Faculty Bibliography

INTRODUCTION/BACKGROUND:Obesity prevalence has dramatically increased; candidates with obesity have higher waitlist mortality and are less likely to undergo liver transplantation. The association of obesity with post-transplant mortality is inconsistent. MATERIALS AND METHODS/METHODS:. Risks of waitlist and post-transplant mortality were quantified using adjusted competing risks and Cox proportional hazards. RESULTS:Of 103,640 candidates and 58,692 recipients, candidates with higher obesity classes had higher listing MELD that increased over time. Candidates with class III obesity were listed and transplanted at higher MELD compared to candidates without obesity, class I and II obesity; nearly 40% of candidates with class III obesity had listing MELD≥30. From 2013-2017 to 2018-2023, waitlist mortality decreased 35% in candidates with class III obesity (SHR:0.65(0.58-0.73),p<0.001) and post-transplant mortality decreased 20% for recipients with class III obesity (HR:0.80(0.66-0.96),p=0.02). However, over time, post-transplant mortality differed by obesity class with no reduction in post-transplant mortality for recipients with class I or II obesity. CONCLUSION/CONCLUSIONS:Candidates and recipients with class III obesity are being listed and transplanted at higher MELD scores with improvement in outcomes over time. Although higher risk, temporal trends for LT in this population are favorable. Given the higher disease severity at listing for candidates with class III obesity, referral patterns for LT evaluation in these patients should be evaluated.

BACKGROUND AND HYPOTHESIS/OBJECTIVE:Early steroid withdrawal (ESW) is often preferred over conventional steroid maintenance (CSM) therapy for kidney transplant recipients with low immunological risks because it may minimize immunosuppression-related adverse events while achieving similar transplant outcomes. However, the risk-benefit balance of ESW could be less favorable in retransplant recipients given their unique immunological risk profile. We hypothesized that the association of ESW with transplant outcomes would differ between first-transplant and retransplant recipients. METHODS:To assess whether the impact of ESW differs between first and retransplant recipients, we studied 210 086 adult deceased-donor kidney transplant recipients using the Scientific Registry of Transplant Recipients. Recipients who discontinued maintenance steroids before discharge from transplant admission were classified with ESW; all others were classified with CSM. We quantified the association of ESW (vs. CSM) with acute rejection, death-censored graft failure, and death, addressing retransplant as an effect modifier, using logistic/Cox regression with inverse probability weights to control for confounders. RESULTS:In our cohort, 26 248 (12%) were retransplant recipients. ESW was used in 30% of first-transplant and 20% of retransplant recipients. Among first-transplant recipients, ESW was associated with no significant difference in acute rejection (aOR = 1.04 [95% CI = 1.00-1.09]), slightly higher hazard of graft failure (HR = 1.09 [95% CI = 1.05-1.12]), and slightly lower mortality (HR = 0.93 [95% CI = 0.91-0.95]) compared to CSM. Nonetheless, among retransplant recipients, ESW was associated with notably higher risk of acute rejection (OR = 1.42 [95% CI = 1.29-1.57]; interaction p < 0.001) and graft failure (HR = 1.24 [95% CI = 1.14-1.34]; interaction p = 0.003), and similar mortality (HR = 1.01 [95% CI = 0.94-1.08]; interaction p = 0.04). CONCLUSIONS:In retransplant recipients, the negative impacts of ESW on transplant outcomes appear to be non-negligible. A more conservatively tailored approach to ESW might be necessary for retransplant recipients.

BACKGROUND:As the inflammatory bowel disease (IBD) patient population is aging, the prevalence of polypharmacy is rising. However, data exploring the prevalence, risk factors, and clinical outcomes associated with polypharmacy among older adults with IBD are limited. AIMS/OBJECTIVE:To determine (i) prevalence of polypharmacy (≥5 medications) and potentially inappropriate medication (PIM) utilization in older adults with IBD, (ii) changes in medications over time (iii) predictors of polypharmacy, and (iv) the impact of polypharmacy/PIMs on one-year hospitalization rates. METHODS:We conducted a retrospective single-center study of older adults with IBD from September 1st 2011 to December 31st 2022. Wilcoxon-signed rank and McNemar's tests were used to assess changes in polypharmacy between visits, with ordinal logistic regression and Cox proportional hazards models used to determine risk factors for polypharmacy and time to hospitalization, respectively. RESULTS:Among 512 older adults with IBD, 74.0% experienced polypharmacy at initial visit, with 42.6% receiving at least one PIM. Additionally, severe polypharmacy (≥10 medications) was present among 28.6% individuals at index visit and increased to 38.6% by last visit (p<0.01). Multivariable analysis revealed that age ≥70 years, BMI ≥30.0 kg/m2, prior IBD-related surgery, and the presence of comorbidities were associated with polypharmacy. Moreover, severe polypharmacy (adjHR 1.95, 95%CI 1.29-2.92), as well as PIM use (adjHR 2.16, 95%CI 1.37-3.43) among those with polypharmacy, were significantly associated with all-cause hospitalization within a year of index visit. DISCUSSION/CONCLUSIONS:Severe polypharmacy was initially present in more than 25% of older adults with IBD and increased to 34% within 4 years of index visit. Severe polypharmacy, as well as PIM utilization among those with polypharmacy, were also associated with an increased risk of hospitalization at one-year, highlighting the need for deprescribing efforts in this population.

