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)

The nephrotoxic potential of the macrolide immunosuppressants, FK506 and rapamycin, was compared with that of cyclosporin (CsA) in male Wistar rats. FK506 induced a reduction of creatinine clearance, hypomagnesemia and hyperuricemia as previously described for CsA. In contrast, equidosed rapamycin did not alter the glomerular filtration rate. FK506 caused proximal tubular epithelial changes consisting of atrophy, vacuolization, inclusion bodies, microcalcification and focal mononuclear interstitial infiltrate as described for CsA. The most striking alteration was hypertrophy of the juxtaglomerular apparatus (JGA). The percentage of renin-containing JGA and the extent of renin immunoreactivity along afferent vessels were significantly increased in FK506- and CsA-treated rats. By contrast, no renal morphologic lesions were found in rapamycin-treated animals. Renal cortical extracts contained abundant cyclophilin and FK506-binding protein (FKBP), the main intracytoplasmic receptors for CsA and FK506, respectively. Furthermore, we demonstrated that receptor bound CsA and FK506, but not rapamycin, formed complexes with the phosphatase calcineurin, as shown previously for lymphocytes. Thus, it is hypothesized that both the immunosuppressive and toxic effects of FK506 and CsA, but not of rapamycin, are mediated through an immunophilin-drug-calcineurin complex. The renal substrate of calcineurin, which mediates renal vasoconstriction is yet to be identified.
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PMID:Nephrotoxicity of immunosuppressants in rats: comparison of macrolides with cyclosporin. 753 90

Organ transplantation offers new life to patients who suffer from incurable disease. The problem of rejection of the transplanted organ has been overcome with the use of potent immunosuppressive drugs. These drugs, although they allow graft tolerance and graft survival, also are associated with complications such as osteoporosis. Although factors such as nutrition, gonadal status, and ambulatory status are important, the use of immunosuppressive drugs appears to be the main factor in the development of osteoporosis. The drugs that are responsible for this bone loss are glucocorticoids and the calcineurin phosphatase inhibitors, cyclosporine and tacrolimus. The incidence of bone disease depends, in part, on which organ is transplanted. Kidney transplant recipients appear to be less susceptible to the development of overt osteoporosis than do heart or liver transplant recipients. The most critical period of bone loss in organ recipients appears to be within the first 6 months, with the most dramatic reduction occurring within the first 3 months following transplantation. Trabecular (cancellous) bone of the spine appears to be most at risk, with vertebral fractures occurring most commonly. Transplant recipients should be evaluated by bone mineral densitometry and measurement of vitamin D metabolites, blood urea nitrogen, creatinine, calcium, and phosphate. Markers of bone turnover may help in assessing the rate of remodeling. Gonadal function should be ascertained by measurement of serum testosterone (males) or estradiol (females) levels. Therapy should be directed toward prevention of bone loss as well as helping to restore what already may have been lost. Administration of calcium and vitamin D and sex hormone replacement, if indicated, should be considered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Organ transplantation and osteoporosis. 761 20

The nephrotoxic potential of ascomycin, the C21-ethyl analogue of FK506, was defined and ways explored to enhance its detection. After 14-day dosing in the Fischer-344 rat, FK506 and ascomycin reduced creatinine clearance by >50% at doses of 1 and 3 mg/kg, i.p., respectively. Ascomycin also had a 3-fold lower immunosuppressive potency in a popliteal lymph node hyperplasia assay, resulting in an equivalent therapeutic index consistent with a common mechanistic dependence on calcineurin inhibition. Renal impairment with different routes of administration was correlated with pharmacokinetics. Sensitivity of detection was not adequate with shorter dosing durations in rats with unilateral nephrectomy or in mice using a cytochrome P-450 inhibitor, SKF-525A. In 14-day studies, nephrotoxicity was not induced by continuous i.p. infusion of ascomycin at 10 mg/kg/day or daily oral administration (up to 50 mg/kg/day) in rats on a normal diet, nor by continuous i.v. infusion (up to 6 mg/kg/day) in rats on a low salt diet to enhance susceptibility. The lack of toxicity at high oral doses of FK506 or ascomycin, and the finding of non-linear oral pharmacokinetics of ascomycin show that this drug class has an oral absorption ceiling. The negative results with continuous infusion suggest that ascomycin nephrotoxicity is governed by peak drug levels. In addition to defining ways to meaningfully compare the nephrotoxic potential of FK506 derivatives, these results have implications for overall safety assessment and improved clinical use.
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PMID:Nephrotoxicity studies of the immunosuppressants tacrolimus (FK506) and ascomycin in rat models. 957 Mar 31

