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.

Aims: Long-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.

Methods: IMPDH activity was measured in PBMC samples from 54 stable kidney transplant patients, already on MMF (for at least 3 months), before (t(0)) and 2 h after (t(2)) MMF morning dose administration; levels were monitored for up to 15 months, together with total mycophenolic acid (MPA) and free MPA concentrations.

Results: During the 15 months' monitoring, t(0) IMPDH activity in transplant recipients increased from 5.9 +/- 3.7 nmol h(-1) mg(-1)[95% confidence interval (CI) 4.9, 6.9] to 9.0 +/- 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: t(0) 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.

Conclusions: Even 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.

Figure 1

Linear regression model for mycophenolic acid (MPA) concentrations and inosine 5′-monophosphate dehydrogenase (IMPDH) activity. (A) C₀ free MPA level vs. t₀ IMPDH activity. (B) C₀ total MPA level vs. t₀ IMPDH activity. (C) C₂ free MPA level vs. t₂ IMPDH activity. (D) C₂ total MPA level vs. t₂ IMPDH activity

Figure 2

Variation over time of t₀ inosine 5′-monophosphate dehydrogenase (IMPDH) activity during the monitoring period. Data are coefficients of a linear regression model adjusted for treatment group and for time since the start of mycophenolate mofetil (MMF) therapy. Constant (const.) and P shown at each time are the comparison vs. time 0. Constant 5.29 nmol h⁻¹ mg⁻¹ is the intercept of the regression model. Bars indicate the 95% confidence interval

Figure 3

Comparison of the slopes of t₀ inosine 5′-monophosphate dehydrogenase (IMPDH) activity between nonrejecting and rejecting subjects. The slopes were calculated, for the 48 patients that underwent three or more visits, as linear regression of IMPDH activity vs. the 15 months of follow-up period. Black circles indicate the activity in nonrejecting subjects, white squares the activity in rejecting subjects, the horizontal bar indicates the median values. P= 0.019 shows the significance comparing the two groups

Figure 4

Slopes of t₀ inosine 5′-monophosphate dehydrogenase (IMPDH) activity trend measured vs. the relative month since starting mycophenolate mofetil (MMF) therapy. Black circles indicate the activity of nonrejecting subjects, white squares the activity of rejecting subjects

Figure 5

Monitoring of the five patients (A–E) that experienced acute rejection episodes. The black bar indicates t₀ inosine 5′-monophosphate dehydrogenase (IMPDH) activity; the white bar C₂ free mycophenolic acid (MPA); the grey bar t₂ residual IMPDH activity. The arrows indicate the time and grade of rejection episodes