Jeffrey D. Punch

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.

The Efficacy and Safety of 200 Days Valganciclovir Cytomegalovirus Prophylaxis in High-Risk Kidney Transplant Recipients

Late‐onset cytomegalovirus (CMV) disease is a significant problem with a standard 3‐month prophylaxis regimen. This multicentre, double‐blind, randomized controlled trial compared the efficacy and safety of 200 days’ versus 100 days’ valganciclovir prophylaxis (900 mg once daily) in 326 high‐risk (D+/R–) kidney allograft recipients. Significantly fewer patients in the 200‐day group versus the 100‐day group developed confirmed CMV disease up to month 12 posttransplant (16.1% vs. 36.8%; p < 0.0001). Confirmed CMV viremia was also significantly lower in the 200‐day group (37.4% vs. 50.9%; p = 0.015 at month 12). There was no significant difference in the rate of biopsy‐proven acute rejection between the groups (11% vs. 17%, respectively, p = 0.114). Adverse events occurred at similar rates between the groups and the majority were rated mild‐to‐moderate in intensity and not related to study medication. In conclusion, this study demonstrates that extending valganciclovir prophylaxis (900 mg once daily) to 200 days significantly reduces the incidence of CMV disease and viremia through to 12 months compared with 100 days’ prophylaxis, without significant additional safety concerns associated with longer treatment. The number needed to treat to avoid one additional patient with CMV disease up to 12 months posttransplant is approximately 5.

Two-dimensional and dobutamine stress echocardiography in the preoperative assessment of patients with end-stage liver disease prior to orthotopic liver transplantation.

Orthotopic liver transplantation is an established therapy for end-stage liver disease. This study evaluated the range of cardiovascular abnormalities in patients undergoing evaluation for orthotopic liver transplantation and determined the prognostic implications of abnormal echocardiographic features, including ischemia during dobutamine stress echocardiography, in predicting postoperative cardiac events. Two-dimensional echocardiography was performed in 190 patients for assessment of left ventricular function, valvular pathology, and pulmonary hypertension. Dobutamine stress echocardiography was performed in 165 patients for evaluation of inducible ischemia. Contrast echocardiography for detection of intrapulmonary shunting was performed in 125 patients at rest and in 99 during dobutamine stress. Left ventricular dysfunction, significant valvular regurgitation, and inducible ischemia were identified in <1O% of patients. Pulmonary hypertension, left ventricular hypertrophy and > or = moderate intrapulmonary shunting were present in 12%, 16%, and 26% of patients, respectively. Severe intrapulmonary shunting predicted death prior to transplantation (P=0.01). Of the 71 transplanted patients, major perioperative events included global left ventricular dysfunction in four patients and myocardial infarction in one patient with normal coronary arteries. No preoperative echocardiographic parameters, including ischemia on dobutamine echocardiography, predicted these perioperative events. No cardiac events related to obstructive coronary artery disease occurred in the 154 patients without ischemia on dobutamine stress echocardiography. The majority of patients with end-stage liver disease, including those with alcoholic cirrhosis, have normal cardiac function on two-dimensional echocardiography. Severe intrapulmonary shunting portends a poor prognosis in patients awaiting transplantation. A negative dobutamine stress echocardiogram appears useful in excluding patients at risk for perioperative cardiac events related to obstructive coronary artery disease.

Increased impact of acute rejection on chronic allograft failure in recent era.

Background. Acute rejection (AR) remains a major risk factor for the development of chronic renal allograft failure (CAF), which is a major cause of late graft loss. With the introduction of several newer immunosuppressive agents (e.g., mycophenolate mofetil, tacrolimus and neoral) acute rejection rates have been steadily decreasing. However, the incidence of CAF has not decreased as dramatically as the incidence of acute rejection. One possible explanation is that the impact of AR on CAF is changing. The goal of this study was to analyze the relative impact of AR era on the development of CAF. Methods. We evaluated 63,045 primary renal transplant recipients reported to the USRDS from 1988 to 1997. CAF was defined as graft loss after 6 months posttransplantation, censored for death, acute rejection, thrombosis, infection, surgical complications, or recurrent disease. A Cox proportional hazard model correcting for 15 possible confounding factors evaluated the relative impact of AR on CAF. The era effect (years 1988–1989, 1990–1991, 1992–1993, 1994–1995 and 1996–1997) was evaluated by an era versus AR interaction term. Results. An AR episode within the first 6 months after transplantation was the most important risk factor for subsequent CAF (RR=2.4, CI 2.3–2.5). Compared with the reference group (1988–89 with no rejection), having an AR episode in 1988–89, 1990–1991, 1992–1993, 1994–1995, and 1996–1997, conferred a 1.67, 2.35, 3.4, 4.98 and 5.2-fold relative risk for the subsequent development of CAF (P <0.001). Conclusions. Independently of known confounding variables, the impact of AR on CAF has significantly increased from 1988 to 1997. This effect may in part explain the relative lack of improvements in long term renal allograft survival, despite a decline in AR rates.

