Mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, causes a paradoxical elevation of GTP in erythrocytes of renal transplant patients (original) (raw)
Related papers
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.
American Journal of Transplantation, 2004
Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase (IMPDH) activity, is usually administered as a standard dose of 1 g b.i.d. after renal transplantation. Because MMF dose reductions are associated with inferior outcome, we investigated pre-transplant IMPDH activity, MMF dose reductions and outcome. IMPDH activity was determined in isolated peripheral mononuclear cells immediately prior to renal transplantation. We observed considerable inter-individual variability in pre-transplant IMPDH activity (9.35 ± 4.22 nmol/mg/h). Thirty of 48 patients (62.5%) with standard MMF dose (1 g b.i.d.) had dose reductions within 3 years post-transplant; these patients also had significantly lower IMPDH activity. The area under the receiver-operating characteristics curve (AUC-ROC) for prediction of dose reduction within 6 months post-transplant was 0.75 (95% CI, 0.61-0.89; p < 0.004). IMPDH activity above the cutoff value, MMF dose reduction and age of recipient were significant contributors for the occurrence of acute rejection in the multivariate logistic regression. Patients with high IMPDH activity and MMF dose reduction had the highest rejection rate (81.8% vs. 36.4%; p < 0.01). Conclusion: Patients with low IMPDH activity experienced more complications of MMF therapy. High pre-transplant IMPDH activity and MMF dose reductions were associated with rejection. Determination of IMPDH activity prior to transplantation may help to improve MMF therapy after renal transplantation.
Transplantation Proceedings, 2006
The aim of this study was to assess the effects of 1 g of mycophenolate mofetil (MMF) on T-cell function and inosine monophosphate dehydrogenase (IMPDH) activity among patients undergoing kidney transplantation. Five patients undergoing renal transplantation from a living donor were enrolled in this study. Compared to baseline (before MMF intake), CD25 and CD71 expression were significantly decreased during the first hour following MMF intake. T-cell proliferation and IMPDH activity also decreased dramatically. Thereafter, all biomarker levels increased over time. At 4 hours, CD25 and CD71 levels, as well as IMPDH activity, returned to almost baseline values, whereas T-cell proliferation remained below baseline. Intracytoplasmic IL-2 expression remained unchanged after MMF ingestions. In conclusion, administration of 1 g of MMF was associated with a transient decrease in CD25 expression in addition to a temporary dramatic decrease in both T-cell proliferation and IMPDH activity.
Transplantation Proceedings, 2006
Introduction. Azathioprine (AZA) and mycophenolate mofetil (MMF) are major immunosupressants used to prevent rejection following renal transplantation. Bone marrow suppression is a potential adverse effect of these agents manifesting itself as leukopenia, thrombocytopenia, and anemia. The aim of this study was to compare the effects of AZA versus MMF immunosuppressive regimens on the erythropoietic system of renal transplant recipients within 6 months after transplantation. Methods. Eighty kidney allograft recipients who were on AZA (n ϭ 40) or MMF (n ϭ 40) plus cyclosporine and prednisolone were enrolled in this study. Hematologic parameters included red blood cell counts, hemoglobin (Hb), hematocrit, mean corpuscular volume, mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) and were measured before and at 1 week, as well as 1 and 6 months posttransplantation. Plasma erythropoietin level was measured at the end of 6 months. Statistical analysis was performed with Student t test; a P value less than .05 was considered significant.
