Faculty Bibliography

Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Older adults initiating dialysis have a high risk of mortality and that risk may be related to potentially inappropriate medications (PIMs). Our objective was to identify and validate mortality risk associated with American Geriatrics Society Beers Criteria PIM classes and concomitant PIM use. METHODS:We used US Renal Data System data to establish a cohort of adults aged ≥ 65 years initiating dialysis (2013-2014) and had no PIM prescriptions in the 6 months prior to dialysis initiation. In a development cohort (40% sample), adjusted Cox proportional hazards models were performed to determine which of 30 PIM classes were associated with mortality (or "high-risk" PIMs). Adjusted Cox models were performed to assess the association of the number of "high-risk" PIM fills/month with mortality. All models were repeated in the validation cohort (60% sample). RESULTS:In the development cohort (n = 15,570), only 13 of 30 PIM classes were associated with a higher mortality risk. Compared with those with no "high-risk" PIM fills/month, patients having one "high-risk" PIM fill/month had a 1.29-fold (95% confidence interval 1.21-1.38) increased risk of death; those with two or more "high-risk" PIM fills/month had a 1.40-fold (95% confidence interval 1.24-1.58) increased risk. These findings were similar in the validation cohort (n = 23,569). CONCLUSIONS:Only a minority of Beers Criteria PIM classes may be associated with mortality in the older dialysis population; however, mortality risk increases with concomitant use of "high-risk" PIMs. Additional studies are needed to confirm these associations and their underlying mechanisms.

Anti-spike binding antibody (Ab) levels are used by some providers to inform COVID-19 risk assessment for solid organ transplant recipients (SOTRs). As has been observed with other Ab assays, in the setting of high binding Ab, quantitative results may demonstrate artifactually low values (i.e., “hook” or prozone effect). Within two studies of SARS-CoV-2 vaccination of SOTRs (an observational cohort and a single-center trial), Ab levels were assessed using the semiquantitative Roche Elecsys anti-SARS-CoV-2 S assay. In the observational cohort, we flagged 9 samples with either a paradoxical decrease or weak (<10x) rise after Tixagevimab/Cilgavimab (T/C) administration. This prompted retesting with up-front 1:50 dilution, with serial dilution performed until returning two results within expected assay variation. Subsequently, all post-vaccination clinical trial samples were retested. Hook effect was suspected if retest level was both ≥15% and ≥200U/mL higher than original level. From the observational cohort, all 9 flagged samples demonstrated a hook effect. Of 377 clinical trial samples (all rerun), 34/377 (9%) demonstrated a hook effect. Among the hook effect samples (n=43), the original median (IQR) titer was 1950 (650 – 4390) U/mL, and upon retesting this increased to 5685 (2981 – 9853) U/mL representing a 1.6 (1.3–6.0)-fold increase (p=0.03). Marked hook effect (>700x increase) was observed in two participants with recent vaccination plus breakthrough infection. Hook effect was observed in SOTRs tested using a SARS-CoV-2 clinical Ab assay in the setting of high analyte. Laboratories and clinicians should be aware of this artifact and consider serial dilution to confirm accurate quantitative results.

