Pre-Transplant Inosine Monophosphate Dehydrogenase Activity is Associated with Clinical Outcome After Renal Transplantation (original) (raw)
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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 (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. RESULTS During the 15 months’ monitoring, t0 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: 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. 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.
Mycophenolate mofetil in solid-organ transplantation
Expert Opinion on Pharmacotherapy, 2003
This review focuses on the use of mycophenolate mofetil (MMF) as an immunosuppressive agent in solid-organ transplantation. MMF, a non-competitive inhibitor of inosine monophosphate dehydrogenase, blocks de novo purine synthesis in T and B lymphocytes, resulting in the selective inhibition of proliferation of these cells in response to antigenic stimuli. MMF may also promote apoptosis of these cells. The immunosuppressive ability of MMF is thought to derive mainly from the inhibition of inosine monophosphate dehydrogenase. The other effects of MMF include suppression of antibody synthesis by B lymphocytes, inhibition of proliferation of smooth muscle cells in culture and impaired glycosylation of adhesion molecules. MMF may exhibit anti-inflammatory effects resulting from decreased activity of the inducible form of nitric oxide synthase, a consequence of depletion of tetrahydrobiopterin, which leads to decreased generation of peroxynitrite, a pro-inflammatory molecule. The pharmacokinetics, pharmacodynamics and principles underlying therapeutic drug monitoring of MMF are reviewed. The results of the pivotal clinical trials of MMF in kidney and heart transplantation are discussed and a summary of the major studies demonstrating a positive effect of MMF on renal transplantation outcomes is presented. The use of MMF in the context of ABO-incompatible renal transplantation, renal transplantation in highly sensitised and cross-match positive recipients, humoral rejection of renal allografts, chronic allograft nephropathy and steroid/calcineurin inhibitor minimisation in renal transplantation are also discussed.
Mycophenolate Mofetil: Ten Years' Experience of a Renal Transplant Unit
Transplantation Proceedings, 2008
Mycophenolate mofetil (MMF) use in renal transplantation has allowed a significant decrease in early acute rejection rates. We retrospectively evaluated the incidence of acute rejection episodes, renal function at the first year posttransplant, patient and graft survivals, cytomegalovirus (CMV) infection rate, influence of the degree of sensitization, and number of MHC antigen mismatches on graft survival in two groups of patients receiving either MMF or azathioprine. Group 1 included 149 patients receiving cyclosporine, MMF, and prednisolone; group 2 included 191 patients receiving cyclosporine, azathioprine, and prednisolone. The two groups did not differ in terms of age, sex, degree of sensitization (expressed as percentage of antibodies reactive to panel), MHC mismatch number, cold ischemia time, donor age, or anti-thymocyte globulin induction. In group 1 (MMF) there was a significant decrease in early acute rejection rate (19% vs 57%, P Ͻ .0001), longer graft survival at 10 years (92% vs 75%, P ϭ .006), and higher rate of CMV infection (22% vs 12%, P ϭ .004). Renal function at the first year posttransplant and patient survival during follow-up did not differ between the groups. The degree of sensitization influenced graft survival in group 2. The number of MHC mismatches did not influence graft survival in either group. With MMF, there was a significant reduction in early acute rejection rate, a significant increase in graft survival at 10-year follow-up, and diminished impact of the degree of sensitization on graft survival.
Journal of the American Society of Nephrology, 2007
The Mycophenolate Steroids Sparing (MYSS) study found that in renal transplant recipients who were on immunosuppressive therapy with the cyclosporine microemulsion Neoral, mycophenolate mofetil (MMF) was not better than azathioprine in preventing acute rejection at 21 mo after transplantation and was 15 times more expensive. The MYSS Follow-up Study, an extension of MYSS, was aimed at comparing long-term outcome of 248 MYSS patients according to their original randomization to MMF (1 g twice daily) or azathioprine (75 to 100 mg/d). Primary outcome was estimated GFR at 5 yr after transplantation. Mean 5-yr GFR difference between azathioprine and mycophenolate was 4.67 ml/min per 1.73 m 2 (95% confidence interval [CI] ؊0.43 to 9.77 ml/min per 1.73 m 2 ; P ؍ 0.07). GFR from month 6 (mean ؎ SEM: 54.3 ؎ 1.6 versus 53.9 ؎ 1.5 ml/min per 1.73 m 2 ; P ؍ 0.83) to month 72 after transplantation (49.5 ؎ 2.2 versus 47.3 ؎ 2.4 ml/min per 1.73 m 2 ; P ؍ 0.50); GFR slopes (mean ؎ SEM: ؊1.10 ؎ 0.56 versus ؊1.23 ؎ 0.31 ml/min per 1.73 m 2 per year; P ؍ 0.83); and 72-mo patient mortality (4.0 versus 4.0% [P ؍ 0.95]; HR 0.96; 95% CI 0.28 to 3.31; P ؍ 0.95), graft loss (6.8 versus 6.1% [P ؍ 0.82]; HR 0.89; 95% CI 0.32 to 2.46; P ؍ 0.83), incidence of persistent proteinuria (25.0 versus 27.4%; P ؍ 0.72), late (>6 mo after transplantation) rejections (25.3 versus 21.2%; P ؍ 0.53), and adverse events were similar on azathioprine (n ؍ 124) and MMF (n ؍ 124), respectively. Outcomes in the two groups were comparable also among patients with or without steroid therapy, considered separately. In kidney transplantation, the long-term risk/benefit profile of MMF and azathioprine therapy in combination with cyclosporine Neoral is similar. In view of the cost, standard immunosuppression regimens for kidney transplantation should perhaps include azathioprine rather than MMF.