Transplantation Proceedings, 2000
A PART from death with functioning graft, chronic rejection (CR) is the most common cause of late graft loss in this cyclosporine (CyA) era. Chronic rejection in the renal transplantation is defined as a progressive, sustained, and significant decrease in kidney function from baseline values, which means a doubling of serum creatinine or a 20% decline in calculated creatinine clearance 3 months after transplantation or later. The Banff classification 1 for kidney transplant pathology defines the term of chronic transplant nephropathy on the basis of interstitial fibrosis and tubular atrophy with the clinical manifestation of progressive rising of serum creatinine, proteinuria, and hypertension. The term CR implies that the immunologic fact or is the main pathogenesis, and the pathology also includes the vascular intimal hyperplasia from smooth muscle cell proliferation. The incidence of CR is as high as 50% in cadaveric donor renal transplantation at 2 years. 2 In our center, with double immunosuppressive regimen (CyA ϩ steroid), we experienced a CR rate of 29% in 5 years. 3 Many risk factors contribute to the cause of CR. These are immunologic and nonimmunologic factors. The immunologic factors or antigen-dependent factors include histocompatibility, acute rejection episode (frequency, severity, response to treatment) and suboptimal immunosuppression. The nonimmunologic risk factors include: prolonged cold ischemic time, ischemic-reperfusion injury, donor age, cytomegalovirus infection, hyperlipidemia, hypertension, diabetes mellitus, 4 and drug toxicity. Inadequate immunosuppression not only results in late acute rejection, but also induces CR. So the addition of another immunosuppression to CyA can potentiate the immunosuppression effect without increasing the CyA effect on CR like the overproduction of tumor growth factor-. In our center, we found that the dose of CyA, which is less than 3 mg/kg per day, is associated with a significant risk of CR, irrespective of blood level. Mycophenolate mofetil (MMF) is the morpholinoethylester of mycophenolic acid (MPA), which is the active immunosuppressant compound. 6 MMF is a selective antimetabolite with a completely different mode of action from CyA and has no effect on cytokine production. MMF can inhibit the proliferation of T and B lymphocytes, adhesion molecules, glycosylation, and smooth muscle cell proliferation. 7,8 Besides preventing acute rejection effectively, 9 MMF also shows a beneficial effect on CR in an animal model. 10, In primates McManus 12 used a cynomolgus monkeys-baboon cardiac xenograft model to show the effect of MMF in reducing cellular infiltration and intimal proliferation in coronary arteries of the transplant animal. All the evidence imply that MMF may have some role in the treatment of CR. We reported our preliminary results of 6 months' experience in addition of MMF to treat CR in our renal allograft. 13 We demonstrated the improvement of renal function in 37% of our patients and stable in 47%, but the benefits were not statistically significant. Therefore, this study aimed to evaluate the efficacy of MMF vs Aza thioprine (Aza) as the additive immunosuppression to treat CR.
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.
RS-61443 (Mycophenolate Mofetil) A Multicenter Study for Refractory Kidney Transplant Rejection
Annals of Surgery, 1992
mycophenolate mofetil) inhibits a key enzyme fo the de novo synthesis of purine nucleotides in T and B lymphocytes. The purpose of this study was to evaluate the efficacy of RS-61443 in patients with refractory renal allograft rejection. Patients eligible for the study had previously undergone anti-rejection therapy with high-dose steroids or OKT3 monoclonal antibody. All rejection episodes were proven by renal biopsy. Successful rescue was achieved in 52 (69%) patients. Rescue was more successful when patients were entered with a creatinine of 4 mg/dL or lower (79%), versus a 52% rescue rate in patients entered with a creatinine of4 mg/dL or above. Major side effects were predominantly gastrointestinal, but there was no overt nephrotoxicity, hepatotoxicity, or bone marrow suppression. The overall infection rate was 40%, with the spectrum of infections characteristic for the highly immunocompromised patient. The conclude that this pilot study suggests that RS-61443 is effective in refractory kidney allograft rejection. Based on this study, prospectively randomized multi-center trails have been planned and are in progress.
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.
Therapeutics and Clinical Risk Management, 2009
Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an inhibitor of inosine monophosphate dehydrogenase (IMPDH). It preferentially inhibits denovo pathway of guanosine nucleotide synthesis in T and B-lymphocytes and prevents their proliferation, thereby suppresses both cell mediated and humoral immune responses. Clinical trials in kidney transplant recipients have shown the effi cacy of MMF in reducing the incidence and severity of acute rejection episodes. It also improves long term graft function as well as graft and patient survival in kidney transplant recipients. MMF is useful as a component of toxicity sparing regimens to reduce or avoid exposure of steroids or calcineurin inhibitor (CNI). Enteric-coated mycophenolate sodium (EC-MPS) can be used as an alternative immunosuppressive agent in kidney transplant recipients with effi cacy and safety profi le similar to MMF.