Faculty Bibliography

Acute kidney injury (AKI) and frailty are major drivers of outcomes among patients with cirrhosis. What is unknown is the impact of physical frailty on the development of AKI. We included adults with cirrhosis without hepatocellular carcinoma listed for liver transplantation at nine US centers (n = 1,033). Frailty was assessed using the Liver Frailty Index (LFI); "frail" was defined by LFI ≥ 4.2. Chronic kidney disease as a baseline estimated glomerular filtration rate <60 mL/min/1.73 m² . Our primary outcome, AKI, was defined as an increase in serum creatinine ≥0.3 mg/dL or a serum creatinine ≥1.5-fold increase. Wait-list mortality was defined as either a death on the wait list or removal for being too sick. We performed Cox regression analyses to estimate the hazard ratios (HRs) for AKI and wait-list mortality. Of 1,033 participants, 41% were frail and 23% had CKD. Twenty-one percent had an episode of AKI during follow-up. Frail versus nonfrail patients were more likely to develop AKI (25% vs. 19%) and wait-list mortality (21% vs. 13%) (P < 0.01 for each). In multivariable Cox regression, each of the following groups was associated with a higher risk of AKI as compared with not frail/no CKD: frail/no CKD (adjusted HR [aHR] = 1.87, 95% confidence interval [CI] = 1.29-2.72); not frail/CKD (aHR = 4.30, CI = 2.88-6.42); and frail/CKD (aHR = 4.85, CI = 3.33-7.07). We use a readily available metric, LFI, to identify those patients with cirrhosis most at risk for AKI. We highlight that serum creatinine and creatinine-based estimations of glomerular filtration rate may not fully capture a patient's vulnerability to AKI among the frail phenotype. Conclusion: Our work lays the foundation for implementing physical frailty in clinical practice to identify AKI earlier, implement reno-protective strategies, and expedite liver transplantation.

BACKGROUND:Cognitive impairment is common among persons with chronic kidney disease (CKD) due in part to reduced kidney function. Given that physical activity (PA) is known to mitigate cognitive decline, we examined whether associations between CKD stage and global/domain-specific cognitive function differs by PA. METHODS:We leveraged 3,223 participants (aged≥60years) enrolled in National Health and Nutrition Examination Survey (NHANES,2011-2014), with at least one measure of objective cognitive function (immediate recall [CERAD-WL], delayed recall [CERAD-DR], verbal fluency [AF], executive function/processing speed [DSST], global [average of 4 tests]) or self-perceived memory decline [SCD]. We quantified the association between CKD stage (no CKD: eGFR≥60 mL/min/1.73m2 and albuminuria(ACR)<30 mg/g; stage G1-G3: eGFR≥60mL/min/1.73m2 and ACR≥30mg/g or eGFR 30-59mL/min/1.73m2; stage G4-G5: eGFR<30mL/min/1.73m2) and cognitive function using linear regression (objective measures) and logistic regression (SCD), accounting for sampling weights for nationally-representative estimates. We tested whether associations differed by physical activity (Global Physical Activity Questionnaire, high PA≥600MET*min/week vs. low PA<600MET*min/week) using a Wald test. RESULTS:Among NHANES participants, 34.9% had CKD stageG1-G3, 2.6% had stageG4-G5, and 50.7% had low PA. CKD stageG4-G5 was associated with lower global cognitive function (difference = -0.38SD, 95%CI:-0.62,-0.15). This association differed by PA (pinteraction = 0.01). Specifically, among participants with low PA, those with CKD stageG4-G5 had lower global cognitive function (difference = -0.57SD, 95%CI: -0.82,-0.31) compared to those without CKD. Among those with high PA, no difference was found (difference = 0.10SD, 95%CI:-0.29,0.49). Similarly, CKD stage was only associated with immediate recall, verbal fluency, executive function, and processing speed among those with low PA; no associations were observed for delayed recall or self-perceived memory decline. CONCLUSIONS:CKD is associated with lower objective cognitive function among those with low, but not high PA. Clinicians should consider screening older patients with CKD who have low PA for cognitive impairment and encourage them to meet PA guidelines.

