Inosine monophosphate dehydrogenase variability in renal transplant patients on long‐term mycophenolate mofetil therapy

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Mycophenolic acid (MPA) is a potent, selective and reversible inhibitor of inosine 5′-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme for de novo guanosine triphosphate biosynthesis.• The large IMPDH interindividual variability could be responsible for the differences in therapeutic effects and side-effects observed with MPA.• Induction of IMPDH activity has been observed in whole blood during immunosuppressive therapy. WHAT THIS STUDY ADDS• Our data were acquired in long-term mycophenolate mofetil-treated renal transplant recipients on different combinations of immunosuppressive agents (ciclosporin, tacrolimus, sirolimus) and with different treatment duration (up to 8.8 years post transplant).• The increasing trend in IMPDH activity that we observed throughout our 12-month observation period was significantly higher in rejecting than in nonrejecting subjects. AIMSLong-term mycophenolate mofetil (MMF) therapy may induce inosine 5′-monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells (PBMCs), thus decreasing MMF immunosuppressive properties. Pharmacodynamic monitoring was used to investigate whether biological activity is altered after long-term therapy. METHODSIMPDH activity was measured in PBMC samples from 54 stable kidney transplant patients, already on MMF (for at least 3 months), before (t0) and 2 h after (t2) MMF morning dose administration; levels were monitored for up to 15 months, together with total mycophenolic acid (MPA) and free MPA concentrations. RESULTSDuring the 15 months' monitoring, t0 IMPDH activity in transplant recipients increased from 5.9 Ϯ 3.7 nmol h -1 mg -1 [95% confidence interval (CI) 4.9, 6.9] to 9.0 Ϯ 3.9 nmol h -1 mg -1 (95% CI 7.2, 10.8), with an intra-and interpatient variability of 28% and 42%. Five patients experienced acute rejection during the follow-up: t0 IMPDH activity was increased during rejection vs. nonrejection, and the trend was significantly higher in rejecting than in nonrejecting subjects for the whole monitoring period. CONCLUSIONSEven though a correlation has been found between IMPDH activity and rejection, its efficacy as a predictive tool in long-term transplant outcomes may be affected by high interpatient variability; on the other hand, continuous monitoring of the IMPDH trend could make an effective prognostic parameter of rejection. Other trials also including pre-transplant data on both IMPDH expression and activity are warranted to better assess their role as biomarkers for MPA effect in clinical practice.

Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid

“…Hence, the observed discrepancy between a pronounced increase in total MPA and only a marginal corresponding decline in IMPDH activity can be explained by unchanged exposure to free MPA, although this was not explicitly measured in the present study. This line of reasoning is supported by the observations of Chiarelli et al, who reported on a significant inverse correlation of the concentration of free MPA 2 h after the morning dose and IMPDH activity, but not of total MPA-C 2 or -C 0 [14]. Hence, it appears that the degree of IMPDH inhibition is rather a function of the concentration of free MPA than of total MPA.…”

“…In addition, pre-transplant IMPDH activity has been associated with clinical outcome in adult renal transplant recipients [36]. It is currently being debated whether the determination of pre-transplant IMPDH activity is sufficient to guide MMF dosing for improving outcome [36] or whether pre-dose IMPDH activity [14] or maximal IMPDH inhibition is superior in identifying patients at risk of acute rejection and MMF-related side-effects. The observed similarities between the paediatric and adult populations regarding variability of IMPDH activity and suppression in response to MPA suggest that a comparable relationship between IMPDH activity and clinical outcome may also exist in the paediatric patient population.…”

“…IMPDH activity displayed a high inter-individual variability throughout the entire age range studied. In view of the known association of IMPDH activity and clinical outcome [13,14,36,37] and the variable pharmacokinetics of MPA [29], an integrated approach that combines pharmacokinetic monitoring of MPA and pharmacodynamic monitoring of IMPDH has the potential to optimise immunosuppressive therapy with MMF.…”

“…The analysis of IMPDH activity in response to MPA is also interesting for the evolving field of pharmacodynamic monitoring of MPA [11][12][13][14]. In addition, we sought to analyze whether genetic variants of the IMPDH gene contribute to the large between-subject variability in IMPDH activity [15][16][17][18][19] as a secondary objective.…”

Pharmacokinetics and Pharmacodynamics of Mycophenolate in Patients After Renal Transplantation

“…Also, the degree of inhibition of IMPDH activity was comparable in the three groups, indicating considerable interindividual pharmacodynamic variability (77). In a cross-sectional analysis patients experiencing acute rejection episodes had increased IMPDH activity during rejection episodes (78). Additional information was gained in a genotyping study in 191 kidney transplant patients.…”