Post-transplant lymphoproliferative disorders in lung transplant recipients: 20-yr experience at the University of Minnesota.

Post-transplant lymphoproliferative disorders (PTLD) are potentially fatal complications of solid organ transplantation. The natural history of PTLD varies considerably among the different types of organs transplanted. While lung transplant recipients are highly susceptible to PTLD, there are only a few small studies that detail PTLD in this setting. We undertook this study to better describe the characteristics and treatment response in PTLD after lung transplantation. We conducted a retrospective chart review of lung and heart/lung-transplant recipients between 1985 and 2008. A total of 32 cases (5%) of PTLD were identified in 639 patients. The median interval after transplantation to the diagnosis was 40 (3-242) months. Eight patients (25%) were diagnosed within one yr of transplantation and had PTLD predominantly within the thorax and allograft. Twenty-four patients (75%) were diagnosed more than one yr after transplantation and their tumors mainly affected the gastrointestinal tract. Monomorphic PTLD, diffuse large B-cell lymphoma, was diagnosed in 91%. Treatment of PTLD varied according to stage and clinical circumstances. Twenty-four patients (75%) have died. The median overall survival was 10 (0-108) months. PTLD after lung transplantation remains a challenge as a result of its frequency, complexity and disappointing outcome.

Effect of preoperative pulmonary artery pressure on early survival after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the second largest indication for lung transplantation worldwide. Average 90-day mortality rates for this procedure are 22%. It is unclear what factors predispose patients with IPF to this increased early posttransplant mortality. Pulmonary hypertension may increase the risk of development of early posttransplant complications through several mechanisms. We examined the effect of secondary pulmonary hypertension on 90-day mortality after lung transplantation for IPF. METHODS: An International Society for Heart and Lung Transplant Registry cohort study of 830 patients with IPF transplanted from January 1995 to June 2002 was undertaken. Risk factors were assessed individually and adjusted for confounding by a multivariable logistic regression model. RESULTS: In the univariate analysis, pulmonary hypertension and bilateral-lung transplantation were significant risk factors for increased 90-day mortality. Multivariate analysis confirmed that mean pulmonary artery pressure and bilateral procedure remain independent risk factors after adjustment for potential confounders. Recipient age, ischemia time, cytomegalovirus status mismatch, and donor age were not independent risk factors for early mortality. CONCLUSIONS: Bilateral-lung transplantation carries a greater risk of early mortality than single-lung transplantation for IPF. Increasing pulmonary artery pressure is a risk factor for death after single-lung transplantation in IPF. Mean pulmonary artery pressure should be included in the overall risk assessment of patients with IPF evaluated for lung transplantation.

RAD in stable lung and heart/lung transplant recipients: safety, tolerability, pharmacokinetics, and impact of cystic fibrosis.

BACKGROUND: RAD is a novel macrolide with potent immunosuppressive and antiproliferative activities. This study characterizes the safety, tolerability, and pharmacokinetics of two different single oral doses of RAD in stable lung and heart/lung transplant recipients with and without cystic fibrosis (CF). METHODS: This was a Phase I, multicenter, randomized, double-blind, two-period, two-sequence, crossover study. Single doses of RAD capsules at doses of 0.035 mg/kg (2.5 mg maximum) or 0.10 mg/kg (7.5 mg maximum) were administered with cyclosporine (Neoral [cyclosporine, USP] modified), steroids, and azathioprine on Day 1. The alternate dose was administered on Day 16. Laboratory assessments, vital signs, and adverse events were recorded throughout the study. RAD pharmacokinetic profiles were assessed over a 7-day period following each dose. Steady-state cyclosporine (CsA) profiles were assessed at baseline and with each RAD dose; RAD and CsA trough concentrations were obtained throughout the study period. RESULTS: Of the 20 patients randomized, 8 had CF and 12 did not. Single doses of RAD were safe and well tolerated. Headache was the most common side effect. RAD produced a mild, dose-dependent, reversible decrease in platelet and leukocyte counts. Cholesterol and triglycerides were minimally affected. At both doses, CF patients had significantly lower peak concentrations of RAD than did non-CF patients (p = 0.03); however, overall exposure (area under the curve/dose) was not different between the groups (p = 0.63). At the higher dose, there was a clinically minor under-proportionality in AUC, averaging -11%. Steady-state pharmacokinetics of CsA were not affected by RAD co-administration.RAD was safe and well tolerated by stable lung and heart/lung transplant recipients with and without CF. The presence of CF did not influence the extent of RAD exposure. Single doses of RAD did not affect the pharmacokinetics of CsA. Ongoing studies are assessing the long-term safety and efficacy of RAD in lung and heart/lung transplantation.

Temporary ECMO support following lung and heart-lung transplantation.

7 days) failure. Seven (78%) patients in the early group were weaned off ECMO and 5 (56%) survived to hospital discharge. In the late group, none of the patients could be weaned off ECMO, yielding 100% mortality. ECMO support instituted for pulmonary graft failure that occurred within 24 hours of transplantation may improve patient survival.

gamma-Glutamyl transpeptidase is a polarized alveolar epithelial membrane protein.

In many diseases the lung is injured by oxidants. gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme on the apical plasma membrane of many epithelial cells that protects against oxidants by replenishing intracellular glutathione. We sought to localize GGT within rat lungs in vivo and in cultured alveolar epithelial cells. In the adult rat lung, indirect immunofluorescence (IF) with a polyclonal antibody to triton-solubilized GGT revealed linear staining outlining the alveoli. Immunoelectron microscopy (IEM) localized the protein on the apical surface of the alveolar epithelial cells, but more densely on type I cells than type II cells, as well as on the apical surface of some ciliated bronchial cells. On Western blots of whole lung and isolated type II cell membrane proteins, the antibody predominantly recognized a broad protein band of 110-120 kDa, consistent with the uncleaved, glycosylated form of GGT. Over time in culture, isolated rat type II cells had increasing immunoreactivity on Western blots and indirect IF but decreasing enzyme activity. At 2 days in culture, confocal laser scanning microscopy demonstrated that GGT was polarized to the apical surface of nonconfluent type II cells. Thus GGT is a polarized apical membrane protein in type I and II cells, suggesting a role in the metabolic functions of these cells. The increased immunoreactive GGT of cultured type II cells is consistent with their acquisition of properties similar to type I cells, but the lack of correlation between immunoreactive protein and enzyme activity awaits explanation.