Sandy Feng

Characteristics associated with liver graft failure: The concept of a donor risk index

Transplant physicians and candidates have become increasingly aware that donor characteristics significantly impact liver transplantation outcomes. Although the qualitative effect of individual donor variables are understood, the quantitative risk associated with combinations of characteristics are unclear. Using national data from 1998 to 2002, we developed a quantitative donor risk index. Cox regression models identified seven donor characteristics that independently predicted significantly increased risk of graft failure. Donor age over 40 years (and particularly over 60 years), donation after cardiac death (DCD), and split/partial grafts were strongly associated with graft failure, while African‐American race, less height, cerebrovascular accident and ‘other’ causes of brain death were more modestly but still significantly associated with graft failure. Grafts with an increased donor risk index have been preferentially transplanted into older candidates (>50 years of age) with moderate disease severity (nonstatus 1 with lower model for end‐stage liver disease (MELD) scores) and without hepatitis C. Quantitative assessment of the risk of donor liver graft failure using a donor risk index is useful to inform the process of organ acceptance.

National Conference to Assess Antibody-Mediated Rejection in Solid Organ Transplantation

The process of humoral rejection is multifaceted and has different manifestations in the various types of organ transplants. Because this process is emerging as a leading cause of graft loss, a conference was held in April 2003 to comprehensively address issues regarding humoral rejection.

Expanded criteria donors for kidney transplantation.

TransLife-Florida Hospital Medical Center, Orlando, FL Massachusetts General Hospital, Boston, MA University of California San Francisco, San Francisco, CA Scientific Registry of Transplant Recipients (SRTR)/ University Renal Research and Education Association (URREA), Ann Arbor, MI Medical College of Georgia, Augusta, GA SRTR/University of Michigan, Ann Arbor, MI *Corresponding author: Friedrich K. Port, fport@urrea.org

Excellent Outcome Following Down-Staging of Hepatocellular Carcinoma Prior to Liver Transplantation: An Intention-to-Treat Analysis

We previously reported encouraging results of down‐staging of hepatocellular carcinoma (HCC) to meet conventional T2 criteria (one lesion 2–5 cm or two to three lesions <3 cm) for orthotopic liver transplantation (OLT) in 30 patients as a test of concept. In this ongoing prospective study, we analyzed longer‐term outcome data on HCC down‐staging in a larger cohort of 61 patients with tumor stage exceeding T2 criteria who were enrolled between June 2002 and January 2007. Eligibility criteria for down‐staging included: (1) one lesion >5 cm and up to 8 cm; (2) two to three lesions with at least one lesion >3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or (3) four to five lesions with none >3 cm, with total tumor diameter up to 8 cm. A minimum observation period of 3 months after down‐staging was required before OLT. Tumor down‐staging was successful in 43 patients (70.5%). Thirty‐five patients (57.4%) had received OLT, including two who had undergone live‐donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent OLT, 13 had complete tumor necrosis, 17 met T2 criteria, and five exceeded T2 criteria. The Kaplan‐Meier intention‐to‐treat survival at 1 and 4 years after down‐staging were 87.5% and 69.3%, respectively. The 1‐year and 4‐year posttransplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median posttransplantation follow‐up of 25 months. The only factor predicting treatment failure was pretreatment alpha‐fetoprotein >1,000 ng/mL. Conclusion: Successful down‐staging of HCC can be achieved in the majority of carefully selected patients and is associated with excellent posttransplantation outcome. (HEPATOLOGY 2008.)

Report of the Crystal City Meeting to Maximize the Use of Organs Recovered from the Cadaver Donor

A consensus meeting to develop guidelines that would improve the recovery and transplantation of organs from the cadaver donor was held on 28–29 March 2001, in Crystal City, Virginia, sponsored by the American Society of Transplant Surgeons and the American Society of Transplantation. The crisis in organ supply persists and the continuing shortage presents a compelling responsibility for the transplant community to maximize the use of organs procured from cadaver donors.

The Survival Benefit of Deceased Donor Liver Transplantation as a Function of Candidate Disease Severity and Donor Quality

The survival benefit of liver transplantation depends on candidate disease severity, as measured by MELD score. However, donor liver quality may also affect survival benefit. Using US data from the SRTR on 28 165 adult liver transplant candidates wait‐listed between 2001 and 2005, we estimated survival benefit according to cross‐classifications of candidate MELD score and deceased donor risk index (DRI) using sequential stratification. Covariate‐adjusted hazard ratios (HR) were calculated for each liver transplant recipient at a given MELD with an organ of a given DRI, comparing posttransplant mortality to continued wait‐listing with possible later transplantation using a lower‐DRI organ. High‐DRI organs were more often transplanted into lower‐MELD recipients and vice versa. Compared to waiting for a lower‐DRI organ, the lowest‐MELD category recipients (MELD 6–8) who received high‐DRI organs experienced significantly higher mortality (HR = 3.70; p < 0.0005). All recipients with MELD ≥20 had a significant survival benefit from transplantation, regardless of DRI. Transplantation of high‐DRI organs is effective for high but not low‐MELD candidates. Pairing of high‐DRI livers with lower‐MELD candidates fails to maximize survival benefit and may deny lifesaving organs to high‐MELD candidates who are at high risk of death without transplantation.

Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality

Background. Recent studies suggest an association between diabetes mellitus and hepatitis C virus (HCV) infection. Our aim was to determine (1) the prevalence and determinants of new onset posttransplant diabetes mellitus (PTDM) in HCV (+) liver transplant (OLT) recipients, (2) the temporal relationship between recurrent allograft hepatitis and the onset of PTDM, and (3) the effects of antiviral therapy on glycemic control. Methods. Between January of 1991 and December of 1998, of 185 OLTs performed in 176 adult patients, 47 HCV (+) cases and 111 HCV (-) controls were analyzed. We reviewed and analyzed the demographics, etiology of liver failure, pretransplant alcohol abuse, prevalence of diabetes mellitus, and clinical characteristics of both groups. In HCV (+) patients, the development of recurrent allograft hepatitis and its therapy were also studied in detail. Results. The prevalence of pretransplant diabetes was similar in the two groups, whereas the prevalence of PTDM was significantly higher in HCV (+) than in HCV (-) patients (64% vs. 28%, P =0.0001). By multivariate analysis, HCV infection (hazard ratio 2.5, P =0.001) and methylprednisolone boluses (hazard ratio 1.09 per bolus, P =0.02) were found to be independent risk factors for the development of PTDM. Development of PTDM was found to be an independent risk factor for mortality (hazard ratio 3.67, P <0.0001). The cumulative mortality in HCV (+) PTDM (+) versus HCV (+) PTDM (-) patients was 56% vs. 14% (P =0.001). In HCV (+) patients with PTDM, we could identify two groups based on the temporal relationship between the allograft hepatitis and the onset of PTDM: 13 patients developed PTDM either before or in the absence of hepatitis (group A), and 12 concurrently with the diagnosis of hepatitis (group B). In gr. B, 11 of 12 patients received antiviral therapy. Normalization of liver function tests with improvement in viremia was achieved in 4 of 11 patients, who also demonstrated a marked improvement in their glycemic control. Conclusion. We found a high prevalence of PTDM in HCV (+) recipients. PTDM after OLT was associated with significantly increased mortality. HCV infection and methylprednisolone boluses were found to be independent risk factors for the development of PTDM. In approximately half of the HCV (+) patients with PTDM, the onset of PTDM was related to the recurrence of allograft hepatitis. Improvement in glycemic control was achieved in the patients who responded to antiviral therapy.

A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation

In patients with hepatocellular carcinoma (HCC) exceeding conventional (T2) criteria for orthotopic liver transplantation (OLT), the feasibility and outcome following loco‐regional therapy intended for tumor downstaging to meet T2 criteria for OLT are unknown. In this first prospective study on downstaging of HCC prior to OLT, the eligibility criteria for enrollment into a downstaging protocol included 1 lesion >5 cm and ≤8 cm, 2 or 3 lesions at least 1 >3 cm but ≤5 cm with total tumor diameter of ≤8 cm, or 4 or 5 nodules all ≤3 cm with total tumor diameter ≤8 cm. Patients were eligible for living‐donor liver transplantation (LDLT) if tumors were downstaged to within proposed University of California, San Francisco (UCSF) criteria. 13 A minimum follow‐up period of 3 months after downstaging was required before cadaveric OLT or LDLT, with imaging studies meeting criteria for successful downstaging. Among the 30 patients enrolled, 21 (70%) met criteria for successful downstaging, including 16 (53%) who had subsequently received OLT (2 with LDLT), and 9 patients (30%) were classified as treatment failures. In the explant of 16 patients who underwent OLT, 7 had complete tumor necrosis, 7 met T2 criteria, but 2 exceeded T2 criteria. No HCC recurrence was observed after a median follow‐up of 16 months after OLT. The Kaplan‐Meier intention‐to‐treat survival was 89.3 and 81.8% at 1 and 2 yr, respectively. In conclusion, successful tumor downstaging can be achieved in the majority of carefully selected patients, but longer follow‐up is needed to further access the risk of HCC recurrence after OLT. (Liver Transpl 2005;11:1505–1514.)

Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation

Guidelines on Evaluation for Liver Transplantation (LT) were published in 2005 by the American Association for the Study of Liver Diseases (AASLD). In the interim there have been major advances in the management of chronic liver disease, most notably in antiviral therapy for chronic viral hepatitis. Nonalcoholic fatty liver disease (NAFLD) has assumed increasing prominence as a cause of cirrhosis and hepatocellular carcinoma (HCC) requiring liver transplant. Furthermore, individual disease indications for LT such as HCC have been refined and specific guidelines have appeared for chronic viral hepatitis. Reflecting the need for a multidisciplinary approach to the evaluation of this complex group of patients who have the comorbidities typical of middle age, recommendations have been developed to assist in their cardiac management. With an increasing number of long-term survivors of LT there has been a greater focus on quality of life and attention to comorbid conditions impacting recipient longevity. The purpose of the current Guidelines is to provide an evidence-based set of recommendations for the evaluation of adult patients who are potentially candidates for LT. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic; (2) guideline policies covered by the AASLDPolicy on Development and Use of Practice Guidelines; and (3) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the quality of evidence designated by high (A), moderate (B), or low quality (C); and the strength of recommendations classified as strong or weak.*

Complete Immunosuppression Withdrawal and Subsequent Allograft Function Among Pediatric Recipients of Parental Living Donor Liver Transplants

CONTEXT Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality. OBJECTIVE To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. DESIGN, SETTING, AND PATIENTS Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months). MAIN OUTCOME MEASURES The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection. RESULTS Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n = 1), acute rejection (n = 2), or indeterminate rejection (n = 5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P = .03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P = .04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P = .03). CONCLUSION In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology.