Molecular Nephrology
1) Individualization of immunosuppressive therapy with mycophenolic acid precursors by pharmacokinetic, pharmacodynamic and pharmacogenetic testing.
This study is designed to define groups of renal transplant patients who would either not profit from a therapy with mycophenolic acid (MPA) prodrugs or need a higher than conventional dose to respond.
Mainly there are 3 possible explanations for inter-patient differences in responsiveness to MPA therapy:
- Based on a gene mutation in the inosine monophosphate dehydrogenase 2 (IMPDH2) transcript as target enzyme of the mycophenolic acid pathway, MPA cannot exert its effect.
- Based on a high enzyme activity of IMPDH in an individual a higher MPA dose than in the conventional regimens is needed.
- Due to a large inter-individual variability of MPA pharmacokinetics, patients with low MPA plasma levels may have less MPA effect.
To study the significance of these possible explanations there are 3 objectives in this study:
Objective 1:
Finding SNPs in the IMPDH2 gene in 100 healthy volunteers and testing SNPs for functional relevance in a lymphocyte proliferation assay. Afterwards screening of functional relevant SNP in 100 renal transplant patients in a prospective study.
Objective 2:
Parallel to the genotyping experiments, IMPDH activity will be measured in 150 kidney transplant patients prospectively.
Objective 3:
Simultaneously also MPA plasma levels will be measured in 150 renal transplant patients prospectively.
An association between functional relevant IMDH2 SNP and various IMPDH activity levels and MPA plasma levels with MPA responsiveness will be prospectively examined in 150 kidney transplant patients.
End of the recruiting phase: July 2013
2) Simultaneous use of pharmacokinetic and pharmacodynamic parameters to individualize MPA therapy.
IMPDH activity and MPA trough levels in 25 transplant patients at the time of a rejection and 80 with a stable kidney function are studied. Recruiting has ended.