HEPATOLOGY Vo1. 34, NO. 4, Pt. 2, 2001 AASLD ABSTRACTS 647A

1899

ALLOIMMUNITY TO KUPFFER CELLS AND LIVER SINUSOIDAL ENDO- THELIAL CELLS: MODULATION BY CYTOKINES AND SYNGENEIC K-UPFFER CELLS. Bettina Jagemann, Johannes Herkel, Johannes Gutenberg - University Mainz, Mainz Germany; Percy A Lohse, Zentrum fiir Molekulare Biologie Heidelberg (ZMBH), Heidelberg Germany; Ansgar W Lohse,Johannes Gutenberg - University Mainz, Mainz Germany

After an initial period when acute rejection may occur, hepatic aflografts are usually tolerized better than other organ grafts; chronic rejection is rare. How- ever, the mechanisms of hepatic tolerance induction remain to be clarified. Because liver sinusoidal endothelial cells (LSEC) and Kupffer cells (KC) are the major hepatic graft cells with the inherent capability of antigen presenta- tion that contact allogeneic T lymphocytes, we wanted to assess the role of LSEC and KC in the alloresponse to liver grafts. Therefore, we studied the stimulation of murine lymphocytes by allogeneic LSEC and KC and wanted to learn whether the alloresponse to KC and LSEC could be modulated by local hepatic factors. We found that KC and particularly LSEC induced a potent initial inflammatory alloresponse, marked by the production of Interferon- T(6225 pg/ml vs. 882 pg/ml after stimulation by bone marrow-derived macro- phages). However, the alloreactive lymphocytes were not committed to TH1 differentiation; secondary stimulation induced both pro- and anti-inflamma- tory cytokines (15.1 ng/ml Interferon-Tand 9.2 ng/ml Interleukin-4). The al- loresponse may be influenced by the local hepatic cytokine setting. Indeed, the production of Interferon-Tcould be suppressed by addition of Interleukin-10 or, in particular, transforming growth factor-/3 (595 pg/ml vs. 6225 pg/ml Interferon-T). Bacterial lipopolysaccharide at physiological concentrations in- creased the initial inflammatory alloresponse; the secondary alloresponse, however, was suppressed. Since grafted KC are rapidly replaced by KC that originate from the recipient, the recipient KC may influence the response to the allograft. Indeed, we found that the presence of recipient KC strongly sup- pressed the inflammatory response to allogeneic LSEC, notably in the presence of lipopolysaccharide (97 pg/ml vs. 1174 pg/ml interferon-T). In conclusion, acute rejection of liver grafts seems to be related mainly to the CD8-mediated alloresponse to LSEC. However, delivery of Interleukin-10 or transforming growth factor-/3 may downregulate the immediate inflammatory alloresponse. After the initial inflammatory response, grafted LSEC and KC may promote graft acceptance by the induction of anti-inflammatory cytokines. Host-de- rived KC may further down-regulate the inflammatory alloresponse and con- tribute to the acceptance of liver allografts.

1900

DIABETES MELLITUS POST-LIVER TRANSPLANTATION. Alnoor S Ramji, Ahmed A Aldosary, Tom G Elliott, Sandra M Sirrs, David M Thompson, Siegfried R Erb, Urs P Steinbrecher, Eric M Yoshida, University of British Columbia, Vancouver, BC Canada

OBJECTIVE: To determine the prevalence and predictive factors of developing Diabetes Mellitus post-liver transplantation. METHODS: A retrospective study was performed on all liver transplant recipients from British Columbia be- tween 1989 to March 2000. Diabetes Mellitus was defined as patients requiring treatment with insulin or oral hypoglycemic agents. Patient characteristics, etiology of liver disease at transplant, and immunosuppression regimen were considered. A univariate and multiple logistic regression analysis were per- formed. RESULTS: Post-transplant diabetes mellitus (PTDM) occurred in 46 (24%) of 181 transplant recipients included in final analysis. The majority of patients were treated with insulin (80%). On univariate analysis, transplanta- tion for HCV liver disease was associated with a higher incidence of PTDM (OR 2.83 95%CI 1.4-5.8). Older recipients developed significantly more PTDM with a mean age of 49. Recipient gender, steroid dosage and immunosuppres- sion regimen were not predictive of PTDM. The incidence of acute rejection, graft loss and death rate were similar between the two groups. On logistic regression, HCV related liver disease (OR 3.40, C195% 1.63-7.11, p = 0.001) was an independent predictive factor for PTDM. CONCLUSION: Diabetes mellitus post liver-transplantation is a common occurrence. Factors associated with PTDM include transplantation for HCV-related liver disease, and older age. Immunosuppression regimen is not predictive of PTDM.

