Faculty Bibliography

Background:Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource. Objective:To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non-HCV-infected recipients (that is, HCV D+/R- transplantation). Design:Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649). Setting:Single center. Participants:10 HCV D+/R- kidney transplant candidates older than 50 years with no available living donors. Intervention:Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR-EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR-EBR for 12 weeks of triple therapy. Measurements:The primary safety outcome was the incidence of adverse events related to GZR-EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis. Results:Among 10 HCV D+/R- transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. Limitation:Nonrandomized study design and a small number of patients. Conclusion:Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R- kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection. Primary Funding Source:Merck Sharp & Dohme.

BACKGROUND:Allografts from older liver donors (OLDs), 70 years or older are often discarded for fear of inferior outcomes. We previously identified "preferred recipients" who did not suffer the higher risk of graft loss and mortality associated with OLDs. Preferred recipients were first-time, non-status 1 registrants older than 45 years, body mass index less than 35, indication other than hepatitis C, and cold ischemia time less than 8 hours. METHODS:We assessed the validity of the preferred recipient construct in a larger, more recent cohort (38 891 patients, 2006-2013). We compared recipients of OLD grafts to recipients of average liver donors (ALDs, age = 40-69) and ideal liver donors (ILDs, age = 18-39) grafts using multilevel Cox regression adjusting for recipient and transplant factors. RESULTS:The use of OLD grafts in preferred recipients has increased from 2006 to 2013 (P = 0.02). Preferred recipients Model for End-Stage Liver Disease scores ranged 6 to 40. Preferred recipients had similar 5-year all-cause graft loss (ACGL) with OLD versus ALD and ILD grafts (25.4% vs 24.5% and 21.6%). Conversely, nonpreferred recipients had higher 5-year ACGL with OLD versus ALD and ILD grafts (41.4% vs 32.9% and 25.6%). After adjustment, preferred recipients had similar graft loss with OLD versus ALD grafts (hazard ratio [HR], 0.921.081.27; P = 0.3) and ILD grafts (HR, 0.981.161.39, P = 0.09); however, nonpreferred recipients had higher ACGL risk with OLD grafts versus ALD (HR, 1.281.411.56, P < 0.001) and ILD grafts (HR, 1.501.671.86, P < 0.001). Similar trends are seen with mortality. CONCLUSIONS:Because preferred recipients comprise 43.3% (n = 2916) of the current waitlist and span the full range of Model for End-Stage Liver Disease scores, transplanted OLD allografts could be distributed without added risk of graft loss or mortality.

BACKGROUND:A prolonged living kidney donor evaluation may result in worse outcomes for transplant recipients. Better knowledge of the duration of this process may help inform future donors and identify opportunities for improvement. STUDY DESIGN:1 prospective and 1 retrospective cohort study. SETTING & PARTICIPANTS:At 16 Canadian and Australian transplantation centers (prospective cohort) and 5 Ontario transplantation centers (retrospective cohort), we assessed the duration of living kidney donor evaluation and explored donor, recipient, and transplantation factors associated with longer evaluation times. Data were obtained from 2 sources: donor medical records using chart abstraction and health care administrative databases. PREDICTORS:Donor and recipient demographics, direct versus paired donation, center-level variables. OUTCOMES:Duration of living donor evaluation. RESULTS:The median total duration of transplantation evaluation (time from when the candidate started the evaluation until donation) was 10.3 (IQR, 6.5-16.7) months. The median duration from evaluation start until approval to donate was 7.9 (IQR, 4.6-14.1) months, and from approval until donation was 0.7 (IQR, 0.3-2.4) months, respectively. The median time between the first and last consultation among donors who completed a nephrology, surgery, and psychosocial assessment in the prospective cohort was 3.0 (IQR, 1.0-6.3) months, and between computed tomography angiography and donation was 4.8 (IQR, 2.6-9.2) months. After adjustment, the total duration of transplantation evaluation was longer if the donor participated in paired donation (6.6 [95% CI, 1.6-9.7] months) and if the recipient was referred later relative to the donor's evaluation start date (0.9 [95% CI, 0.8-1.0] months [per month of delayed referral]). Results depended on whether the recipient was receiving dialysis. LIMITATIONS:Living donor candidates who did not donate were not included and proxy measures were used for some dates in the donor evaluation process. CONCLUSIONS:The duration of kidney transplant donor evaluation is variable and can be lengthy. Better understanding of the reasons for a prolonged evaluation may inform quality improvement initiatives to reduce unnecessary delays.

