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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

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.

Keywords

Tacrolimus Intra-patient variability Rejection Graft survival Non-adherence 

Notes

Supplementary material

467_2019_4346_MOESM1_ESM.docx (32 kb)
ESM 1 (DOCX 32 kb)

References

  1. 1.
    Emmes Corporation. 2014 Annual Transplant Report. Collab Stud NAPRTCS 2014;102Google Scholar
  2. 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):155–162CrossRefGoogle Scholar
  3. 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):968–975CrossRefGoogle Scholar
  4. 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):1157–1167CrossRefGoogle Scholar
  5. 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;3114–3122Google Scholar
  6. 6.
    Prytuła A, van Gelder T (2018) Clinical aspects of tacrolimus use in paediatric renal transplant recipients. Pediatr Nephrol:1–13Google Scholar
  7. 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 28:1–10CrossRefGoogle Scholar
  8. 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):78–84CrossRefGoogle Scholar
  9. 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):900–905CrossRefGoogle Scholar
  10. 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):2562–2575CrossRefGoogle Scholar
  11. 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):1666–1672CrossRefGoogle Scholar
  12. 12.
    Opelz G. CTS Collaborative Transplant Study Newsletter 1 : 2014. 2014;5–8Google Scholar
  13. 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):2345–2352CrossRefGoogle Scholar
  14. 14.
    Wallemacq PE, Verbeeck RK (2001) Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 40(4):283–295CrossRefGoogle Scholar
  15. 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):2670–2675CrossRefGoogle Scholar
  16. 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 16:2085–2096CrossRefGoogle Scholar
  17. 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;2350–2358Google Scholar
  18. 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):2757–2763CrossRefGoogle Scholar
  19. 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):1158–1167CrossRefGoogle Scholar
  20. 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):613–618CrossRefGoogle Scholar

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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