Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Emmes Corporation. 2014 Annual Transplant Report. Collab Stud NAPRTCS 2014;102

  2. Eid L, Tuchman S, Moudgil A (2014) Late acute rejection: incidence, risk factors, and effect on graft survival and function. Pediatr Transplant 18(2):155–162

    Article  Google Scholar 

  3. Pollock-Barziv SM, Finkelstein Y, Manlhiot C, Dipchand AI, Hebert D, Ng VL et al (2010) Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplant 14(8):968–975

    Article  Google Scholar 

  4. Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ et al (2012) Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant 12(5):1157–1167

    Article  CAS  Google Scholar 

  5. Hricik DE, Formica RN, Nickerson P, Rush D, Fairchild RL, Poggio ED, et al. Adverse outcomes of tacrolimus withdrawal in immune–quiescent kidney transplant recipients. 2015;3114–3122

  6. Prytuła A, van Gelder T (2018) Clinical aspects of tacrolimus use in paediatric renal transplant recipients. Pediatr Nephrol:1–13

  7. Wiebe C, Rush DN, Nevins TE, Birk PE, Blydt-Hansen T, Gibson IW et al (2017) Class II Eplet mismatch modulates tacrolimus trough levels required to prevent donor-specific antibody development. J Am Soc Nephrol 28:1–10

    Article  Google Scholar 

  8. Shuker N, van Gelder T, Hesselink DA (2015) Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management. Transplant Rev (Orlando) 29(2):78–84

    Article  Google Scholar 

  9. Laskow DA, Vincenti F, Neylan JF, Mendez R, Matas AJ (1996) An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group. Transplantation. 62(7):900–905

    Article  CAS  Google Scholar 

  10. Ekberg H, Tedesco-Silva H, Demirbas A, Vítko Š, Nashan B, Gürkan A et al (2007) Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 357(25):2562–2575

    Article  CAS  Google Scholar 

  11. Grenda R, Watson A, Vondrak K, Webb NJA, Beattie J, Fitzpatrick M et al (2006) A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation. Am J Transplant 6(7):1666–1672

    Article  CAS  Google Scholar 

  12. Opelz G. CTS Collaborative Transplant Study Newsletter 1 : 2014. 2014;5–8

  13. Pizzo HP, Ettenger RB, Gjertson DW, Reed EF, Zhang J, Gritsch HA et al (2016) Sirolimus and tacrolimus coefficient of variation is associated with rejection, donor-specific antibodies, and nonadherence. Pediatr Nephrol 31(12):2345–2352

    Article  Google Scholar 

  14. Wallemacq PE, Verbeeck RK (2001) Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 40(4):283–295

    Article  CAS  Google Scholar 

  15. Pallet N, Etienne I, Buchler M, Bailly E, Hurault de Ligny B, Choukroun G et al (2016) Long-term clinical impact of adaptation of initial tacrolimus dosing to CYP3A5 genotype. Am J Transplant 16(9):2670–2675

    Article  CAS  Google Scholar 

  16. Shuker N, Bouamar R, Van Schaik RH, Clahsen-van Groningen MC, Damman J, Baan CC et al (2016) A randomized controlled trial comparing the efficacy of Cyp3a5 genotype-based with body- weight-based tacrolimus dosing after living donor kidney transplantation. Am J Transplant 16:2085–2096

    Article  CAS  Google Scholar 

  17. Kim JJ, Balasubramanian R, Michaelides G, Wittenhagen P, Sebire NJ, Mamode N, et al. The clinical spectrum of de novo donor-specific antibodies in pediatric renal transplant recipients. 2014;2350–2358

  18. Borra LCP, Roodnat JI, Kal JA, Mathot RAA, Weimar W, van Gelder T (2010) High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant 25(8):2757–2763

    Article  CAS  Google Scholar 

  19. Shuker N, Shuker L, van Rosmalen J, Roodnat JI, Borra LCP, Weimar W et al (2016) A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation. Transpl Int 29(11):1158–1167

    Article  CAS  Google Scholar 

  20. Prytula AA, Bouts AH, Mathot RAA, Van Gelder T, Croes LK, Hop W et al (2012) Intra-patient variability in tacrolimus trough concentrations and renal function decline in pediatric renal transplant recipients. Pediatr Transplant 16(6):613–618

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Paediatric Nephrology, Nottingham University Hospital, Nottingham, UK

    Karmila Abu Bakar, Alun Williams, Martin Christian & Jon Jin Kim

  2. University Malaya Medical Center, Kuala Lumpur, Malaysia

    Karmila Abu Bakar

  3. Institute for Public Health, Kuala Lumpur, Malaysia

    Nor Asiah Mohamad

  4. Department of Histopathology, Nottingham University Hospital, Nottingham, UK

    Zsolt Hodi & Tom McCulloch

  5. Histocompatibility and Immunogenetics Sheffield, NHS Blood and Transplant, Watford, UK

    Tim Key

Authors
  1. Karmila Abu Bakar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nor Asiah Mohamad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zsolt Hodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tom McCulloch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alun Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin Christian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tim Key
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jon Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jon Jin Kim.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 32 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abu Bakar, K., Mohamad, N.A., Hodi, Z. et al. Defining a threshold for tacrolimus intra-patient variability associated with late acute cellular rejection in paediatric kidney transplant recipients. Pediatr Nephrol 34, 2557–2562 (2019). https://doi.org/10.1007/s00467-019-04346-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-019-04346-z

Keywords

Search

Navigation