Michael A. Zimmerman

Optimal Utilization of Donor Grafts With Extended Criteria: A Single-Center Experience in Over 1000 Liver Transplants

Objective:Severely limited organ resources mandate maximum utilization of donor allografts for orthotopic liver transplantation (OLT). This work aimed to identify factors that impact survival outcomes for extended criteria donors (ECD) and developed an ECD scoring system to facilitate graft-recipient matching and optimize utilization of ECDs. Methods:Retrospective analysis of over 1000 primary adult OLTs at UCLA. Extended criteria (EC) considered included donor age (>55 years), donor hospital stay (>5 days), cold ischemia time (>10 hours), and warm ischemia time (>40 minutes). One point was assigned for each extended criterion. Cox proportional hazard regression model was used for multivariate analysis. Results:Of 1153 allografts considered in the study, 568 organs exhibited no extended criteria (0 score), while 429, 135 and 21 donor allografts exhibited an EC score of 1, 2 and 3, respectively. Overall 1-year patient survival rates were 88%, 82%, 77% and 48% for recipients with EC scores of 0, 1, 2 and 3 respectively (P < 0.001). Adjusting for recipient age and urgency at the time of transplantation, multivariate analysis identified an ascending mortality risk ratio of 1.4 and 1.8 compared to a score of 0 for an EC score of 1, and 2 (P < 0.01) respectively. In contrast, an EC score of 3 was associated with a mortality risk ratio of 4.5 (P < 0.001). Further, advanced recipient age linearly increased the death hazard ratio, while an urgent recipient status increased the risk ratio of death by 50%. Conclusions:Extended criteria donors can be scored using readily available parameters. Optimizing perioperative variables and matching ECD allografts to appropriately selected recipients are crucial to maintain acceptable outcomes and represent a preferable alternative to both high waiting list mortality and to a potentially futile transplant that utilizes an ECD for a critically ill recipient.

Recurrence of Hepatocellular Carcinoma Following Liver Transplantation A Review of Preoperative and Postoperative Prognostic Indicators

OBJECTIVE To review the preoperative and postoperative variables that predict hepatocellular carcinoma (HCC) recurrence following orthotopic liver transplantation (OLT). DATA SOURCES A collective review of the literature was conducted by searching the MEDLINE database using several key words: hepatocellular carcinoma, recurrence, liver transplantation, and salvage transplantation. STUDY SELECTION Reviews and original articles containing basic scientific observations and long-term clinical outcomes were included. DATA EXTRACTION Critical observations from peer-reviewed sources were incorporated in this review. DATA SYNTHESIS Overall, 11 studies were reviewed to determine the incidence of HCC recurrence following OLT and to identify prognostic variables of recurrence. Four studies were evaluated to determine the efficacy of salvage transplantation following liver resection. CONCLUSIONS Liver transplantation is a viable treatment option for select patients with HCC and end-stage liver disease. However, in approximately 20% of patients, recurrent HCC is the rate-limiting factor for long-term survival. Despite identification of clinical parameters that may stratify patients at high risk and exhaustive preoperative staging, cancer recurrence is likely the result of microscopic extrahepatic disease. With a desperate donor organ shortage, locoregional ablation techniques and resection are being employed in patients on the waiting list to serve as a bridge to OLT. Furthermore, some have advocated aggressive surgical resection of isolated metastasis in both the liver and extrahepatic viscera. Whether these creative strategies confer a survival advantage is unknown; it will require long-term follow-up to determine their efficacy.

Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma.

