Faculty Bibliography

Organs from uncontrolled DCD donors (uDCDs) have expanded donation in Europe since the 1980s, but are seldom used in the United States. Cited barriers include lack of knowledge about the potential donor pool, lack of robust outcomes data, lack of standard donor eligibility criteria and preservation methods, and logistical and ethical challenges. To determine whether it would be appropriate to invest in addressing these barriers and building this practice, we sought to enumerate the potential pool of uDCD donors. Using data from the Nationwide Emergency Department Sample, the largest all-payer emergency department (ED) database, between 2013 and 2016, we identified patients who had refractory cardiac arrest in the ED. We excluded patients with contraindications to both deceased donation (including infection, malignancy, cardiopulmonary disease) and uDCD (including hemorrhage, major polytrauma, burns, and poisoning). We identified 9828 (range: 9454-10 202) potential uDCDs/y; average age was 32 years, and all were free of major comorbidity. Of these, 91.1% had traumatic deaths, with major causes including nonhead blunt injuries (43.2%) and head injuries (40.1%). In the current era, uDCD donors represent a significant potential source of unused organs. Efforts to address barriers to uDCD in the United States should be encouraged.

BACKGROUND:The growth of the aging population coupled with the increasing incidence of thyroid cancer warrants a better understanding of thyroid cancer in older adults. We aimed to investigate the variation of treatment patterns and determine if the extent of surgery is associated with disease-specific mortality in older adults with differentiated thyroid cancer (DTC). METHODS:We performed a population-based study using the Surveillance, Epidemiology, and End Results 18 program to examine patients diagnosed with DTC between 2004 and 2015. Patients were stratified by age: younger adults (aged 18-54 y), middle adults (aged 55-64 y), older adults (aged 65-79 y), and super elderly (aged ≥80 y). Disease-specific mortality was estimated using Kaplan-Meier curves and compared using the log-rank test. Multivariable Cox regression was used to assess associations between clinicopathologic characteristics and treatment patterns on disease-specific mortality. RESULTS:Of 117,098 patients with DTC, 72,368 were younger adults, 23,726 middle adults, 18,119 older adults, and 2885 were super elderly. In patients with DTC, compared with younger adults, fewer middle, older, and super elderly adults underwent any surgery (99.0%, 98.4%, 97.4%, and 89.1%, respectively; P < 0.001) or received radioactive iodine (RAI; 48.7%, 42.5%, 39.7%, and 30.7%, respectively; P < 0.001). Furthermore, middle, older, and super elderly adults had higher risk of mortality from DTC (hazard ratio [HR]: 4.0, 95% confidence interval [CI]: 3.2-4.8, P < 0.001; HR: 7.6, 95% CI: 6.3-9.1, P < 0.001; and HR: 17.2, 95% CI: 13.8-21.3, P < 0.001, respectively). On multivariable Cox regression while adjusting for clinicopathologic confounders, management was a significant prognostic factor (no surgery HR: 3.8, 95% CI: 3.1-4.6, P < 0.001; and RAI HR: 0.7, 95% CI: 0.6-0.8, P < 0.001). CONCLUSIONS:In patients with DTC, fewer older adults (≥65 y) underwent surgery or treatment with RAI, and this was associated with a worse disease-specific survival. Surgical decision-making in the older population is complex, and future prospective studies are needed to assess this age-related treatment variation.

