Christine E. Haugen

Three-year Results of a Pilot Program in Early Liver Transplantation for Severe Alcoholic Hepatitis.

Objective: To examine our pilot to transplant selected patients with acute alcoholic hepatitis, initiated in October 2012. Background: Six months of alcohol abstinence is typically required before liver transplant. A Franco-Belgian protocol showed that early transplant in severe alcoholic hepatitis could improve survival with low incidence of alcohol relapse. Application of this controversial indication is growing despite unclear generalizability. Methods: Data was collected on all patients with alcohol-related liver disease since initiation of the pilot through June 2015. Patients were stratified into two groups: severe alcoholic hepatitis as first liver decompensation (Group 1), alcoholic cirrhosis with ≥6 months abstinence (Group 2). Alcohol relapse was defined as any evidence of alcohol consumption after transplant, which was assessed for harmful patterns of binge or frequent drinking. Results: Forty-three patients underwent liver transplant, including 17 patients in Group 1. Six-month survival was 100% versus 89% for Groups 1 and 2, respectively (P = 0.27). Alcohol relapse was similar in Group 1 versus Group 2: 23.5% versus 29.2% (P > 0.99). Harmful drinking was higher in Group 1 versus Group 2, despite lack of statistical significance: 23.5% versus 11.5% (P = 0.42). Conclusions: In this pilot with carefully selected patients, early liver transplant provided excellent short-term survival, and similar rates of alcohol relapse compared with patients with 6 months of abstinence. Harmful patterns of relapse remain challenging in this population, highlighting the need for validated models to predict alcohol relapse, and need for extreme caution in selecting patients for this exceptional indication. Larger prospective studies and longer follow up are necessary.

Individual Frailty Components and Mortality in Kidney Transplant Recipients

Background Frailty increases early hospital readmission and mortality risk among kidney transplantation (KT) recipients. Although frailty represents a high-risk state for this population, the correlates of frailty, the patterns of the 5 frailty components, and the risk associated with these patterns are unclear. Methods Six hundred sixty-three KT recipients were enrolled in a cohort study of frailty in transplantation (12/2008-8/2015). Frailty, activities of daily living (ADL)/instrumental ADL (IADL) disability, Centers for Epidemiologic Studies Depression Scale depression, education, and health-related quality of life (HRQOL) were measured. We used multinomial regression to identify frailty correlates. We identified which patterns of the 5 components were associated with mortality using adjusted Cox proportional hazards models. Results Frailty prevalence was 19.5%. Older recipients (adjusted prevalence ratio [PR], 2.22; 95% confidence interval [CI], 1.21-4.07) were more likely to be frail. The only other factors that were independently associated with frailty were IADL disability (PR, 3.22; 95% CI, 1.72-6.06), depressive symptoms (PR, 11.31; 95% CI, 4.02-31.82), less than a high school education (PR, 3.10; 95% CI, 1.30-7.36), and low HRQOL (fair/poor: PR, 3.71; 95% CI, 1.48-9.31). The most common pattern was poor grip strength, low physical activity, and slowed walk speed (19.4%). Only 2 patterns of the 5 components emerged as having an association with post-KT mortality. KT recipients with exhaustion and slowed walking speed (hazards ratio = 2.43; 95% CI, 1.17-5.03) and poor grip strength, exhaustion, and slowed walking speed (hazard ratio, 2.61; 95% CI, 1.14-5.97) were at increased mortality risk. Conclusions Age was the only conventional factor associated with frailty among KT recipients; however, factors rarely measured as part of clinical practice, namely, HRQOL, IADL disability, and depressive symptoms, were significant correlates of frailty. Redefining the frailty phenotype may be needed to improve risk stratification for KT recipients.

Frailty, Length of Stay, and Mortality in Kidney Transplant Recipients: A National Registry and Prospective Cohort Study