Experience with sirolimus (SRL)‐based immunosuppression following orthotopic liver transplantation (OLT) is rapidly accumulating. In combination with calcineurin inhibitors (CNIs), SRL may reduce the incidence of acute rejection and lower overall required drug levels. This study sought to quantify long‐term outcome following OLT in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC) who were treated with an SRL‐based regimen as a primary therapy. From January 2000 to June 2007, 97 patients underwent OLT for end‐stage liver disease and HCC at the University of Colorado Health Sciences Center. Of those, 45 patients received SRL, in addition to CNIs, as a component of their primary immunosuppression regimen post‐OLT. Conversely, 52 patients received the standard immunosuppression regimen including CNIs, mycophenolate mofetil, and corticosteroids. The 2 treatment groups were compared with respect to the following variables: age, gender, tumor stage by explant, grade, size, presence of vascular invasion, focality, Childs class, baseline creatinine, and warm and cold ischemic times. The 2 groups were comparable by all factors save for cold ischemic time, which was significantly longer in the CNI‐treated group. Overall survival at 1 and 5 years post‐OLT for patients treated with SRL was 95.5% and 78.8%, respectively. Conversely, survival in patients treated with CNIs exclusively at the same time intervals was 83% and 62%. Although there was no difference in the incidence of major complications, the SRL group experienced a modest improvement in renal function. Cumulatively, these data suggest a potential survival benefit with SRL‐based therapy in patients undergoing OLT for end‐stage liver disease and concomitant malignancy. Liver Transpl 2008.

A Crucial Role for Kupffer Cell-Derived Galectin-9 in Regulation of T Cell Immunity in Hepatitis C Infection

Approximately 200 million people throughout the world are infected with hepatitis C virus (HCV). One of the most striking features of HCV infection is its high propensity to establish persistence (∼70–80%) and progressive liver injury. Galectins are evolutionarily conserved glycan-binding proteins with diverse roles in innate and adaptive immune responses. Here, we demonstrate that galectin-9, the natural ligand for the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3), circulates at very high levels in the serum and its hepatic expression (particularly on Kupffer cells) is significantly increased in patients with chronic HCV as compared to normal controls. Galectin-9 production from monocytes and macrophages is induced by IFN-γ, which has been shown to be elevated in chronic HCV infection. In turn, galectin-9 induces pro-inflammatory cytokines in liver-derived and peripheral mononuclear cells; galectin-9 also induces anti-inflammatory cytokines from peripheral but not hepatic mononuclear cells. Galectin-9 results in expansion of CD4+CD25+FoxP3+CD127low regulatory T cells, contraction of CD4+ effector T cells, and apoptosis of HCV-specific CTLs. In conclusion, galectin-9 production by Kupffer cells links the innate and adaptive immune response, providing a potential novel immunotherapeutic target in this common viral infection.

Liver transplantation for autoimmune hepatitis and the success of aggressive corticosteroid withdrawal.

Our center has attempted to minimize corticosteroid (CS) use in all of our orthotopic liver transplantation (OLT) recipients. Because patients with autoimmune hepatitis (AIH) typically require CSs after transplantation, we reviewed our experience in this cohort of patients to determine (1) patient outcomes including recurrent disease and (2) long‐term requirements for CS use in AIH patients. From 1988 to 2006, 1102 OLTs were performed in 1032 adult patients at the University of Colorado, of whom 66 (6%) with AIH received 68 allografts. Recurrence was defined by a clinically worsening examination and histological evidence from biopsy. Bivariate and multivariate analyses were used to evaluate predictors of CS withdrawal. Twelve potential predictors of CS discontinuation were considered: age, gender, presence of inflammatory bowel disease (IBD), type of graft (cadaver or living donor), recurrence of AIH, warm ischemia time, follow‐up time (time since transplant), and immunosuppressants (cyclosporine, tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil). Overall survival at 5 years was 91%. The 1‐ and 5‐year recurrence‐free survival was 88% and 59%, respectively. Risk (incidence) of recurrent AIH at 1, 3, and 5 years was 12%, 26%, and 36%, respectively. Disease recurred in 23 of 66 patients or 34.8%. Of the 23 patients who developed recurrent disease, none received a second transplant because of recurrent disease. CSs were withdrawn in 50% of patients at the time of review. Only 2 factors on multivariate analysis were strongly associated negatively with CS withdrawal: (1) an increasing dose of the immunosuppressant and (2) the presence of IBD. Controlling for these other factors, we found that recurrent disease did not strongly influence CS withdrawal. In conclusion, outcomes in AIH patients were quite favorable, and none of the patients required retransplantation for recurrent AIH. With a CS minimization approach, one‐half of the patients were able to remain CS‐free. Liver Transpl 14:1281–1286, 2008.

