Faculty Bibliography

BACKGROUND:Kidney transplantation (KT) candidates often present with multiple comorbidities. These patients also have a substantial burden of frailty, which is also associated with increased mortality. However, it is unknown if frailty is merely a surrogate for comorbidity, itself an independent domain of risk, or if frailty and comorbidity have differential effects. Better understanding the interplay between these 2 constructs will improve clinical decision making in KT candidates. OBJECTIVE:To test whether comorbidity is equally associated with waitlist mortality among frail and nonfrail KT candidates and to test whether measuring both comorbidity burden and frailty improves mortality risk prediction. METHODS:We studied 2,086 candidates on the KT waitlist (November 2009 - October 2017) in a multicenter cohort study, in whom frailty and comorbidity were measured at evaluation. We quantified the association between Charlson comorbidity index (CCI) adapted for end-stage renal disease and waitlist mortality using an adjusted Cox proportional hazards model and tested whether this association differed between frail and nonfrail candidates. RESULTS:At evaluation, 18.1% of KT candidates were frail and 51% had a high comorbidity burden (CCI score ≥2). Candidates with a high comorbidity burden were at 1.38-fold (95% CI 1.01-1.89) increased risk of waitlist mortality. However, this association differed by frailty status (p for interaction = 0.01): among nonfrail candidates, a high comorbidity burden was associated with a 1.66-fold (95% CI 1.17-2.35) increased mortality risk; among frail candidates, here was no statistically significant association (HR 0.75, 95% CI 0.44-1.29). Adding this interaction between comorbidity and frailty to a mortality risk estimation model significantly improved prediction, increasing the c-statistic from 0.640 to 0.656 (p < 0.001). CONCLUSIONS:Nonfrail candidates with a high comorbidity burden at KT evaluation have an increased risk of waitlist mortality. Importantly, comorbidity is less of a concern in already high-risk patients who are frail.

BACKGROUND & AIMS:Frailty is associated with mortality in patients with cirrhosis. We measured frailty using 3 simple tests and calculated Liver Frailty Index (LFI) scores for patients at multiple ambulatory centers. We investigated associations between LFI scores, ascites, and hepatic encephalopathy (HE) and mortality. METHODS:Adults without hepatocellular carcinoma who were on the liver transplantation waitlist at 9 centers in the United States (N = 1044) were evaluated using the LFI; LFI scores of at least 4.5 indicated that patients were frail. We performed logistic regression analyses to assess associations between frailty and ascites or HE and competing risk regression analyses (with liver transplantation as the competing risk) to estimate sub-hazard ratios (sHRs) of waitlist mortality (death or removal from the waitlist). RESULTS:Of study subjects, 36% had ascites, 41% had HE, and 25% were frail. The odds of frailty were higher for patients with ascites (adjusted odd ratio 1.56, 95% confidence interval [CI] 1.15-2.14) or HE (odd ratio 2.45, 95% CI 1.80-3.33) than for those without these features. Larger proportions of frail patients with ascites (29%) or HE (30%) died while on the waitlist compared with patients who were not frail (17% of patients with ascites and 20% with HE). In univariable analysis, ascites (sHR 1.52, 95% CI 1.14-2.05), HE (sHR 1.84, 95% CI 1.38-2.45), and frailty (sHR 2.38, 95% CI 1.77-3.20) were associated with waitlist mortality. In adjusted models, only frailty remained significantly associated with waitlist mortality (sHR 1.82, 95% CI 1.31-2.52); ascites and HE were not. CONCLUSIONS:Frailty is a prevalent complication of cirrhosis that is observed more frequently in patients with ascites or HE and independently associated with waitlist mortality. LFI scores can be used to objectively quantify risk of death related to frailty-in excess of liver disease severity-in patients with cirrhosis.

