Systematic evaluation of distribution of transgene expression after adenovirus-mediated gene transfer to the transplanted heart

In the transplantation setting, the study and potential treatment of acute and chronic rejection by means of gene therapy will require widespread transgene expression in the donor organ. The distribution of transgene expression after adenovirus-mediated gene transfer via the coronary vasculature in a model of abdominal heterotopic heart transplantation in syngeneic rats (n = 6) was evaluated at 1 week. Reporter gene expression was evenly distributed in the base, the midventricle, and the apex of the transplanted hearts. This study demonstrates that intracoronary administration of the adenoviral vector to the donor heart results in widespread transgene expres- sion. Received: 9 December 1997 Received after revision: 24 March 1998 Accepted: 15 April 1998     

A comparison of pedriatric and adult kidney donors for adult recipients

The high demand for organs for transplantation has made it necessary to consider using even the oldest and youngest of potential donors in order to increase the organ supply. In this retrospective study, the outcome of kidney transplantation using cadaveric pediatric donors was compared with that of an adult control series. Graft procurement took place in two regions of Italy (Emilia-Romagna and Piemonte) over an 11-year period. A group of pediatric donors ( < 15 years old, n = 30) was compared with an adult donor group (n = 67). All recipients were adults who received cyclosporin as immunosuppression. Actuarial patient and graft survival rates did not differ significantly between the two groups (patient survival 96 % and 96 % for pediatric donors versus 98 % and 92 % for adult donors at 1 and 5 years post-transplantation; graft survival 76 % and 68 % for pediatric donors versus 88 % and 74 % for adult donors 1 and 5 y post-transplantation). Complications were also evaluated, but no difference was found (the only exception being the creatinine level in the 5th year). Renal transplantation with cadaveric donors starting at 4 years of age gave results comparable to kidneys coming from adults. These data show that cadaveric pediatric donor kidneys may be used in adult recipients with good results. The ethical implications of the subject are extensively reviewed. Received: 5 November 1997 Received after revision: 15 October 1998 Accepted: 18 December 1998     

Lesions in donor kidneys: nature, incidence, and influence on graft function

The aim of this study was to assess the influence of kidney-donor transmitted pathology on graft function. Light and immunofluorescent microscopic findings from a surgical biopsy taken prior to transplantation from 114 cadaveric kidney donors were analyzed. Moderate to severe mesangial IgA deposits were considered consistent with IgA nephropathy. Pathological abnormalities were correlated together with donor age, number of mismatches, and type of immunosuppression by multivariate statistical analysis with the serum creatinine values from patients who experienced no acute rejection at 1 year. Serum creatinine values (n = 52) were not correlated with either nonspecific light microscopic lesions or immunofluorescent deposits found in the majority of kidney donors or with changes consistent with IgA nephropathy observed in 9 % of the cases. There was, however, a correlation with donor age, which was also correlated with the extent of chronic lesions (P < 0.001). Received: 5 March 1997 Received after revision: 8 July 1997 Accepted: 21 August 1997     

Long-term transplant outcomes of donor hearts with left ventricular dysfunction

Objective

Despite small single-center reports demonstrating acceptable outcomes using donor hearts with left ventricular dysfunction, 19% of potential donor hearts are currently unused exclusively because of left ventricular dysfunction. We investigated modern long-term survival of transplanted donor hearts with left ventricular dysfunction using a large, diverse cohort.

Donor hypo‐ and hypernatremia are predictors for increased 1‐year mortality after cardiac transplantation

