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.

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.

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.

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.

IgM marks persistent IgG anti-human leukocyte antigen antibodies in highly sensitized heart transplant patients.

BACKGROUND: Sensitization to human leukocyte antigens (HLA) is a persistent problem in heart transplant (HT) candidates. We sought to characterize the anti-HLA antibody and circulating B cell repertoire in a cohort of highly sensitized HT candidates. METHODS: We assessed immunoglobulin G (IgG) and immunoglobulin M (IgM) anti-HLA antibodies using Luminex single antigen bead assays in a cohort of 11 highly sensitized (HS; calculated panel reactive antibody ≥ 90%) and 3 mildly sensitized (MS) candidates. We also performed B cell receptor repertoire sequencing (BCRseq) in HS candidates and 33 non-candidate controls. HLA antibody strength was measured by mean fluorescence intensity (MFI). RESULTS: We found that IgM anti-HLA antibodies were present in all HS candidates, but with a lower breadth and strength as compared to IgG. When anti-HLA IgG specificities intersected with IgM, binding strength was higher. In contrast, there were IgM but no intersecting IgG specificities for the MS group. In four candidates in the HS group, IgG anti-HLA antibodies decreased in both breadth and strength after HT, but the decrease in strength was smaller if the IgG possessed a specificity that intersected with pre-transplant IgM. BCRseq revealed larger B cell clonotypes in HS candidates but similar diversity as compared to controls. CONCLUSIONS: IgM marks IgG anti-HLA antibodies with higher strength before HT and persistence after HT. The presence of IgM intersecting IgG for an anti-HLA specificity may be a useful approach to determine which donor HLA should be avoided for a sensitized candidate.

ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. Methods: We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Results: Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

Detection and management of HLA sensitization in candidates for adult heart transplantation.

Heart transplantation (HT) remains the preferred therapy for patients with advanced heart failure. However, for sensitized HT candidates who have antibodies to human leukocyte antigens , finding a suitable donor can be challenging and can lead to adverse waitlist outcomes. In recent years, the number of sensitized patients awaiting HT has increased likely due to the use of durable and mechanical circulatory support as well as increasing number of candidates with underlying congenital heart disease. This State-of-the-Art review discusses the assessment of human leukocyte antigens antibodies, potential desensitization strategies including mechanisms of action and specific protocols, the approach to a potential donor including the use of complement-dependent cytotoxicity, flow cytometry, and virtual crossmatches, and peritransplant induction management.

Atypical cardiac amyloidosis phenotypes identified at transplant: a case series.

Background: Transthyretin amyloidosis (TTR) is increasingly implicated as an aetiology of advanced cardiomyopathy. Typically, both genetic variant (TTRv) and wild-type (TTRwt) amyloidosis present with a restrictive phenotype. We present a series of three patients who were found to have cardiac amyloidosis on explant following heart transplant (HT) who had atypical, non-restrictive phenotypes. Case Summary: All three patients were men, three were Black, and only one had an alternative pre-HT explanation for their advanced, dilated cardiomyopathy. Pre-HT transthoracic echocardiograms were notable for left ventricular (LV) dilation (>95th percentile for height and gender), low EF, and normal LV wall thickness. Explants showed varying amounts of amyloid deposition, ranging from diffuse biventricular patterns to perivascular involvement. Mass spectrometry confirmed the presence of TTRv (two cases) and TTRwt (one case). Discussion: Patients with dilated cardiomyopathy may harbour cardiac amyloidosis. Uncertainty remains regarding the contribution of amyloidosis to the development of a dilated phenotype. The pathogenic Val142Ile variant seen in two of these patients, a variant common in Black patients, suggests a need for further investigation into the potential relationship between TTRv amyloidosis and dilated cardiomyopathy.

Assessment and management of allosensitization following heart transplant in adults.

Immunological injury to the allograft, specifically by antibodies to de novo donor specific human leukocyte antigen (dnDSA) and antibody mediated injury and rejection are the major limitations to graft survival after heart transplantation (HT). As such, our approach to allosensitization remains limited by the inability of contemporaneous immunoassays to unravel pathogenic potential of dnDSA. Additionally, the role of dnDSA is continuously evaluated with emerging methods to detect rejection. Moreover, the timing and frequency of dnDSA monitoring for early detection and risk mitigation as well as management of dnDSA remain challenging. A strategic approach to dnDSA employs diagnostic assays to determine relevant antibodies in conjunction with clinical presentation and injury/rejection of allograft to tailor therapeutics. In this review, we aim to outline contemporary knowledge involving detection, monitoring and management of dnDSA after HT. Subsequently, we propose a diagnostic and therapeutic approach that may mitigate morbidity and mortality while balancing adverse reactions from pharmacotherapy.

Donor hyperoxia is a novel risk factor for severe cardiac primary graft dysfunction.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). Donor risk factors for the development of PGD are incompletely characterized. Donor management goals (DMG) are predefined critical care endpoints used to optimize donors. We evaluated the relationship between DMGs as well as non-DMG parameters, and the development of PGD after HT. METHODS: A cohort of HT recipients from 2 transplant centers between 1/1/12 and 12/31/19 was linked to their respective donors in the United Network for Organ Sharing (UNOS) DMG Registry (n = 1,079). PGD was defined according to modified ISHLT criteria. Variables were subject to univariate and multivariable multinomial modeling with development of mild/moderate or severe PGD as the outcome variable. A second multicenter cohort of 4,010 donors from the DMG Registry was used for validation. RESULTS: Mild/moderate and severe PGD occurred in 15% and 6% of the cohort. Multivariable modeling revealed 6 variables independently associated with mild/moderate and 6 associated with severe PGD, respectively. Recipient use of amiodarone plus beta-blocker, recipient mechanical circulatory support, donor age, donor fraction of inspired oxygen (FiO2), and donor creatinine increased risk whereas predicted heart mass ratio decreased risk of severe PGD. We found that donor age and FiO2 ≥ 40% were associated with an increased risk of death within 90 days post-transplant in a multicenter cohort. CONCLUSIONS: Donor hyperoxia at heart recovery is a novel risk factor for severe primary graft dysfunction and early recipient death. These results suggest that excessive oxygen supplementation should be minimized during donor management.

Three year post heart transplant outcomes of desensitized durable mechanical circulatory support patients.

BACKGROUND: The risks and benefits of desensitization therapy (DST) in highly sensitized mechanical circulatory support (MCS) patients are not well known. We investigated 3 year post-transplant outcomes of desensitized durable MCS patients. METHODS: Among 689 consecutively enrolled heart transplantation recipients between 2010 and 2016, we categorized them into Group A (desensitized MCS patients, n = 21), Group B (desensitized non-MCS patients, n = 28) and Group C (all nondesensitized patients, n = 640). Post-transplant outcomes included the incidence of primary graft dysfunction, 3-year survival, freedom from cardiac allograft vasculopathy, nonfatal major adverse cardiac events, any treated rejection, acute cellular rejection, antibody mediated rejection (AMR) and infectious complications. RESULTS: The types of DST in Groups A and B were similar and included combinations of rituximab/intravenous immunoglobulin and plasmapheresis/bortezomib. Group A, compared with Group B, showed significantly higher pre-DST panel reactive antibody (PRA) (92.2 ± 9.8 vs. 83.3 ± 15.6, P = 0.007) and higher PRA reduction after DST (-22.2 ± 26.9 vs. -6.3 ± 7.5, P = 0.015). Groups A and C showed comparable primary graft dysfunction, 3-year survival, freedom from cardiac allograft vasculopathy, nonfatal major adverse cardiac events, any treated rejection, acute cellular rejection, and AMR. Although statistically not significant, Group A showed numerically higher 3-year freedom from AMR than Group B. Infectious complications were similar in both Groups A and B. CONCLUSIONS: DST for MCS patients showed significant PRA reduction, resulting in an expansion of the donor pool. The post-transplant outcome of desensitized MCS patients showed comparable clinical outcomes to non-desensitized control patients in the same study period, revealing the safety and efficacy of DST.

Heart Transplant in Older Adults.

Purpose of Review: Older adults with end-stage heart failure may be candidates for heart transplantation (HT) and changing guidelines and institutional policies have increased the availability of HT for septuagenarians. This review explores historical, pre-HT evaluation, and post-HT outcomes for older adult HT recipients. Recent Findings: Rates of HT in older adults have increased in the past decade and more than 800 septuagenarians have undergone HT. Older adult HT recipients have similar survival, rehospitalization, and graft failure rates when compared to younger patients despite additional comorbidities and higher risk donors. Summary: HT is feasible in carefully selected older adults. As the number of older adults who are considered for HT increases, additional research into population-specific assessment tools will be needed. Furthermore, age-related immune changes warrant population-specific studies on immunosuppressive regimens.

Dapsone-Associated Anemia in Heart Transplant Recipients with Normal Glucose-6-Phosphate Dehydrogenase Activity.

Dapsone is considered an alternative for pneumocystis jirovecii pneumonia (PJP) prophylaxis in sulfa-allergic or -intolerant transplant patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Despite normal G6PD activity, anemia can still occur while on dapsone therapy. We retrospectively reviewed heart transplant patients transplanted at our center between January 2016 and June 2018 and identified those taking dapsone prophylaxis. There were 252 heart transplant recipients at our center between January 2016 and June 2018. 36 patients received dapsone prophylaxis. All had normal G6PD activity assessed prior to dapsone initiation. 8 (22%) patients developed significant anemia attributed to dapsone: 2 were hospitalized for anemia, 1 of whom required blood transfusion. These patients had a median reduction in hemoglobin of 2.1 g/dL from baseline prior to dapsone initiation. Overt evidence of hemolysis was present in six patients. Once dapsone was discontinued, Hgb increased by at least 2 g/dL in a median of 30 days. Anemia from dapsone may occur in a significant proportion of patients despite normal G6PD activity and resulting in significant morbidity. Careful monitoring of transplant recipients on dapsone prophylaxis is warranted, as well as consideration of alternative agents.

HLA Homozygosity and Likelihood of Sensitization in Kidney Transplant Candidates.

Background: Homozygosity for HLAs has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization. Methods: We measured sensitization using the calculated panel reactive antibody value for a large cohort of 147 461 patients added to the US OPTN/United Network for Organ Sharing kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62 510 sensitized patients to 84 955 unsensitized controls. Results: We found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within mildly, highly, or extremely sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared with men, with attenuation of this effect in Black candidates. In a multivariable logistic model, the number of homozygous HLA loci interacted with female sex but not with other factors associated with sensitization, including recipient ethnicity and a history of prior kidney transplant. Conclusions: This study shows that HLA homozygosity is an innate genetic factor that affects the likelihood of HLA sensitization. Further research is needed to identify the immunologic mechanisms that underlie this observation.