Importance of Transplant Era on Post-Heart Transplant Predictive Models: A UNOS Cohort Analysis.

BACKGROUND: The application of posttransplant predictive models is limited by their poor statistical performance. Neglecting the dynamic evolution of demographics and medical practice over time may be a key issue. OBJECTIVES: Our objective was to develop and validate era-specific predictive models to assess whether these models could improve risk stratification compared to non-era-specific models. METHODS: We analyzed the United Network for Organ Sharing (UNOS) database including first noncombined heart transplantations (2001-2018, divided into four transplant eras: 2001-2005, 2006-2010, 2011-2015, 2016-2018). The endpoint was death or retransplantation during the 1st-year posttransplant. We analyzed the dynamic evolution of major predictive variables over time and developed era-specific models using logistic regression. We then performed a multiparametric evaluation of the statistical performance of era-specific models and compared them to non-era-specific models in 1000 bootstrap samples (derivation set, 2/3; test set, 1/3). RESULTS: A total of 34 738 patients were included, 3670 patients (10.5%) met the composite endpoint. We found a significant impact of transplant era on baseline characteristics of donors and recipients, medical practice, and posttransplant predictive models, including significant interaction between transplant year and major predictive variables (total serum bilirubin, recipient age, recipient diabetes, previous cardiac surgery). Although the discrimination of all models remained low, era-specific models significantly outperformed the statistical performance of non-era-specific models in most samples, particularly concerning discrimination and calibration. CONCLUSIONS: Era-specific models achieved better statistical performance than non-era-specific models. A regular update of predictive models may be considered if they were to be applied for clinical decision-making and allograft allocation.

Characteristics and outcomes of heart transplant recipients with a pretransplant history of malignancy.

We aimed to investigate the characteristics and outcomes of HTx recipients with a history of pretransplant malignancy (PTM). Among 1062 HTx recipients between 1997 and 2013, 73 (7.1%) patients had PTMs (77 cancer cases). We analyzed post-HTx outcome, recurrence of PTM, and development of de novo malignancies. Post-HTx outcome included overall survival, 10-year survival, 10-year freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). Four most common PTMs were lymphoproliferative disorders (18.2%), prostate cancers (18.2%), non-melanoma skin cancers (18.2%), and breast cancers (13.0%). Median time from PTM and HTx was 9.0 years. During a median follow-up of 8.6 years after HTx, patients with PTM, compared to those without, showed significantly higher incidence of posttransplant malignancies (43.8% vs. 20.8%, p < .001) including 9.6% (n = 7) of PTM recurrences. However, patients with PTM, compared to those without, showed comparable overall survival, 10-year survival, 10-year freedom from CAV, NF-MACE, ATR, ACR, and AMR. Therefore, a history of PTM should not disqualify patients from HTx listing, while further research is necessary for early detection of posttransplant malignancies in these patients.

Heterogeneity of liver fibrosis in patients with congestive hepatopathy: A biopsy and explant comparison series.

PURPOSE: Patients with end-stage heart failure and concomitant irreversible liver injury may be candidates for combined heart liver transplant (CHLT). Determining appropriate candidates for CHLT is essential given organ scarcity. Transjugular liver biopsy (TJLB) is used to evaluate the severity of parenchymal liver injury in transplant candidates. In patients with congestive hepatopathy (CH), the fibrosis pattern may be heterogenous. METHODS: We reviewed all CHLT cases between 2007 and 2017, as well as lone-heart transplant cases with post-mortem autopsy. Pre-transplant TJLB was compared to explant to assess the performance of biopsy fibrosis staging. RESULTS: 12 patients were included. Median age at time of transplant was 58 and the cohort was predominantly male (75%). Seven (64%) TJLB were predominantly stage 4 fibrosis and 4 (36%) were stage 1. Advanced fibrosis was the dominant pattern in 7 (70%) explants and 5 (50%) explants had heterogenous fibrosis. In 50% of CH cases, there was discordance between the TJLB and explant. In the autopsy cases, the TJLB and autopsy findings differed. CONCLUSIONS: In this series of matched TJLB and explanted livers, we found variable performance of TJLB in predicting the predominant fibrosis stage present in the liver.

Stem cell donor HLA typing improves CPRA in kidney allocation.

