CLINICAL IMMUNOSUPPRESSION - KIDNEY LATE

M. Molinaro¹, L.R. Chiarelli², C. Libetta³, C. Tinelli⁴, L. Cosmai³, G. Valentini², A. Dal canton⁵, M. Regazzi^1
1Pharmacokinetics Unit, Foundation IRCCS Policlinico San Matteo, Pavia/ITALY, ²Department Of Biochemistry, University of Pavia, Pavia/ITALY, ³Unit Of Nephrology, Dialysis And Transportation, Foundation IRCCS Policlinico San Matteo, Pavia/ITALY, ⁴Clinical Epidemiology And Biometric Unit, Foundation IRCCS Policlinico San Matteo, Pavia/ITALY, ⁵Unit Of Nephrology, Dialysis And Transplantation, Foundation IRCCS Policlinico San Matteo, Pavia/ITALY

Body: Introduction Individualization of mycophenolic acid (MPA) therapy is limited by the complex pharmacokinetic (PK) and pharmacodynamic (PD) behavior of MPA. New approaches able to reflect individual responses are required to monitor specific biomarkers of exposure and the biological effects of immunosuppressive drugs. Methods Fifty-nine kidney transplant recipients on cyclosporin A (CyA) and mycophenolate mofetil (MMF) were sampled for plasma total/free MPA concentrations (at 0, 0.67 and 2h) and IMPDH activity in peripheral blood mononuclear cells (PBMCs) (at 0 and 2h). The study patients were enrolled at different post-transplant times, up to > 48 months. Our patients underwent intensive PK/PD monitoring for a period ranging from enrolment to a minimum of 6 months and up to a maximum of 15 months. Results While on PK/PD monitoring, 7 patients experienced one acute rejection (AR) each. Median AUC values were > 20mg.h/L in all patients but < 30mg.h/L in 4 of 7 rejecting patients. MPA trough free concentrations remained quite constant throughout the monitoring period, with a median value of 0.039 mcg/mL. Just like the total plasma concentration at time 0, the trough levels of free MPA were not significantly different between rejectors and non-rejectors (0.039 vs. 0.033 mcg/mL). An increasing trend in inosine monophosphate dehydrogenase (IMPDH) predose activity levels was seen throughout the observation period, from 4.4 nmol h^-1 mg^-1 (interquartile range 1.57-5.97) to 11.4 nmol h^-1 mg^-1 (interquartile range 6.5-13.66), P=0.0007. IMPDH activity at T₀ was significantly higher (about 180%) in AR than in non-AR patients (16.73 vs. 5.95 nmol h^-1 mg^-1, P=0.020). This trend was confirmed also when IMPDH variability was plotted against time in individual patients: intrasubject variability in T₀ IMPDH activity, as described by the slopes of each of our 59 patients who underwent three or more visits versus the corresponding follow-up time, showed a median slope of 1.4 vs. 0.2 in AR versus non-AR patients (P=0.018). Conclusions IMPDH activity might be an additional tool for monitoring the effectiveness of MMF therapy oral dosage in some patients: since higher baseline activity is correlated with higher intracellular enzyme concentration, a greater amount of inhibitor could be required to obtain an adequate response. We need further advances in research in order to be able to identify patients who are at higher risk of exhibiting greater variability in IMPDH activity, for instance by studying IMPDH I/II gene expression.

Disclosure: All authors have declared no conflicts of interest.