Progressive multifocal leukoencephalopathy in a heart transplant recipient following rituximab therapy for antibody-mediated rejection.

We report the case of a male heart transplant recipient who developed acute antibody-mediated rejection and was treated with 5 weeks of a rituximab-containing regimen. Two months later he presented with progressive motor and cognitive impairments and was diagnosed with progressive multifocal leukoencephalopathy (PML). He was treated with reduction of his immunosuppressive medications, mirtazapine, IVIG and plasmapheresis. He died within weeks. We reviewed the current literature on PML and its association with immunosuppression, highlighting its impact in the setting of solid organ transplantation and considering the potential effect of newer biologic drugs on the incidence of this devastating disease in the transplant population.

The effect of recipient hepatitis C virus infection on outcomes following heart transplantation.

BACKGROUND: Insufficient data exist on the clinical course of hepatitis C virus (HCV) infection in heart transplant (HT) recipients. Our study reports the outcomes of heart transplantation in pretransplantation HCV-positive (HCV+) recipients. METHODS: A retrospective analysis of the heart transplantation database at our institution was performed to identify HT recipients who were HCV+ prior to transplantation. Chart reviews yielded demographic features, liver function tests, graft function, incidence of posttransplantation acute hepatitis and transplant coronary artery disease, and patient survival data. RESULTS: Between 1995 and 2006, 10 HCV+ patients underwent cardiac transplantation. The recipient mean age was 47 years (range, 23-69). Seven recipients were males and 3 were females. At listing 9 patients had no cirrhosis. One patient with Child-B cirrhosis was listed for combined heart-liver transplantation. Two of 10 donors were known to be HCV carriers. Posttransplantation in-hospital survival rate was 100%. At a mean follow-up of 58 months (range, 1.6-145), 3 deaths occurred, yielding an overall survival rate of 70%. Only 1 death (10%) was linked to accelerated acute hepatitis. Transplant coronary artery disease was detected in 2 patients (20%). Echocardiograms of survivors at last follow-up revealed normal ejection fractions. In addition, there were no cases of hepatocellular carcinoma; all survivors were without evidence of hepatic dysfunction. CONCLUSIONS: Transplanting recipients known to have HCV did not seem to affect overall posttransplantation survival or to increase the risk of liver dysfunction or graft-related complications.

Correlation of donor-specific antibodies, complement and its regulators with graft dysfunction in cardiac antibody-mediated rejection.

Antibody-mediated rejection (AMR) is an immunopathologic process in which activation of complement often results in allograft injury. This study correlates C4d and C3d with HLA serology and graft function as diagnostic criteria for AMR. Immunofluorescence staining for C4d and C3d was performed on 1511 biopsies from 330 patients as part of routine diagnostic work-up of rejection. Donor-specific antibodies were detected in 95% of those with C4d+C3d+ biopsies versus 35% in the C4d+C3d- group (p = 0.002). Allograft dysfunction was present in 84% in the C4d+ C3d+ group versus 5% in the C4d+C3d- group (p < 0.0001). Combined C4d and C3d positivity had a sensitivity of 100% and specificity of 99% for the pathologic diagnosis of AMR and a mortality of 37%. Since activation of complement does not always result in allograft dysfunction, we correlated the expression pattern of the complement regulators CD55 and CD59 in patients with and without complement deposition. The proportion of patients with CD55 and/or CD59 staining was highest in C4d+C3d- patients without allograft dysfunction (p = 0.03). We conclude that a panel of C4d and C3d is diagnostically more useful than C4d alone in the evaluation of AMR. CD55 and CD59 may play a protective role in patients with evidence of complement activation.

Heart retransplantation.