Donor hypernatremia is known to be associated with initial graft dysfunction in liver transplantation. Controversial data exist regarding the impact of sodium dysregulation on patient survival after heart transplantation (HTX). The aim of this study was to investigate the influence of donor sodium levels on survival in a large cohort of heart transplant recipients from the Eurotransplant registry. From 1997 to 2005, all consecutive adult HTX performed in the Eurotransplant region were included into this study (n = 4641 patients). Multivariate analysis was applied to investigate possible clinical predictors for 1‐year post‐transplant survival after cardiac transplantation (donor sodium levels, donor age, donor cause of death, recipient age, primary disease, urgency status, cold ischemia time). In multivariate analysis, recipients receiving a donor heart with serum sodium level lower than 130 mmol/l or higher than 170 mmol/l had a 1.25‐fold higher risk for 1‐year post‐transplant mortality than patients with normal donor sodium ranges (P = 0.007). Other independent risk factors for impaired 1‐year survival were recipient age, the indication for transplantation and the urgency status of the recipient. Our study demonstrates that hyponatremia as well as hypernatremia show a strong U‐shaped correlation with poor survival after cardiac transplantation. Accurate donor management to avoid electrolyte disorder seems to be crucial for ensuring good quality of donor hearts.     

Treatment with monoclonal antibodies to ICAM-1 and LFA-1 in rat heart allograft rejection

During allograft rejection, leukocyte infiltration in the graft is regulated by various adhesion molecules. Treatment with monoclonal antibodies to ICAM-1 and LFA-1 (CD11 a) induces specific tolerance after murine heart transplantation. In this study, we investigated the possibility of tolerance induction using these antibodies in a fully incompatible rat heart transplant model. Heterotopic, intra-abdominal heart transplantation was performed using Dark Agouti (DA) rats as donors and Lewis (LEW) rats as recipients. Group A (n = 6) received no immunosuppression and served as controls. In group B (n = 6) 500 μg/kg per day 1A29 (anti-ICAM-1) was administered intravenously (i. v.) for 5 days; group C rats received the same dosage of WT.1 (anti-CD11 a) i. v. for 5 days. In group D (n = 6), rats received combined i. v. administration of anti-CD11 a and anti-ICAM-1 (500 μg/kg per day of each, for 5 days. The antibodies used were monoclonal mouse anti-rat antibodies produced from hybridomas. Allograft survival was monitored by daily palpation of the graft. There was no statistically significant difference in allograft survival between the groups (A: 5.7 ± 0.5 days; B: 5.7 ± 0.5 days; C: 5.7 ± 0.5 days; D: 6.2 ± 0.4 days). Treatment with monoclonal antibodies to ICAM-1 and LFA-1 alone or in combination had no effect on allograft survival after heart transplantation between fully incompatible rat strains. We conclude that induction of tolerance using these antibodies seems inconceivable in human heart transplantation. Received: 1 July 1996 Received after revision: 25 September 1996 Accepted: 28 October 1996     

Donor des-gamma-carboxy prothrombin positivity is a risk factor for poor early graft function in liver transplantation

Des-gamma-carboxy prothrombin (DCP) is an abnormal prothrombin that lacks coagulating activity. The aim of this study was to determine if the presence of DCP in the donor could be used as a marker of post-transplant graft function. We collected data and serum samples on 90 organ donors. DCP level was correlated with donor-specific factors and with graft function intraoperatively and in the early post-transplant period. Twenty-seven donors (30.0 %) had positive DCP levels before harvesting. Although recipients were similar in demographics, preoperative liver function, and primary disease distribution, patients transplanted with livers from DCP-positive donors needed significantly more intraoperative transfusion. Furthermore, donor DCP positivity was identified as a preoperative risk factor for poor early graft function based on multivariate analysis (odds ratio = 6.58, P = 0.0032). Our findings suggest that DCP is another valuable marker for evaluating the quality of donor livers. Received: 30 June 1997 Received after revision: 14 October 1997 Accepted: 19 November 1997     

Impact of local donor and regionalization on a German transplantation center

Optimal allocation of donor organs is an ongoing matter of debate. We report on the impact of the foundation of UNI NRW, a close transplant collaboration of seven university centers with the intention of improving donor organ allocation, on the heart transplant program in Münster. All donor organs retrieved were offered first to the patients within this region before going into the Eurotransplant (ET) Foundation pool. The heart transplant program data were prospectively (for 1997) and retrospectively (for 1996) analyzed with regard to donor organ availability and allocation. There was a slight decrease in the number of donor hearts offered and accepted within the UNI NRW region in 1997 as compared to in 1996. However, due to the significantly lower organ export rate, the number of heart transplantations performed in UNI NRW rose from 47 to 72 procedures. In Münster, only six donor organs (16 %) were procured from outside UNI NRW in 1997, and these were, in part, due to special urgency requests. In conclusion, the institutionalization of UNI NRW within the framework of ET offers more flexibility, decreases total ischemic time, and may help to lower costs. Received: 26 May 1998 Received after revision: 22 September 1998 Accepted: 12 October 1998     

