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 ability to estimate rather than measure the glomerular filtration rate (GFR) in patients before and after liver transplantation would be helpful in estimating risk, dosing drugs, and assessing long-term toxicity of calcineurin inhibitors. Currently available equations for estimating the GFR have not been validated in either the pre- or post-liver transplant population. We have evaluated the performance of currently used formulas for the estimation of the GFR in this setting. Data were collected prospectively on patients who underwent liver transplantation between 1984 and 2001. GFR per 1.73 m2 was measured by I125 iothalamate in patients at the pretransplant evaluation and at 3 months, 1 year, and yearly posttransplant thereafter. GFR estimated by the Cockcroft-Gault equation, the Nankivell equation, and the equations from the Modification of Diet in Renal Disease (MDRD) Study (6, 5, and 4 variables) was compared with the measured GFR. Pretransplant GFR was available in 1,447 patients. The mean GFR was 90.7 +/- 40.5 mL/min. Values for r and r2 were highest for the MDRD Study 6-variable equation (0.70 and 0.49, respectively). Only 66% of estimates were within 30% of the measured GFR. At 3 months, 1 year, and 5 years posttransplant, the mean GFR was 59.5 +/- 27.1 mL/min, 62.7 +/- 27.8 mL/min, and 55.3 +/- 26.1 mL/min, respectively. Values for r and r(2) for the MDRD Study 6-variable equations at 1 and 5 years posttransplant were 0.74 (0.55) and 0.76 (0.58), respectively. At these time points, however, only 67% and 64% of the estimated GFR were within 30% of the measured GFR. MDRD Study equations had greater precision than other equations, but the precision was lower than reported for MDRD estimation of GFR in other populations. Better methods for estimating the GFR are required for evaluation of renal function before and after liver transplantation.
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PMID:Estimation of glomerular filtration rates before and after orthotopic liver transplantation: evaluation of current equations. 1476 71

Sirolimus, a macrocyclic lactone that displays a novel mechanism of immunosuppressive action, is a critical-dose drug requiring therapeutic drug monitoring for optimal outcomes. This immunosuppressive agent was studied in two multicenter, blinded clinical trials to reduce the incidence of acute rejection episodes when used in combination with cyclosporine and steroids versus azathioprine or placebo comparators. Cyclosporine withdrawal studies documented a long-term benefit of chronic sirolimus therapy on renal function, albeit with a modestly enhanced incidence of acute rejection episodes. I believe that minimal initial cyclosporine exposures de novo mitigate the need for eventual withdrawal for chronic nephropathy while preserving the immunosuppressive synergy during the maintenance phase. Recipients treated de novo with a sirolimus-cyclosporine combination tolerate steroid withdrawal at 1 month after living-donor or at 3 to 6 months after cadaveric kidney transplantation with only a 5% risk of acute rejection episodes and 6% incidence of chronic reactions within 3 years. However, sirolimus exacerbates the hypertriglyceridemic and hypercholesterolemic proclivities of transplant recipients and exerts myelosuppressive effects. Due to its apparent lack of nephrotoxicity, sirolimus has been employed for induction therapy in a calcineurin antagonist-free regimen in combination with either basiliximab or rabbit antilymphocyte sera for weak or strong immune responders, respectively, followed by introduction of a calcineurin antagonist upon resolution of the ischemia-reperfusion injury.
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PMID:Sirolimus: a ten-year perspective. 1501 4

