Faculty Bibliography

The Johns Hopkins University School of Medicine organized 2 multistakeholder symposia on February 2, 2018 and January 11, 2019 to address the problem of high graft failure in adolescent and young adult (AYA) solid organ transplant (SOT) recipients. Participants included international experts in transplantation, behavioral psychology, patient/parent advocacy, and technology. The objectives of the symposia were as follows: (1) to identify and discuss the barriers to and facilitators of effective transfer of care for AYA SOT recipients; (2) to actively explore strategies and digital solutions to promote their successful transfer of care; and (3) to develop meaningful partnerships for the successful development, evaluation, implementation, and dissemination of these digital solutions. Additionally, data were collected from 152 AYA SOT recipients demonstrating a substantial gap in how this population uses technologies for health-related activities, alongside an increased interest in an app to help them manage their transplant.

BACKGROUND:Despite providing survival benefit, increased risk for infectious disease (IRD) kidney offers are declined at 1.5 times the rate of non-IRD kidneys. Elucidating sources of variation in IRD kidney offer acceptance may highlight opportunities to expand use of these life-saving organs. METHODS:To explore center-level variation in offer acceptance, we studied 6765 transplanted IRD kidneys offered to 187 transplant centers between 2009 and 2017 using Scientific Registry of Transplant Recipients data. We used multilevel logistic regression to determine characteristics associated with offer acceptance and to calculate the median odds ratio (MOR) of acceptance (higher MOR indicates greater heterogeneity). RESULTS:Higher quality kidneys (per 10 units kidney donor profile index; adjusted odds ratio [aOR], 0.94; 95% confidence interval [CI], 0.92-0.95), higher yearly volume (per 10 deceased donor kidney transplants; aOR, 1.08, 95% CI, 1.06-1.10), smaller waitlist size (per 100 candidates; aOR, 0.97; 95% CI, 0.95-0.98), and fewer transplant centers in the donor service area (per center; aOR, 0.88; 95% CI, 0.85-0.91) were associated with greater odds of IRD acceptance. Adjusting for donor and center characteristics, we found wide heterogeneity in IRD offer acceptance (MOR, 1.96). In other words, if listed at a center with more aggressive acceptance practices, a candidate could be 2 times more likely to have an IRD kidney offer accepted. CONCLUSIONS:Wide national variation in IRD kidney offer acceptance limits access to life-saving kidneys for many transplant candidates.

We examined a novel linkage of national US donor registry data with records from a pharmacy claims warehouse (2007-2016) to examine associations (adjusted hazard ratio, _LCL aHR_UCL ) of post-donation fills of antidiabetic medications (ADM, insulin or non-insulin agents) with body mass index (BMI) at donation and other demographic and clinical factors. In 28 515 living kidney donors (LKDs), incidence of ADM use at 9 years rose in a graded manner with higher baseline BMI: underweight, 0.9%; normal weight, 2.1%; overweight, 3.5%; obese, 8.5%. Obesity was associated with higher risk of ADM use compared with normal BMI (aHR, _3.36 4.59_6.27 ). Metformin was the most commonly used ADM and was filled more often by obese than by normal weight donors (9-year incidence, 6.87% vs 1.85%, aHR, _3.55 5.00_7.04 ). Insulin use was uncommon and did not differ significantly by BMI. Among a subgroup with BMI data at the 1-year post-donation anniversary (n = 19 528), compared with stable BMI, BMI increase >0.5 kg/m² by year 1 was associated with increased risk of subsequent ADM use (aHR, _1.03 1.48_2.14, P = .04). While this study did not assess the impact of donation on the development of obesity, these data support that among LKD, obesity is a strong correlate of ADM use.

OBJECTIVE:To develop and validate an integrative system to predict long term kidney allograft failure. DESIGN:International cohort study. SETTING:Three cohorts including kidney transplant recipients from 10 academic medical centres from Europe and the United States. PARTICIPANTS:Derivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157). MAIN OUTCOME MEASURE:Allograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed. RESULTS:Among the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% confidence interval 0.79 to 0.83). The performance of the iBox was also confirmed in the validation cohorts from Europe (C index 0.81, 0.78 to 0.84) and the US (0.80, 0.76 to 0.84). The iBox system showed accuracy when assessed at different times of evaluation post-transplant, was validated in different clinical scenarios including type of immunosuppressive regimen used and response to rejection therapy, and outperformed previous risk prediction scores as well as a risk score based solely on functional parameters including estimated glomerular filtration rate and proteinuria. Finally, the accuracy of the iBox risk score in predicting long term allograft loss was confirmed in the three randomised controlled trials. CONCLUSION:An integrative, accurate, and readily implementable risk prediction score for kidney allograft failure has been developed, which shows generalisability across centres worldwide and common clinical scenarios. The iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials. TRIAL REGISTRATION:Clinicaltrials.gov NCT03474003.

