Eliezer Katz

Corticosteroid‐free immunosuppression with daclizumab in HCV+ liver transplant recipients: 1‐year interim results of the HCV‐3 study

This work is a 1‐yr interim analysis of a prospective, randomized, multicenter trial evaluating the effect of corticosteroid‐free immunosuppression on hepatitis C virus–positive (HCV+) liver transplant recipients following liver transplantation (LT). Patients received tacrolimus and corticosteroids (Arm 1; n = 80); tacrolimus, corticosteroids, and mycophenolate mofetil (MMF) (Arm 2; n = 79); or daclizumab induction, tacrolimus, and MMF (Arm 3; n = 153). At 1 yr, 64.1%, 63.4%, and 69.4% of patients achieved the composite primary endpoint of freedom from rejection, freedom from HCV recurrence, and freedom from treatment failure, respectively. Excellent patient and graft survival did not differ significantly among treatment arms. Freedom from HCV recurrence at 1 yr was 61.8 ± 6.2%, 60.1 ± 6.1%, and 67.0 ± 4.3% in Arms 1, 2, and 3, respectively (P = not significant). Freedom from rejection was significantly higher in Arm 3 compared to Arm 1 (93.0 ± 2.2% vs. 81.9 ± 4.4%; P = 0.011). Multivariate analysis identified acute rejection (hazard ratio = 2.692; P = 0.001) and donor age (hazard ratio = 1.015; P = 0.001) as significant risk factors for HCV recurrence. HCV recurrence was not influenced by recipient demographics, HCV genotype, or immunosuppression. In conclusion, these results suggest that a corticosteroid‐free regimen of tacrolimus and MMF following daclizumab induction is safe and effective in HCV+ liver transplant recipients. Liver Transpl 13:1521–1531, 2007.

Liver resection under total vascular isolation. Variations on a theme.

Total vascular isolation (TVI) of the liver was employed during parenchymal transection in 16 patients undergoing hepatic resection for large tumors (mean diameter, 10.7 cm) located near hilar structures, hepatic veins, or the inferior vena cava (IVC). In 14 cases, TVI was achieved by clamping the suprahepatic and infrahepatic IVC and the porta hepatis, with or without aortic occlusion; in two, selective hepatic vein clamping was possible, obviating IVC occlusion. Procedures included standard and extended right and left lobectomies and caudate lobe resections. Concomitant resection and reconstruction of the portal vein (one case), IVC (one case), and bile duct (three cases) was required. Postoperative hepatic and renal failure did not occur. Mean intensive care unit and hospital stays were 2.8 ± 1.9 and 12.5 ± 5.2 days, respectively. There were two perioperative deaths. Total vascular isolation permits safe resection of large, critically located tumors that would otherwise present prohibitive operative risks.

Benefits of chronic plasmapheresis and intravenous heme-albumin in erythropoietic protoporphyria after orthotopic liver transplantation.

Erythropoietic protoporphyria (EPP) is characterized by a deficiency of ferrochelatase the final enzyme of the heme biosynthetic pathway. Patients with EPP may overproduce protoporphyrin IX, chiefly in developing erythrocytes. In some, protoporphyrin accumulates and causes toxicity, particularly to the skin and liver. Orthotopic liver transplantation (OLT) treats the severe liver disease that sometimes occurs in EPP; however, it does not correct the underlying metabolic disorder. We recently reported a patient with EPP who was improved with plasmapheresis and i.v. heme-albumin before OLT. Subsequently he developed histological and biochemical evidence of recurrent hepatotoxicity from protoporphyrin in the graft liver. We now report successful treatment of the patient with additional plasmapheresis and heme-albumin with improvement of hepatic histological and biochemical abnormalities. We conclude that plasmapheresis and heme-albumin are of benefit in EPP complicated by hepatotoxicity before and after liver transplantation.

The value of intravenous heme-albumin and plasmapheresis in reducing postoperative complications of orthotopic liver transplantation for erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is marked by a deficiency of ferrochelatase, which occurs in all cells and tissues, preventing effective conversion of proto porphyrin IX to heme and thereby blocking effective feedback inhibition of heme synthesis. The major source of the excess protoporphyrin is the bone marrow. Protoporphyrin IX may accumulate, with resultant toxicity chiefly of the marrow, skin, nervous system, and liver. Orthotopic liver transplantation (OLT) is, at present, the only adequate intervention for severe liver compromise secondary to protoporphyrin deposition, but it has been complicated by severe photosensitivity and polyneuropathy. Intravenous heme and plasmapheresis have been proposed but not previously reported as means to reduce the protoporphyrin burden before liver transplantation. We report a man with EPP who underwent preoperative heme-albumin administration and plasmaphereses that led to marked reductions in plasma and erythrocyte protoporphyrin levels. His OLT was uneventful, and he developed neither polyneuropathy nor exacerbation of photosensitivity.

