G. Palmieri

A pilot study on the safety and effectiveness of immunosuppression without prednisone after liver transplantation

BACKGROUND Corticosteroids are commonly used in the immunosuppression therapy after liver transplantation, yet are associated with considerable side effects. Retrospective studies have shown that corticosteroids can be safely withdrawn from months to years after transplant. We prospectively investigated the effects of early immunosuppression without the use of corticosteroids on graft outcome and transplant complications. METHODS Forty-five patients undergoing liver transplantation were randomized to receive immunosuppression composed of cyclosporine microemulsion and azathioprine with (n=22) or without prednisone (n=23), in conventional doses. In those patients who received prednisone, this was withdrawn within 3 months after transplant. The median follow-up of survivors was 14 months (range: 6-24). The study end points were to determine graft survival and function, infectious complications, including hepatitis C virus (HCV)-RNA levels in HCV-infected recipients, acute rejection, kidney function, and metabolic complications. RESULTS Eleven deaths occurred, 6 of which were in the prednisone group. Two-year survival did not differ between patients treated with or without prednisone (70.2% vs. 78.3%, P=0.83), nor did the causes of death. No differences were observed with regard to graft function, renal function, and infectious complications. In the subset of patients who received transplants for HCV-related cirrhosis, the dynamics of virus replication HCV-RNA was faster among those treated with prednisone. The incidence and severity of acute rejection was similar in the two groups. More than 80% of acute rejections in both groups were classified as mild or moderate and underwent spontaneous resolution. Only two patients in each group had severe acute rejection requiring additional treatment with high-dose steroids. Patients receiving prednisone tended to have greater biochemical signs of cholestasis, higher serum cholesterol and glucose levels, and more frequent insulin requirement than those treated without corticosteroids. CONCLUSIONS Liver transplantation can be performed safely without using corticosteroids in the early postoperative course, and there is no need for routine aggressive steroid treatment of established acute rejections.

Correlation Between Liver Fibrosis and Inflammation in Patients Transplanted for HCV Liver Disease

Hepatitis C virus (HCV) re‐infection after liver transplantation (LT) is characterized by an accelerated disease progression in recent years with unclear mechanisms. We evaluate the relationship between progression of liver fibrosis and histological necro‐inflammation in HCV recipients, according to age of transplant. Fifty‐five patients transplanted (1993–2002) for HCV liver disease, were included in the study. Recipients were retrospectively stratified in three different age of transplant, of 40 months each: group 1) from January 1993 to May 1996; group 2) from June 1996 to august 1999; group 3) from September 1999 to December 2002. Grading (necro‐inflammation) and staging (fibrosis) scores were evaluated in liver biopsies at 1, 2 and 3 years from LT (Ishak classification). For all age of transplant the main factor associated with fibrosis progression, was grading score (p < 0.05). However mean staging score for each point of grading increased from 0.3 ± 0.2 in older LT to 0.7 ± 0.5 in newer ones (p = 0.01). In conclusion in HCV–LT patients (1) liver fibrosis is strictly associated to histological necro‐inflammation; (2) the proportion of this relationship has been changing in recent years since newer LT patients, show an increased amount of fibrosis in comparison with the older ones, for similar grading score.

TUDCA prevents cholestasis and canalicular damage induced by ischemia‐reperfusion injury in the rat, modulating PKCα–ezrin pathway

