High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation.
BACKGROUND
We hypothesized that a high within-patient variability in clearance of tacrolimus and mycophenolate mofetil (MMF) would put patients at risk for periods of over- or underimmunosuppression and would thus lead to long-term chronic allograft nephropathy and graft loss after transplantation.


METHODS
From 297 patients transplanted between 1 January 2000 and 31 December 2004, the within-patient variability in clearance was calculated from tacrolimus whole-blood concentrations and mycophenolic acid (MPA) plasma concentrations drawn between 6 and 12 months post-transplantation. As a primary outcome, a composite end point consisting of graft loss, biopsy-proven chronic allograft nephropathy and 'doubling in plasma creatinine concentration in the period between t = 12 months post-transplantation and last follow-up' was used.


RESULTS
In the study population of 297 patients, 34 patients reached the primary end point of graft failure. The within-patient variability in the clearance of tacrolimus and three other covariates are significant risk factors for reaching the composite end point of failure [P-values for intraindividual tacrolimus variability = 0.003, biopsy-proven acute rejection (BPAR) = 0.003, recipient age at transplantation = 0.005]. The mean tacrolimus concentration for controls [7.4 (+/- 2.9) ng/mL] and for failures [6.9 (+/- 2.5) ng/mL] was similar. Within-patient variability in the clearance of MPA was not related to reaching the composite end point of failure.


CONCLUSIONS
This study shows a significant relationship between the high within-patient variability in the clearance of tacrolimus, but not for MPA, and long-term graft failure.
Borra
Lennaert C P
LC
Department of Hospital Pharmacy, Molewaterplein 40, Rotterdam, The Netherlands.
Roodnat
Joke I
JI
Kal
Judith A
JA
Mathot
Ron A A
RA
Weimar
Willem
W
van Gelder
Teun
T
D000328:Adult; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000453:epidemiology*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood; D011237:Predictive Value of Tests; D012044:Regression Analysis; D012189:Retrospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000097:blood*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D009173:Mycophenolic Acid; D016559:Tacrolimus