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)

Hepatitis C is the most common cause of end-stage liver disease leading to liver transplant. The disease can recur after transplant, resulting in clinical hepatitis in up to 75% of patients and severe disease in approximately 7%. Treatment of rejection with steroid boluses and treatment of steroid-resistant rejection with OKT3 have both been shown to increase the incidence of recurrent hepatitis C. The use of OKT3 for steroid-resistant rejection is reportedly associated with more severe recurrence. The calcineurin inhibitors tacrolimus and cyclosporine have not been conclusively associated with different rates or severity of recurrence. Viral levels rise 10- to 15-fold after transplant and appear to be associated with the use of immunosuppression. Studies suggest that high viral levels, either pretransplant or early after transplant, may be associated with severe recurrent disease. Although the role of genotype is still unclear, genotype 1b is known to be associated with a poorer prognosis in nontransplanted patients and a lesser response to treatment than other genotypes. Furthermore, some reports suggest that after transplant, recurrent disease may progress more rapidly in patients with genotype 1. Treatment options after recurrence remain poor. Neither interferon nor ribavirin alone provides any true benefit. Combination therapy appears to have a better short-term outcome but may be poorly tolerated, and long-term benefits are unknown. Prophylaxis with combination therapy may be a better option but requires further study. Finally, retransplantation for recurrent hepatitis C is complicated not by rapid recurrence of disease in the new allograft but by high perioperative mortality that may be predicted by the presence of renal failure or sepsis preretransplant.
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PMID:Hepatitis C after liver transplantation. 1094 24

Patients with chronic renal diseases (CRD) have a high prevalence of lipid abnormalities. Elevated levels of total and low density lipoprotein cholesterol are associated with cardiovascular diseases in patients with CRD. The 3-hydroxy-methylglutaryl co-enzyme A reductase inhibitors appear to be the most effective agents to lower LDL cholesterol in this category of patients and are generally safe if used with caution. They should be drugs of first choice in CRD but dosage reduction and close monitoring may be required to avoid side effects in case of renal failure or in combination with calcineurin inhibitors. Moreover recent studies suggest that in addition to lowering plasma LDL cholesterol, theses compounds may modify several factors implicated in the development of atherosclerosis and the progression of chronic renal failure. Such newly defined effects may contribute to extend the use of statins in the management of renal patients.
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PMID:[Kidney and statins]. 1124 Apr 14

Chronic renal failure is a major cause of morbidity and mortality after orthotopic liver transplantation. We did a randomised controlled trial of mycophenolate mofetil monotherapy in liver transplant patients who developed renal failure associated with calcineurin-inhibitor (ciclosporin or tacrolimus) immunosuppressive therapy. Although renal failure improved when the calcineurin-inhibitor dose was reduced and ultimately stopped, the trial was stopped when three of five patients on monotherapy developed organ rejection requiring a second transplantation.
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PMID:Mycophenolate mofetil monotherapy in liver transplantation. 1155 93

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

Liver-kidney transplantation (LKT) should be reserved for those recipients with primary disease affecting both organs. However, increasing transplant list waiting times have increased the development and duration of acute renal failure before liver transplantation. Furthermore, the need for posttransplant calcineurin inhibitors can render healing from acute renal failure difficult. Because of the increasing requests for and controversy over the topic of a kidney with a liver transplant (OLT) when complete failure of the kidney is not known, the following article will review the impact of renal failure on liver transplant outcome, treatment of peri-OLT renal failure, rejection rates after LKT, survival after LKT, and information on renal histology and progression of disease into the beginnings of an algorithm for making a decision about combined LKT.
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PMID:Identification of patients best suited for combined liver-kidney transplantation: part II. 1191 May 64

The pretransplant evaluation of a patient with a rare diagnosis requires knowledge of the pathophysiology and the transplant literature. A 55-year-old man presented with hypertensive kidney failure and the clinical diagnosis of acute intermittent porphyria. Complications of acute intermittent porphyria, which is a defect of heme production, are due to the accumulation of heme intermediates often precipitated by medications. Based on animal data, cyclosporine is considered unsafe in patients with acute intermittent porphyria. As part of the pretransplant evaluation, the patient received separate trials of tacrolimus and cyclosporine, which did not stimulate his acute intermittent porphyria. Four months after a kidney transplant, the patient still had no signs of rejection or symptoms of acute intermittent porphyria. This is the first documented patient with acute intermittent porphyria who successfully received a kidney transplant using tacrolimus. Because of individual variations, pretransplant testing of calcineurin inhibitors should be continued in patients with acute intermittent porphyria.
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PMID:Pretransplant evaluation of a patient with acute intermittent porphyria. 1194 65

