Frailty Changes After Liver Transplantation. Results From a Spanish Multicenter Prospective Cohort Study.

Introduction: Until now, there has been limited evidence, primarily from US cohorts, focusing on frailty as a patient-oriented outcome after liver transplantation (LT). Our study aimed to explore the relationship between pre- and post-LT frailty in a multicenter European cohort of outpatients with cirrhosis undergoing LT. Methods: We conducted a prospective analysis of data from 180 LT recipients recruited between 2018 and 2020 from 5 Spanish centers. Participants underwent objective and subjective frailty assessments using the Liver Frailty Index (LFI) and the Subjective Clinician Assessment (SCA) pretransplant and at 3- and/or 6-mo posttransplant. Results: The median pretransplant LFI was 3.9, showing minimal change at 3 mo (3.8; P = 0.331) and improvement at 6-mo post-LT (3.6; P = 0.001). Conversely, the SCA significantly improved early post-LT: at 3 mo, poor SCA decreased from 11% to 1%, and good SCA increased from 54% to 89% (P < 0.001), remaining stable between 3- and 6-mo post-LT. Multivariable analysis revealed that each 0.1 increase in pretransplant LFI correlated with a reduced probability of being robust at 3-mo (odds ratio [OR] = 0.75; P < 0.001) and 6-mo post-LT (OR = 0.74; P < 0.001). There was poor concordance between SCA and LFI, with SCA underestimating frailty both pre- and post-LT (Kappa < 0.20). Conclusion: In our European cohort, incomplete improvement of physical frailty was observed, with <20% achieving robust physical condition within 6-mo post-LT. The pretransplant LFI strongly predicted posttransplant frailty. As the SCA tends to overestimate physical function, we recommend using both subjective and objective tools for frailty assessment in LT candidates and recipients.

Waiting time dictates impact of frailty: A Spanish multicenter prospective study.

Background & Aims: Frailty is prevalent in liver transplant (LT) candidates. It is considered an independent predictor of adverse outcomes pre- and post-transplant according to data obtained in the United States. We aimed to externally validate the liver frailty index (LFI) in a multicenter cohort of LT candidates. Methods: Outpatients with cirrhosis were prospectively recruited from five Spanish centers (2018-2020). Patients were defined as "frail" by an optimal cut-off of LFI ≥4.5. Patients were followed for at least 6 months to study associations of pre-LT frailty with pre- and post-transplant mortality, length of hospital and intensive care unit (ICU) stays, risk of early (<30 days) and late (30-90 days) post-transplant complications, retransplantation and cardiovascular events. Results: Of 212 patients included, 45 patients (21%) were frail pre-LT, and the median LFI was 3.9 (IQR 3.5-4.4). After a median waiting time of 78 days, 2% died or were delisted for clinical worsening. The LFI at baseline was not predictive of mortality/delisting in LT candidates in univariable or multivariable analyses after adjusting for age and MELD-Na score (hazard ratio 1.48; p = 0.586). In contrast, compared to non-frail patients, frail LT candidates had a significantly higher length of hospital stay (9 vs. 13 days; p = 0.001) and rate of early (<30 days) post-transplant complications (55% vs. 100%; p = 0.021). Conclusions: In the context of a short LT waiting time, frailty does not impact pretransplant mortality and/or delisting. In contrast, LT frailty is predictive of higher post-transplant complication rates and length of hospital stay. Whether strategies aimed at pre- and/or re-habilitation are beneficial in settings with short waiting times needs to be confirmed in prospective studies. Impact and implications: Literature is scarce on the actual impact of physical frailty on adverse outcomes in the liver transplant scenario outside North America. Evidence-based justification to extend the use of objective frailty tools in the decision-making processes in other liver transplant settings is needed. This study is the first to evaluate the predictive value of the liver frailty index in outpatients in the European liver transplant setting, showing that in a low MELD, high access system, frailty does not impact pretransplant mortality and/or delisting but is predictive of higher complication rates and longer post-transplant length of stay. In practical ways, physicians should consider physical frailty as a vital sign to be measured systematically and routinely during clinic visits; researchers are encouraged to initiate prospective studies to evaluate the benefit of applying strategies aimed at pre- and or re-habilitation in liver transplant settings with short waiting times.