Sirolimus (SRL) provides effective immunosuppression for kidney transplantation and may be useful in patients with delayed allograft function after kidney transplantation. We review our experience with SRL in liver transplant recipients for whom calcineurin inhibitors are undesirable. Fourteen patients with renal insufficiency or acute mental status impairment were administered SRL after liver transplantation (5- to 10-mg load, 1 to 4 mg/d). Immunosuppression also consisted of mycophenolate mofetil and corticosteroids. On resolution of neurological or renal dysfunction (return to baseline mental status or serum creatinine level), tacrolimus (TAC) therapy was initiated. Twelve patients received primary transplants, 1 patient received a combined liver-kidney transplant, and 1 patient received a third transplant. Follow-up was 2 to 7 months. Calcineurin inhibitors were initially withheld in 9 patients, and therapy was aborted because of toxicity in the remaining 5 patients. Mean times to the initiation of SRL and TAC therapy were 5.4 +/- 4.6 and 26.8 +/- 24.4 days, respectively. Serum trough levels of SRL did not correlate with dose or other patient variables. Two patients died after prolonged pretransplantation hospital courses in the intensive care unit. Six patients experienced acute rejection, but only 1 patient required antilymphocyte therapy. Serum creatinine levels at the start of SRL therapy were 2.2 +/- 1.1 and 1.2 +/- 0.6 mg/dL at 3 months. All 3 patients with neurological indications for SRL had a return to their baseline mental status. All patients had improved liver function chemistry test results and prothrombin times. No patients developed leukopenia or thrombocytopenia. SRL is safe after liver transplantation in patients with acute neurological or renal impairment. SRL is an attractive alternative when calcineurin inhibitors are undesirable, but serum trough levels of SRL should be monitored. A prospective randomized study of an SRL-based calcineurin inhibitor-avoiding regimen compared with standard therapy in patients with renal insufficiency will further evaluate the role for SRL in liver transplantation.
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PMID:Experience with the use of sirolimus in liver transplantation--use in patients for whom calcineurin inhibitors are contraindicated. 1108 60

Delayed graft function (DGF) after renal transplantation is a significant risk factor for early acute rejection and graft loss. Sirolimus (SRL) can be administered in the setting of DGF without exacerbating the impaired renal function after transplantation. We examined a calcineurin-sparing regimen using SRL during the early post-operative period in renal transplant patients with delayed or impaired graft function. A retrospective review of 14 consecutive kidney transplant recipients with delayed or impaired graft function who received SRL was performed. The immunosuppressive regimen consisted of daclizumab induction (2 mg/kg), SRL (5-15 mg load followed by 2 5 mg daily maintenance therapy), corticosteroids, and mycophenolate mofetil (MMF, 1.5-3 g/d). Patients were monitored for allograft function, acute rejection, graft survival, thrombocytopenia, and leukopenia. Serum levels of SRL were determined by high-performance liquid chromatography performed at an independent commercial laboratory. Donors were cadaveric in 13 cases and living related in one. The duration of follow-up was 0.5-5.2 months. Nine patients required hemodialysis after transplantation. The mean time to initiation of calcineurin inhibitors was 21 +/- 13 d. Average serum creatinine levels at the initiation of SRL and at 1 month after transplantation were 8.4 +/- 2.7 and 2.1 +/- 1.2 mg/dL, respectively. There were 2 patients (14%) who experienced acute rejection within the first month after transplantation -1 with type I (steroid therapy) and 1 with type II (anti-thymocyte therapy). Serum levels of SRL were initially undetectable in the 2 patients with acute rejection. No grafts were lost during the period of follow-up. Three patients developed thrombocytopenia (platelets < 100 x 10(9)) and no patients developed leukopenia. The combination of SRL with anti-CD25 mAb, MMF, and corticosteroids appears to provide effective non-nephrotoxic immunosuppression for kidney transplantation without the need for a lymphocyte-depleting regimen. However, it is important to monitor serum SRL levels to determine the optimal dosing regimen. Furthermore, long-term follow-up of these patients will be helpful to determine whether improved immunosuppression can be achieved with a fully calcineurin-sparing regimen using SRL.
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PMID:A calcineurin inhibitor-sparing regimen with sirolimus, mycophenolate mofetil, and anti-CD25 mAb provides effective immunosuppression in kidney transplant recipients with delayed or impaired graft function. 1112 7

