Baburao Koneru

Everolimus With Reduced Tacrolimus Improves Renal Function in De Novo Liver Transplant Recipients: A Randomized Controlled Trial

In a prospective, multicenter, open‐label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced‐exposure tacrolimus (EVR+Reduced TAC) or (iii) standard‐exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy‐proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (−3.0%; 95% CI −8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m2, 97.5% CI 3.74, 13.27 mL/min/1.73 m2, p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Locoregional recurrences are frequent after radiofrequency ablation for hepatocellular carcinoma

BACKGROUND Enthusiasm for radiofrequency ablation (RFA) therapy for patients with unresectable hepatocellular carcinoma (HCC) has increased. The data for recurrence after RFA for patients with HCC is not well documented. The purpose of this study was to evaluate tumor recurrence patterns after RFA in patients with unresectable HCC. STUDY DESIGN Over a 3-year period, 50 patients having RFA for unresectable HCC were identified at a single institution. Medical records and radiologic studies were reviewed and outcomes factors analyzed. RESULTS Of the entire cohort, 46 patients underwent RFA by a percutaneous approach under CT guidance. Most patients underwent either one (n = 22) or two ablations (n = 23). At the time of this report, 14 patients (28%) were tumor-free by radiologic and biochemical (alpha-fetoprotein) parameters. Eighteen additional patients had persistence of tumor at the ablation site and 14 patients had recurrence in the liver at sites different from the ablation site. An additional four patients had recurrence in extrahepatic sites. Twelve patients underwent orthotopic liver transplantation after RFA. Of these 12, 5 (42%) demonstrated no viable tumor in the explanted liver. Independent predictors of tumor recurrence included tumor size, serum AFP levels, and the presence of hepatitis. CONCLUSIONS These data suggest that factors such as tumor size should be considered before employing RFA therapy. In addition to treating the primary tumor, other therapies aimed at the livers inflammatory state might also be important in achieving a durable response after RFA.

Liver Transplantation for Hepatoblastoma the American Experience

The current role of liver transplantation in treating malignant tumors of the liver is uncertain, except for select histologic types. Pooled data on the results of liver transplantation in 12 children with hepatoblastoma is presented here. One half of the children are alive 24 to 70 (44 +/- 19) months after transplantation with no evidence of recurrence. Three patients (25%) died of tumor recurrence and three (25%) died of other causes. Unifocal and intrahepatic tumors were associated with better prognosis compared to the multifocal tumors and tumors with extrahepatic spread (p = 0.04 and 0.13). Microscopically vascular invasion and the predominance of embryonal and/or anaplastic epithelium were associated with a poor prognosis compared to the tumors with no vascular invasion and with predominantly fetal epithelium (p = 0.08 and 0.1). It is concluded that continued efforts to treat unresectable hepatoblastomas by liver transplantation is justified and the role of adjuvant chemotherapy in improving the results needs to be better defined.

Ischemic preconditioning in deceased donor liver transplantation: A prospective randomized clinical trial of safety and efficacy

Ischemic preconditioning (IPC) has the potential to decrease graft injury and morbidity after liver transplantation. We prospectively investigated the safety and efficacy of 5 minutes of IPC induced by hilar clamping in local deceased donor livers randomized 1 : 1 to standard (STD) recovery (N = 28) or IPC (N = 34). Safety was assessed by measurement of heart rate, blood pressure, and visual inspection of abdominal organs during recovery, and efficacy by recipient aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT], both measured in U/L), total bilirubin, and international normalized ratio of prothrombin time (INR) after transplantation. IPC performed soon after laparotomy did not cause hemodynamic instability or visceral congestion. Recipient median AST, median ALT, and mean INR, in STD vs. IPC were as follows: day 1 AST 696 vs. 841 U/L; day 3 AST 183 vs. 183 U/L; day 1 ALT 444 vs. 764 U/L; day 3 ALT 421 vs. 463 U/L; day 1 INR 1.7 ± .4 vs. 2.0 ± .8; and day 3 INR 1.3 ± .2 vs. 1.4 ± .3; all P > .05. No instances of nonfunction occurred. The 6‐month graft and patient survival STD vs. IPC were 82 vs. 91% and median hospital stay was 10 vs. 8 days; both P > .05. In conclusion, deceased donor livers tolerated 5 minutes of hilar clamping well, but IPC did not decrease graft injury. Further trials with longer periods of preconditioning such as 10 minutes are needed. (Liver Transpl 2005;11:196–206.)

Hepatic steatosis and liver transplantation current clinical and experimental perspectives.

Hepatic steatosis has diverse clinical implications in liver transplantation, hepatology, and hepatic surgery. This review will focus on issues related to liver transplantation; the prevalence and diagnosis of hepatic steatosis in potential donors, the impact of steatosis on graft and recipient survival after transplantation and on donor liver supply. In addition, we will review available animal models to investigate this problem and the data in humans and in experimental animals that help understand how steatosis leads to increased liver ischemia/reperfusion (I/RP) injury.

