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)

Immunosuppressant-induced nephrotoxicity, in particular chronic progressive tubulointerstitial fibrosis/arteriopathy induced by the calcineurin inhibitors cyclosporin and tacrolimus, has become the 'Achilles heel' of immunosuppressive agents. The use of calcineurin inhibitors as primary immunosuppressants in hepatic and cardiac transplantation has led to end-stage renal disease and dialysis. Calcineurin inhibitor-induced acute renal failure may occur as early as a few weeks or months after initiation of cyclosporin therapy. The clinical manifestations of acute renal dysfunction are caused by vasoconstriction of renal arterioles, and include reduction in glomerular filtration rate, hypertension, hyperkalaemia, tubular acidosis, increased reabsorption of sodium and oliguria. The acute adverse effects of calcineurin inhibitors on renal haemodynamics are thought to be directly related to the cyclosporin or tacrolimus dosage and blood concentration. However, new clinical data indicate that calcineurin inhibitor-induced chronic nephropathy can occur independently of acute renal dysfunction, cyclosporin dosage or blood concentration. Several strategies have been evaluated to attenuate cyclosporin-induced nephropathy, but their efficacy remains unknown. Cytokine release syndrome associated with the use of muronomab-CD3 (OKT-3) can also contribute to the pathogenesis of transient acute tubular necrosis and renal dysfunction following renal transplantation. Continued research and clinical experience should provide information regarding the aetiology of cyclosporin-induced chronic progressive tubulointerstitial fibrosis/arteriopathy and its potential treatment.
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PMID:Immunosuppressant-induced nephropathy: pathophysiology, incidence and management. 1061 71

In puromycin aminonucleoside (PAN)-treated nephrotic rats, sodium retention is associated with increased (Na+/K+)-ATPase activity in the cortical collecting ducts (CCD). This study was undertaken to determine whether stimulation of (Na+/K+)-ATPase in the CCD is a feature of other experimental nephrotic syndromes, whether it might be responsible for renal sodium retention, and whether it is mediated by increased plasma vasopressin levels or activation of calcineurin. For this purpose, the time courses of urinary excretion of sodium and protein, sodium balance, ascites, and (Na+/K+)-ATPase activities in microdissected CCD were studied in rats with PAN or adriamycin nephrosis or HgCl2 nephropathy. The roles of vasopressin and calcineurin in PAN nephrosis were evaluated by measuring these parameters in Brattleboro rats and in rats treated with cyclosporin or tacrolimus. Despite different patterns of changes in urinary sodium and protein excretion in the three nephrotic syndrome models, there was a linear relationship between CCD (Na+/K+)-ATPase activities and sodium excretion in all three cases. The results also indicated that there was no correlation between proteinuria and sodium retention, but ascites was present only when proteinuria was associated with marked reduction of sodium excretion. Finally, the lack of vasopressin in Brattleboro rats or the inhibition of calcineurin by administration of either cyclosporin or tacrolimus did not prevent development of the nephrotic syndrome in PAN-treated rats or stimulation of CCD (Na+/K+)-ATPase. It is concluded that stimulation of Na(+/K+)-ATPase in the CCD of nephrotic rats might be responsible for sodium retention and that this phenomenon is independent of proteinuria and vasopressin and calcineurin activities.
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PMID:Collecting duct (Na+/K+)-ATPase activity is correlated with urinary sodium excretion in rat nephrotic syndromes. 1075 19

Alterations in the cell division:cell death ratio induce multiple autoimmune and transformation processes. Phosphoinositide 3-kinase (PI3K) controls cell division and cell death in vitro, but its effect on the function of the cellular immune system and on tumor formation in mammals is poorly characterized. Here we show that transgenic mice expressing in T lymphocytes an active form of PI3K derived from a thymic lymphoma, p65(PI3K), developed an infiltrating lymphoproliferative disorder and autoimmune renal disease with an increased number of T lymphocytes exhibiting a memory phenotype and reduced apoptosis. This pathology was strikingly similar to that described in mice exhibiting heterozygous loss of the tumor suppressor PTEN, a lipid and protein phosphatase. We show that overexpression of PTEN selectively blocks p65(PI3K)-induced 3T3 fibroblast transformation. Moreover, the early development of T cell lymphomas in p65(PI3K) Tg p53(-/-) mice indicated that PI3K contributes to tumor development. These observations demonstrate that constitutive activation of PI3K extends T cell survival in vivo, affects T cell homeostasis, and contributes to tumor generation, supporting a model in which selective increases in one type of PTEN substrate, the PI3K-derived lipid products, induce tumorigenesis. PI3K thus emerges as a potential target in autoimmune disease and cancer therapy.
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PMID:Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. 1078 43

