Update on the management of the liver transplant patient.

REVIEW URRENT C OPINION

Update on the management of the liver transplant patient Allison J. Kwong a and Oren K. Fix b

Purpose of review To review and highlight recent literature regarding the medical management of adult patients undergoing liver transplantation. Recent findings The addition of serum sodium concentration to the model for end-stage liver disease (MELD) score more accurately predicts 90-day waitlist mortality. Predictors of waitlist mortality and posttransplant survival include lower albumin and the presence of ascites, varices, and encephalopathy, as well as more nontraditional predictors such as older age, obesity, frailty, and sarcopenia. Indications for liver transplantation are evolving with the advent of effective therapy for hepatitis C and the increased prevalence of nonalcoholic steatohepatitis. Disparities persist in the current allocation system, including geographic variation and MELD inflation for hepatocellular carcinoma. Share 35 allows for broader regional sharing of organs for patients with the highest need, without detrimental effects on waitlist mortality or survival. Everolimus is a recently approved option for posttransplant immunosuppression that spares renal function. Summary The MELD score has enabled the liver transplant community to equitably allocate organs. Recent literature has focused on the limitations of the MELD score and the disparities inherent in the current system. The next steps for liver transplantation will be to develop strategies to further optimize waitlist prioritization and organ allocation. Keywords allocation, liver transplantation, model for end-stage liver disease, updates, waiting list

INTRODUCTION Candidate selection for liver transplantation is a complex process. Since 2002, organ allocation in the United States has been determined by the model for end-stage liver disease (MELD) score, an urgencybased system that commits to transplanting those in greatest need of a liver, that is, ‘sickest first’. Other countries have adopted similar allocation systems based on the MELD. In 2012, 6256 adult liver transplants were performed in the United States [1 ]. Compared with previous years, recipients were older (14.6% >65-years old), reflecting an aging population with chronic liver disease, and more obese [35.5% with a body mass index (BMI) >30 kg/m2]. There has been improved graft and patient survival overall, but in parallel with increased waitlist mortality and dropout in the face of a persistent organ shortage [1 ]. Europe has reported similar trends and transplant outcomes, with 82% 1-year and 71% 5-year survival [2].

End-stage liver disease (ESLD) due to hepatitis C virus (HCV) infection remains the primary indication for liver transplantation, though transplantation for nonalcoholic steatohepatitis (NASH) is increasing and is expected to overtake HCV, especially with new effective therapies for HCV [3,4]. Due to MELD exceptions, the rate of transplantation for hepatocellular carcinoma (HCC) in the United States continues to outpace the rate of those without exception points.

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a Department of Medicine, University of California, San Francisco, California and bOrgan Transplant Department, Swedish Medical Center, Seattle, Washington, USA

Correspondence to Oren K. Fix, MD, MSc, FACP, AGAF, Organ Transplant Department, Swedish Medical Center, 1101 Madison Street Suite 200, Seattle, WA 98104-1321, USA. Tel: +1 206 386 3660; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:224–232 DOI:10.1097/MOG.0000000000000173 Volume 31 Number 3 May 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Management of the liver transplant patient Kwong and Fix

KEY POINTS Indications for liver transplantation are evolving with the advent of effective antiviral therapy for hepatitis C, and the increased prevalence of NASH. The addition of serum sodium concentration to the MELD score more accurately predicts 90-day waitlist mortality, particularly in low MELD patients. It is becoming increasingly important to address disparities in the current allocation system, including MELD inflation for HCC and geographic variation. Everolimus-based immunosuppression can reduce exposure to tacrolimus and spare renal function after liver transplantation.

components of the MELD, and is superior to MELDNa in predicting 3-month mortality. Expanded models using such variables may be able to more accurately predict short-term mortality on the waitlist and can help risk-stratify patients awaiting liver transplantation, particularly among those with lower MELD scores. Studies of patients with low MELD, for example, less than 18, have revealed clinical factors such as ascites, varices, and hepatic encephalopathy to be predictive of waitlist mortality [10 ,11 ]. However, these subjective variables would be susceptible to manipulation if introduced into the allocation model, resurrecting the challenges encountered during the Child-Pugh era. The recognition of acute-on-chronic liver failure (ACLF) may also facilitate early identification of patients at high risk for waitlist mortality but nonetheless excellent posttransplant outcomes [12 ]. Similarly, the CLIF Consortium Acute Decompensation score predicts 3-month mortality better than the Child-Pugh, MELD, and MELD-Na scores in patients with acute decompensation but without ACLF [13 ]. The maximum liver function capacity (LiMAx) test quantitatively measures liver function using the liver’s ability to metabolize 13C-labeled methacetin [14 ,15 ]. The development and availability of LiMAx and other direct tests of liver function may circumvent the need for surrogate markers. &

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Despite overall improved outcomes and fairer allocation in the MELD era [5], there remain waitlist candidates whose mortality risk is underestimated by the MELD, with disproportionate rates of dropout and mortality on the waitlist. In addition to wide geographic variation, there is now recognition of subtler disparities, from race and sex to HCC and socioeconomic status.

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Prognosis, prediction, and staging The current organ allocation model is designed to capture the severity of liver disease, but it is increasingly recognized that factors beyond the MELD also influence waitlist outcomes, mortality, and perioperative risk. Variations of the MELD score have been proposed in order to better predict mortality on the waitlist and thus identify patients who may benefit from earlier transplantation or revised allocation policies. Serum sodium concentration is an important predictor of waitlist mortality, perhaps as a surrogate marker for the presence of ascites. This has prompted creation and validation of a MELD-Na score, which has been shown to more accurately predict 90-day mortality compared with MELD alone [6]. There is significant interaction between the MELD and the serum sodium concentration, suggesting that those with low MELD but nonetheless high risk of mortality may derive the most benefit from this revised score. Incorporation of the serum sodium concentration into the MELD-based United States allocation policy is anticipated in the near future. Albumin also predicts waitlist mortality, particularly for patients with MELD less than 20 [7 ]. Myers et al. [8 ,9 ] have proposed and validated a five-variable MELD (5vMELD), which includes serum albumin in addition to sodium and the usual &

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Obesity More patients undergoing liver transplantation meet criteria for obesity because of its rising prevalence in the developed world and the increased recognition and prevalence of NASH. Coincident with national trends, the proportion of recipients with a BMI greater than 30 kg/m2 has increased steadily, now accounting for 35% of the United States patients transplanted in 2012 [1 ]. Prior literature had been inconclusive regarding the effect of obesity on transplant outcomes, with some older evidence for decreased 5-year survival in patients with BMI greater than 35 kg/m2, and more contemporary data showing no survival difference in obese patients compared with those of normal weight [16–18]. In one recent study, patients with morbid obesity were sicker at the time of transplant and experienced higher posttransplant morbidity, including length of stay; however, there was no difference in 2-year patient and graft survival [19 ]. A similar effect was noted in a meta-analysis of obese liver transplant recipients, with no difference in mortality but higher morbidity, including postoperative infectious complications and mean intensive care and hospital lengths of stay [20 ].

0267-1379 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.

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More systematic investigation will be needed to identify obese patients who are at highest risk for poorer outcomes posttransplant, and how to best optimize them perioperatively. Exploratory studies in bariatric surgery, either at the time of transplant or afterward, have demonstrated effective posttransplant weight loss in those patients; this is an area that warrants further investigation given the obesity epidemic [21 ,22 ]. &

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major contributor to the frailty syndrome [31 ]. Sarcopenia, usually measured by psoas muscle thickness on computed tomography (CT) imaging, has been linked to increased mortality both pretransplant and posttransplant, as well as an increased incidence of infection and longer length of stay posttransplant [32 –35 ]. Morphometric age using parameters such as abdominal aortic calcification, psoas area, and psoas density have also been shown to predict mortality after liver transplantation better than chronologic age [36 ]. Frailty and sarcopenia are potentially modifiable risk factors that may be reversible with interventions such as physical therapy and nutritional support peritransplantation [31 ,37 ]. These factors, which take into account the nutritional and metabolic sequelae of ESLD, may one day be incorporated into allocation, risk stratification, and optimization of patients awaiting liver transplantation. Before they are put into more widespread use, these measures will need to be further validated beyond singlecenter studies. &

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Transplant in older adults Due to observed lower overall survival rates, liver transplantation in older adults is considered with caution. Nevertheless, there has been a steadily increasing trend toward older recipients in the United States and Europe; the number of recipients over 65 years made up 17.5% of patients transplanted in the United States in 2013 [2,23]. Four recent large national United States cohort studies and the European Liver Transplant Registry have confirmed increased 5-year mortality with increasing age and decreased long-term overall patient and graft survival for patients greater than 60-years old [2,24 –27 ]. However, this effect could be attenuated after propensity matching [26 ], competing risk analysis [25 ], or modeling for MELD less than 28 [24 ]. Transplant-specific variables, such as hospital length of stay, costs, and perioperative outcomes, did not appear to be affected by recipient age. Older adults experience decreased overall survival rates as they are prone to more comorbidities and frailty that are under-recognized by the current allocation system. However, selected older patients can benefit from liver transplantation, and the next challenge will be to better define which older patients benefit most and how to optimize their long-term outcomes. &

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Sarcopenia and frailty Functional status is an increasingly recognized predictor of outcomes both pretransplant and posttransplant, though definitions of frailty and how to evaluate it vary. Standard frailty assessments, adapted from geriatrics, have been used to successfully predict the risk of waitlist mortality, adjusted for the severity of liver disease [28 ]. Routine cardiopulmonary testing can also reliably predict both 90-day mortality and posttransplant survival [29 ,30]. Validated tools to evaluate frailty and functional status such as these may allow for objective assessments of patients and their ability to tolerate major surgery. Patients with cirrhosis, who have deranged energy metabolism and protein synthesis, are at high risk for skeletal muscle depletion, or sarcopenia, a &&

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ETIOLOGY The distribution of etiology among patients undergoing liver transplantation is set to change with the increasing burden of metabolic syndrome and NASH and new therapies for HCV.

Nonalcoholic steatohepatitis The number of transplants performed for NASH is increasing rapidly each year, from 1.2% in 2001 to 9.7% in 2009 [4,38 ]. NASH is now recognized as the most common cause of chronic liver disease in the United States and the third most common indication for liver transplantation [39], and has been projected to overtake HCV as the primary indication for liver transplantation in the next 10 years [4]. Due to their comorbidities, patients transplanted for NASH cirrhosis are at higher risk for cardiovascular events and death because of cardiovascular disease and sepsis compared with those transplanted for other causes of cirrhosis, such as alcoholic liver disease [40,41 ]. Nonetheless, transplantation for NASH cirrhosis results in excellent posttransplant outcomes and survival rates [42]. &

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Hepatitis C Patients with HCV have historically demonstrated worse posttransplant survival compared with transplantation for other causes of liver disease [43 ,44]. Without antiviral treatment, recurrent HCV after transplantation is nearly inevitable and leads to &

Volume 31 Number 3 May 2015


Management of the liver transplant patient Kwong and Fix

severe liver damage, graft loss, and death [44,45]. However, these outcomes can now be mitigated with effective treatments for HCV both pretransplant and posttransplant. Achieving sustained virologic response (SVR) either before or after transplantation prevents recurrent HCV, graft loss, and the need for retransplantation [46–49]. With the advent of all-oral directacting antiviral regimens, this can be achieved with remarkable efficacy and tolerability. Data now exist for sofosbuvir and ribavirin, either pretransplant [70% posttransplant SVR at week 12 (SVR12)] or posttransplant (70% SVR12) [50 ,51 ], and more recently, posttransplant ombitasvir-paritaprevirritonavir and dasabuvir with ribavirin for recipients with recurrent HCV (97% SVR12 and SVR24) [52 ]. Newer, effective regimens are now available, including sofosbuvir/ledipasvir, sofosbuvir/simeprevir, and sofosbuvir/daclatasvir, with or without ribavirin [53 ,54–56]. Treatment-experienced patients and those with advanced fibrosis and cirrhosis remain relatively challenging to treat, though the development of optimal therapies for these populations is evolving and advancing rapidly. &

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Alcoholic hepatitis Transplantation for alcoholic hepatitis is now recognized as a potentially life-saving procedure for those who do not respond to medical therapy [57]. Nonetheless, in the context of organ shortage and an already stringent selection process for transplant candidates, it continues to be highly controversial [58 ]. Most centers have implemented a 6-month abstinence policy prior to transplantation eligibility, though this cutoff is increasingly recognized as arbitrary, not predictive of recidivism, and unrealistic for patients with acute alcoholic hepatitis [59 ,60]. Models and systems to predict recidivism and graft loss may be able to better distinguish patients who will comply with posttransplant management and maintain abstinence from alcohol, and make transplant a viable option for selected patients with alcohol-related liver disease who do not respond to medical therapy. &

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United States between 2005 and 2012, 29.3% were listed with exception points. Overall, they exhibited shorter waitlist times (237 versus 426 days), higher rates of transplant (79 versus 40.6%), and lower waitlist mortality (4.5 versus 24.6%) compared with those without exception points [61 ]. &&

Hepatocellular carcinoma Liver transplantation for HCC is steadily increasing, now making up approximately 20% of patients transplanted in the United States and Europe [1 ,2]. Current adjustment policies for HCC in the United States have not changed since 2005, though nontransplant therapies have evolved over time and resulted in improved 5-year survival (77.2%) [62 ]. The quarterly adjustment score for patients with HCC allows patients to rapidly accrue points despite what is now a relatively low risk of dropout or death, disadvantaging patients without exception points [61 ]. Transplantation for HCC beyond Milan criteria, while still controversial, is increasingly accepted, generally following appropriate downstaging using locoregional therapy. With excellent posttransplant outcomes even for larger and more tumors, it has become more evident that not all HCC behaves similarly [63 ]. Certain tumor characteristics and response to locoregional therapy can predict recurrence after liver transplantation [64 ,65 ]. Paradoxically, longer time on the waitlist for patients with HCC predicts improved posttransplant survival and lower rates of recurrence [65 –67 ]. Longer waitlist time may select for more favorable tumor types at lower risk for posttransplant recurrence, as candidates with more aggressive tumors progress and become ineligible for transplant. As a result, an ‘ablate and wait’ approach, that is, locoregional therapy with institution of a mandatory wait time, has been proposed [68 ,69]. Models involving HCC size, number, a-fetoprotein (AFP), MELD, and response to locoregional therapy are being developed in order to better estimate transplant benefit for these patients [70 ,71 ]. &&

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Share 35 ALLOCATION Overall, outcomes and waitlist mortality have improved in the MELD era. However, allocation remains a challenge due to the persistent organ shortage, with disparities inherent in the current allocation system becoming more apparent. Though the exception point system was meant to balance and allow for equitable access to transplantation, it has become controversial [61 ]. Of adult liver transplantation candidates listed in the &&

A recent change to the United Network for Organ Sharing (UNOS) organ allocation through a policy called Share 35 commits to an urgency-based, ‘sickest first’ allocation system and provides for broader regional sharing of available organs, intended to decrease waitlist death and minimize the distance traveled by donor organs. In the year after implementation of Share 35, preliminary data have shown an increase in overall number of transplants, rate of transplantation for MELD greater than 35, median




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allocation MELD at the time of transplant, regional sharing, multiorgan transplants, and median distance traveled by donor organs (Table 1) [72 , 73,74]. There was no difference in median cold ischemic time and donor risk index (DRI), or in short-term waitlist mortality, 6-month posttransplant survival, or rate of organ discard [75 ]. &&

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liver-kidney (SLK) transplants, making up 7.7% of deceased donor liver transplantations in the United States in 2012 [82,83]. It remains challenging to reliably predict those who will recover renal function after transplant – 12% of patients listed for SLK transplants end up undergoing liver transplantation alone, of whom 33–87% recover renal function in the year following transplant [84 ,85 ]. However, receiving SLK did result in improved 5-year patient survival (76%) compared with liver transplantation alone (55%) [84 ]. Current consensus guidelines and proposals attempt to balance the optimal allocation of organs and the possibility of renal recovery. One such guideline suggests SLK for candidates with persistent acute kidney injury (with glomerular filtration rate 2–3 g/day, >30% glomerulosclerosis or interstitial fibrosis on biopsy, or metabolic disease) for more than 3 months [82,86 ]. These criteria would decrease the number of SLK transplants and may result in higher mortality among patients with liver disease and irreversible renal failure. Further investigation will be needed in order to evaluate patients for potential renal recovery and distinguish those who would benefit from SLK from those who may not require kidney transplantation. &

Access to liver transplantation and disparities

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Despite many steps toward improvement in the current allocation system, it is clear that certain populations remain disadvantaged. Geographic variation is well recognized: 1-year graft failure can range anywhere from 5.9 to 20.2% among centers, even when stratified by region and donor service area [76 ]. Long wait times in certain regions motivate patients with certain means to seek multiple listings and transplantation at other centers, resulting in even further disparity and higher mortality rates among patients with lower incomes [77]. Patients with lower socioeconomic status also experience decreased long-term survival posttransplant, independent of center, location, or recipient or donor characteristics [78 ]. In the United States, patients of male sex and African American race have decreased access to the waitlist, and African Americans experience lower overall and 5-year posttransplant survival [79 ,80]. Distance from a transplant center is also associated with a lower likelihood of being listed or transplanted [81 ]. &&

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ORGANS Following implementation of the MELD-based allocation system, prioritization of renal dysfunction has led to an increase in the number of simultaneous Table 1. Pros and cons of Share 35 Pro

Con

Increase in overall number of transplants More transplants for MELD 35

Increase in organ travel distance

Broader regional sharing

More organs discarded in certain regions [73]

Decrease in waitlist mortality

Potential increase in length of stay and costs

Increase in cold ischemic time

Impact on local donation [74]


Calcineurin inhibitors such as tacrolimus and cyclosporine are standard components of the posttransplant immunosuppressive regimen, but these are known to cause long-term renal toxicity. In 2013, everolimus was approved in the United States and Europe to prevent organ rejection in adult liver transplantation patients. An everolimus-based immunosuppressive strategy in patients after transplantation improves long-term renal function due to reduced tacrolimus levels, with acceptable tolerability (Table 2) [87 ,88 ,89 ]. Evidence remains mixed as to whether tacrolimus remains necessary with the use of everolimus, or if everolimus may be used effectively as monotherapy [89 ,90 ]. In addition, everolimus plays a role as an antineoplastic agent that can benefit patients transplanted with HCC. There is also a subpopulation of patients who may not require immunosuppression at all. In one study, 41 of 98 patients (42%) were able to discontinue all immunosuppressive drugs entirely, without evidence of rejection up to 3 years following withdrawal [91 ]. This is an attractive option for selected patients that deserves further investigation [92 ]. &

Share 35: regional sharing of livers to MELD/PELD 35 && candidates [72 ]

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IMMUNOSUPPRESSION

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Management of the liver transplant patient Kwong and Fix Table 2. Comparison of tacrolimus-containing and everolimus-containing regimens for initial immunosuppression in liver transplant recipients Tacrolimus (TAC)

TAC þ EVR

Everolimus (EVR)

Mechanism of action

Calcineurin inhibitor

mTOR inhibitor

Efficacy failure rate (treated biopsy-proven rejection, graft loss, and death) at 12 and 24 months Dosing

9.5%

6.5%

19.5%

TAC trough 8–12 ng/ml until month 4 and 6–10 ng/ml thereafter

EVR trough 3–8 ng/ml with TAC trough 3–5 ng/ml

Trough 6–12 ng/ml with calcineurin inhibitor elimination at month 4

Drug discontinuation for adverse events

14.1%

25.7%

Not applicable

Adverse effects

Decreased renal function at 12 and 24 months

Hyperlipidemia, leukopenia, peripheral edema, stomatitis, thrombocytopenia, hypertension, anemia

mTOR, mammalian target of rapamycin.

CONCLUSION The MELD score has enabled the liver transplant community to fairly prioritize patients for transplantation. Recent literature has focused on the limitations of the MELD score and the disparities inherent in the current system. The next steps for liver transplantation will be to develop strategies to improve the MELD score, mitigate MELD inflation for HCC, and develop policies for more equitable allocation. Acknowledgements None. Financial support and sponsorship This work was supported in part by Health Resources and Services Administration contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Kim WR, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 Annual Data Report: liver. Am J Transplant 2014; 14 (Suppl 1):69–96. The annual data report published by Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) summarizes key statistics and trends for patients listed and undergoing liver transplantation in the United States. 2. Adam R, Karam V, Delvart V, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol 2012; 57:675–688.

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3. Singal AK, Guturu P, Hmoud B, et al. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation 2013; 95:755–760. 4. Charlton MR, Burns JM, Pedersen RA, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141:1249–1253. 5. Freeman RB, Wiesner RH, Edwards E, et al. Results of the first year of the new liver allocation plan. Liver Transpl 2004; 10:7–15. 6. Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med 2008; 359:1018– 1026. 7. Porrett PM, Baranov E, Ter Horst M. Serum hypoalbuminemia predicts late & mortality on the liver transplant waiting list. Transplantation 2015; 99:158– 163. Low serum albumin predicts late mortality in 5-year follow-up, particularly among patients listed with MELD scores of 20 or less. 8. Myers RP, Shaheen AA, Faris P, et al. Revision of MELD to include serum & albumin improves prediction of mortality on the liver transplant waiting list. PLoS One 2013; 8:e51926. The use of a five-variable MELD, which includes albumin and sodium in addition to INR, bilirubin, and creatinine, to predict 90-day waitlist mortality is superior to MELD and MELD-Na. 9. Myers RP, Tandon P, Ney M, et al. Validation of the five-variable Model for End& stage Liver Disease (5vMELD) for prediction of mortality on the liver transplant waiting list. Liver Int 2014; 34:1176–1183. Hypoalbuminemia independently predicts mortality on the waitlist, and validation of a revised MELD score to include albumin and sodium can predict 1-year waitlist mortality with a c-statistic that is superior to MELD or MELD-Na. 10. Biselli M, Dall’agata M, Gramenzi A, et al. A new prognostic model to predict & dropout from the waiting list in cirrhotic candidates for liver transplantation with MELD score 40 kg/m2) made up 3.3% of all liver transplants in the linked University HealthSystem Consortium (UHC) and SRTR databases and were more likely to experience longer lengths of stay posttransplant but had similar 2-year patient and graft survival compared to those with BMI less than 40 kg/m2. 20. Hakeem AR, Cockbain AJ, Raza SS, et al. Increased morbidity in overweight & and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom. Liver Transpl 2013; 19:551–562. There is higher morbidity, but not mortality, in patients with BMI greater than 35 kg/ 2 m undergoing liver transplantation. 21. Heimbach JK, Watt KD, Poterucha JJ, et al. Combined liver transplantation & and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease. Am J Transplant 2013; 13:363–368. Substantial weight loss posttransplant was achieved in seven patients with BMI greater than 35 kg/m2 who underwent combined liver transplant and sleeve gastrectomy. 22. Al-Nowaylati AR, Al-Haddad BJ, Dorman RB, et al. Gastric bypass after liver & transplantation. Liver Transpl 2013; 19:1324–1329. Seven patients who underwent Roux-en-Y gastric bypass after orthotopic liver transplantation achieved improved glycemic control and significant weight loss. 23. Organ Procurement and Transplantation Network. Data. 2014; Available at: http://optn.transplant.hrsa.gov/converge/data/. [Accessed 1 December 214] 24. Sharpton SR, Feng S, Hameed B, et al. Combined effects of recipient age and & model for end-stage liver disease score on liver transplantation outcomes. Transplantation 2014; 98:557–562. In a study of 15 677 candidates listed between 2005 and 2010, age greater than 70 years was found to be independently associated with graft loss at 1 year (P < 0.001). In an age þ MELD model, there was higher-than-predicted risk of graft loss specifically if age was greater than 70 years and if MELD was greater than 28, though this effect was attenuated if MELD was less than 28. 25. Malinis MF, Chen S, Allore HG, Quagliarello VJ. Outcomes among older adult & liver transplantation recipients in the model of end stage liver disease (MELD) era. Ann Transplant 2014; 19:478–487. In a cohort of 35 686 candidates listed from 2002 to 2011, there was increased 5year mortality with increasing age. However, when adjusted for death as a competing risk, long-term (5-year) graft survival was not affected by recipient age. 26. Wilson GC, Quillin RC, Wima K, et al. Is liver transplantation safe and effective & in elderly (>/¼70 years) recipients? A case-controlled analysis. HPB (Oxford) 2014; 16:1088–1094. In a cohort of 12 445 patients using a linkage of the SRTR and UHC databases, there was worse long-term overall survival (P ¼ 0.009) at an age cutoff of 70 years, but this effect was not preserved when propensity matched. All other parameters and secondary outcomes, including graft survival, perioperative outcomes, costs, and length of stay, were similar in the two matched cohorts. 27. Kim J, Ko ME, Nelson RA, et al. Increasing age and survival after orthotopic & liver transplantation for patients with hepatocellular cancer. J Am Coll Surg 2014; 218:431–438. There was no difference in disease-specific survival (i.e., death from HCC) among patients with HCC aged 65 years or older compared with patients 50–64-years old. Patients aged 65 years and older did experience lower 5-year survival (60 versus 67%) and higher rate of death from nonhepatic causes (17.5 versus 13.7%), compared with patients aged 50–64. 28. Lai JC, Feng S, Terrault NA, et al. Frailty predicts waitlist mortality in liver && transplant candidates. Am J Transplant 2014; 14:1870–1879. Frailty is prevalent among liver transplant candidates and predicts mortality on the waitlist. 29. Ow MM, Erasmus P, Minto G, et al. Impaired functional capacity in potential & liver transplant candidates predicts short-term mortality before transplantation. Liver Transpl 2014; 20:1081–1088. Poorer performance and lower scores on cardiopulmonary exercise testing predict 90-day mortality in patients awaiting liver transplantation. &

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30. Prentis JM, Manas DM, Trenell MI, et al. Submaximal cardiopulmonary exercise testing predicts 90-day survival after liver transplantation. Liver Transpl 2012; 18:152–159. 31. Masuda T, Shirabe K, Ikegami T, et al. Sarcopenia is a prognostic factor in & living donor liver transplantation. Liver Transpl 2014; 20:401–407. Sarcopenia determined by psoas muscle area on preoperative CT scan independently predicts postoperative sepsis and mortality after living donor liver transplantation (LDLT), though this effect was attenuated with early enteral nutrition within 48 h after LDLT. 32. Durand F, Buyse S, Francoz C, et al. Prognostic value of muscle atrophy in & cirrhosis using psoas muscle thickness on computed tomography. J Hepatol 2014; 60:1151–1157. Transverse psoas muscle thickness divided by height measured by CT at the level of the umbilicus was associated with mortality, independent of the MELD and MELD-Na scores. Discrimination of a MELD-psoas score outperformed the MELD score and may be a more reliable score in patients with refractory ascites. 33. Krell RW, Kaul DR, Martin AR, et al. Association between sarcopenia and the & risk of serious infection among adults undergoing liver transplantation. Liver Transpl 2013; 19:1396–1402. Sarcopenia, determined by total psoas area on preoperative CT scan, was associated with higher risk of severe infection posttransplant, as well as 1-year mortality. 34. Hamaguchi Y, Kaido T, Okumura S, et al. Impact of quality as well as quantity & of skeletal muscle on outcomes after liver transplantation. Liver Transpl 2014; 20:1413–1419. Higher intramuscular adipose tissue content and lower psoas muscle mass index were associated with higher mortality after LDLT. 35. Kaido T, Ogawa K, Fujimoto Y, et al. Impact of sarcopenia on survival in & patients undergoing living donor liver transplantation. Am J Transplant 2013; 13:1549–1556. Sarcopenia measured by body composition analyzer predicted lower survival, though this effect was attenuated for patients who received perioperative nutritional therapy. 36. Waits SA, Kim EK, Terjimanian MN, et al. Morphometric age and mortality after & liver transplant. JAMA Surg 2014; 149:335–340. Calculated morphometric age, using psoas area, psoas density, and abdominal aorta calcification, in a series of 348 patients who underwent liver transplant, predicts overall mortality better than standard chronologic age. 37. Montano-Loza AJ, Meza-Junco J, Baracos VE, et al. Severe muscle depletion & predicts postoperative length of stay but is not associated with survival after liver transplantation. Liver Transpl 2014; 20:640–648. Sarcopenia, determined by the skeletal muscle cross-sectional area measured by CT, predicted longer hospital stays and higher frequency of bacterial infections in the first 90 days after transplantation. Sarcopenia in this study was not associated with increased mortality. 38. Kemmer N, Neff GW, Franco E, et al. Nonalcoholic fatty liver disease epidemic & and its implications for liver transplantation. Transplantation 2013; 96:860– 862. Liver transplantation for NASH is steadily increasing (7.7% in 2007–2010), particularly among recipients older than 65 years of age (10% in 2007, 13% in 2010). It is now the most common nonmalignant indication for liver transplantation in patients greater than 65-years old. There was also significant geographic and ethnic disparity: liver transplant recipients with NASH were more likely to be Caucasian than Hispanic, Asian, or African American. 39. Rinella ME, Loomba R, Caldwell SH, et al. Controversies in the diagnosis and management of NAFLD and NASH. Gastroenterol Hepatol (N Y) 2014; 10:219–227. 40. Vanwagner LB, Bhave M, Te HS, et al. Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events. Hepatology 2012; 56:1741–1750. 41. Wang X, Li J, Riaz DR, et al. Outcomes of liver transplantation for nonalcoholic && steatohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014; 12:394.e1–402.e1. A meta-analysis investigating outcomes for patients transplanted with NASH found similar rates of short-term and long-term survival up to 5 years after transplant, though they experienced greater risk of death from cardiovascular and infectious complications. 42. Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States. Liver Transpl 2012; 18:29–37. 43. Wong RJ, Chou C, Bonham CA, et al. Improved survival outcomes in patients & with nonalcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data. Clin Transplant 2014; 28:713–721. In the 2002–2012 UNOS registry, patients transplanted for NASH and alcoholic liver disease without HCC experienced higher posttransplant survival and lower rates of graft failure when compared with patients transplanted for HCV. 44. Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002; 122:889–896. 45. Sanchez-Fueyo A, Restrepo JC, Quinto L, et al. Impact of the recurrence of hepatitis C virus infection after liver transplantation on the long-term viability of the graft. Transplantation 2002; 73:56–63.



Management of the liver transplant patient Kwong and Fix 46. Everson GT, Terrault NA, Lok AS, et al. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation. Hepatology 2013; 57:1752–1762. 47. Picciotto FP, Tritto G, Lanza AG, et al. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation. J Hepatol 2007; 46:459–465. 48. Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant 2008; 8:679–687. 49. Carrion JA, Navasa M, Garcia-Retortillo M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology 2007; 132:1746–1756. 50. Curry MP, Forns X, Chung RT, et al. Sofosbuvir and ribavirin prevent & recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology 2015; 148:100–107. This is a phase 2 study of sofosbuvir and ribavirin for 48 weeks for patients with HCV cirrhosis, Child-Turcotte-Pugh score less than 7 prior to liver transplantation. This regimen resulted in 70% (30/43) posttransplant virologic response at week 12, with 23% recurrence. 51. Charlton M, Gane E, Manns MP, et al. Sofosbuvir and ribavirin for treatment of & compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterology 2015; 148:108–117. This is a pilot study of sofosbuvir and ribavirin for 24 weeks for patients with recurrent HCV infection after transplant (40% had cirrhosis). This regimen resulted in 70% SVR12, with 30% relapse. 52. Kwo PY, Mantry PS, Coakley E, et al. An interferon-free antiviral regimen for & HCV after liver transplantation. N Engl J Med 2014; 371:2375–2382. Thirty four liver transplant recipients with recurrent HCV received an interferon-free regimen of ombitasvir, ritonavir-boosted paritaprevir, dasabuvir, and ribavirin, with 97% SVR12. 53. Pellicelli AM, Montalbano M, Lionetti R, et al. Sofosbuvir plus daclatasvir for & posttransplant recurrent hepatitis C: potent antiviral activity but no clinical benefit if treatment is given late. Dig Liver Dis 2014; 46:923–927. A cohort of 18 patients received sofosbuvir and daclatasvir with or without ribavirin, with high virological efficacy in patients with recurrent hepatitis C after liver transplantation. 54. Reddy KR, Everson GT, Flamm SL, et al. Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with post transplant recurrence: preliminary results of a prospective, multicenter study. Hepatology 2014; 60:200A–201A. 55. Pungpapong S, Werner KT, Aqel B, et al. Multicenter experience using sofosbuvir and simeprevir with/without ribavirin to treat HCV genotype 1 after liver transplantation. Hepatology 2014; 60(S1):201A. 56. Bzowej NH, Joshi S, Therapondos G, et al. Posttransplant treatment of severe recurrent hepatitis C (HCV) with daclatasvir and sofosbuvir plus or minus ribavirin. Hepatology 2014; 60(S1):543A. 57. Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011; 365:1790–1800. 58. Donckier V, Lucidi V, Gustot T, Moreno C. Ethical considerations regarding & early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy. J Hepatol 2014; 60:866–871. An analysis of ethical principles as applied to transplantation for severe alcoholic hepatitis, concluding that there are no major ethical barriers to further exploring this option for appropriately selected patients. 59. Testino G, Burra P, Bonino F, et al. Acute alcoholic hepatitis, end stage & alcoholic liver disease and liver transplantation: an Italian position statement. World J Gastroenterol 2014; 20:14642–14651. An Italian position statement proposing an abbreviated mandatory period of sobriety prior to liver transplantation for selected patients with severe alcoholic hepatitis, recognizing the high mortality of alcoholic liver disease and the arbitrary – and impractical – nature of a 6-month waiting period for this patient population. 60. Singal AK, Chaha KS, Rasheed K, Anand BS. Liver transplantation in alcoholic liver disease: current status and controversies. World J Gastroenterol 2013; 19:5953–5963. 61. Northup PG, Intagliata NM, Shah NL, et al. Excess mortality on the liver && transplant waiting list: unintended policy consequences and model for End-stage Liver Disease (MELD) inflation. Hepatology 2015; 61:285– 291. Shorter waitlist times, higher rates of transplant, and lower waitlist mortality for liver transplant candidates listed with exception points. 62. Wong RJ, Devaki P, Nguyen L, et al. Increased long-term survival among & patients with hepatocellular carcinoma after implementation of Model for Endstage Liver Disease score. Clin Gastroenterol Hepatol 2014; 12:1534.e1– 1540.e1. Compared with 1998–2003, patients with HCC listed from 2004 to 2010 experienced increased 5-year survival across all treatment groups, including no therapy, locoregional therapy, resection, and transplantation. 63. Bittermann T, Niu B, Hoteit MA, Goldberg D. Waitlist priority for hepatocellular & carcinoma beyond Milan criteria: a potentially appropriate decision without a structured approach. Am J Transplant 2014; 14:79–87. Of 2184 patients listed with HCC, there was significantly higher risk of waitlist mortality and dropout for those exceeding UCSF criteria; however, posttransplant outcomes were similar.

