Faculty Bibliography

BACKGROUND:Fewer than 20% of donated lungs are transplanted. We examined the impacts of donor management and recovery at an in-hospital donor care unit (DCU) established in 2021 versus the donor hospital (DH). METHODS:(P/F ratio) were examined as a hypothesized effect modifier. We projected the national impact of improved utilization on lung transplant volume. RESULTS:After adjusting for donor differences, lung utilization was 88% higher (aRR: 1.88; 95% CI: 1.40, 2.53) in the DCU versus DH setting. Median P/F ratio increased from 275 to 348 mmHg (p<0.0001) in the DCU and explained approximately 38% of the improvement in lung utilization. Non-lung organ utilization was either improved or non-inferior in the DCU. Lung graft survival and pulmonary function were similar for recipients of DCU versus DH-managed donors. Nationally, an 88% improvement in lung utilization among donors not currently transferred to a DCU could theoretically result in ≥300 more lung transplants per year. CONCLUSIONS:Lung transplantation can be nearly doubled through lung-centric donor management in a DCU, without sacrificing recipient outcomes nor the utilization of other organs. Donor management practices to optimize lung utilization should be proliferated by establishing more DCUs and, where feasible, applying lung-centric protocols in donor hospitals.

People with HIV have higher risk for rejection after kidney transplantation but the mechanism is poorly understood. As HIV latency promotes immune dysregulation and chronic inflammation, we evaluated whether the size of the HIV latent viral reservoir (LVR) at baseline and through 52-weeks is associated with rejection in kidney transplant recipients with HIV from donors with and without HIV. Using the intact proviral DNA assay, we found no differences in the LVR between those who experienced rejection (n=14) versus those who did not (N=55) regardless of donor HIV status. These data support the feasibility of HIV+ to HIV+ organ transplantation. Clinical Trials Registration. NCT03500315.

BACKGROUND:Transplanting kidneys from donors with HIV to recipients with HIV has become standard clinical practice. However, donors with HIV may have higher prevalence of viral and bacterial infections and autoimmunity that could increase allograft rejection in recipients. METHODS:We included deceased kidney donors (60 with HIV and 41 without HIV) who participated in a multicenter prospective study of HIV kidney transplantation between April 2018-September 2021. Using Phage ImmunoPrecipitation Sequencing, we compared the human antibody repertoire (allergens, autoantibodies, viruses and bacterial toxins) between donors with and without HIV, and evaluated their association with recipient allograft rejection. Moderated t-tests were used to assess reactivity and a multivariate logistic regression model adjusted for donor sex and KDPI assessed the association between donor adenovirus reactivity and recipient allograft rejection. RESULTS:Compared to donors without HIV, donors with HIV had lower BMI and were more likely to be African American. The median number of positive autoantibodies was marginally higher among donors with HIV (499 [IQR = 357, 579]) compared to donors without HIV (395 [IQR = 256, 538] (P = 0.058). Donors with HIV additionally had significantly higher antibody reactivity to Epstein-Barr virus and cytomegalovirus (q < 0.05). Among all donors with and without HIV, antibodies to adenovirus were significantly associated with increased rejection among recipients, including after adjusting for false discovery (q < 0.05) and also adjusting for demographic factors using multivariable logistic regression (odds ratio = 4.97, 95% CI = 1.89-13.61). CONCLUSION/CONCLUSIONS:The presence of antibodies to adenovirus infection in kidney donors with HIV may be associated with allograft rejection. CLINICALTRIALS/RESULTS:gov NCT03500315. FUNDING/BACKGROUND:US National Institute of Health.

BACKGROUND:Kidney transplantation (KT) from donors with human immunodeficiency virus (HIV-1) to recipients with HIV (HIV D+/R+) is noninferior to KT from donors without HIV (HIV D-/R+) with regard to safety. However, there may be differences in posttransplant infections. METHODS:We performed a secondary analysis of the HOPE in Action KT Study (NCT02602262) comparing the time to first clinically relevant infection within 24 months posttransplantation in 99 HIV D+/R+ versus 99 HIV D-/R+. Secondary outcomes included incidence rates, infection-related death, and timing of clinically relevant infection, each stratified by donor HIV status. RESULTS:The cumulative incidence of a clinically relevant infection at 24 months posttransplantation was 73.8% (95% confidence interval [CI]: 63.1%-81.2%) for HIV D+/R+ versus 64.7% (95% CI: 53.0%-73.4%) for HIV D-/R+. Comparing time to first clinically relevant infection in HIV D+/R+ versus HIV D-/R+, the adjusted hazard ratio (aHR) was 1.44 (95% CI: 1.01-2.04) at 24 months posttransplantation; for infections associated with hospitalization, the aHR was not significantly higher (1.21 [95% CI: .78-1.86). There were no significant differences in the number of infections, death from infection, duration, or site of infection between HIV D+/R+ versus HIV D-/R+, though viral infections were numerically more common in HIV D+/R+ (40% vs 35%). CONCLUSIONS:Although there was a statistically significant association between receipt of a kidney from a donor with HIV and time to first clinically relevant infection in the 24 months posttransplantation, there were no differences in infections associated with hospitalization. These data are overall reassuring as this emerging practice expands into clinical care. Clinical Trials Registration. NCT02602262.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

Historically, liver transplant (LT) candidates with human immunodeficiency virus (HIV) have experienced high waitlist mortality. Since the HIV Organ Policy Equity (HOPE) Act expands access to organs from donors with HIV, we assessed the impact of HOPE on LT rate and wait time for this population. We linked data from a multicenter HOPE in Action study to Scientific Registry of Transplant Recipients (February 21, 2019 to June 1, 2024) and used Poisson regression to compare transplant rates among 99 candidates willing to accept HOPE donors (HOPE candidates) to 13 495 candidates with or without HIV not listed as willing to accept HOPE donors (non-HOPE candidates) matched on transplant center. The median time to any deceased donor liver transplant (DDLT) was 2.3 months for HOPE and 1.1 years for non-HOPE candidates. Within 2 years of listing, 90.9% of HOPE versus 58.5% of non-HOPE candidates received a DDLT (P < .001). HOPE was associated with an overall 3.11-fold higher DDLT incident rate ratio (95% CI 2.48-3.88, P < .001). Stratified by model for end-stage liver disease score categories 6 to 14, 15 to 24, 25 to 34, and 35 to 40/status 1; HOPE candidates had 10.12-fold, 5.31-fold, 1.41-fold and 2.90-fold higher DDLT rates, respectively. Willingness to accept livers from donors with HIV improves access to liver transplantation for candidates with HIV.