Randomized controlled trial of total immunosuppression withdrawal in liver transplant recipients: role of ursodeoxycholic acid.
BACKGROUND
Total immunosuppression withdrawal (TIW) without causing rejection has been reported in stable liver recipients. The role of ursodeoxycholic acid (UDCA) and patient characteristics that predict the success of this tolerance are unclear. There are two goals, to determine: 1) whether TIW is frequently associated with rejection; and 2) whether UDCA decreases the risk of liver disease (both rejection and recurrence) after TIW.


METHODS
Twenty-six liver recipients who had been free of rejection while on immunosuppressive agents for a minimum of 2 years were randomized to receive either (15 mg/kg) of UDCA (n=14) or identical placebo (n=12) followed by sequential withdrawal of their immunosuppressive regimen over several months. Endpoints were defined as biochemical and histological evidence of rejection, graft dysfunction without rejection, recurrence of pretransplant disease, or 6 months without immunosuppression and no rejection or dysfunction on repeat liver biopsy.


RESULTS
Rejection occurred in 6 of 14 (43%) of the UDCA group and 9 of 12 (75%) of those receiving placebo (P=0.09). Degree of rejection was mild, moderate, and severe in 73%, 20%, and 7% of patients respectively. All responded to rescue therapy and none developed chronic rejection. Nine of the remaining 11 patients (eight of the UDCA recipients and three of controls) who did not develop rejection developed graft dysfunction which responded to reintroduction of immunosuppressive agents in each case. Disease recurrence was most common in patients with underlying immune-mediated disorders of the liver. One year after withdrawal only two patients were free of immunosuppression, 80% were able to discontinue prednisone therapy (steroid free), and 50% were able to reduce their dose of cyclosporine. Age, underlying cause of liver disease, and regimen of immunosuppression were favorable predictors.


CONCLUSIONS
The results of this study suggest that TIW: 1) is frequently associated with subsequent rejection, 2) increases the risk of underlying disease recurrence, and 3) is not facilitated by UDCA use and responds properly to the reintroduction of immunosuppressive therapy.
Assy
Nimer
N
Section of Hepatology, University of Manitoba, Winnipeg, Manitoba. Canada, and Liver Unit, Sieff Hospital, Safed, Israel. anny.n@ziv.health.gov.il
Adams
Paul C
PC
Myers
Paul
P
Simon
Verra
V
Minuk
Gerry Y
GY
Wall
William
W
Ghent
Cameron N
CN
D000328:Adult; D000368:Aged; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy / Q000453:epidemiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008107:Liver Diseases / Q000601:surgery; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010349:Patient Compliance; D010919:Placebos; D011241:Prednisone / Q000627:therapeutic use; D012449:Safety; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
D002756:Cholagogues and Choleretics; D007166:Immunosuppressive Agents; D010919:Placebos; D014580:Ursodeoxycholic Acid; D016572:Cyclosporine; D011241:Prednisone