The introduction of cyclosporine (CSA) into organ transplantation was a landmark achievement leading to a substantial improvement of the early transplant results. It was particularly the reduction in early severe acute rejections that accounted for this improvement. However, on a long-term basis development of chronic transplant nephropathy did not seem to become counteracted by CSA. Conversely, CSA may cause both acute and chronic nephrotoxicity, with reduced renal transplant function along with arteriolopathy and interstitial fibrosis. This is the shortcoming of CSA as well as other calcineurin inhibitors (CNIs) such as tacrolimus (TAC). Other immunosuppressive agents were developed subsequently, including Target of Rapamycin (ToR) blockers and mycophenolate mofetil (MMF), which were not nephrotoxic. Current strategies to overcome CNI toxicity include reduction or even stopping administration of CSA or TAC along with switching to a sirolimus, everolimus or MMF based regimen. This strategy has been documented (and there are currently additional ongoing studies) to cause an improvement in renal transplant function or to reduce the deterioration rate. These measures to deal with CSA toxicity need further documentation, since a preserved good renal function seems to not only have an important impact on graft survival but also on patient survival.
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PMID:Cyclosporine nephrotoxicity. 1504 41

The polypeptide immunosuppressant cyclosporine is a prodrug that binds an intracellular immunophilin. The complex cyclosporine-cyclophilin binds and inhibits the phosphatase activity of calcineurin interfering with the dephosphorilation of members of the nuclear factor of activated T cells, which is involved in the regulation of genes encoding many cytokines. However, calcineurin is not exclusive from T cells; it is also present in many organs, such as the kidney, and their inhibition accounts for both the immunosuppressive and the nephrotoxic effects of cyclosporine. In renal transplantation, it was shown that graft survival improved progressively between 1998 to 1996, mainly due to reduction of acute rejection episodes. There is no doubt that cyclosporine contributed to that success. After 20 years, cyclosporine targets for maintenance immunosuppression have not been defined and the magnitude of chronic cyclosporine nephrotoxicity in renal allografts is not known, in part by the limitations of histologic classification of chronic allograft nephropathy. In the future, the new technology based on DNA microarrays can be a valuable tool to separate chronic drug toxicity from other causes of graft deterioration. On the other hand, in the cyclosporine era, chronic renal failure has emerged as a frequent adverse event after transplantation of nonrenal organs and it is associated with increased risk of death. Although there is not yet enough evidence to support a generalization of calcineurin-free immunosuppression, we should open our minds to the upcoming new concepts on immunosuppression.
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PMID:Cyclosporine nephrotoxicity. 1504 45

Congenital obstructive nephropathy is the principal cause of renal failure in infants and children. The underlying molecular and cellular mechanisms of this disease, however, remain largely undetermined. We generated a mouse model of congenital obstructive nephropathy that resembles ureteropelvic junction obstruction in humans. In these mice, calcineurin function is removed by the selective deletion of Cnb1 in the mesenchyme of the developing urinary tract using the Cre/lox system. This deletion results in reduced proliferation in the smooth muscle cells and other mesenchymal cells in the developing urinary tract. Compromised cell proliferation causes abnormal development of the renal pelvis and ureter, leading to defective pyeloureteral peristalsis, progressive renal obstruction, and, eventually, fatal renal failure. Our study demonstrates that calcineurin is an essential signaling molecule in urinary tract development and is required for normal proliferation of the urinary tract mesenchymal cells in a cell-autonomous manner. These studies also emphasize the importance of functional obstruction, resulting from developmental abnormality, in causing congenital obstructive nephropathy.
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PMID:Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. 1505

Rapamycin is a new immunosuppressive agent approved for maintenance therapy after kidney transplantation. It may allow calcineurin-inhibitor-free, non-nephrotoxic immunosuppression. We report, however, on four kidney-transplant recipients who developed post-transplantation glomerulonephritis after conversion from a calcineurin-inhibitor-based immunosuppression to rapamycin. In all four patients nephrotic-range proteinuria occurred 2-9 months after conversion to rapamycin. Renal biopsy confirmed membrano-proliferative glomerulonephritis type 1 in one case, membranous glomerulonephritis in another and IgA-nephropathy in two cases, respectively. Calcineurin-inhibitor-based immunosuppression was reintroduced and resulted in complete remission of proteinuria and in stabilised renal function in all patients. We conclude that in the case of rapamycin-associated post-transplantation glomerulonephritis an attempt should be made to replace rapamycin by a calcineurin inhibitor.
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PMID:Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy. 1511 32

