Robert N. Brown

Interactions among donor characteristics influence post-transplant survival: A multi-institutional analysis

BACKGROUND Quantification of donor-associated risk in a specific heart transplant recipient is often difficult. Our aim was to identify donor characteristics that affect survival in the contemporary era. METHODS Between 1990 and 2006, 7,322 patients from 32 centers in the Cardiac Transplant Research Database underwent heart transplantation. Multivariable logistic regression analysis was used to identify donor-associated risk predictors and important interactions between these donor characteristics. Recipient survival was examined using parametric regression analysis in the hazard function domain. RESULTS Donor characteristics associated with post-transplant death included donor age, donor requirement for vasoactive therapy, positive donor cytomegalovirus serology, longer graft ischemic time, and lower donor body weight. Several interactions between individual donor characteristics affected survival. In male donors, history of hypertension and diabetes mellitus were risk factors for death (p = 0.006, p = 0.04, respectively), but not in female donors (p = 0.5, p = 0.8, respectively). There was a significant interaction between donor age and recipient-donor weight difference. If the donor was of younger age, increasing recipient-donor weight difference did not result in increased death. With increasing donor age, weight difference did result in compromised survival (p < 0.0003). Donor and recipient gender further modified the degree of risk: risk was higher in female donors and when recipients were male (p < 0.0003). CONCLUSIONS This multi-institutional analysis identified important interactions between donor characteristics that affect post-transplant survival that explain some of the discrepancies in the results of previous studies. The results are likely to aid in efficient organ allocation.

Clinical outcomes after cardiac transplantation in muscular dystrophy patients

BACKGROUND Patients with muscular dystrophy are at risk of developing a dilated cardiomyopathy and can progress to advanced heart failure. At present, it is not known whether such patients can safely undergo cardiac transplantation. METHODS This was a retrospective review of the Cardiac Transplant Research Database, a multi-institutional registry of 29 transplant centers in the United States, from the years 1990 to 2005. The post-cardiac transplant outcomes of 29 patients with muscular dystrophy were compared with 275 non-muscular dystrophy patients with non-ischemic cardiomyopathy, matched for age, body mass index, gender, and race. RESULTS Beckers muscular dystrophy was present in 52% of the patients. Survival in the muscular dystrophy patients was similar to the controls at 1 year (89% vs 91%; p = 0.5) and at 5 years (83% vs 78%; p = 0.5). The differences in rates of cumulative infection, rejection, or allograft vasculopathy between the 2 groups were not significant (p > 0.5 for all comparisons). CONCLUSIONS Recognizing the limitations of the present investigation (ie, selection bias and data lacking in the functional capacity of the muscular dystrophy patients), the current study suggests that the clinical outcomes after cardiac transplantation in selected patients with muscular dystrophy are similar to those seen in age-matched patients with non-ischemic cardiomyopathy.

A 16-Year Multi-Institutional Study of the Role of Age and EBV Status on PTLD Incidence Among Pediatric Heart Transplant Recipients

The objective was to determine the incidence and hazard for posttransplant lymphoproliferative disease (PTLD) in a study of 3170 pediatric primary heart transplants between 1993 and 2009 at 35 institutions in the Pediatric Heart Transplant Study. 147 of 151 reported malignancy events were classified as PTLD. Overall freedom from PTLD was 98.5% at 1 year, 94% at 5 years and 90% at 10 years. Freedom from PTLD was lowest in children (ages 1 to < 10 years) versus infants (<1 year) and adolescents (10 to < 18 years) with children at highest risk for PTLD with a relative risk of 2.4 compared to infants and 1.7 compared to adolescents. Positive donor EBV status was a strong risk factor for PTLD in the seronegative recipient, but risk magnitude was dependent on recipient age at the time of transplantation. Nearly 25% of EBV seronegative recipients of EBV+ donors at ages 4–7 at transplantation developed some form of PTLD. The overall risk for PTLD declined in the most recent transplant era (2001–2009, p = 0.003). These findings indicate that EBV status and the age of the recipient at the time of transplantation are important variables in the development of PTLD in the pediatric heart transplant recipient.