BACKGROUND:Restoration of kidney function after kidney transplant generally improves cognitive function. It is unclear whether frail recipients, with higher susceptibility to surgical stressors, achieve such post-transplant cognitive improvements or whether they experience subsequent cognitive decline as they age with a functioning graft. METHODS:In this two-center cohort study, we assessed pretransplant frailty (Fried physical frailty phenotype) and cognitive function (Modified Mini-Mental State Examination) in adult kidney transplant recipients. To investigate potential short- and medium-term effects of frailty on post-transplant cognitive trajectories, we measured cognitive function up to 4 years post-transplant. Using an adjusted mixed effects model with a random slope (time) and intercept (person), we characterized post-transplant cognitive trajectories by pretransplant frailty, accounting for nonlinear trajectories. RESULTS:Of 665 recipients (mean age 52.0 years) followed for a median of 1.5 years, 15.0% were frail. After adjustment, pretransplant cognitive scores were significantly lower among frail patients compared with nonfrail patients (89.0 versus 90.8 points). By 3 months post-transplant, cognitive performance improved for both frail (slope =0.22 points per week) and nonfrail (slope =0.14 points per week) recipients. Between 1 and 4 years post-transplant, improvements plateaued among nonfrail recipients (slope =0.005 points per week), whereas cognitive function declined among frail recipients (slope =-0.04 points per week). At 4 years post-transplant, cognitive scores were 5.8 points lower for frail recipients compared with nonfrail recipients. CONCLUSIONS:On average, both frail and nonfrail recipients experience short-term cognitive improvement post-transplant. However, frailty is associated with medium-term cognitive decline post-transplant. Interventions to prevent cognitive decline among frail recipients should be identified.

BACKGROUND:Recipients of nonkidney solid organ transplants (nkSOT) are living longer, and 11%-18% will develop end stage renal disease (ESRD). While our general inclination is to treat nkSOT recipients who develop ESRD with a kidney transplant (KT), an increasing number are developing ESRD at an older age where KT may not be the most appropriate treatment. It is possible that the risk of older age and prior nkSOT might synergize to make KT too risky, but this has never been explored. METHODS:To examine death-censored graft loss and mortality for KT recipients with and without prior nkSOT, we used Scientific Registry of Transplant Recipients data to identify 42 089 older (age ≥65) KT recipients between 1995 and 2016. Additionally, to better understand treatment options for these patients and survival benefit of KT, we identified 5023 older (age ≥65) with prior nkSOT recipients listed for subsequent KT, of whom 863 received transplants. RESULTS:Compared with 41 159 older KT recipients without prior nkSOT, death-censored graft loss was similar (adjusted hazard ratio [aHR]: 1.13, 95% CI: 0.93-1.37, P = 0.2), but mortality (aHR: 1.40, 95% CI: 1.28-1.54, P < 0.001) was greater for older KT recipients with prior nkSOT. Nonetheless, in a survival benefit model (survival with versus without the transplant), among older prior nkSOT recipients, KT decreased the risk of mortality by more than half (aHR: 0.47, 95% CI: 0.42-0.54, P < 0.001). CONCLUSIONS:Older prior nkSOT recipients who subsequently develop ESRD derive survival benefit from KT, but graft longevity is limited by overall survival in this population. These findings can help guide patient counseling for this challenging population.