Chronic allograft nephropathy is a devastating complication of kidney transplantation that is responsible for a significant proportion of graft loss. This complication is characterized by a progressive decline in kidney function, which is not attributable to a specific cause. Many risk factors exist for the development of chronic allograft nephropathy, including donor-, recipient-, and transplant-related factors (eg, use of calcineurin inhibitors and acute rejection episodes), as well as comorbid conditions such as hypertension and hyperlipidemia. There is no definitive treatment for this complication; management has focused on minimization or withdrawal of calcineurin inhibitors in conjunction with addition of sirolimus or mycophenolate mofetil. Alterations in the immunosuppressive regimen must be done cautiously, as precipitating acute rejection will cause further damage to the allograft. Optimal control of blood pressure, particularly with the use of agents such as angiotensin II receptor blockers, in conjunction with management of dyslipidemia may be effective concurrent therapies in patients with chronic allograft nephropathy.
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PMID:Chronic allograft nephropathy: pathogenesis and management of an important posttransplant complication. 1526 52

Chronic allograft nephropathy is one of the leading causes of long-term graft failure in kidney transplant recipients. The etiology of this condition is multifactorial, but administration of calcineurin inhibitors is often implicated. With the introduction of newer immunosuppressive agents, strategies for calcineurin inhibitor minimization, avoidance, and withdrawal have been emerging in the literature. These strategies may improve long-term kidney allograft function, but are not without risks. Results from recent clinical trials evaluating the safety and efficacy of these strategies to prevent chronic allograft nephropathy in kidney transplant recipients are summarized and reviewed. Patients who had never received a calcineurin inhibitor or who had cyclosporine withdrawn from their regimens had better kidney function than patients who received or kept receiving a calcineurin inhibitor. The impact of the improvement in kidney function on long-term graft survival remains to be determined. In addition, the benefit in renal function must be weighed against the bone marrow toxicities and/or metabolic complications associated with these regimens.
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PMID:Strategies to prevent chronic allograft nephropathy in kidney transplantation: focus on calcineurin inhibitors. 1526 60

We reviewed the outcome of three methods employed for living-related renal transplantation (RTx) in our institution to assess triple immunosuppressive regimens. Between January 1989 and July 2003, a total of 35 living-related RTxs were performed at our institution. The immunosuppressive regimen given to 16 patients (group A) was cyclosporine (CsA), steroid and azathoprine (AZ) that given to 9 patients (group B) was tacrolimus (TAC), steroid and AZ and that given 9 patients (group C) was TAC, steroid and mycophenolate mofetil (MMF). Graft survival rate, serum creatinine, proteinuria, acute rejection, chronic allograft nephropathy (CAN), cytomegalovirus (CMV) infection and drug-induced nephropathy were investigated. There was no significant difference in graft survival rate among the three groups. Although serum creatinine levels (mg/dl) at 3 months post-transplant were 1.22+/-0.37 in group A, 1.43+/-0.14 in group B, 1.30+/-0.34 in group C, respectively (p<0.05; A vs. B), there was no significant difference at 1 year post-transplant. Frequency of proteinuria in groups A, B and C was 75.0, 50.0, 25.0%, respectively (p<0.05; A vs. C). The incidences of acute rejection and CAN within 1 year post-transplant were, respectively, 56.3% and 43.8% in group A, 37.5% and 37.5% in group B; and, 25.0% and 12.5% in group C (NS). The incidence of drug-induced nephrotoxicity was 12.5, 50.0% and 37.5% in groups A, B and C, respectively (p<0.05; A vs. B). The triple immunosuppressive therapy including calcineurin inhibitors, especially the regime of TAC, MMF, and steroids decreased the frequencies of proteinuria and rejections, which deteriorated the long-term outcome in living-related RTxs.
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PMID:[Clinical results of immunosuppressive triple therapies in living-related renal transplantation--a single center experience]. 1551 24

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.
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PMID:Renal transplantation 2004: where do we stand today? 1557 92


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