Objective: To test whether frailty, a novel measure of physiologic reserve, is associated with longer kidney transplant (KT) length of stay (LOS), and modifies the association between LOS and mortality. Background: Better understanding of LOS is necessary for informed consent and discharge planning. Mortality resulting from longer LOS has important regulatory implications for hospital and transplant programs. Which recipients are at risk of prolonged LOS and its effect on mortality are unclear. Frailty is a novel preoperative predictor of poor KT outcomes including delayed graft function, early hospital readmission, immunosuppression intolerance, and mortality. Methods: We used registry-augmented hybrid methods, a novel approach to risk adjustment, to adjust for LOS risk factors from the Scientific Registry of Transplant Recipients (n = 74,859) and tested whether (1) frailty, measured immediately before KT in a novel cohort (n = 589), was associated with LOS (LOS: negative binomial regression; LOS ≥2 weeks: logistic regression) and (2) whether frailty modified the association between LOS and mortality (interaction term analysis). Results: Frailty was independently associated with longer LOS [relative risk = 1.15, 95% confidence interval (CI): 1.03–1.29; P = 0.01] and LOS ≥2 weeks (odds ratio = 1.57, 95% CI: 1.06–2.33; P = 0.03) after accounting for registry-based risk factors, including delayed graft function. Frailty also attenuated the association between LOS and mortality (nonfrail hazard rate = 1.55 95% CI: 1.30–1.86; P < 0.001; frail hazard rate = 0.97, 95% CI: 0.79–1.19, P = 0.80; P for interaction = 0.001). Conclusions: Frail KT recipients are more likely to experience a longer LOS. Longer LOS among nonfrail recipients may be a marker of increased mortality risk. Frailty is a measure of physiologic reserve that may be an important clinical marker of longer surgical LOS.

Pre-Kidney Transplant Lower Extremity Impairment and Post-Kidney Transplant Mortality

Prediction models for post‐kidney transplantation mortality have had limited success (C‐statistics ≤0.70). Adding objective measures of potentially modifiable factors may improve prediction and, consequently, kidney transplant (KT) survival through intervention. The Short Physical Performance Battery (SPPB) is an easily administered objective test of lower extremity function consisting of three parts (balance, walking speed, chair stands), each with scores of 0–4, for a composite score of 0–12, with higher scores indicating better function. SPPB performance and frailty (Fried frailty phenotype) were assessed at admission for KT in a prospective cohort of 719 KT recipients at Johns Hopkins Hospital (8/2009 to 6/2016) and University of Michigan (2/2013 to 12/2016). The independent associations between SPPB impairment (SPPB composite score ≤10) and composite score with post‐KT mortality were tested using adjusted competing risks models treating graft failure as a competing risk. The 5‐year posttransplantation mortality for impaired recipients was 20.6% compared to 4.5% for unimpaired recipients (p < 0.001). Impaired recipients had a 2.30‐fold (adjusted hazard ratio [aHR] 2.30, 95% confidence interval [CI] 1.12–4.74, p = 0.02) increased risk of postkidney transplantation mortality compared to unimpaired recipients. Each one‐point decrease in SPPB score was independently associated with a 1.19‐fold (95% CI 1.09–1.30, p < 0.001) higher risk of post‐KT mortality. SPPB‐derived lower extremity function is a potentially highly useful and modifiable objective measure for pre‐KT risk prediction.

Kidney exchange match rates in a large multicenter clearinghouse

Kidney paired donation (KPD) can facilitate living donor transplantation for candidates with an incompatible donor, but requires waiting for a match while experiencing the morbidity of dialysis. The balance between waiting for KPD vs desensitization or deceased donor transplantation relies on the ability to estimate KPD wait times. We studied donor/candidate pairs in the National Kidney Registry (NKR), a large multicenter KPD clearinghouse, between October 2011 and September 2015 using a competing‐risk framework. Among 1894 candidates, 52% were male, median age was 50 years, 66% were white, 59% had blood type O, 42% had panel reactive antibody (PRA)>80, and 50% obtained KPD through NKR. Median times to KPD ranged from 2 months for candidates with ABO‐A and PRA 0, to over a year for candidates with ABO‐O or PRA 98+. Candidates with PRA 80‐97 and 98+ were 23% (95% confidence interval , 6%‐37%) and 83% (78%‐87%) less likely to be matched than PRA 0 candidates. ABO‐O candidates were 67% (61%‐73%) less likely to be matched than ABO‐A candidates. Candidates with ABO‐B or ABO‐O donors were 31% (10%‐56%) and 118% (82%‐162%) more likely to match than those with ABO‐A donors. Providers should counsel candidates about realistic, individualized expectations for KPD, especially in the context of their alternative treatment options.