The Organ Procurement and Transplantation Network (OPTN) Kidney Allocation System provides a priority to sensitized candidates based on the calculated panel reactive antibody (CPRA) value. The human leukocyte antigen (HLA) haplotype reference panel used for calculation of the CPRA by the United Network for Organ Sharing (UNOS), the OPTN contractor, has limitations. We derived a novel panel from the National Marrow Donor Program HLA haplotype data set and compared the accuracy of CPRA values generated with this panel (NMDP-CPRA) to those generated from the UNOS panel (UNOS-CPRA), using predicted and actual deceased donor kidney offers for a cohort of 24 282 candidates. The overall accuracy for kidney offers was similar using NMDP-CPRA and UNOS-CPRA. Accuracy was slightly higher for NMDP-CPRA than UNOS-CPRA for candidates in several highly sensitized CPRA categories, with deviations in linkage disequilibrium for Caucasians and the smaller size of the UNOS panel as contributing factors. HLA data derived from stem cell donors yields CPRA values that are comparable to those derived from deceased kidney donors while improving upon several problems with the current reference panel. Consideration should be given to using stem cell donors as the reference panel for calculation of CPRA to improve equity in kidney transplant allocation.

Differential Impact of Class I and Class II Panel Reactive Antibodies on Post-Heart Transplant Outcomes.

BACKGROUND: Sensitized patients awaiting heart transplantation spend a longer time on the waitlist and have higher mortality. We are now able to further characterize sensitization by discriminating antibodies against class I and II, but the differential impact of these has not been assessed systematically. METHODS AND RESULTS: Using United Network for Organ Sharing data (2004-2015), we analyzed 17,361 adult heart transplant patients whose class I and II panel reactive antibodies were reported. Patients were divided into 4 groups: class I and II ≤25% (group 1); class I ≤25% and class II ˃25% (group 2); class II ≤25% and class I >25% (group 3); and both class I and II >25% (group 4). Outcomes assessed were treated rejection at 1-year mortality, all-cause mortality, and rejection-related mortality. Compared with group 1, only group 4 was associated with a higher risk of treated rejection at 1 year (odds ratio 1.31, 95% confidence interval [CI] 1.05-1.64), all-cause mortality (hazard ratio 1.24, 95% CI 1.06-1.46), and mortality owing to rejection (subhazard ratio 1.84, 95% CI 1.18-2.85), whereas groups 2 and 3 were not (P > .05). CONCLUSIONS: Combined elevation in class I and II panel reactive antibodies seem to increase the risk of treated rejection and all-cause mortality, whereas risk with isolated elevation is unclear.

Eculizumab for antibody-mediated rejection in heart transplantation: A case-control study.

Complement inhibition offers a novel treatment approach for antibody-mediated rejection (AMR). We examined patients with hemodynamic compromise AMR 2010-2020, comparing eight patients supplemented with eculizumab to 10 patients without; administration was at the treating physician's discretion. There were no significant differences between groups though eculizumab patients had a non-significantly higher inotrope score (208.8 mcg/kg/min vs. 2.6 mcg/kg/min; P = .22), more extracorporeal membrane oxygenation (ECMO) (62.5% vs. 20%; P = .066), and worse 1-year survival (37.5% vs. 60%; P = .63). The role of eculizumab is uncertain in AMR; multicenter collaborative studies are essential to better define its role.

The effects of donor-specific antibody characteristics on cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) causes late graft dysfunction and post-transplant mortality. Currently, the effects of different donor-specific antibodies (DSA) on the severity of CAV remain unclear. METHOD: We evaluated 526 adult heart transplant recipients at a single center between January 2010 and August 2015. Subjects were divided into those with DSA (n = 142) and those without DSA (n = 384, control). The DSA group was stratified into persistent DSA (n = 34), transient DSA (n = 105), 1:8 dilution DSA (n = 45), complement-binding (C1q) DSA (n = 36), Class I DSA (n = 37), and Class II DSA (n = 105). The primary outcome was the incidence of moderate-to-severe CAV (CAV 2/3) at 5-year follow-up. RESULTS: Subjects with persistent DSA, 1:8 dilution DSA, and C1q DSA had higher incidence of CAV 2/3 compared the control group (17.6%, 13.3%, and 16.7% vs. 3.1%, respectively; P≤ .001). The incidence of CAV 2/3 between subjects with transient DSA and the control group was similar (2.8% vs. 3.1%; P = .888). Subjects with Class II DSA also had higher incidence of CAV 2/3 (7.6% vs. 3.1%; P = .039). CONCLUSION: DSA that are persistent, 1:8 dilution positive, C1q positive, and Class II are associated with more severe grades of CAV. These DSA characteristics may prognosticate disease and warrant consideration for treatment.