A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C

This randomized, prospective, multicenter trial compared the safety and efficacy of steroid‐free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA–positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid‐free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid‐free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS. Liver Transpl, 2011.

Cyclosporine and its metabolites in mother and baby

Cyclosporine (CsA) is a potent immunosuppressive agent that has significantly improved allograft survival in recipients of human organ transplants (1, 2). Recently there have been a few cases of successful pregnancies in transplant patients receiving CsA alone or in combination with steroids (3, 4). A general concern regarding pregnancy in transplant patients is the potential harmful effect of chronic maternal immunosuppression on the fetus. It is essential to determine the extent of exposure of the fetus to the immunosuppressive drug and its metabolites. We recently studied the concentrations of CsA and several of its metabolites in maternal and cord blood, placenta, and the umbilical cord in two patients receiving chronic CsA therapy. The first patient was a 26-year-old woman with primary biliary cirrhosis secondary to common bile duct obstruction who received a successful liver transplantation in November 1985. Immunosuppression was achieved with CsA and steroids. During the second postoperative week she also received the monoclonal antibody OKT 3. In February 1987, she delivered a 3208 g baby boy. At the time of delivery she was receiving CsA 200 mg orally b.i.d., prednisone 10 mg, hydralazine 50 mg q.i.d., ferrous sulphate 300 t.i.d, furosemide 40 mg q.d. and multivitamin therapy. On the day of the delivery she received CsA at 10 A.M. and the baby was born at 5:45 P.M. Maternal blood was obtained at 8.5 hr after CsA administration while cord blood was obtained at 7.8 hr after CsA administration. Maternal and cord blood along with placenta and umbilical cord were analyzed for CsA and several of its metabolites using a gradient high-pressure liquid chromatographic method developed in our laboratory (5). The second patient was a 25-year-old woman who received an orthotopic liver transplant in November 1985 for cirrhosis of unknown cause. Immunosuppression was achieved with CsA and steroids. Four weeks following the transplant, the patient developed cytomegalovirus hepatitis from which she recovered with reduction in immunosuppression. She did well for 10 months and then developed biliary obstruction that was corrected surgically. At this time she became pregnant. Pregnancy was complicated by anemia requiring blood transfusions and preeclampsia. At gestational age 36 weeks, she had a caesarean section because of fetal distress, and a live baby boy (weight 1690 g) was delivered at 8 A.M. At the time of delivery her medications included Riopan 30 ml p.o. every 4 hr, ranitidine 150 mg orally b.i.d., ferrous sulfate 300 mg orally t.i.d., prednisone 15 mg orally every day and CsA 125 mg orally every 12 hr. Maternal and fetal cord blood were drawn simultaneously at the time of delivery 10 hr after the previous oral cyclosporine dose. The baby had intrauterine growth retardation, as the weight and head circumference were below the fifth percentile. The blood samples, umbilical cord, and placenta were refrigerated at 4°C until analyzed by HPLC. Table 1 lists the concentrations of CsA and its metabolites in blood and in different tissues. The highest concentration of CsA was seen in the umbilical cord of patient 1. The placenta contained CsA concentrations nearly five to ten times greater thon the maternal and the fetal blood, and had the highest concentrations of all the metabolites measured. While small concentrations of M 21 were observed in the placenta and the maternal blood of patient 1, M 18 concentrations were below measurable levels in most of the specimens. Table 1 Cyclosporine and its metabolites in mother and childa Cyclosporine is very lipid-soluble, extensively distributed in the body, and highly metabolized. Previous studies have reported the presence of CsA in cord blood, placenta, amniotic fluid, and breast milk (4). In addition to CsA, we have observed high concentrations of CsA metabolites in the placenta, indicating the presence of CsA metabolizing enzymes in this tissue and/or accumulation of these metabolites in the placenta. Very high concentrations of CsA (nearly 30 times that of the maternal blood) were also observed in the umbilical cord of one patient. Some of the metabolites, particularly M 17, appear in very high concentrations in the blood and also possess significant immunosuppressive effect (6, 7). Whether the metabolites of CsA also contribute to the toxicity is not known. In this study we report for the first time the concentrations of CsA metabolites in cord blood, placenta, and umbilical cord. Of interest is the relatively high concentration of all the metabolites in the placenta. While no specific harmful effects attributable to CsA were observed in the baby, it is clear that the fetus is exposed not only to CsA but also to its metabolites. According to the tests conducted by Sandoz Inc. (Basel, Switzerland) CsA is not mutagenic in the Ames test and did not produce any chromosomal abnormalities in animals. However, since the fetus is exposed to chronic CsA and its metabolites, the immediate septic complications and the possible long-term effects on gestationally immunosuppressed children should be investigated.

