G. Feltrin

Nonadherent Behaviors After Solid Organ Transplantation

BACKGROUND AND AIM The effectiveness of any treatment depends not only on the choice of therapy, but also, to a large extent, on the patients active cooperation. Adherence to medical prescriptions and particularly to immunosuppressive therapy is crucial to prevent medical complications that negatively influence graft function and patient survival after organ transplantation. The aim of this study was to assess, among patients who underwent solid organ transplantation, nonadherent behaviors (NAB) to immunosuppressive therapy, to correct lifestyle, and to general medical prescriptions. MATERIALS AND METHODS We evaluated patients who underwent solid organ transplantation from March 2008 to June 2009. All participants completed an anonymous 15-item questionnaire to assess NAB. RESULTS We enrolled 218 organ transplant patients: 103 liver, 50 kidney, 52 heart, and 13 lung. There were 152 men and the overall age was 52.2 ± 0.8 years (mean ± standard deviation [SD]) time from transplantation, 83.6 ± 4.5 months (mean ± SD). Overall 37.9%, 38.8%, and 12.8% of patients reported nonadherence to immunosuppressive therapy, to correct lifestyle, and to general medical prescriptions, respectively. Considering nonadherence to immunosuppressive therapy and to general prescriptions, the percentage of kidney transplant patients who referred NAB was significantly lower compared with other organ transplant patients (P = .008 and P = .04, respectively). Nonadherent patients to immunosuppressive therapy and to general medical prescriptions displayed a longer interval from transplantation compared with adherent patients (P = .02 and P = .03, respectively). Among patients nonadherent to the correct lifestyle, the rates of men and of patients with disability pension were significantly higher compared to adherent patients (P = .001 and P = .002, respectively). CONCLUSIONS Poor adherence to medical prescriptions and to adequate lifestyle is common among organ transplant patients, especially those who have undergone liver transplantation. Psychoeducational interventions for transplanted patients and their families are needed to improve adherence.

Coronary Flow Reserve by Transthoracic Echocardiography Predicts Epicardial Intimal Thickening in Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is the leading cause of morbidity and mortality in heart transplantation (HT). We sought to investigate the role of coronary flow reserve (CFR) by contrast‐enhanced transthoracic echocardiography (CE‐TTE) in CAV diagnosis. CAV was defined as maximal intimal thickness (MIT) assessed by intravascular ultrasound (IVUS) ≥0.5 mm. CFR was assessed in the left anterior descending coronary artery in 22 HT recipients at 6 ± 4 years post‐HT. CAV was diagnosed in 10 patients (group A), 12 had normal coronaries (group B). The mean MIT was 0.7 ± 0.1 mm (range 0.03–1.8). MIT was higher in group A (1.16 ± 0.3 mm vs. 0.34 ± 0.07 mm, p < 0.0001). CFR was 3.1 ± 0.8 in all patients and lower in group A (2.5 ± 0.6 vs. 3.7 ± 0.3, p < 0.0001). CFR was inversely related with MIT (r =−0.774, p < 0.0001). A cut point of ≤2.9, identified as optimal by receiver operating characteristics analysis was 100% specific and 80% sensitive (PPV = 100%, NPV = 89%, Accuracy = 91%). CFR assessment by CE‐TTE is a novel noninvasive diagnostic tool in the detection of CAV defined as MIT ≥0.5 mm. CFR by CE‐TTE may reduce the need for routine IVUS in HT.

Extracorporeal photochemotherapy after cardiac transplantation: a new therapeutic approach to allograft rejection.

Photopheresis (ECP) is a new immunomodulatory therapy in which recipient lymphocytes are treated extracorporeally with 8-methoxypsoralen and ultraviolet light. The treatment seems to induce an inhibition of both humoral and cellular rejection after transplantation. Objective Since recurrent rejection (RR) continues to be a severe complication after heart transplantation (HTx) and the immunosuppressive regimes used for the treatment are often associated with increased morbidity and mortality, we investigated whether ECP could have a beneficial effect on the number and severity of rejection episodes. Methods Eleven HTX recipients (5 M and 6 F, mean age 48.5 yrs) with RR were enrolled in the study. ECP was performed at weekly intervals during the 1st month, at 2 week intervals during the 2nd and 3rd month, and then monthly for another 3 months. Results The fraction of biopsies (EMB) with a grade 0/1A rejection increased during ECP from 46% to 72% while the EMB showing a 3A/3B rejection decreased from 42% to 18%. It is also noteworthy that out of the 78 EMB performed during ECP only one showed a 3B rejection in comparison with 13 out of 110 EMB in the pre-ECP period. Six rejection relapses were observed in a total follow-up of 60 months, two of them occurring during the tapering of oral steroid. Four relapses were reversed by ECP, one by IV steroids and the last by methotrexate after the failure of both IV steroids and ECP. The mean doses of immunosuppressive drugs resulted lower after 6 months of ECP: steroids were reduced from 13 to 8.25 mg/day, cyclosporine from 375 to 285 mg/day, azathioprine from 55 to 35 mg/day. Conclusions ECP is a well tolerated treatment. Its administration allows better RR control and significant reduction in immunosuppressive therapy. (Int J Artif Organs 2000; 23: 49–54)

Inflammatory cell burden and phenotype in endomyocardial biopsies with antibody-mediated rejection (AMR): a multicenter pilot study from the AECVP.

