Faculty Bibliography

BACKGROUND/UNASSIGNED:Fewer minoritized patients with end-stage kidney disease (ESKD) receive kidney transplantation (KT); efforts to mitigate disparities have thus far failed. Pinpointing the specific stage(s) within the transplant care continuum (being informed of KT options, joining the waiting list, to receiving KT) where disparities emerge among each minoritized population is pivotal for achieving equity. We therefore quantified racial and ethnic disparities across the KT care continuum. METHODS/UNASSIGNED:We conducted a retrospective cohort study (2015-2020), with follow-up through 12/10/2021. Patients with incident dialysis were identified using the US national registry data. The exposure was race and ethnicity (Asian, Black, Hispanic, and White). We used adjusted modified Poisson regression to quantify the adjusted prevalence ratio (aPR) of being informed of KT, and cause-specific hazards models to calculate adjusted hazard ratios (aHR) of listing, and transplantation after listing. FINDINGS/UNASSIGNED:Among 637,951 adults initiating dialysis, the mean age (SD) was 63.8 (14.6), 41.8% were female, 5.4% were Asian, 26.3% were Black, 16.6% were Hispanic, and 51.7% were White (median follow-up in years [IQR]:1.92 [0.97-3.39]). Black and Hispanic patients were modestly more likely to be informed of KT (Black: aPR = 1.02, 95% confidence interval [CI]:1.01-1.02; Hispanic: aPR = 1.03, 95% CI: 1.02-1.03) relative to White patients. Asian patients were more likely to be listed (aHR = 1.18, 95% CI: 1.15-1.21) but less likely to receive KT (aHR = 0.56, 95% CI: 0.54-0.58). Both Black and Hispanic patients were less likely to be listed (Black: aHR = 0.87, 95% CI: 0.85-0.88; Hispanic: aHR = 0.85, 95% CI: 0.85-0.88) and receive KT (Black: aHR = 0.61, 95% CI: 0.60-0.63; Hispanic: aHR = 0.64, 95% CI: 0.63-0.66). INTERPRETATION/UNASSIGNED:Improved characterization of the barriers in KT access specific to each racial and ethnic group, and the interventions to address these distinct challenges throughout the KT care continuum are needed; our findings identify specific stages most in need of mitigation. FUNDING/UNASSIGNED:National Institutes of Health.

BACKGROUND/UNASSIGNED:Prioritization of HLA antigen-level matching in the US kidney allocation system intends to improve post-transplant survival but causes racial disparities and thus has been substantially de-emphasized. Recently, molecular matching based on eplets has been found to improve risk stratification compared to antigen matching. METHODS/UNASSIGNED:To assign eplets unambiguously, we utilized a cohort of 5193 individuals with high resolution allele-level HLA genotypes from the National Kidney Registry. Using repeated random sampling to simulate donor-recipient genotype pairings based on the ethnic composition of the historical US deceased donor pool, we profiled the percentage of well-matched donors for candidates by ethnicity. RESULTS/UNASSIGNED:The percentage of well-matched donors with zero-DR/DQ eplet mismatch was 3-fold less racially disparate for Black and Asian candidates than percentage of donors with zero-ABDR antigen mismatches, and 2-fold less racially disparate for Latino candidates. For other HLA antigen and eplet mismatch thresholds, the percentage of well-matched donors was more similar across candidate ethnic groups. CONCLUSIONS/UNASSIGNED:Compared to the current zero-ABDR antigen mismatch, prioritizing a zero-DR/DQ eplet mismatch in allocation would decrease racial disparities and increase the percentage of well-matched donors. High resolution HLA deceased donor genotyping would enable unambiguous assignment of eplets to operationalize molecular mismatch metrics in allocation. KEY POINTS/UNASSIGNED:

BACKGROUND/UNASSIGNED:In initial COVID-19 clinical trials, menstrual health was not formally monitored, yet anecdotal reports of menstruation changes surfaced on social media. This study aims to assess the association between COVID-19 vaccines and menstruation using Clue, a period-tracking application. STUDY DESIGN/UNASSIGNED:-test compared the mean of these changes between vaccinated and unvaccinated groups. RESULTS/UNASSIGNED:Of 7,559 participants, 6,897 (91 %) were vaccinated. Compared to PRIOR, individuals vaccinated during their menstrual period demonstrated a statistically significant increase in the DURING period length, but not AFTER1 (p = 0.463) and AFTER2 (p = 0.692). No statistically significant changes were observed in period lengths of those vaccinated in between periods or in cycle lengths overall. CONCLUSION/UNASSIGNED:A small but statistically significant change in period length was observed only in individuals vaccinated for COVID-19 during their menstrual period. Providers can better counsel menstruating individuals to reduce vaccine misinformation.

BACKGROUND/UNASSIGNED:Real-world evidence of coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) booster effectiveness among patients with immune dysfunction are limited. METHODS/UNASSIGNED:We included data from patients in the United States National COVID Cohort Collaborative (N3C) who completed ≥2 doses of mRNA vaccination between 10 December 2020 and 27 May 2022. Immune dysfunction conditions included human immunodeficiency virus infection, solid organ or bone marrow transplant, autoimmune diseases, and cancer. We defined incident COVID-19 BTI as positive results from laboratory tests or diagnostic codes 14 days after at least 2 doses of mRNA vaccination; and severe COVID-19 BTI as hospitalization, invasive cardiopulmonary support, and/or death. We used propensity scores to match boosted versus nonboosted patients and evaluated hazards of incident and severe COVID-19 BTI using Cox regression after matching. RESULTS/UNASSIGNED:Among patients without immune dysfunction, the relative effectiveness of booster (3 doses) after 6 months from the primary (2 doses) vaccination against BTI ranged from 69% to 81% during the Delta-predominant period and from 33% to 39% during the Omicron-predominant period. Relative effectiveness against BTI was lower among patients with immune dysfunction but remained statistically significant in both periods. Boosted patients had lower risk of COVID-19-related hospitalization (hazard ratios [HR] ranged from 0.5 [95% confidence interval {CI}, .48-.53] to 0.63 [95% CI, .56-.70]), invasive cardiopulmonary support, or death (HRs ranged from 0.46 [95% CI, .41-.52] to 0.63 [95% CI, .50-.79]) during both periods. CONCLUSIONS/UNASSIGNED:Booster vaccines remain effective against severe COVID-19 BTI throughout the Delta- and Omicron-predominant periods, regardless of patients' immune status.

BACKGROUND:Recent clinical trials demonstrate benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with chronic kidney disease, but data on use in kidney transplant (KTx) recipients are limited. METHODS:). RESULTS:vs. prior years). CONCLUSION:SGLT2i use is increasing in KTx recipients but varies with factors including race, education, and insurance. While ongoing study is needed to define risks and benefits of SGLT2i use in KTx patients, attention should also focus on reducing treatment disparities related to sociodemographic traits.

UNLABELLED:Solid organ transplant recipients (SOTRs) suffer more frequent and more severe infections due to their compromised immune responses resulting from immunosuppressive treatments designed to prevent organ rejection. Pharmacological immunosuppression can adversely affect immune responses to vaccination. A cohort of kidney transplant recipients (KTRs) received their third dose of ancestral, monovalent COVID-19 vaccine in the context of a clinical trial and antibody responses to the vaccine strain, as well as to Omicron variants BA.1 and BA.5 were investigated and compared with healthy controls. Total IgG and live virus neutralizing antibody titers were reduced in KTRs compared to controls for all variants. KTRs displayed altered IgG subclass switching, with significantly lower IgG3 antibodies. Responses in KTRs were also very heterogeneous, with some individuals showing strong responses but a significant number showing no Omicron-specific neutralizing antibodies. Taken together, immune responses after COVID-19 vaccination in KTRs were not only lower than healthy controls but highly variable, indicating that simply increasing the number of vaccine doses alone may not be sufficient to provide greater protection in this population. IMPORTANCE/UNASSIGNED:This study addresses the challenges faced by kidney transplant recipients (KTRs) in mounting effective immune responses against COVID-19. By evaluating the antibody responses to a third dose of monovalent mRNA COVID-19 vaccine and its effectiveness against Omicron subvariants (BA.1 and BA.5), this study reveals significant reductions in both binding and neutralizing antibodies in KTRs compared to healthy controls. The research highlights altered IgG subclass switching and heterogeneous responses within the KTR population. Reduced recognition of variants, coupled with differences in IgG subclasses, decreases both the quality and quantity of protective antibodies after vaccination in KTRs. These findings underscore the need for tailored vaccination strategies for immunosuppressed populations such as KTRs. Alternative formulations and doses of COVID-19 vaccines should be considered for people with severely compromised immune systems, as more frequent vaccinations may not significantly improve the response, especially regarding neutralizing antibodies.

