Faculty Bibliography

The construct of frailty was first developed in gerontology to help identify older adults with increased vulnerability when confronted with a health stressor. This article is a review of studies in which frailty has been applied to pre- and post-kidney transplantation (KT) populations. Although KT is the optimal treatment for end-stage kidney disease (ESKD), KT candidates often must overcome numerous health challenges associated with ESKD before receiving KT. After KT, the impacts of surgery and immunosuppression represent additional health stressors that disproportionately impact individuals with frailty. Frailty metrics could improve the ability to identify KT candidates and recipients at risk for adverse health outcomes and those who could potentially benefit from interventions to improve their frail status. The Physical Frailty Phenotype (PFP) is the most commonly used frailty metric in ESKD research, and KT recipients who are frail at KT (~20% of recipients) are twice as likely to die as nonfrail recipients. In addition to the PFP, many other metrics are currently used to assess pre- and post-KT vulnerability in research and clinical practice, underscoring the need for a disease-specific frailty metric that can be used to monitor KT candidates and recipients. Although frailty is an independent risk factor for post-transplant adverse outcomes, it is not factored into the current transplant program risk-adjustment equations. Future studies are needed to explore pre- and post-KT interventions to improve or prevent frailty.

We surveyed US transplant centers to assess practices regarding the evaluation and selection of living kidney donors based on metabolic, cardiovascular, and substance use risk factors. Our companion article describes renal aspects of the evaluation. Response rate was 31%. Compared with 2005, programs have become more accepting of hypertensive candidates: 65% in 2017% vs 41% in 2005 consider candidates with hypertension well controlled with 1 medication. One notable exception is black hypertensive candidates, who are frequently excluded regardless of severity. The most common body mass index (BMI) cutoff remains 35 kg/m² , and fewer programs now consider candidates with BMI >40 kg/m² . A 2-hour oral glucose tolerance test of ≥140 mg/dL remains the most common criterion for exclusion of prediabetic candidates. One quarter to one third of programs exclude based on isolated cardiac abnormalities, such as mild aortic stenosis; a similar proportion consider these candidates only if older than 50 years. Cigarette or marijuana smoking are infrequently criteria for exclusion, although 45% and 37% programs, respectively, require cessation 4 weeks prior to surgery. In addition to providing an overview of current practices in living kidney donor evaluation, our study highlights the importance of research evaluating outcomes with various comorbidities to guide practice.

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.

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.

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 AND OBJECTIVES:Black patients referred for kidney transplantation have surpassed many obstacles but likely face continued racial disparities before transplant. The mechanisms that underlie these disparities are unclear. We determined the contributions of socioeconomic status (SES) and comorbidities as mediators to disparities in listing and transplant. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:=1561 white) of patients with kidney failure who were referred for and started the transplant process (2009-2018). We estimated the direct and indirect effects of SES (self-reported income, education, and employment) and medical comorbidities (self-reported and chart-abstracted) as mediators of racial disparities in listing using Cox proportional hazards analysis with inverse odds ratio weighting. Among the 983 black and 1085 white candidates actively listed, we estimated the direct and indirect effects of SES and comorbidities as mediators of racial disparities on receipt of transplant using Poisson regression with inverse odds ratio weighting. RESULTS:Within the first year, 876 (60%) black and 1028 (66%) white patients were waitlisted. The relative risk of listing for black compared with white patients was 0.76 (95% confidence interval [95% CI], 0.69 to 0.83); after adjustment for SES and comorbidity, the relative risk was 0.90 (95% CI, 0.83 to 0.97). The proportion of the racial disparity in listing was explained by SES by 36% (95% CI, 26% to 57%), comorbidity by 44% (95% CI, 35% to 61%), and SES with comorbidity by 58% (95% CI, 44% to 85%). There were 409 (42%) black and 496 (45%) white listed candidates transplanted, with a median duration of follow-up of 3.9 (interquartile range, 1.2-7.1) and 2.8 (interquartile range, 0.8-6.3) years, respectively. The incidence rate ratio for black versus white candidates was 0.87 (95% CI, 0.79 to 0.96); SES and comorbidity did not explain the racial disparity. CONCLUSIONS:SES and comorbidity partially mediated racial disparities in listing but not for transplant.

An increasing number of studies claim machine learning (ML) predicts transplant outcomes more accurately. However, these claims were possibly confounded by other factors, namely, supplying new variables to ML models. To better understand the prospects of ML in transplantation, we compared ML to conventional regression in a "common" analytic task: predicting kidney transplant outcomes using national registry data. We studied 133 431 adult deceased-donor kidney transplant recipients between 2005 and 2017. Transplant centers were randomly divided into 70% training set (190 centers/97 787 recipients) and 30% validation set (82 centers/35 644 recipients). Using the training set, we performed regression and ML procedures [gradient boosting (GB) and random forests (RF)] to predict delayed graft function, one-year acute rejection, death-censored graft failure C, all-cause graft failure, and death. Their performances were compared on the validation set using -statistics. In predicting rejection, regression (C = _0.601 0.611_0.621 ) actually outperformed GB (C = _0.581 0.591_0.601 ) and RF (C = _0.569 0.579_0.589 ). For all other outcomes, the C-statistics were nearly identical across methods (delayed graft function, 0.717-0.723; death-censored graft failure, 0.637-0.642; all-cause graft failure, 0.633-0.635; and death, 0.705-0.708). Given its shortcomings in model interpretability and hypothesis testing, ML is advantageous only when it clearly outperforms conventional regression; in the case of transplant outcomes prediction, ML seems more hype than helpful.

We surveyed US transplant programs to assess practices used to assess kidney health in living kidney donor candidates in 2017; the response rate was 31%. In this report, we focus on the kidney; a companion piece focuses on the metabolic and cardiovascular aspects of candidate evaluation. Compared to 2005, programs have become more stringent in accepting younger candidates and less stringent in accepting older candidates. The 24-hour creatinine clearance remains the mainstay for kidney function assessment, with 74% continuing to use a value below 80 mL/min/1.73 m² for exclusion and 22% using age-based criteria. ApoL1 genotyping is obtained routinely or selectively by 45%, half of which use the high-risk genotype as an absolute exclusion criterion. For history of symptomatic stones, 49% accept if there is no current radiographic evidence of stones and urine profile is low risk, 80%-95% consider candidates with unilateral asymptomatic stones, but only 33%-48% consider if stones are bilateral. In addition, 14% use the risk assessment tool developed by Grams et al routinely for decision-making, and 42% use it sometimes. Also, 57% reported not having yet determined a risk threshold for acceptable postdonation risk above which candidates are excluded. Contemporary practice variation underscores the need for better evidence to guide the donor selection process.

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.

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence. The strengths of recommendations are provided in the full report. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.