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)

Thrombotic microangiopathy is a rare but important finding in the context of organ transplantation. Acute renal insufficiency in the setting of hemolysis and thrombocytopenia, a triad that constitutes 'hemolytic uremic syndrome', can be associated with, or triggered by, conditions such as verocytotoxin-producing Escherichia coli, viral infections, malignant hypertension, scleroderma, allograft rejection, lupus erythematosus, pregnancy, and medications including mitomycin C, calcineurin inhibitors, and oral contraceptives. After renal transplantation, it can occur, as either a de novo episode, or recurrent disease. Calcineurin inhibitors have long been associated with post-transplantation thrombotic microangiopathy. Sirolimus has been used as a primary immunosuppressant in patients transplanted with a history of earlier hemolytic-uremic syndrome, and also as rescue therapy in patients with calcineurin-inhibitor-associated thrombotic microangiopathy. We describe four cases where there was significant thrombotic microangiopathy in the context of contemporaneous or contiguous calcineurin inhibitor and sirolimus usage. As the intrarenal cyclosporin concentration is thought to be significantly elevated when cyclosporin and sirolimus are used together, this may explain these findings, and mandates caution in their co-administration.
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PMID:Thrombotic micro-angiopathy with sirolimus-based immunosuppression: potentiation of calcineurin-inhibitor-induced endothelial damage? 1261 89

A retrospective survey was performed to establish patient and graft outcome for all 41 patients at our centre receiving sirolimus (SRL) in combination with calcineurin inhibition (CNI) as primary therapy for the 6 years prior to March 2002. Patient mortality [12%; n = 5 (TTP, lymphoma, mucormycosis, and small bowel perforation] was significantly higher at 3 months compared with those not receiving SRL, but not thereafter. 12.8% had delayed graft function and 33% had one or more episodes of rejection in the first 6 months. Mean GFR at 12 months was significantly lower (47.3 mL/min) in the SRL group compared with those not receiving SRL (51.3 mL/min). Twenty-two patients had a 12-month protocol biopsy; CNI toxicity was present in 36%. SRL was associated with significant hyperlipidaemia (serum cholesterol, 5.2 +/- 1.4 at baseline vs 7.3 +/- 1.7 mmol/L at 3 months, P <.001; triglycerides, 2.3 +/- 1.4 at baseline vs 2.7 +/- 1.1 mmol/L at 3 months, P <.05). Mild thrombocytopenia occurred in 23% but was not associated with haemorrhagic events. LDH increased by 62%, remaining elevated out to 2 years post engraftment. Seven patients developed insulin requiring diabetes mellitus, similar to the rate observed in our general transplant population.Thus, in this early experience, SRL in combination with CNI was associated with significant mortality and morbidity including CNI toxicity, presumably a reflection of a heavy burden of immunosuppression. However, 1-year graft survival on SRL was similar to the mean Australia-wide graft survival regardless of immunosuppression. The future use of SRL may center around CNI sparing and avoidance type protocols.
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PMID:Sirolimus: a single center experience in combination with calcineurin inhibitors. 1274 76

Thrombotic microangiopathy (TMA) in renal transplant recipients is commonly associated with calcineurin inhibitors (CNIs), though several factors such as vascular rejection, viral infections and other drugs may play a contributory role. We report a series of 29 patients with TMA, all of whom were on CNIs. Though plasma exchange (PEx) is widely used to treat TMA, therapeutic guidelines are not well defined. All our patients were treated with PEx and discontinuation of CNIs. Thrombotic microangiopathy was diagnosed at a median of 7 days post-transplant. The mean decrease in Hgb and platelets during TMA was 66% and 64%, respectively, and peak serum creatinine during TMA was 7.4 +/- 2.9 mg%. Mean duration of PEx therapy was 8.5 (range 5-23) days. Recovery of platelet count to 150K/mcL and Hgb to 8-10 g/dL were used as endpoints for PEx. Twenty-three/29 (80%) patients recovered graft function after PEx. Twenty/23 (87%) patients who recovered were placed back on CNl. Nineteen/20 (95%) patients tolerated reinstitution of CNl without recurrence of TMA. In post-transplant TMA, PEx was associated with a graft salvage rate of 80%, reversal of hematological changes can be used as the endpoint for PEx therapy and CNl can be reintroduced without risk of recurrence in the majority of patients.
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PMID:Outcome of plasma exchange therapy in thrombotic microangiopathy after renal transplantation. 1451 Jul 3

Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P=.03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P=.04). Only the use of sirolimus (exact odds ratio, 3.49; P=.02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P=.0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P=.02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.
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PMID:Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. 1598 55

Thrombotic microangiopathy (TMA) after hematopoietic stem-cell transplantation (HSCT) or solid-organ transplantation is a serious complication that may be associated with diverse clinical conditions. The reported incidence varies widely, in part due to different diagnostic criteria. Currently, the diagnosis is based mostly on clinical features and is often uncertain; many disease or therapy-related complications in transplantation and malignancy can manifest clinical features of TMA. Risk factors for TMA post HSCT include the type of conditioning regimen, the presence graft-versus-host disease (GVHD), the use of calcineurin inhibitors (cyclosporine and tacrolimus) for GVHD prophylaxis, and infection. Cyclosporin and tacrolimus are the most commonly reported agents associated with TMA in solid-organ (mainly kidney) transplantations. Cancer-related TMA may be associated with chemotherapy or the malignancy itself. Compared with idiopathic TMA (thrombotic thrombocytopenic purpura), the outcome for patients with TMA post-HSCT or disseminated malignancy is poor. The efficacy of plasma exchange in the treatment of TMA post-HSCT or malignancy is uncertain. In the future, objective criteria integrating laboratory features (including tissue pathology, quantitative hematology, and endothelial cell functionality) with clinical features may assist in the diagnostic accuracy of TMA post HSCT, which would allow better evaluation of treatment modalities and better prediction of prognosis and outcomes.
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PMID:Thrombotic microangiopathy in transplantation and malignancy. 1638 20

Thrombotic microangiopathy has been reported in association with calcineurin inhibitors and less frequently with sirolimus in renal transplant patients. The diagnosis of thrombotic microangiopathy is typically made by diagnostic biopsy in the setting of allograft dysfunction. The finding of thrombotic microangiopathy on surveillance biopsy without a significant elevation of baseline serum creatinine is unusual. The optimal treatment of this disorder remains controversial. Treatment strategies have included dose adjustment, drug substitution, plasmapheresis, and intravenous immunoglobulin G. We report a case of de novo thrombotic microangiopathy diagnosed by surveillance biopsy in a patient without hematologic abnormalities or elevated serum creatinine. This patient had resolution of the renal lesion following conversion from tacrolimus to sirolimus-based immunosuppression.
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PMID:Diagnosis of de novo localized thrombotic microangiopathy by surveillance biopsy. 1721 52

Thrombotic microangiopathy (TMA) is a well-documented but severe complication that occurs after solid-organ transplant. Administration of calcineurin inhibitors is considered a major cause of this fatal complication; prompt initiation of plasma exchange therapy after reduction or conversion of calcineurin inhibitors has been recommended. Nevertheless, little is known about clinical evidence of this strategy against TMA after solid-organ, especially non-renal-organ, transplantation. Medical records of 63 patients who were hospitalized at Artificial Organ and Transplantation Division in Tokyo University Hospital and underwent blood purification therapy between January 1999 and May 2005 were reviewed. Twenty-eight living-donor liver transplantation (LDLT) recipients who received plasma exchange therapy were identified, and 18 of them were found retrospectively to receive a diagnosis of having TMA. Of the 18 patients, 10 (56%) responded to this therapy and survived after the treatment was stopped, whereas eight (44%) patients died before improvement. Subsequent follow-up of patients clarified that 1-yr survival rate of post-LDLT TMA was approximately 30%. Multivariate Cox proportional-hazards regression analysis demonstrated that the interval between transplant surgery and onset of TMA (hazard ratio 1.35 per 30 d; 95% confidence interval 1.07 to 1.71; P = 0.021) and pretreatment blood urea nitrogen level (hazard ratio 1.39 per 10 mg/dl; 95% confidence interval 1.02 to 1.90; P = 0.037) predicted mortality. Analyses identified post-LDLT recipients with TMA as being at high risk for poor prognosis. Effective strategies are needed for late-onset TMA after LDLT to improve treatment response and survival.
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PMID:Clinical outcome of thrombotic microangiopathy after living-donor liver transplantation treated with plasma exchange therapy. 1769 91