BACKGROUND/UNASSIGNED:Among heart transplant candidates, atrial fibrillation (AF) is a common comorbidity; however, little is known about the impact of pre-transplant AF on incidence of post-transplant AF or other transplant outcomes. METHODS/UNASSIGNED:Adult heart transplant recipients transplanted from 07/01/2012 to 07/01/2021 with data available in both the Scientific Registry of Transplant Recipients and Symphony Health pharmacy databases were included. Recipients were categorized by presence of pre-transplant AF using prescription fill data. Perioperative outcomes and survival out to 5 years post-transplant were compared between those with and without pre-transplant AF. RESULTS/UNASSIGNED:Of the 11,789 heart transplant recipients, 2,477 (21.0%) had pre-transplant AF. Pre-transplant AF was associated with an increased likelihood of pre-discharge stroke (aOR 2.13 [95%CI: 1.07-4.26], p=0.03) and dialysis (aOR 1.45 [1.05-2.00], p=0.02), as well as of post-transplant AF at 6 months (aOR 2.42 [1.44-1.48], p=0.001) and 1 year (aOR 2.81 [1.72-4.56], p<0.001). Pre-transplant AF was associated with increased post-transplant mortality at 30 days (aHR 2.39 [1.29-4.44], p=0.006) and 1 year (aHR 1.46 [95% CI: 1.01-2.13], p=0.04), but similar mortality at 5 years (aHR 1.23 [0.96-1.58], p=0.11). CONCLUSION/UNASSIGNED:Heart transplant recipients with pre-transplant AF had worse short-term outcomes and increased risk of developing post-transplant AF but comparable survival at 5 years post-transplant. Our findings emphasize the importance of increased monitoring for perioperative complications and highlight the long-term safety of heart transplantation in this population. WHAT IS NEW?/UNASSIGNED:Patients with atrial fibrillation who undergo heart transplantation have worse short term survival (30-days and 1-year) but similar long term survival (5-years) compared to recipients without pre-transplant atrial fibrillation.Pre-transplant atrial fibrillation increases the risk of clinically significant post-transplant atrial fibrillation and peri-operative stroke.Rate vs rhythm control pharmacotherapy for atrial fibrillation is not associated with differences in survival in heart transplant recipients with pre-transplant atrial fibrillation. WHAT ARE THE CLINICAL IMPLICATIONS?/UNASSIGNED:Atrial fibrillation should not deter heart transplantation in appropriate candidates, though cardiovascular and stroke risk adjustment may be warranted.Use of amiodarone at doses ≤ 200 mg/day is not associated with reduced survival in heart transplant recipients with pre-transplant atrial fibrillation.

