Ari J. Cohen

Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy.

Background. In 2001, we published early results of a prospective randomized trial of 71 patients who received either steroids or rabbit antithymocyte globulin (RATG) for orthotopic liver transplantation (OLT). We now report follow-up on these patients and additional patients undergoing steroid-free OLT. Methods. A total of 119 adult OLT recipients were prospectively randomized to receive either methylprednisolone 1,000 mg followed by a 3-month steroid taper or a steroid-free regimen of RATG 1.5 mg/kg during the anhepatic phase followed by a 1.5 mg/kg dose on posttransplant day 1. Maintenance immunosuppression consisted of tacrolimus and mycophenolate mofetil in both groups. Mycophenolate mofetil was weaned over 3 months in the first 71 patients and over 2 weeks in the last 48 patients, achieving tacrolimus monotherapy by 2 weeks posttransplant. Subsequently, a group of 24 sequential OLT recipients received the steroid-free (RATG) protocol. Endpoints of the study were survival, rejection, infectious complications, posttransplant diabetes, and recurrent hepatitis C virus. Results. One-year patient survival was 85% in each group of the prospective randomized trial with a mean follow-up of 18.5 months. One-year graft survival was 82% in the RATG group and 80% in the steroid group (P =not significant). Patient and graft survival of the 24 nonrandomized RATG patients was 96% with a mean follow-up of 3 months. The incidence of rejection was not significantly different; however, 50% of the patients in the steroid group required pulse steroids to reverse the rejection compared with only one patient (1.6%) in the RATG group (P =.03). The incidence of cytomegalovirus infection (P <.05) and posttransplant diabetes was higher in the steroid group (P =.03). There was a trend toward decreased severity of hepatitis C virus in the RATG group. Conclusions. Steroid-free liver transplantation using RATG and early tacrolimus monotherapy effectively reduces immunosuppression-related complications with excellent survival.

Subclinical Rejection in Tacrolimus-treated Renal Transplant Recipients

Background. Subclinical rejection, defined as histologic acute rejection in the absence of graft dysfunction, has been suggested as a cause of chronic allograft rejection. In cyclosporine-treated patients, the incidence of subclinical rejection 3 months after transplant is reported to be approximately 30%. The intent of our study was to determine the incidence of subclinical rejection in tacrolimus-treated renal allograft recipients. Methods. We prospectively studied the incidence of subclinical rejection on surveillance biopsies performed 3 months after transplantation in 114 patients transplanted between September 1, 1998 and November 30, 2000. All patients received tacrolimus, mycophenolate mofetil, and prednisone, and 56% received antibody induction. Results. Subclinical rejection was detected in 2.6% of patients (3/114, 95% confidence interval 0.5–7.5%). Borderline changes were detected in 11% (12/114). Subclinical rejections were treated with bolus methylprednisolone. Conclusions. The incidence of subclinical rejection early after kidney transplantation is extremely low in tacrolimus-treated patients in whom early rejections are aggressively treated, suggesting that surveillance biopsies may not be necessary with this regimen.

Tolerance: Is it worth the risk?

Background. The success of orthotopic liver transplantation (OLT) has been limited by the adverse effects of immunosuppression. The purpose of this study was to determine the safety and feasibility of withdrawing immunosuppression in OLT recipients to achieve tolerance. Methods. Eighteen adult OLT recipients in our steroid-free protocol without rejection were selected for this protocol. All patients chosen for this trial were on tacrolimus monotherapy with normal liver function tests (LFTs). Tacrolimus was weaned as long as LFTs remained stable. Weaning was halted for elevations of liver enzymes and tacrolimus was increased to the last dosage at which the patients had normal LFTs. Rejection was treated by increasing tacrolimus to levels of 10–15 ng/ml. Mycophenolate mofetil (MMF) or sirolimus was added if there was severe rejection by biopsy. Steroids were used if there was no improvement. Results. One patient has been weaned off immunosuppression. Three additional patients were weaned completely off but had tacrolimus resumed because of mild elevations in LFTs. Eleven of 18 (61%) patients had rejection. Two patients required steroid therapy and one required rabbit antithymocyte globulin in addition to MMF and steroids. One of the patients with rejection developed diabetes and one patient had renal failure, which subsequently resolved. One patient died following a stroke. Conclusions. Clinical tolerance can be achieved in a minority of patients, even when being maintained on minimum immunosuppression. The potential benefit of achieving tolerance must be weighed against the risks of rejection therapy in patients doing well on low-dose immunosuppression.

