Identification of Patients With High Probability of Poorly Responding to Therapy With Mycophenolic Acid Prodrugs

Study Overview
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Brief Summary
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This study is designed to define groups of patients (among patients with a heart or kidney graft or a glomerular disease and nephrotic range proteinuria) who would either not profit from a therapy with mycophenolate-mofetil (MMF) or need a higher than conventional dose to respond. Mainly there are 2 possible explanations for inter-patient differences in responsiveness to MMF therapy: Based on a mutation (in this study single nucleotide polymorphisms-SNPs-) in the inosine monophosphate dehydrogenase 2 (IMPDH 2) transcript as the target enzyme of mycophenolic acid (MPA) pathway, MMF cannot exert its effect. Based on a high enzyme activity of IMPDH 2 a higher MMF dose than in the conventional regimens is needed. To study the significance of these possible explanations there are 4 objectives in this study: Objective 1: Since there are no data on SNPs with functional relevance in IMPDH 2 transcript, we will first sequence all 14 exons of this gene in their entirety in 100 gender and age matched healthy individuals. Objective 2: The functional relevance of a detected SNP will be tested in vitro in a lymphocyte proliferation assay using various MPA concentrations. Objective 3: These functionally relevant SNPs will be searched in patients with kidney graft in a retrospective as well as prospective manner. Objective 4: Parallel to the genotyping experiments, IMPDH 2 activity and MPA plasma levels will be measured in all patients recruited in the study prospectively. An association between these SNPs or various IMPDH 2 activity / MPA plasma levels with MMF responsiveness will be examined. Objective 5: Strongyloides IgG titers are screened to evaluate the prevalence of helminth carriers in patients with immunosuppressive therapy.

Official Title
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Identification of Patients With High Probability of Not or Poorly Responding to Mycophenolate-mofetil (Cellcept®) or Mycophenolate-natrium (Myfortic®) Therapy

Conditions
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Renal Transplantation

Intervention / Treatment
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* Genetic: MPA SNP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with a de novo kidney graft and age >18 and < 75 Exclusion Criteria: pregnancy panel of antigens reactivity > 40%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| All patients<br> | Genetic: MPA SNP<br>* Functional relevant MPA SNP will be sought in patients DNA isolated from leucocytes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Detection of functionally relevant SNPs in IMPDH 2 gene. |  | 6 months | 
| The association of detected SNPs in inosine monophosphate dehydrogenase-2 transcript or high IMPDH 2 activity with the lack of response to MPA therapy defined as - number of biopsy proven acute rejections in the first year after transplantation |  | 12 months per patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Screening for strongyloides IgG titers |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplantation, immunosuppression, single nucleotide polymorphism, IMPDH