Optimization of maintenance immunosuppression (mIS) regimens in the transplant recipient requires a balance between sufficient potency to prevent rejection and avoidance of excessive immunosuppression to prevent toxicities and complications. The optimal regimen after simultaneous liver-kidney (SLK) transplantation remains unclear, but small single-center reports have shown success with steroid-sparing regimens. We studied 4184 adult SLK recipients using the Scientific Registry of Transplant Recipients, from March 1, 2002, to February 28, 2017, on tacrolimus-based regimens at 1 year post-transplant. We determined the association between mIS regimen and mortality and graft failure using Cox proportional hazard models. The use of steroid-sparing regimens increased post-transplant, from 16.1% at discharge to 88.0% at 5 years. Using multi-level logistic regression modeling, we found center-level variation to be the major contributor to choice of mIS regimen (ICC 44.5%; 95% CI: 36.2%-53.0%). In multivariate analysis, use of a steroid-sparing regimen at 1 year was associated with a 21% decreased risk of mortality compared to steroid-containing regimens (aHR 0.79, P = .01) and 20% decreased risk of liver graft failure (aHR 0.80, P = .01), without differences in kidney graft loss risk (aHR 0.92, P = .6). Among SLK recipients, the use of a steroid-sparing regimen appears to be safe and effective without adverse effects on patient or graft survival.

BACKGROUND:Optimizing antithymocyte globulin (ATG) dosage is critical, particularly for high-risk kidney transplant (KT) recipients without cytomegalovirus (CMV) prophylaxis. METHODS:We studied 630 KT recipients with expanded criteria donors or panel reactive antibody ≥50% at Hospital do Rim, Brazil (January 1, 2013 to May 21, 2015) to determine whether a single ATG dose was safe and effective in patients without CMV prophylaxis. Patients received ≥4 doses (1-1.5 mg/kg/per dose) until June 17, 2014, when the induction protocol changed to a single ATG dose (3 mg/kg). We used Cox regression to compare the risk of CMV infection and acute rejection (AR) among KT recipients by ATG dose. RESULTS:Adjusting for clinical and transplant factors, a single ATG dose was associated with a lower risk of CMV infection (adjusted hazard ratio [aHR]: 0.63; 95% confidence interval [CI], 0.42-0.93; P = 0.02) and a similar risk of AR (aHR: 1.16; 95% CI, 0.47-2.83; P = 0.8), compared to multiple doses. We found no differences in death-censored graft loss (5.0% versus 4.8%, aHR: 1.06; 95% CI, 0.51-2.23; P = 0.9) or mortality (4.7% versus 3.4%; aHR: 1.42; 95% CI, 0.62-3.24; P = 0.4) at 1-year post-KT by ATG dose. CONCLUSIONS:In our study of high-risk KT recipients without CMV prophylaxis, a single ATG dose decreased the risk of CMV infection without increasing the risk of AR or compromising graft or patient survival.

In March 2020, COVID-19 infections began to rise exponentially in the United States, placing substantial burden on the healthcare system. As a result, there was a rapid change in transplant practices and policies, with cessation of most procedures. Our goal was to understand changes to pediatric kidney transplantation (KT) at the national level during the COVID-19 epidemic. Using SRTR data, we examined changes in pediatric waitlist registration, waitlist removal or inactivation, and deceased donor and living donor (DDKT/LDKT) events during the start of the disease transmission in the United States compared to the same time the previous year. We saw an initial decrease in DDKT and LDKT by 47% and 82% compared to expected events and then a continual increase, with numbers reaching expected pre-pandemic levels by May 2020. In the early phase of the pandemic, waitlist inactivation and removals due to death or deteriorating condition rose above expected values by 152% and 189%, respectively. There was a statistically significant decrease in new waitlist additions (IRR _0.49 0.65 _0.85 ) and LDKT (IRR _0.17 0.38 _0.84 ) _{in states with high vs low COVID activity. Transplant recipients during the pandemic were more likely to have received a DDKT, but had similar cPRA, waitlist time and cause of ESRD as before the pandemic. The COVID-19 pandemic initially reduced access to kidney transplantation among pediatric patients in the United States, but has not had a sustained effect.}