Metabolic syndrome before liver transplantation: does it have an impact on post liver transplantation outcome?

Introduction: metabolic syndrome (MS) and cardiovascular risk factors are common in liver transplant (LT) candidates and recipients. Cardiovascular events and de novotumors are increasingly common causes of mortality inliver transplant recipients. The aims of this study were i)to assess the prevalence of MS in LT recipients and itsgrowth over the years, and ii) to determine if the presenceof MS pre-LT is associated with a higher risk of post-LTcardiovascular events (CVE), de novo tumors, or early andlate survival.Patients and methods: a retrospective study was performedthat included LT recipients from January 2012 to December2017. Baseline features (MS before LT and at 1year post-LT)and outcomes (CVE, de novo tumors and survival) wererecorded. Results: a total of 483 recipients were included, MS waspresent in 20 % of pre-LT subjects with an increasingprevalence over time, from 16 % in 2012 to 34 % in 2017(p = 0.025). One-year post-LT, an additional 12 % had developed de novo MS. At a median of 56 months of follow-up,13 % developed a CVE and 9 % a de novo tumor. One and5-year survival rates were 91 % and 83 % in those with preLT MS, and 93 % and 85 % in those without it (p = 0.94). Thepresence of MS before LT was independently associatedwith a higher risk of post-LT CVE (HR: 2.66, 95 % CI: 1.6-4.4,p < 0.001) but not with de novo tumors (p = 0.94) nor earlyand late survival (p = 0.58 and p = 0.87).Conclusion: pre-LT MS is increasing among LT candidatesand is associated with a higher risk of post-LT morbidity(CVE) yet without affecting mortality. (AU)

Metabolic syndrome before liver transplantation: does it have an impact on post liver transplantation outcome?

INTRODUCTION: Metabolic syndrome (MS) and cardiovascular risk factors are common in liver transplant (LT) candidates and recipients. Cardiovascular events and de novo tumors are increasingly common causes of mortality in liver transplant recipients. The aim of this study were (i) assess the prevalence of MS in LT recipients and its growth over the years and (ii) determine if the presence of MS pre-LT is associated with a higher risk of post-LT cardiovascular events (CVE), de novo tumors or early and late survival. PATIENTS AND METHODS: A retrospective study was performed that included LT recipients from January 2012 to December 2017. Baseline features (MS before LT and at 1year post-LT) and outcomes (CVE, de novo tumors and survival) were recorded. RESULTS: 483 recipients were included, MS was present in 20% of pre-LT with an increasing prevalence over time, from 16% in 2012 to 34% in 2017 (p=0.025). One-year post-LT, an additional 12% had developed de novo MS. At a median of 56-months follow-up, 13% developed a CVE and 9% a de novo tumor. One and 5-yr survival rates were 91% and 83% in those with pre-LT MS and 93% and 85% in those without (p=0.94).The presence of MS before LT was independently associated with a higher risk of post-LT CVE (HR: 2.66 IC (95%): 1.6-4.4 p< 0.001), but not with de novo tumors (p=0.94) nor early and late survival (p=0.58 and p=0.87). CONCLUSION: Pre-LT MS is increasing among LT candidates and is associated with a higher risk of post-LT morbidity CVE yet without affecting mortality. .

Non-guided self-learning program for high-proficiency optical diagnosis of diminutive and small colorectal lesions: A single-endoscopist pilot study.

