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)

It remains elusive what factors affect posterior reversible encephalopathy syndrome (PRES). Eleven PRES children, all with acute glomerulonephritis, Alport syndrome, and lupus nephritis, 5 with nephrosis, and 3 renal transplant recipients, were studied. PRES recurred in 1 patient. Neurological symptoms were graded as 1: mild (headache, nausea/vomiting, or tremor), 2: moderate (vision change), and 3: severe (mental dysfunction, cerebellar symptoms, seizures, recurrence of seizures, and coma). Magnetic resonance imaging was graded as 1: subtle change, 2: abnormal large areas, and 3: complete involvement of the regions. The common symptoms were seizures (100%), headache (82%), nausea/vomiting (73%), coma (55%), and vision change (46%). Seizures recurred in 7 (64%). All but one (91%) developed hypertension and 7 (64%) received calcineurin inhibitors (CNI). Edema occurred in 7 (64%) and renal insufficiency/end-stage renal disease (ESRD) in 4 (36%). Seizures recurred frequently in younger patients. Symptoms were severe in girls. Duration or severity of the condition with predisposing factors (hypertension, CNI, nephrosis or renal insufficiency/ERSD) did not make a difference in the symptoms and neuroimaging. Two patients developed chronic epilepsy. Age and gender may affect PRES symptoms. Our results are limited by small sample size and should be determined using larger numbers of patients.
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PMID:Age and gender may affect posterior reversible encephalopathy syndrome in renal disease. 2182 8

The incidence of neurotoxicity from calcineurin inhibitors varies by the organ transplanted. Akinetic mutism is characterized by the inability to perform voluntary movements and express language, without alterations in mental status. This process has been reported in neurotoxicity due to high serum levels of calcineurin inhibitors, but in rare cases, it presents as a form of tacrolimus toxicity after renal transplantation, despite normal serum levels. We report a clinical case of a renal transplant patient in whom reversible acute encephalopathy and akinetic mutism developed. Brain lesions appeared on magnetic resonance imaging, and the condition resolved after the drug was withdrawn.
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PMID:Reversible acute encephalopathy with mutism, induced by calcineurin inhibitors after renal transplantation. 2225 46

Acquired haemophilia A (AH) is defined as the presence of autoantibodies or inhibitors against factor VIII (FVIII) with a clinical bleeding onset that can be life-threatening. Immunosuppressant therapy must be initiated rapidly to eradicate the inhibitor. Current treatments based on steroids plus cyclophosphamide or rituximab are quite effective, but with significant side-effects. Based on previous described AH cases treated with cyclosporine, with a good side-effect profile, we aimed at assessing prospectively a first-line calcineurin inhibitor based immunosuppressive therapy. We included a total of 11 patients affected with AH. Once diagnosed, pulse steroids and calcineurin inhibitors were started. Time to achieve sustained response (SR), defined as testing negative for inhibitor and with stable FVIII level >50%, immunosuppressant side-effects, and relapse of AH were evaluated. Eight patients received cyclosporine and three patients received tacrolimus. SR was achieved in 10 of 11 patients (90.9%) in a median time of 3 weeks (range 2-8 weeks), and none of them relapsed during a median follow-up time of 14 months (range 4-120). One major side-effect appeared (posterior encephalopathy) that forced to discontinue cyclosporine. Overall 5-year survival rate was 54.5%, with a total of five patients dying during the follow-up (mortality rate of 45.5%). These five patients had achieved SR and died because of complications of basal morbidities and/or senescence, not related to AH (bleeding) or to immunosuppressant's (infection) side-effects. Combination therapy of calcineurin inhibitors and pulse steroids seems clinically effective as a first-line treatment of AH.
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PMID:Acquired haemophilia A. First line treatment with calcineurin inhibitors and steroid pulses: a 10-year follow-up study. 2242 59