Renal transplants may undergo changes secondary to the decrease of the renal mass, the effects of rejection, and various other risk factors that contribute to the progression of renal insufficiency. We have performed a prospective study of 285 cadaveric renal transplants recipients, that were receiving various maintenance immunosuppressives regimens, to study the evolution of their renal function and to evaluate the influence of various factors in the progression of renal insufficiency. All variables were analysed in a regression model of multivariate analysis. We found a progressive increase of the serum creatinine in the studied population. The mean initial creatinine was 1.70 +/- 0.84 mg/dl and final creatinine in the study 2.17 +/- 2.06 mg/dl, difference statistically significant (p = 0.000). We calculated the increase of creatinine in each patient. We observed that 113 patients (42.2%), had stable serum creatinine but the remaining 155 patients (57.8%) had a mean increase of 0.04 +/- 0.8 mg/dl/month. We analysed the patients according to various variables. Although in most the final creatinine is significantly greater than the initial, this increase of creatinine level was not present in patients with delayed graft function, in patients with no acute rejection, in the extreme age groups, in the grafts from younger donors and in those patients without initial proteinuria. The patients transplanted from younger donor had the best renal function, without any decrease in their function during the study. The advanced age of the donor has a great negative impact in the evolution of the renal transplant. According to our study, proteinuria and its quantity is a major predictor of progressive renal insufficiency. The multivariate analysis confirms that the age of the donor and initial proteinuria predict decrease of renal function. It is important to identify the factors that they could predict a greater progression to the failure of the graft. We have the possibility of acting on them, establishing immunosuppressive strategies that reduce the deleterious effects of the calcineurin inhibitors in the recipients of grafts from older donors' and to encourage the use of drugs which reduce proteinuria.
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PMID:[Changes in renal function in renal transplantation. Predictive factors for functional deterioration]. 1147 10

Few studies have systematically investigated what changes in chronic renal allograft function best predict subsequent graft failure, when these changes occur, and whether they occur soon enough to allow possible intervention. We collected serum creatinine values (mean, 183 +/- 75 values/patient) measured over a maximum follow-up of 22 years in 101 consecutive renal transplant recipients (excluding creatinine levels from periods of acute rejection). We determined the dates of first decline in inverse creatinine (Delta1/Cr; < -20%, -30%, -40%, -50%, and -70%), declines in estimated creatinine clearance (CCr; <55, 45, 35, 25, and 15 mL/min), and declines in measured slope of 1/Cr over time. We used time-dependent covariates in Cox proportional hazards analyses to determine the relative effect of each renal function parameter on outcomes while adjusting for other risk factors. The best predictor of subsequent graft failure was Delta1/Cr. Delta1/Cr less than -40% first occurred at a median of 1.28 years after transplantation in 73 patients, and 67 patients went on to have graft failure a median of 3.28 years after Delta1/Cr less than -40%. The independent relative risk for graft failure attributable to Delta1/Cr less than -40% was 5.91 (95% confidence interval, 3.25 to 10.8; P < 0.0001). A decline in CCr, eg, less than 45 mL/min, also was a strong predictor of subsequent graft failure. Conversely, declines in allograft function estimated from slopes of 1/Cr were poor predictors of graft failure. In analysis limited to patients followed up for 2.5 years or less, Delta1/Cr continued to predict graft failure, suggesting that Delta1/Cr will be a useful predictor in populations with shorter follow-up. If confirmed in other populations, eg, patients treated with calcineurin inhibitors, this simple marker of chronic allograft dysfunction may prove to be a practical tool for defining patients at high risk for late graft failure.
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PMID:Comparing methods for monitoring serum creatinine to predict late renal allograft failure. 1168 61