BACKGROUND:Kidney disease and dialysis significantly impact cognitive function across the age spectrum. Cognitive training (CT) and/or exercise training (ET) are promising approaches to preserve cognitive function among community-dwelling older adults, but have not been tested for cognition preservation in hemodialysis patients of all ages. In this manuscript, we summarize the protocol for the Interventions Made to Preserve Cognitive Function Trial (IMPCT). METHODS:We will perform a 2 × 2 factorial randomized controlled trial (RCT) of eligible adult (≥18 years) hemodialysis initiates (n = 200) to test whether intradialytic CT (brain games on a tablet PC), ET (foot peddlers) and combined CT + ET while undergoing hemodialysis preserves executive function compared to standard of care (SC). Participants will engage in the interventions to which they are randomized for 6 months. The primary objective is to compare, among interventions, the 3-month change in executive function measured using the Trail Making Test A (TMTA) and B (TMTB); specifically, executive function is calculated as TMTB-TMTA to account for psychomotor speed. This primary outcome was selected based on findings from our pilot study. The secondary objectives are to compare the risk of secondary cognitive outcomes, ESKD-specific clinical outcomes, and patient-centered outcomes at 3-months and 6-months. All data collection and interventions are conducted in the dialysis center. DISCUSSION:We hypothesize that receiving intradialytic CT or ET will better preserve executive function than SC but receiving combined CT + ET, will be the most effective intervention. The current trial will be an important step in understanding how intradialytic interventions might preserve cognitive health. TRIAL REGISTRATION:Clinicaltrials.Gov (Date: 8/6/18): # NCT03616535 . Protocol Version: 10 (April 2020). FUNDING:NIDDK R01DK114074.

BACKGROUND:HIV-infected (HIV+) donor to HIV+ recipient (HIV D+/R+) transplantation might improve access to transplantation for people living with HIV. However, it remains unknown whether transplant candidates living with HIV will accept the currently unknown risks of HIV D+/R+ transplantation. METHODS:We surveyed transplant candidates living with HIV from 9 US transplant centers regarding willingness to accept HIV+ donor organs. RESULTS:Among 116 participants, the median age was 55 years, 68% were men, and 78% were African American. Most were willing to accept HIV+ living donor organs (87%), HIV+ deceased donor organs (84%), and increased infectious risk donor organs (70%). Some (30%) were concerned about HIV superinfection; even among these respondents, 71% were willing to accept an HIV D+ organ. Respondents from centers that had already performed a transplant under an HIV D+/R+ transplantation research protocol were more willing to accept HIV+ deceased donor organs (89% vs. 71%, P = 0.04). Respondents who chose not to enroll in an HIV D+/R+ transplantation research protocol were less likely to believe that HIV D+/R+ transplantation was safe (45% vs. 77%, P = 0.02), and that HIV D+ organs would work similar to HIV D- organs (55% vs. 77%, P = 0.04), but more likely to believe they would receive an infection other than HIV from an HIV D+ organ (64% vs. 13%, P < 0.01). CONCLUSIONS:Willingness to accept HIV D+ organs among transplant candidates living with HIV does not seem to be a major barrier to HIV D+/R+ transplantation and may increase with growing HIV D+/R+ transplantation experience.