Management of recurrent hepatitis C after liver transplantation: a concise review

Recurrent hepatitis C infection and subsequent graft failure are increasingly recognized problems after orthotopic liver transplantation. Although many prospective therapeutic, controlled trials in primary hepatitis C disease have been reported, large-scale studies are yet to be performed in patients with posttransplant recurrent hepatitis C after liver transplantation. In this review, we summarize the current literature on the therapeutic approaches for recurrent hepatitis C and discuss the results of published studies on therapy with ribavirin or interferon (IFN) alone and on combination therapy with IFN plus ribavirin. Further, we discuss results of prophylactic approaches to the problem of recurrent hepatitis C after transplant. Finally, we discuss additional aspects of anti–hepatitis C virus therapy after liver transplantation.

Preemptive Strategy for Ganciclovir Administration Against Cytomegalovirus in Liver Transplantation Recipients

In utilizing a preemptive strategy to minimize the occurrence of symptomatic cytomegalovirus (CMV) infection following liver transplant, only patients with proven CMV activity by direct detection are treated. We applied the following preemptive strategy for CMV infection to 49 sequential liver transplant recipients between 1998 and 2001. Patients were monitored for CMV activity using CMV p65 antigen assay for the first 10 months of the study. Thereafter, we changed the detection method to a quantitative PCR for plasma CMV‐DNA. All patients were monitored post transplant, weekly for the first 3 months and then monthly. Only patients with detected CMV activity were treated with ganciclovir. Patients were divided into four groups, based on donor (D) and recipient (R) CMV status. In seven out of 49 patients (14.3%) CMV activity was detected: four in group D +/R –, and three in group D –/R –. Five out of these seven patients had asymptomatic CMV infection. Symptomatic CMV infection developed only in two of these seven patients, to give total rate of 4.1% (2/49). All seven patients developed CMV IgG antibody. ‘Transient’ CMV replication detected by PCR in five patients in group D +/R+ was not defined as infection. No patients developed organ‐invasive CMV disease. The cost of anti‐CMV treatment using the preemptive strategy was

A Novel Three-Dose Regimen of Daclizumab in Liver Transplant Recipients With Hepatitis C: A Pharmacokinetic and Pharmacodynamic Study

1000/patient/1st year. Using preemptive strategy, early detection of CMV infection was achieved, allowing timely treatment. The use of ganciclovir for CMV infection in only 4.3% of the patients should have a positive impact on minimizing the risk of ganciclovir‐resistant virus, and should reduce the cost of CMV prevention strategies.

YSPSL (rPSGL-Ig) for improvement of early renal allograft function: a double-blind, placebo-controlled, multi-center Phase IIa study1,2,3: Ph2a trial of rPSGL-Ig in renal transplant

This study evaluated the pharmacokinetics and pharmacodynamics of a novel 3‐dose regimen of daclizumab in de novo hepatitis C liver transplant recipients. In 30 of 156 recipients receiving daclizumab, mycophenolate mofetil, tacrolimus, and no steroids (Arm 3 of Hep C 3 Liver Study), daclizumab (2, 2, and 1 mg/kg, respectively) was given on days 1, 3, and 8 posttransplant, respectively, with trough, peak (Cmax), and CD25 saturation (CDsat) measured sequentially. Mean daclizumab Cmax was 50.3 μg/mL on day 1, and mean trough levels were 21.8, 25.7, and 9.9 μg/mL on days 3, 8, and 30, respectively. A significant decline in CDsat (mean, 15.7% to 4.7%) was observed on day 1 and was sustained throughout the study (2.8% on day 30). Daclizumab concentration ≥5 μg/mL was the level where most of the effect on CDsat was noticed. Elevated baseline CDsat was observed in African Americans, patients weighing ≤75 kg, and patients <60 years of age. After 365 days, 2 patients had experienced 3 rejections, 10 patients had recurrent hepatitis C, 4 patients died, and 2 grafts were lost. In conclusion, this novel 3‐dose regimen is effective in rapidly achieving high therapeutic concentration of daclizumab and a significant decline in CDsat lasting over 30 days. Liver Transpl 12:585–591, 2006.

YSPSL (rPSGL‐Ig) for improvement of early renal allograft function: a double‐blind, placebo‐controlled, multi‐center Phase IIa study1,2,3

Gaber AO, Mulgaonkar S, Kahan BD, Woodle ES, Alloway R, Bajjoka I, Jensik S, Klintmalm GB, Patton PR, Wiseman A, Lipshutz G, Kupiec‐Weglinski J, Gaber LW, Katz E, Irish W, Squiers EC, Hemmerich S. YSPSL (rPSGL‐Ig) for improvement of early renal allograft function: A double‐blind, placebo‐controlled, multi‐center Phase IIa study. 
Clin Transplant 2011: 25: 523–533.

The splenic artery as the inflow in arterial revascularization of the liver graft in clinical liver transplantation.

Gaber AO, Mulgaonkar S, Kahan BD, Woodle ES, Alloway R, Bajjoka I, Jensik S, Klintmalm GB, Patton PR, Wiseman A, Lipshutz G, Kupiec‐Weglinski J, Gaber LW, Katz E, Irish W, Squiers EC, Hemmerich S. YSPSL (rPSGL‐Ig) for improvement of early renal allograft function: A double‐blind, placebo‐controlled, multi‐center Phase IIa study. 
Clin Transplant 2011: 25: 523–533.