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)

With the advent of calcineurin inhibitors, the success of kidney and other solid-organ transplants has improved significantly from the standpoint of reducing the incidence of acute rejection. Over the past 2 decades, both short-term allograft survival and acute rejection rates have dramatically improved with improved diagnostic and therapeutic techniques such as standardized pathology scoring; potent antirejection drugs such as anti-thymocyte globulin, interleukin-2 receptor antibodies, cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil; and improved infection control such as valganciclovir and antifungal therapy. However, long-term graft loss has remained at nearly constant levels over the same period of time, with the average half-life of a deceased-donor kidney transplant in the United States remaining approximately 1 decade. In addition to death with a functioning allograft and calcineurin toxicity, a chronic fibrotic process-known at various times as chronic rejection, chronic allograft dysfunction, and chronic allograft nephropathy (CAN)-account for the leading causes of transplant failure.
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PMID:Chronic allograft nephropathy. 1641 71

Chronic kidney disease (CKD) following myeloablative allogeneic hematopoietic cell transplantation (HCT) occurs in 20% of survivors at 1 year and is believed to be due to radiation nephritis. Non-myeloablative allogeneic HCT is a recent procedure that employs significantly lower doses of chemoradiotherapy, however, incidence and risk factors for CKD following non-myleoablative HCT have not been defined. We performed a retrospective cohort study of 122 patients from three institutions who were available for analysis at 6 months following non-myeloablative HCT. Patients received two Gy of radiation; 62% received fludarabine as preconditioning. CKD was defined as at least a 25% reduction in glomerular filtration rate (GFR) from baseline using the abbreviated modified diet in renal disease (MDRD) equation. Eighty-one of 122 patients (66%) showed evidence of CKD at follow-up. Multivariate analysis revealed that acute renal failure (ARF) during the first 100 days post-transplant was associated with development of CKD (Adjusted OR 32.8 with 95% CI 4.3-250) after controlling for other variables. Previous autologous HCT, long-term calcineurin inhibitor use and extensive chronic GVHD were independently associated with CKD. CKD following non-myeloablative HCT appears to be a distinct clinical entity and likely not related to radiation nephritis. Future research should focus on possible mechanisms for alleviating chronic injury and decreasing use of calcineurin inhibitors.
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PMID:Chronic kidney disease following non-myeloablative hematopoietic cell transplantation. 1643 61

Cardiac allograft vasculopathy (CAV), is characterized by heterogeneous proliferative thickening of the vascular intima of the cardiac allograft vasculature. Since its presentation is commonly clinically silent, early diagnosis and preventative therapy are critical. Preventative therapy including optimization of immunosuppressive therapy and treatment of comorbidities associated with CAV progression must be initiated early since most of the intimal thickening occurs during the first year posttransplant. Long-term use of calcineurin inhibitors is associated with a high incidence of chronic renal disease and also contributes to hyperlipidemia and hypertension, all of which may exacerbate CAV. In addition, statins, antihypertensive agents and anti-CMV agents all have demonstrated benefits in reducing CAV. Once established, the limited treatment options include nonpharmacologic interventions such as retransplantation, percutaneous coronary interventions, coronary artery bypass grafting, transmyocardial laser revascularization and heparin-induced/mediated extracorporeal LDL plasmapheresis (HELP). As the use of new assessment tools increases our understanding of this disease, better preventative and treatment strategies are evolving.
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PMID:Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. 1668 47

Chronic allograft nephropathy is a major cause for allograft loss in renal transplantation. Sirolimus was recently introduced as a potent non-nephrotoxic alternative to calcineurin inhibitors. In the present study, effects of a conversion protocol were investigated in pediatric chronic allograft nephropathy with declining glomerular filtration rate (GFR), defined by a Schwartz formula clearance below 60 mL/1.73 m(2)/min, steadily increasing serum creatinine and allograft biopsy. In eight children with a median age of 12.8 yr, sirolimus was started at median 32 months after transplantation with a loading dose of 0.24 mg/kg bodyweight (BW), followed by 0.2 mg/kgBW/day, aimed at trough levels of 15-20 ng/mL. Calcineurin inhibitors were reduced to 50% at the start of sirolimus and discontinued at median 7 days when target levels of sirolimus were reached. Following conversion, changes of GFR significantly stabilized (-2.9 vs. +0.4 mL/min/1.73 m(2)/month, p = 0.025). Individual GFR increased in five out of eight patients (p = 0.026), and only one child exhibited unaltered progression of graft failure. In the responders, mean serum creatinine improved by 0.3 mg/dL (p = 0.043). Effects were not dependent on GFR at conversion, or on time post-transplantation. Blood pressure, hematological parameters and proteinuria remained stable during the observation period, and serum lipids increased transiently. About half of the children suffered from infectious complications. No child had to be taken off sirolimus; there was no graft loss during the observation period. In conclusion, conversion from calcineurin inhibitors to sirolimus is an effective protocol with tolerable side effects to stabilize renal graft function for at least one yr in the majority of children with biopsy-proven chronic allograft nephropathy.
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PMID:Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy. 1671 6