Early Postoperative Hepatic Sonography as a Predictor of Vascular and Biliary Complications in Adult Orthotopic Liver Transplant Patients

OBJECTIVE Our objective was to quantitatively assess the value of early posttransplantation hepatic artery resistive indexes in predicting vascular and nonvascular complications in adult orthotopic liver transplant (OLT) patients. MATERIALS AND METHODS Between 1999 and 2001, 110 consecutive adults received grafts. Doppler sonographic graft evaluations measured main, right, and left resistive indexes within 24 to 48 hr after surgery (normal resistive index cutoff, 0.6). Clinical, operative, procedural, and radiologic reports were reviewed for vascular and biliary complications. Frequency, Students t test, logistic, and regression statistical analyses were performed. RESULTS even patients (6.4%) had vascular complications, including two (1.8%) hepatic artery and two (1.8%) hepatic vein stenoses, one (0.9%) hepatic vein thrombosis, two (1.8%) portal vein thromboses, and one (0.9%) thrombosis and two (1.8%) stenoses of the inferior vena cava (IVC). In 19 patients (17.3%), biliary complications included anastomotic strictures and leaks 1 week to 18 months after transplantation. In 11 patients (10%), sonographically large hematomas required surgical evacuation. In grafts with vascular complications or large hematomas, the mean early posttransplant main, right, and left indexes were significantly lower (< or = 0.6) than without these complications (p < 0.01). In grafts with and without biliary complications, mean early posttransplant main, right, and left indexes did not differ significantly. CONCLUSION In adult OLT patients, low early posttransplant hepatic artery resistive indexes were sensitive (100%) and specific (80%) predictors for vascular complications (e.g., hepatic artery, portal vein, hepatic vein, and IVC) but not for biliary complications. All patients with indexes less than 0.6 within 24-48 hr after surgery should be monitored closely for vascular complications.

Induction with rabbit antithymocyte globulin versus induction with corticosteroids in liver transplantation : Impact on recurrent hepatitis C virus infection

This study compares the clinical course of recurrent hepatitis C virus (HCV) infection between 64 patients, who were randomized to receive either rabbit antithymocyte globulin (RATG) or steroids as induction therapy with tacrolimus for maintenance. The HCV recurrence was assessed by HCV RNA levels, peak ALT at 3–6 months, the grade of inflammation at biopsy at 3–6 months posttransplant, progression of fibrosis, and survival. All patients had also received antiviral therapy with interferon alpha 2b and ribavirin, if there were no contraindications. There was no statistically significant difference between the two groups in terms of inflammation at 3 months, peak ALT, or HCV RNA. The survival between the two groups of patients was similar. It appears that steroid-free liver transplantation with RATG induction does not have any negative influence on HCV recurrence in hepatitis C patients after liver transplantation.

Thrombolytic protocol minimizes ischemic‐type biliary complications in liver transplantation from donation after circulatory death donors

Liver transplantation (LT) with donation after circulatory death (DCD) donors has been associated with a high rate of ischemic‐type biliary strictures (ITBSs) and inferior graft survival. To investigate the impact of an intraoperative tissue plasminogen activator (tPA) on outcomes following DCD LT, we conducted a retrospective analysis of DCD LT at the Toronto General Hospital (TGH) and the Ochsner Medical Center (OMC). Between 2009 and 2013, 85 DCD LTs were performed with an intraoperative tPA injection (n = 30 at TGH, n = 55 at OMC), and they were compared with 33 DCD LTs without a tPA. Donor and recipient characteristics were similar in the 2 groups. There was no significant difference in the intraoperative packed red blood cell transfusion requirement (3.2 ± 3.4 versus 3.1 ± 2.3 U, P = 0.74). Overall, biliary strictures occurred less commonly in the tPA‐treated group (16.5% versus 33.3%, P = 0.07) with a much lower rate of diffuse intrahepatic strictures (3.5% versus 21.2%, P = 0.005). After 1 and 3 years, the tPA group versus the non‐tPA group had superior patient survival (97.6% versus 87.0% and 92.7% versus 79.7%, P = 0.016) and graft survival (96.4% versus 69.7% and 90.2% versus 63.6%, P < 0.001). In conclusion, a tPA injection into the hepatic artery during DCD LT reduces ITBSs and improves graft and patient survival without increasing the risk for bleeding. Liver Transpl 21:321–328, 2015.

Management of von Willebrand disease: a survey on current clinical practice from the haemophilia centres of North America.

The optimal treatment of patients with von Willebrand’s disease (vWD) remains to be defined. Moreover, it has not been firmly established which, if any, commonly measured parameters of von Willebrand factor (vWF) protein in the plasma are useful in guiding treatment. To better understand what guidelines physicians follow in the management of vWD, we surveyed 194 North American physicians who are members of the Hemophilia Research Society. Ninety‐nine per cent of responding physicians depend on factor VIII (FVIII):C, vWF:RCo activity and vWF:AG to diagnose vWD, while only 49% use the bleeding time. The minimal goals of treatment for patients undergoing major surgery/trauma or central nervous system haemorrhage were FVIII:C and vWF:RCo activity greater than 80% while levels of more than 50% for minor surgery and dental extractions were considered adequate. Treatment of vWD was based on the type of vWD with type 1 patients being treated most often with desmopressin acetate (DDAVP) alone, types 2A and 2B patients with a combination of DDAVP and a vWF‐containing FVIII product, type 3 patients with vWF‐containing concentrate. Viral infections, including human immunodeficiency virus, hepatitis A, B and C viruses, and parvovirus have been seen in vWD and the efficacy of viral attenuation processes is a major criterion for the selection of treatment by physicians. Based on this survey, prospective studies need to be designed to address the clinical efficacy, safety and predictive value of laboratory monitoring of patients with vWD.

