Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunosuppressant-induced nephrotoxicity, in particular chronic progressive tubulointerstitial fibrosis/arteriopathy induced by the calcineurin inhibitors cyclosporin and tacrolimus, has become the 'Achilles heel' of immunosuppressive agents. The use of calcineurin inhibitors as primary immunosuppressants in hepatic and cardiac transplantation has led to end-stage renal disease and dialysis. Calcineurin inhibitor-induced acute renal failure may occur as early as a few weeks or months after initiation of cyclosporin therapy. The clinical manifestations of acute renal dysfunction are caused by vasoconstriction of renal arterioles, and include reduction in glomerular filtration rate, hypertension, hyperkalaemia, tubular acidosis, increased reabsorption of sodium and oliguria. The acute adverse effects of calcineurin inhibitors on renal haemodynamics are thought to be directly related to the cyclosporin or tacrolimus dosage and blood concentration. However, new clinical data indicate that calcineurin inhibitor-induced chronic nephropathy can occur independently of acute renal dysfunction, cyclosporin dosage or blood concentration. Several strategies have been evaluated to attenuate cyclosporin-induced nephropathy, but their efficacy remains unknown. Cytokine release syndrome associated with the use of muronomab-CD3 (OKT-3) can also contribute to the pathogenesis of transient acute tubular necrosis and renal dysfunction following renal transplantation. Continued research and clinical experience should provide information regarding the aetiology of cyclosporin-induced chronic progressive tubulointerstitial fibrosis/arteriopathy and its potential treatment.
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PMID:Immunosuppressant-induced nephropathy: pathophysiology, incidence and management. 1061 71

Nephrotoxicity is one of the main side effects of calcineurin-inhibitors. The influence of tacrolimus on the renal vasculature has not been well described. We have therefore examined the effects of tacrolimus on renal functional parameters as well as the contribution of the NO-system in a model of ischemic acute renal failure (ARF). Induction of ARF was achieved by clamping both renal arteries of female Sprague-Dawley rats. During the experiment, RBF, GFR, MAP, RVR and FENa were determined during infusion of vehicle, TAC, TAC and the NOS-activator L-arginine, and TAC and NOS-inhibition due to L-NMMA. TAC induced a significant rise in RVR with further decrease of RBF and GFR. Simultaneous L-arginine-infusion could reverse these effects during the infusion without complete restoration to preischemic levels. NOS-inhibition increased MAP and RBF without any effect on GFR. FENa did not differ significantly between the groups. Tacrolimus in the situation of ischemic acute renal failure causes vasoconstriction of pre- and postglomerular vessels with a further deterioration of renal function. L-arginine abolishes the functional deterioration, most likely due to increased NO-liberation.
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PMID:Tacrolimus in acute renal failure: does L-arginine-infusion prevent changes in renal hemodynamics? 1114 Feb 42

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

Kidney grafts from suboptimal donors are more likely to suffer the nephrotoxic side-effects of cyclosporine than kidneys from standard donors. In an attempt to avoid the use of cyclosporine, we carried out a prospective study in low-immunological risk recipients of suboptimal kidneys, using an immunosuppressive protocol combining Thymoglobuline in induction with a bi-therapy of mycophenolate mofetil (MMF) and steroids. Patients with panel reactive antibodies (PRA) <50% receiving a first renal transplant from a suboptimal donor (age >or=50, non heart beating, arterial hypertension, or acute renal failure) or a kidney at risk of delayed graft function (DGF) because of a prolonged cold ischaemia time (CIT) of 24 h or more, were eligible for this trial. Between September 1996 and December 1999, 30 patients were enrolled for the trial and treated with MMF 2 g orally, pre-operatively, and 3 g daily, post-operatively; Thymoglobuline 2 mg/kg IV pre-operatively, 1.5 mg/kg IV the next day, and for doses of 1 mg/kg IV given on alternate days; and prednisolone 0.25 mg/kg per day, reduced progressively from the end of the first month to 0.1 mg/kg per day by 3 months post-transplant. Cyclosporine was added only if rejection grade II or higher, or a reduction in MMF below 1 g daily, occurred. Ten patients (30%) suffered from DGF, and one kidney suffered primary non function. Seven patients (24%) suffered acute rejection (six were biopsy proven, 3 grade I and 3 grade II). MMF dosage was reduced in 28 patients because of adverse events, and calcineurin inhibitors were introduced in 16 patients. There were 14 episodes of opportunistic infection (cytomegalovirus (CMV 10), Herpes zoster 2, Listeria monocytogenes 1, Pseudomonas aeuruginosa 1), and 7 malignancies (skin 2, thyroid 1, lung 1, Kaposi's sarcoma 2, post-transplantation lymphoproliferative disorder 1). Mean serum creatinine was 178, 199, 213, and 218 micromol/l at 1, 2, 3 and 5 years after transplantation, respectively. Actuarial patient and graft (after censoring for death) survival was 94% and 83% after 1 year and 79% and 65% after 5 years, respectively. These results show that with the combination of MMF, Thymoglobuline and steroids the use of cyclosporine can be delayed, and in a few cases completely avoided, with good efficacy in terms of prevention of rejection and recovery of renal function. Regardless of acceptable patient and graft survival, side-effects of MMF at the doses used in this protocol were common and led to overimmunosuppression in the long-term. Starting MMF at low dose, MPA monitoring and probably CMV prophylaxis may improve the results of this regimen.
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PMID:Calcineurin inhibitor-free immunosuppression based on antithymocyte globulin and mycophenolate mofetil in cadaveric kidney transplantation: results after 5 years. 1287 30

