Faculty Bibliography

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.

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.

In the past decade, there have been increasing efforts to better define and quantify the short- and long-term risks of living kidney donation. Recent studies have expanded upon the previous literature by focusing on outcomes that are important to potential and previous donors, applying unique databases and/or registries to follow large cohorts of donors for longer periods of time, and comparing outcomes with healthy nondonor controls to estimate attributable risks of donation. Leading outcomes important to living kidney donors include kidney health, surgical risks, and psychosocial effects of donation. Recent data support that living donors may experience a small increased risk of severe CKD and ESKD compared with healthy nondonors. For most donors, the 15-year risk of kidney failure is <1%, but for certain populations, such as young, black men, this risk may be higher. New risk prediction tools that combine the effects of demographic and health factors, and innovations in genetic risk markers are improving kidney risk stratification. Minor perioperative complications occur in 10%-20% of donor nephrectomy cases, but major complications occur in <3%, and the risk of perioperative death is <0.03%. Generally, living kidney donors have similar or improved psychosocial outcomes, such as quality of life, after donation compared with before donation and compared with nondonors. Although the donation process should be financially neutral, living kidney donors may experience out-of-pocket expenses and lost wages that may or may not be completely covered through regional or national reimbursement programs, and may face difficulties arranging subsequent life and health insurance. Living kidney donors should be fully informed of the perioperative and long-term risks before making their decision to donate. Follow-up care allows for preventative care measures to mitigate risk and ongoing surveillance and reporting of donor outcomes to inform prior and future living kidney donors.

Several single-center reports of using HCV-viremic organs for HCV-uninfected (HCV-) recipients were recently published. We sought to characterize national utilization of HCV-exposed donors for HCV- recipients (HCV D+/R-) in kidney transplantation (KT) and liver transplantation (LT). Using SRTR data (April 1, 2015-December 2, 2018) and Gini coefficients, we studied center-level clustering of 1193 HCV D+/R- KTs and LTs. HCV-viremic (NAT+) D+/R- KTs increased from 1/month in 2015 to 22/month in 2018 (LTs: 0/month to 12/month). HCV-aviremic (Ab+/NAT-) D+/R- KTs increased from < 1/month in 2015 to 26/month in 2018 (LTs: <1/month to 8/month). HCV- recipients of viremic and aviremic kidneys spent a median (interquartile range [IQR]) of 0.7 (0.2-1.6) and 1.6 (0.4-3.5) years on the waitlist versus 1.8 (0.5-4.0) among HCV D-/R-. HCV- recipients of viremic and aviremic livers had median (IQR) MELD scores of 24 (21-30) and 25 (21-32) at transplantation versus 29 (23-36) among HCV D-/R-. 12 KT and 14 LT centers performed 81% and 76% of all viremic HCV D+/R- transplants; 11 KT and 13 LT centers performed 76% and 69% of all aviremic HCV D+/R- transplants. There have been marked increases in HCV D+/R- transplantation, although few centers are driving this practice; centers should continue to weigh the risks and benefits of HCV D+/R- transplantation.

Pediatric kidney transplant candidates often have multiple potential living donors (LDs); no evidence-based tool exists to compare potential LDs, or to decide between marginal LDs and deceased donor (DD) kidney transplantation (KT). We developed a pediatric living kidney donor profile index (P-LKDPI) on the same scale as the DD KDPI by using Cox regression to model the risk of all-cause graft loss as a function of living donor characteristics and DD KDPI. HLA-B mismatch (adjusted hazard ratio [aHR] per mismatch = _1.04 1.27_1.55 ), HLA-DR mismatch (aHR per mismatch = _1.02 1.23_1.49 ), ABO incompatibility (aHR = _1.20 3.26_8.81 ), donor systolic blood pressure (aHR per 10 mm Hg = _1.01 1.07_1.18 ), and donor estimated GFR (eGFR; aHR per 10 mL/min/1.73 m² = _0.88 0.94_0.99 ) were associated with graft loss after LDKT. Median (interquartile range [IQR]) P-LKDPI was -25 (-56 to 12). 68% of donors had P-LKDPI <0 (less risk than any DD kidney) and 25% of donors had P-LKDPI >14 (more risk than median DD kidney among pediatric KT recipients during the study period). Strata of LDKT recipients of kidneys with higher P-LKDPI had a higher cumulative incidence of graft loss (39% at 10 years for P-LDKPI ≥20, 28% for 20> P-LKDPI ≥-20, 23% for -20 > P-LKDPI ≥-60, 19% for P-LKDPI <-60 [log rank P < .001]). The P-LKDPI can aid in organ selection for pediatric KT recipients by allowing comparison of potential LD and DD kidneys.

