stopped all his medication, was a rejection episode diagnosed. We conclude that in patients with a low donor-specific CTLp frequency it is safe to reduce the immunosuppression.
Nephrol Dial Transplant 2004 Jul
PMID:Tapering immunosuppression in recipients of living donor kidney transplants. 1524 Aug 52

In spite of considerable progress in immunosuppressive and supportive treatment, numerous problems persist which interfere with the success of renal transplantation. Before transplantation has been performed, factors impacting on outcome include the donor (living vs cadaver, age and HLA system) as well as the recipient (age, immunological reactivity, potential sensitization and duration of dialysis). These are the main factors that affect the outcome of the transplant, particularly in the long-term. After transplantation a number of events may put graft function at risk: potential recurrence of the primary renal disease in the allograft; 'de novo' renal disease triggered by infections, drugs or autoimmunity; and non-specific progression promoters, such as diabetes, hypertension, proteinuria, nephrotoxic agents and/or viral infections. The two most frequent causes of chronic allograft dysfunction are (i) chronic rejection (often triggered by preceding acute rejection, delayed graft function or poor compliance) and (ii) calcineurin-inhibitor nephrotoxicity (more likely to develop in kidneys of older donors or in marginal kidneys). The differential diagnosis between these two entities is generally difficult, but some histological clues (reduplication of glomerular basement membrane, obliterating vasculopathy and C4d deposits) as well as the demonstration of humoral antibodies are pointers suggesting rejection. Treatment of chronic graft dysfunction is difficult, whatever the cause, particularly in cases with advanced renal lesions. Therefore, early diagnosis is of paramount importance. In this regard, graft biopsy can be of great help. In spite of many problems and complications, not only short-term but also long-term results of renal transplantation are improving progressively, as documented by CTS data showing that in Europe for transplants performed between 1982 and 1984 the mean graft half-life was 7 years, while for transplants performed between 1997 and 1999 it was 20 years.
Nephrol Dial Transplant 2004 Dec
PMID:Renal transplantation 2004: where do we stand today? 1557 92

Reversible leukoencephalopathy syndrome (RLS) is a rare brain disorder, characterized by diffuse attenuation of cerebral white matter, which has been most commonly observed in transplant patients receiving calcineurin inhibitors or in patients with severe hypertension. We report an episode of RLS in a 22-year-old male patient on chronic hemodialysis with well-controlled moderate hypertension who presented with de novo headache and generalized seizures. Cranial magnetic resonance image (MRI) revealed multiple areas of increased signal intensity in the white matter on T2-weighed images which resolved spontaneously at subsequent MRIs. White blood cell count showed leucopenia with normal CD4 count at flow cytometry. A viral etiology could not be demonstrated. Reversible leukoencephaolopathy syndrome symptoms remitted within 72 h but leukopenia persisted over 10 months. The patient received a kidney transplant 15 months after RLS onset and has received cyclosporine since the second post-transplant day. No recurrence of RLS symptoms has been observed. The etiology of the MRI changes in the present case seemed not to be either vasogenic or cytotoxic.
Ther Apher Dial 2005 Feb
PMID:Reversible leukoencephalopathy syndrome associated to leukopenia in a chronic hemodialysis patient. 1582 10

Over the last decade, there has been a decrease in acute graft rejection rates following renal transplantation; however, this has not corresponded with an improvement in long-term outcomes of transplantation. One of the major causes of long-term morbidity and mortality in renal transplant recipients is cardiovascular disease. Immunosuppressive regimens, especially those including steroids and calcineurin inhibitors, have a negative role in the induction of cardiovascular risk factors. The proliferation signal inhibitors (PSIs)/mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown considerable promise in reducing acute rejection in renal transplant recipients. Although PSIs are associated with an increase in hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia), which is a major risk factor for atherosclerosis and associated cardiovascular disease, recent studies with sirolimus have demonstrated protection from atheroma progression in hyperlipidaemic apolipoprotein E-deficient mice. Here, we summarize the results of pre-clinical and clinical studies with sirolimus and everolimus, with particular emphasis on the beneficial and adverse effects that these drugs exert on the cardiovascular system, and the underlying molecular mechanisms.
Nephrol Dial Transplant 2006 Jul
PMID:Potential role of proliferation signal inhibitors on atherosclerosis in renal transplant patients. 1681 51

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.
Nephrol Dial Transplant 2006 Jul
PMID:Cardiovascular risk factors in renal transplantation--current controversies. 1681 54

The calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus are currently an important part of immunosuppressive regimens, but are associated with increased cardiovascular risk factors, including hyperlipidaemia, hypertension and diabetes mellitus. Conversion from CNI-based regimens to proliferation signal inhibitors or mammalian target of rapamycin inhibitors, such as everolimus and sirolimus, has been associated with an improvement in cardiovascular risk. This case study describes a 59-year-old renal transplant recipient who presented with angina pectoris while receiving immunosuppression with CsA, azathioprine and steroids. The patient developed angina pectoris 5 years after receiving a cadaveric renal transplant. At the time, the patient was obese, with hypertension controlled with diuretics and calcium channel blockers, and hyperlipidaemia controlled with statins. A scintigram revealed plurisegmental myocardial ischaemia, and a coronary angiogram showed the presence of occlusions in the left anterior descending artery and circumflex coronary artery. The patient also had 70% stenosis of the right coronary artery, which was corrected by angioplastic percutaneous intervention. The patient was converted from azathioprine to sirolimus 2 mg/day (trough blood level, 6-10 ng/ml), while the CsA dose was tapered and withdrawn. The angina pectoris subsequently resolved, no progression of coronary artery disease (CAD) has been observed during follow-up and stable renal function has been maintained throughout. Conversion to an immunosuppressive regimen of sirolimus with CsA withdrawal, along with angioplastic percutaneous correction of right coronary artery stenosis, therefore led to the complete resolution of angina pectoris and no progression of the CAD was noticed in this obese renal transplant patient with drug-controlled hypertension and hyperlipidaemia.
Nephrol Dial Transplant 2006 Jul
PMID:Conversion to a proliferation signal inhibitor in a patient with coronary artery disease--a case report. 1681 56

Non-melanoma skin cancer (NMSC) affects a large proportion of renal transplant recipients, with estimates suggesting that at least half of white-skinned transplant recipients will develop NMSC following transplantation. Squamous-cell carcinoma is the most frequent NMSC following transplantation occurring at a 100-times greater risk than in the general population, while the incidence of basal cell carcinoma is increased 10-fold over the general population. The most important risk factor for the development of NMSC in renal transplant recipients is prior exposure to ultraviolet radiation, therefore, geographical location and skin type highly influence the risk of NMSC. However, both the intensity and type of immuno-suppressive therapy have been associated with an increased risk of NMSC. Given the potential anti-cancer actions of the proliferation signal inhibitors (PSIs), everolimus and sirolimus, demonstrated in both pre-clinical and clinical studies, we have analysed the effect of conversion to PSIs in 53 renal transplant recipients developing NMSC after transplantation. Remission of NMSC was observed in 37 patients and was generally well tolerated with minimal adverse events reported. Fifteen patients developed new lesions following conversion, two of these were receiving low-dose calcineurin inhibitors (CNIs) as part of their immuno-suppressive regimen suggesting that there was insufficient reduction of CNIs. PSI blood levels did not seem to affect the outcomes of conversion. These data, along with published clinical trial data suggest that conversion from CNIs to PSIs may be useful in the management of NMSC following renal transplantation.
Nephrol Dial Transplant 2007 May
PMID:Use of proliferation signal inhibitors in non-melanoma skin cancer following renal transplantation. 1745 15

Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases characterized by abnormal lymphoid proliferation following transplantation. These lymphomas, in particular, have been shown to have a higher incidence in renal transplant recipients compared with the general age-matched population. The effect of different immunosuppressive regimens on the incidence of PTLD has been assessed in a number of studies. Although there are conflicting data on the role of calcineurin inhibitors (CNIs) in promoting the development of PTLD, an increase in risk is described in most studies and is usually related to the aggressiveness of immunosuppression. The proliferation signal inhibitors (PSIs), everolimus and sirolimus, have both immunosuppressive and antiproliferative actions and pre-clinical data suggest that everolimus has an inhibitory effect on the growth of PTLD-derived cell lines. There is currently limited clinical data on the use of PSIs in the management of PTLD, therefore, clinical experience from nine European Transplant centres has been pooled and analysed to assess their potential. Conversion to PSIs and subsequent minimization or withdrawal of CNIs was analysed in 19 renal transplant recipients with PTLD and remission was observed in 15 patients. These data suggest that PSIs may assist with the management of PTLD following renal transplantation.
Nephrol Dial Transplant 2007 May
PMID:Post-transplant lymphoproliferative disorder--the potential of proliferation signal inhibitors. 1828 44

Since the beginning of organ transplantation, graft preservation has been one of the most important concerns. Ischemia reperfusion injury (IRI), which plays an important role in the quality and function of the graft, is a major cause for increased length of hospitalization and decreased long term graft survival. Among numerous attempts which have been made to minimize graft damage associated with IRI, the use of Thymoglobulin (TG) seems to offer potential benefits. TG is a polyclonal antibody which blocks multiple antigens related to IRI, in addition to its better known T cell depleting effects. This review will focus on the use of TG in preventing IRI in kidney transplantation (KTx) and liver transplantation (LTx). Different studies in experimental and clinical transplantation have shown that TG protects renal and liver grafts from IRI. Improvement in early graft function and decreased delayed graft function (DGF) rates are some of the clinical benefits of TG. Additionally, it is used in patients with hepatorenal syndrome to support the recovery of kidney function after LTx, by allowing reduced exposure to nephrotoxic calcineurin inhibitors as well as improving liver graft function by minimizing IRI. TG can reduce acute rejection rates in kidney and liver transplant recipients, decrease the length of hospital stay, and hence reduce transplantation costs. TG can play an important role in expanding the donor pool in both KTx and LTx by improving long-term graft and patient survival rates which increases the possibility of using marginal donors. Although controversial, the development of post-transplant lymphoproliferative disorder is a potential side effect of TG. No single optimal immunosuppressive regimen has given consistent results in decreasing the graft damage following IRI; however, TG usage in KTx and LTx appears to have some benefits in reducing IRI.
Nephrol Dial Transplant 2007 Sep
PMID:Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. 1789 Feb 65


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