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Successful drug withdrawal after family kidney transplantation
31 March 2009
Dutch Kidney Foundation
Researchers from the Erasmus Medical Centre in Rotterdam showed in a study funded by the Dutch Kidney Foundation (DKF) that immunosuppressive drugs can be largely withdrawn after transplantation of a kidney from an HLA-identical sibling donor (Transplantation, 2009 Mar 27, 87(6): 907-14 and 2009 Mar 15, 87(5): 740-4).
Transplant patients have to take lifelong medication to prevent rejection. These drugs have many serious side effects like an elevated risk for cancer and for cardiovascular disease. In 2008 in the Netherlands, more than half of all transplanted kidneys were from living donors. The importance of living donation is internationally growing because of the serious shortage of organs from postmortal donors. It is estimated that as a consequence, each year up to 200 patients die on the Dutch kidney transplant waiting list.
Project leader Dr. Nicole van Besouw: 'In 27 patients out of 29 azathioprine and mycophenolate mofetil were withdrawn completely to leave only a low dose of steroids. There resulted no acute rejection. The underlying renal disease returned in 4 patients, but this was not a different result from the group that continued immunosuppression.'
All patients had received a kidney from an HLA-identical brother or sister. The HLA system of tissue types (human leukocyte antigens) forms the basis for matching donor and recipient before transplantation. When the HLA-types are identical the risk of later organ rejection is minimal. Living related kidney transplants result in a higher patient survival rate compared to postmortal kidneys.
Van Besouw: 'We are constantly looking for ways to minimize medication after transplantation. We wondered why recipients from HLA-identical family donation would still need immunosuppression. So we started this study to see if withdrawal could be performed safely while measuring donor specific reactions of immune cells in the patients' blood.'
In general, data on withdrawal in this relatively small patient group are scarce and probably many of these patients remain on usual dosing of immunosuppression. The total Rotterdam group consisted of 83 patients transplanted from 1982 up to 2005, time from transplantation in the study group varied from 1 to 22 years.
The researchers found small changes in the immune reactions after withdrawal. Dr. van Besouw: 'We looked at reactive immune cells producing the signalling molecules interferon-γ, granzyme-B and interleukin-10, which have a modulating function in immune reactions. We found that after stopping azathioprine or mycophenolate mofetil the numbers of interleukin-10 producing cells increased significantly. This suggests that the drugs hinder interleukin-10 in its immune suppressive function.'
'Further, we found that the dendritic cells had shifted to more mature types after medication withdrawal. It may be that the drugs are impeding the dendritic cell maturation process.' Dendritic cells are specialized in presenting foreign material to reactive immune cells. This way they play an important role in setting off immune reactions against germs and also transplant rejection.
Dr. van Besouw: 'Withdrawal of immunosuppressive drugs is important to improve quality of life. We need more and larger clinical trials to better investigate withdrawal and to find reliable biomarkers for predicting rejection risks.'