Outcome in Cardiac Recipients of Donor Hearts With Increased Left Ventricular Wall Thickness

The ongoing shortage of donors for cardiac transplantation has led to a trend toward acceptance of donor hearts with some structural abnormalities including left ventricular hypertrophy. To evaluate the outcome in recipients of donor hearts with increased left ventricular wall thickness (LVWT), we retrospectively analyzed data for 157 cardiac donors and respective recipients from January 2001 to December 2004. There were 47 recipients of donor heart with increased LVWT >or=1.2 cm, which constituted the study group and 110 recipients of a donor heart with normal LVWT < 1.2 cm that formed the control group. At 3 +/- 1.5 years, recipient survival was lower (50% vs. 82%, p = 0.0053) and incidence of allograft vasculopathy was higher (50% vs. 22%, p = 0.05) in recipients of donor heart with LVWT > 1.4 cm as compared to LVWT 1.4 cm (p = 0.003), recipient preoperative ventricular assist device (VAD) support (p = 0.04) and bypass time > 150 min (p = 0.05) were predictors of reduced survival. Our results suggest careful consideration of donor hearts with echocardiographic evidence of increased LVWT in the absence of hypovolemia, because they may be associated with poorer outcomes; such hearts should potentially be reserved only for the most desperately ill recipients.     

Temporal trends and outcomes of patients waiting on left ventricular assist devices and inotropes for heart transplantation

We sought to evaluate the trends and outcomes of patients with left ventricular assist devices (LVADs) and inotropes at the time of listing for heart transplantation. Adults with an LVAD implanted and listed with 1A status were identified in the United Network for Organ Sharing (UNOS) registry between 2010 and 2017. Patients were grouped according to the presence or absence of inotropes at the time of listing and transplantation. A total of 2714 patients were included in the study including 664 patients on inotropes at the time of listing, 235 at the time of transplantation, and 118 on inotropes both at listing and at the time of transplantation. Patients on LVAD and inotropes at the time of listing were more frequently supported with a right ventricular assist device (RVAD) (P < .001), had higher risk of death in the waiting list (sub-hazard ratio [SHR] = 1.48, 95% CI 1.14-1.90, P = .002), and were less likely to be transplanted (SHR = 0.70, 95% CI 0.63-0.78, P < .001) compared with those not on inotropes, after adjusting for described confounders. Approximately 1 in 10 LVAD recipients listed as status 1A are on inotropic therapy at the time of heart transplantation. Patients on LVAD and inotropes have worse outcomes in terms of survival and lower rates of transplantation.     

Impact of Donor Spontaneous Intracranial Hemorrhage on Outcome after Heart Transplantation

Donor cause of death has been suggested to have a significant impact on cardiac transplant morbidity and mortality. Our objective was to evaluate the impact of donor spontaneous intracranial bleeding on clinical outcome after heart transplantation. A group of 160 recipients underwent cardiac transplantation from donors with spontaneous intracranial bleeding (ICB group). These were compared with 197 recipients who were transplanted from trauma donors (Trauma group). A higher 4-year mortality rate was noted in the ICB group (24% vs. 14%, p=0.015). ICB as a cause of donor death was an independent predictor of recipient mortality (adjusted hazard ratio 2.02, 95% CI 1.27-3.40, p<0.0001). Compared with the Trauma group, the ICB group had an increased incidence of post-transplant graft dysfunction during the first week of transplant (10% vs. 3%, p=0.007), and higher incidence of interstitial myocardial fibrosis on their endomyocardial biopsies within 4 weeks of transplant (21% vs. 9%, p=0.0012). There was a trend towards an increased rate of allograft vasculopathy in the ICB group (competing risks adjusted hazard ratio 1.39, 95% CI 0.90-2.13, p = 0.14).     

