Abstract

Background: Long-term therapy with MMF may induce IMPDH activity in peripheral blood mononuclear cells (MNC), reducing its immunosuppressive properties.
Material/Methods: IMPDH activity was measured in MNCs samples from 73 stable kidney transplant patients (median treatment time: 34 months, range: 3-75), before (t0) and 2 hours after (t2) MMF administration and monitored for up to 12 months. MMF treatment was combined with cyclosporine (CsA group) in 24 subjects, tacrolimus (TAC group) in 33, and sirolimus (SRL group) in 16. Samples from 95 healthy subjects were used as controls.
Results: IMPDH activity in healthy subjects was highly variable, mean 8.33±6.93 nmol/h/mg, with no relevant association with sex or age. In transplant recipients, during 12 months of MMF therapy, t0 IMPDH activity increased from 5.5±3.93 to 11.66±6.45 nmol/h/mg, with considerable intra- and interpatient variability (about 60%), and with no decrease in inhibition level (73.3%, range: 54.0-96.6). No significant intergroup differences were found. Mean concentrations of CsA, TAC, SRL and MPA were 142.4, 9.4, 12.9 ng/ml and 3.38 μg/ml. Four patients experienced acute rejection (AR) during the 12-month follow-up. IMPDH activity at t0 was increased during rejection versus non-rejection in 3 patients. No differences in enzyme inhibition levels were observed.
Conclusions: Despite the association found between IMPDH activity and AR, the high intrapatient variability affects its effectiveness as a predictive tool in long-term transplant outcomes. Further trials, also including pre-transplant data on both IMPDH expression and biological activity, are warranted to better assess the rule of IMPDH activity as biomarker for MPA effect in clinical practice.

Keywords: Mycophenolate Mofetil, combined therapy, Pulsed Doppler tissue imaging Dobutamine stress echocardiography