Autoimmune hepatitis (AIH) is an immune-mediated liver disorder characterised by female preponderance, elevated transaminase and immunoglobulin G levels, seropositivity for autoantibodies and interface hepatitis. Presentation is highly variable, therefore AIH should be considered during the diagnostic workup of any increase in liver enzyme levels. Overlap/variant forms of the disease, presenting with concomitant features of primary biliary cirrhosis or primary sclerosing cholangitis are increasingly recognised. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil or, failing that, calcineurin inhibitors. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure (encephalopathy grade II-IV) at diagnosis, will require liver transplantation. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4(pos) T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. Animal models faithfully representing the human condition are needed to unravel the contribution of innate and adaptive, effector and regulatory immune responses. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells, which ultimately aim to restore tolerance to liver-derived antigens.
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PMID:Autoimmune hepatitis: a comprehensive review. 2321 32

Posterior reversible encephalopathy syndrome (PRES) is a disorder characterized by gray and white matter abnormalities in the temporal, parietal, and occipital lobes of the brain. Its etiology has been attributed to renal failure, immunosuppressive drugs such as cyclosporine and tacrolimus, and other potential entities leading to acute hypertension. Clinical findings include headaches, altered mental status, seizures, visual changes, and focal neurologic deficits. We report the case of a child who developed PRES with intracerebral and subarachnoid hemorrhages associated with tacrolimus exposure 10 days after heart transplantation for restrictive cardiomyopathy. The patient initially presented with complex partial seizures, headache, agitation, and hypertension. Head MRI was suggestive of PRES along with intracerebral and subarachnoid hemorrhages. Tacrolimus was discontinued and blood pressure was controlled. The patient's encephalopathy resolved, but he has had ongoing neurologic symptoms secondary to hemorrhage. Generally, PRES is less common in children than in the adult population and is a rare complication of calcineurin inhibitors (CNI). Presentation with secondary hemorrhage also can occur. In children receiving CNIs presenting with new neurologic symptoms, PRES should be considered as prompt discontinuation of the offending agent can induce resolution of symptoms. Children can develop hemorrhage in the context of PRES, leading to increased morbidity.
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PMID:Posterior reversible encephalopathy syndrome and hemorrhage associated with tacrolimus in a pediatric heart transplantation recipient. 2333 14

Posterior reversible encephalopathy syndrome (PRES) is a small vessel microangiopathy of the cerebral vasculature that occurs in 0.5-5% of solid organ transplant recipients, most commonly associated with tacrolimus (Tac). Clinical manifestations include hypertension and neurologic symptoms. We report an adult multivisceral transplant recipient who experienced recurrent PRES initially associated with Tac and subsequently with sirolimus. A 49-year-old woman with short bowel syndrome underwent multivisceral transplantation due to total parenteral nutrition-related liver disease. She was initially maintained on Tac, mycophenalate mofetil (MMF) and prednisone. Three months after transplantation, she developed renal dysfunction, leading to a reduction in Tac and the addition of sirolimus. Eight months after transplantation, she developed PRES. Tac was discontinued and PRES resolved. Sirolimus was increased to maintain trough levels of 12-15 ng/mL. Fourteen months after transplant, she experienced recurrent PRES which resolved after discontinuing sirolimus. Currently 3 years posttransplant, she is maintained on cyclosporine, MMF and prednisone with no PRES recurrence. In addition to calcineurin inhibitors, sirolimus may also be associated with PRES after solid organ transplantation. Ours is the first report of sirolimus-associated PRES in the setting of multivisceral transplantation. Identifying a safe alternative immunosuppression regimen was challenging but ultimately successful.
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PMID:Posterior reversible encephalopathy syndrome independently associated with tacrolimus and sirolimus after multivisceral transplantation. 2333 5

Depression affects up to 60% of solid-organ recipients and is independently associated with both mortality (hazard ratio for death of ~2) and de novo malignancy after transplantation, although the mechanism is not clear. Both pretransplantation psychosis and depression occurring more than 2 years after transplantation are associated with increased noncompliance and graft loss. It remains to be shown that effective treatment of depression is associated with improved outcomes and quality of life. Immunosuppressive drugs (especially corticosteroids and calcineurin inhibitors) and physiologic challenges can precipitate deterioration in mental health. All potential transplant candidates should be assessed for mental health problems and preexisting medical conditions that can mimic mental health problems, such as uremic, hepatic, or hypoxic encephalopathy, should be identified and treated appropriately. Expert mental health review of those with identified risk factors (such as previous suicide attempts, history of mental illness or noncompliance with medications) is advisable early in the transplant assessment process to mitigate risk and support the patient. Patients with mental health disorders, when adequately controlled and socially supported, have outcomes similar to the general transplant population. Therefore, exclusion from transplantation based on the diagnosis alone is neither ethically nor medically justified. However, it is ethically and clinically justifiable to deny access to transplantation to those who, despite full support, would have a quality of life that is unacceptable to the candidate or are likely to be noncompliant with treatment or follow-up, which would lead to graft loss.
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PMID:Mental health disorders and solid-organ transplant recipients. 2374 26