Pretransplant left ventricular hypertrophy in association with postoperative myocardial injury in liver transplantation

Pretransplant left ventricular hypertrophy (LVH) is a common finding during preoperative cardiac evaluation. We hypothesized that patients with pretransplant LVH were associated with a higher risk of postoperative myocardial injury (PMI) in adult patients undergoing liver transplantation (LT). A retrospective cohort analysis was performed by reviewing the medical records of adult patients who underwent LT between January 2006 and October 2013. Of 893 patients, the incidences of mild, moderate, and severe LVH were 7.8%, 5.6%, and 2.5%, respectively. Propensity match was used to eliminate the pretransplant imbalance between the LVH and non-LVH groups. In after-match patients, 23.5% of LVH patients developed PMI compared to 11.8% in the control group (P = .011). The incidence of PMI in patients with moderate-severe degrees of LVH was significantly higher compared with that in patients with mild LVH (27.9% vs 19.1%, P = .016). When controlling intraoperative variables, patients with LVH had 4.5 higher odds of developing PMI (95% CI1.18-17.19, P = .028). Patients experiencing PMI had significantly higher 1-year mortality (37.5% vs 15.7%, log-rank test P < .001). Our results suggest that patients with pretransplant LVH were at a high risk of developing PMI and should be monitored closely in the perioperative period. More studies are warranted.     

Atrial Septal Defect Revealed by Repeat Echocardiography in a Brain-Dead Donor: A Case Report

BackgroundThe number of patients undergoing heart transplantation is limited because of the shortage of donor hearts. Expanding the donor pool with precise evaluation of donor heart is the most practical way to increase the number of patients undergoing heart transplantation. However, echocardiographic evaluation of especially right ventricle (RV) in brain-dead donors is challenging. Repeated echocardiography with volume overload may reveal unrecognized congenital heart disease such as atrial septal defect (ASD).Materials and MethodsA case of repeated echocardiography revealed ASD secundum in a donor with significant RV enlargement and dysfunction from previously unknown origin. An almost-discarded donor heart was used in heart transplantation after simple patch closure.ResultsThe patient was discharged after a month. One year later, he has been doing well without significant adverse events.ConclusionsRV dysfunction prior to heart transplantation increases the risk of post-transplant graft failure. Secundum-type ASD and ventricular septal defect, which are relatively common adult congenital heart diseases that cause RV enlargement and dysfunction, are not contraindications for heart transplantation. Our case showed that repeat echocardiography revealed congenital heart disease and rescued the almost-discarded heart. This simple maneuver is essential in donor heart evaluation to maximize the utility of marginal donors.     

Effects of drug abuse,smoking and alcohol on donor hearts and lungs

Potential heart and lung donors with a history of illicit drugs and/or smoking and alcohol are frequently offered, though there is no clear guidance on when it is safe to use these organs. A review of the literature on effects of drugs, alcohol and smoking on donor outcomes, and the effects of these on the intact heart and lung was undertaken. There has been a marked increase in deaths from opioid abuse in many developed countries, though recent evidence suggests that outcomes after cardiothoracic transplantation are equivalent to nonopioid donor causes of death. For donor smoking, there is an increased risk with lung transplantation; however, that risk is less when compared to further waiting on the transplant list for a nonsmoking alternative. Heavy alcohol consumption does not adversely affect heart transplantation, and there is no clear evidence of adverse outcomes after lung transplantation. There are no overall effects of cannabis or cocaine on survival after heart or lung transplantation. In all these cases, careful donor assessment can establish if a particular organ can be used. In most cases, use of drugs requires careful assessment, but is not in of itself a contraindication to cardiothoracic transplantation.     