BACKGROUND & AIMS:To date, studies evaluating the association between frailty and mortality in patients with cirrhosis have been limited to assessments of frailty at a single time point. We aimed to evaluate changes in frailty over time and their association with death/delisting in patients too sick for liver transplantation. METHODS:Adults with cirrhosis, listed for liver transplantation at 8 US centers, underwent ambulatory longitudinal frailty testing using the liver frailty index (LFI). We used multilevel linear mixed-effects regression to model and predict changes in LFI (ΔLFI) per 3 months, based on age, gender, model for end-stage liver disease (MELD)-Na, ascites, and hepatic encephalopathy, categorizing patients by frailty trajectories. Competing risk regression evaluated the subhazard ratio (sHR) of baseline LFI and predicted ΔLFI on death/delisting, with transplantation as the competing risk. RESULTS:We analyzed 2,851 visits from 1,093 outpatients with cirrhosis. Patients with severe worsening of frailty had worse baseline LFI and were more likely to have non-alcoholic fatty liver disease, diabetes, or dialysis-dependence. After a median follow-up of 11 months, 223 (20%) of the overall cohort died/were delisted because of sickness. The cumulative incidence of death/delisting increased by worsening ΔLFI group. In competing risk regression adjusted for baseline LFI, age, height, MELD-Na, and albumin, a 0.1 unit change in ΔLFI per 3 months was associated with a 2.04-fold increased risk of death/delisting (95% CI 1.35-3.09). CONCLUSION:Worsening frailty was significantly associated with death/delisting independent of baseline frailty and MELD-Na. Notably, patients who experienced improvements in frailty had a lower risk of death/delisting. Our data support the longitudinal measurement of frailty, using the LFI, in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty. LAY SUMMARY:Frailty, as measured at a single time point, is predictive of death in patients with cirrhosis, but whether changes in frailty over time are associated with death is unknown. In a study of over 1,000 patients with cirrhosis who underwent frailty testing, we demonstrate that worsening frailty is strongly linked with mortality, regardless of baseline frailty and liver disease severity. Notably, patients who experienced improvements in frailty over time had a lower risk of death/delisting. Our data support the longitudinal measurement of frailty in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty.

Simple (Bosniak I) renal cysts are considered acceptable in living kidney donor selection in terms of cancer risk. However, they tend to increase in number and size over time and might compromise renal function in donors. To clarify their implications for long-term renal function, we characterized the prevalence of renal cysts in 454 individuals who donated at our center from 2000 to 2007. We estimated the association between the presence of cysts in the kidney remaining after nephrectomy (ie, retained cysts) and postdonation eGFR trajectory using mixed-effects linear regression. Donors with retained cysts (N = 86) were older (P < .001) and had slightly lower predonation eGFR (median 94 vs 98 mL/min/1.73 m² , P < .01) than those without cysts. Over a median 7.8 years, donors with retained cysts had lower baseline eGFR (_-8.7 -5.6 _-2.3  mL/min/1.73 m² , P < .01) but similar yearly change in eGFR (_-0.4 0.02 _0.4  mL/min/1.73 m² , P = .2) compared to those without retained cysts. Adjusting for predonation characteristics, there was no difference in baseline eGFR (P = .6) or yearly change in eGFR (P > .9). There continued to be no evidence of an association when we considered retained cyst(s) ≥10 mm or multiple retained cysts (all P > .05). These findings reaffirm current practices of accepting candidates with simple renal cysts for donor nephrectomy.

The outcomes of benzodiazepine and opioid co-prescription are not well-defined in transplant populations. We examined linked national transplant registry and pharmaceutical records to characterize benzodiazepine and opioid use in the years before and after transplant in large US cohort of kidney transplant recipients (2007-2016; N = 98 620), and associations (adjusted hazard ratio, _LCL aHR_UCL ) with death and graft failure. Among the cohort, 15.6% filled benzodiazepine prescriptions in the year before transplant, and 14.0% filled benzodiazepine prescriptions in the year after transplant (short-acting, 9.5%; long-acting, 3.3%; both 1.1%). Use of short-acting benzodiazepines in the year before transplant was associated with a 22% increased risk of death in the year after transplant (aHR, _1.08 1.22_1.38 ), while use of all classes in the year after transplant was associated with increased risk of death from >1 to 5 years (aHR: short-acting _1.29 1.39_1.48 ; long-acting _1.12 1.25_1.40 ; both _1.46 1.74_2.07 ). Recipients who used benzodiazepines were also more likely to fill opioid prescriptions. Recipients who filled both classes of benzodiazepine and the highest level of opioids had a 2.9-fold increased risk of death compared to recipients who did not use either. Co-prescription of benzodiazepines and opioids in kidney transplant recipients is associated with increased mortality. Ongoing research is needed to understand mechanisms of risk relationships.