BACKGROUND:HLA-DQ mismatch has been identified as a predictor of de novo donor-specific HLA antibody formation and antibody-mediated rejection. There are insufficient data to guide the incorporation of DQ mismatch into organ allocation decisions. METHODS:We used a retrospective longitudinal cohort of adult living donor kidney transplant recipients from 11 centers across the United States for whom high-resolution class II typing was available. HLA-DQαβ heterodimer allele mismatch was quantified for all donor-recipient pairs, and outcome data were obtained through linkage with the Scientific Registry of Transplant Recipients. RESULTS:We studied 3916 donor-recipient pairs. Recipient characteristics were notable for a median age of 51 (38-61) y, primarily unsensitized, with 74.5% of the cohort having 0% calculated panel-reactive antibody, and 60.4% with private insurance, for a median follow-up time of 5.86 y. We found that the HLA-DQαβ allele and HLA-DR antigen mismatch were each individually associated with an increased hazard of all-cause graft failure (adjusted hazard ratio [aHR] DQ = 1.03 1.14 1.28; aHR DR = 1.03 1.15 1.328), death-censored graft failure (aHR DQ =1.01 1.19 1.40; aHR DR = 0.099 1.18 1.39), and rejection. Having 2 HLA-DQαβ allele mismatches further increased the hazard of rejection even when controlling for HLA-DR mismatch (aHR 1.03 1.68 2.74). CONCLUSIONS:HLA-DQαβ allele mismatch predicted allograft rejection even when controlling for HLA-DR antigen mismatch and were both independently associated with increased risk of graft failure or rejection in adult living kidney transplant recipients. Given the strong burden of disease arising from the HLA-DQ antibody formation, we suggest that HLA-DQαβ should be prioritized over HLA-DR in donor selection.

Developing real-world evidence from electronic health records (EHR) is vital to advance kidney transplantation (KT). We assessed the feasibility of studying KT using the Epic Cosmos aggregated EHR dataset, which includes 274 million unique individuals cared for in 238 U.S. health systems, by comparing it with the Scientific Registry of Transplant Recipients (SRTR). We identified 69,418 KT recipients transplanted between January 2014 and December 2022 in Cosmos (39.4% of all US KT transplants during this period). Demographics and clinical characteristics of recipients captured in Cosmos were consistent with the overall SRTR cohort. Survival estimates were generally comparable, although there were some differences in long-term survival. At 7 years post-transplant, patient survival was 80.4% in Cosmos and 77.8% in SRTR. Multivariable Cox regression showed consistent associations between clinical factors and mortality in both cohorts, with minor discrepancies in the associations between death and both age and race. In summary, Cosmos provides a reliable platform for KT research, allowing EHR-level clinical granularity not available with either the transplant registry or healthcare claims. Consequently, Cosmos will enable novel analyses to improve our understanding of KT management on a national scale.

Solid organ transplant recipients (SOTRs) have heightened risk of adverse COVID-19 outcomes due to immunosuppression and medical comorbidity. We quantified the burden of COVID-19 mortality in US SOTRs. A sample of deaths documented in the US solid organ transplant registry from June 2020 through December 2022 were linked to the National Death Index to identify COVID-19 deaths and weighted to represent all SOTR deaths during the study period. Among 505,757 SOTRs, 57,575 deaths occurred and based on the linkage, 12,396 (21.5%) were due to COVID-19. COVID-19 mortality was higher in males (mortality rate ratio [MRR]: 1.13), SOTRs aged 65 and older (MRR: 1.50 in ages 65-74 vs. ages 55-64), and non-Hispanic Black and Hispanic SOTRs (MRRs: 1.55 and 1.79 vs. non-Hispanic White SOTRs). Kidney and lung recipients had the highest COVID-19 mortality, followed by heart, then liver recipients. COVID-19 mortality also varied over time and across US states. Overall, SOTRs had 7-fold increased risk of COVID-19 death compared to the US general population. SOTRs comprised 0.13% of the US population but accounted for 1.46% of all US COVID-19 deaths. SOTRs experience greatly elevated COVID-19 mortality. Clinicians should continue to prioritize COVID-19 prevention and treatment in this high-risk population.

