Faculty Bibliography

Normothermic machine perfusion (NMP) may increase utilization of non-ideal donor kidneys through improved preservation and assessment. We assessed the use of a centralized perfusion service to rescue declined kidneys for transplant. Kidneys that exhausted standard OPTN allocation underwent 2 hours of NMP for additional assessment. The primary outcome was rescue for transplantation. Outcomes of NMP kidneys were compared to non-NMP kidneys transplanted during the study period at the same transplant centers. NMP was performed on 104 declined kidneys, and 94 (90%) were rescued for transplant. NMP donors were older, with a higher kidney donor profile index (KDPI) compared to non-NMP donors. Cold ischemia time was significantly longer in the NMP cohort (median 37.6 vs. 22.1 hours, p<0.001). The weighted percentage of delayed graft function (DGF) was 26.3% in the NMP group vs 60.2% in the non-NMP group (p=0.023). Overall graft survival was similar between the groups. With the use of a centralized NMP service, kidneys declined based on standard clinical parameters may be evaluated, rescued, and successfully transplanted. Kidneys undergoing NMP experienced significantly lower rates of DGF compared to non-NMP kidneys. Additional follow up is needed to determine the effects of NMP on long-term graft function.

BACKGROUND/UNASSIGNED:Kidney transplant recipients are at risk for adverse health outcomes. Digital health tools such as wearable accelerometers and continuous glucose monitors (CGMs) can provide detailed, noninvasive tracking of health behaviors and measures, such as physical activity, sleep, and glucose levels, that may offer insights into future health concerns, such as posttransplant diabetes mellitus, cognitive health, and transplant rejection. However, there is limited evidence on the feasibility and acceptability of these devices in kidney transplant candidates older than 50 y. METHODS/UNASSIGNED:This observational cross-sectional pilot study aimed to examine the feasibility of 2 digital health tools: an accelerometer and a continuous glucose monitor. Participants were eligible for the study if they were living donor kidney transplant candidates, aged 50 y or older, had no known cognitive impairments, and could provide informed consent. Participants were asked to wear a CGM and an accelerometer for up to 14 d before their kidney transplant surgery. Device feasibility was quantified by (1) the total time the devices were worn, and (2) the validated System Usability Scale survey administered after the devices were returned. RESULTS/UNASSIGNED:20 participants enrolled in the study (mean age 64 ± 9 y, 25% women, 40% with type 2 diabetes). The median number of days of accelerometer and CGM wear were 7 (interquartile range, 6-10) d and 7 (interquartile range, 7-10) d, respectively. Ninety percent of participants reported a favorable opinion of both devices. Participants wore the CGM 100% of the time and the accelerometer 90% of the time, indicating high adherence. CONCLUSIONS/UNASSIGNED:The use of digital devices was acceptable among kidney transplant candidates aged older than 50 y, paving the way for larger studies to identify early digital biomarkers of health outcomes in this high-risk population.

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.

We sought to understand the potential impacts of a rapidly evolving donor pool on the annual recalibration of the kidney donor profile index (KDPI). Using OPTN data, we examined the kidney donor risk index (KDRI) among deceased kidney donors recovered 2011-2024. We mimicked the OPTN's annual re-mapping process to measure the KDRI-to-KDPI calibration drift and used Cox regression to translate this drift into all-cause graft failure rate differences. The 50th/75th/95th KDRI percentile among recovered donors rose from 1.19/1.47/2.0 in 2011 to 1.40/1.77/2.36 in 2024. For donors with the same KDRI, the KDPI assigned in 2024 was as much as 13 points lower than the KDPI assigned in 2012. Holding other factors constant, the KDRI-KDPI calibration shift equated to 7 years of increased age (65 vs. 58) for KDPI 86% donors. Five-year graft failure risk was 9% higher (RR: _1.0871.093_1.097) for a kidney assigned a KDPI of 86% in 2024 versus 2012. Organ recovery practices have changed. The relationship between KDPI and organ quality has become a moving target, complicating shared decision-making and altering the meaning of allocation policy thresholds. Alternative solutions to annually remapping KDPI, such as establishing a fixed reference cohort or migrating away from KDPI, could be considered.

Older (aged ≥55 years) kidney transplant (KT) recipients diagnosed with a sleep disorder after transplantation may be at increased risk for developing dementia. Using the United States Renal Data System/Medicare claims (2010-2020), we identified 16 573 older KT recipients with a functioning graft 1-year post-KT. First-time sleep disorders and newly prescribed sleep medications were ascertained within the first year post-KT. We used cause-specific hazard models to estimate the adjusted hazard ratio of diagnosed dementia with inverse probability of treatment weights. Overall, 3615 (21.8%) KT recipients were newly diagnosed with sleep disorders. Recipients diagnosed with a sleep disorder had a 1.32-fold increased risk for dementia (95% CI:1.15-1.51); those with insomnia had a 1.56-fold increased risk (95% CI:1.20-2.03). Of those diagnosed with insomnia, only 7.5% underwent cognitive behavioral therapy for insomnia. Of the recipients, 12.9% with a sleep disorder were prescribed sleep medications. Recipients prescribed sleep medication had a 1.44-fold increased risk for dementia (95% CI:1.16-1.77). Those prescribed zolpidem, the most commonly prescribed medication (80.1%), had a 1.41-fold increased risk (95% CI:1.12-1.78) for dementia; those prescribed other sleep medications had 3.13-fold (95% CI:1.41-6.98) increased risk for dementia. Post-KT sleep disorders are modifiable dementia risk factors; medication-associated dementia risk should be weighed against other therapies such as cognitive behavioral therapy for insomnia during management.

