Tacrolimus-related cerebral microbleeds after lung transplantation.

Posterior reversible encephalopathy syndrome is a well-known complication of treatment by tacrolimus. We report 2 cases of lung transplant recipients treated with tacrolimus who developed cerebral microbleeds on T2∗-weighted sequences in the acute setting of posterior reversible encephalopathy syndrome. Cerebral microbleeds may be a marker of tacrolimus-induced vasculopathy that may be detected earlier by neuropsychological and magnetic resonance imaging monitoring in transplant recipients treated with tacrolimus.

Cyclosporine-related posterior reversible encephalopathy syndrome after heart transplantation: should we withdraw or reduce cyclosporine?: case reports.

Cyclosporine (CsA) related encephalopathy has not been well documented after heart transplantation. We report 2 cases of posterior reversible encephalopathy syndrome (PRES). The first case was a 68-year-old woman who underwent heart transplantation and received immunosuppression with mycophenolate mofetil, prednisone, and CsA. On day 14, she developed arterial hypertension, headache, visual disturbances, and generalized seizures. Fluid-attenuated inversion recovery magnetic resonance imaging (MRI) of the brain showed diffuse and bilateral high signals in the frontal posterior and the occipital areas. The second case was a 19-year-old man with a heart transplant receiving immunosuppression with prednisone and CsA. On day 44, he developed acute headache and generalized seizures. T2-weighted MRI of the brain showed diffuse high signals in the cerebellum, right lenticular and occipital areas. In both cases blood CsA concentration was therapeutic. Both cases recovered but in the first case neurologic findings were reversed only after CsA withdrawal.

Identification and characterization of two genes (MIP-1beta, VE-CADHERIN) implicated in acute rejection in human heart transplantation: use of murine models in tandem with cDNA arrays.

BACKGROUND: Genes and mechanisms of action involved in human acute rejection after allogeneic heart transplantation remain to be elucidated. The use of a murine allograft model in tandem with cDNA arrays and quantitative real-time polymerase chain reaction (Q-PCR) can greatly help in identifying key genes implicated in human heart acute rejection. METHODS AND RESULTS: Hearts from Balb/c mice were either not transplanted or transplanted heterotopically in the abdomen of Balb/c (isografts) and C57BL/6 (allografts) mice. Histological analysis showed acute rejection only in allografts. Total RNA was extracted from isografts (n=3), allografts (n=4), and not transplanted hearts (n=4); reverse transcribed; and labeled with P32. Each probe was hybridized to cDNA macroarrays. Eight genes were overexpressed and 7 genes were underexpressed in allografts compared with isografts. Macrophage inflammatory protein-1beta (MIP-1beta), an overexpressed gene, and VE-cadherin, an underexpressed gene, were validated by immunohistochemistry and Q-PCR in the murine models. Genes of interest, validated in the 3 murine groups, were then investigated in human heart tissues. Immunohistochemistry and Q-PCR performed on endomyocardial biopsies after heart transplantation showing no rejection (n=10) or grade IB (n=10) or IIIA (n=10) rejection, according to International Society of Heart and Lung Transplantation criteria, confirmed the results obtained from the murine model. CONCLUSIONS: We have demonstrated that the upregulation of MIP-1beta and downregulation of VE-cadherin may strongly participate in human acute heart rejection.

Chronic renal failure and end-stage renal disease are associated with a high rate of mortality after heart transplantation.