SDZ RAD (everolimus, Certican is a novel macrolide immunosuppressant that blocks growth factor-driven transduction signals in the T-cell response to alloantigen. After stimulation of the IL-2 receptor on the activated T-cell, SDZ RAD inhibits p70S6 kinase, acting at a later stage in the T-cell mediated response than do cyclosporine and other calcineurin inhibitors (CNIs). Unlike the CNIs, SDZ RAD is a proliferation signal inhibitor, blocking growth factor-driven proliferation of both hematopoietic and nonhematopoietic cells. These activities are complementary to those of cyclosporine and provide a rationale for the addition of SDZ RAD to cyclosporine-based immunosuppression, with the potential for minimizing CNI nephrotoxicity, reducing the incidence of acute rejection, and favoring long-term graft survival. Potential also exists for beneficial effects on other factors that may influence the development of chronic rejection. These factors include comorbid diseases such as hypertension, which may affect transplant vasculopathy, and opportunistic infection with cytomegalovirus (CMV) and other viruses, which may increase the risk of chronic rejection. The synergistic effect of SDZ RAD and cyclosporine has been confirmed in preclinical models, with graft survival being significantly prolonged in rat models of kidney and heart allotransplantation. Clinical experience with SDZ RAD in cyclosporine-based immunosuppression, including low-dose cyclosporine regimens, has also resulted in predictable and favorable clinical outcomes. Low rates of acute rejection, excellent rates of patient and graft survival, lower incidence of CMV infections, better cholesterol, triglyceride and creatinine profiles, and better renal function have been demonstrated with SDZ RAD and lower doses of cyclosporine (Neoral; Novartis) in recipients of renal transplants. These findings, combined with good tolerability rates and an acceptable side-effect profile, indicate that the synergistic profile of SDZ RAD in combination with nontoxic dosages of CNI's and IL2 inhibitors will further improve longterm results in renal transplantation.
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PMID:Early clinical experience with a novel rapamycin derivative. 1180 23

Many heart transplant recipients experience nephrotoxicity caused by cyclosporine. Tacrolimus has been associated with similar efficacy and safety in heart transplant recipients compared with cyclosporine. It is unknown whether there is any benefit to switching calcineurin inhibition from cyclosporine to tacrolimus in heart transplant recipients with presumed cyclosporine nephrotoxicity. We report five such cases in which this approach was used successfully. In these cases, the heart transplant recipients had bland urine sediments, low urinary sodium concentrations, adequate cardiovascular and systemic hemodynamics, and cyclosporine levels within or below the therapeutic range as defined by heart transplant criteria. The mechanism of renal failure in these patients was believed to be consistent with renal hypoperfusion secondary to cyclosporine-induced renal vasoconstriction. Conversion to tacrolimus resulted in a prompt and significant improvement in serum creatinine concentrations in these patients (P = 0.002). This report shows that conversion to tacrolimus may represent a useful therapeutic strategy to reduce cyclosporine-associated renal failure in recipients of orthotopic heart transplants.
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PMID:Conversion to tacrolimus for the treatment of cyclosporine-associated nephrotoxicity in heart transplant recipients. 1187 96

Recent studies provide conflicting conclusions regarding the impact of delayed graft function (DGF) on the long-term outcome of renal transplantation. Some centres report DGF as an independent risk factor for reduced long-term graft and patient survival, while others report no impact on long-term outcome. Further scrutiny of data from these studies reveals differences in the definition of DGF, definition of long-term outcome, and statistical methods that may partly explain the variability. The commonest definition of DGF is the need for dialysis in the first week post-transplant, but this may be less informative than definitions that consider DGF as a continuous variable such as time to achieving creatinine clearance > 10ml/min. Acute rejection (AR) occurs more commonly in patients with DGF and variability in the impact of DGF may also relate to strategies to detect and treat AR during DGF. Centres with a vigilant strategy are likely to note a lower impact of DGF because the associated long-term adverse impact of AR is minimised. Furthermore, many centres reduce the dose of calcineurin inhibiting drugs and/or use polyclonal antibody therapy during DGF but the long-term impact of this strategy is unclear. Newer agents such as humanised anti-IL2 monoclonal antibodies and rapamycin may have a role, but controlled studies are required to define the optimal immunosuppressive regimen for patients with DGF. In the meantime, measures to minimise ischaemic damage to the transplant kidney and intensive surveillance for AR with weekly renal biopsy in patients with DGF are recommended.
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PMID:The impact of delayed graft function on the long-term outcome of renal transplantation. 1193 21


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