Renal Function at Two Years in Liver Transplant Patients Receiving Everolimus: Results of a Randomized, Multicenter Study

In a 24‐month prospective, randomized, multicenter, open‐label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy‐proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference −2.2%, 97.5% confidence interval [CI] −8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m2 (97.5% CI 1.9, 11.4 mL/min/1.73 m2, p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m2 in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m2 in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced‐exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Studies Of Hepatic Warm Ischemia In The Obese Zucker Rat

The effects of warm ischemia were investigated in obese Zucker rats with severe hepatic steatosis in order to develop a nontransplant fatty liver ischemia model. Obese (Ob) and lean (Ln) Zucker rats were subjected to in vivo partial hepatic warm ischemia of 45 or 90 min. Injury was assessed by serum alanine aminotransferase, animal survival, and liver histology. Liver lipids were quantified in control animals. After 90-min ischemia and 2-hr reperfusion, liver malondialdehyde was measured and neutrophils in 12 microscopic fields were counted after esterase staining. After 45 and 90 min of ischemia, Ob animals had significantly higher alanine aminotransferase at 1-hr and 24-hr reperfusion, compared with Ln animals (P < 0.01). After 90 min of ischemia, none of the Ln and 8/9 Ob animals died within 48 hr (P < 0.01). Histologically, Ob animals had more hepatocyte necrosis than did Ln animals. Hepatic neutral and phospholipid content (mg/g) in Ob versus Ln animals was 45.2 +/- 2.6 versus 8.2 +/- 0.7 (P < 0.01) and 36.2 +/- 1.9 versus 27 +/- 2.2 (P < 0.05), respectively. After reperfusion, liver malondialdehyde content increased significantly in Ob animals (8.5 +/- 0.4 vs. 12.3 +/- 0.8 pM/mg protein; P < 0.05), but not in Ln animals. Neutrophils, scant in control livers, increased significantly (P < 0.01) after ischemia/RP, but it increased to a similar degree in Ob and Ln animals. Obese Zucker rats with hepatic steatosis are more susceptible to warm ischemia/reperfusion injury than lean animals, and lipid peroxidation may be an important contributory mechanism. Further studies in this model might help to investigate the human problem.

Bile duct strictures after liver transplantation: A changing landscape of the Achilles' heel

Technical complications lead to significant morbidity and increased mortality during the early postoperative period after liver transplantation. Among the technical complications, vena caval and portal vein stenoses and thromboses occur in 1-2% and 2-3% of the liver recipients, respectively. Diagnostic and treatment algorithms for those problems are well standardized with radiologists being an integral part of the diagnostic and therapeutic armamentarium. Hepatic arterial stenosis and thrombosis, the most common vascular complication after liver transplantation, occurs in about 3-9% of adults and children in the more recent series. The clinical sequela of the biliary ischemia from hepatic arterial stenosis and thrombosis vary from none to multiple bile infarcts, necrosis of the extrahepatic bile duct and bile peritonitis, and multiple and often long strictures in both intra and extrahepatic biliary tree. However, the majority of biliary complications after liver transplantation occur without hepatic arterial stenosis and thrombosis. Biliary complications are considered the Achilles’ heel of liver transplantation because of their frequency and their potential lethal effects on the eventual survival of the graft and patients. With the marked decrease in the routine use of T tubes at the time of transplantation, bile leaks usually occur now at the anastomosis within the first few weeks after transplantation. The second major type of biliary complication, stricture, generally occurs later, and 2 reports in this issue of Liver Transplantation address this topic in adult and pediatric liver recipients. Both series are the largest to date that address the outcomes of bile duct strictures (BDS) in adults and children. The incidence of BDS increases, cumulatively, with the length of follow-up. The median interval after transplantation to the diagnosis of BDS was a year in the report of Sunku et al., but in most reports including the current adult series, an overwhelming majority of BDS occur within the first year after transplantation. Bile duct strictures after liver transplantation are easily and conveniently classified as anastomotic strictures (AS) and nonanastomotic strictures (NAS). The clinical outcomes of the 2 groups are markedly different, rendering the classification extremely useful clinically, as well. Among the etiological factors for the AS technical issues are the most important: improper surgical technique, small caliber of the bile ducts, inappropriate suture material, tension at the anastomosis, and infection. Although the evidence to incriminate ischemia as an important etiological factor in the causation of AS is not as strong as it is in the NAS group, ischemia as an indirect result of the donor conditions probably does play a role. With expertise increasing in the techniques of liver transplantation both worldwide and at individual centers, one would expect a decrease in the incidence of biliary complications over time, especially of AS. The overall incidence of biliary complications after liver transplantation appears to be on the decrease, from the 30% in the pioneering years to about 20% in the 1980s to the current levels of 15%, barring an occasional series with a very low incidence. Whether the incidence of AS would decrease further or remain at the current levels would be answered only with more time. In this regard, it would have been informative had the Austrian study, which spanned 11 years, examined whether the incidence of AS differed in the earlier vs. the later part of the authors’ experience.