Over the last decade, polyomavirus-associated nephropathy (PVAN) has occurred with increasing frequency after renal transplantation, leading to significant renal dysfunction and graft loss. More than 95% of all cases are caused by the human polyomavirus type 1 called the BK virus. The primary treatment for PVAN is immunosuppression reduction, which must be carefully balanced against increased risks of rejection. Although no validated protocols exist, a first step commonly involves reduction of calcineurin inhibitors with antiproliferative agents by more than one-third, e.g., reaching trough levels of tacrolimus <6 ng/mL, of cyclosporine <150 ng/mL, dosing of mycophenolate mofetil to <1 g/day, and azathioprine <75 mg/day. When rejection is diagnosed together with PVAN, a transient pulse treatment is recommended before subsequent reduction in immunosuppression. No antiviral treatments for PVAN have been approved by the United States Food and Drug Administration. The antiviral drug cidofovir has shown in vitro activity against murine polyomaviruses, and has been used in some patients in lower doses in an effort to minimize the nephrotoxic effects of cidofovir while treating PVAN. Small series of PVAN patients treated with leflunomide, intravenous immune globulin therapy, and fluoroquinolones have also been reported recently.
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PMID:Polyomavirus-associated nephropathy: update of clinical management in kidney transplant patients. 1673 30

In renal transplantation the calcineurin inhibitors (CNIs) have played a crucial role in the reduction in acute rejection rates. Unfortunately this has not been matched by an improvement in long-term graft survival rate. The development of chronic allograft nephropathy (CAN) is the second most common cause of graft loss, after death from cardiovascular causes. CAN has a multifactorial aetiology that includes immunological and nonimmunological factors relating to both donor and recipient. The use of CNIs has been strongly implicated as a risk factor for the development of CAN. With the ongoing development of new immunosuppressant agents the possibility of avoiding the CNIs now exists. Many studies have been designed to investigate strategies to minimise or avoid CNI exposure and to prolong graft survival. To achieve CNI withdrawal whilst avoiding rejection, additional immunosuppressants need to be substituted into the drug regimen. Long-term side effects of the immunosuppressant used need to be taken into account when drug changes are being considered. In light of current evidence, CNI reduction with optimal use of mycophenolate mofetil appears to be the most effective strategy in managing the patient with CAN.
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PMID:Chronic renal allograft dysfunction: the evidence for a change in immunosuppression. 1676 Aug 81

Ongoing improvements in survival following liver transplantation have necessitated a re-evaluation of immunosuppression protocols. Corticosteroids and calcineurin inhibitors (CNIs) are the most frequently used immunosuppressive drugs for liver transplantation but are associated with a wide range of adverse effects, such as hypertension, hyperlipidemia and nephrotoxicity. The need for hemodialysis after liver transplantation is associated with poor outcomes. Renal dysfunction in this setting may be caused by pre-existing renal disease, hepatorenal syndrome and/or post-transplant factors, including the use of nephrotoxic drugs, most notably CNIs such as cyclosporine and tacrolimus. The methods that address this problem include the diligent control of metabolic factors (eg, hypertension and hyperlipidemia), therapeutic monitoring of CNIs and withdrawal or reduction of the dosage of CNIs, combined with the use of newer non-nephrotoxic agents. Although there is no clear consensus about the most effective strategy, the optimal long-term immunosuppressive regimen would prevent rejection without causing nephrotoxicity or other significant adverse effects. Recent evidence suggests that the liver is a tolerogenic organ and that some patients may need little, if any, long-term immunosuppression.
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PMID:Renal dysfunction in liver transplantation: the problem and preventive strategies. 1680 24