MELD as a metric for survival benefit of liver transplantation

Currently, there is debate among the liver transplant community regarding the most appropriate mechanism for organ allocation: urgency‐based (MELD) versus utility‐based (survival benefit). We hypothesize that MELD and survival benefit are closely associated, and therefore, our current MELD‐based allocation already reflects utility‐based allocation. We used generalized gamma parametric models to quantify survival benefit of LT across MELD categories among 74 196 adult liver‐only active candidates between 2006 and 2016 in the United States. We calculated time ratios (TR) of relative life expectancy with transplantation versus without and calculated expected life years gained after LT. LT extended life expectancy (TR > 1) for patients with MELD > 10. The highest MELD was associated with the longest relative life expectancy (TR = 1.051.201.37 for MELD 11‐15, 2.292.492.70 for MELD 16‐20, 5.305.726.16 for MELD 21‐25, 15.1216.3517.67 for MELD 26‐30; 39.2643.2147.55 for MELD 31‐34; 120.04128.25137.02 for MELD 35‐40). As a result, candidates with the highest MELD gained the most life years after LT: 0.2, 1.5, 3.5, 5.8, 6.9, 7.2 years for MELD 11‐15, 16‐20, 21‐25, 26‐30, 31‐34, 35‐40, respectively. Therefore, prioritizing candidates by MELD remains a simple, effective strategy for prioritizing candidates with a higher transplant survival benefit over those with lower survival benefit.

Incidence, risk factors, and sequelae of post-kidney transplant delirium

Background Frail kidney transplant (KT) recipients may be particularly vulnerable to surgical stressors, resulting in delirium and subsequent adverse outcomes. We sought to identify the incidence, risk factors, and sequelae of post-KT delirium.Methods We studied 125,304 adult KT recipients (1999-2014) to estimate delirium incidence in national registry claims. Additionally, we used a validated chart abstraction algorithm to identify post-KT delirium in 893 adult recipients (2009-2017) from a cohort study of frailty. Delirium sequelae were identified using adjusted logistic regression (length of stay ≥2 weeks and institutional discharge [skilled nursing or rehabilitation facility]) and adjusted Cox regression (death-censored graft loss and mortality).Results Only 0.8% of KT recipients had a delirium claim. In the cohort study, delirium incidence increased with age (18-49 years old: 2.0%; 50-64 years old: 4.6%; 65-75 years old: 9.2%; and ≥75 years old: 13.8%) and frailty (9.0% versus 3.9%); 20.0% of frail recipients aged ≥75 years old experienced delirium. Frailty was independently associated with delirium (odds ratio [OR], 2.05; 95% confidence interval [95% CI], 1.02 to 4.13; P=0.04), but premorbid global cognitive function was not. Recipients with delirium had increased risks of ≥2-week length of stay (OR, 5.42; 95% CI, 2.76 to 10.66; P<0.001), institutional discharge (OR, 22.41; 95% CI, 7.85 to 63.98; P<0.001), graft loss (hazard ratio [HR], 2.73; 95% CI, 1.14 to 6.53; P=0.03), and mortality (HR, 3.12; 95% CI, 1.76 to 5.54; P<0.001).Conclusions Post-KT delirium is a strong risk factor for subsequent adverse outcomes, yet it is a clinical entity that is often missed.

Baseline and Center-Level Variation in Simultaneous Liver-Kidney Listing in the United States

Background The Organ Procurement and Transplantation Network has implemented medical criteria to determine which candidates are most appropriate for simultaneous liver-kidney (SLK) transplantation in comparison to liver-alone transplantation. We investigated prepolicy center-level variation among SLK listing practice, in light of such criteria. Methods We identified 4736 SLK-eligible candidates after Share-35 in the United States. We calculated the proportion of candidates at each center who were listed for SLK transplantation within 6 months of eligibility. Multilevel logistic regression and parametric survival model was used to estimate the center-specific probability of SLK listing, adjusting for patient and center-level characteristics. Results Among 4736 SLK-eligible candidates, 64.8% were listed for SLK within 6 months of eligibility. However, the percentage of SLK listing ranged from 0% to 100% across centers. African American race, male sex, transplant history, diabetes, and hypertension were associated with a higher likelihood of SLK listing. Conversely, older age was associated with a lower likelihood of SLK listing. After adjusting for candidate characteristics, the percentage of SLK listing still ranged from 3.8% to 80.2% across centers; this wide variation persisted even after further adjusting for center-level characteristics. Conclusions There was significant prepolicy center-level variation in SLK listing for SLK-eligible candidates. Implementation of standardized SLK listing practices may reduce center-level variation and equalize access for SLK candidates across the United States.