Adverse cardiac events after orthotopic liver transplantation: A cross‐sectional study in 389 consecutive patients

Current American College of Cardiology/American Heart Association guidelines caution that preoperative noninvasive cardiac tests may have poor predictive value for detecting coronary artery disease in liver transplant candidates. The purpose of our study was to evaluate the role of clinical predictor variables for early and late cardiac morbidity and mortality and the predictive values of noninvasive cardiac tests for perioperative cardiac events in a high‐risk liver transplant population. In all, 389 adult recipients were retrospectively analyzed for a median follow‐up time of 3.4 years (range = 2.3‐4.4 years). Overall survival was 83%. During the first year after transplantation, cardiovascular morbidity and mortality rates were 15.2% and 2.8%. In patients who survived the first year, cardiovascular morbidity and mortality rates were 3.9% and 2%, with cardiovascular etiology as the third leading cause of death. Dobutamine stress echocardiography (DSE) and single‐photon emission computed tomography had respective sensitivities of 9% and 57%, specificities of 98% and 75%, positive predictive values of 33% and 28%, and negative predictive values of 89% and 91% for predicting early cardiac events. A rate blood pressure product less than 12,000 with DSE was associated with an increased risk for postoperative atrial fibrillation. Correspondence analysis identified a statistical association between nonalcoholic steatohepatitis/cryptogenic cirrhosis and postoperative myocardial ischemia. Logistic regression identified 3 risk factors for postoperative acute coronary syndrome: age, history of coronary artery disease, and pretransplant requirement for vasopressors. Multivariable analysis showed statistical associations of the Model for End‐Stage Liver Disease score and the development of acute kidney injury as risk factors for overall cardiac‐related mortality. These findings may help in identifying high‐risk patients and may lead to the development of better cardiac tests. Liver Transpl 21:13‐21, 2015.

Thymoglobulin induction decreases rejection in solitary pancreas transplantation

BACKGROUND Solitary pancreas transplants, both pancreas transplant alone (PTA) and pancreas after kidney (PAK), have higher rejection rates and lower graft survivals than simultaneous pancreas-kidney transplants (SPK). The aim of this study is to compare three different antibody induction regimens in solitary pancreas transplant recipients and to assess the role of surveillance pancreas biopsies in the management of these patients. METHODS Solitary pancreas transplant recipients between 01/98 to 02/00 (n=29) received induction with either daclizumab (1 mg/kg on day 0, 7, 14), OKT 3 (5 mg/day x0-7), or thymoglobulin (1.5 mg/kg/day x0-10). Maintenance immunosuppression was similar for the three groups. All rejections were biopsy-proven either by surveillance/protocol or when clinically indicated. RESULTS The 1-year graft survival was 89.3% overall and 91.7% in the thymoglobulin group. Thymoglobulin significantly decreased rejection in the first 6 months when compared with OKT3 or daclizumab (7.7 vs. 60 vs. 50%). Acute rejections were seen on surveillance biopsies in the absence of biochemical abnormalities in 40% of patients. CONCLUSIONS Thymoglobulin induction regimen led to a low incidence of acute rejection and a high rate of graft survival in solitary pancreas transplants. In addition, surveillance biopsies were useful in the detection of early acute rejection in the absence of biochemical abnormalities.

Liver transplantation in hepatitis B core–negative recipients using livers from hepatitis B core–positive donors: A 13‐year experience

The use of livers from hepatitis B surface antigen–negative (HBsAg−)/hepatitis B core antibody–positive (HBcAb+) donors in liver transplantation (LT) for HBsAg−/HBcAb− recipients is still controversial because of a lack of standard antiviral prophylaxis and long‐term follow‐up. We present our 13‐year experience with the use of HBcAb+ donor livers in HBcAb− recipients. Patients received prophylaxis with hepatitis B immunoglobulin at the time of LT and then lamivudine daily. De novo hepatitis B virus (HBV) was defined as positive HBV DNA detection. Between January 1999 and December 2010, 1013 adult LT procedures were performed at our center. Sixty‐four HBsAg−/HBcAb− patients (6.3%) received an HBsAg−/HBcAb+ liver. All donor sera were negative for HBcAb immunoglobulin M and HBV DNA. The mean follow‐up was 48.8 ± 40.1 months (range = 1.2‐148.8). Both the patient survival rates and the graft survival rates were 92.2% and 69.2% at 1 and 5 years, respectively. No graft losses or deaths were related to de novo HBV. Nine of the 64 patients (14.1%) developed de novo HBV. The mean time from LT to de novo HBV was 21.4 ± 26.1 months (range = 10.8‐92.8 months). De novo HBV was successfully treated with adefovir or tenofovir. In conclusion, HBcAb+ allografts can be safely used in HBcAb− recipients without increased mortality or graft loss. Lifelong prophylaxis, continuous surveillance, and compliance are imperative for success. Should a de novo infection occur, our experience suggests that a variety of treatments can be employed to salvage the graft and obtain serum HBV DNA clearance. Liver Transpl 19:611–618, 2013.