Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Although patients with end-stage renal disease can be maintained with dialysis therapy, the superiority of patient survival with renal transplantation makes transplantation the preferred method of renal replacement. Potent immunosuppressive therapies, particularly calcineurin inhibitors, have greatly reduced the incidence of acute rejection. However, long-term allograft survival remains limited. We discuss the impact of acute rejection on long-term allograft survival and discuss other factors leading to late allograft loss, including calcineurin inhibitor toxicity, chronic allograft nephropathy, and BK virus nephropathy, as well as donor and recipient factors associated with long-term allograft loss.
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PMID:Why hasn't eliminating acute rejection improved graft survival? 1700 51

Cancer has been reported to be more common among kidney transplant recipients than waiting-list patients or the general population. Use of anticalcineurin agents and azathioprine are relevant risk factors. Nine renal allograft recipients (seven men and two women) of mean age 67.6 (55-77) years and mean time after transplantation of 30.7 (58-216) months were switched to everolimus-based immunosuppression because of the presence of biopsy-proven malignancies (eight patients) or neurological tacrolimus toxicity (one patient). One patient with posttransplant lymphoproliferative disease also received chemotherapy with a good evolution at 6 months. He showed an initial increase in the protein to creatinine ratio (peak 3.3 mg/mg at 3 months) that was controlled by increasing the enalapril dose. One patient with skin cancer and severe atheromatosis (baseline SCr 2.5 mg/dL, creatinine clearance 17 mL/min, and protein to creatinine ratio 3.2 mg/mg), had cyclosporine and everolimus overlapped for 25 days, showing a continued poor evolution requiring dialysis initiation at 3 months after switch. The other six patients with recurrent skin cancers had good cancer evolution, with no new skin tumors and regression of skin lesions in three, including not biopsied actinic keratosis. Sudden switching from calcineurin inhibitors to everolimus is safe and may be used in long-term transplant recipients with malignancies. In patients with advanced chronic nephropathy this approach appeared to be less beneficial.
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PMID:Conversion from calcineurin inhibitors to everolimus in kidney transplant recipients with malignant neoplasia. 1709 65

Enormous advancements in visceral transplantation have led to significant improvements in the quality of life of patients. However, despite these developments, the average graft half-life after transplantation has remained almost unchanged and chronic rejection is still considered a major problem. In this regard, more concerns have shifted to factors influencing long-term graft survival, patient survival, and quality of life. To achieve this goal, detrimental effects of immunosuppressive (IS) agents, which have deleterious influence on the quality of life and/or patient survival, should be reduced. In the course of recent years, the transplant community has worked on reducing these side effects by developing new ISs, employing new combination regimens, or finding and adjusting optimal dosages and blood level concentrations. Among the IS agents, the antifungal, antitumoral and IS activity of mammalian target of rapamycin (mTOR) inhibitors without nephrotoxicity, have received special attention regarding this new class of IS. Sirolimus (SRL), as the first member of mTOR inhibitors, has been utilized in many clinical trials with respect to its benefit-risk assessment. In our review, the clinical evolution of SRL, as well as the evidence-based clinical benefits of SRL in kidney and liver transplantation (KTx, LTx), are summarized. Various studies of SRL in KTx and LTx have shown that combination therapy with SRL will enrich the variety of IS modalities. It also can be regarded as a safe base therapy to which other necessary drugs can be added. In addition to the enhanced acute rejection prophylaxis, and in contrast to the calcineurin inhibitors (CNI) and steroids, this drug solely does not have common side effects such as nephrotoxicity, neurotoxicity, diabetes mellitus and hypertension. Moreover, this agent might diminish vasculopathic processes that mediate chronic allograft nephropathy (CAN). Therefore, by reducing the likelihood of CAN it can decrease the rate of long-term organ failure. One possibly desirable characteristic of SRL is its antiproliferative effect, which could provoke antitumoral or antiatherogenic activity following transplantation. Despite all promising impacts of SRL in organ transplantation, there are some concerns regarding the adverse effects of this drug, for instance dyslipidemia, pneumonitis and wound healing problems. However, the majority of these side effects can be reduced or ceased by careful dose adjustments and correct timing of use. In conclusion, after a decade of both in vivo and in vitro studies on SRL, it can be advocated that SRL is a promising, potent and effective IS agent as it reduces the rate of acute rejection episodes in de novo transplants. It could improve the quality of life, graft and patient survival rate, and achieve excellent outcomes with few adverse effects when wisely used in combination with other immunosuppressants.
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PMID:The role and value of sirolimus administration in kidney and liver transplantation. 1710 Jun 99

