Minimization of Immunosuppressive Therapy After Renal Transplant
Minimization of Immunosuppressive Therapy After Renal Transplant
Modern immunosuppressive regimens reduce the acute rejection rate by combining a cornerstone immunosuppressant like tacrolimus or cyclosporine with adjunctive agents like corticosteroids, mycophenolate mofetil (MMF) or azathioprine, often associated with untoward side effects.
A 6-month randomized study was conducted in 47 European centers. Triple therapy with tacrolimus (trough levels 5-15 ng/mL), corticosteroids (dosage 10 mg/day) and MMF (1 g/day) was administered for 3 months. From day 92, patients either continued with triple therapy (control, n = 277), or stopped steroids (n = 279), or stopped MMF (n = 277). Surrogate markers for long-term benefits were changes in lipid profiles and occurrence of hematological, gastrointestinal and infectious complications.
The 6-month acute rejection incidence (biopsy-proven) was similar in all groups (17.0% vs. 15.1% vs. 14.8%, p = 0.744), although the incidence after month 3 was higher in the steroid stop group than in the two other groups. Mean reductions in total cholesterol (18.9 mg/dL [0.49 mmol/L]) and LDL-cholesterol (8.1 mg/dL [0.21 mmol/L]) between months 4 and 6 were greater in the steroid stop group (p < 0.001). Leukopenia (p = 0.0082), serious CMV infection (p = 0.024), anemia (p = NS) and diarrhea (p = NS) were less frequent in the MMF stop group.
In a study population of immunologically low-risk patients' withdrawal of corticosteroids or MMF from a tacrolimus-based therapy at 3 months was feasible. A longer follow-up will be needed to confirm the expected advantages for the long-term outcome and to assess the long-term safety of this minimization of immunosuppressive therapy.
In recent years, renal transplantation has seen the advent of a number of new immunosuppressive agents. Including monoclonal antibodies, the transplant physician is currently able to choose among at least eight immunosuppressive agents to devise an efficacious and safe regimen and tailoring of immunosuppressive therapy to the individual patient becomes conceivable. However, there is also the danger to devise regimens that result in over-immunosuppression leading to an increased susceptibility to infections and malignancies, and higher rates of cardiovascular complications and hematological disorders.
In our study we investigated a controlled withdrawal of two adjunctive immunosuppressants from a tacrolimus-based therapy. Corticosteroids are associated with numerous post-transplant complications predominantly related to the cardiovascular system. Hyperlipidemia, which is increased in patients receiving steroids, is one of the most important risk factors for cardiovascular diseases. Although it has been shown that the addition of mycophenolate mofetil (MMF) to either tacrolimus or cyclosporine reduces the incidence of acute rejection, its use has been associated with the development of hematological and gastrointestinal side effects, and increased incidences of viral infections.
Since the advantages of minimizing the immunosuppressive medication may only become apparent in the long term, we used two surrogate markers to assess the benefits in our trial, namely the change in the lipid profile after steroid withdrawal and the occurrence of hematological, gastrointestinal and infectious side effects following stop of MMF.
Modern immunosuppressive regimens reduce the acute rejection rate by combining a cornerstone immunosuppressant like tacrolimus or cyclosporine with adjunctive agents like corticosteroids, mycophenolate mofetil (MMF) or azathioprine, often associated with untoward side effects.
A 6-month randomized study was conducted in 47 European centers. Triple therapy with tacrolimus (trough levels 5-15 ng/mL), corticosteroids (dosage 10 mg/day) and MMF (1 g/day) was administered for 3 months. From day 92, patients either continued with triple therapy (control, n = 277), or stopped steroids (n = 279), or stopped MMF (n = 277). Surrogate markers for long-term benefits were changes in lipid profiles and occurrence of hematological, gastrointestinal and infectious complications.
The 6-month acute rejection incidence (biopsy-proven) was similar in all groups (17.0% vs. 15.1% vs. 14.8%, p = 0.744), although the incidence after month 3 was higher in the steroid stop group than in the two other groups. Mean reductions in total cholesterol (18.9 mg/dL [0.49 mmol/L]) and LDL-cholesterol (8.1 mg/dL [0.21 mmol/L]) between months 4 and 6 were greater in the steroid stop group (p < 0.001). Leukopenia (p = 0.0082), serious CMV infection (p = 0.024), anemia (p = NS) and diarrhea (p = NS) were less frequent in the MMF stop group.
In a study population of immunologically low-risk patients' withdrawal of corticosteroids or MMF from a tacrolimus-based therapy at 3 months was feasible. A longer follow-up will be needed to confirm the expected advantages for the long-term outcome and to assess the long-term safety of this minimization of immunosuppressive therapy.
In recent years, renal transplantation has seen the advent of a number of new immunosuppressive agents. Including monoclonal antibodies, the transplant physician is currently able to choose among at least eight immunosuppressive agents to devise an efficacious and safe regimen and tailoring of immunosuppressive therapy to the individual patient becomes conceivable. However, there is also the danger to devise regimens that result in over-immunosuppression leading to an increased susceptibility to infections and malignancies, and higher rates of cardiovascular complications and hematological disorders.
In our study we investigated a controlled withdrawal of two adjunctive immunosuppressants from a tacrolimus-based therapy. Corticosteroids are associated with numerous post-transplant complications predominantly related to the cardiovascular system. Hyperlipidemia, which is increased in patients receiving steroids, is one of the most important risk factors for cardiovascular diseases. Although it has been shown that the addition of mycophenolate mofetil (MMF) to either tacrolimus or cyclosporine reduces the incidence of acute rejection, its use has been associated with the development of hematological and gastrointestinal side effects, and increased incidences of viral infections.
Since the advantages of minimizing the immunosuppressive medication may only become apparent in the long term, we used two surrogate markers to assess the benefits in our trial, namely the change in the lipid profile after steroid withdrawal and the occurrence of hematological, gastrointestinal and infectious side effects following stop of MMF.
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