Differential Effects of Plasma and Red Blood Cell Transfusions on Acute Lung Injury and Infection Risk Following Liver Transplantation

Patients with chronic liver disease have an increased risk of developing transfusion‐related acute lung injury (TRALI) from plasma‐containing blood products. Similarly, red blood cell transfusions have been associated with postoperative and nosocomial infections in surgical and critical care populations. Patients undergoing liver transplantation receive large amounts of cellular and plasma‐containing blood components, but it is presently unclear which blood components are associated with these postoperative complications. A retrospective cohort study of 525 consecutive liver transplant patients revealed a perioperative TRALI rate of 1.3% (7/525, 95% confidence interval = 0.6%‐2.7%), which was associated with increases in the hospital mortality rate [28.6% (2/7) versus 2.9% (15/518), P = 0.02] and the intensive care unit length of stay [2 (1‐11 days) versus 0 days (0‐2 days), P = 0.03]. Only high‐plasma‐containing blood products (plasma and platelets) were associated with the development of TRALI. Seventy‐four of 525 patients (14.1%) developed a postoperative infection, and this was also associated with increased in‐hospital mortality [10.8% (8/74) versus 2.0% (9/451), P < 0.01] and a prolonged length of stay. Multivariate logistic regression determined that the number of transfused red blood cell units (adjusted odds ratio = 1.08, 95% confidence interval = 1.02‐1.14, P < 0.01), the presence of perioperative renal dysfunction, and reoperation were significantly associated with postoperative infection. In conclusion, patients undergoing liver transplantation have a high risk of developing postoperative complications from blood transfusion. Plasma‐containing blood products were associated with the development of TRALI, whereas red blood cells were associated with the development of postoperative infections in a dose‐dependent manner. Liver Transpl 17:149–158, 2011.

Predictors of long‐term outcome following liver transplantation for hepatocellular carcinoma: a single‐center experience

Orthotopic liver transplantation (OLT) is increasingly being applied for cure in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC). In recipients with limited tumor burden, OLT achieves reasonable long‐term outcome. This study sought to identify clinical and pathologic variables predictive of long‐term disease‐free survival and the presence of vascular invasion. From 1992 to 2006, 130 patients underwent OLT for cirrhosis and HCC. Malignancy was diagnosed in 107 patients prior to OLT and in 23 patients on pathologic examination of the explant. Nine clinical and pathologic variables were considered including: TNM stage, nodularity, vascular invasion, Milan criteria, incidental lesion, differentiation, tumor size, preOLT transarterial chemoembolization (TACE), and administration of sirolimus‐based immunosuppression. The overall incidence of HCC recurrence was 17% with the majority (82%) being stage III. Cumulatively, tumor recurrence‐free survival (RFS) is 84, 74, and 67% at 1, 3, and 5 years respectively. Independent predictors of RFS included stage III and poorly differentiated lesions (P < 0.05). Furthermore, stage III tumors and those >3.5 cm in size were predictive of vascular invasion. Importantly, preOLT, TACE and postOLT sirolimus had no influence on survival. Pathologic variables including tumor stage and grade have a significant impact on outcome. Importantly, it seems that TACE and sirolimus had no beneficial effect.