Prediction model for cardiac allograft vasculopathy: Comparison of three multivariable methods.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains an important cause of graft failure after heart transplantation (HT). Although many risk factors for CAV have been identified, there are no clinical prediction models that enable clinicians to determine each recipient's risk of CAV. METHODS: We studied a cohort of 14 328 heart transplant recipients whose data were reported to the International Society for Heart and Lung Transplantation Registry between 2000 and 2010. The cohort was divided into training (75%) and test (25%) sets. Multivariable modeling was performed in the test set using variables available at the time of heart transplant using three methods: (i) stepwise Cox proportional hazard, (ii) regularized Cox proportional hazard, and (iii) Bayesian network. RESULTS: Cardiac allograft vasculopathy developed in 4259 recipients (29.7%) at a median time of 3.0 years after HT. The regularized Cox proportional hazard model yielded the optimal performance and was also the most parsimonious. We deployed this model as an Internet-based risk calculator application. CONCLUSIONS: We have developed a clinical prediction model for assessing a recipient's risk of CAV using variables available at the time of HT. Application of this model may allow clinicians to determine which recipients will benefit from interventions to reduce the risk of development and progression of CAV.

Angiogenesis on coronary angiography is a marker for accelerated cardiac allograft vasculopathy as assessed by intravascular ultrasound.

BACKGROUND: Errant neovascularization and coronary artery fistulae (CAF) are frequently observed after cardiac transplantation. The relationship between angiographic neovascularization/CAF and coronary plaque progression is unknown. METHODS: Angiography and intravascular ultrasound were routinely performed at 4-6 weeks and 1-year post-transplant. Pts were divided into three groups: no angiographic angiogenesis (Group 1), neovascularization only (Group 2), and CAF (Group 3). First-year changes in maximal intimal thickness (MIT), maximal intimal area (MIA), and percent atheroma volume (PAV) were compared between groups. RESULTS: The 106 pts were included, 40/106 in Group 1, 42/106 in Group 2, and 24/106 in Group 3. Respectively, first-year ΔMIT was 0.14 ± 0.13 mm, 0.32 ± 0.26 mm, and 0.50 ± 0.34 mm, P < .001. ΔMIA was 0.6 ± 0.6 mm2 , 1.7 ± 1.8 mm2 , and 3.0 ± 2.6 mm2 , P < .001. ΔPAV was 2.3 ± 2.5%, 6.0 ± 5.1%, and 9.6 ± 9.0%, P < .001. Rapid plaque progression occurred in 1/40 (2.5%) pts in Group 1, 12/42 (28.6%) in Group 2, and 12/24 (50%) in Group 3, P < .001. Multivariate analysis identified both antithymocyte globulin and presence of CAF as independently associated with rapid plaque progression: OR 0.29 (P = .038) and 4.04 (P = .014). CONCLUSION: Neovascularization and CAF are commonly present on surveillance angiography after cardiac transplantation and may signify amplified angiogenesis. Their presence is associated with accelerated coronary plaque progression by IVUS.

Chagas disease in solid organ and heart transplantation.

PURPOSE OF REVIEW: The diagnosis and management of acute and chronic infections with the microorganism Trypanosoma cruzi, which causes Chagas disease, is important in solid organ transplantation in both endemic and nonendemic countries. In this review, we examine recently published data on the topic of Chagas disease in solid organ transplantation, with an emphasis on data relevant to heart transplantation. RECENT FINDINGS: Most people with chronic T. cruzi infection have the intermediate form of disease, but approximately 2% of infected persons will progress to Chagas cardiomyopathy per year. The risk of T. cruzi transmission with liver or kidney transplantation appears to be substantially less than that with heart transplantation. For patients with Chagas cardiomyopathy undergoing heart transplant, a structured clinical and laboratory monitoring protocol is necessary to monitor for T. cruzi reactivation. Recent data indicate that laboratory monitoring of peripheral blood with polymerase chain reaction testing can identify reactivation prior to the occurrence of symptoms and allograft injury. SUMMARY: Transplant clinicians should exercise vigilance in surveillance for Chagas disease in both organ donors and recipients. Although Chagas disease may seem uncommon, it is pervasive in endemic and several nonendemic countries, including the United States and Spain.