A. Anselmo

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 Retrospective studies have shown that corticosteroids can be safely withdrawn from months to years after transplant.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 In those patients who received prednisone, this was withdrawn within 3 months after transplant.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.

Conversion to rapamycin immunosuppression for malignancy after kidney transplantation

INTRODUCTION Malignancies are a well-known complication of immunosuppressive therapy among renal transplant recipients, representing an important cause of long-term morbidity and mortality. Rapamycin has been shown to limit the proliferation of a number of malignant cell lines in vivo and in vitro. METHODS Fifteen patients developed the following malignancies at a mean of 90.3 months (range = 10-252) after kidney transplantation: metastatic gastric cancer (n = 1), metastatic colon cancer (n = 1), bilateral nephrourothelioma (n = 1), skin cancer (n = 2), Kaposis sarcoma (n = 2), posttransplant lymphoproliferative disorder (PTLD; n = 4), renal cell carcinoma T1 (n = 1), MALT lymphoma (n = 1), intramucous colon carcinoma (n = 1), liposarcoma of the spermatic cord (n = 1). After the diagnosis of malignancy, the patients were switched from calcineurin inhibitor-based immunosuppression to rapamycin (monotherapy, n = 3), or associated with steroids (n = 6) or with mycophenolate mofetil (n = 6). RESULTS Both patients with metastatic cancer underwent chemotherapy but succumbed after 6 and 13 months. Two patients with PTLD who underwent chemotherapy died after 12 and 36 months. At a mean follow-up of 32.7 months (range = 7-56), the remaining 11 patients are cancer-free. Two patients lost their grafts after 24 and 36 months after the switch due to chronic rejection. Renal graft function remained stable in all other patients from diagnosis throughout follow-up. CONCLUSION Our observations suggested that rapamycin-based immunosuppression offers the possibility for regression of nonmetastatic tumors. Nevertheless, it is difficult to assess whether tumor regression was due to rapamycin treatment or to the reduced immunosuppression.

Glycogen Storage Disease Type Ia and VI Associated With Hepatocellular Carcinoma: Two Case Reports

Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism due to intracellular enzyme deficiency resulting in abnormal storage of glycogen in tissues. GSD represents an indication for liver transplantation (OLT) when medical treatment fails to control the metabolic dysfunction and/or there is an high risk of malignant transformation of hepatocellular adenomas (HCA). Herein we have reported two cases of GSD, type Ia and type VI, which were both associated with rapidly growing HCA, and underwent OLT because of suspect changes in their radiological features. Final histological findings in the explanted liver showed the presence of hepatocellular carcinoma (HCC) in both cases. In GSD type Ia and VI, OLT is considered to be the treatment of choice when a liver neoplasm is suspected. While the association of HCC with GSD type Ia is well known, this is the first case of HCC in GSD type VI so far reported to the best of our knowledge.

Protective role of tauroursodeoxycholate during harvesting and cold storage of human liver: a pilot study in transplant recipients.

Background. Ischemia-reperfusion injury is a major cause of early graft dysfunction after liver transplantation. Tauroursodeoxycholic acid (TUDCA), a natural amidated hydrophilic bile salt, protects from cholestasis and hepatocellular damage in a variety of experimental models, as well as from ischemia-reperfusion injury. We investigated in the human liver transplantation setting the effect of the addition of TUDCA at time of liver harvesting and cold storage on the intra- and postoperative enzyme release and liver histopathology at the end of cold storage, at reperfusion, and 7 days after transplantation. Methods. Eighteen patients undergoing elective liver transplantation were studied, including 6 serving as controls. In six patients, TUDCA was added to the University of Wisconsin solution used during harvesting and cold storage, to reach final concentrations of 2 mM. In three of these patients, TUDCA (3 g) was infused in the portal vein of the donor before organ explantation; in the other three cases, TUDCA was given through both routes. Results. The use of TUDCA did not cause adverse events. The release of aspartate aminotransferase in the inferior vena cava blood during liver flushing was significantly lower (P =0.05) in TUDCA-treated than in control grafts, as were cytolytic enzyme levels in peripheral blood during the first postoperative week (P <0.02). At electron microscopy, an overt endothelial damage (cytoplasmic vacuolization, cell leakage, and destruction with exposure of hepatocytes to the sinusoidal lumen) was invariably found in control grafts, both at reperfusion and at day 7 after transplant. These features were significantly ameliorated by TUDCA (P <0.001). Several ultrastructural cytoplasmic abnormalities of hepatocytes were seen. Among these, damage to mitochondria matrix and crystae was significantly reduced in TUDCA-treated versus control grafts (P <0.01). Mild to severe damage of bile canaliculi was a constant feature in control biopsies, with dilatation of canalicular lumen and loss of microvilli. Both these abnormalities were markedly ameliorated (P <0.001 by TUDCA). The best preservation was observed when TUDCA was given through both routes. Conclusions. The use of TUDCA during harvesting and cold storage of human liver is associated with significant protection from ischemia-reperfusion injury. The clinical significance of this findings must be studied.