Effect of Nonviral Factors on Hepatitis C Recurrence After Liver Transplantation

Objective:Hepatitis C (HCV) is now the most common indication for orthotopic liver transplantation (OLT). While graft reinfection remains universal, progression to graft cirrhosis is highly variable. This study examined donor, recipient, and operative variables to identify factors that affect recurrence of HCV post-OLT to facilitate graft-recipient matching. Methods:Retrospective review of 307 patients who underwent OLT for HCV over a 10-year period at our center. Recurrence of HCV was identified by the presence of biochemical graft dysfunction and concurrent liver biopsy showing diagnostic pathologic features. Time to recurrence was the endpoint for statistical analysis. Five donor, 6 recipient, and 2 operative variables that may affect recurrence were analyzed by univariate comparison and Cox proportional hazard regression models. Results:Recurrence-free survival in the 307 study patients was 69% and 34% at 1 and 5 years, respectively. Four predictive variables related to either donor or recipient characteristics were identified. Advanced donor age, prolonged donor hospitalization, increasing recipient age, and elevated recipient MELD scores were found to increase the relative risk of HCV recurrence. Examination of HLA disparity between donors and recipients demonstrated no correlation between class I or class II mismatches and recurrence-free survival. Conclusions:We have identified donor and recipient characteristics that significantly predict hepatitis C recurrence following liver transplantation. These factors are identifiable before transplant and, if considered when matching donors to HCV recipients, may decrease the incidence of HCV recurrence after OLT. A change in the current national liver allocation system would be needed to realize the full value of this benefit.

Development, management, and resolution of biliary complications after living and deceased donor liver transplantation: a report from the adult-to-adult living donor liver transplantation cohort study consortium.

Adult recipients of living donor liver transplantation (LDLT) have a higher incidence of biliary complications than recipients of deceased donor liver transplantation (DDLT). Our objective was to define the intensity of the interventions and the time to resolution after the diagnosis of biliary complications after liver transplantation. We analyzed the management and resolution of posttransplant biliary complications and investigated the comparative effectiveness of interventions in LDLT and DDLT recipients. For the analysis of biliary complications (leaks or strictures), we used a retrospective cohort of patients who underwent liver transplantation at 8 centers between 1998 and 2006 (median follow‐up from onset=4.7 years). The numbers, procedure types, and times to resolution were compared for LDLT and DDLT recipients. Posttransplant biliary complications occurred in 47 of the 189 DDLT recipients (25%) and in 141 of the 356 LDLT recipients (40%). Biliary leaks constituted 38% of the post‐DDLT biliary complications (n=18) and 65% of the post‐LDLT biliary complications (n=91). The median times to first biliary complications were similar for DDLT and LDLT (11 versus 14 days for leaks, P=0.63; 69 versus 107 days for strictures, P=0.34). Overall, 1225 diagnostic and therapeutic procedures, including reoperation and retransplantation, were performed (6.5±5.4 per recipient; 5.5±3.6 for DDLT versus 6.8±5.8 for LDLT, P=0.52). The median number of months to the resolution of a biliary complication (i.e., a tube‐, stent‐, and drain‐free status) did not significantly differ between the DDLT and LDLT groups for leaks (2.3 versus 1.3 months, P=0.29) or strictures (4.9 versus 2.3 months, P=0.61). Although the incidence of biliary complications is higher after LDLT versus DDLT, the treatment requirements and the time to resolution after the development of a biliary complication are similar for LDLT and DDLT recipients. Liver Transpl 19:259–267, 2013.

When shouldn't we retransplant?

1 In the setting of early graft failure after primary transplantation, orthotopic liver retransplantation (re‐OLT) should be undertaken within the first 7 days, but it should be discouraged within 8‐30 days, since re‐OLT within this intermediate frame is associated with the worst results. 2 Late retransplantation should be cautioned in severely ill patients who exhibit Model for End‐Stage Liver Disease (MELD) scores >25, require mechanical ventilation, have advanced renal insufficiency, and in advanced‐age recipients. 3 Re‐OLT should not be undertaken with extended and older donors particularly when retransplantation for recurrent disease is considered. 4 Prognostic models that take into account the severity of disease and the effect of the organ to be transplanted should be developed to better predict outcomes after re‐OLT. 5 Accurate definitions of acceptable outcomes after retransplantation and “futile re‐OLT” are desperately needed. (Liver Transpl 2005;11:S14–S20.)