The modern Fontan operation shows no increase in mortality out to 20 years: A new paradigm

OBJECTIVE Dating back to the first published report of the Fontan circulation in 1971, multiple studies have examined the long-term results of this standard procedure for palliation of single-ventricle heart disease in children. Although the technique has evolved over the last 4 decades to include a polytetrafluorethylene (PTFE) conduit for a large percentage of patients, the long-term outcome has not yet been established. The aim of the current study was to investigate the possibility of a late increasing risk for death after 15 years among patients with a modern Fontan operation and to evaluate late morbidity. METHODS Between January 1, 1988, and December 31, 2011, 207 patients underwent the Fontan procedure using an internal or external PTFE conduit plus a bidirectional cavopulmonary connection. Survival and late adverse events were analyzed. Risk factors for early and late mortality were examined using hazard function methodology. RESULTS At 1, 10, and 20 years, survival for the entire cohort was 95%, 88%, and 76%, respectively, with no deaths in the last 6 years of the study. Hazard modeling showed a 1.3% risk of death per year 24 years after the Fontan procedure, with no late increasing hazard phase. Freedom from reoperations was greater than 90% at 20 years and freedom from thrombotic complications was 98% at 20 years (with greater than 80% of patients on aspirin alone). Survival curves were superimposable for 16- to 20-mm conduits, and the freedom from any reoperation including transplantation was greater than 90% after 20 years. Multivariable risk factor analysis identified only earlier date of operation as a predictor of early and late mortality. By era of surgery, the 10-year predicated survival is 89% for patients undergoing surgery in 2000 and 94% for patients in 2010. CONCLUSIONS Early and late survival after a Fontan operation with a PTFE conduit is excellent, with no late phase of increasing death risk after 20 years. Late functional status is good, the need for late reoperation is rare, and thrombotic complications are uncommon on a standard medical regimen including aspirin as the only anticoagulation medication.

Minimizing infection and rejection death: Clues acquired from 19 years of multi-institutional cardiac transplantation data

BACKGROUND The purpose of this study was to estimate the relationship of age, race and gender to rejection and infection across time with respect to age at time of transplant, year of transplantation and immunosuppressive era. METHODS The study group consisted of 10,131 patients from 29 institutions in the Cardiac Transplant Research Database (n = 7,368, from 1990 to 2008) and 32 institutions in the Pediatric Heart Transplant Study (n = 2,763, from 1993 to 2008). The probabilities of rejection death and infection death were estimated with a parametric time-related model and adjusted for gender, ethnicity, date of transplant and age. RESULTS Actuarial survival by age at transplant showed that, when compared with the majority of patients transplanted between the ages of 30 to 60 years, death due to rejection at 5 years was highest among those transplanted at 10 to 30 years of age (p < 0.0001) and lowest in those transplanted at >60 years of age. Death due to infection at 5 years was highest among patients >60 years of age. Risk factors for death from rejection included age (p < 0.0001), female gender (p = 0.0001), black race (p < 0.0001) and transplant date (p < 0.0001); for infection death, risk factors were age (p < 0.0001), date of transplant (p < 0.0001), age (p = 0.002) and black race (p = 0.01). Modeling with respect to age at time of transplant showed an inverse relationship between infection and rejection death. Among patients transplanted at >60 years of age, there was a steep increase in infection-related deaths and a decrease in rejection deaths. Risk for rejection was elevated among young adults 10 to 30 years of age at time of transplant, particularly for black females. CONCLUSION Death from rejection affects adolescents and young adults preferentially, especially black recipients, whereas death from infection preferentially affects patients >60 years of age. Relative risk of infection vs rejection death with respect to recipient age should be considered in therapeutic plans for recurrent rejection, particularly in adolescents and the elderly.

