Long-term follow-up of pediatric transplant recipients: mycophenolic acid trough levels are not a good indicator for long-term graft function.
BACKGROUND
Mycophenolate mofetil (MMF) has the potential of decreasing acute rejection episodes early following renal transplantation. Pharmocokinetic monitoring of mycophenolic acid (MPA) trough levels is performed by many centers. MMF has also proved successful in improving long-term graft function in patients with chronic allograft nephropathy (CAN). However, no data for long-term monitoring of MPA in children have yet been published.


METHODS
MMF therapy with a dose of 600 mg/m2 twice daily was initiated in 42 children (median age 9.4 yr, range 1.4-15.1) after a median period of 3.8 yr (range 1.0-10.6) post-transplantation-- according to significant increases in serum creatinine. CAN was diagnosed by renal biopsy and the amount of fibrosis was quantified with PicroSiriusRed staining. MMF therapy was combined with ciclosporin A and prednisolone. MPA-C0-levels, measured by high-pressure liquid chromatography, were tested every 3 months. In 12 children a full MPA area under the curve concentration (AUC) was measured. The glomerular filtration rate (GFR) was calculated at the start of MMF therapy and 2 yr later.


RESULTS
After initiation of MMF, the calculated GFR did not decrease further in 22 children and mean GFR remained stable for 2 yr in the whole study group. There was a significant correlation between MPA levels 75 min after administration and the full AUC (r = 0.94, p < 0.001) but no correlation between trough levels and AUC (r = -0.07, p > 0.05). The mean MPA trough level was 2.8 +/- 1.3 ng/mL. The intra-individual coefficient of variation was 2.6 +/- 1.4. There was no correlation between mean MPA trough levels and GFR development after 2 yr (r = 0.03, p > 0.05). In children with an MPA level below 1.2 mg/L (n = 5), the mean GFR decline was no different to those with a higher level (p > 0.05).


CONCLUSIONS
Drug monitoring of MPA trough levels had no impact on long-term graft function in kidney recipients. MPA levels taken 75 min after administration showed a high correlation with MPA-AUC whereas C0-levels did not correlate. The value of C75 drug measurements for monitoring renal allograft survival will have to be judged in future studies.
Pape
L
L
Department of Pediatric Nephrology, Medical School of Hannover, Hannover, Germany. larspape@t-online.de
Ehrich
J H H
JH
Offner
G
G
D000293:Adolescent; D019540:Area Under Curve; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use; D016903:Drug Monitoring; D005260:Female; D005355:Fibrosis; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005938:Glucocorticoids / Q000627:therapeutic use; D006085:Graft Survival / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D016030:Kidney Transplantation / Q000502:physiology*; D008137:Longitudinal Studies; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D011239:Prednisolone / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D011355:Prodrugs; D016572:Cyclosporine; D011239:Prednisolone; D003404:Creatinine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid