High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation
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Updated: Jun 15, 2026
Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
Published on: November 8, 2015
Lennaert C P Borra1, Joke I Roodnat, Judith A Kal
1Department of Hospital Pharmacy, Molewaterplein 40, Rotterdam, The Netherlands.
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.
Insights
High variability in tacrolimus clearance, not mycophenolate mofetil (MMF), significantly increases kidney transplant failure risk. Monitoring tacrolimus variability is crucial for long-term graft survival.
Area of Science:
- Nephrology
- Transplantation Immunology
- Pharmacokinetics
Background:
- High within-patient variability in immunosuppressant drug clearance can lead to suboptimal drug exposure.
- This variability may increase the risk of chronic allograft nephropathy and graft loss after kidney transplantation.
Purpose of the Study:
- To investigate the association between within-patient variability in tacrolimus and mycophenolic acid (MPA) clearance and long-term kidney transplant outcomes.
- To identify risk factors for graft failure, including chronic allograft nephropathy and graft loss.
Main Methods:
- Retrospective analysis of 297 kidney transplant recipients from 2000-2004.
- Within-patient variability in tacrolimus and MPA clearance was calculated between 6-12 months post-transplantation.
- Primary outcome was a composite endpoint of graft loss, biopsy-proven chronic allograft nephropathy, or doubling of serum creatinine.
Main Results:
- Within-patient variability in tacrolimus clearance was a significant risk factor for graft failure (P=0.003).
- Biopsy-proven acute rejection and recipient age at transplantation were also significant risk factors.
- Within-patient variability in MPA clearance was not associated with graft failure.
Conclusions:
- High within-patient variability in tacrolimus clearance is significantly linked to long-term kidney transplant failure.
- MPA clearance variability does not appear to impact long-term graft outcomes.
- Monitoring tacrolimus pharmacokinetics variability may improve long-term graft survival.
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