Steroid free immunosuppression or calcineurin inhibitor minimization after Basiliximab induction therapy in kidney transplantation: Comparison with a standard quadruple immunosuppressive regimen.

Rationale: Quadruple immunosuppression consisting of an induction treatment,
followed by mycophenolate mofetil, a calcineurin inhibitor and steroids results
in low rejection rates and excellent graft survival. Especially in
retransplantation graft survival has been improved in the last decade . Despite
this success, mortality and morbidity in transplant recipients is relatively
high due to side effects of immunosuppressive strategies. The incidence of
hypertension, hypercholesterolemia and diabetes mellitus is relatively high.
This is one of the reasons for the high cardiovascular mortality in renal
transplant recipients. A potential cause is the use of steroids and calcineurin
inhibitors. Calcineurin inhibitors may play an important role in the
development of chronic allograft nephropathy causing poor kidney function and
cardiovascular disease. However differences between calcineurin inhibitors are
shown with regard to the incidence of these side effects and graft function.
Also infections and malignancies are the result of immunosuppression in
general. In some countries malignancies are the most frequent cause of death in
kidney transplant recipients. Steroids play an important role in the
development of osteoporosis in renal transplant recipients.

Objectives: A prospective, open label, randomized trial, in which we aim to
achieve optimal immunosuppression after renal renal transplantation with
maximal reduction of side effects, especially of vascular injury, chronic
allograft nephropathy, osteoporosis and malignancies. Immunosuppression without
steroids and CNI minimization is compared to standard immunosuppression,
consisting of tacrolimus OD, mycophenolate mofetil and corticosteroids.

Group 1 patients will start with quadruple immunosuppression, consisting of
basiliximab (Simulect) induction 20 mg intraveneously on day 0 and day 4, three
days steroids followed by tacrolimus OD (Advagraf) and mycophenolate mofetil
(MMF, Cellcept). Appendix I shows the exact dosage schedule. Advagraf will be
given orally in a dosage of 0,2 mg/kg. Trough levels will be monitored. Target
values of tacrolimus trough level will be 8-12 ng/ml for the first 5 weeks
after transplantation thereafter 6-10 ng/ml. MMF will be given twice daily 1000
mg orally for the first two weeks after transplantation followed by 2 x 750 mg
thereafter. Corticosteroids will be given intravenously on day 0, 1 and 2
respectively 500, 250 and 125 mg of methylprednisolone. In group 1 no more
steroids will be given other than during rejection episodes. In group 2,
induction treatment with basiliximab (Simulect) 20 mg intravenously on day 0
and day 4 is used. Advagraf will be given orally in a dosage of 0,2 mg/kg.
Trough levels will be monitored. Target values of tacrolimus trough level will
be 8-12 ng/ml for the first 5 weeks after transplantation and thereafter 6-10
ng/ml. MMF will be given twice daily 1000 mg orally for the first two weeks
after transplantation followed by 2 x 750 mg thereafter. Corticosteroids will
be given intravenously on day 0, 1 and 2 respectively 500, 250 and 125 mg
methylprednisolone. From day 3, 10 mg prednisolone orally once daily will be
given and from week 6 7,5 mg once daily. Group 3 will receive induction
treatment with basiliximab (Simulect) 20 mg intravenously on day 0 and day 4.
Advagraf will be given orally in a dosaege of 0,2 mg/kg. Trough levels will be
monitored. Target values of Tacrolimus trough level will be 8-12 ng/ml for the
first 5 weeks and thereafter 6-10 ng/ml until 6 months after transplantation.
After 6 months a fixed dose reduction of 50% of Advagraf will take place and
target values of tacrolimus trough level will be 3-5 ng/ml. MMF will be given
twice daily 1000 mg orally for the first two weeks after transplantation
followed by 2 x 750 mg thereafter. Corticosteroids will be given intravenously
on day 0, 1 and 2 respectively 500, 250 and 125 mg methylprednisolone. From day
3 10 mg prednisolone orally once daily will be given and from week 6 7,5 mg
once daily.

Concomitant therapy
Concomitant therapy will consist of omeprazol, antihypertensives and
atorvastatine when needed. Patients at risk for CMV infection (donor or
recipient seropositive) wil receive 6 months valgancyclovir prophylaxis. All
patients will receive Pneumocystis Jirovecii prophylaxis the first year after
transplantation. Rejection documented by percutaneous biopsy, will be treated
with 500 mg of methylprednisone (Solu-Medrol) i.v. for six consecutive days
according to local practice. Steroid resistant rejection episodes will be
treated with rabbit antithymocyte globulin (Thymoglobuline Genzyme) according
to local practice. Patients with acute rejection will remain or will resume low
dose steroid therapy (7.5 mg prednisolone once daily) after their rejection
treatment (37).
Interruption or discontinuation of treatment
Every patient will have the right to discontinue study participation at any
time. All data generated up to the time of discontinuation from the study will
be analyzed and the reason(s) for discontinuation will be recorded.
Treatment compliance
Compliance to the treatment will be demonstrated by adequate drug levels.

The burden associated with participation consists of some more frequent
outpatient visits during conversion. In all three groups the amount of
examinations is the same.
The risk associated with Advagraf is an increase in new onset Diabetes
Mellitus, the risk associated with reducing immunosuppression is a higher
incidence of acute rejection.
The benefits associated with reducing immunosuppression are a decreased risk
for infections, cardiovascular diseases and malignancies .