1901

THE PREVALENCE OF VDRE-POSITIVE DONORS AND IMPACT ON GRAFT SURVIVAL IN LIVER TRANSPLANT RECIPIENTS. ANALYSIS OF THE UNOS DATABASE. Vinod K Rustgi, Gustavo Marino, Georgetown Uni- versity, Washington, DC; Michael T Halpern, Charles River Associates, Wash- ington, DC; Christine Tolleris, United Network for Organ Sharing, Richmond, VA

Background Livers from VDRL positive donors are currently accepted for use in transplantation. However, little information is available regarding the fre- quency of VDRL-positive donated livers or the impact of donor VDRL status on graft survival. The UNOS database was analyzed for these issues. Materials and methods A review of the UNOS database including 32,515 liver transplants performed from 1992 through 2000 with at least one follow-up visit was performed. Transplants involving donor with unknown VDRL status were excluded. Associations between donor VDRL and hepatiitis status were evalu- ated using Fisher's Exact test. The impact of donor VDRL status was examined using proportional hazards regression to control for differences in follow up time. Results Data from 30,847 liver transplants were analyzed; 1,962 trans- plants were excluded due to unknown donor VDRL status. A total of 246 donors (0.80%) were VDRL positive. Compared to VDRL negative donors, VDRL positive donors were significantly more likely to also be hepatitis B positive (1.63% vs. 0.10%, p<0.0005) and to be hepatiitis C positive (4.83% vs. 1.59%, p<0.005). Graft failure rates were essentially identical for trans- plants with VDRL positive donors (12.6%) versus VDRL negative donors (11.9%, p=0.73). Controlling for follow-up time and recipient demographic and clinical characteristics, donor VDRL status did not significantly impact graft failure rates. Analysis and conclusions: While the prevalence of VDRL- positive status is low among liver transplant donors, it is significantly associ- ated with donor hepatiitis B and C positive status. However, donor VDRL status does not significantly impact graft failure rates. Thus, it is appropriate to continue the use of livers from VDRL positive donors.

1902

CALCULATED GFR DOES NOT PREDICT THE DEGREE OF NEPHRO- TOXICITY POST LIVER TRANSPLANTATION. Nitika Arora, Liver Unit, Birmingham Children's Hospital, Birmingham Uk; David Milford, Sally Hul- ton, Mark Taylor, Renal Unit, Birmingham Children's Hospital, Birmingham Uk; Susan V Beath, Patrick J McKieman, Jean de Villa De Goyet, Liver Unit, Birmingham Childrens Hospital, Birmingham Uk; Deirdre A Kelly Dr, Liver Unit, Birmingham Children's Hospital, Birmingham Uk

Introduction: Nephroxicity is an important side effect of the calcinenrin inhib- itor drug, Cyclosporin, the major immnosnppressive agent post liver trans- plantation (OLT). It is important to predict the development of nephrotoxicity in order to prevent irreversible renal damage.C[ Aim: To evaluate whether serial calculated GFR by the Schwartz formula (cGFR) is useful in predicting renal damage.C[ Subjects and methods: A retrospective analysis of all children sur- viving one year post OLT was performed. All children received triple irnmu- nosuppression post OLT with Cyclosporin, Azathioprine and steroids as per protocol, cGFR was calculated by the Schwartz formula at regular intervals. A renal biopsy was performed if the cGFR was below 65mls /m i rd l . 73m 2, The severity of histological damage was correlated with age at OLT, sex, underlying diagnosis, time since OLT and cGFR at time of biopsy.q Results: 12 children underwent a renal biopsy (M:F 5:7). Median (range) age at OLT was 50m (7-182m). The commonest indication for OLT was Extra Hepatic Biliary Atre- sia (n=4). Median time from OLT to renal biopsy was 51m (3-I32m) and the median cGFR was 53 (25-64) mls/min/1.73m 2. Changes secondary to Cyclo- sporin nephrotoxicity such as tubular atrophy and interstitial fibrosis were present in all biopsies. 7 had glomerulosclerosis and 8 had vascular changes. There was no correlation beween severity of renal damage and either the reduction in cGFR or time since OLT. Children with fulminant hepatic failure (n=2) and Hepatoblastoma had a more rapid progression to nephrotoxicity as compared to those with EHBA.q[ Conclusion: A reduction in cGFR was asso- ciated with renal damage but did not predict the degree of nephrotoxicity. Early monitoring and investigations are required to prevent irreversible renal damage.