BACKGROUND:Dialysis-dependent patients and kidney transplant recipients may be at increased risk for Achilles tendon rupture (ATR). METHODS:We studied Medicare patients with end-stage renal disease (ESRD) from 1999 through 2013. Patients were categorized as waitlisted for a transplant, not waitlisted, or received a transplant. We performed multivariate negative binomial regression using demographic characteristics, comorbidities, and year of study entry to estimate adjusted incidence rate ratios (aIRRs), identify ATR risk factors, and determine treatment patterns and outcomes. RESULTS:We identified 1091 ATRs (incidence, 3.80/10 000 person-years; 95% confidence interval [CI], 3.58-4.03). Compared with transplant recipients, nonwaitlisted patients had a lower incidence (aIRR, 0.44; 95% CI, 0.37-0.53), and waitlisted patients had a similar incidence (aIRR, 0.94; 95% CI, 0.78-1.12) of ATR. ATR incidence was higher among patients taking fluoroquinolones (aIRR, 1.65; 95% CI, 1.32-1.84) and corticosteroids (aIRR, 1.72; 95% CI, 1.44-2.05) compared with those who did not. Patients with ATR were younger, had higher mean body mass index, and had fewer comorbidities than patients without ATR. Seventeen percent of patients received operative treatment within 14 days of ATR diagnosis. The 30-day cumulative incidence of operative site infections was 6.5%. CONCLUSION:The incidence of ATR was higher among transplant recipients and waitlisted patients compared with nonwaitlisted patients. Younger age, higher body mass index, fewer comorbidities, fluoroquinolone use, and corticosteroid use were risk factors for ATR. Patients were more likely to receive nonoperative than operative treatment for ATR. Those who underwent operative treatment had a low incidence of operative site infection. LEVEL OF EVIDENCE:Prognostic level III, comparative study.

The practice of kidney paired donation (KPD) is expanding annually, offering the opportunity for live donor kidney transplant to more patients. We sought to identify if voluntary KPD networks such as the National Kidney Registry (NKR) were selecting or attracting a narrower group of donors or recipients compared with national registries. For this purpose, we merged data from the NKR database with the Scientific Registry of Transplant Recipients (SRTR) database, from February 14, 2008, to February 14, 2017, encompassing the first 9 years of the NKR. Compared with all United Network for Organ Sharing (UNOS) live donor transplant patients (49 610), all UNOS living unrelated transplant patients (23 319), and all other KPD transplant patients (4236), the demographic and clinical characteristics of NKR transplant patients (2037) appear similar to contemporary national trends. In particular, among the NKR patients, there were a significantly (P < .001) greater number of retransplants (25.6% vs 11.5%), hyperimmunized recipients (22.7% vs 4.3% were cPRA >80%), female recipients (45.9% vs 37.6%), black recipients (18.2% vs 13%), and those on public insurance (49.7% vs 41.8%) compared with controls. These results support the need for greater sharing and larger pool sizes, perhaps enhanced by the entry of compatible pairs and even chains initiated by deceased donors, to unlock more opportunities for those harder-to-match pairs.

BACKGROUND:Among community-dwelling older adults, frailty is associated with heightened markers of inflammation and subsequent mortality. Although frailty is common among end-stage renal disease (ESRD) patients, the role of frailty and markers of inflammation in this population remains unclear. We quantified these associations in patients on the kidney transplant waitlist and tested whether frailty and/or markers of inflammation improve waitlist mortality risk prediction. METHODS:We studied 1975 ESRD patients on the kidney transplant waitlist (November 1, 2009, to February 28, 2017) in a multi-center cohort study of frailty. Serum inflammatory markers (interleukin-6 [IL-6], soluble tumor necrosis factor-α receptor-1 [sTNFR1], and C-reactive protein [CRP]) were analyzed in 605 of these participants; we calculated the inflammatory index score using IL-6 and sTNFR1. We compared the C-statistic of an established registry-based prediction model for waitlist mortality adding frailty and/or inflammatory markers (1 SD change in log IL-6, sTNFR1, CRP, or inflammatory index). RESULTS:The registry-based model had moderate predictive ability (c-statistic = 0.655). Frailty was associated with increased mortality (2.19; 95% confidence interval [CI], 1.26-3.79) but did not improve risk prediction (c-statistic = 0.646; P = 0.65). Like frailty, IL-6 (2.13; 95% CI, 1.41-3.22), sTNFR1 (1.70; 95% CI, 1.12-2.59), CRP (1.68; 95% CI, 1.06-2.67), and the inflammatory index (2.09; 95% CI, 1.38-3.16) were associated with increased mortality risk; unlike frailty, adding IL-6 (c-statistic = 0.777; P = 0.02), CRP (c-statistic = 0.728; P = 0.02), or inflammatory index (c-statistic = 0.777; P = 0.02) substantially improved mortality risk prediction. CONCLUSIONS:Frailty and markers of inflammation were associated with increased waitlist mortality risk, but only markers of inflammation significantly improved ESRD risk prediction. These findings help clarify the accelerated aging physiology of ESRD and highlight easy-to-measure markers of increased waitlist mortality risk.