BACKGROUND:on dementia may be more severe in this population. METHODS:and dementia risk factors using a Wald test. Models were adjusted for confounders, including social determinants of health. RESULTS:was associated with 1.90-fold higher odds of global cognitive impairment (95% CI: 1.48-2.46), and 3.29-fold higher risk of dementia (95% CI: 1.14-9.55). CONCLUSION/CONCLUSIONS:neighborhoods should discuss cognitive assessments and ways to increase physical activity with providers.

BACKGROUND:Frail kidney transplant (KT) candidates, characterized by low physical activity/function, have decreased chances of listing and increased risk of waitlist mortality. Impairments in these physical domains contribute to perceived physical burden and may exacerbate one another. Further, understanding the association of each domain individually with adverse outcomes may improve pre-KT risk stratification. METHODS:We leveraged 2708 KT candidates (age ≥ 18) from a two-center prospective cohort study (2014-2024). We assessed physical activity (Minnesota Leisure Time Physical Activity Questionnaire), physical function (gait speed), and physical burden (10 questions from the Kidney Disease Quality of Life Short Form) at evaluation. We quantified the association of these three physical domains with listing (Cox proportional hazards) and waitlist mortality (competing risks, Harrell's C-statistic). RESULTS:Among 2708 candidates, 40% had low physical activity, 16% had low physical function, and 54% had high physical burden. Candidates with impairment in these three physical domains were less likely to be listed (activity: adjusted hazard ratio [aHR] = 0.86, 95% confidence interval [CI]: 0.75-0.99; function: aHR = 0.54, 95%CI: 0.45-0.64; burden: aHR = 0.75, 95%CI: 0.67-0.83) and had a higher risk of waitlist mortality (activity: adjusted sub-hazard ratio [aSHR] = 1.51, 95%CI: 1.11-2.04; function: aSHR = 1.83, 95%CI: 1.30-2.58; burden: aSHR = 1.40, 95%CI: 1.09-1.82). Physical burden showed the best discrimination in predicting mortality after adjustment (Harrell's C-statistic = 0.6899). CONCLUSION/CONCLUSIONS:Although impairment in physical activity, function, and burden was all associated with KT listing and waitlist mortality, physical burden was the strongest predictor of waitlist mortality. KT centers should consider measuring physical burden - a simple, low-cost tool to help identify high-risk candidates for prehabilitation.

BACKGROUND AND HYPOTHESIS/OBJECTIVE:Hepatitis C virus (HCV) positive-to-negative kidney transplants (KT) require direct acting antiviral therapy, but the optimal timing and duration remain unclear. We hypothesized that 14-day prophylactic course of glecaprevir/pibrentasvir 300/120 mg (GLE/PIB) would be safe and effective at treating donor-derived HCV viremia. METHODS:This was a prospective, single-center, single-arm, open-label pilot study. 20 adult HCV negative recipients of HCV nucleic acid amplification test positive deceased-donor kidneys (HCV positive-to-negative) received a 14-day course of GLE/PIB, with the first dose pre-transplant. HCV RNA viral loads (VL) were monitored on post-operative days (POD) 1, 3, 7, and 13. If VL was undetectable on POD 13, GLE/PIB was stopped, and if detectable, GLE/PIB was continued to complete an 8-week course. Surveillance monitoring continued after treatment to ensure sustained viral response (SVR). The primary outcome was efficacy of 14-day prophylactic GLE/PIB. Secondary outcomes included patient and allograft survival, the incidence, timing, and clearance of HCV viremia, and safety events. RESULTS:7/20 subjects (35%) never developed detectable HCV viremia. Only one subject had a detectable, but nonquantifiable, VL on POD 13 and completed an 8-week course. All subjects achieved SVR 12 weeks post-treatment with no relapses through 1-year follow-up. Mean time to undetectable HCV RNA VL was 10.5 (±4.7) days and mean peak VL was 371 (±715) copies/mL. 6-month and 1-year patient and allograft survival were 100% and 95%. CONCLUSION/CONCLUSIONS:A 14-day course of prophylactic GLE/PIB is safe and effective for HCV positive-to-negative KT and may prevent HCV transmission or significantly reduce the VL for those with detectable transmission allowing for rapid clearance within 2 weeks.