Impact of removing OPTN region from vascularized composite allograft allocation.

On 6/18/2020, the Organ Procurement and Transplantation Network (OPTN) implemented new policy replacing OPTN region with a 500 nautical mile (NM) circle around the donor hospital for the purpose of vascularized composite allograft (VCA) allocation. We used OPTN data to assess deceased donor VCA transplants in the 3 years pre- (6/19/2017-6/17/2020) vs. post-implementation (6/18/2020-6/17/2023). A total of 19 deceased donor VCA transplants were performed pre-policy (10 uterus, 3 bilateral upper limb, 1 unilateral upper limb, 3 face, 1 abdominal wall and 1 penis), and 11 post-policy (4 uterus, 1 bilateral upper limb, 2 face, 1 trachea, 2 abdominal wall, and 1 bilateral upper limb and face). Median distance from donor hospital to transplant hospital increased from 70 NM (range: 0-524 NM) pre-policy to 119 NM (range: 0-464 NM) post-policy. The majority of transplants in both policy eras were within 500 NM of the donor hospital [89.5% (N = 17/19) vs. 100% (N = 11/11)] and most remained within the same OPTN region as the donor hospital [68.4% (N = 13/19) vs. 90.9% (N = 10/11)]. Although it is difficult to draw strong conclusions about the policy's impact due to the low transplant volume and timing of implementation relative to the COVID-19 pandemic, data in the 3 years post-implementation suggest that 500 NM circles were a reasonable replacement for OPTN region in VCA allocation. The OPTN will continue to review data to monitor the policy's impact and inform future changes to VCA allocation, such as the transition to continuous distribution, a points-based framework expected to replace the current framework.

Temporal Trends, Risk Factors, and Clinical Outcomes of De Novo Lymphoproliferative Disorders After Heart Transplantation.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is an important cause of morbidity and mortality in heart transplant (HTx) recipients. However, previous studies of PTLD after HTx are limited to single-center analyses or extrapolated from all solid organ transplantations. OBJECTIVES: The authors analyzed the temporal trends, risk factors, and clinical outcome of de novo PTLD specifically after HTx. METHODS: Using multi-institutional, multinational data from the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry, the authors evaluated the real-world data of PTLD after HTx, transplanted between January 2000 and June 2015. Multivariable analysis was done to identify risk factors for PTLD development after HTx. RESULTS: Among 28,136 HTx recipients, 1,069 (3.8%) developed PTLD within 10 years of transplantation. PTLD showed a bimodal age pattern with peak incidence in patients of pediatric age and late adulthood at transplantation. The early transplant era (2000-2007 vs 2008-2015), male recipient, and EBV donor-positive-recipient-negative match were independent risk factors of PTLD development within 3 years of transplantation, whereas maintenance therapy with cyclosporine vs tacrolimus at initial discharge was associated with a lower incidence. PTLD development within 3 years of transplantation was significantly associated with mortality (HR: 2.42 [95% CI: 2.01-2.91]; P < 0.001). Survival after PTLD diagnosis was higher in the recent transplant era. CONCLUSIONS: PTLD is relatively rare, but potentially fatal, post-transplant malignancy. PTLD incidence and mortality after HTx have decreased in the recent era. Strategies to minimize the risk of PTLD, and ensure early diagnosis and effective treatment are likely to improve outcomes in HTx.

Informing preconception counseling: Outcomes among female heart transplant recipients in the ISHLT registry.

BACKGROUND: The numbers of women of child-bearing age undergoing heart transplantation (HT) and female pediatric HT recipients surviving to child-bearing age have increased, along with improvements in post-transplant survival. Data regarding life expectancy and comorbidities in reproductive-aged female HT recipients are needed to inform shared decision-making at the time of preconception counseling. METHODS: The International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry was investigated for HT recipients between January 1, 2000 and June 30, 2017. Women of childbearing age were defined as those aged 15-45 years, either at transplant, or at the respective post-transplant follow-up. Characteristics and outcomes of female recipients of childbearing age at transplant, 5-, 10-, and 15-year follow-up were compared to females > 45 years of age, males 15-45 years and males > 45 years of age at the corresponding time intervals. Outcomes included survival, development of diabetes (DM), severe renal dysfunction (CKD), and cardiac allograft vasculopathy (CAV). RESULTS: During the study period, 71,585 HT recipients were included: 24% (n = 17,194) were female and 9.2% (n = 6602) were of childbearing age at HT. A pre-transplant diagnosis of peripartum cardiomyopathy was associated with significantly worse post-transplant survival, a finding that remained independent of panel reactive antibody levels. The presence of pre-transplant DM and/or severe CKD was significantly associated with lower survival as were the presence of CAV, DM, and CKD post-HT. CONCLUSION: Knowledge of the impact of pre-existing comorbidities and complications post-HT on survival are important for risk stratification for preconception counseling post-HT.