The aim of the study was to analyze the etiology, the factors for progression of chronic renal failure to end-stage-renal disease (ESRD), and the influence of ESRD on the survival rate among a cohort of 59 heart transplant patients (HTP) referred for the management of chronic renal failure (CRF). At the time of the first nephrology consultation (6 +/- 4.25 years after cardiac transplantation) the mean creatininemia was 261.5 +/- 99 micromol/L and mean creatinine clearance (Cockcroft formula) was 32 +/- 15 mL/min. The cause of CRF were calcineurin inhibitor toxicity in 38.9% of patients, vascular events in 15.2%, hemolytic uremic syndrome in 5%, membranous glomerulopathy in 3.3%, diabetes in two patients, focal/segmental glomerulosclerosis in 3.3%, renal hypoplasia in 1.7%, and unknown in 27%. Evolution to ESRD occurred in 38.9% of patients: 17 patients started hemodialysis, three peritoneal dialysis, and two received a preemptive kidney transplantation. Creatininemia (micromol/L) at the time of nephrology referral was 229.2 +/- 72.6 versus 315.8 +/- 113.4 (P < .001) and creatinine clearance (mL/min) was 34.9 +/- 15.1 versus 27.3 +/- 13.7 (P = .049) for patients with CRF versus ESRD, respectively. Both proteinuria (g/24 hours) of 1 +/- 2.2 versus 2.3 +/- 1.8 (P = .02) and tobacco use in 35.1% versus 54.4% (P = .045) were significantly associated with progression of CRF, while age at the time of heart transplantation, cause of cardiac failure and renal failure, high blood pressure, type 2 diabetes, dyslipidemia, alcoholism, cirrhosis, and cerebral vascular accident were not. Death occurred in 18 HTP: 50% of patients with ESRD and 18.5% of patients with CRF-a 2.6 relative risk of of death in HTP patients with ESRD compared with HTP with CRF only (P < .01).

Alteration of the left ventricular contractile reserve in heart transplant patients: a dobutamine stress strain rate imaging study.

BACKGROUND: Strain rate imaging (SRI), a recently developed Doppler-derived process, allows quantification of myocardial systolic function. We investigate whether SRI quantifies the contractile reserve during dobutamine stress tests in heart transplant patients (HT), when compared with normal individuals. METHODS: An incremental dobutamine test (5 to 40 microg/kg per minute) was performed in 10 HT and 15 control subjects, all of whom displayed normal coronary angiography. Gray-scale and color myocardial Doppler data were acquired in standard B-mode views at baseline, low-dose, peak, and recovery. Longitudinal SR was processed from the myocardial velocities for each segment. The changes in maximal systolic SR were used to quantify myocardial contractile reserve. RESULTS: Dobutamine infusion failed to induce clinical symptoms or electrocardiographic (ECG) changes in either group. Visually determined wall motion score was considered normal in all segments for each stage of the dobutamine stress. Heart rate was augmented similarly in both groups during dobutamine infusion. In controls, systolic SR increased gradually with incremental dobutamine dose and returned to baseline values upon recovery. Conversely, in HT patients, the increase in systolic SR was blunted at peak dobutamine, at which point it was significantly different vs controls. CONCLUSIONS: Quantitative assessment of myocardial function using SRI during dobutamine stress revealed an impaired contractile reserve in HT patients with normal coronary angiography. These subtle changes in regional myocardial function could not be identified using visual wall motion scoring. Additional studies are necessary to evaluate whether SR imaging detection of contractile reserve impairment will improve clinical efficiency or event prediction in this population.

Should we still perform angioplasty and stenting of an unprotected left main coronary artery stenosis in heart transplant patients? Two new cases and a review of the literature.

Coronary balloon angioplasty with stent implantation has emerged as a possible alternative to bypass grafting or repeat transplantation in left main coronary stenosis in heart transplant patients. We report 2 new cases of stent implantation for unprotected and isolated left main stenosis in heart transplant patients. Despite an initially successful procedure, restenosis prompted the performance of bypass surgery in both patients. The relative advantages and disadvantages of available techniques of revascularization are discussed in the context of the literature.

Thiopurine S-methyltransferase gene polymorphism is predictive of azathioprine-induced myelosuppression in heart transplant recipients.

