Anti-Mycophenolic Acid polyclonal antibody

Mycophenolic acid (MPA) is commonly prescribed for preventing graft rejection after kidney transplantation. The primary metabolic pathways of MPA are hepatic glucuronidation through UDP-glucuronosyltransferase (UGT) enzymes in the formation of MPA-glucuronide (MPAG, major pathway) and MPA-acyl glucuronide (AcMPAG). p-Cresol, a potent uremic toxin known to accumulate in patients with renal dysfunction, can potentially interact with MPA via the inhibition of glucuronidation. We hypothesized that the interaction between MPA and p-cresol is clinically relevant and that the estimated exposure changes in the clinic are of toxicological significance. Using in vitro approaches (ie, human liver microsomes and recombinant enzymes), the potency and mechanisms of inhibition by p-cresol towards MPA glucuronidation were characterized. Inter-individual variabilities, effects of clinical co-variates, in vitro-in vivo prediction of likely changes in MPA exposure, and comparison to other toxins were determined for clinical relevance. p-Cresol inhibited MPAG formation in a potent and competitive manner (K-i=5.2 mu M in pooled human liver microsomes) and the interaction was primarily mediated by UGT1A9. This interaction was estimated to increase plasma MPA exposure in patients by approximately 1.8-fold, which may result in MPA toxicity. The mechanism of inhibition for AcMPAG formation was noncompetitive (K-i=127.5 mu M) and less likely to be clinically significant. p-Cresol was the most potent inhibitor of MPA-glucuronidation compared with other commonly studied uremic toxins (eg, indole-3-acetic acid, indoxyl sulfate, hippuric acid, kynurenic acid, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid) and its metabolites (ie, p-cresol sulfate and p-cresol glucuronide). Our findings indicate that the interaction between p-cresol and MPA is of toxicological significance and warrants clinical investigation.

INTRODUCTION Renal transplantation is a treatment of choice for patients with end-stage renal disease. The main goal of transplant care is to achieve the best long-term patient survival (PS) and graft survival (GS). OBJECTIVES We aimed to assess the impact of various immunosuppression (IS) protocols on PS and GS following renal transplantation. PATIENTS AND METHODS This was a retrospective single-center cohort study including a total of 765 consecutive adult renal transplant recipients (RTRs) who underwent transplantation between 1998 and 2003. The primary endpoints included PS and GS. The secondary endpoints were graft function determined by estimated glomerular filtration rate and hospitalization length per patient per year. RESULTS Ten-year PS and GS rates were 88.6% and 78.7%, respectively. The intent-to-treat (ITT) group received IS that was later changed, whereas in the group on randomized therapy (ORT), the same IS protocol was maintained during follow-up. The ITT group had significantly better PS and GS than the ORT group. In the ITT group, patients treated with a combination of tacrolimus (TAC) and azathioprine (AZA), cyclosporine (CSA) and AZA, or CSA and mycophenolic acid metabolites (MPAs) had significantly better PS than those treated with TAC and MPA. The ORT group receiving AZA in any combination also had significantly better PS than MPA-treated individuals. CONCLUSIONS The effect of IS protocols on long-term outcomes varies depending on patient subpopulations. Immunosuppressive therapy solves rejection-related problems but does not address the increasing mortality of RTRs due to cardiovascular diseases, malignancies, or infections. Therefore, treatment recommendations should be individualized and posttransplant care, provided mainly by internists, should be carefully structured to improve long-term outcomes of renal transplantation.