Rethinking Donor and Recipient Risk Matching in Europe and North America: Using Heart Transplant Predictors of Donor and Recipient Risk.

BACKGROUND: In Europe, there is greater acceptance of hearts from higher-risk donors for transplantation, whereas in North America, the donor heart discard rate is significantly higher. A Donor Utilization Score (DUS) was used to compare European and North American donor characteristics for recipients included in the International Society for Heart and Lung Transplantation registry from 2000 to 2018. DUS was further evaluated as an independent predictor for 1-year freedom from graft failure, after adjusting for recipient risk. Lastly, we assessed donor-recipient risk matching with the outcome of 1-year graft failure. METHODS: DUS was applied to the International Society for Heart and Lung Transplantation cohort using meta-modeling. Posttransplant freedom from graft failure was summarized by Kaplan-Meier survival. Multivariable Cox proportional hazard regression was applied to quantify the effects of DUS and Index for Mortality Prediction After Cardiac Transplantation score on the 1-year risk of graft failure. We present 4 donor/recipient risk groups using the Kaplan-Meier method. RESULTS: European centers accept significantly higher-risk donor hearts compared to North America. DUS 0.45 versus 0.54, P<0.005). DUS was an independent predictor for graft failure with an inverse linear relationship when adjusted for covariates (P<0.001). The Index for Mortality Prediction After Cardiac Transplantation score, a validated tool to assess recipient risk, was also independently associated with 1-year graft failure (P<0.001). In North America, 1-year graft failure was significantly associated with donor-recipient risk matching (log-rank P<0.001). One-year graft failure was highest with pairing of high-risk recipients and donors (13.1% [95% CI, 10.7%-13.9%]) and lowest among low-risk recipients and donors (7.4% [95% CI, 6.8%-8.0%]). Matching of low-risk recipients with high-risk donors was associated with significantly less graft failure (9.0% [95% CI, 8.3%-9.7%]) than high-risk recipients with low-risk donors (11.4% [95% CI, 10.7%-12.2%]) Conclusions: European heart transplantation centers are more likely to accept higher-risk donor hearts than North American centers. Acceptance of borderline-quality donor hearts for lower-risk recipients could improve donor heart utilization without compromising recipient survival.

Influence of chronic kidney disease and other risk factors pre-heart transplantation on malignancy incidence post-heart transplantation.

Aims: Chronic kidney disease (CKD) pre-heart transplantation (HTx) has been proposed as a risk factor for malignancy risk post-HTx. Using multicenter registry data, our aim was to calculate the death-adjusted annual incidence of malignancies post-HTx, corroborate the association between CKD pre-HTx and malignancy risk post-HTx, and determine other risk factors for post-HTx malignancies. Methods and materials: We used data from patients transplanted in North American HTx centers between January 2000 and June 2017 and registered in the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry. We excluded recipients with missing data on post-HTx malignancies, heterotopic heart transplant, retransplantation, multi-organ transplantation, and patients with a total artificial heart pre-HTx. Results: Overall, 34,873 patients were included to determine the annual incidence of malignancies, 33,345 patients were included in the risk analyses. The incidence of any malignancy, solid-organ malignancy, post-transplant lymphoproliferative disease (PTLD), and skin cancer adjusted for death 15 years post-HTx, was 26.6%, 10.9%, 3.6%, and 15.8% respectively. Besides widely acknowledged risk factors, CKD stage ≥4 pre-HTx was associated with the development of all malignancies post-HTx (HR 1.17 compared to CKD stage 1, p = 0.023), as well as solid-organ malignancies (HR 1.35, p = 0.01), but not for PTLD (HR 0.73, p = 0.057), and skin cancer (HR 1.06, p = 0.59). Conclusion: Risk of malignancy post-HTx remains high. CKD stages ≥4 pre-HTx was associated with an increased risk for any malignancy and solid-organ malignancy post-HTx. Strategies to mitigate the impact of pre-HTx patient factors on the risk of post-HTx malignancy are needed.

Epidemiology, risk factors, and outcomes of lung retransplantation: An analysis of the International Society for Heart and Lung Transplantation Thoracic Transplant Registry.