BACKGROUND: The implementation of optical diagnosis (OD) of diminutive colorectal lesions in clinical practice has been hampered by differences in performance between community and academic settings. One possible cause is the lack of a standardized learning tool. Since the factors related to better learning are not well described, strong evidence upon which a consistent learning tool could be designed is lacking. We hypothesized that a self-designed learning program may be enough to achieve competency in OD of diminutive lesions of the colon. AIM: To assess the accuracy of OD of diminutive lesions in real colonoscopies after application of a self-administered learning program. METHODS: This was a single-endoscopist prospective pilot study, in which an experienced endoscopist followed a self-designed, self-administered learning program in OD of colorectal lesions. An assessment phase divided in two halves with a 6-mo period in between without performance of OD was developed in a population-based colorectal cancer screening program. The accomplishment of the Preservation and Incorporation of Valuable Endoscopic Innovations criteria and performance measures were calculated overall and in the two halves of the assessment phase, assessing their response to the 6-mo stopping period. The evolution of performance through blocks of 50 lesions was also assessed. RESULTS: Overall, 152 patients and 522 lesions (≤ 5 mm: 399, and 6-9 mm: 123) were included. The negative predictive value for the OD of adenoma in rectosigmoid lesions diagnosed with high confidence was 91.7% [95% confidence interval (CI): 87.3-96.6]. The proportion of agreement on surveillance interval between OD and pathological diagnosis was higher than 95%. Overall accuracy for diminutive lesions diagnosed with high confidence was 89.5% (95%CI: 86.3-92.7). The overall accuracy of OD was similar in the two halves of the assessment phase [90.1 (95%CI: 85.6-94.7) vs 88.2 (95%CI: 87.9-95.9)]. All the other performance parameters were also equivalent, except for specificity. Specificity, negative predictive value and accuracy were the parameters most affected by the stopping period between the two halves. Upon analyzing trends on blocks of 50 lesions, an improvement on sensitivity (P = 0.02) was detected only in the first half and an improvement on accuracy (P = 0.01) was detected only in the second half. CONCLUSION: A self-administered learning program is sufficient to achieve expert-level OD. To maintain performance, continuous practice is needed, with a refresher course following any long non-practice period.

Cytomegalovirus reactivation in liver transplant recipients due to hepatitis C cirrhosis is associated with higher cardiovascular risk - an observational, retrospective study.

The association between cytomegalovirus (CMV) reactivation and cardiovascular risk has been reported in solid organ transplant populations; however, it has yet to be assessed in liver transplantation (LT). We aim to evaluate whether CMV reactivation is associated with cardiovascular events (CVE) in HCV-LT patients. LT patients (2010 and 2014) due to HCV cirrhosis were included. Clinically significant CMV (CS-CMV) was defined as viral load (VL) >5000 copies/ml, need of therapy or CMV disease. Baseline variables and endpoint measures (CVE, survival, severe recurrent hepatitis C, de novo tumors, and diabetes) were collected. One hundred and forty patients were included. At LT, a history of AHT was present in 23%, diabetes 22%, tobacco use 45%, obesity 20%, and renal impairment (eGFR < 60 ml/min) in 26.5%. CS-CMV reactivation occurred in 25% of patients. Twenty-six patients (18.5%) developed a CVE. Cox regression analysis revealed two factors significantly associated with CVE: Pre-LT DM [HR = 4.6 95% CI (1.6, 13), P = 0.004] and CS-CMV [HR = 4.7 95% CI (1.8, 12.5), P = 0.002]. CS-CMV was not independently associated with the remaining endpoints except for survival (P = 0.03). In our series, CS-CMV reactivation was associated with a greater risk of developing CVE, thus confirming data from other solid organ transplant populations and emphasizing the need for adequate CMV control.

Association of Cardiac Abnormalities to the Frail Phenotype in Cirrhotic Patients on the Waitlist: From the Functional Assessment in Liver Transplantation Study.

BACKGROUND: Frailty is a syndrome of decreased physiologic reserve that results from compromise of multiple physiologic systems including cardiovascular system. We aimed to determine the association between the frail phenotype and cardiac abnormalities in liver transplant (LT) candidates through evaluation of transthoracic echocardiography (TTE) indices. METHODS: Included were consecutive outpatients listed for LT who underwent a frailty assessment from January 1, 2014, to June 30, 2016 (using the Liver Frailty Index) and a 2-dimensional/Doppler TTE examination. Patients were categorized as robust, intermediate frail, or frail by the Liver Frailty Index based on scores of less than 3.2, between 3.2 and 4.5, or 4.5 or greater. Linear regression assessed associations between the Liver Frailty Index and TTE indices. RESULTS: Of 335 patients, 19% were robust, 65% intermediate frail, and 16% frail. TTE indices of left atrial (LA) dilatation differed significantly by frailty status: median LA dimension (P = 0.03), LA volume index (LAVI mL/m; P < 0.001) and %LAVI > 34 mL/m (P = 0.001). In linear regression adjusted for age, sex, hypertension, and diabetes, the Liver Frailty Index was positively associated with LA dimension (coeff, 0.20; 95% confidence interval [CI], 0.07-0.34), LAVI mL/m (coeff, 0.01; 95% CI, 0.005-0.02), ejection fraction (coeff, 1.59; 95% CI, 0.32-2.85), and pulmonary artery systolic pressure (coeff, 0.01; 95% CI, 0.003-0.02), and negatively associated with LV hypertrophy (coeff, -0.22; 95% CI, -0.37 to -0.06). CONCLUSIONS: In LT candidates, frailty is associated with cardiac structural and functional changes, independent of known risk factors. Our study provides evidence to support that measures of frailty in cirrhotic patients encompass abnormalities of the cardiovascular system and may inform assessments of cardiovascular reserve in this population.