OBJECTIVE:To examine whether body mass index (BMI) changes modify the association between kidney donation and incident hypertension. BACKGROUND:Obesity increases hypertension risk in both general and living kidney donor (LKD) populations. Donation-attributable risk in the context of obesity, and whether weight change modifies that risk, is unknown. METHODS:Nested case-control study among 1558 adult LKDs (1976-2020) with obesity (median follow-up: 3.6 years; interquartile range: 2.0-9.4) and 3783 adults with obesity in the Coronary Artery Risk Development in Young Adults (CARDIA) and Atherosclerosis Risk in Communities (ARIC) studies (9.2 y; interquartile range: 5.3-15.8). Hypertension incidence was compared by donor status using conditional logistic regression, with BMI change investigated for effect modification. RESULTS:Overall, LKDs and nondonors had similar hypertension incidence [incidence rate ratio (IRR): 1.16, 95% confidence interval (95% CI): 0.94-1.43, P =0.16], even after adjusting for BMI change (IRR: 1.25, 95% CI: 0.99-1.58, P =0.05). Although LKDs and nondonors who lost >5% BMI had comparable hypertension incidence (IRR: 0.78, 95% CI: 0.46-1.34, P =0.36), there was a significant interaction between donor and >5% BMI gain (multiplicative interaction IRR: 1.62, 95% CI: 1.15-2.29, P =0.006; relative excess risk due to interaction: 0.90, 95% CI: 0.24-1.56, P =0.007), such that LKDs who gained weight had higher hypertension incidence than similar nondonors (IRR: 1.83, 95% CI: 1.32-2.53, P <0.001). CONCLUSIONS:Overall, LKDs and nondonors with obesity had similar hypertension incidence. Weight stability and loss were associated with similar hypertension incidence by donor status. However, LKDs who gained >5% saw increased hypertension incidence versus similar nondonors, providing support for counseling potential LKDs with obesity on weight management postdonation.

BACKGROUND:Short and long sleep durations are associated with cognitive dysfunction. Given the increased prevalence of sleep abnormalities in the CKD population, we tested whether the association between sleep duration and cognitive function differed between older adults with and without CKD. METHODS:This was a study of 3215 older adults (aged ≥ 60years) enrolled in the National Health and Nutrition Examination Survey (2011-2014) evaluating sleep duration, cognitive function (immediate recall, delayed recall, verbal fluency, executive function and processing speed, and global cognition), and kidney function. We quantified the association between sleep duration and cognitive function using linear regression and tested whether the associations differed among those with CKD and without using a Wald test for interaction. RESULTS:Among 3215 participants, 13.3% reported 2-5 hours of sleep per day, 75.2% reported 6-8 hours, and 11.5% reported ≥ 9 hours. Persons with CKD were more likely to sleep ≥ 9 hours (OR = 1.73, 95% CI: 1.22-2.46). Among participants with CKD, those with sleep duration ≥ 9 hours demonstrated worse global cognitive function (p for interaction = 0.01), immediate recall (p for interaction = 0.01), and verbal fluency (p for interaction = 0.004) than those with 6-8 hours sleep duration; no differences were observed for participants with CKD who slept 2-5 hours. Among participants without CKD, sleep was not associated with any measures of cognitive function. CONCLUSIONS:Longer sleep duration is associated with worse cognitive function only among persons with CKD and global cognition, delayed recall, and verbal fluency are particularly affected. Studies should identify interventions to improve sleep patterns and quality in this population.

SIGNIFICANCE STATEMENT:Cardiovascular diseases account for 32% of deaths among kidney transplant recipients. Statin therapy is common in this population. However, its effect on mortality prevention remains unclear among kidney transplant recipients, whose clinical risk profile might be unique because of concomitant immunosuppressive therapy. In this national study of 58,264 single-kidney transplant recipients, statin use was associated with a 5% decrease in mortality. More importantly, this protective association was stronger among those who used a mammalian target of rapamycin (mTOR) inhibitor for immunosuppression (27% decrease in mTOR inhibitor users versus 5% in nonusers). Our results suggest that statin therapy may reduce mortality in kidney transplant recipients and that the strength of this protective association may vary by immunosuppression regimen. BACKGROUND:Cardiovascular diseases are the leading cause of mortality in kidney transplant (KT) recipients, accounting for 32% of deaths. Statins are widely used in KT recipients, but effectiveness for preventing mortality remains unclear in this population, especially because of interaction between statins and immunosuppressive agents. We analyzed a national cohort to assess the real-world effectiveness of statins for reducing all-cause mortality in KT recipients. METHODS:We studied statin use and mortality among 58,264 adults (18 years or older) who received single kidneys between 2006 and 2016 and had Medicare part A/B/D. Statin use was ascertained from Medicare prescription drug claims and deaths from Center for Medicare and Medicaid Services records. We estimated the association of statin use with mortality using multivariable Cox models, with statin use as a time-varying exposure and immunosuppression regimen as effect modifiers. RESULTS:Statin use increased from 45.5% at KT to 58.2% at 1-year post-KT to 70.9% at 5-year post-KT. We observed 9785 deaths over 236,944 person-years. Overall, statin use was significantly associated with lower mortality (adjusted hazard ratio [aHR], 0.95; 95% confidence interval [CI], 0.90 to 0.99). The strength of this protective association varied by calcineurin inhibitor use (among tacrolimus users, aHR, 0.97; 95% CI, 0.92 to 1.03 versus among calcineurin nonusers, aHR, 0.72; 95% CI, 0.60 to 0.87; interaction P =0.002), mammalian target of rapamycin (mTOR) inhibitor use (among mTOR inhibitor users, aHR, 0.73; 95% CI, 0.57 to 0.92 versus among nonusers, aHR, 0.95; 95% CI, 0.91 to 1.00; interaction P =0.03), and mycophenolate use (among mycophenolate users, aHR, 0.96; 95% CI, 0.91 to 1.02 versus among nonusers, aHR, 0.76; 95% CI, 0.64 to 0.89; interaction P =0.002). CONCLUSION:Real-world evidence supports statin therapy for reducing all-cause mortality in KT recipients. Effectiveness might be greater when combined with mTOR inhibitor-based immunosuppression.