The Journal of Clinical Pharmacology, 2011
Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)-induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)-guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra-and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AU C0-12 h) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory E max model (EC 50 = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pre-transplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.
Journal of the American Society of Nephrology, 2007
The Mycophenolate Steroids Sparing (MYSS) study found that in renal transplant recipients who were on immunosuppressive therapy with the cyclosporine microemulsion Neoral, mycophenolate mofetil (MMF) was not better than azathioprine in preventing acute rejection at 21 mo after transplantation and was 15 times more expensive. The MYSS Follow-up Study, an extension of MYSS, was aimed at comparing long-term outcome of 248 MYSS patients according to their original randomization to MMF (1 g twice daily) or azathioprine (75 to 100 mg/d). Primary outcome was estimated GFR at 5 yr after transplantation. Mean 5-yr GFR difference between azathioprine and mycophenolate was 4.67 ml/min per 1.73 m 2 (95% confidence interval [CI] ؊0.43 to 9.77 ml/min per 1.73 m 2 ; P ؍ 0.07). GFR from month 6 (mean ؎ SEM: 54.3 ؎ 1.6 versus 53.9 ؎ 1.5 ml/min per 1.73 m 2 ; P ؍ 0.83) to month 72 after transplantation (49.5 ؎ 2.2 versus 47.3 ؎ 2.4 ml/min per 1.73 m 2 ; P ؍ 0.50); GFR slopes (mean ؎ SEM: ؊1.10 ؎ 0.56 versus ؊1.23 ؎ 0.31 ml/min per 1.73 m 2 per year; P ؍ 0.83); and 72-mo patient mortality (4.0 versus 4.0% [P ؍ 0.95]; HR 0.96; 95% CI 0.28 to 3.31; P ؍ 0.95), graft loss (6.8 versus 6.1% [P ؍ 0.82]; HR 0.89; 95% CI 0.32 to 2.46; P ؍ 0.83), incidence of persistent proteinuria (25.0 versus 27.4%; P ؍ 0.72), late (>6 mo after transplantation) rejections (25.3 versus 21.2%; P ؍ 0.53), and adverse events were similar on azathioprine (n ؍ 124) and MMF (n , respectively. Outcomes in the two groups were comparable also among patients with or without steroid therapy, considered separately. In kidney transplantation, the long-term risk/benefit profile of MMF and azathioprine therapy in combination with cyclosporine Neoral is similar. In view of the cost, standard immunosuppression regimens for kidney transplantation should perhaps include azathioprine rather than MMF.
Clinical Science, 2004
The immunosuppressant MMF (mycophenolate mofetil) has increasingly replaced AZA (azathioprine) in renal transplantation. MMF is a prodrug of MPA (mycophenolic acid), which inhibits lymphocyte IMPDH (inosine monophosphate dehydrogenase), thereby drastically decreasing GTP concentrations essential to lymphocyte proliferation in vitro and in vivo. Erythrocyte GTP concentrations are commonly elevated in severe renal disease, but normalize following successful engraftment. Consequently, elevated GTP in renal transplant recipients might signal impending loss of immunosuppression and graft failure. In the present study, we compared erythrocyte nucleotides and plasma metabolites in two groups of 25 patients after renal transplantation, both receiving prednisolone and cyclosporin A, but one group receiving MMF and the other AZA. No patients had recent allograft biopsy evidence of rejection. Erythrocyte GTP concentrations at MMF commencement were 50.4±23.4 μmol/l. An increase occurred during ...
Mycophenolate mofetil reduces late renal allograft loss: a 4-year study
Transplantation Proceedings, 2002
Background. Mycophenolate Mofetil (MMF) has been shown to significantly decrease the number of acute rejection episodes in renal transplant recipients during the 1st year. A beneficial effect of MMF on long-term graft survival has been more difficult to demonstrate. This beneficial effect has not been detected, despite the impact of acute rejection on the development of chronic allograft nephropathy and experimental evidence that MMF may have a salutary effect on chronic allograft nephropathy independent of that of rejection. Methods. Data on 66,774 renal transplant recipients from the U.S. renal transplant scientific registry were analyzed. Patients who received a solitary renal transplant between October 1, 1988 and June 30, 1997 were studied. The Cox proportional hazard regression was used to estimate relevant risk factors. Kaplan-Meier analysis was performed for censored graft survival. Results. MMF decreased the relative risk for development of chronic allograft failure (CAF) by 27% (risk ratio [RR] 0.73, P<0.001). This effect was independent of its outcome on acute rejection. Censored graft survival using MMF versus azathioprine was significantly improved by Kaplan-Meier analysis at 4 years (85.6% v. 81.9%). The effect of an acute rejection episode on the risk of developing CAF seems to be increasing over time (RR,9.1؍ 1988 -91; RR,9.2؍ 1992-94; RR,7.3؍ 1995-97).