AASLD: Spare the Tacrolimus and Save the Kidneys

BOSTON, Nov. 4 -- For liver transplant recipients, lowering the dose and delaying the introduction of tacrolimus (Prograf) and adding two other agents can help preserve renal function without compromising graft or patient survival.
Action Points
Explain to patients that some immunosuppressant drugs used to prevent organ rejection after transplantation can result in kidney damage and possible renal failure with prolonged use.
Explain that this study suggests a regimen that may prevent or lessen kidney damage but that data on long-term survival is not yet available.
Note that this study was published as an abstract and presented at a conference. The data and conclusions should be considered to be preliminary until published in a peer-reviewed publication.
Among more than 500 adult liver graft recipients followed for one year, immunosuppression with a reduced dose of tacrolimus introduced on the fifth rather than the first post-surgical day resulted in significantly better renal function compared with standard tacrolimus dosing, James M. Neuberger, M.D., and A. David Mayer, M.D., of Queen Elizabeth Hospital in Birmingham, England, at the American Association for the Study of Liver Diseases meeting here.
"Of the many risk factors that are associated with renal failure late after transplantation, the extent and degree of calcineurin inhibitor exposure -- either cyclosporine or tacrolimus -- is a major risk factor," said Dr. Neuberger.
Renal function at one year is also a good predictor of late renal failure, he added.
Dr. Neuberger and colleagues conducted a study to see whether mycophenolate mofetil (CellCept), in combination with either reduced dose tacrolimus or delayed tacrolimus, could be associated with a lower risk for nephrotoxicity at one year in patients undergoing orthoptic liver transplantation, without jeopardizing survival of the patient or graft.
A total of 525 adults who were recipients of a first liver graft at 30 European centers were randomly assigned to one of three treatment groups:
Tacrolimus at the recommended dose to achieve target levels ≥10ng/mL for the first month (183 patients)
Tacrolimus at a lower dose to achieve trough target levels 8ng/mL for the first month and mycophenolate mofetil 2g/day (170 patients) and group
Daclizumab (Zenapax) on day one and seven, mycophenolate mofetil 2g/day and tacrolimus introduced on day five with trough target levels 8 ng/mL).
Corticosteroids were given according to local practice in each group.
Dr. Neuberger noted that because they were delaying the initiation of tacrolimus without clear supporting data, they covered patients in the delayed therapy group.
They used the Cockcroft-Gault formula to calculate glomerular filtration rate and estimate creatinine clearance to measure renal function.
They found that the calculated glomerular filtration rate at baseline for patients on standard tacrolimus was 103 mL/min, compared with 107 mL/min for those on the reduced dose schedule, and 98 mL/min for those on the delayed tacrolimus plus daclizumab schedule.
The rates fell by 25, 24, and 17 mL/min, respectively at one year, but the difference between patients in the standard and delayed group was significant at P=0.003.
Withdrawals because of adverse events occurred in 29% of patients on the standard tacrolimus regimen, 18% of those on reduced dose tacrolimus, and 21% of those on the delayed schedule. Withdrawals related to renal impairment occurred in 12%, 2% and 1% of the patients, respectively.
In all, 9.2% of patients on standard tacrolimus died within the first year, compared with 10% of those on the reduced dose, and 5% of those on the delayed dose.
Graft loss occurred in 6.0 of patients on standard, 5.9% of patients on reduced, and 6.6% of patients on delayed tacrolimus.
There were no significant differences in biopsy-proven acute rejection, which occurred in 31%, 30%, and 25% of patients on standard, reduced, and delayed regimens respectively.
Diarrhea was seen in 21% of patients on standard tacrolimus, 31% of those on reduced tacrolimus, and 25% of those in the delayed tacrolimus group.
"What I believe this study shows is that mycophenolate, corticosteroids, and induction therapy with daclizumab, combined with delayed introduction of low-dose tacrolimus was associated with less impairment of renal function 12 months after liver transplantation," Dr. Neuberger said. "Whether, of course, this translates into reduced risk of renal impairment five or 10 years down the line, we'll just have to wait and see."
The study is supported by F. Hoffman-La Roche Ltd and the Queen Elizabeth Hospital Birmingham NHS Trust. Dr. Neuberger is on the speakers' bureaus of Roche, Astellis, and Novartis.
Primary source: American Association for the Study of Liver DiseasesSource reference: Neuberger JM and Mayer AD. "Delayed and reduced dose tacrolimus with mycophenolate mofetil and daclizumab reduces renal impairment after liver transplant: results of a one-year prospective, randomized international trial." Abstract 1, presented Nov. 4.