Background:The epidemic of drug overdose deaths in the United States has led to an increase in organ donors. Objective:To characterize donors who died of overdose and to analyze outcomes among transplant recipients. Design:Prospective observational cohort study. Setting:Scientific Registry of Transplant Recipients, 1 January 2000 to 1 September 2017. Participants:138 565 deceased donors; 337 934 transplant recipients at 297 transplant centers. Measurements:The primary exposure was donor mechanism of death (overdose-death donor [ODD], trauma-death donor [TDD], or medical-death donor [MDD]). Patient and graft survival and organ discard (organ recovered but not transplanted) were compared using propensity score-weighted standardized risk differences (sRDs). Results:A total of 7313 ODDs and 19 897 ODD transplants (10 347 kidneys, 5707 livers, 2471 hearts, and 1372 lungs) were identified. Overdose-death donors accounted for 1.1% of donors in 2000 and 13.4% in 2017. They were more likely to be white (85.1%), aged 21 to 40 years (66.3%), infected with hepatitis C virus (HCV) (18.3%), and increased-infectious risk donors (IRDs) (56.4%). Standardized 5-year patient survival was similar for ODD organ recipients compared with TDD organ recipients (sRDs ranged from 3.1% lower to 3.9% higher survival) and MDD organ recipients (sRDs ranged from 2.1% to 5.2% higher survival). Standardized 5-year graft survival was similar between ODD and TDD grafts (minimal difference for kidneys and lungs, marginally lower [sRD, -3.2%] for livers, and marginally higher [sRD, 1.9%] for hearts). Kidney discard was higher for ODDs than TDDs (sRD, 5.2%) or MDDs (sRD, 1.5%); standardization for HCV and IRD status attenuated this difference. Limitation:Inability to distinguish between opioid and nonopioid overdoses. Conclusion:In the United States, transplantation with ODD organs has increased dramatically, with noninferior outcomes in transplant recipients. Concerns about IRD behaviors and hepatitis C among donors lead to excess discard that should be minimized given the current organ shortage. Primary Funding Source:National Institutes of Health.

In the United States, the Centers for Medicare and Medicaid Services (CMS) use Systems Improvement Agreements (SIAs) to require transplant programs repeatedly flagged for poor-performance to improve performance or lose CMS funding for transplants. We identified 14 kidney transplant (KT) programs with SIAs and 28 KT programs without SIAs matched on waitlist volume and characterized kidney acceptance using SRTR data from 12/2006-3/2015. We used difference-in-differences linear regression models to identify changes in acceptance associated with an SIA independent of program variation and trends prior to the SIA. SIA programs accepted 26.9% and 22.1% of offers pre- and post-SIA, while non-SIA programs accepted 33.9% and 44.4% of offers in matched time periods. After adjustment for donor characteristics, time-varying waitlist volume, and secular trends, SIAs were associated with a 5.9 percentage-point (22%) decrease in kidney acceptance (95% CI: -10.9 to -0.8, P = .03). The decrease in acceptance post-SIA was more pronounced for KDPI 0-40 kidneys (12.3 percentage-point decrease, P = .007); reductions in acceptance of higher KDPI kidneys occurred pre-SIA. Programs undergoing SIAs substantially reduced acceptance of kidney offers for waitlisted candidates. Attempts to improve posttransplant outcomes might have the unintended consequence of reducing access to transplantation as programs adopt more restrictive organ selection practices.