tacrolimus and Vascular-Diseases

Cardiac allograft vasculopathy (CAV) is the leading cause of death after the first year post-heart transplantation (HT). Numerous factors have been implicated in the development of CAV. The aim of this prospective randomized study was to assess the impact of cyclosporine (CsA) and tacrolimus (Tac) on the development of CAV.. From November 2006 to October 2008, 49 HT patients in our center were randomized to receive CsA or Tac. The additional treatment for all patients consisted of daclizumab induction and maintenance treatment with mycophenolate mofetil (1 g/12 hours) and steroids (withdrawal was not attempted). Thirteen patients died before coronary arteriography plus intravascular ultrasound of the left anterior descending artery was performed at 1 year after HT. Hence, the final number of patients included was 36 (18 per group). We considered significant CAV to be the presence of intimal proliferation>1 mm and/or>0.5 mm in 180°. The statistical methods were Student t and chi-square tests.. There were no differences in baseline characteristics between the two groups. Nor were there significant differences in maximum intimal proliferation between the groups (CsA 0.65±0.29 vs Tac 0.82±0.51 mm; P=.292) or in the development of significant CAV when both criteria were combined (CsA 31.6% vs Tac 38.9%; P=.642).. One year after HT, no differences were detected in the development of significant CAV according to the type of calcineurin inhibitor used when combined with daclizumab induction and maintenance treatment with mycophenolate mofetil and steroids.

Topics: Cyclosporine; Heart Transplantation; Humans; Immunosuppressive Agents; Prospective Studies; Tacrolimus; Vascular Diseases

We conducted an analysis of biopsy specimens of non-episode renal allografts from patients treated with tacrolimus (FK506) or cyclosporine (CsA) to evaluate chronic drug-induced nephropathy in stable allografts. A total of 38 biopsy specimens from stable functioning renal allografts were examined. The patients had been treated with FK506 (n = 16) or CsA (n = 18) as main immunosuppressant for 0.3 to 7.4 years. Of the 38 biopsy specimens, 15 showed mild drug-induced arteriolopathy (hyalinosis or insudative change of arterioles and small arteries) with striped-form interstitial fibrosis, 10 showed minimum interstitial cellular infiltration (borderline rejection), 2 showed IgA nephropathy, 4 showed evidence of chronic rejection (transplant nephropathy) and 12 showed no abnormal findings. Of 34 renal allograft biopsy specimens with stable function, 22 (65%) showed pathological evidence of drug-induced nephropathy. There were no significant qualitative or quantitative differences between FK506- and CsA-associated nephropathy.

Topics: Biopsy; Cyclosporine; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Postoperative Complications; Tacrolimus; Vascular Diseases

Topics: Adult; Cyclosporine; Female; Graft Rejection; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Reoperation; Safety; Tacrolimus; Vascular Diseases

A 17-year-old girl received lung transplantation after chronic respiratory failure. She developed a fever (> 38 °C) once or twice weekly starting 2 months after surgery, and multiple papulopustules on the skin waxed and waned for 4 months. She then developed blood-tinged sputum. She had been treated with triple immunosuppressants, including prednisolone, tacrolimus, and mycophenolate mofetil after lung transplantation, and her symptoms appeared during prednisolone dose reduction.

Topics: Adolescent; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Prednisolone; Tacrolimus; Vascular Diseases

We report a case of tacrolimus vascular toxicity found on a protocol biopsy shortly after a deceased donor renal transplantation. The patient was immunologically high-risk and acute antibody-mediated rejection during post-transplant dialysis phase was suspected on the protocol biopsy. Although the patient was stable after treatment of rejection, a further examination showed a very rare but specific side-effect of tacrolimus. It is sometimes difficult to make a differential diagnosis during postoperative dialysis period among AMR, primary non-functioning, drug toxicity, infection or just prolonged recovery from the damage of a long agonal phase on the non-heart beating donor. Although the possibilities of coexistence of rejection or other causes such as infection have not been completely excluded, it is important to be aware of this unusual side effect of tacrolimus.