BACKGROUND: Lung retransplantation is a complex surgical decision that represents the only potential treatment option for recipients suffering from lung allograft failure. We sought to describe the modern landscape of lung retransplantation and to compare the relative importance of selected clinical, donor, and recipient factors on mortality in the year following lung retransplantation. METHODS: We conducted a retrospective cohort study of first-time adult recipients of deceased donor lung retransplants reported to the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry from May 2005 through June 2017. In addition to describing the characteristics of lung retransplant recipients, we examined 1 year survival overall, and by initial transplant-retransplant procedure type, recipient age, retransplant indication, and time-to-lung retransplantation (i.e., inter-transplant interval). We used the Somers' Dxy rank correlation statistic for censored data to assess the relative importance of several potential prognostic risk factors for mortality in the year following lung retransplantation. RESULTS: Our cohort included 1,597 lung retransplant recipients. 2005 was the first year with more than 100 retransplants, and since 2007, 138 to 188 retransplants (approximately 4%-6% of all transplants) were reported annually to the ISHLT Registry. The median inter-transplant interval was 3.4 years (interquartile range: 1.6-6.2 years). Forty-three percent of the cohort had an obliterative bronchiolitis retransplant indication, whereas 17% had primary graft failure. One-third (32%) were retransplanted within 2 years of their primary transplant, and 64% received a double lung transplant both times, whereas 36% received consecutive single lung transplants. Six-month and 1 year survival (82% and 76%) were higher for double-double lung retransplant recipients than for single-single recipients (76% and 69%). The 3 strongest prognostic factors for 1 year mortality were the inter-transplant interval (decreasing hazard with longer intervals), donor age (increasing hazard with older age), and need for mechanical ventilation preceding lung retransplantation. CONCLUSIONS: Retransplants comprise approximately 5% of annual lung transplants worldwide. The factor most strongly associated with 1 year mortality in this population was the duration of time since the primary lung transplant, with a persistent reduction in risk as more time elapses.

New-onset Diabetes Mellitus After Adult Heart Transplantation and the Risk of Renal Dysfunction or Mortality.

BACKGROUND: Diabetes mellitus (DM) may occur either pre-heart transplantation (HT) or as new-onset DM post-HT. We sought to define the contemporary incidence of post-HT DM, evaluate risk factors for post-HT DM, and assess the impact of post-HT DM on major outcomes. METHODS: The cohort included International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry adult primary HT-alone recipients, transplanted January 1995-June 2017, who survived to 1 y post-HT. DM status was characterized as (1) no DM pre-HT or post-HT; (2) pre-HT DM; or (3) post-HT DM (onset within 5 y of HT). Cox proportional hazards models were constructed to identify risk factors for post-HT DM onset, as well as risk factors for post-HT severe renal dysfunction and death/retransplantation. RESULTS: Of 26 263 eligible subjects, 57% had no DM pre-HT or post-HT, 22% had pre-HT DM, and 21% had new-onset post-HT DM. Risk factors for the development of post-HT DM included use of tacrolimus or steroids at 1 y post-HT, as well as higher recipient age, female sex, ischemic cardiomyopathy, higher body mass index, pre-HT dialysis, and pre-HT steroid use. Post-HT DM within 5 y was associated with increased subsequent severe renal dysfunction (hazard ratio, 1.89; 95% confidence interval, 1.77-2.01) and death/retransplantation (hazard ratio, 1.38; 95% confidence interval, 1.32-1.45), compared with patients without post-HT DM. CONCLUSIONS: Post-HT DM is common, occurring in 21% of recipients within 5 y of HT. Post-HT DM is associated with increased risk of severe renal dysfunction and death or retransplantation.

A challenge to equity in transplantation: Increased center-level variation in short-term mechanical circulatory support use in the context of the updated U.S. heart transplant allocation policy.