BACKGROUND:Arteriovenous fistulas (AVF) and grafts (AVG) have been associated with significant cardiac morbidity that often improves after ligation. However, AV access ligation after kidney transplant (KT) is controversial due to concern for potential long-term allograft failure. We investigated US trends in AV access ligation after KT and the association between ligation and allograft failure. METHODS:All adult Medicare patients on pretransplant hemodialysis with a functioning AVF or AVG who underwent first-time KT were studied using the United States Renal Data Systems (January 2011 to December 2013). Post-transplant AV access ligation was determined using current procedural terminology codes. The incidence of post-transplant AV access ligation was described, and characteristics for patients undergoing ligation vs no ligation were compared. Kaplan-Meier curves and Cox proportional hazard models were then used to determine the association of AV access ligation with long-term allograft failure and all-cause mortality after accounting for patient characteristics, donor characteristics, and variation in transplant center practices. RESULTS:), spent longer on dialysis pretransplant (4.2 vs 4.0 years), and were less likely to have renal failure secondary to diabetes compared with other etiologies (25.0% vs 34.9%) (all, P ≤ .03). Patients who underwent ligation were also more likely to have steal syndrome (77.2% vs 4.1%) and AV access infectious or aneurysmal complications (2.7% vs 0.7%) (both, P < .001). After adjusting for donor and recipient characteristics, increasing age (adjusted hazards ratio [aHR], 1.01; 95% confidence interval [CI], 1.00-1.01), increasing years on dialysis (aHR, 1.06; 95% CI, 1.00-1.13), zero human leukocyte antigen mismatch (aHR, 1.82; [95% CI, 1.09-3.05), and steal syndrome (aHR, 41.00; 95% CI, 34.56-48.64) were associated with post-transplant AV access ligation. Black race (aHR, 0.82; 95% CI, 0.69-0.98) and congestive heart failure (aHR, 0.66; 95% CI, 0.54-0.82) were negatively associated with ligation. Three-year allograft failure occurred in 4.9% ± 1.3% transplant recipients who underwent access ligation vs 9.5% ± 0.5% transplant recipients with functioning access (log-rank, P = .30), and was not significantly different between groups after risk adjustment (aHR, 0.81; 95% CI, 0.47-1.40). There was also no significant association between AV access and all-cause mortality after risk adjustment (aHR, 0.84; 95% CI, 0.46-1.54). CONCLUSIONS:Post-transplant AV access ligation is uncommon and generally reserved for patients with steal syndrome. Importantly, ligation is not associated with post-transplant allograft failure, which occurs in less than 10% of patients at 3 years. There also appears to be no reduction in all-cause mortality with AV access ligation. These data suggest that AV access ligation after KT can likely be reserved for access-related complications because the systemic benefits appear to be minimal.

The number of live kidney donors has declined since 2005. This decline parallels the evolving knowledge of risk for biologically related, black, and younger donors. To responsibly promote donation, we sought to identify declining low-risk donor subgroups that might serve as targets for future interventions. We analyzed a national registry of 77 427 donors and quantified the change in number of donors per 5-year increment from 2005 to 2017 using Poisson regression stratified by donor-recipient relationship and race/ethnicity. Among related donors aged <35, 35 to 49, and ≥50 years, white donors declined by 21%, 29%, and 3%; black donors declined by 30%, 31%, and 12%; Hispanic donors aged <35 and 35 to 49 years declined by 18% and 15%, and those aged ≥50 increased by 10%. Conversely, among unrelated donors aged <35, 35 to 49, and ≥50 years, white donors increased by 12%, 4%, and 24%; black donors aged <35 and 35 to 49 years did not change but those aged ≥50 years increased by 34%; Hispanic donors increased by 16%, 21%, and 46%. Unlike unrelated donors, related donors were less likely to donate in recent years across race/ethnicity. Although this decline might be understandable for related younger donors, it is less understandable for lower-risk related older donors (≥50 years). Biologically related older individuals are potential targets for interventions to promote donation.