Stem cell transplantation is one therapy employed in the management of children with high-risk solid tumors. However, this therapy is not without risk, having been associated with multiple end-organ toxicities. Both acute renal failure and chronic renal insufficiency have been reported in marrow transplant recipients, primarily in the context of the use of calcineurin inhibitors and radiation therapy. This report reviews our experience in managing an adolescent with metastatic Ewing's sarcoma who developed rapid progression to end-stage renal disease following a pretransplant conditioning regimen with high-dose carboplatinum. She had not received radiation or prior cisplatinum therapy. The possible reasons for the patient's highly unusual course and recommendations on ways to prevent this complication are discussed.
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PMID:End-stage renal disease after high-dose carboplatinum in preparation of autologous stem cell transplantation. 1473 5

Renal dysfunction, one of the most common complications after liver transplantation, influences patient outcomes. Little is known, however, about it in Korea. The aims of this study were to determine the incidence and to identify the risk factors for renal dysfunction after liver transplantation. Sixty-two patients who survived over 6 months after transplantation were enrolled. Renal function was classified by creatinine clearance (Ccr, mL/min), which was estimated using the Cockcroft-Gault formula. Twenty-seven patients (44%) showed mild renal dysfunction (60 < or = Ccr < 90), and 27 patients (44%), moderate dysfunction (30 < or = Ccr < 60). The others were found to have normal function (Ccr > or = 90). None displayed severe dysfunction (Ccr < 30). Compared to a control group (Ccr > or = 60), the renal dysfunction group showed lower preoperative Ccr (91 +/- 28.6, 63 +/- 21.9, respectively, P < .01) and lower Ccr at 3 months after transplantation (72 +/- 17.1, 49 +/- 14.6, respectively, P < .05). Age, sex, immunosuppressive drug usage, serum tacrolimus levels, and the frequency of postoperative acute renal failure did not affect the postoperative renal dysfunction. Twenty-six patients received mycophenolate mofetil while reducing the dose of calcineurin inhibitors because of compromised renal function. With mycophenolate mofetil treatment, the renal function seemed to improve, although the difference was not statistically significant (P = .057). These data demonstrate that renal dysfunction is common after liver transplantation and that preoperative renal function is the important factor predicting postoperative renal dysfunction.
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PMID:Incidence and risk factors of renal dysfunction after liver transplantation in Korea. 1556 Dec 36

Acute renal failure (ARF) after liver transplantation is a factor of poor prognosis associated with a high mortality. Selection of the donor, recipient, and intraoperative and postoperative treatment has crucial importance in the management of these critical patients. Thus, optimization of the use of calcineurin inhibitors (CNI), the main nephrotoxic substances in the immediate postoperative period, may decrease ARF incidence, allowing for early recovery of renal function in this period. Most protocols are based on the reduction or late introduction of CNI, based on the use of mycophenolate mofetil (MMF) with/without antiCD25 (basilximab/daclizumab). Recently, thymoglobulin (ATG) is also being tested to further delay the use of the CNI. A 20%-30% acute rejection incidence with the usual protocols allows recovery of renal function in more than 80% of patients without increasing the incidence of infections or adverse effects. However, it is still unknown whether there is a long-term negative effect of chimeric-humanized monoclonal antibodies and MMF combination on reinfection with hepatitis C virus in transplant recipients.
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PMID:Initial immunosuppression in liver transplant recipients with impaired renal function. 1638 81

