Abstract

Background: Mycophenolic acid - the active metabolite of MMF - inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH). Monitoring IMPDH activity could be a target to optimize MMF therapy. In this study we investigated the relationship between IMPDH activity and risk of BPAR in renal transplant patients.
Material/Methods: 101 de novo renal transplant patients were prospectively monitored for pharmacokinetics and pharmacodynamics of MMF treatment. One blood sample was taken pre transplant and 6 samples on day 6 post transplantation. The enzyme activity of IMPDH in PBMCs was measured using a validated HPLC method. IMPDH activity and MPA exposure was calculated as the area under the activity/concentration-time curve (AUC[sub]act [/sub]and AUC[sub]MPA[/sub]) using a linear trapezoidal rule. All acute rejection episodes were biopsy proven according Banff classification.
Results: Samples for IMPDH activity measurement were available from 78 patients (age 19-76 years) on day 6 (range 3-11) post transplantation. In 17 of the patients a BPAR was documented within one year after transplantation. The AUC[sub]act[/sub] of patients with BPAR was significantly higher compared to non-BPAR patients (394±287 vs. 255±156 h*μmol/s/mol AMP, p=0.017). No significant correlation was found between IMPDH activity pre (48±27 vs. 54±41 h*μmol/s/mol AMP; p=0.97) and at single time points post transplantation compared to BPAR. The AUC[sub]MPA[/sub] was not significantly different for both groups (36.5±17.0 and 37.0±19.7 h*mg/L; p=0.95).
Conclusions: In the largest patient series to date, IMPDH activity, measured as AUC[sub]act[/sub] on day 6, is signifi cantly correlated with BPAR after renal transplantation. Monitoring IMPDH activity is a promising, novel biomarker to optimize MMF treatment in renal transplant patients.

Keywords: Mycophenolic Acid, IMPDH, Percutaneous transsplenic