Retransplants comprise only a small minority (3-4%) of heart transplants, however outcome following retransplantation is compromised. Risk factors for a poor outcome following retransplantation include retransplantation early (<6 months) after primary transplant, retransplantation for acute rejection or early allograft failure, and retransplantation in an earlier era. The incidence of rejection and infection is similar following primary transplant and retransplantation. The compromised outcomes and risk factors for a poor outcome are similar in adult and pediatric heart retransplantation. However, due to the short half-life of the transplanted heart, it is an expectation that patients transplanted in childhood may require retransplantation. Based on the data available and the opinion of the working group, indications for heart retransplantation are (i) chronic severe cardiac allograft vasculopathy with symptoms of ischemia or heart failure (should be considered) or asymptomatic moderate or severe left ventricular dysfunction (may be considered) or (ii) chronic graft dysfunction with symptoms of progressive heart failure in the absence of active rejection. Patients with graft failure due to acute rejection with hemodynamic compromise, especially <6 months post-transplant, are inappropriate candidates for retransplantation. In addition, guidelines established for primary transplant candidacy should be strictly followed.

Post-transplant ischemic injury is associated with up-regulated AlloMap gene expression.

BACKGROUND: The AlloMap gene expression test is used for the non-invasive detection of rejection. However, the impact of early post-transplant ischemic injury on subsequent AlloMap gene expression analysis has not been evaluated before. METHODS: Sixty seven heart transplant recipients, mean age 53 years, were evaluated at a mean 34 months post-transplant. AlloMap score was determined on the same day of heart biopsies. Nineteen patients had evidence of early post-transplant ischemic injury (Injury group). These were compared with the remaining 48 patients, Control group. RESULTS: Using multiple regression model with a backward selection method, post-transplant ischemic injury was found to be associated with significant increased AlloMap score compared with controls (31.5 +/- 4.6 vs. 26 +/- 6.2, p < 0.001). The Injury group had increased transplant vasculopathy (KM 5-year freedom from vasculopathy: 34% vs. 52%, p = 0.015), than Controls. CONCLUSIONS: Post-transplant ischemic injury is associated with up-regulated AlloMap gene expression, and hence, may provide another explanation for a high score in the absence of rejection.

Attrition from heart transplant waiting list for patients on ventricular assist devices is not affected by desensitization strategies.

BACKGROUND: Ventricular assist device (VAD) patients, who are commonly sensitized, can be successfully transplanted using strategies aimed at diminishing antibody burden. However, the impact of these therapies on outcomes for VAD patients on the waiting list is ill-defined. The following study was conducted to ascertain the relationship between desensitization therapies and attrition rate from the waiting list for VAD patients. METHODS: The VAD patients listed between July 1996 and June 2002 were used for this report. Transplant and inpatient pharmacy databases were queried for demographics, date of transplantation, degree of allosensitization, use of desensitization therapy, immunosuppressive strategies, and specific causes of death. RESULTS: Among 232 patients listed for heart transplantation who required bridging to transplantation with a VAD, 79 (34%) died while on the waiting list. Common causes of death included multisystem organ failure in 32 (40.5%), sepsis in 19 (24.0%), and stroke in 10 (12.6%) patients. While nearly 50% of these patients were sensitized at listing, only 5 (6.3%) patients received desensitization therapy following VAD implantation. Therapies included mycophenolate mofetil in 3 (3.7%) and IVIG in 2 (2.5%) patients. Not a single patient underwent plasmapheresis or OKT3 therapy. CONCLUSION: For patients bridged to heart transplantation with a VAD, attrition from the waiting list was associated with factors other than desensitization or induction regimens.

Survival beyond 10 years following heart transplantation: The Cleveland Clinic Foundation experience.

BACKGROUND: Long-term survival after heart transplantation is a desirable although challenging goal. METHODS: We analyzed clinical outcomes in the cohort of 170 patients who have undergone heart transplantation at The Cleveland Clinic Foundation and survived >10 years. RESULTS: We found 10-year and 15-year survival rates of 54% and 41%, respectively, in these patients, but there was also a high incidence of complications, such as hypertension, renal dysfunction, transplant vasculopathy, and malignancy. CONCLUSIONS: Long-term survival following cardiac transplantation is possible although complications are frequent. Beyond 10 years, malignancy is a major cause of death.