BACKGROUND:Highly effective modulator therapies (HEMT) including ivacaftor (IVA) and elexacaftor/tezacaftor/ivacaftor (ETI) have transformed treatment for people with cystic fibrosis (pwCF). However, non-HEMT-responsive mutations are more common in pwCF of non-White race/ethnicity; introduction of HEMT might have exacerbated racial/ethnic disparities in CF care. METHODS:Using the Scientific Registry of Transplant Recipients, we identified all lung transplant candidates and recipients 05/2005-12/2022 and categorized them by diagnosis (CF/non-CF), race/ethnicity (non-Hispanic White/Black/Hispanic) and era [Pre-HEMT (2005-1/30/2012), IVA (1/31/2012-10/30/2019), ETI (10/31/2019-12/31/2022)]. We compared the percentage of patients listed, delisted/died, or transplanted by race/ethnicity and era. RESULTS:34,659 lung transplants were performed: 10,521 pre-HEMT, 15,944 in IVA era, and 7,888 in ETI era. Over the three eras, the percentage of lung recipients with CF of White race decreased (94.5 % to 92.4 % to 78.4 %) and of Black race (1.7 % to 2.4 % to 5.7 %) or Hispanic ethnicity increased (3.5 % to 4.6 % to 14.2 %; p < 0.001). Similarly, among candidates listed for CF over the three eras, the percentage that were of White race decreased (82.0 % vs. 78.6 % vs. 71.0 %) and of Black race (9.2 % vs. 10.0 % vs. 10.3 %) or Hispanic ethnicity increased (6.4 % vs. 8.6 % vs. 13.6 %; p < 0.001). CONCLUSION/CONCLUSIONS:The introduction of HEMT appears to have benefitted CF lung transplant candidates and recipients of Black race or Hispanic ethnicity less than those of White race. This is likely due to the higher prevalence of HEMT-ineligible CFTR mutations among Black and Hispanic patients and underscores the need for therapies aimed at non-HEMT-responsive mutations prevalent in these racial/ethnic populations.

RATIONALE & OBJECTIVE/OBJECTIVE:Despite substantial growth in the population of older adults with kidney disease, there remains a lack of evidence to guide clinical care for this group. The Kidney Disease and Aging Research Collaborative (KDARC) conducted a Delphi study to build consensus on research priorities for clinical geriatric nephrology. STUDY DESIGN/METHODS:Asynchronous modified Delphi study. SETTING & PARTICIPANTS/METHODS:Clinicians and researchers in the US and Canada with clinical experience and/or research expertise in geriatric nephrology. OUTCOME/RESULTS:Research priorities in geriatric nephrology. ANALYTICAL APPROACH/METHODS:In the first Delphi round, participants submitted free-text descriptions of research priorities considered important for improving the clinical care of older adults with kidney disease. Delphi moderators used inductive content analysis to group concepts into categories. In the second and third rounds, participants iteratively reviewed topics, selected their top 5 priorities, and offered comments used to revise categories. RESULTS:Among 121 who were invited, 57 participants (47%) completed the first Delphi round and 48 (84% of enrolled participants) completed all rounds. After 3 rounds, the 5 priorities with the highest proportion of agreement were: 1) Communication and Decision-Making about Treatment Options for Older Adults with Kidney Failure (69% agreement), 2) Quality of Life, Symptom Management, and Palliative Care (67%), 3) Frailty and Physical Function (54%), 4) Tailoring Therapies for Kidney Disease to Specific Needs of Older Adults (42%), and 5) Caregiver and Social Support (35%). Health equity and person-centricity were identified as cross-cutting features that informed all topics. LIMITATIONS/CONCLUSIONS:Relatively low response rate and limited participation by private practitioners and older clinicians and researchers. CONCLUSIONS:Experts in geriatric nephrology identified clinical research priorities with the greatest potential to improve care for older adults with kidney disease. These findings provide a roadmap for the geriatric nephrology community to harmonize and maximize the impact of research efforts.

BACKGROUND/UNASSIGNED:With the introduction of sirolimus as medical therapy for lymphangioleiomyomatosis (LAM), an updated evaluation of LAM lung transplant (LT) outcomes and characterization of peritransplant sirolimus use is needed. METHODS/UNASSIGNED:We identified adult LT recipients from 2005-2021 using the Scientific Registry of Transplant Recipients database and stratified by diagnosis (LAM vs other). Multivariable Cox regression was performed to calculate the adjusted hazard ratio for LAM vs other diagnoses. A pharmacy claims database was linked to provide sirolimus prescription information, and a subgroup analysis comparing outcomes with pre- vs posttransplant sirolimus use was performed. RESULTS/UNASSIGNED: = .003). CONCLUSIONS/UNASSIGNED:This study supports lung transplant as a treatment for severe pulmonary LAM and identifies increased mortality associated with pre-LT sirolimus, though this may be due to uncharacterized baseline differences.