Portal Vein Thrombosis and Survival in Patients with Cirrhosis

The effects of occlusive portal vein thrombosis (PVT) on the survival of patients with cirrhosis are unknown. This was a retrospective cohort study at a single center. The main exposure variable was the presence of occlusive PVT. The primary outcome measure was time‐dependent mortality. A total of 3295 patients were analyzed, and 148 (4.5%) had PVT. Variables independently predictive of mortality from the time of liver transplant evaluation included age [hazard ratio (HR), 1.02; 95% confidence interval (CI), 1.01‐1.03], Model for End‐Stage Liver Disease (MELD) score (HR, 1.10; 95% CI, 1.08‐1.11), hepatitis C (HR, 1.44; 95% CI, 1.24‐1.68), and PVT (HR, 2.61; 95% CI, 1.97‐3.51). Variables independently associated with the risk of mortality from the time of liver transplant listing included age (HR, 1.02; 95% CI, 1.01‐1.03), transplantation (HR, 0.65; 95% CI, 0.50‐0.81), MELD (HR, 1.08; 95% CI, 1.06‐1.10), hepatitis C (HR, 1.50; 95% CI, 1.18‐1.90), and PVT (1.99; 95% CI, 1.25‐3.16). The presence of occlusive PVT at the time of liver transplantation was associated with an increased risk of death at 30 days (odds ratio, 7.39; 95% CI, 2.39‐22.83). In conclusion, patients with cirrhosis complicated by PVT have an increased risk of death. Liver Transpl 16:83–90, 2010.

Association of center volume with outcome after liver and kidney transplantation.

Outcomes for certain surgical procedures have been linked with volume: hospitals performing a high number of procedures demonstrate better outcomes than do low‐volume centers. This study examines the effect of volume on hepatic and renal transplant outcomes. Data from the Scientific Registry of Transplant Recipients were analyzed for transplants performed from 1996–2000. Transplant centers were assigned to volume quartiles (kidney) or terciles (liver). Logistic regression models, adjusted for clinical characteristics and transplant center clustering, demonstrate the effect of transplant center volume quantile on 1‐year post‐transplant patient mortality (liver) and graft loss (kidney). The unadjusted rate of renal graft loss within 1 year was significantly lower at high volume centers (8.6%) compared with very low (9.6%), low (9.9%) and medium (9.7%) volume centers (p = 0.0014). After adjustment, kidney transplant at very low [adjusted odds ratio (AOR) 1.22; p = 0.043) and low volume (AOR 1.22 p = 0.041) centers was associated with a higher incidence of graft loss when compared with high volume centers. Unadjusted 1‐year mortality rates for liver transplant were significantly different at high (15.9%) vs. low (16.9%) or medium (14.7%) volume centers. After adjustment, low volume centers were associated with a significantly higher risk of death (AOR 1.30; p = 0.0036). There is considerable variability in the range of failure between quantiles after kidney and liver transplant. Transplant outcomes are better at high volume centers; however, there is no clear minimal threshold volume.

Model for End-Stage Liver Disease (MELD) exception guidelines: Results and recommendations from the MELD exception study group and conference (MESSAGE) for the approval of patients who need liver transplantation with diseases not considered by the standard MELD formula

Richard B. Freeman Jr., Robert G. Gish, Ann Harper, Gary L. Davis, John Vierling, Leslie Lieblein, Goran Klintmalm, Jamie Blazek, Robert Hunter, and Jeffrey Punch Division of Transplantation, Department of Surgery, Tufts–New England Medical Center, Boston, MA; Departments of Medicine and Transplantation and the Division of Hepatology and Complex GI, Physicians Foundation, California Pacific Medical Center, San Francisco, CA; United Network for Organ Sharing, Richmond, VA; Baylor Regional Transplant Institute, Baylor University Medical Center, Dallas, TX; Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA; Ochsner Multi-Organ Transplant Center, New Orleans, LA; and Department of Surgery, University of Michigan, Ann Arbor, MI