Immunosuppression for cardiac transplantation--the past, present and future.

The field of cardiac transplant immunosuppression is rapidly developing and has evolved over the past 35 years. Anecdote, experience and registry based practice is giving way to an increasing bounty of well designed, randomized controlled trials which will guide future therapy. Current therapy is based on triple therapy with corticosteroids, a calcineurin inhibitor and an antimetabolite, but these regimens may be replaced by substitution or addition of newer antiproliferative agents. The true nemesis is coronary graft vasculopathy, which affects 50% of patients at 5 years and until recently had very few preventive therapeutic options. Renal toxicity remains among the most challenging adverse effects of immunosuppression to be overcome.

A novel neoplastic primary tumor-derived human prostate epithelial cell line.

Research into molecular and genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro models of prostate tumors representing primary tumors. The generation of immortalized primary prostate cancer cells that will accurately reflect the in situ characteristics of malignant epithelium is greatly needed. We have successfully established a neoplastic immortalized human prostate epithelial (HPE) cell culture derived from a primary tumor. The RC-9 cells transduced through infection with a retrovirus vector expressing the E6 and E7 genes (E6E7) of human papilloma virus-16 (HPV-16) are currently growing well at passage 40, whereas RC-9 cells senesced at passage 7. RC-9/E6E7 cells exhibit epithelial morphology and high level of telomerase activity. More importantly, these immortalized cells produced tumors (SCID5038D) when inoculated into SCID mice. RC-9/E6E7 cells and SCID-5038D cells exhibit a high level of telomerase activity and androgen-responsiveness when treated with R1881. Expression of prostate specific antigen (PSA), androgen receptor (AR), prostate stem cell antigen (PSCA), an androgen-regulated prostate specific gene (NKX3.1), p16, cytokeratins 8, 15 and HPV-16 E6 gene was detected in both of these cells. RC-9/E6E7 and SCID5038D cells also showed growth inhibition when exposed to retinoic acid and transforming growth factor (TGF)-beta1, potent inhibitors of prostate epithelial cell growth. A number of chromosome alterations were observed including the loss of chromosomes 2p, 3p, 8p, 13, 14, 16, 17, 18, 21 and the gain of 7 and 20 in the tumor cell line (SCID5038D). These results demonstrate that this primary tumor-derived HPE cell line retained its neoplastic phenotypes and its prostate-specific markers and should allow studies to elucidate molecular and genetic alterations involved in prostate cancer. This is the first documented case of a malignant AR and PSA positive established human prostate cancer cell line from a primary tumor of a prostate cancer patient.

Worldwide thoracic organ transplantation: a report from the UNOS/ISHLT international registry for thoracic organ transplantation.

Based on data reported to the UNOS/ISHLT Thoracic and International Registry for Thoracic Organ Transplantation: 1. The number of heart transplant operations performed in the United States decreased between 1998-1999 and 17 (1%) more procedures were performed in 1999 (2,181) than in 2000 (2,198). Sixty-nine more lung transplants (an 8% increase) were reported in 2000 than in 1999. 2. Coronary artery disease and cardiomyopathy were the most frequently cited indications for heart transplantation in the US and have been reported at similar rates during the past 10 years. Combined, these diagnoses account for approximately 85% of all heart transplants. In 2000, half of all lung transplants were performed for emphysema/COPD or alpha-1 antitrypsin deficiency. The most frequently reported diagnoses for thoracic transplantation outside the US were: cardiomyopathy (49%) for heart, cystic fibrosis (30%) for double lung, emphysema/COPD (34%) for single lung and primary pulmonary hypertension (21%) for heart-lung transplants. 3. US heart transplant recipients were predominately male (76%), aged 50-64 (51%) and white (81%). US lung transplant recipients were also predominately between ages 50-64 (47%) and white (90%), but unlike heart recipients were more likely to be female (51%). No meaningful variance from the US recipient demographic profile was noted for the non-US recipients during the same time period. 4. Pediatric recipients (< 18 years of age) received 11% of the reported heart transplants and 6% of the reported lung transplants in the US. 5. Among US thoracic transplant recipients during 1999, the one-year survival rates were 84% for heart, 59% for heart-lung and 77% for lung. The 5-year survival rates for transplants performed during 1995 were: 71% for heart, 56% for heart-lung and 44% for lung transplants. 6. The long-term patient survival rates were: 23% at 19 years for heart, 16% at 11 years for lung and 23% at 14 years for heart-lung recipients. 7. During the first year after transplantation, 66% of heart recipients and 44% of lung recipients did not require rehospitalization. Among those recipients who were rehospitalized, the major cause was infection.

Immunosuppressive therapies after heart transplantation: best, better, and beyond.

Despite the significant advances in transplantation immunology and immunosuppressive therapies over the past 30 years, current immunosuppressive regimens are still inadequate in the majority of cardiac transplant recipients. Although short- and long-term survival rates have improved significantly, only 50% will survive 10 years and very few will survive 20 years. Complications of overimmunosuppression and underimmunosuppression account for the majority of these deaths. Only true "immunologic" tolerance can provide the outcome we pursue, namely, prolonged allograft function and otherwise normal immune function without chronic immunosuppressive therapy and its risks. Until a successful tolerance-inducing protocol is developed, we must use the current and upcoming immunosuppressive agents and techniques.

Cardiac transplantation in survivors of lymphoma: a multi-institutional survey.

BACKGROUND: Cardiac transplantation has been successfully performed in patients with a history of presumably cured Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Though the risk of recurrence is a major concern, the long-term influence of prior cancer and cancer therapy on posttransplant outcome has not been previously investigated. METHODS: Questionnaires were sent to 130 cardiac transplant centers in the United States registered with the United Network for Organ Sharing. Data collected included patient demographics; type, stage, and timing of HD/NHL; treatment for HD/NHL; posttransplant immunosuppressive regimen, rejection history, and outcomes; and Epstein-Barr virus status. RESULTS: Thirty-four cardiac transplant recipients with a previous history of HD (n=16) or NHL (n=18) were identified. HD patients averaged 41+/-15 years of age, with a mean disease-free interval of 15+/-9 years at the time of transplantation. NHL patients averaged 42+/-17 years of age with a mean disease-free interval of 10+/-9 years at the time of transplantation. The mean follow-up for the entire group was 50 months (range, 2 days to 136 months), and mean follow-up for the survivors was 67 months (range, 23-136 months). The 1-, 3-, 5-, 7-, and 10-year actuarial survival estimates for the entire group are 77%, 64%, 64%, 64%, and 50%, respectively. Actuarial survival was lower in HD patients (P=0.04) and in patients who had previously undergone splenectomy (P=0.008). Cox regression analysis identified only prior splenectomy (P=0.02) as an independent risk factor for mortality after cardiac transplantation with an adjusted relative risk of 6.2 (1.7-21.9, 95% confidence intervals). CONCLUSIONS: Although the numbers are small, these data strongly suggest that there is an increased mortality risk for cardiac transplant recipients with prior HD who have undergone splenectomy.

New UNOS rules: historical background and implications for transplantation management. United Network for Organ Sharing.

The algorithm for the allocation of donor hearts used by the United Network for Organ Sharing (UNOS) was changed in January 1999. The new scheme alters the medical urgency criteria from a 2-tiered to a 3-tiered system. Blood type O and blood type B candidates are less disadvantaged and pediatric candidates are somewhat advantaged with regard to adolescent donors. The new allocation algorithm allows an individual with life-threatening ventricular arrhythmias to be listed in the highest urgency status. Increased regulation will occur with the establishment of a review for the highest urgency status and the establishment of regional review boards.