Neurologic complications are relatively common after solid organ transplantation and affect 15%-30% of liver transplant recipients. Etiology is often related to immunosuppressant neurotoxicity and opportunistic infections. Most common complications include seizures and encephalopathy, and occurrence of central pontine myelinolysis is relatively specific for liver transplant recipients. Delayed allograft function may precipitate hepatic encephalopathy and neurotoxicity of calcineurin inhibitors typically manifests with tremor, headaches and encephalopathy. Reduction of neurotoxic immunosuppressants or conversion to an alternative medication usually result in clinical improvement. Standard preventive and diagnostic protocols have helped to reduce the prevalence of opportunistic central nervous system (CNS) infections, but viral and fungal CNS infections still affect 1% of liver transplant recipients, and the morbidity and mortality in the affected patients remain fairly high. Critical illness myopathy may also affect up to 7% of liver transplant recipients. Liver insufficiency is also associated with various neurologic disorders which may improve or resolve after successful liver transplantation. Accurate diagnosis and timely intervention are essential to improve outcomes, while advances in clinical management and extended post-transplant survival are increasingly shifting the focus to chronic post-transplant complications which are often encountered in a community hospital and an outpatient setting.
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PMID:Neurologic complications after liver transplantation. 2402 79

Neurologic complications following kidney transplant are more common than in the general population with the reported incidence around 10-21%. Need for multiple drugs, decreased cellular immunity, accelerated atherosclerotic disease, and frequency of metabolic abnormalities are the most common predisposing factors for neurologic abnormalities. Neurologic side-effects of calcineurin inhibitors range from mild tremors to paraplegia or posterior reversible encephalopathy syndrome (PRES) and are generally reversible by lowering the dose or complete discontinuation of the drug when possible. Clinical presentation of central nervous system infection in transplant recipients can be different from the normal population as the anti-inflammatory effects of immunosuppressive therapy may obscure signs of meningeal inflammation and changes in the level of consciousness may be subtle. Bacterial infections remain the most common infections but unusual pathogens figure prominently in the differential diagnosis. The most frequent malignancies of the brain are lymphomas and metastatic tumors which are for the most part, de novo malignancies from immunosuppression. Decreasing immunosuppression is almost always a part of treating malignancy. The prevalence of stroke is reported to be around 8% with age>40 years, diabetic nephropathy as the underlying cause of end-stage kidney disease, and peripheral vascular disease being the strongest predictors.
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PMID:Neurologic complications in renal transplantation. 2436 16

Tacrolimus is an immunosuppressive drug mainly used to lower the risk of transplant rejection in individuals who are post solid organ or hematopoietic transplantation. It is a macrolide which reduces peptidyl-propyl isomerase activity and inhibits calcineurin, thus inhibiting T-lymphocyte signal transduction and interleukin-2 (IL-2) transcription. It has been associated with Posterior Reversible Encephalopathy Syndrome (PRES), a disease of sudden onset that can present as a host of different symptoms, depending on the affected area of the brain. While infectious causes of encephalopathy must always be entertained, the differential diagnosis should also include PRES in the appropriate context. We report three cases of PRES in patients with acute myeloid leukemia (AML) placed on tacrolimus after receiving a bone marrow transplant (BMT). The focus of this review is to enhance clinical recognition of PRES as it is related to an adverse effect of Tacrolimus in the setting of hematopoietic transplantation.
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PMID:Tacrolimus associated posterior reversible encephalopathy syndrome - a case series and review. 2467 91


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