This multicenter case‐controlled pilot study evaluated myocardial inflammatory burden (IB) and phenotype in endomyocardial biopsies (EMBs) with and without pathologic antibody‐mediated rejection (pAMR). Sixty‐five EMBs from five European heart transplant centers were centrally reviewed as positive (grade 2, n = 28), suspicious (grade 1, n = 7) or negative (n = 30) for pAMR. Absolute counts of total, intravascular (IV) and extravascular (EV) immunophenotyped mononuclear cells were correlated with pAMR grade, capillary C4d deposition, donor specific antibody (DSA) status and acute cellular rejection (ACR). In pAMR+ biopsies, equivalent number of IV CD3+ T lymphocytes (23 ± 4/0.225 mm2) and CD68+ macrophages (21 ± 4/0.225 mm2) were seen. IB and cell phenotype correlated with pAMR grade, C4d positivity and DSA positivity (p < 0.0001). High numbers of IV T lymphocytes were associated with low grade ACR (p = 0.002). In late‐occurring AMR EV plasma cells occurring in 34% of pAMR+ EMBs were associated with higher IB. The IB in AMR correlated with pAMR+, C4d positivity and DSA positivity. In pAMR+ equivalent numbers of IV T lymphocytes and macrophages were found. The presence of plasma cells was associated with a higher IB and occurrence of pAMR late after transplantation.

Intraplaque Hemorrhage in Cardiac Allograft Vasculopathy

Plaque hemorrhage, inflammation and microvessel density are key determinants of plaque vulnerability in native coronary atherosclerosis (ATS). This study investigates the role of intraplaque hemorrhage (IPH) and its relation with inflammation and microvessels in cardiac allograft vasculopathy (CAV) in posttransplanted patients. Seventy coronary plaques were obtained from 12 patients who died because of CAV. For each patient we collected both native heart and the allograft, at the time of transplantation and autopsy, respectively. Intralesion inflammation, microvessels and IPH were assessed semi‐quantitatively. IPH was observed in 21/35 (60%) CAV lesions and in 8/35 (22.9%) native ATS plaques, with a strong association between fibrocellular lesions and IPH (p = 0.0142). Microvessels were detected in 26/35 (74.3%) of CAV lesions with perivascular leakage as sign of endothelial damage in 18/26 (69.2%). IPH was strongly associated with microvessels (p < 0.0001). Inflammation was present in 31/35 (88.6%) of CAV lesions. CAV IPH+ lesions were characterized by presence of both fresh and old hemorrhage in 12/21 (57.1%). IPH, associated with microvessel damage and inflammation, is an important feature of CAV. Fresh and old intralesion hemorrhage suggests ongoing remodeling processes promoting the lesion progression and vulnerability.

Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients

BACKGROUND Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.

Coronary Microvascular Dysfunction Correlates With the New Onset of Cardiac Allograft Vasculopathy in Heart Transplant Patients With Normal Coronary Angiography

Coronary microvascular dysfunction is emerging as a strong predictor of outcome in heart transplantation (HT). We assessed the validity of microvascular dysfunction, defined by means of a reduced coronary flow reserve (CFR), as a factor associated with new onset epicardial cardiac allograft vasculopathy (CAV) or death. We studied 105 patients at 4 ± 1 years post‐HT with a normal coronary angiography (CA). New onset CAV was assessed by CA. CFR was assessed in the left anterior descending (LAD) coronary artery by transthoracic Doppler echocardiography and calculated as the ratio of hyperaemic to basal blood flow velocity. A CFR ≤ 2.5 was considered abnormal. Epicardial CAV onset or death was assessed during a follow‐up of 10 years. New onset CAV was diagnosed in 30 patients (28.6%) (Group A), and the CA was normal in the remaining 75 patients (71.4%) (Group B). Group A had reduced CFR compared with group B (2.4 ± 0.6 vs. 3.2 ± 0.7, p < 0.0001). A CFR ≤ 2.5 was independently associated with a higher probability of new onset CAV (p < 0.0001) and a higher probability of death, regardless of CAV onset (p < 0.01). Microvascular dysfunction is independently associated with the onset of epicardial CAV, and associated with a higher risk of death, regardless of CAV onset.

HLA-DRB1 Typing by Micro-Bead Array Assay Identifies the Origin of Early Lymphoproliferative Disorder in a Heart Transplant Recipient

We report the case of a 68‐year‐old woman who underwent heart transplantation for hypertrophic cardiomyopathy. Two months after the transplant she developed mild fever and dyspnea with a marked drop in left ventricle ejection fraction of 31%. Coronary angiography was negative for cardiac allograft vasculopathy. Endomyocardial biopsy revealed ischemic damage with no evidence of acute cellular rejection, antibody‐mediated rejection or viral myocarditis. A neoplastic process was suspected even though full‐body computerized tomography was negative for malignancy. The patient died 4 months after transplantation. The autopsy showed acute antero‐septal myocardial infarction due to a nodular epicardial EBV‐related posttransplant lymphoproliferative disorder (PTLD) infiltrating the left anterior descending coronary artery with occlusive neoplastic thrombosis. We highlight two major aspects of this case: (1) the unusual occurrence of early PTLD involving the cardiac allograft and causing a fatal outcome, (2) the application of an immunological technique for HLA‐DRB1 typing to posttransplant paraffin‐embedded autopsy material to identify the recipient origin of this early malignancy, thus excluding a possible donor‐transmitted neoplasm.

Heart transplantation in patients with neoplastic disease

THE presence or history of neoplastic disease was a traditional contraindication to heart transplantation (HTx), because of the fear of increased risk of tumor recurrence and lymphoproliferative disorders with chronic immunosuppression. More recently, recipient selection criteria have been extended both in kidney and in HTx, including patients (pts) cured for neoplastic disease and without recurrence for at least 2 years. Here we report our 12-year experience of HTx in pts with heart disease and a history of cancer involving other organs, and in those in whom chemotherapy for cancer resulted in heart failure due to toxic cardiomyopathy.