An intention-to-treat analysis of liver transplantation for hepatocellular carcinoma using organ procurement transplant network data

Single‐center studies have shown acceptable long‐term outcomes following orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) when tumors are within the Milan criteria. However, the overall survival and waiting list removal rates have not been described at a national level with pooled registry data. To evaluate this, a retrospective cohort of patients listed for OLT with a diagnosis of HCC between January 1998 and March 2006 was identified from Organ Procurement Transplant Network data. Analysis was performed from the time of listing. Adjusted Cox models were used to assess the relative effect of potential confounders on removal from the waiting list as well as survival from the time of wait listing. A total of 4482 patients with HCC were placed on the liver waiting list during the study period. Of these, 65% underwent transplantation, and 18% were removed from the list because of tumor progression or death. The overall 1‐ and 5‐year intent‐to‐treat survival for all patients listed was 81% and 51%, respectively. The 1‐ and 5‐year survival was 89% and 61% for those listed with tumors meeting the Milan criteria versus 70% and 32% for those exceeding the Milan criteria (P < 0.0001). On multivariate analysis, advanced liver failure manifested by Child‐Pugh class B or C increased the risk of death, while age < 55 years, meeting the Milan criteria, and obtaining a liver transplant were associated with better survival. The current criteria for liver transplantation of candidates with HCC lead to acceptable 5‐year survival while limiting the dropout rate. Liver Transpl 15:859–868, 2009.

Long‐term survival after liver transplantation in children with metabolic disorders

Abstract: Background: Liver transplantation for inherited metabolic disorders aims to save the patients life when the disorder is expected to progress to organ failure, and to cure the underlying metabolic defect. Methods: We retrospectively analyzed 146 pediatric liver transplants (28 metabolic; 118 non‐metabolic) performed between 1986 and 2000. Results: Twenty‐eight transplants were performed in 24 children with metabolic disease (8 females; 16 males; age range 3 months to 17 yr). Indications included α−1‐antitrypsin deficiency (n = 8), two cases each of hyperoxaluria type 1, Wilsons disease, hereditary tyrosinemia type I, citrullinemia, methylmalonic acidemia, and one case each of propionic acidemia, Crigler–Najjar syndrome type I, neonatal hemachromatosis, hemophilia B, Niemann–Pick disease type B, and cystic fibrosis. Eighteen transplants were whole organ grafts and 10 were lobar or segmental. Auxiliary liver transplants were performed in two patients and three received combined liver‐kidney transplants. There were three deaths from sepsis, two from chronic rejection, and one from fulminant hepatitis. Seven of 10 patients currently of school age are within 1 yr of expected grade and three who had pretransplant developmental delay have remained in special education. Actuarial survival rates at 5 and 10 yr are 78% and 68%, respectively, with mean follow‐up in excess of 5 yr. These results compare favorably to 100 pediatric patients transplanted for non‐metabolic etiologies (65% and 61%, respectively) (p= NS). Conclusions: Pediatric liver transplantation for metabolic disorders results in excellent clinical and biochemical outcome with long survival and excellent quality of life for most recipients.

Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12‐ and 36‐month results

Everolimus is a macrolide immunosuppressive agent with known consistent absorption. In this double‐blind study, we examined the safety and tolerability of everolimus vs. placebo in de novo liver transplant recipients. One hundred and nineteen liver allograft recipients were randomized to 1 of 4 groups: everolimus 0.5 mg bid, everolimus 1.0 mg bid, everolimus 2 mg bid, or placebo. Patients received oral cyclosporine to achieve a target trough level of 150‐400 ng/mL in combination with prednisone. Primary and secondary endpoints of safety, tolerability, and efficacy were determined at 12 months, and patients were followed through 36 months. There was a trend toward fewer treated acute rejections in the everolimus group than in the placebo group: everolimus 0.5 mg: 39.3%; everolimus 1.0 mg: 30.0%; everolimus 2 mg: 29.0%; placebo: 40.0% (P = not significant). Adverse events were higher in everolimus‐treated patients especially at the 4‐mg/day dose, but there was no difference in the incidence of thrombocytopenia or leukopenia between all groups and renal function as determined by serum creatinine, and creatinine clearance remained stable to 36 months in everolimus‐treated patients. Mean cholesterol and triglycerides increased from baseline in all treatment groups, and maximum levels were seen at 6 months. In conclusion, this study demonstrates that everolimus in combination with oral cyclosporine had an acceptable safety and tolerability profile, paving the way for additional studies in this transplant indication. Liver Transpl, 2006.