BACKGROUND:Evidence suggests that older patients are less frequently placed on the waiting list for kidney transplantation (KT) than their younger counterparts. The trends and magnitude of this age disparity in access to first KT and repeat KT (re-KT) remain unclear. METHODS:Using the US Renal Data System, we identified 2 496 743 adult transplant-naive dialysis patients and 110 338 adult recipients with graft failure between 1995 and 2018. We characterized the secular trends of age disparities and used Cox proportional hazard models to compare the chances of listing and receiving first KT versus re-KT by age (18-64 y versus ≥65 y). RESULTS:Older transplant-naive dialysis patients were less likely to be listed (adjusted hazard ratio [aHR] = 0.18; 95% confidence interval [CI], 0.17-0.18) and receive first KT (aHR = 0.88; 95% CI, 0.87-0.89) compared with their younger counterparts. Additionally, older patients with graft failure had a lower chance of being listed (aHR = 0.40; 95% CI, 0.38-0.41) and receiving re-KT (aHR = 0.76; 95% CI, 0.72-0.81). The magnitude of the age disparity in being listed for first KT was greater than that for re-KT ( Pinteraction  < 0.001), and there were no differences in the age disparities in receiving first KT or re-KT ( Pinteraction  = 0.13). Between 1995 and 2018, the age disparity in listing for first KT reduced significantly ( P  < 0.001), but the age disparities in re-KT remained the same ( P  = 0.16). CONCLUSIONS:Age disparities exist in access to both first KT and re-KT; however, some of this disparity is attenuated among older adults with graft failure. As the proportion of older patients with graft failure rises, a better understanding of factors that preclude their candidacy and identification of appropriate older patients are needed.

Immune responses to COVID-19 vaccination are attenuated in adult solid organ transplant recipients (SOTRs) and additional vaccine doses are recommended for this population. However, whether COVID-19 mRNA vaccine responses are limited in pediatric SOTRs (pSOTRs) compared to immunocompetent children is unknown. Due to SARS-CoV-2 evolution and mutations that evade neutralizing antibodies, T cells may provide important defense in SOTRs who mount poor humoral responses. Therefore, we assessed anti-SARS-CoV-2 IgG titers, surrogate neutralization, and spike (S)-specific T-cell responses to COVID-19 mRNA vaccines in pSOTRs and their healthy siblings (pHCs) before and after the bivalent vaccine dose. Despite immunosuppression, pSOTRs demonstrated humoral responses to both ancestral strain and Omicron subvariants following the primary ancestral strain monovalent mRNA COVID-19 series and multiple booster doses. These responses were not significantly different from those observed in pHCs and significantly higher six months after vaccination than responses in adult SOTRs two weeks post-vaccination. However, pSOTRs mounted limited S-specific CD8⁺ T-cell responses and qualitatively distinct CD4⁺ T-cell responses, primarily producing IL-2 and TNF with less IFN-γ production compared to pHCs. Bivalent vaccination enhanced humoral responses in some pSOTRs but did not shift the CD4⁺ T-cell responses toward increased IFN-γ production. Our findings indicate that S-specific CD4⁺ T cells in pSOTRs have distinct qualities with unknown protective capacity, yet vaccination produces cross-reactive antibodies not significantly different from responses in pHCs. Given altered T-cell responses, additional vaccine doses in pSOTRs to maintain high titer cross-reactive antibodies may be important in ensuring protection against SARS-CoV-2.

INTRODUCTION/UNASSIGNED:Uremic toxins contributing to increased risk of death remain largely unknown. We used untargeted metabolomics to identify plasma metabolites associated with mortality in patients receiving maintenance hemodialysis. METHODS/UNASSIGNED:We measured metabolites in serum samples from 522 Longitudinal US/Canada Incident Dialysis (LUCID) study participants. We assessed the association between metabolites and 1-year mortality, adjusting for age, sex, race, cardiovascular disease, diabetes, body mass index, serum albumin, Kt/Vurea, dialysis duration, and country. We modeled these associations using limma, a metabolite-wise linear model with empirical Bayesian inference, and 2 machine learning (ML) models: Least absolute shrinkage and selection operator (LASSO) and random forest (RF). We accounted for multiple testing using a false discovery rate (pFDR) adjustment. We defined significant mortality-metabolite associations as pFDR < 0.1 in the limma model and metabolites of at least medium importance in both ML models. RESULTS/UNASSIGNED:limma. CONCLUSION/UNASSIGNED:Quinolinate and mesaconate were significantly associated with a 1-year risk of death in incident patients receiving maintenance hemodialysis. External validation of our findings is needed.