Chronic kidney disease (CKD) following myeloablative allogeneic hematopoietic cell transplantation (HCT) occurs in 20% of survivors at 1 year and is believed to be due to radiation nephritis. Non-myeloablative allogeneic HCT is a recent procedure that employs significantly lower doses of chemoradiotherapy, however, incidence and risk factors for CKD following non-myleoablative HCT have not been defined. We performed a retrospective cohort study of 122 patients from three institutions who were available for analysis at 6 months following non-myeloablative HCT. Patients received two Gy of radiation; 62% received fludarabine as preconditioning. CKD was defined as at least a 25% reduction in glomerular filtration rate (GFR) from baseline using the abbreviated modified diet in renal disease (MDRD) equation. Eighty-one of 122 patients (66%) showed evidence of CKD at follow-up. Multivariate analysis revealed that acute renal failure (ARF) during the first 100 days post-transplant was associated with development of CKD (Adjusted OR 32.8 with 95% CI 4.3-250) after controlling for other variables. Previous autologous HCT, long-term calcineurin inhibitor use and extensive chronic GVHD were independently associated with CKD. CKD following non-myeloablative HCT appears to be a distinct clinical entity and likely not related to radiation nephritis. Future research should focus on possible mechanisms for alleviating chronic injury and decreasing use of calcineurin inhibitors.
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PMID:Chronic kidney disease following non-myeloablative hematopoietic cell transplantation. 1643 61

Previous studies have shown that renal injury initiated by a lethal dose of S-1,2-dichlorovinyl-l-cysteine (DCVC) progresses due to inhibition of cell division and hence renal repair, leading to acute renal failure (ARF) and death in mice. Renal injury initiated by low to moderate doses of DCVC is repaired by timely and adequate stimulation of renal cell division, tubular repair, restoration of renal structure and function leading to survival of mice. Recent studies have established that mice primed with a low dose of DCVC (15 mg/kg i.p.) 72 h before administration of a normally lethal dose (75 mg/kg i.p.) are protected from ARF and death (nephro-autoprotection). We showed that renal cell division and tissue repair stimulated by the low dose are sustained even after the lethal dose administration resulting in survival from ARF and death. If renal cell division induced by the low dose is indeed the critical mechanism of this autoprotection, then its ablation by the antimitotic agent colchicine (1.5 mg CLC/kg i.p.) should abolish autoprotection. The present interventional experiments were designed to test the hypothesis that DCVC autoprotection is due to stimulated cell division and tissue repair by the priming low dose. CLC intervention at 42 and 66 h after the priming dose resulted in marked progressive elevation of plasma blood urea nitrogen and creatinine resulting in ARF and death of mice. Light microscopic examination of hematoxylin and eosin-stained kidney sections revealed progression of renal necrosis concordant with progressively failing renal function. With CLC intervention, S-phase stimulation (as assessed by BrdU pulse labeling), G(1)-to-S phase clearance, and cell division were diminished essentially abolishing the promitogenic effect of the priming low dose of DCVC. Phospho-retinoblastoma protein (P-pRB), a crucial protein for S-phase stimulation, and other cellular signaling mechanisms regulating P-pRB were investigated. We report that decreased P-pRB via activation of protein phosphatase-1 by CLC is the critical mechanism of this inhibited S-phase stimulation and ablation of autoprotection with CLC intervention. These findings lend additional support to the notion that stimulated cell division and renal tissue repair by the priming dose of DCVC are the critical mechanisms that allow sustained compensatory tissue repair and survival of mice in nephro-autoprotection.
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PMID:Preplaced cell division: a critical mechanism of autoprotection against S-1,2-dichlorovinyl-L-cysteine-induced acute renal failure and death in mice. 1649 11

Haemolytic uraemic syndrome (HUS) is the most common cause of acute renal failure in children. The syndrome is defined by triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure (ARF). Incomplete HUS is ARF with either haemolytic anaemia or thrombocytopenia. HUS is classified into two subgroups. Typical HUS usually occurs after a prodrome of diarrhoea (D+HUS), and atypical (sporadic) HUS (aHUS), which is not associated with diarrhoea (D-HUS). The majority of D+HUS worldwide is caused by Shiga toxin-producing Esherichia coli (STEC), type O157:H7, transmitted to humans via different vehicles. Currently there are no specific therapies preventing or ameliorating the disease course. Although there are new therapeutic modalities in the horizon for D+HUS, present recommended therapy is merely symptomatic. Parenteral volume expansion may counteract the effect of thrombotic process before development of HUS and attenuate renal injury. Use of antibiotics, antimotility agents, narcotics and non-steroidal anti-inflammatory drugs should be avoided during the acute phase. Prevention is best done by preventing primary STEC infection. Underlying aetiology in many cases of aHUS is unknown. A significant number may result from underlying infectious diseases, namely Streptococcus pneumoniae and human immunedeficiency virus. Variety of genetic forms include HUS due to deficiencies of factor H, membrane cofactor protein, Von Willebrand factor-cleaving protease (ADAMTS 13) and intracellular defect in vitamin B12 metabolism. There are cases of aHUS with autosomal recessive and dominant modes of inheritance. Drug-induced aHUS in post-transplantation is due to calcineurin-inhibitors. Systemic lupus erythematosus and catastrophic antiphospholipid syndrome may also present with aHUS. Therapy is directed mainly towards underlying cause.
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PMID:Haemolytic uraemic syndrome: an overview. 1675 34


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