Successful renal transplantation is associated with abnormalities of function of the musculoskeletal system. Some of these problems result from incomplete resolution of abnormalities of mineral metabolism associated with end-stage renal disease, such as persistent hyperparathyroidism, hypercalcemia and decreased vitamin D. However, it is now appreciated that skeletal abnormalities, especially osteopenia with subsequent fractures, develop following transplantation. Most of the new disorders of bone and mineral metabolism are secondary to the immunosuppression required to prevent rejection. Glucocorticoids can not only induce osteonecrosis, but also increase the risk for fractures by decreasing cancellous bone mass and synthesis of bone matrix, and dampen the linear growth response in pediatric recipients. Other immunosuppressive agents, especially the calcineurin-phosphate inhibitors, independently exert a negative effect on bone. Future investigation is required to develop a better understanding of the pathophysiologic mechanisms involved in post-transplant bone disease in order to develop rational approaches for prevention and treatment.
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PMID:Mechanism of transplantation-associated bone loss. 1091 36

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

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.
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PMID:Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation. 1136 39

The kidney transplant program at the Ospedali Riuniti of Bergamo, Italy was established in 1989. Since its inception, 367 patients have been transplanted, including 357 kidney transplants from cadaveric donors and 10 from living-related donors. Overall 8-year patient and graft survival rates were 94% and 77%, respectively. By 1995 our unit co-ordinated the activity of the Department of Immunology and Clinics of Organ Transplantation, Ospedali Riuniti--Mario Negri Institute for Pharmacological Research, Bergamo. The dual "marginal" kidney transplant program in the same recipient was launched in August 1997, as a part of an international cooperative network which established the "Double Kidney Transplant Group" (DKG). To date, 19 dual kidney transplants have been successfully performed in our center. Four combined heart-kidney transplants and 2 combined liver-kidney transplants have also been performed. During the past 4 years several studies involving conventional antirejection drugs were carried out, particularly focussing our attention on cyclosporine (CsA) through pharmacokinetic and pharmacodynamic approaches: 1) a simplified method to evaluate daily exposure to CsA has been set up; 2) the monitoring of calcineurin activity in whole blood samples was evaluated as a way to optimize CsA dosing. As for the new immunosuppressants, studies are ongoing with mycophenolate mofetil (MMF). We are co-ordinating a prospective multicenter randomized trial of steroid sparing in kidney transplant recipients given MMF or azathioprine as a part of their immunosuppression therapy (MY.S.S. study). This involves 9 Italian transplant centers and 2 European centers. Up to now 325 patients have been randomized. Moreover we have set up an HPLC method for measuring plasma mycophenolic acid (MPA), and examined the possibility of optimizing MMF dosing by drug pharmacokinetic monitoring. Further studies have been addressed to chronic allograft nephropathy. The nature and mediators of renal lesions in kidney transplant patients given CsA have been explored taking into account the gene expression of endothelin-1, RANTES and MCP-1 in graft specimens from patients who had evidence of CsA nephrotoxicity, chronic rejection, or no lesions at histological examination. The impact of percutaneous transluminal angioplasty and stenting of posttransplant renal artery stenosis on renal function recovery was also recently examined. From this study we conclude that the procedure is safe and effective to normalize the functional changes sustained by hemodynamically significant artery stenosis. Moreover, Doppler ultrasound scanning is an useful, reliable, non-invasive tool to monitor the renal function response to artery revascularization. Thanks to the long-lasting co-operation with the Negri Bergamo Laboratories, we had in the past and still have an active program in experimental animals to investigate strategies for transplant tolerance and transplant gene therapy, besides addressing some issues related to the immunological barrier of xenotransplantation.
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PMID:The kidney transplant program at the Bergamo Center. 1151 11