Kidney Transplant: Usefulness of Real-Time Elastography (RTE) in the Diagnosis of Graft Interstitial Fibrosis

The aim of this study is to evaluate the usefulness of real-time elastography (RTE) in the diagnosis of graft interstitial fibrosis. We prospectively enrolled 50 patients clinically suspected of graft fibrosis. RTE was performed with a broadband linear transducer using a dedicated ultrasound machine. Tissue mean elasticity (TME) was calculated by two blinded operators. All patients underwent biopsy after RTE. To determine cortical fibrosis Banff score was used. The receiver operating characteristic curves analysis was performed to evaluate the accuracy of TME to discriminate between patients with mild fibrosis (F1) versus patients with moderate to severe fibrosis (F2-F3). Inverse correlation between TME values and the degree of fibrosis has been shown (p < 0.05). Patients with F1 had mean TME values significantly higher compared with TME in patients with F2 (p = 0.005) and F3 (p = 0.004). The diagnostic accuracy of TME measurement for F2-F3 evaluated by area under the curve-receiver operating characteristic analysis was 0.95. RTE was able to evaluate kidney fibrosis in a non-invasive way and could be used as complementary imaging during follow-up of renal transplant patients.

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.

Intragastric Balloon Followed by Biliopancreatic Diversion in a Liver Transplant Recipient: A Case Report

Liver transplantation is a life-saving procedure for end-stage liver disease. In liver transplant recipients, morbid obesity influences post-operative survival and graft function. In 1996, our patient underwent a successful liver transplantation because of a HCV-related liver failure (body mass index (BMI) 31). Follow-up showed a functional graft and the development of severe obesity up to a BMI of 61 in January 2006. In January 2007, he was submitted to intragastric balloon therapy for 6 months, reaching a BMI of 54. In September 2007, he underwent a biliopancreatic diversion. During follow-up to March 2008, he reached a BMI of 42 with ameliorations of comorbidities. In May 2008, during a hospital admission, he suddenly died of a heart attack. Post mortem study revealed a myocardial infarction. This is the first world case report for this approach. According to our opinion, patient’s death was not related to bariatric surgery.

Surgical versus percutaneous technique for veno-venous bypass during orthotopic liver transplantation: a prospective randomized study.

THE VENO-VENOUS bypass (VVBP) was introduced in orthotopic liver transplantation (OLTx) to prevent venous stasis in the caval compartment and splanchnic venous pooling during the anhepatic phase. VVBP has made OLT an easier procedure by stabilizing patient hemodynamics; decreasing blood losses; and reducing third space fluid losses, visceral edema, and splanchnic venous pooling. Various alternative techniques have been described for establishing the VVBP. The aim of this prospective randomized study was to compare the results of the percutanous technique versus the traditional open surgical technique in terms of hemodynamics, performance, complications, and operating time in a series of 40 consecutive OLTx performed on 39 patients in our Transplant Unit.

Switch from Twice-Daily Tacrolimus (Prograf) to Once-Daily Prolonged-Release Tacrolimus (Advagraf) in Kidney Transplantation

Advagraf is a new modified-release once-daily formulation of tacrolimus. The aim of this study was to define the efficacy and safety of switching from Prograf to Advagraf immunosuppression in kidney transplant recipients. The switched dose ratio of Prograf to Advagraf was 1:1. Forty-one patients (34 men and 7 women) were switched at 36.6 ± 16.1 months after kidney transplantation. All patients maintained stable renal function and the conversion. In 16 subjects it was possible to withdraw steroid administration after obtaining adequate Advagraf blood levels, among whom 14 remained steroid free. Adverse events, including dizziness and tinnitus, were reported in 1 patient, who was reverted to Prograf. One patient who was receiving triple therapy with low tacrolimus blood levels experienced are acute rejection episode. The switch to Advagraf was safe and efficacious in kidney transplant recipients with or without steroid administration. Moreover, interruption of steroid was possible and well tolerated after achieving adequate stable blood levels with Advagraf.

Cyclosporine A versus tacrolimus monotherapy. Comparison on bile lipids in the first 3 months after liver transplant in humans

Biliary lipids output is reduced after liver transplantation and tends to normalize thereafter. Cyclosporine A (CyA) is reported to interfere with the normal bile‐restoring process after liver grafting, but data are inconclusive, in particular regarding the comparison with the other widely used calcineurin inhibitor tacrolimus (TCR). Furthermore, previous researches were conducted in patients taking multiple immunosuppressive therapies and with a short follow up. In this study we readdressed this issue by comparing biliary lipids in the first 3 months after liver transplant, in 20 patients randomized to receive immunosuppression with CyA or TCR monotherapy. Bile samples, harvested through a T‐tube at days 1, 3, 7, 15, 30, 60 and 90 were assessed for cholesterol, phospholipids, and total and individual concentrations of bile acids (BA). Liver and kidney function tests were evaluated as well. We found no differences between CyA and TCR in biochemical findings or in total biliary BAs, cholesterol, and phospholipids. However, CyA‐treated patients showed lower levels of glycochenodeoxycholic acid at day 15, compared to those treated with TCR (P < 0.04). This difference normalized thereafter, without any biochemical or clinical effect at 3‐month follow up.