Azathioprine (AZA) is metabolized via the cytosolic enzyme thiopurine S-methyltransferase (TPMT). TPMT activity exhibits genetic polymorphism with four prevalent (75%) mutant alleles TPMT*2 (G238C) and TPMT*3 (A719G and/or G460A) and a wild-type allele TPMT*1. To test the hypothesis that presence of these mutations is associated with greater toxicity of AZA in heart transplant recipients, 30 consecutive patients treated with AZA were followed up for the first month after heart transplant. Mutation of TPMT gene (mutation-specific polymerase chain reaction-based methods) was observed in four patients (A719G: n = 2; A719G plus G460: n = 2). Agranulocytosis did not occur in patients with the wild genotype. It occurred in the two patients with mutation A719G and there was a 40% drop in neutrophils in the two other patients. Discontinuation of AZA in the four mutant patients corrected for the drop. Presence of TPMT mutations is associated with a greater likelihood of agranulocytosis. Determination of these mutations could reduce the risk for hematological side-effects.

Parvovirus B19 infection in thoracic organ transplant recipients.

BACKGROUND: Clinical manifestations of parvovirus B19 infection in immunocompromised patients are mostly reported as acute or chronic hematologic disorders. More recently, respiratory or renal involvement has been described. OBJECTIVE: We started in 1994 a prospective study of parvovirus B19 infection in a group of lung (LTP) and heart-lung (HLTP) transplanted patients, including occasionally heart transplanted (HTP) patients. STUDY DESIGN: 62 patients (49 LTP, 11 HLTP, 2 HTP) were included in a serological survey and DNA detection by PCR was performed on each serum sample of the first 29 patients; later we performed it only when serology could suggest an acute episode, or when parvovirus infection could be suspected on clinical or biological observations. A total of 1655 sera were examined by serological tests and DNA detection was done in 500 samples. Specific IgM, seroconversion, significant increase of specific IgG levels, and/or parvovirus B19 DNA detection, were considered as markers of viral infection. RESULTS: We observed the presence of both markers of infection in 24 patients (39%), with an individual combination of positive antibody and PCR results. Acute or chronic anaemia, neutropenia were associated to these laboratory findings in 19 patients, but in five cases, an asymptomatic clinical infection suggested viral persistence. CONCLUSIONS: We report parvovirus associated acute or chronic anaemia and pancytopenia in a group of LTP, HLTP and HTP patients, as well as asymptomatic cases of infection. In the hypothesis of a parvoviral persistent or latent infection, current diagnosis methods may be unreliable to identify any other clinical manifestations.

[Reversible graft dysfunction after cardiac transplantation]. / Dysfonction réversible du greffon après transplantation cardiaque.

The authors report 3 cases of major graft dysfunction after cardiac transplantation which recovered completely with biventricular mechanical assistance in 4 to 8 days. All three cases were primary biventricular graft failures in patients with normal preoperative pulmonary resistances. These early dysfunctions (with no signs of myocardial infarction on electro- or echocardiography and in the absence of abnormal increased peri-operative enzyme levels) associated with total functional recovery conforming to the definition of the phenomenon of myocardial stunning. These results argue in favour of aggressive management of primary graft dysfunction.

Ticlopidine increases nitric oxide generation in heart-transplant recipients: a possible novel property of ticlopidine.

The objective of this study was to evaluate the effects of ticlopidine on the generation of eicosanoids and nitric oxide in heart-transplant recipients. In a randomized double-blind study, we studied the urinary excretion of the stable metabolites of thromboxane, prostacyclin, and nitric oxide before and after ticlopidine (250 mg/day). Platelet aggregation was significantly reduced in ticlopidine-treated patients [from 40.2 +/- 24.2% of maximal aggregation to 14.7 +/- 8.2% in response to adenosine diphosphate (ADP); p < 0.001] but not in the placebo group, confirming the efficacy of the drug with that dosage in these specific patients. The 24-h urinary excretion of prostacyclin metabolites was not modified by ticlopidine (1,865 +/- 833 ng/24 h at day 14 and 1,664 +/- 425 ng/24 h at day 0), whereas the excretion of thromboxane B2 tended to increase in the ticlopidine group (from 3,854 +/- 1,163 ng/24 h at day 0 to 5,014 +/- 2,914 ng/24 h at day 14), although not significantly. The excretion of nitric oxide metabolites (although not different from that of healthy nonimmunosuppressed subjects) was significantly (p < 0.005) increased in the ticlopidine group (from 3,082 +/- 1,683 micromol/24 h at day 0 to 4,133 +/- 2,262 micromol/24 h at day 14), but not in controls. Thus ticlopidine does not reduce prostacyclin but increases the systemic generation of nitric oxide, both substances having major antiplatelet and vasodilator properties. Further studies are warranted to examine whether ticlopidine could reduce the incidence of thromboembolic complications in these patients and whether this possible novel property of ticlopidine is restricted to immunosuppressed heart-transplant recipients.