Frailty and Postkidney Transplant Health-Related Quality of Life

Background Health-related quality of life (HRQOL) reflects a patient’s disease burden, treatment effectiveness, and health status and is summarized by physical, mental, and kidney disease-specific scales among end-stage renal disease patients. Although on average HRQOL improves postkidney transplant (KT), the degree of change depends on the ability of the patient to withstand the stressor of dialysis versus the ability to tolerate the intense physiologic changes of KT. Frail KT recipients may be extra vulnerable to either of these stressors, thus affecting change in HRQOL after KT. Methods We ascertained frailty, as well as physical, mental, and kidney disease-specific HRQOL in a multicenter prospective cohort of 443 KT recipients (May 2014 to May 2017) using Kidney Disease Quality of Life Instrument Short Form. We quantified the short-term (3 months) rate of post-KT HRQOL change by frailty status using adjusted mixed-effects linear regression models. Results Mean HRQOL scores at KT were 43.3 (SD, 9.6) for physical, 52.8 (SD, 8.9) for mental, and 72.6 (SD, 12.8) for kidney disease-specific HRQOL; frail recipients had worse physical (P < 0.001) and kidney disease-specific HRQOL (P = 0.001), but similar mental HRQOL (P = 0.43). Frail recipients experienced significantly greater rates of improvement in physical HRQOL (frail, 1.35 points/month; 95% confidence interval [CI], 0.65-2.05; nonfrail, 0.34 points/month; 95% CI, −0.17-0.85; P = 0.02) and kidney disease-specific HRQOL (frail, 3.75 points/month; 95% CI, 2.89-4.60; nonfrail, 2.41 points/month; 95% CI, 1.78-3.04; P = 0.01), but no difference in mental HRQOL (frail, 0.54 points/month; 95% CI, −0.17-1.25; nonfrail, 0.46 points/month; 95% CI, −0.06-0.98; P = 0.85) post-KT. Conclusions Despite decreased physiologic reserve, frail recipients experience improvement in post-KT physical and kidney disease-specific HRQOL better than nonfrail recipients.

Inflammatory Frailty Index and Mortality after Kidney Transplantation

Frailty is a clinical phenotype of decreased physiologic reserve to stressors and is associated with a pro-inflammatory state. Fried frailty (measured by 5 components: slowed walk speed, unintentional weight loss, decreased grip strength, low physical activity, and exhaustion) was developed and validated in community dwelling older adults and is associated with poor outcomes after kidney transplant (KT) including mortality, longer length of stay after KT, early hospital readmission, and delayed graft function. However, Fried frailty does not directly capture inflammatory biomarkers like interleukin 6 (IL6) and tumor necrosis factor alpha (TNFalpha) that are associated with increased post-KT mortality. Therefore, we sought to identify a novel frailty index that combines inflammatory biomarkers and measured physical components. Methods We identified 378 KT recipients at Johns Hopkins Hospital from 2009-2013 who consented to enrollment in a prospective cohort. Fried frailty and inflammatory markers (IL6, TNFalpha, highly sensitive C reactive protein [(HSCRP]) were collected at the time of admission for KT. We evaluated novel inflammatory-frailty indices combining Fried frailty phenotype (comprised of 5 components) plus the addition of individual inflammatory biomarkers (highest tertile of IL6, TNFalpha, HSCRP, or inflammatory index, separately) as a 6th component. Therefore, scores for each novel inflammatory frailty index were 0-6 points, and the presence of ≥3 components was considered frail. We used Kaplan-Meier methods and Cox proportional hazards model to assess mortality risk after KT by inflammatory frailty index. We adjusted Cox models for recipient age, sex, race, Charlson comorbidity index, and donor type. Results Five-year survival for patients with and without each novel inflammatory frailty index for frail vs nonfrail was: 81% vs 93% (IL6-frailty), 87% vs 89% (HSCRP-frailty), 83% vs 91% (TNFalpha-frailty), and 83% vs 91% (Inflammatory index-frailty). After adjustment, mortality was 2.04-fold higher for IL6-frail recipients compared to non-IL6-frail (95%CI:1.02-4.10, p=0.05); there were no associations between the mortality and the other inflammatory-frailty indices (HSCRP-frail:1.01,95%CI:0.51-0.98,p=0.9; TNFalpha-frail:1.94,95%CI:0.98-3.83,p=0.06; or inflammatory index-frail:1.66,95%CI:0.84-3.30,p=0.14) recipients. After adjustment, mortality was similar between nonfrail and frail KT recipients measured with Fried frailty (1.63,95%CI:0.75-3.51, p=0.2) and the highest tertile of IL-6 (1.37,95%CI:0.68-2.73, p=0.4). Conclusions IL-6 frailty is a unique frailty phenotype, combining biomarkers and physical components that improves upon the Fried frailty phenotype and is more strongly associated with post-KT mortality. Measurement of biomarkers at KT evaluation and transplantation can guide risk assessment and patient counseling. National Institutes of Health. Figure. No caption available. Table. No title available.