With current immunosuppression, elevated blood pressure is found in almost 90% of renal graft recipients. Major causes of this are impairment of renal function (secondary to chronic allograft nephropathy or less frequently recurrence of primary renal disease), the use of calcineurin inhibitors as immunosuppressants, uncontrolled renin secretion by the shrunken kidneys of the recipient, stenosing lesions of the transplant artery (or the upstream arteries of the recipient), polycythemia, and genetic predisposition to hypertension of the graft donor. Even minor degrees of blood pressure elevation have a significant impact on survival of the recipient and on graft survival, presumably by amplifying vascular injury to the graft. In this respect, elevation of systolic blood pressure and an abnormal circadian blood pressure profile are of particular relevance. In contrast to previous opinion, angiotensin converting enzyme inhibitors are indicated in treatment, but given the causal role of sodium retention and graft vasoconstriction, diuretics and calcium channel blockers remain mainstays of antihypertensive treatment in the renal allograft recipient.
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PMID:Hypertension after renal transplantation. 1155 80

Although only very few new immunosuppressive drugs have been approved over the past two decades, the introduction of each new drug has progressively reduced the incidence of acute rejection and raised hopes that there would be an increase in long-term allograft survival. It is now consistently possible to achieve acute rejection rates of between 10 and 20%, and in many studies the rate has fallen below 10%. This is important, as acute rejection is one of the most important factors reducing the long-term survival of the allograft as a consequence of the development of chronic allograft nephropathy. The availability of these new agents has allowed experimentation with diverse protocols that explore the possibility of reduced exposure to calcineurin inhibitors and corticosteroids. These include both 'avoidance' and 'withdrawal' protocols. The target of rapamycin inhibitors, sirolimus and everolimus, have extended this paradigm. It is possible, but not yet proved, that their antiproliferative effect on smooth muscle will retard the vascular remodelling characteristic of chronic allograft nephropathy, atherosclerosis and hypertension. This review concentrates on the current progress being made in clinical immunosuppression, and includes data presented at the Transplant 2001 meeting of the American Society of Transplantation and the American Society of Transplant Surgeons, held in May 2001.
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PMID:Progress in the clinical application of immunosuppressive drugs in renal transplantation. 1170 3

Sirolimus (Rapamune), Wyeth-Ayerst, Madison, NJ) is a new, potent, immunosuppressant that is emerging as a foundation for long-term immunosuppressive therapy in renal transplantation. The drug acts during both co-stimulatory activation and cytokine-driven pathways via a unique mechanism: inhibition of a multifunctional serine-threonine kinase, mammalian target of rapamycin (mTOR). Although there is no a priori reason to assume it, sirolimus displays a synergistic interaction to enhance the efficacy of cyclosporin A (CsA). In trials wherein the concentrations of CsA and sirolimus were tightly controlled, rates of acute rejection episodes were < 10%, despite markedly reduced exposures to each agent. In pivotal multi-centre blinded dose-controlled trials, the rates of acute rejection episodes within 12 months following administration of 2 or 5 mg/day sirolimus in combination with CsA and steroids were reduced to 19 and 14%, respectively. Since the inhibitory effect of sirolimus disables virtually all responses to cytokine mediators due to the widespread involvement of mTOR in multiple signalling pathways, the agent is likely also to retard proliferation of endothelial and vascular smooth muscle cells, an important component of the immuno-obliterative processes associated with chronic rejection. The advantages of this unique therapeutic action combined with an intrinsic lack of nephrotoxicity are counterbalanced by myelosuppressive and hyperlipidaemic side effects. Ongoing studies are assessing whether the long-term benefits of sirolimus to permit reduction in exposure to or elimination of calcineurin inhibitors ameliorate the progression of chronic nephropathy, the condition that erodes long-term renal transplant survival.
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PMID:Sirolimus: a comprehensive review. 1182 25


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