Kidney disease after transplantation of a nonrenal organ has been described to be the result of the nephrotoxicity from the commonly used calcineurin-inhibitors as well as other factors. The aim of this study was to evaluate renal function and potential risk factors for the development of chronic renal failure among nonrenal organ recipients. We designed a single-center retrospective study including all 165 of our cardiac and liver recipients between February 1998 and October 2003, collecting clinical, analytic, and therapeutic data. We excluded double transplants and patients with survival less than 6 months. Creatinine clearance was calculated according to the Cockcroft-Gault and the Levey Modification of Diet in Renal Disease (MDRD)-5 equations. Although 165 patients received a cardiac or liver transplantation, 17 died in the first 6 months and three were double transplants; therefore we analyzed 145 patients: 107 (74%) cardiac transplantations and 38 (26%) liver transplantations. There were 106 male and 39 female recipients. The mean age (+/-SD) at the time of transplantation was 54 +/- 10 years and the mean follow-up was 2.9 +/- 1.7 years. Urinalysis before transplantation was only performed in 33 patients (22.8%) including three (2.1%) who had proteinuria. Serum creatinine increased until 12 months after transplantation (P < .001), then it recovered its average level. Creatinine clearance calculated using the aforementioned equations showed a similar pattern, with a progressive decline to 12 months (P < .05), with eventual stabilization or even improvement. The factors that we observed to increase the risk of renal damage were age, female sex, obesity, and the presence of proteinuria prior to transplantation. There was a good correlation (r = 0.96) between cyclosporine but not tacrolimus trough levels and serum creatinine at 48 hours after transplantation.
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PMID:Study of the renal function in nonrenal organ transplantation. 1711 81

Kidney transplantation is the treatment of choice for patients with end-stage renal disease, in part because of ongoing efforts towards improving immunosuppressive strategies. Although calcineurin inhibitors remain the mainstay of immunosuppression in kidney transplant recipients, within this class of drug there has been a shift from use of ciclosporin to use of tacrolimus. Mycophenolate mofetil and mycophenolate sodium are now the antimetabolites of choice. A new class of drugs (inhibitors of mammalian target of rapamycin) that includes sirolimus is being increasingly used in stable kidney transplant recipients. New data, however, indicate that a more cautious approach to the use of this drug is warranted. Many transplant centers are now using steroid avoidance, minimization and withdrawal protocols. The impact of these different drugs and therapeutic strategies on outcomes has to be weighed against their immunosuppressive benefit. As more and more community-based nephrologists and primary care physicians are becoming involved in the care of stable kidney transplant recipients, it is important for these clinicians to familiarize themselves with novel immunosuppressive drugs and their pharmacokinetic properties.
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PMID:Drug insight: maintenance immunosuppression in kidney transplant recipients. 1712 26

Sirolimus is a novel immunosuppressant with potent antiproliferative actions through its ability to inhibit the raptor-containing mammalian target of rapamycin protein kinase. Sirolimus represents a major therapeutic advance in the prevention of acute renal allograft rejection and chronic allograft nephropathy. Its role in the therapy of glomerulonephritis, autoimmunity, cystic renal diseases and renal cancer is under investigation. Because sirolimus does not share the vasomotor renal adverse effects exhibited by calcineurin inhibitors, it has been designated a 'non-nephrotoxic drug'. However, clinical reports suggest that, under some circumstances, sirolimus is associated with proteinuria and acute renal dysfunction. A common risk factor appears to be presence of pre-existing chronic renal damage. The mechanisms of sirolimus-associated proteinuria are multifactorial and may be due to an increase in glomerular capillary pressure following calcineurin inhibitor withdrawal. It has also been suggested that sirolimus directly causes increased glomerular permeability/injury, but evidence for this mechanism is currently inconclusive. The acute renal dysfunction associated with sirolimus (such as in delayed graft function) may be due to suppression of compensatory renal cell proliferation and survival/repair processes. Although these adverse effects occur in some patients, their occurrence could be minimised by knowledge of the molecular effects of sirolimus on the kidney, the use of sirolimus in appropriate patient populations, close monitoring of proteinuria and renal function, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers if proteinuria occurs and withdrawal if needed. Further long-term analysis of renal allograft studies using sirolimus as de novo immunosuppression along with clinical and laboratory studies will refine these issues in the future.
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PMID:Sirolimus-associated proteinuria and renal dysfunction. 1714 61

Increased organ ischemia time leads to delayed graft function (DGF), increased acute rejection (AR), enhanced chronic allograft nephropathy (CAN), and reduced long-term allograft survival. The mechanisms by which IRI predisposes to AR and CAN are unknown. We hypothesized that gene expression profiling of ischemia-reperfusion injury (IRI)-affected kidney would identify how IRI predisposes to AR and CAN. Furthermore, we examined how current immunosuppressive drug molecular targets are altered by IRI. C57BL/6J mice were exposed to 30 (n = 3) or 60 (n = 3) minutes of bilateral kidney ischemia or sham surgery (n = 5). At 36 hour kidney tissue was collected and analyzed using Affymetrix 430MOEA (22626 genes) array and GC-RMA-SAM pipeline. Genes with the false discovery rate (q < 1%) and +/-50% fold change (FC) were considered affected by IRI. Genes coding for histocompatibility and antigen-presenting factors, calcineurin, and mammalian target of rapamycin (mTOR) pathway-associated proteins were selected using Gene Ontology (GO) analysis. GO analysis identified 10 and 17 alloimmunity-related genes affected by IRI induced by 30 and 60 minutes of ischemia, respectively, including Traf6 (FC = 2.99) and H2-D1 (FC = 2.58). We also detected significant IRI genomic responses in calcineurin and mTOR pathways represented by Fkbp5 (FC = 4.18) and Fkbp1a (FC = 2.0), and Eif4ebp1 (FC = 16.8) and Akt1 (FC = 3.64), respectively. These data demonstrated that IRI up-regulates expression of several alloimmunity-associated genes, which can in turn enhance alloimune responses. Our discovery of IRI-induced up-regulation of genes associated with calcineurin and mTOR pathways are consistent with clinical observations that FK506 and Rapamycin can alter the course of DGF. Further validation and dissection of these pathways can lead to novel approaches by which improved management of early "nonimmune" transplant events can decrease susceptibility to more classic "immune" changes and CAN.
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PMID:Genomic profiling of kidney ischemia-reperfusion reveals expression of specific alloimmunity-associated genes: Linking "immune" and "nonimmune" injury events. 1717 65