Malignant neoplasms following cardiac transplantation.

OBJECTIVE: Malignancies have long been recognized as a complication of long lasting immunosuppressive therapy. We reviewed our experience to investigate the incidence and the spectrum of non cutaneous de novo malignant neoplasms. METHODS: Between March 1987 and March 1996, 296 patients underwent 303 cardiac transplantation in our service. The population at risk consists of all patients surviving more than 1 month after transplantation, leading to a total of 267 patients. A triple-immunosuppressive therapy was employed. Moderate doses of antilymphocyte globulin was used as an induction immunotherapy. RESULTS: Neoplasms developed in 18 (6.7%) of the 267 patients at risk. Seventeen patients were male. Mean age was 56 +/- 7 years. Fourteen patients (78%) reported a significant smoking history. Mean interval between transplantation and clinical diagnosis was 36 months. Lung neoplasms (especially adenocarcinoma) were the most commonly encountered tumors (11 of 268 patients, 4.1%). Three Non-Hodgkins' Lymphoma (NHL) were identified (1.1%). No Kaposi's sarcoma were diagnosed. Mean survival after a diagnostic of tumor was 11.7 months. CONCLUSIONS: The incidence of NHL is low in our transplant recipients. Conversely, we observed a high incidence of lung neoplasms (especially adenocarcinoma) which can be correlated with a heavy cigarette use in the study population.

A drug interaction study between ticlopidine and cyclosporin in heart transplant recipients.

OBJECTIVES: Previous uncontrolled studies have suggested an interaction between ticlopidine, a major antiplatelet agent, and cyclosporin in heart- and kidney-transplant recipients. The aims of this study were to examine in a randomised, double-blind fashion, the possible interaction between cyclosporin A and ticlopidine (250 mg per day) and the tolerability of this combination in heart-transplant recipients. METHODS: Twenty heart-transplant recipients were randomised into either a treated or a placebo group. Blood samples were drawn for time-course evaluation of cyclosporin blood levels over a period of 12 h, following the morning intake of cyclosporin and, for platelet aggregation studies, before and after 14 days of ticlopidine administration. Twenty four-hour urine samples were collected for 6-beta-hydroxycortisol measurements, before and after 14 days of ticlopidine. RESULTS: Although given at half the recommended daily dosage, ticlopidine significantly reduced platelet aggregation. Pharmacokinetic parameters indicate that the bioavailability of cyclosporin A was not significantly modified by ticlopidine. However, one patient in the ticlopidine group was withdrawn because of a major fall in cyclosporin blood level within 3 days of treatment. Urinary excretion of 6-beta-hydroxycortisol was augmented after treatment in the ticlopidine group compared with the placebo group, suggesting that induction of drug metabolism might have occurred. Data also show quite a large intra-individual variability in cyclosporin bioavailability in the placebo group, suggesting that poor absorption of the drug formulation and/or poor compliance might have contributed to the decreased cyclosporin blood levels in the patient withdrawn from this study and in previous uncontrolled studies. CONCLUSION: Cyclosporin bioavailability was not clearly modified by a half dosage of ticlopidine in this study. We, however, recommend closely monitoring cyclosporin blood levels when prescribing ticlopidine. Further studies will be needed with new formulations of cyclosporin or when using the full dosage of ticlopidine.