Impact of donor left ventricular hypertrophy on survival after heart transplant

Left ventricular hypertrophy (LVH) of the donor heart is believed to increase the risk of allograft failure after transplant. However this effect is not well quantified, with variable findings from single-center studies. The United Network for Organ Sharing database was used to analyze the effect of donor LVH on recipient survival. Three cohorts, selected in accordance with the American Society of Echocardiography guidelines, were examined: recipients of allografts without LVH (<1.1 cm), with mild LVH (1.1-1.3 cm) and with moderate-severe LVH (≥ 1.4 cm). The study group included 2626 patients with follow-up of up to 3.3 years. Mild LVH was present in 38% and moderate-severe LVH in 5.6% of allografts. Predictors of mortality included a number of donor and recipient characteristics, but not LVH. However, a subgroup analysis showed an increased risk of death in recipients of allografts with LVH and donor age >55 years, and in recipients of allografts with LVH and ischemic time ≥ 4 h. In the contemporary era, close to half of all transplanted allografts demonstrate LVH, and survival of these recipients is similar to those without LVH. However, the use of allografts with LVH in association with other high-risk characteristics may result in increased mortality.     

Outcomes of Donor Evaluations for Adult-to-Adult Right Hepatic Lobe Living Donor Liver Transplantation

The purpose of this study is to determine the role of liver biopsy and outcome of patients undergoing donor evaluation for adult-to-adult right hepatic lobe living donor liver transplantation (LDLT). Records of patients presenting for a comprehensive donor evaluation between 1997 and February 2005 were reviewed. Liver biopsy was performed only in patients with risk factors for abnormal histology. Two hundred and sixty patients underwent a comprehensive donor evaluation and 116 of 260 (45%) were suitable for donation, 14 of 260 (5.4%) did not complete evaluation and 130 of 260 (50%) were rejected. Four patients underwent unsuccessful hepatectomy surgery due to discovery of intraoperative abnormalities. Between 1997 and 2001, the acceptance rate of donor candidates (63%) was higher than 2002-2005 (36%), p < 0.0001. Sixty-six of the 150 eligible patients (44%) fulfilled criteria for liver biopsy and 28 of 66 (42%) had an abnormal finding. Less than half of the patients undergoing donor evaluation were suitable donors and the donor acceptance rate has declined over time. A large proportion of the patients undergoing liver biopsy have abnormal findings. Our evaluation process failed to identify 4 of 103 who had aborted donor surgeries.     

Cardiogenic shock and coronary endothelial dysfunction predict cardiac allograft vasculopathy after heart transplantation

Cardiac allograft vasculopathy remains one of the major causes of death post‐heart transplantation. Its etiology is multifactorial and prevention is challenging. The aim of this study was to prospectively determine factors related to cardiac allograft vasculopathy after heart transplantation. This research was planned on 179 patients submitted to heart transplant. Performance of an early coronary angiography with endothelial function evaluation was scheduled at three‐month post‐transplant. Patients underwent a second coronary angiography after five‐yr follow‐up. At the 5‐ ± 2‐yr follow‐up, 43% of the patients had developed cardiac allograft vasculopathy (severe in 26% of them). Three independent predictors of cardiac allograft vasculopathy were identified: cardiogenic shock at the time of the transplant operation (OR: 6.49; 95% CI: 1.86–22.7, p = 0.003); early coronary endothelial dysfunction (OR: 3.9; 95% CI: 1.49–10.2, p = 0.006), and older donor age (OR: 1.05; 95% CI: 1.00–1.10, p = 0.044). Besides early endothelial coronary dysfunction and older donor age, a new predictor for development of cardiac allograft vasculopathy was identified: cardiogenic shock at the time of transplantation. In these high‐risk patient subgroups, preventive measures (treatment of cardiovascular risk factors, use of novel immunosuppressive agents such as mTOR inhibitors) should be earlier and much more aggressive.     