The increasing number of patients on waiting lists and the relatively stable organ procurement rate provide the groundwork for the use of expanded criteria deceased donors. While calcineurin-inhibitors (CNI) are excellent immunosuppressive drugs, their nephrotoxicity is largely responsible for the lack of improvement in long-term graft survival. The objective of this study was to analyze the results obtained with the use of a calcineurin inhibitor-free immunosuppressive protocol (polyclonal antibody induction, plus sirolimus, mycophenolate mofetil, and low doses of steroids) in terms of graft and patient survival as well as posttransplant clinical complications over 2 years. Under this immunosuppressive protocol, 78.04% of the patients completed the follow-up. A protocol biopsy was performed on 17 patients (53.1%) within 2 years posttransplant of which 82.31% were diagnosed as chronic allograph nephropathy grade I. The incidence of clinical complications was low and not significantly different from that reported with other immunosuppressive schemes. Death-censored graft survival was 95.12%. In conclusion, the use of a calcineurin inhibitor-free protocol in renal-transplant recipients of expanded criteria deceased donors was associated with excellent graft and patient survival rates and a low incidence of adverse events.
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PMID:Results of a calcineurin-inhibitor-free immunosuppressive protocol in renal transplant recipients of expanded criteria deceased donors. 1717 6

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that inhibits cell cycle progression and has proven to be a potent immunosuppressive agent for use in solid organ transplant recipients. The drug was initially studied as an adjunct to ciclosporin (cyclosporine) to prevent acute rejection in kidney transplant recipients. Subsequent studies have shown efficacy when combined with a variety of other immunosuppressive agents. The most common adverse effects of sirolimus are hyperlipidaemia and myelosuppression. The drug has unique antiatherogenic and antineoplastic properties, and may promote immunological tolerance and reduce the incidence of chronic allograft nephropathy. Although sirolimus is relatively non-nephrotoxic when administered as monotherapy, it pharmacodynamically enhances the toxicity of calcineurin inhibitors. Ironically, the drug has been used to facilitate calcineurin inhibitor-free protocols designed to preserve renal function after solid organ transplantation. Whether sirolimus can be used safely over the long term with low doses of calcineurin inhibitors requires further study. The use of sirolimus as a corticosteroid-sparing agent also remains to be proven in controlled trials. Postmarketing studies have revealed a number of unforeseen adverse effects including impaired wound healing and possibly proteinuria, oedema, pneumonitis and thrombotic microangiopathy. Overall, sirolimus is a powerful agent when used judiciously with other available immunosuppressants. As is true for all immunosuppressive drugs available for treatment of solid organ transplant recipients, the efficacy of the drug must be balanced against its considerable adverse effects.
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PMID:Use of sirolimus in solid organ transplantation. 1733 96

Sirolimus (SRL) is a potent immunosuppressive drug used in organ transplantation for prophylaxis of acute allograft rejection. Conversion from calcineurin inhibitors to SRL has become an important alternative in patients with chronic allograft nephropathy. Recently, some reports have described the appearance of proteinuria after the use of SRL. The aim of the present study was to describe the incidence of proteinuria in transplant recipients receiving SRL in our transplant center. We studied 78 patients receiving SRL either de novo or after conversion. Eighteen transplant recipients (23.1%) developed proteinuria after SRL treatment. Proteinuria was diagnosed at 11.2 +/- 2.1 months after the initiation of SRL; in eight patients (44.4%) it occurred in the first 6 months. The mean value of proteinuria was 2.6 +/- 0.6 g/24 hours. In 5 patients (27.8%), proteinuria reached nephrotic levels, and in 13 patients (72.2%) was associated with edema. Renal allograft biopsies were performed before conversion to SRL, and a new biopsy, after the appearance of proteinuria. The light microscopy of biopsies performed after the onset of proteinuria showed no specific glomerular changes, except in 2 cases wherein the diagnosis was focal segmental glomerulosclerosis. Immunofluorescence was negative in all cases. In conclusion, in this study proteinuria was observed in 21.3% of patients receiving SRL therapy either as de novo protocol or after conversion to SRL. Proteinuria occurred early after the initiation of SRL therapy and in these cases, withdrawal of SRL was associated with reversion of proteinuria.
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PMID:Proteinuria in transplant patients associated with sirolimus. 1736 56


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