Topics: Allografts; Arterioles; Biopsy; Calcineurin Inhibitors; Diagnosis, Differential; Diagnostic Errors; Graft Rejection; Humans; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Predictive Value of Tests; Tacrolimus; Treatment Outcome; Vascular Diseases; Young Adult

Nodular regenerative hyperplasia is a histopathological diagnosis characterized by the diffuse transformation of the liver parenchyma into regenerative nodules associated with rheumatologic and hematologic disorders, azathioprine immunosuppression or vascular injuries. The authors report the case of a 60-year-old female patient with a diagnosis of familial systemic paramyloidosis submitted to liver transplantation complicated by a hepatic artery thrombosis. A second liver transplant was performed and after 6 months she developed ascites and peripheral edema. The abdominal computed tomography (CT) showed an inferior vena cava stenosis. She underwent balloon angioplasty and an endovascular prosthesis was placed. The patient remained asymptomatic under immunosuppression with tacrolymus for 4 years, when she complained of peripheral edema and ascites. Laboratory work-up showed anemia and hypoalbuminemia with liver chemistry within the normal range. The ascites fluid analysis revealed a serum ascites albumin gradient superior to 1.1 g/L. Abdominal Doppler ultrasound and abdominopelvic CT angiogram confirmed endovascular prosthesis permeability. A percutaneous hepatic biopsy specimen was taken and histologic analysis showed, with reticulin stain, focal regenerative nodules of hyperplastic hepatocytes and internodular hepatocyte atrophy, compatible with the diagnosis of nodular regenerative hyperplasia. The case described is of particular interest as the nodular regenerative hyperplasia occurred after liver transplantation complicated with inferior vena cava stenosis, which might have contributed in a crucial way to liver parenchyma transformation.

Topics: Amyloidosis, Familial; Angioplasty, Balloon; Biopsy; Constriction, Pathologic; Female; Focal Nodular Hyperplasia; Hemodynamics; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Phlebography; Risk Factors; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome; Vascular Diseases; Vena Cava, Inferior

Topics: Cord Blood Stem Cell Transplantation; Food Hypersensitivity; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Male; Tacrolimus; Vascular Diseases

A key determinant of long-term survival in heart transplant recipients is the development of coronary vasculopathy. Both coronary macrovascular and microvascular disease are prognostically important. However, the relationship between these in transplant patients and the determinants of microvascular disease are not known.. We reviewed the simultaneously obtained endomyocardial biopsies and intravascular ultrasound (IVUS) images of coronary arteries in 33 heart transplant recipients. Coronary microvascular disease was classified by light microscopy into four grades based on thickening of endothelial cell layer and stenotic versus nonstenotic medial wall thickening. Macrovascular disease was evaluated from IVUS studies and assigned into one of five grades based on the Stanford classification. Coronary microvascular and macrovascular diseases were compared.. Age at transplantation was 26 (18) years; 67% were men, and the average time to posttransplantation study was 4 years. Endomyocardial biopsy revealed more advanced grade C and D microvascular disease in 45% and 36% of the patients, respectively. However, IVUS analysis for macrovascular disease revealed mostly lesser changes with grade 1 in 12%, grade 2 in 61%, and grade 3 in 21%. There was no significant correlation between grades of microvascular and macrovascular disease (P=0.10). Microvascular disease correlated positively with donor age (P=0.06) and treatment with tacrolimus (0=0.02) and statins (P=0.05).. There is a poor relationship between coronary microvascular and macrovascular disease in patients with cardiac transplants, likely indicating divergent pathogenetic mechanisms. Microvascular disease increases with donor age. There is an intriguing positive relationship between microvascular disease and treatment with statins and tacrolimus.

Topics: Adolescent; Adult; Age Factors; Biopsy; Child; Child, Preschool; Coronary Artery Disease; Endocardium; Endothelium, Vascular; Female; Graft Rejection; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infant; Male; Microvessels; Middle Aged; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; Tunica Media; Ultrasonography, Interventional; Vascular Diseases; Young Adult