Polyoma virus nephropathy (BK virus) is being recognized as an important cause of graft failure. It is usually confused with acute rejection. No cases have been reported from the kingdom of Saudi Arabia. We report a case of a Saudi gentleman, who was transplanted outside the country, with persistently elevated creatinine and urethral stenosis. He was treated for acute rejection on more than one occasion with no significant improvement in his renal function. Polyoma virus nephropathy was diagnosed by detecting the virus DNA by the Poly chain reaction technique (PCR). The patient's renal function stabilized after the calcineurin inhibitors were discontinued.
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PMID:Polyoma virus nephropathy, first reported case in Saudi Arabia. 1690 28

Although short-term kidney allograft survival has improved significantly since the introduction of the calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus, long-term transplant survival remains a major concern, chronic allograft nephropathy (CAN) being the principal reason for graft loss after the first post-transplant year. This is particularly major for pediatric renal transplant recipients because of their higher life expectancy compared with adults. The mechanisms leading to CAN are multiple, including acute and chronic alloimmune responses and nephrotoxicity of CNIs. CNI-induced nephrotoxicity is also a long-term concern in other pediatric solid organ transplant recipients, such as liver and heart. Prevention of allograft nephropathy requires a balance of maintaining adequate immunosuppression, while avoiding the toxic effects of CNIs. Regimens that are based on mycophenolate mofetil (MMF) alone or in combination with newer agents may allow for reduced reliance on CNIs and thus may represent an effective treatment paradigm for long-term maintenance of a renal allograft. From the available data it appears that the currently safest treatment strategy in pediatric renal and heart transplant recipients with CNI toxicity is an MMF-based therapy with low-dose CNIs +/- low-dose steroids, while in pediatric liver transplant recipients, CNI-free MMF-based immunosuppressive therapy with or without steroids appears feasible in a significant subset of patients. In renal transplant recipients, the benefit of a CNI-free MMF/steroid therapy on renal function is gained at the cost of increased rejection in a subset of patients, although the relative importance of rejection vs. overall renal function requires further clinical investigation. The introduction of mammalian target of rapamycin (mTOR) inhibitors provides an opportunity for unique CNI-sparing regimens that combine two antiproliferative agents (MMF and TOR inhibitors). It is possible that a sirolimus-based CNI-free immunosuppressive regimen in terms of renal transplant survival is superior to CNI minimization, where the detrimental effects of CNIs on allograft function and structure are still operative, albeit to a lesser degree. Substitution of CNIs by mTOR inhibitors is therefore promising, but requires validation in long-term studies in large cohorts.
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PMID:Treatment strategies in pediatric solid organ transplant recipients with calcineurin inhibitor-induced nephrotoxicity. 1691 97

Mycophenolate mofetil (MMF) and sirolimus (SRL) are potent non-nephrotoxic xenobiotic immunosuppressants. Their complementary properties may provide the rationale for their combination in induction and maintenance regimens. MMF, a reversible inhibitor of inosin monophosphate dehydrogenase (IMPDH) acts as an antiproliferative drug; and SRL, an mTOR (mammalian target of rapamycin) inhibitor, inhibits cell proliferation driven by growth factors. Early experiences with the use of the SRL, MMF and steroid combination yielded insufficient prophylaxis of acute rejection. However, the introduction of induction therapy with mono- or polyclonal antilymphocyte antibodies to the SRL-MMF and steroid combination brings an efficient acute rejection prophylaxis, while improving renal function and/or reducing of chronic allograft nephropathy (CAN). However, adverse events related to the use of this drug combination (mainly haematological and surgery-related) result in a high rate of discontinuations in some trials, which may hamper the potential benefits of this calcineurin-inhibitor (CNI)-free strategy. Also, currently under investigation is whether in long-term immunosuppression, in MMF-treated patients, CNIs can be replaced by SRL to avoid and/or halt progression of chronic nephropathy and to improve graft survival. However, some authors reported a high proportion of patients with oral ulcers and proteinuria after switching to SRL. In short, refining the use of MMF and SRL may provide a better risk/benefit ratio to pave the way towards non-nephrotoxic immunosuppression.
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PMID:Mycophenolate mofetil and sirolimus combination in renal transplantation. 1693 Mar 95


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