Real-World Multicenter Experience of Immunosuppression Minimization Among 661 Liver Transplant Recipients.

BACKGROUND Long-term morbidity and mortality in liver transplant recipients is frequently secondary to immunosuppression toxicity. However, data are scarce regarding immunosuppression minimization in clinical practice. MATERIAL AND METHODS In this cross-sectional, multicenter study, we reviewed the indications of immunosuppression minimization (defined as tacrolimus levels below 5 ng/mL or cyclosporine levels below 50 ng/mL) among 661 liver transplant recipients, as well as associated factors and the effect on renal function. RESULTS Fifty-three percent of the patients received minimized immunosuppression. The median time from transplantation to minimization was 32 months. The most frequent indications were renal insufficiency (49%), cardiovascular risk (19%), de novo malignancy (8%), and cardiovascular disease (7%). The factors associated with minimization were older age at transplantation, longer post-transplant follow-up, pre-transplant diabetes mellitus and renal dysfunction, and the hospital where the patients were being followed. The patients who were minimized because of renal insufficiency had a significant improvement in renal function (decrease of the median serum creatinine level, from 1.50 to 1.34 mg/dL; P=0.004). Renal function significantly improved in patients minimized for other indications, too. In the long term, glomerular filtration rate significantly decreased in non-minimized patients and remained stable in minimized patients. CONCLUSIONS Immunosuppression minimization is frequently undertaken in long-term liver transplant recipients, mainly for renal insufficiency. Substantial variability exists regarding the use of IS minimization among centers.

Framingham score, renal dysfunction, and cardiovascular risk in liver transplant patients.

Cardiovascular (CV) events represent major impediments to the long-term survival of liver transplantation (LT) patients. The aim of this study was to assess whether the Framingham risk score (FRS) at transplantation can predict the development of post-LT cardiovascular events (CVEs). Patients transplanted between 2006 and 2008 were included. Baseline features, CV risk factors, and CVEs occurring after LT (ischemic heart disease, stroke, heart failure, de novo arrhythmias, and peripheral arterial disease) were recorded. In total, 250 patients (69.6% men) with a median age of 56 years (range, 18-68 years) were included. At transplantation, 34.4%, 34.4%, and 33.2% of patients, respectively, had a low, moderate, and high FRS with a median FRS of 14.9 (range, 0.09-30); 14.4% of LT recipients developed at least 1 CVE at a median of 2.619 years (range, 0.006-6.945 years). In the univariate analysis, factors associated with the development of CVEs were the continuous FRS at LT (P = 0.003), age (P = 0.007), creatinine clearance [estimated glomerular filtration rate (eGFR); P = 0.020], and mycophenolate mofetil use at discharge (P = 0.011). In the multivariate analysis, only the eGFR [hazard ratio (HR), 0.98; 95% confidence interval (CI), 0.97-1.00; P = 0.009] and FRS (HR, 1.06; 95% CI, 1.02-1.10; P = 0.002) remained in the model. Moreover, an association was also found between the FRS and overall survival (P = 0.004) with 5-year survival rates of 82.5%, 77.8%, and 61.4% for the low-, moderate-, and high-risk groups, respectively. Continuous FRS, eGFR, and hepatitis C virus infection were independent risk factors for overall mortality. In our series, the FRS and eGFR at LT were able to predict the development of post-LT CVEs and poor outcomes. Liver Transpl 21:812-822, 2015. © 2015 AASLD.