Beta-2 Microglobulin and Serum Creatinine for Differentiating Between Immunoactivation and Renal Failure After Liver Transplantation E. Erez, Z. Ben-Ari, E. Sharoni, D. Aravot, G. Sahar, R. Tur-Kaspa, B.A. Vidne, and A. Erman B ETA-2 MICROGLOBULIN (B2m), a low molecular weight plasma protein (11,800 daltons), is associated with histocompatibility class 1 antigens on cell surface membranes (particularly abundant on lymphocytes and monocytes). It might be important for immunologic moni- toring. 1 It is filtered (95%) at the glomerulus and reab- sorbed (99.9%) by the proximal tubule, where it is cathabo- lized. 2 Several studies in renal, 3,4 liver, 5 and heart 6 transplantation have demonstrated a high correlation be- tween increasing serum B2m and graft rejection. B2m has been studied extensively. In renal transplant recipients, B2m has been found to increase its serum level earlier than creatinine in heralding rejection, and to decrease with resolution of rejection. 3 In liver transplant patients, increased expression of B2m in bile ducts, hepatocytes, and endothelial cells were observed during rejection. 7 Control of rejection by appropriate treat- ment was matched by decreased B2m expression. 8 Both an elevated production of B2m by activated lymphocytes (im- munoactivation) and an impaired renal function (cyclospo- rine nephrotoxicity), with consecutively diminished renal metabolism of B2m, may contribute to the increased serum level seen in transplanted patients. We studied the role of serum B2m and creatinine measurements in differentiating between cyclosporine nephrotoxicity and immunoactivation in 36 clinically stable liver-transplanted patients. PATIENTS AND METHODS Thirty-six liver-transplanted patients (mean age 56  9 years), 18 males and 18 females, with good graft function were studied. Graft function was evaluated by serum liver enzymes (alanine-amin- otransferase, aspartate-aminotransferase, alkaline phosphatase, gamma glutamyl transferase), bilirubin, albumin, prothrombin time, ultrasound Doppler, and a liver biopsy. At the time of evaluation, there was no increase in serum bilirubin; no evidence of acute cellular rejection in liver histology 9 ; no signs of active infection (no fever, normal white cell counts, normal chest X-ray); and no evidence of biliary tract obstruction (normal serum biliru- bin, and no ultrasonic evidence of biliary tract dilatation). Five patients had recurrent hepatitis B (HBV) infection that was diagnosed by increased serum liver enzymes, serum-positive HBsAg, HBV DNA (by hybridization), and a compatible liver histology. Eight patients had recurrent hepatitis C (HCV) infection diag- nosed by increased serum liver enzymes, serum-positive HCV RNA (by PCR), and a compatible liver histology. Patients were receiving maintenance doses of immunosuppressive therapy: cyclo- sporine 10 mg/kg (21/36) or FK506 0.02 mg/kg (15/36), azathio- prine 1.5 mg/kg (2/36), and prednisone 0.8 mg/kg (34/36). They were evaluated at least 3 months posttransplantation (mean 37 months, range 8 to 92 months). Patients were divided into two subgroups: LTxnor (n = 21), normal renal function: serum creat- inine (SCr)  1.3 mg/dL; and LTxabnor (n = 15) impaired renal function: SCr  1.3 mg/dL. Two control groups were used: C1 (n = 15), normal individuals, and C2 (n = 10), patients with chronic renal failure (age- and sex-matched). Renal function was evaluated by measuring serum creatinine (using a Beckman creatinine ana- lyzer). Serum samples for B2m measurements were collected at the time of clinical and laboratory evaluation and kept at -20°C until determination by immunoradiometric assay (Coat-A-Count B2m IRMA kit, Diagnostic Products Corporation, Los Angeles, Calif, USA). Serum B2m and serum creatinine values were expressed as mean  SD. To analyze statistical differences in mean serum B2m and serum creatinine, analysis of variance was performed using the Duncan multiple comparison option. To study the correlation between B2m and serum creatinine in the control and study groups, linear regression analysis was performed. P values of  .05 were considered statistically significant. RESULTS Individual values of B2m in the study and control groups are expressed in Fig 1. The group of transplanted patients with normal renal function (LTxnor) had a mean serum creatinine similar to the control group (C1), (1.08  0.2 ng/dL and 1.014  0.12 mg/dL, respectively). However, serum B2m in Txnor was statistically higher than the control group (C1) (3.7  1.4 g/mL and 1.66  0.12 g/mL, respectively; P  .0005). From the Department of Cardiothoracic Surgery (E.E., E.S., D.A., G.S., B.A.V.), Liver Institute and Department of Medicine D (Z.B.A., R.T.-K.), Rabin Medical Center, Beilinson Campus, Pe- tah Tiqva, Israel, and Institute of Nephrology and Hypertension (A.E.), Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Address reprint requests to Ziv Ben-Ari, MD, Liver Institute and Department of Medicine D, Rabin Medical Center, Beilinson Campus, PO Box 102, Petah Tiqva 49100, Israel. 0041-1345/01/$–see front matter © 2001 by Elsevier Science Inc. PII S0041-1345(01)02251-5 655 Avenue of the Americas, New York, NY 10010 2920 Transplantation Proceedings, 33, 2920–2923 (2001)