Association between Primary Graft Dysfunction among Lung,Kidney and Heart Recipients from the Same Multiorgan Donor

Even organs from an ideal donor will occasionally develop primary graft dysfunction (PGD) causing a significant morbidity and mortality after transplantation. It is likely that this situation represents subtle undetectable levels of ongoing donor organ dysfunction. The aim of this study is to investigate the association of PGD between lung, kidney and heart recipients from the one donor. From 202 multiorgan donors, contributed 231 consecutive lung transplants at the Alfred Hospital, 378 kidney and 114 heart transplants were subsequently performed at multiple centers across Australia and New Zealand. Eight hundred seventy‐five organs were used for 723 transplants. The incidence of PGD after lung, kidney and heart transplants was 20% (47/231), 24% (92/378) and 20% (23/114), respectively. In paired single organ recipients, PGD in one of the pair was a significant risk factor for the development of PGD in the other [lung: odds ratio = 5.63 (1.72–18.43), p = 0.004; kidney: odds ratio = 3.19 (1.90–5.35), p < 0.0001]. In multivariate analysis, same donor heart PGD [3.37 (1.19–9.50), p = 0.02] was an independent risk factor for lung PGD and same donor lung PGD was significant risk factor for kidney PGD [1.94 (1.01–3.73), p = 0.04], if the PGD status of the paired kidney was not known. There was a significant association for the development of PGD across different organs transplanted from the same donor.     

Expanding the horizons: Uncontrolled donors after circulatory death for lung transplantation—First comparison with brain death donors

Uncontrolled donation after cardiac death is an appealing source of organs for lung transplantation. We compare early and long‐term outcomes of lung transplantation with these donors with a cohort of transplants from brain death donors at our institution. Retrospective analysis of all lung transplantations was performed from 2002 to 2012. We collected variables regarding recipients, donors, recover and transplant procedures, early and late complications, and survival. We included 292 lung transplants from brain death donors and 38 from uncontrolled donors after cardiac death. Both groups were comparable except for sex mismatch (male recipient‐female donor was more frequent in the brain death cohort, 17.8% vs 0%, P 0.002), total ischemic time (longer for donors after cardiac death, 657 minutes for the first lung and 822 minutes for the second vs 309 and 425 minutes, P < 0.001), and ex vivo evaluation (more frequent in cardiac death donors, 21.1% vs 1.4%, P < 0.001). Early and late outcomes were not different (ICU stay [9 vs 10.5 days], hospital stay [33.5 vs 35 days], primary graft dysfunction G3 [24 vs 34.2%], and chronic graft dysfunction HR 1.19 [0.61‐2.32]), but overall survival was significantly lower for patients transplanted from cardiac death donors [HR 1.67 (1.06‐2.64)]. Lung transplantation after uncontrolled cardiac death offers poorer results in terms of survival compared to brain death donation. Refinement of current strategies for graft preservation and evaluation is essential to improve outcomes with this source of grafts.     

Fatal primary multidrug-resistant tuberculosis in a heart transplant recipient

The incidence of tuberculosis (TB) worldwide is currently on the rise, not only in the general population but also quite notably among immunosuppressed patients. Its incidence among patients undergoing antirejection therapy is considerably higher than in the general population, and heart transplant recipients have been found to carry the highest risk of TB. There are no reported data, however, on primary TB caused by multidrug-resistant (MDR) Mycobacterium tuberculosis (M. tuberculosis) in heart transplant recipients. We describe the case of a patient who developed active primary MDR TB following the reactivation of a latent tuberculous infection 6 months after transplantation. The patient was most likely infected by M. tuberculosis during a period of time he spent in prison 10 years before undergoing transplantation, but he never developed active tuberculosis, nor did he ever receive antituberculous medication prior to transplantation. Because of the atypical clinical presentation, establishment of the diagnosis was postponed, and the resistance pattern of the isolate grown from bronchoalveolar lavage (BAL) specimens (resistant to isoniazid and rifampicin) led to treatment failure and a fatal outcome. The adoption of the most rapid diagnostic tools for the identification of M. tuberculosis and for a quick screening of drug-resistant isolates is urgently needed in those centers where organ transplantation is carried out. Received: 16 December 1997 Received after revision: 25 February 1998 Accepted: 16 March 1998