The FKBP-12-binding ligand FK506 has been successfully used to stimulate nerve regeneration and prevent the rejection of peripheral nerve allografts. The immunosuppressant rapamycin, another FKBP-12-binding ligand, stimulates axonal regeneration in vitro, but its influence on nerve regeneration in peripheral nerve isografts or allografts has not been studied. Sixty female inbred BALB/cJ mice were randomized into six tibial nerve transplant groups, including three isograft and three allograft (C57BL/6J) groups. Grafts were left untreated (groups I and II), treated with FK506 (groups III and IV), or treated with rapamycin (groups V and VI). Nerve regeneration was quantified in terms of histomorphometry and functional recovery, and immunosuppression was confirmed with mixed lymphocyte reactivity assays. Animals treated with FK506 and rapamycin were immunosuppressed and demonstrated significantly less immune cell proliferation relative to untreated recipient animals. Although every animal demonstrated some functional recovery during the study, animals receiving an untreated peripheral nerve allograft were slowest to recover. Isografts treated with FK506 but not rapamycin demonstrated significantly increased nerve regeneration. Nerve allografts in animals treated with FK506, and to a lesser extent rapamycin, however, both demonstrated significantly more nerve regeneration and increased nerve fiber widths relative to untreated controls. The authors suggest that rapamycin can facilitate regeneration through peripheral nerve allografts, but it is not a neuroregenerative agent in this in vivo model. Nerve regeneration in FK506-treated peripheral nerve isografts and allografts was superior to that found in rapamycin-treated animals. Rapamycin may have a role in the treatment of peripheral nerve allografts when used in combination with other medications, or in the setting of renal failure that often precludes the use of calcineurin inhibitors such as FK506.
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PMID:The effects of rapamycin in murine peripheral nerve isografts and allografts. 1204 68

The side effects of calcineurin inhibitors (CI) have a unique spectrum in pediatric recipients of organ transplants. These include a lifelong risk of mortality due to sepsis, a nearly 5% risk of renal failure from protracted exposure to CI, and a significantly higher risk of posttransplant lymphoproliferative disorder (PTLD) when compared with adults (10% versus 2%). This led us to explore the use of the new antiproliferative immunosuppressant sirolimus (SRL) for rescue and primary immunosuppression in recipients of pediatric abdominal and thoracic organs at the Children's Hospital of Pittsburgh. Following initial success with SRL in 50 such children, we also explored its use for the elimination of tacrolimus (TAC) in patients experiencing toxicity and for maintenance immunosuppression in steroid-sparing regimens in liver transplantation. These early results suggest that sirolimus may hold promise as a primary immunosuppressive agent under defined protocol conditions. The salient features of our experience with SRL in over 85 children are summarized here.
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PMID:Sirolimus in pediatric transplant recipients. 1274 79

A rare but well-documented serious adverse reaction to the administration of the calcineurin inhibitors tacrolimus and cyclosporine in renal transplant recipients is the development of medication-induced thrombotic microangiopathy. The recently introduced immunosuppressive medication sirolimus has a very similar molecular structure to tacrolimus and also binds to the same intracellular proteins. Despite these similarities with tacrolimus, sirolimus has a different side-effect profile and reportedly lacks documented specific renal toxicity. This is a case report of the isolated administration of sirolimus without a concomitant calcineurin inhibitor being associated with the development of renal transplant biopsy-proven thrombotic microangiopathy. The patient is a 47-year-old African-American woman whose primary cause of renal failure was not thrombotic micrangiopathy, and she received a 5-antigen mismatched cadaveric renal transplant. Because of preexisting nephrosclerosis in the renal transplant, this patient was never administered a calcineurin inhibitor but was always maintained on sirolimus. With recent animal data showing that sirolmus can be nephrotoxic in a renal ischemic-reperfusion model (similar to what happens with a renal transplant), the authors speculate on a mechanism for this adverse reaction.
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PMID:Sirolimus-induced thrombotic microangiopathy in a renal transplant recipient. 1283 Apr 73

Kidney transplantation is the optimal form of renal replacement therapy for many with end-stage kidney disease. However, kidney transplantation comes with a unique set of medical complications, important among them is bone disease. Posttransplant bone disorders are manifestations of pathologic processes occurring posttransplant that are superimposed on preexisting disorders of bone and mineral metabolism secondary to kidney failure and/or diabetes mellitus. As a consequence of early rapid bone loss, which is seen commonly within the first 3 to 6 months of transplant, the fracture risk posttransplant increases and has been reported as high as 5% to 44%. Posttransplant fractures occur more commonly at peripheral than central sites. Patients with a history of diabetes mellitus are at particular risk for fracture. Parathyroid hormone (PTH) and osteocalcin levels generally decrease after transplantation. Alkaline phosphatase and urinary collagen cross-links are unpredictable. Bone histology varies. No single biomarker unequivocally distinguishes between the various bone disorders found on biopsy examination. Immunosuppression is a major cause of posttransplant bone disorders. Glucocorticoids lead to decreased bone formation whereas the calcineurin inhibitors appear to cause increased bone turnover. Evaluating and managing posttransplant bone disease is an integral part of posttransplant medical care.
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PMID:Bone disease after kidney transplantation. 1473 May 14


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