IMPROVEMENT OF RENAL FUNCTION BY CONVERSION OF TACROLIMUS TO EVEROLIMUS 3 MONTHS AFTER KIDNEY TRANSPLANTATION

At present, combination therapy consisting of a CNI together with mycophenolic
acid (MPA) is the most frequently used immunosuppressive drug regimen after
kidney transplantation. Treatment with CNIs is an important cause of late
kidney allograft dysfunction. These drugs have both acute nephrotoxic effects,
which are in general fully reversible after cessation or dose reduction, and
chronic nephrotoxic effects. Nankivell and colleagues observed that 10 years
after transplantation, histologic findings of cyclosporine-related
nephrotoxicity were almost universally present and usually irreversible with
ongoing cyclosporine therapy, despite dose reductions. The main challenge now
facing transplant physicians is to further improve the long-term
transplantation outcomes, while maintaining the excellent short-term results
that are currently achieved. Several investigators have tried to use an mTOR
inhibitor-based rather than a CNI-based immunosuppressive regimen to avoid the
nephrotoxicity associated with the latter. However, the results from several
clinical trials have demonstrated that the use of mTOR inhibitors without CNIs
in de novo renal transplant recipients results in unacceptably high rates of
acute rejection. An alternative strategy to obtain a low incidence of acute
rejection while maintaining renal function is to treat patients initially with
a CNI-based immunosuppressive regimen followed by CNI withdrawal and conversion
to a mTOR inhibitor-based immunosuppressive regimen several months after
transplantation. Several studies have investigated the efficacy and safety of
early conversion from a CNI-based immunosuppressive regimen to sirolimus-based
immunosuppression. Taken together, conversion to sirolimus appears to improve
or maintain renal function but the drug had to be discontinued in a high
percentage of patients (approximately 30%) due to side-effects.
With regard to everolimus, fewer data on the conversion from CNI-based
immunosuppressive regimens are available. Unlike, sirolimus, everolimus has a
much shorter elimination half-life which makes the drug easier to use in
clinical practice. Recently, De Simone et al. converted 145 liver transplant
recipients experiencing CNI-related renal impairment from a CNI to an
everolimus-containing immunosuppressive regimen. The creatinine clearance was
comparable between the CNI group and the everolimus group six months after
conversion but this may be explained that in the patients who remained on CNIs,
the CNI dose was reduced. In a small study among kidney transplant recipients
with established CNI-nephrotoxicity or CAN, conversion of a CNI-based
immunosuppressive regimen to everolimus, resulted in a 42% increase of the
creatinine clearance. At present, several prospective studies are ongoing with
the aim to investigate the efficacy and safety of everolimus-containing
regimens for renal transplantation. In the ZEUS-study, the efficacy, safety and
tolerability of a regimen with everolimus plus enteric coated mycophenolate
sodium (EC-MPS; Myfortic®, Novartis Pharma) vs. a regimen containing
cyclosporine plus EC-MPS is compared in de novo renal transplant recipients.
Preliminary data on 285 patients from the ZEUS trial have demonstrated a
significant difference in renal function at 12 months favouring everolimus over
cyclosporine: GFR 72.3 vs. 62.2 ml/min per1.73 m2, respectively.

The aim of this study is to investigate if conversion of tacrolimus-based
immunosuppression to everolimus-based immunosuppression results in
preservation of renal function as compared to continued tacrolimus-based
immunosuppression. Apart from renal function also changes in renal histology
following conversion of tacrolimus-based immunosuppression to everolimus-based
immunosuppression will be studied.

At three months after transplantation patients will be randomised for
continuation of tacrolimus or conversion of tacrolimus to everolimus
maintenance therapy (Certican®, Novartis Pharma). The starting dose of
everolimus will be 1.5 mg twice daily, and dosages will be adjusted based on
trough level monitoring, aiming for whole blood concentrations of 4 to 7 ng/mL.
Tacrolimus will be stopped one week after the initation of everolimus.
Scheduled follow-up will last until month 12 after transplantation.

All patients participating in study METC-2010-080 have undergone protocol
biopsies at t = 0 (pre-implantation biopsy) and at months 3. For this
conversion study the already taken biopsy at month 3 will be used as the
reference biopsy, and will be compared with a subsequent biopsy taken at 12
months after transplantation (i.e. 9 months after randomization). However if
the patient was not included in METC-2010-080 than the biopsy at month 3 will
be taken in this study.

Patient randomized for the tacrolimus-group will continue the tacrolimus-based
immunnosuppressive regimen, while patients randomized for the everolimus-group
will start everolimus (1.5 mg twice a day) in stead of tacrolimus. The
tacrolimus and everolimus doses will be adjusted to therapeutic drug monitoring
levels.

All patients will undergo protocol biopsies at month 3 (if not already taken in
study METC-2010-080) and at 12 months after transplantation.

The risk of the venapuncture are the occurence of a bruise after puncture and
possible pain-symptoms at the site of puncture. A biopsy is more torough and
gives a risk on bleeding. Approximately 1-2% of the patients have a clinical
important bleeding after kidney biopsy. Graftloss due to biopsy is very rare.