Importance:In light of the growing population of older adults in the United States, older donors (aged ≥70 years) represent an expansion of the donor pool; however, their organs are underused. Liver grafts from older donors were historically associated with poor outcomes and higher discard rates, but clinical protocols, organ allocation, and the donor pool have changed in the past 15 years. Objective:To evaluate trends in demographics, discard rates, and outcomes among older liver donors and transplant recipients of livers from older donors in a large national cohort. Design, Setting, and Participants:Prospective cohort study of 4127 liver grafts from older donors and 3350 liver-only recipients of older donor grafts and 78 990 liver grafts from younger donors (aged 18-69 years) and 64 907 liver-only recipients of younger donor grafts between January 1, 2003, and December 31, 2016, in the United States. The Scientific Registry of Transplant Recipients, which includes data on all transplant recipients in the United States that are submitted by members of the Organ Procurement and Transplantation Network, was used. Exposures:Year of liver transplant and age of liver donor. Main Outcomes and Measures:Odds of graft discard and posttransplant outcomes of all-cause graft loss and mortality. Results:In this study, 4127 liver grafts from older donors were recovered for liver transplant across the study period (2003-2016); 747 liver grafts from older donors were discarded, and 3350 liver grafts from older donors were used for liver-only recipients. After adjusting for donor characteristics other than age and accounting for Organ Procurement Organization-level variation, liver grafts from older donors were more likely to be discarded compared with liver grafts from younger donors in 2003-2006 (adjusted odds ratio [aOR], 1.97; 95% CI, 1.68-2.31), 2007-2009 (aOR, 2.55; 95% CI, 2.17-3.01), 2010-2013 (aOR, 2.04; 95% CI, 1.68-2.46), and 2013-2016 (aOR, 2.37; 95% CI, 1.96-2.86) (P < .001 for all). Transplants of liver grafts from older donors represented a progressively lower proportion of all adult liver transplants, from 6.0% (n = 258 recipients) in 2003 to 3.2% (n = 211 recipients) in 2016 (P = .001). However, outcomes in recipients of grafts from older donors improved over time, with 40% lower graft loss risk (adjusted hazard ratio, 0.60; 95% CI, 0.53-0.68; P < .001) and 41% lower mortality risk (adjusted hazard ratio, 0.59; 95% CI, 0.52-0.68; P < .001) in 2010 through 2016 vs 2003 through 2009; these results were beyond the general temporal improvements in graft loss (interaction P = .03) and mortality risk (interaction P = .04) among recipients of liver grafts from younger donors. Conclusions and Relevance:These findings show that from 2003 to 2016, liver graft loss and mortality among recipients of liver grafts from older donors improved; however, liver graft discard from older donors remained increased and the number of transplants performed with liver grafts from older donors decreased. Expansion of the donor pool through broader use of liver grafts from older donors might be reasonable.

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.

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.

BACKGROUND:Inflammation is more common among African Americans (AAs), and it is associated with frailty, poor physical performance, and mortality in community-dwelling older adults. Given the elevated inflammation levels among end-stage renal disease (ESRD) patients, inflammation may be associated with adverse health outcomes such as frailty, physical impairment, and poor health-related quality of life (HRQOL), and these associations may differ between AA and non-AA ESRD patients. METHODS:One thousand three ESRD participants were recruited at kidney transplant evaluation (4/2014-5/2017), and inflammatory markers (interleukin-6 [IL-6], tumor necrosis factor-a receptor-1 [TNFR1], C-reactive protein [CRP]) were measured. We quantified the association with frailty (Fried phenotype), physical impairment (Short Physical Performance Battery [SPPB]), and fair/poor HRQOL at evaluation using adjusted modified Poisson regression and tested whether these associations differed by race (AA vs. non-AA). RESULTS:Non-AAs had lower levels of TNFR1 (9.7 ng/ml vs 14.0 ng/ml, p < 0.001) and inflammatory index (6.7 vs 6.8, p < 0.001) compared to AAs, but similar levels of IL-6 (4.5 pg/ml vs 4.3 pg/ml, p > 0.9) and CRP (4.7 μg/ml vs 4.9 μg/ml, p = 0.4). Non-AAs had an increased risk of frailty with elevated IL-6 (RR = 1.58, 95% CI:1.27-1.96, p < 0.001), TNFR1 (RR = 1.60, 95% CI:1.25-2.05, p < 0.001), CRP (RR = 1.41, 95% CI:1.10-1.82, p < 0.01), and inflammatory index (RR = 1.82, 95% CI:1.44-2.31, p < 0.001). The associations between elevated inflammatory markers and frailty were not present among AAs. Similar results were seen with SPPB impairment and poor/fair HRQOL. CONCLUSIONS:Non-AAs with elevated inflammatory markers may need closer follow-up and may benefit from prehabilitation to improve physical function, reduce frailty burden, and improve quality of life prior to transplant.

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.