BACKGROUND:The Omicron BA.5 subvariant of SARS-CoV-2 markedly escapes neutralizing antibodies induced by vaccination due to mutations in the Spike (S) protein. Solid organ transplant recipients (SOTRs) suffer high COVID-19 morbidity and demonstrate poor Omicron strain recognition after COVID-19 vaccination. T cell responses may provide a crucial second line of defense. Therefore, it is critical to understand which vaccine regimens induce robust, conserved T cell responses. METHODS:We evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective observational trial (n=75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or two doses of mRNA followed by Ad26.COV2.S (heterologous boosting). RESULTS:Homologous boosting with three mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated significantly lower pseudo-neutralization against BA.5 compared to the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared to ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared to BNT¬¬162b2. IL-21+ cells robustly correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting. CONCLUSIONS:These data demonstrate that boosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants of concern in SOTRs, but alterative vaccine strategies are required to induce robust CD8+ T cell responses. TRIAL REGISTRATION/BACKGROUND:IRB00248540FUNDING. U01AI138897, U54CA260492, Emory COVID-19 research repository.

BACKGROUND:The Organ Procurement and Transplantation Network (OPTN) is eliminating geographic boundaries in liver allocation, in favor of continuous distribution. Continuous distribution allocates organs via a composite allocation score (CAS): a weighted sum of attributes like medical urgency, candidate biology, and placement efficiency. The opportunity this change represents, to include new variables and features for prioritizing candidates, will require lengthy and contentious discussions to establish community consensus. Continuous distribution could instead be implemented rapidly by computationally translating the allocation priorities for pediatric, status 1, and O/B blood type liver candidates that are presently implemented via geographic boundaries into points and weights in a CAS. METHODS:Using simulation with optimization, we designed a CAS that is minimally disruptive to existing prioritizations, and that eliminates geographic boundaries and minimizes waitlist deaths without harming vulnerable populations. RESULTS:Compared with Acuity Circles (AC) in a 3-year simulation, our optimized CAS decreased deaths from 7771.2 to 7678.8 while decreasing average (272.66 NM vs. 264.30 NM) and median (201.14 NM vs. 186.49 NM) travel distances. Our CAS increased travel only for high MELD and status 1 candidates (423.24 NM vs. 298.74 NM), and reduced travel for other candidates (198.98 NM vs. 250.09 NM); overall travel burden decreased. CONCLUSION/CONCLUSIONS:Our CAS reduced waitlist deaths by sending livers for high-MELD and status 1 candidates farther, while keeping livers for lower MELD candidates nearby. This advanced computational method can be applied again after wider discussions of adding new priorities conclude; our method designs score weightings to achieve any specified feasible allocation outcomes.