Cholestasis, induced by liver ischemia‐reperfusion injury (IRI), is characterized by dilatation of bile canaliculi and loss of microvilli. Tauroursodeoxycholic acid (TUDCA) is an anti‐cholestatic agent, modulating protein kinase C (PKC) α pathway. PKC reduces ischemic damage in several organs, its isoform α modulates ezrin, a key protein in the maintenance of cell lamellipoidal extensions. We evaluated the effects of TUDCA on cholestasis, canalicular changes and PKCα–ezrin expression in a rat model of liver IRI. Livers flushed and stored with Belzer solution or Belzer + 10 mm TUDCA (4 °C for 6 h) were reperfused (37 °C with O2) with Krebs–Ringer bicarbonate + 2.5 μmol/min of Taurocholate or TUDCA. Bile was harvested for bile flow assessment. Liver tissue was employed for Electron Microscopy (EM) and for PKCα and ezrin immunoblot and immunofluorescence. The same experiments were conducted with the PKCα inhibitor Go‐6976. TUDCA‐treated livers showed increased bile flow (0.25 ± 0.17 vs. 0.042 ± 0.02 μl/min/g liver, P < 0.05) and better preservation of microvilli and bile canalicular area at EM. These effects were associated with increased PKCα and ezrin expression (P = 0.03 and P = 0.04 vs. control respectively), as also confirmed by immunofluorescence data. PKCα inhibition abolished these TUDCA effects. TUDCA administration during IRI reduces cholestasis and canalicular damage in the liver modulating PKCα–ezrin pathway.

Immunosuppression without prednisone after liver transplantion is safe and associated with normal early graft function: preliminary results of a randomized study.

Abstract Prednisone has been commonly considered the mainstay of immunosuppressive therapy after liver transplantation. Recent data suggest that prednisone withdrawal late after transplant reduces complications without affecting graft function. We report here the preliminary results of an open‐label, randomized study aimed at investigating whether prednisone therapy can be completely avoided during the first 3 months after transplantation. Twenty‐seven consecutive patients were randomized to receive double (group A: cyclosporine and azathioprine) or triple (group B: prednisone, cyclosporine, and azathioprine) immunosuppressive therapy after liver transplantation. Six patients died within the first 3 weeks in each group and were excluded from the calculations. The present results refer to 10 patients in group A and 11 in group B. The actuarial 1‐year survival did not differ between the two groups (90.9 % vs 88.8 %). There were no differences with respect to infectious complications or episodes of histological acute graft rejections. Only one severe acute rejection occurred in group A and two in group B. During the first month after transplant, liver and kidney functions tended to be better in the group of patients treated without prednisone, although there were no differences in the mean cyclosporine blood levels. These data, though preliminary, indicate that early immunosuppression without the use of prednisone is safe and tends to be associated with improved liver and renal functions compared to conventional triple therapy.

Randomized study on in situ liver perfusion techniques: Gravity perfusion VS high-pressure perfusion

T HE VIABILITY of the donor liver depends on many factors such as perfusion techniques, perfusion solution and preservation methods. To date a number of studies have focused on perfusion solutions and preservation methods, but little is known about the effects of perfusion techniques and flow rate on organ viability in the clinical setting. In situ the liver can be easily perfused by a gravityidrostatic pressure perfusion of 75 to 100 cm H20. However some authors have advocated a more physiologic method in which the fluid is flushed under pressure (100 mm Hg) similar to the mean arterial blood pressure with the advantage of perfusing the small intrahepatic vessels, particularly those of the biliary tree, reducing post-transplantation ischemic damage and biliary complications. On the other hand, excessively high pressures would cause irreversible organ damage. To assess which in situ liver perfusion technique has the best outcome on early graft function after liver transplant, multiorgan donors were randomized to receive gravity perfusion or high-pressure perfusion.

Effect of steroids amount on hepatitis C recurrence following orthtopic liver transplantation.

ONE of the leading causes for orthotopic liver transplantation (OLTx) is hepatitis C. The presence of viremia post-transplant is reported in 95% of patients; one year after OLTx and 30% to 70% of recipients develop histopathologic recurrence of HCV. The intensity of immunosuppression correlates with viral replication. The number of acute rejection episodes correlated with recurrence of HCV (HCV-R). Feray et al reported a positive correlation of the amount of serum HCV-RNA and the occurrence of hepatitis in the transplanted liver, suggesting that intense HCV replication causes severe histological damage. In agreement there is a recent publication which shows how high serum HCV-RNA levels are associated with severe graft damage. The aim of this study is to correlate histologic recurrence of hepatitis C with the administration of steroids in a group of patients who underwent OLTx for the HCV induced cirrhosis.