BACKGROUND AND OBJECTIVES:Frailty, a syndrome distinct from comorbidity and disability, is clinically manifested as a decreased resistance to stressors and is present in up to 35% of patient with ESKD. It is associated with falls, hospitalizations, poor cognitive function, and mortality. Also, frailty is associated with poor outcomes after kidney transplant, including delirium and mortality. Frailty is likely also associated with decreased access to kidney transplantation, given its association with poor outcomes on dialysis and post-transplant. Yet, clinicians have difficulty identifying which patients are frail; therefore, we sought to quantify if frail kidney transplant candidates had similar access to kidney transplantation as nonfrail candidates. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We studied 7078 kidney transplant candidates (2009-2018) in a three-center prospective cohort study of frailty. Fried frailty (unintentional weight loss, grip strength, walking speed, exhaustion, and activity level) was measured at outpatient kidney transplant evaluation. We estimated time to listing and transplant rate by frailty status using Cox proportional hazards and Poisson regression, adjusting for demographic and health factors. RESULTS:<0.001). CONCLUSIONS:Frailty is associated with lower chance of listing and lower rate of transplant, and is a potentially modifiable risk factor.

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.

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.

Using nonideal kidneys for transplant quickly might reduce the discard rate of kidney transplants. We studied changing kidney allocation to eliminate sequential offers, instead making offers to multiple centers for all nonlocally allocated kidneys, so that multiple centers must accept or decline within the same 1 hour. If more than 1 center accepted an offer, the kidney would go to the highest-priority accepting candidate. Using 2010 Kidney-Pancreas Simulated Allocation Model-Scientific Registry for Transplant Recipients data, we simulated the allocation of 12 933 kidneys, excluding locally allocated and zero-mismatch kidneys. We assumed that each hour of delay decreased the probability of acceptance by 5% and that kidneys would be discarded after 20 hours of offers beyond the local level. We simulated offering kidneys simultaneously to small, medium-size, and large batches of centers. Increasing the batch size increased the percentage of kidneys accepted and shortened allocation times. Going from small to large batches increased the number of kidneys accepted from 10 085 (92%) to 10 802 (98%) for low-Kidney Donor Risk Index kidneys and from 1257 (65%) to 1737 (89%) for high-Kidney Donor Risk Index kidneys. The average number of offers that a center received each week was 10.1 for small batches and 16.8 for large batches. Simultaneously expiring offers might allow faster allocation and decrease the number of discards, while still maintaining an acceptable screening burden.

OBJECTIVES:Older adults who undergo kidney transplantation (KT) are living longer with a functioning graft and are at risk for age-related adverse events including fractures. Understanding recipient, transplant, and donor factors and the outcomes associated with fractures may help identify older KT recipients at increased risk. We determined incidence of hip, vertebral, and extremity fractures; assessed factors associated with incident fractures; and estimated associations between fractures and subsequent death-censored graft loss (DCGL) and mortality. DESIGN:This was a prospective cohort study of patients who underwent their first KT between January 1, 1999, and December 31, 2014. SETTING:We linked data from the Scientific Registry of Transplant Recipients to Medicare claims through the US Renal Data System. PARTICIPANTS:The analytic population included 47 815 KT recipients aged 55 years or older. MEASUREMENTS:We assessed the cumulative incidence of and factors associated with post-KT fractures (hip, vertebral, or extremity) using competing risks models. We estimated risk of DCGL and mortality after fracture using adjusted Cox proportional hazards models. RESULTS:The 5-year incidence of post-KT hip, vertebral, and extremity fracture for those aged 65 to 69 years was 2.2%, 1.0%, and 1.7%, respectively. Increasing age was associated with higher hip (adjusted hazard ratio [aHR] = 1.37 per 5-y increase; 95% confidence interval [CI] = 1.30-1.45) and vertebral (aHR = 1.31; 95% CI = 1.20-1.42) but not extremity (aHR = .97; 95% CI = .91-1.04) fracture risk. DCGL risk was higher after hip (aHR = 1.34; 95% CI = 1.12-1.60) and extremity (aHR = 1.30; 95% CI = 1.08-1.57) fracture. Mortality risk was higher after hip (aHR = 2.31; 95% CI = 2.11-2.52), vertebral (aHR = 2.80; 95% CI = 2.44-3.21), and extremity (aHR = 1.85; 95% CI = 1.64-2.10) fracture. CONCLUSION:Our findings suggest that older KT recipients are at higher risk for hip and vertebral fracture but not extremity fracture; and those with hip, vertebral, or extremity fracture are more likely to experience subsequent graft loss or mortality. These findings underscore that different fracture types may have different underlying etiologies and risks, and they should be approached accordingly. J Am Geriatr Soc 67:1680-1688, 2019.