RATIONALE & OBJECTIVE:There is debate on whether weight loss, a hallmark of frailty, signals higher risk for adverse outcomes among recipients of deceased donor kidney transplantation (DDKT). STUDY DESIGN:Retrospective cohort study. SETTING & PARTICIPANTS:Using national Organ Procurement and Transplantation Network data, we included all DDKT recipients in the United States between December 4, 2004, and December 3, 2014, who were adults (aged ≥ 18 years) when listed for DDKT. EXPOSURES:Relative pre-DDKT weight change as a continuous predictor and categorized as <5% weight change from listing to DDKT, ≥5% to <10% weight loss, ≥10% weight loss, ≥5% to <10% weight gain, and ≥10% weight gain. OUTCOMES:We examined 3 post-DDKT outcomes: (1) transplant hospitalization length of stay (LOS) in days, (2) all-cause graft failure, and (3) mortality. ANALYTIC APPROACH:Unadjusted fractional polynomial methods, multivariable log-gamma models, and multivariable Cox proportional hazards models. RESULTS:Among 94,465 recipients of DDKT, median pre-DDKT weight change was 0 (interquartile range, -3.5 to +3.9) kg. There were nonlinear unadjusted associations between relative pre-DDKT weight loss and longer transplant hospitalization LOS, higher all-cause graft loss, and higher mortality. Compared with recipients with <5% pre-DDKT weight change (n = 49,366; 52%), recipients who lost ≥10% of their listing weight (n = 10,614; 11%) had 0.66 (95% CI, 0.23-1.09) days longer average transplant hospitalization LOS (P = 0.003), 1.11-fold higher graft loss (adjusted HR [aHR], 1.11; 95% CI, 1.06-1.17; P < 0.001), and 1.18-fold higher mortality (aHR, 1.18; 95% CI, 1.11-1.25; P < 0.001) independent of recipient, donor, and transplant factors. Pre-DDKT dialysis exposure, listing body mass index category, and waiting time modified the association of pre-DDKT weight change with hospital LOS (interaction P < 0.10), but not with all-cause graft loss and mortality. LIMITATIONS:Unmeasured confounders and inability to identify volitional weight change. Also, the higher significance level set to increase the power of detecting interactions with the fixed sample size may have resulted in increased risk for type 1 error. CONCLUSIONS:DDKT recipients with ≥10% pre-DDKT weight loss are at increased risk for adverse outcomes and may benefit from augmented support post-DDKT.

Children receiving a LDLT have superior post-transplant outcomes, but this procedure is only used for 10% of transplant recipients. Better understanding about barriers toward LDLT and the sociodemographic characteristics that influence these underlying mechanisms would help to inform strategies to increase its use. We conducted an online, anonymous survey of parents/caregivers for children awaiting, or have received, a liver transplant regarding their knowledge and attitudes about LDLT. The survey was completed by 217 respondents. While 97% of respondents understood an individual could donate a portion of their liver, only 72% knew the steps in evaluation, and 69% understood the donor surgery was covered by the recipient's insurance. Individuals with public insurance were less likely than those with private insurance to know the steps for LDLT evaluation (44% vs 82%; P < 0.001). Respondents with public insurance were less likely to know someone that had been a living donor (44% vs 56%; P = 0.005) as were individuals without a college degree (64% vs 85%; P = 0.007). Nearly all respondents generally trusted their healthcare team. Among respondents, 82% believed they were well-informed about LDLT but individuals with public insurance were significantly less likely to feel well-informed (67% vs 87%; P = 0.03) and to understand how donor surgery might impact donor work/time off (44% vs 81%; P = 0.001). Substantial gaps exist in parental understanding about LDLT, including its evaluation, potential benefits, and complications. Greater emphasis on addressing these barriers, especially to individuals with fewer resources, will be helpful to expand the use of LDLT.

This report describes the results of 2 international randomized trials (total of 508 kidney transplant recipients). The primary objective was to assess the noninferiority of rabbit anti-thymocyte globulin (rATG, Thymoglobulin^® ) versus interleukin-2 receptor antagonists (IL2RAs) for the quadruple endpoint (treatment failure defined as biopsy-proven acute rejection, graft loss, death, or loss to follow-up) to serve as the pivotal data for United States (US) regulatory approval of rATG. The pooled analysis provided an incidence of treatment failure of 25.1% in the rATG and 36.0% in the IL2RA treatment groups, an absolute difference of -10.9% (95% confidence interval [CI] -18.8% to -2.9%) supporting noninferiority (noninferiority margin was 10%) and superiority of rATG to IL2RA. In a meta-analysis of 7 trials comparing rATG with an IL2RA, the difference in the proportion of patients with BPAR at 12 months was -4.8% (95% CI -8.6% to -0.9%) in favor of rATG. In conclusion, a rigorous reanalysis of patient-level data from 2 prior randomized, controlled trials comparing rATG versus IL-2R monoclonal antibodies provided support for regulatory approval for rATG for induction therapy in renal transplant, making it the first T cell-depleting therapy approved for the prophylaxis of acute rejection in patients receiving a kidney transplant in the United States.