64. Mehta N, Dodge JL, Goel A, et al. Identification of liver transplant candidates with hepatocellular carcinoma and a very low dropout risk: implications for the current organ allocation policy. Liver Transpl 2013; 19:1343–1353. Patients with one tumor of 2–3 cm, complete response after first locoregional therapy, and AFP level less than or equal to 20 ng/ml after first locoregional therapy experienced exceedingly low dropout rates of 1.3% at 1 year. 65. Schlansky B, Chen Y, Scott DL, et al. Waiting time predicts survival after liver && transplantation for hepatocellular carcinoma: a cohort study using the United Network for Organ Sharing registry. Liver Transpl 2014; 20:1045–1056. Higher MELD score at liver transplantation for HCC is associated with lower postliver transplantation mortality. 66. Samoylova ML, Dodge JL, Yao FY, Roberts JP. Time to transplantation as a && predictor of hepatocellular carcinoma recurrence after liver transplantation. Liver Transpl 2014; 20:937–944. In a cohort of 5002 liver transplant patients transplanted for HCC between 2006 and 2010, posttransplant HCC recurrence at 1 year was significantly lower for those patients who waited longer than 120 days (2.2 versus 3.9%, P ¼ 0.002), though this difference was not sustained at 2 years. With adjustment for tumor size, AFP, DRI, ablative therapy, and diagnosis, HCC recurrence risk was determined to be reduced by 40% for patients who waited more than 120 days. 67. Halazun KJ, Patzer RE, Rana AA, et al. Standing the test of time: outcomes of a && decade of prioritizing patients with hepatocellular carcinoma, results of the UNOS natural geographic experiment. Hepatology 2014; 60:1957–1962. Analysis of HCC patients stratified by UNOS region revealed increased waitlist mortality in regions with longer waiting times, as well as higher rates of locoregional therapy and higher stage tumors at listing. However, patients transplanted for HCC in those regions experienced better posttransplant survival compared with those transplanted in regions with shorter waiting times. 68. Chan SC, Sharr WW, Chok KS, et al. Wait and transplant for stage 2 & hepatocellular carcinoma with deceased-donor liver grafts. Transplantation 2013; 96:995–999. Initial experience after policy implementation of a mandatory 6-month wait after diagnosis and maintenance of stage 2 HCC showed excellent short-term and longterm survival after liver transplantation. 69. Roberts JP, Venook A, Kerlan R, Yao F. Hepatocellular carcinoma: ablate and wait versus rapid transplantation. Liver Transpl 2010; 16:925–929. 70. Toso C, Majno P, Berney T, et al. Validation of a dropout assessment model of & candidates with/without hepatocellular carcinoma on a common liver transplant waiting list. Transpl Int 2014; 27:686–695. Validation of a revised MELD score accounting for HCC size and number, AFP, and MELD that more accurately estimates the risk of dropout than the current MELD exception policy for HCC, and approximates a similar distribution of MELD scores for patient with non-HCC. 71. Vitale A, Volk ML, De Feo TM, et al. A method for establishing allocation equity & among patients with and without hepatocellular carcinoma on a common liver transplant waiting list. J Hepatol 2014; 60:290–297. A proposed model based on calculated transplant benefit to more equitably stratify patients with and without HCC awaiting liver transplantation. 72. OPTN Liver and Intestinal Organ Transplantation Committee Forum. Preli&& minary data analysis on the effect of Share 35 — broader regional sharing — in its first year after implementation. ‘‘Share 35’’ liver policy: Analysis at 1 year. 2014; Available at: http://transplantpro.org/wp-content/uploads/14-Share35_Edwards. pdf. [Accessed 1 December 2014] Preliminary data analysis on the effect of Share-35 — broader regional sharing — in its first year after implementation. 73. Trotter JF, Arenas JD, Bynon JS, et al. A preliminary analysis of liver allocation based on the ‘‘Share 35’’ policy in UNOS region 4. Hepatology 2014; 60(S1):260A–261A. 74. OPTN Liver and Intestinal Organ Transplantation Committee. Proposal for Regional Distribution of Livers for Critically Ill Candidates. 2012; Available at: http://optn.transplant.hrsa.gov/PublicComment/pubcommentPropSub_288. pdf. [Accessed 27 January 2015] 75. Gentry SE, Chow EK, Wickliffe CE, et al. Impact of broader sharing on the & transport time for deceased donor livers. Liver Transpl 2014; 20:1237–1243. A model of broader regional sharing per recent UNOS allocation policy changes showed no significant impact on cold ischemic times. 76. Asrani SK, Kim WR, Edwards EB, et al. Impact of the center on graft failure && after liver transplantation. Liver Transpl 2013; 19:957–964. 1-year rates of graft failure varied from 5.9% for the lowest quartile of centers to 20.2% for the highest quartile (independent of region and donor service area). Graft failure rates were not associated with a center’s annual liver transplantation volume, and the effect of center variation was consistent across DRI and MELD score quartiles. 77. Schwartz A, Schiano T, Kim-Schluger L, Florman S. Geographic disparity: the dilemma of lower socioeconomic status, multiple listing, and death on the liver transplant waiting list. Clin Transplant 2014; 28:1075–1079. 78. Quillin RC, Wilson GC, Wima K, et al. Neighborhood level effects of socio& economic status on liver transplant selection and recipient survival. Clin Gastroenterol Hepatol 2014; 12:1934–1941. Perioperative outcomes such as in-hospital mortality, 30-day readmissions, and length of stay did not differ among patients of lower and higher socioeconomic status. However, patients of low socioeconomic status experienced inferior 2-year survival posttransplant, independent of recipient or donor characteristics, transplant center, or location. &&