BACKGROUND: The United States National Organ Procurement Transplant Network (OPTN) implemented changes to the adult heart allocation system to reduce waitlist mortality by improving access for those at greater risk of pre-transplant death, including patients on short-term mechanical circulatory support (sMCS). While sMCS increased, it is unknown whether the increase occurred equitably across centers. METHODS: The OPTN database was used to assess changes in use of sMCS at time of transplant in the 12 months before (pre-change) and after (post-change) implementation of the allocation system in October 2018 among 5,477 heart transplant recipients. An interrupted time series analysis comparing use of bridging therapies pre- and post-change was performed. Variability in the proportion of sMCS use at the center level pre- and post-change was determined. RESULTS: In the month pre-change, 9.7% of patients were transplanted with sMCS. There was an immediate increase in sMCS transplant the following month to 32.4% - an absolute and relative increase of 22.7% and 312% (p < 0.001). While sMCS use was stable pre-change (monthly change 0.0%, 95% CI [-0.1%,0.1%]), there was a continuous 1.2%/month increase post-change ([0.6%,1.8%], p < 0.001). Center-level variation in sMCS use increased substantially after implementation, from a median (interquartile range) of 3.85% (10%) pre-change to 35.7% (30.6%) post-change (p < 0.001). CONCLUSIONS: Use of sMCS at time of transplant increased immediately and continued to expand following heart allocation policy changes. Center-level variation in use of sMCS at the time of transplant increased compared to pre-change, which may have negatively impacted equitable access to heart transplantation.

Cytomegalovirus Donor Seropositivity Negatively Affects Survival After Heart Transplantation.

BACKGROUND: Prior studies have shown that cytomegalovirus (CMV) infection is a risk factor for the development of cardiac allograft vasculopathy (CAV) and is associated with reduced long-term survival after heart transplantation (HTx). The aim of this International Society for Heart and Lung Transplantation Transplant Registry study was to compare posttransplant survival in different CMV donor:recipient serologic combinations. METHODS: We performed a retrospective cohort study, using the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, on 15 885 adult primary heart transplant recipients with known CMV serologic status between July 2004 and June 2014. Posttransplant survival and risk of developing CAV were compared across 4 groups: CMV-seronegative recipients (R-) receiving CMV-positive grafts (D+), intermediate-risk patients (D+R+ and D-R+), and low-risk patients (D-R-). RESULTS: Baseline characteristics (donor/recipient age, body mass index, recipient serum creatinine, blood group, donor cause of death, recipient diagnosis, and ischemic time) were mostly balanced between the groups. Kaplan-Meier survival analyses over a follow-up of 10 y revealed significantly worse survival for both D+ groups as compared to the CMV low-risk group (D+R+: 56.61% [95% confidence interval, 53.94-59.41] versus D-R-: 63.09% [59.74-66.64] P < 0.01 and D+R-: 57.69% [56.03-59.39] versus D-R-; P < 0.001), whereas recipient seropositivity alone was not associated with reduced survival (D-R+ versus D-R-P = 0.178). The risk of developing CAV after HTx was not significantly increased in D+ as compared to D- groups. CONCLUSIONS: In a large contemporary cohort, CMV status at the time of HTx was not associated with CAV development. However, there was a significant association between donor CMV seropositivity and reduced short- and long-term survival after HTx. Approaches to mitigate the impact of CMV on posttransplant survival are needed.

Risk of Renal Dysfunction Following Heart Transplantation in Patients Bridged with a Left Ventricular Assist Device.

Acute renal failure (ARF) and chronic kidney disease (CKD) are associated with short- and long-term morbidity and mortality following heart transplantation (HT). We investigated the incidence and risk factors for developing ARF requiring hemodialysis (HD) and CKD following HT specifically in patients with a left ventricular assist device (LVAD). We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry for heart transplant patients between January 2000 and June 2015. We compared patients bridged with durable continuous-flow LVAD to those without LVAD support. Primary outcomes were ARF requiring HD before discharge following HT and CKD (defined as creatinine >2.5 mg/dl, permanent dialysis, or renal transplant) within 3 years. There were 18,738 patients, with 4,535 (24%) bridged with LVAD support. Left ventricular assist device patients had higher incidence of ARF requiring HD and CKD at 1 year, but no significant difference in CKD at 3 years compared to non-LVAD patients. Among LVAD patients, body mass index (BMI) (odds ratio [OR] = 1.79, p < 0.001), baseline estimated glomerular filtration rate (eGFR) (OR = 0.43, p < 0.001), and ischemic time (OR = 1.28, p = 0.014) were significantly associated with ARF requiring HD. Similarly, BMI (hazard ratio [HR] = 1.49, p < 0.001), baseline eGFR (HR = 0.41, p < 0.001), pre-HT diabetes mellitus (DM) (HR = 1.37, p = 0.011), and post-HT dialysis before discharge (HR = 3.93, p < 0.001) were significantly associated with CKD. Left ventricular assist device patients have a higher incidence of ARF requiring HD and CKD at 1 year after HT compared with non-LVAD patients, but incidence of CKD is similar by 3 years. Baseline renal function, BMI, ischemic time, and DM can help identify LVAD patients at risk of ARF requiring HD or CKD following HT.