title: Inosine monophosphate dehydrogenase messenger RNA expression is correlated to clinical outcomes in mycophenolate mofetil-treated kidney transplant patients, whereas inosine monophosphate dehydrogenase activity is not.
abstract: Measurement of the pharmacodynamic biomarker inosine monophosphate dehydrogenase (IMPDH) activity in renal transplant recipients has been proposed to reflect the biological effect better than using pharmacokinetic parameters to monitor mycophenolate mofetil therapy. The IMPDH assays are however labor intensive and this complicates implementation into patient care. Quantification of IMPDH messenger RNA (mRNA) could form an attractive alternative. This study was designed to correlate IMPDH mRNA levels with IMPDH activity and clinical outcome in renal transplant recipients. From a cohort of 101 renal transplant patients, blood samples were drawn pre transplantation and at 4 times after transplantation. IMPDH activity, IMPDH type 1 and type 2 mRNA levels, and mycophenolic acid concentrations were measured and correlated to clinical outcomes. No correlation was found between IMPDH type 1 and type 2 mRNA levels and IMPDH activity in pre- and posttransplant samples. A significant increase in IMPDH mRNA levels was found between day 6 and day 140 after transplantation. IMPDH type 1 and type 2 mRNA levels before transplant showed a trend toward statistically significant higher levels in patients with an acute rejection (P = 0.052 and P = 0.058). After transplant, the IMPDH type 1 and type 2 mRNA levels were significantly lower in patients with an acute rejection (P = 0.026 and P = 0.007). We conclude that IMPDH mRNA levels do not correlate with IMPDH activity but are nevertheless correlated with acute rejections. Furthermore, although the regulation of the expression of the 2 isoforms is presumed to be different, in this study, the changes in the expression of type 1 mRNA closely paralleled those of type 2.
authors.affiliation: Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ferdi
authors.initials: F
authors.lastname: Sombogaard
authors.forename: Annemiek M A
authors.initials: AM
authors.lastname: Peeters
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
authors.forename: Monique E
authors.initials: ME
authors.lastname: Quaedackers
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Vulto
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D015870:Gene Expression / Q000187:drug effects; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007291:Inosine Monophosphate / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D016030:Kidney Transplantation / Q000502:physiology*; D007963:Leukocytes, Mononuclear; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D007291:Inosine Monophosphate; D010088:Oxidoreductases; D009173:Mycophenolic Acid