Weaning Of Immunosuppression In Long-Term Liver Transplant Recipients

Abstract

Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n=4), hepatitis (n=2), patient anxiety (n=5), or lack of cooperation by the local physician (n=2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n=9), HCC (n=1), Wilson's disease (n=4), hepatitides (n=15), Laennec's cirrhosis (n=1), biliary atresia (n=16), cystic fibrosis (n=1), hemochromatosis (n=1), hepatic trauma (n=1), alpha-1-antitrypsin deficiency (n=9), and secondary biliary cirrhosis (n=1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n=8), squamous cell carcinoma (n=2) or verruca vulgaris of skin (n=9), osteoporosis and/or arthritis (n=12), obesity (n=3), hypertension (n=11), and opportunistic infections (n=2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to <5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary.Lifetime immunosuppression has been a presumed necessity after clinical whole-organ transplantation. However, we have suggested elsewhere that liver allograft acceptance without a need for maintenance immunosuppression may have been accidentally achieved more often than realized (1). The recently proposed concept that donor leukocyte migration and long-term microchimerism is the basis of allograft acceptance (2) would account for the

Weaning of Immunosuppression in Liver Transplant Recipients12

“…One is the necessity for close physician surveillance during weaning with frequent assessments of liver function, repeat biopsy with the slightest suspicion of rejection, and prompt restoration of immunosuppression if this is the diagnosis (which it frequently is not). Second, weaning should not be as abrupt as was done in the early patients of this series (3) or in other trials (14)(15)(16)(17)(18). Third, the risk of autoimmune recurrence is a real one, as previously predicted (3).…”

“…The rmding that complete freedom from immunosuppression was sporadically possible in long-surviving recipients of liver (1) and kidney allografts (2) prompted a prospective trial of drug weaning (3). Although it was shown that significant reductions in medication or their discontinuance could be safely accomplished, the danger of consequent rejection has not been completely assessed and guidelines for judicious weaning need to be clarified.…”

“…We present here further observations on 3 cohorts of liver recipients: 5 who self-weaned many years ago (1), 59 who were in the prospective weaning trial of Ramos et a1. (3), and 36 who were subsequently entered.…”

Tolerance for organ recipients: A clash of paradigms

“…14,15 Assessment of the completeness and durability of the tolerance may require follow-ups of 2 or more years since the effects of conditioning with a potent lymphoid depleting antibody are long-lasting. Nevertheless, the observations in the 3 cases described by Donckier et al add to the considerable historical evidence 15,34,[38][39][40][41][42] that drug-free tolerance in a significant number of HLA-mismatched liver transplant recipients is a realizable objective.…”

The lost chord: microchimerism and allograft survival

“…5). More-complete information was obtained in a prospective weaning trial of liver recipients who had at least five years of stable allograft function 42 . The majority of these patients were able to stop immunosuppression or are still in an uninterrupted weaning process 43 ; 30% developed rejection, necessitating resumption of immunosuppression.…”