Defining a threshold for tacrolimus intra-patient variability associated with late acute cellular rejection in paediatric kidney transplant recipients

  • Karmila Abu Bakar
  • Nor Asiah Mohamad
  • Zsolt Hodi
  • Tom McCulloch
  • Alun Williams
  • Martin Christian
  • Tim Key
  • Jon Jin KimEmail author
Original Article
Part of the following topical collections:
  1. What’s New in Renal Transplantation



Late acute cellular rejection (LACR) is associated with poorer graft outcomes and non-adherence. Non-adherence to tacrolimus can be indirectly assessed by the intra-patient variability (IPV) of tacrolimus trough levels. The threshold of IPV associated with rejection is not known.


We conducted a case-control study comparing 25 patients with biopsy-proven LACR against 25 stable controls matched for age group, primary diagnosis and time post-transplant. IPV was calculated using coefficient of variance (CV) and mean absolute deviation (MAD) using tacrolimus levels in the preceding 12 months. We also assessed the percentage time for tacrolimus levels < 4 μg/L (Tac < 4) and the concentration/weight-adjusted dose (C/D) ratio as a proxy marker of tacrolimus metaboliser status.


LACR patients had higher CV (median, IQR 44%, 36–61% v. 24%, 19–35%, p < 0.0001) and higher MAD (33%, 25–48% v. 19%, 15–26%, p < 0.0001). The MAD was less affected by outlying tacrolimus results. Receiver operating curve analysis of the MAD resulted in a sensitivity of 76% and specificity of 76% at a threshold of 26% (AUC 0.85, p < 0.05). LACR patients had more Tac < 4 (50% v. 26%, p < 0.05). There was no difference in C/D suggesting that good IPV can be maintained in fast metabolisers. Patients with LACR had significantly increased creatinine at 12-month follow-up despite treatment (108 v. 5 umol/L increase from baseline) and four patients lost their allograft.


Monitoring of tacrolimus IPV using the MAD may be a clinical marker for LACR. A threshold IPV of 26% can potentially be used as a therapeutic target pending further validation studies.


Tacrolimus Intra-patient variability Rejection Graft survival Non-adherence 


Supplementary material

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ESM 1 (DOCX 32 kb)


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Copyright information

© IPNA 2019

Authors and Affiliations

  1. 1.Department of Paediatric NephrologyNottingham University HospitalNottinghamUK
  2. 2.University Malaya Medical CenterKuala LumpurMalaysia
  3. 3.Institute for Public HealthKuala LumpurMalaysia
  4. 4.Department of HistopathologyNottingham University HospitalNottinghamUK
  5. 5.Histocompatibility and Immunogenetics SheffieldNHS Blood and TransplantWatfordUK

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