Balancing rejection and infection with respect to age, race, and gender: Clues acquired from 17 years of cardiac transplantation data

BACKGROUND Donor and recipient risk factors for rejection and infection have been well characterized. The contribution of demographic factors, especially age at the time of transplantation to morbidity and mortality due to rejection and infection, is much less well understood. METHODS Using parametric hazard analysis and multivariate risk-factor equations for infection and rejection events, we quantitatively determined the relationship of fundamental demographic variables (age, race and gender) to infection and rejection. These analyses were conducted with respect to date of transplant and age at the time of transplantation. The patient group consisted of all primary heart transplants performed at the University of Alabama at Birmingham during the years 1990 to 2007 (n = 526). RESULTS Risk factors for rejection within 12 months post-transplantation were date of transplant (p < 0.0001) and age at the time of transplantation (young adults 10 to 30 years of age, p < 0.0001). Risk factors for infection were date of transplant (p < 0.0001) and age at the time of transplantation (young children and older adults, p < 0.0001). There were three immunosuppressive eras in 1990 to 2007. Notably, although the proportion of patients experiencing rejection and infection events decreased during each successive immunosuppressive era, the relative relationship of infection to rejection, as well as age at the time of transplantation, remained similar into the most recent era. The maximal frequency of rejection events and rejection death occurred among patients transplanted at ages 10 to 30 years. Conversely, the frequency of infection events was minimal within the same group. In the oldest and youngest patients receiving transplants, infection was the predominant cause of death and rates of rejection events decreased. CONCLUSIONS These data show that evolving immunosuppressive strategies have successfully reduced rejection and infection frequencies, and those patients transplanted at 30 to 60 years of age have the lowest frequency of rejection/infection events. However, individuals transplanted at younger or older ages, especially non-white recipients in the 10- to 30-year age group, experience significantly more infection or rejection. Therefore, programs should increase the level of surveillance in these patients and consider modification of immunosuppressive regimens in order to lower the frequency of infection and rejection events.

Increased Incidence and Mortality Associated With Skin Cancers After Cardiac Transplant

Skin cancer incidence has been shown to be increased in the context of transplant‐associated immunosuppression. There is, however, limited information specifically about the incidence of skin cancer after cardiac transplantation in the United States. A 10‐year retrospective cohort study of 6271 heart transplants at 32 US transplant centers revealed increased postprocedure incidence of nonmelanoma and melanoma skin cancers, especially cutaneous squamous cell carcinoma, for which the incidence increased from 4‐ to 30‐fold compared to the age and gender equivalent general population. Incidence of skin cancer in this study was consistent with prior single‐center data regarding cardiac transplant patients. Comparison of all‐cause mortality statistics for patients with basal cell carcinoma, squamous cell carcinoma and melanoma, respectively, demonstrated increased mortality associated with melanoma. Skin cancer screening and prophylaxis may be of some utility in reducing morbidity and mortality in cardiac transplant patients.

Are there specific risk factors for fatal allograft vasculopathy? An analysis of over 7,000 cardiac transplant patients

Allograft vasculopathy is a major cause of late death following cardiac transplantation (C Tx). In order to examine the possibility that allograft vasculopathy is less likely to be fatal in the current era, a multi-institutional analysis was undertaken to examine risk factors and trends in fatal allograft vasculopathy (FAV) over the past decade. METHODS: Among 7259 pts. undergoing primary C Tx at 42 institutions between 1990 and 1/1/2000, deaths and retransplantation caused by FAV were analyzed. FAV included recipient deaths in which allograft coronary artery disease (CAD) was considered the primary cause and retransplantations in which allograft CAD was the primary indication. Multivariable analysis in the hazard function domain was utilized to identify risk factors for the event FAV. RESULTS: With a maximum of 10 yr followup, 239 FAV events occurred, of which 200 caused pt death and 39 prompted retransplantation. FAV accounted for 11% of pt deaths (200/1778) and 37% of retransplants (39/106). A gradually increasing risk of FAV was identified throughout the followup period. By multivariable analysis, risk factors for FAV included older donor age (p,.0001), younger recipient age (p,.0001), earlier date of transplant (p,.0001), ischemic etiology (p,.0001), history of recipient cigarette use (p5.01), history of gouty arthritis (p5.001), black recipient (p,.0001), and positive donor CMV serology (p5.03). The likelihood of FAV within 4 yrs was predicted to be 5% for pt. transplanted in 1990, and fell to 2% for those transplanted in 1995. The adverse effect of older donor age was especially pronounced in younger recipients; for a 20 yr. old recipient, the likelihood of FAV within 8 yrs. more than doubled when donor age increased from 20 yrs to 50 yrs (8% vs. 17%, p,.0001). The impact of a recent smoking history increased the likelihood of FAV within 8 yrs by a factor of 1.6. INFERENCES: 1) With current management techniques, FAV appears somewhat less common in recent years. 2) The selection of older donors (particularly older than about 40 yrs) in younger recipients under 30 yrs of age must be tempered by the realization that late FAV may be 1.3 to 2.3 times more likely. 3) A history of recent cigarette abuse prior to transplantation importantly increases (by a factor of 1.6) the likelihood of late FAV.