Physical frailty and impaired cognition are common in patients with cirrhosis. Physical frailty can be assessed using performance-based tests, but the extent to which impaired cognition may impact performance is not well characterized. We assessed the relationship between impaired cognition and physical frailty in patients with cirrhosis. We enrolled 1,623 ambulatory adult patients with cirrhosis waiting for liver transplantation at 10 sites. Frailty was assessed with the liver frailty index (LFI; "frail," LFI ≥ 4.4). Cognition was assessed at the same visit with the number connection test (NCT); continuous "impaired cognition" was examined in primary analysis, with longer NCT (more seconds) indicating worse impaired cognition. For descriptive statistics, "impaired cognition" was NCT ≥ 45 seconds. Linear regression associated frailty and impaired cognition; competing risk regression estimated subhazard ratios (sHRs) of wait-list mortality (i.e., death/delisting for sickness). Median NCT was 41 seconds, and 42% had impaired cognition. Median LFI (4.2 vs. 3.8) and rates of frailty (38% vs. 20%) differed between those with and without impaired cognition. In adjusted analysis, every 10-second NCT increase associated with a 0.08-LFI increase (95% confidence interval [CI], 0.07-0.10). In univariable analysis, both frailty (sHR, 1.63; 95% CI, 1.43-1.87) and impaired cognition (sHR, 1.07; 95% CI, 1.04-1.10) associated with wait-list mortality. After adjustment, frailty but not impaired cognition remained significantly associated with wait-list mortality (sHR, 1.55; 95% CI, 1.33-1.79). Impaired cognition mediated 7.4% (95% CI, 2.0%-16.4%) of the total effect of frailty on 1-year wait-list mortality. Conclusion: Patients with cirrhosis with higher impaired cognition displayed higher rates of physical frailty, yet frailty independently associated with wait-list mortality while impaired cognition did not. Our data provide evidence for using the LFI to understand mortality risk in patients with cirrhosis, even when concurrent impaired cognition varies.

Despite a documented survival benefit, older liver donor (OLD, age ≥70) graft offers are frequently declined, with utilization worsening over the last decade. To understand how offer acceptance varies by center, we studied 1113 eventually transplanted OLD grafts from 2009 to 2017 using Scientific Registry of Transplant Recipients (SRTR) data and random-intercept multilevel logistic regression. To understand how center-level acceptance of OLD graft offers might be associated with waitlist and posttransplant outcomes, we studied all adult, actively listed, liver-only candidates and recipients during the study period using Poisson regression (transplant rate), competing risks regression (waitlist mortality), and Cox regression (posttransplant mortality). Among 117 centers, OLD offer acceptance ranged from 0 (23 centers) to 95 acceptances, with a median odds ratio of 2.88. Thus, a candidate may be three times as likely to receive an OLD graft simply by listing at a different center. Centers in the highest quartile (Q4) of OLD acceptance (accepted 39% of OLD offers) accepted more nationally shared organs (Q4 versus Q1: 14.1% versus 0.0%, P < 0.001) and had higher annual liver transplant volume (Q4 versus Q1: 80 versus 21, P < 0.001). After adjustment, nationally shared OLD offers (adjusted odds ratio [aOR]: 0.16, 95% confidence interval [CI]: 0.13-0.20) and offers to centers with higher median Model for End-Stage Liver Disease (MELD) at transplant (aOR: 0.74, 95% CI: 0.62-0.87) were less likely to be accepted. OLD offers to centers with higher annual transplant volume were more likely to be accepted (aOR: 1.21, 95% CI: 1.14-1.30). Additionally, candidates listed at centers within the highest quartile of OLD graft offer acceptance had higher deceased donor liver transplantation (DDLT) rates (adjusted incidence rate ratio: 1.45, 95% CI: 1.41-1.50), lower waitlist mortality (adjusted subhazard ratio: 0.76, 95% CI: 0.72-0.76), and similar posttransplant survival (adjusted hazard ratio: 0.93, 95% CI: 0.86-1.01) when compared with those listed at centers in the lowest quartile of OLD graft offer acceptance. The wide variation in OLD offer acceptance supports the need for optimizing the organ offer process and efficiently directing OLD offers to centers more likely to use them.

BACKGROUND:The purpose of this study was to evaluate outcomes in people with cystic fibrosis (CF) who underwent lung transplant (LT) at a transplant center with an accredited Cystic Fibrosis Care Center (CFCC) in the United States. METHODS:We reviewed the Scientific Registry of Transplant Recipients for all adult patients with CF who received a first-time LT from 2005 to 2018. The primary outcome was graft failure. Unadjusted Kaplan-Meier analysis and adjusted multilevel Cox proportional hazards models were used to evaluate outcomes in CF patients undergoing lung transplantation at a CFCC. RESULTS:2,573 patients with CF underwent a first time LT during the study period. Of the 68 lung transplantation centers, 50 were CFCCs (73.5%). After adjustment for potential confounders, patients who underwent lung transplantation at a hospital with an accredited CFCC had a 33% reduction in risk of death or re-transplantation compared to those transplanted at a hospital without an accredited CFCC (HR: 0.67, 95% CI: 0.56-0.82, p < 0.001). CONCLUSIONS:People with CF who undergo LT at a transplant center with a CFCC have improved graft survival and decreased need for re-transplantation compared to those who undergo LT at a non-CFCC, independent of volume.