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Liver 79. Mathur AK, Ashby VB, Fuller DS, et al. Variation in access to the liver transplant waiting list in the United States. Transplantation 2014; 98: 94–99. SRTR and National Center for Health Statistics (NCHS) data from 1999 to 2006 were used to determine a ‘liver wait-listing ratio’ to evaluate access to care; significant disparities persist related to geography, race, and sex. 80. Wong RJ, Ahmed A. Combination of racial/ethnic and etiology/diseasespecific factors is associated with lower survival following liver transplantation in African Americans: an analysis from UNOS/OPTN database. Clin Transplant 2014; 28:755–761. 81. Goldberg DS, French B, Forde KA, et al. Association of distance from a & transplant center with access to waitlist placement, receipt of liver transplantation, and survival among US veterans. JAMA 2014; 311:1234–1243. Analysis of national Veterans Affairs data from 2003 to 2010 revealed that greater distance from a transplant center was associated with lower likelihood of listing and transplantation, and a greater likelihood of death. 82. Nadim MK, Sung RS, Davis CL, et al. Simultaneous liver-kidney transplantation summit: current state and future directions. Am J Transplant 2012; 12:2901–2908. 83. Davis CL, Feng S, Sung R, et al. Simultaneous liver-kidney transplantation: evaluation to decision making. Am J Transplant 2007; 7:1702–1709. 84. Hmoud B, Kuo YF, Wiesner RH, Singal AK. Outcomes of liver transplantation & alone after listing for simultaneous kidney: comparison to simultaneous liver kidney transplantation. Transplantation 2014. [Epub ahead of print] An analysis of patients listed for SLK transplantation compared with those who underwent SLK, those who received only a liver transplant had a higher rate of death within 2 days of transplantation (11 versus 0.5%), as well as higher 5-year mortality (48 versus 27%). 85. Brennan TV, Lunsford KE, Vagefi PA, et al. Renal outcomes of simultaneous & liver-kidney transplantation compared to liver transplant alone for candidates with renal dysfunction. Clin Transplant 2015; 29:34–43. A single-center study of patients with ESLD and renal failure who received liver transplant alone had worse 1-year posttransplant survival compared with patients who underwent SLK (80 versus 91%), though they also had higher MELD scores at transplant and were more likely to have HCV. 86. Chang Y, Gallon L, Jay C, et al. Comparative effectiveness of liver transplant & strategies for end-stage liver disease patients on renal replacement therapy. Liver Transpl 2014; 20:1034–1044. A model exploring different transplantation strategies for patients with ESLD and renal failure suggests that the survival benefit of SLK over sequential transplantation is maximal for patients with longer duration of pretransplant renal replacement therapy and highest MELD score. &

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87. Sterneck M, Kaiser GM, Heyne N, et al. Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation. Am J Transplant 2014; 14:701–710. This is a subgroup analysis of the PROTECT study population, of patients who received a calcineurin inhibitor-free everolimus-based immunosuppressive regimen, showing improved renal function over 3 years, with similar rates of biopsyproven acute rejection, graft loss, and death. 88. Saliba F, De Simone P, Nevens F, et al. Renal function at two years in liver && transplant patients receiving everolimus: results of a randomized, multicenter study. Am J Transplant 2013; 13:1734–1745. Patients assigned to transition to everolimus þ reduced-dose tacrolimus 30 days after transplantation experienced improved estimated glomerular filtration rate (77.6 versus 66.1 ml/min/1.73 m2) after 24 months, compared with a control group that received standard-dose tacrolimus. The everolimus-only arm was terminated prematurely due to increased biopsy-proven acute rejection. United States Food and Drug Administration approval of everolimus was granted based on this study. 89. Alegre C, Jimenez C, Manrique A, et al. Everolimus monotherapy or combined & therapy in liver transplantation: indications and results. Transplant Proc 2013; 45:1971–1974. A Spanish experience using everolimus posttransplant, either as monotherapy or in combination with other immunosuppressants, was generally well tolerated and resulted in improved renal function. 90. Fischer L, Klempnauer J, Beckebaum S, et al. A randomized, controlled study & to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation–PROTECT. Am J Transplant 2012; 12:1855–1865. This study demonstrated improved renal function in 101 patients after transition to everolimus 4 weeks posttransplant, with similar rates of mortality and biopsy-proven acute rejection compared with those who received standard dose tacrolimus. 91. Benitez C, Londono MC, Miquel R, et al. Prospective multicenter clinical trial & of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology 2013; 58:1824–1835. This study of 102 patients demonstrated successful withdrawal of immunosuppression in 41 of 98 patients, with no evidence of rejection on biopsy after 3 years. Factors predictive of success included time since transplantation [odds ratio (OR) 1.35] age (OR 1.073), and male sex (OR 4.66). 92. de la Garza RG, Sarobe P, Merino J, et al. Trial of complete weaning from & immunosuppression for liver transplant recipients: factors predictive of tolerance. Liver Transpl 2013; 19:937–944. This study of 24 patients investigated complete withdrawal of immunosuppression, with 62.5% tolerance at a median of 14 months. Factors predictive of success included time from transplantation (156 versus 71 months, P ¼ 0.003), and lower median phytohemagglutinin stimulation index. &



The adolescent liver transplant patient.

Care of the liver transplant patient.

Management of the hospitalized transplant patient.

Update in intensive care medicine: acute liver failure. Initial management, supportive treatment and who to transplant.

Challenges of recurrent hepatitis C in the liver transplant patient.

[Update on the management of trigeminal neuralgia].

Update on the management of rosacea.

Update on the management of anal fissure.

Hepatitis B Management in the Pregnant Patient: An Update.

Grover's Disease in a Liver Transplant Patient.

The impact of obesity on patient survival in liver transplant recipients: a meta-analysis.

Update on denosumab in the management of postmenopausal osteoporosis: patient preference and adherence.

Update on the management of overactive bladder: patient considerations and adherence.

Post-bone marrow transplant patient management.

When to consider liver transplant during the management of chronic liver disease.

Update on uveitis management.

Update on astigmatism management.

Update on the Management of Fecal Incontinence for the Gastroenterologist.

[Perioperative management for liver transplant in a patient with familial amyloid polyneuropathy with heart involvement].

V Consensus Meeting of the Spanish Society for Liver Transplant on high-risk recipients, immunosupression scenarios and management of hepatocarcinoma on the transplant waiting list.

Update on acute liver failure.

Alcoholic Liver Disease: Update on the Role of Dietary Fat.

An update on the management of bleeding disorders during pregnancy.

Update on the pathogenesis and management of pouchitis.