Intestinal perforation after lung transplantation is common in elderly patients with diverticulitis. The distal intestinal obstruction syndrome (DIOS) is a current complication in patients with cystic fibrosis. Myelosuppressive drugs as in most immunosuppressive regimens can cause cytopenia. Thrombotic microangiopathy is often caused by immunosuppressive regimen with a calcineurin-inhibitor in combination with a proliferation signal-inhibitor. Although renal failure and neurological symptoms are often additional side effects of the immunosuppressive therapy there are no reliable data on CNI-free protocols. Studies have shown that administration of statins is associated with improved function and survival of lung allografts.
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PMID:[Complications after lung transplantation: gastroenterological, hematological and cardiovascular involvement]. 1839 93

Thrombotic microangiopathy (TMA) in renal transplantation (RTX) generally develops during treatment with calcineurin inhibitors. We present a RTX case that developed TMA under everolimus treatment. A 40-year-old woman received a kidney allograft from her 77-year-old mother. She initially received tacrolimus, mycophenolate mofetil and steroids. She was discharged with a creatinine level of 2.2 mg/dl after treatment for a cellular rejection attack within the first two weeks after transplantation. Later on, tacrolimus was replaced with everolimus. One year later, she presented with fever and increased creatinine level (4 mg/dl), anemia and thrombocytopenia. Her peripheral blood smear revealed signs of microangiopathic hemolysis. Bone marrow examination revealed an increased number of megakaryocytes. We diagnosed the case as TMA and initiated plasma exchange, I.V. pulse steroid treatment and stopped everolimus. This approach improved laboratory and clinic abnormalities. The development of TMA after treatment with everolimus and the exclusion of other possible causes suggested TMA associated with proliferating signal inhibitors (PSIs) in our case.
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PMID:Thrombotic thrombocytopenic purpura associated with everolimus use in a renal transplant patient. 2049 69

Thrombotic microangiopathy (TMA) is a known complication of hematopoietic stem cell transplantation (HSCT). The pathogenesis of TMA is controversial but considered to involve various factors such as total body irradiation, use of calcineurin inhibitors for prophylaxis against graft versus host disease (GVHD), viral infection, and GVHD. Herein we describe a case with renal TMA after HSCT, which was probably associated with antibody-mediated endothelial cell injury from chronic GVHD (termed here 'chronic humoral GVHD'). A 49-year-old man presented two years after HSCT with renal dysfunction and proteinuria but without the clinical features of TMA. Histopathological examination of renal biopsy showed chronic glomerular endothelial cell injury with double contour of the glomerular basement membrane, microthrombi and the deposition of complement split product C4d along the glomerular capillaries. Renal tubulitis and peritubular capillaritis were also noted with a multilayered basement membrane and patchy C4d deposition on peritubular capillaries. These findings resemble those of chronic antibody-mediated rejection after kidney transplantation. Furthermore, C4d deposition suggests complement activation. Although circulating anti-blood type and anti-human leukocyte antigen antibodies were not detected, the renal TMA in this case was probably associated with chronic humoral GVHD.
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PMID:Renal thrombotic microangiopathy associated with chronic humoral graft versus host disease after hematopoietic stem cell transplantation. 2116 41


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