FK506 [tacrolimus; hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxa-azacyclotricosine-1,7,20,21(4H,23H)-tetrone] is used clinically to reduce the incidence of allograft rejection; however, chronic administration leads to endothelial dysfunction and hypertension. We have previously shown that FK506 activates Ca(2+)/diacylglycerol-dependent conventional protein kinase C (cPKC), which phosphorylates endothelial nitric oxide synthase (eNOS) at one of its inhibitory sites, Thr495. However, which cPKC isoform is responsible for phosphorylating eNOS Thr495 is unknown. The aim of the current study was to determine the cPKC isoform that is activated by FK506, leading to decreased endothelial function. FK506 reduced endothelium-dependent relaxation responses, yet had no effect on endothelium-independent relaxation responses in aortas from control mice. Of the various cPKC isoforms, only the administration of a PKCβ(II) isoform-specific peptide inhibitor restored aortic relaxation responses to that of controls. In aortic endothelial cells, FK506 significantly increased PKCβ(II) activation compared with vehicle-treated controls, and this was prevented by a PKCβ(II) isoform-specific peptide inhibitor. In addition, a PKCβ(II) isoform-specific peptide inhibitor prevented the increase in eNOS Thr495 phosphorylation induced by FK506. Taken together, our results indicate that β(II) is the cPKC isoform responsible for phosphorylating eNOS at the inhibitory site Thr495 in response to FK506. PKCβ(II) inhibition could prove beneficial in ameliorating the endothelial dysfunction and hypertension in patients treated with FK506.

Topics: Animals; Aorta; Cells, Cultured; Endothelial Cells; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type III; Phosphorylation; Protein Kinase C; Protein Kinase C beta; Rats; Tacrolimus; Threonine; Vascular Diseases

Thrombotic microangiopathy (TMA) is characterized clinically by hemolytic anemia, thrombocytopenia, and renal failure. Cyclosporine (CyA)-associated TMA is a well-documented complication, but tacrolimus (TAC)-associated TMA is rare. We report the case of a renal transplant recipient who developed TMA in the early stage after renal transplantation with a high trough level of TAC. A 56-year-old female suffering from end-stage renal disease received a living renal graft from a blood-type-identical donor. She had developed hemolytic anemia, thrombocytopenia and acute renal failure 4 days after transplantation (6 days after TAC administration). She was diagnosed as having TMA without rejection by the clinical course and pathological findings. Renal function and hemolytic parameters improved by solely a decrease of the TAC trough level. When TAC-associated TMA develops in renal transplant recipients, we recommend a decrease of the TAC trough level before changing to CyA.

Topics: Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Tacrolimus; Vascular Diseases

Increasing shortage of cadaveric grafts demands the utilization of living donor and split liver grafts. The purpose of this study was to 1) define the "small-for-size" graft in a pig liver transplant model 2) evaluate pathological changes associated with small-for-size liver transplantation. Pigs were divided into four groups based on the volume of transplanted liver: (a) control group (n=4), 100% liver volume (LV) (b) group I (n=8), 60% LV (c) group II (n=8), 30% LV (d) group III (n=15), 20% LV. Tacrolimus and methyl prednisone were administered as immunosuppression. Animals were followed for 5 days with daily serum biochemistry, liver biopsies on day 3 and 5 for light microscopy, and tissue levels of thymidine kinase (TK) and ornithine decarboxylase (ODC). Liver grafts were weighed pretransplant and at sacrifice. All the recipients of 100%, 60%, and 30% grafts survived. Transplantation of 20% grafts (group III) resulted in a 47% mortality rate. Group III animals showed significantly prolonged prothrombin times (p<0.05), elevated bilirubin levels (p<0.05), and ascites. The rate of regeneration, as indicated by TK activity and graft weight was inversely proportional to the size of the transplanted graft. The severity of the microvascular injury was inversely proportional to graft size and appeared to be the survival-limiting injury. Frank rupture of the sinusoidal lining, parenchymal hemorrhage, and portal vein injury were prominent in group III animals 1 hour following reperfusion. This study established a reproducible large animal model of partial liver grafting; it defined the small-for-size syndrome in this model and described the associated microvascular injury.

Topics: Animals; Aspartate Aminotransferases; Bilirubin; Female; Graft Survival; Immunosuppressive Agents; Lactic Acid; Liver; Liver Regeneration; Liver Transplantation; Postoperative Period; Reproducibility of Results; Swine; Tacrolimus; Vascular Diseases