Temporal trends in heart transplantation from high-risk donors: Are there lessons to be learned? A multi-institutional analysis

BACKGROUND In 2003 the Department of Health and Human Services sponsored the Organ Donation Breakthrough Collaborative (ODBC) with the aim to increase organ donation. After the ODBC, increases in the number of all solid organs transplanted, except for heart, were seen. The aim of this study was to determine if ODBC resulted in temporal changes in the use of hearts from high-risk donors. METHODS We analyzed data from the Cardiac Transplant Research Database in three eras: 1990-1995, 1996-2002, and 2003-2007. We explored temporal changes in high-risk donor characteristics: age, gender, hypertension, diabetes mellitus, abnormal echocardiogram, and ischemic time. RESULTS Between 1990 and 2007, 7,220 patients underwent transplantation in 26 centers. Donors in the first era were least likely to have high-risk characteristics of higher age (mean, 30 years), female gender (30%), hypertension (8%), diabetes mellitus (1%), structural abnormalities on echocardiogram (7%), and prolonged graft ischemic time (mean, 163 minutes). In the second era, there was a significant increase in the use of donors with the above mentioned high-risk characteristics-32 years, 33%, 10%, 3%, 8% and 181 minutes, respectively. In the third post-ODBC era, no further increase was seen in high-risk donors, but rather a trend for avoidance of risk-32 years, 28%, 10%, 2%, 5% and 186 minutes, respectively. CONCLUSION Significant temporal changes in the characteristics of heart donors have occurred in the past 17 years. Recent temporal changes, however, cannot be directly attributed to the ODBC efforts.

A multi-institutional study of malignancies after heart transplantation and a comparison with the general United States population

BACKGROUND The purpose of these studies was to determine the incidence and survival of patients with specific malignancies with respect to age and transplant year and to compare the data with the normal non-transplant population. METHODS Data from 6,211 primary cardiac transplants between July 31, 1993, and December 30, 2008, were collected by 35 institutions participating in the Cardiac Transplant Research Database. Data were compared with information collected by the Surveillance Epidemiology and End Results (SEER) Cancer Statistics Review 1975-2006. RESULTS Multivariable analysis showed older age (relative risk [RR], 2.1; p < 0.0001) and earlier transplant year (RR, 1.8; p < 0.0001) were highly significant risk factors. Aggregate malignancy incidence in the modern era (2001 to 2008) did not differ significantly from the normal population, which appeared to be attributable to a lower rate of malignancies other than lung cancer, lymphoma, and melanoma (actual/expected ratio, 0.71). From 2001 to 2008, rates were significantly higher for lung cancer (actual/expected ratio, 1.86; p = 0.006) and lymphoma (actual/expected ratio, 4.3, p < 0.0001) than in the normal population. The highest risk for lymphoma was in younger adults who received transplants at ages 18 to 35 years (actual/expected ratio, 27). The highest risk for lung cancer was in patients who underwent transplantation at ages 55 to 65 years (actual/expected ratio, 28). Once diagnosed with malignancy, subsequent survival at 5 years was 21% for lung cancer and 32% for lymphoma. CONCLUSIONS The risk of malignancy has markedly declined during a 15-year period such that the aggregate rate of malignancy approached that of the general population in the United States. However, the distribution of malignancies was not the same, with a greater prominence of lung cancer and lymphoproliferative disease.