Immunosuppressive drugs common in clinical transplantation are known to have untoward effects on the vascular system. The effects of some drugs, notably cyclosporin A (CyA), have been studied on the vascular system, while those of others have not. In the vascular system, endothelial cells are the predominant cell type exposed to intravascular concentrations of immunosuppressive drugs. We therefore studied the effects of drugs common in clinical transplantation on endothelial cells in a capillary tube assay. The endothelial cells in the capillary tubes are morphologically more similar to those in the microvasculature than endothelial cells in monolayers. We studied the kinetics and extent of capillary tube formation and prostacyclin (PGI2) and endothelin-1 (ET-1) release from the in vitro capillaries to determine the morphological and biochemical effects of five immunosuppressive agents on endothelial function. We found a significant difference in the morphological and biochemical effects of the two common calcineurin inhibitors, CyA and tacrolimus (FK506) on capillary morphology in vitro. The former had a pronounced injurious effect on the morphology of the in vitro capillaries, while the latter did not. CyA also significantly increased ET-1 release by the capillaries, but FK506 did not. Mycophenolate mofetil (MMF) was the only other agent that had a moderately injurious effect on the morphology of the in vitro capillaries. Sirolimus (rapamycin) and dexamethasone, similar to FK506, had no effect on the capillary morphology. All these agents, except dexamethasone, increased PGI2 release. Our data suggest that CyA adversely affects the morphology of the microvasculature and that this is mediated, at least partly, by an increased ET-1 release by endothelial cells exposed to CyA. These findings describe a novel effect of CyA and MMF on endothelial cells that could be relevant to understanding the mechanisms of immunosuppressive drug-mediated endothelial injury in clinical transplantation.

Topics: Cell Survival; Cyclosporine; Dexamethasone; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Immunosuppressive Agents; In Vitro Techniques; Mycophenolic Acid; Sirolimus; Tacrolimus; Vascular Diseases

Currently, limited data exist on the role of tacrolimus (FK506) in pediatric allogeneic marrow transplantation. Forty-one patients who received tacrolimus as prophylaxis were reviewed, with a median age of 9 years (range 0.2-16 years). Twenty-one patients underwent related donor transplants and 20 underwent unrelated donor transplants. All patients received tacrolimus beginning the day prior to transplant at a dose of 0.03 mg/kg/day by continuous i.v. infusion. When clinically possible, patients were switched to oral therapy in two divided doses, at four times the intravenous dose. Tacrolimus levels were monitored twice a week, and dosages adjusted to maintain serum levels 5-15 ng/ml. Common adverse effects included hypomagnesemia (98%), hypertension (49%), nephrotoxicity (34%), and tremors (32%). Less common side-effects (<10% cases) included seizures and hyperglycemia. The median time to ANC recovery (ANC >500 x 106/l) was 15 days. For the related donor group, the incidence of grade II-IV acute GVHD was 33%, and grade III-IV GVHD 19%. For the unrelated donor group, the incidence of grade II-IV acute GVHD was 55%, and grade III-IV GVHD 30%. Overall, tacrolimus therapy was well tolerated as prophylaxis for acute GVHD in pediatric patients undergoing allogeneic transplantation.

Topics: Actuarial Analysis; Acute Disease; Adolescent; Child; Child, Preschool; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Infections; Liver Failure; Magnesium Deficiency; Male; Methotrexate; Survival Rate; Tacrolimus; Time Factors; Transplantation, Homologous; Vascular Diseases

We have been performing protocol biopsies since 1995 to predict the outcome of renal allograft. However, histopathological findings in renal allograft with stable function remain unclear. For this reason, we performed non-episode biopsy on long-surviving renal allograft and investigated the histopathological changes. Among the several diseases seen in non-episode biopsies, arteriolopathy, such as drug-induced nephropathy, is one of the most frequent diseases. However, it is unrelated to the dosage and the concentration of cyclosporine or tacrolimus. Consequently, we evaluated the clinicopathological findings of arteriolopathy in this study in order to clarify whether cyclosporine (CsA) or tacrolimus (FK506) is responsible for these findings.. We defined non-episode biopsy as a case with a serum creatinine level less than 2.0 mg/dL and containing less than 500 mg/dL of urinary protein. Final results showed that 71 cases were identified as non-episode biopsy. We then evaluated the histopathological findings and the clinical characteristics of these cases.. Thirty-two of the 71 non-episode biopsy specimens showed findings of arteriolopathy. The frequency and the severity of arteriolopathy are not concerned with dosage and concentration of CsA or FK506. The arteriolopathy seen in non-episode biopsy was related to the time of the biopsy and the kidney age. Arteriolopathy in nonepisode biopsy also had a relationship with hypertension, suggesting that it is important to strictly control blood pressure for graft survival.

Topics: Adult; Biopsy; Chi-Square Distribution; Cyclosporine; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Predictive Value of Tests; Statistics, Nonparametric; Tacrolimus; Vascular Diseases