title: High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury.
abstract: OBJECTIVE
  Lung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury.
  
  
  METHODS
  We retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions.
  
  
  RESULTS
  AKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations (OR 1.55; 95% CI 1.06-2.27), ≥3 other nephrotoxic drugs (OR 1.96; 95% CI 1.02-3.77), infection (OR 2.48; 95% CI 1.31-4.70), and cystic fibrosis (OR 2.17; 95% CI 1.16-4.06). Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%.
  
  
  CONCLUSIONS
  After lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation. What is known about this subject? • Lung transplant recipients often develop acute kidney injury evolving into chronic kidney disease increasing both morbidity and mortality. • To date, the pathophysiology of kidney injury after lung transplantation has not been fully elucidated. • The immunosuppressant tacrolimus is difficult to dose, especially in the unstable clinical setting, and is nephrotoxic.
  
  
  CONCLUSIONS
  • For the first time, supra-therapeutic whole-blood tacrolimus trough concentrations are related to the emergence of acute kidney injury in the first days after lung transplantation. • Supra-therapeutic whole-blood tacrolimus trough concentrations often occur early after lung transplantation. • AKI after lung transplantation shows low recovery rates.
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. m.a.sikma@umcutrecht.nl.|Dutch Poisons Information Center, University Medical Center Utrecht, Utrecht, The Netherlands. m.a.sikma@umcutrecht.nl.|Department of Intensive Care Medicine and Dutch Poisons Information Center, Division of Anesthesiology, Intensive Care and Emergency Medicine, University Medical Center Utrecht, F06.149, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands. m.a.sikma@umcutrecht.nl.
authors.forename: M A
authors.initials: MA
authors.lastname: Sikma
authors.affiliation: Dutch Poisons Information Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: C C
authors.initials: CC
authors.lastname: Hunault
authors.affiliation: Department of Lung Transplantation, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E A
authors.initials: EA
authors.lastname: van de Graaf
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Verhaar
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kesecioglu
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Dutch Poisons Information Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: D W
authors.initials: DW
authors.lastname: de Lange
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Dutch Poisons Information Center, University Medical Center Utrecht, Utrecht, The Netherlands.|Institute for Risk Assessment Sciences, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Meulenbelt
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood*; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D016559:Tacrolimus / Q000097:blood*
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: Nephrotoxic[All Fields] OR nephrotoxicant[All Fields] OR nephrotoxicity[All Fields] OR nephrotoxin[All Fields]; “acute kidney injury”[MeSH Terms] OR acute kidney injury[Text Word]; “lung transplantation” [MeSH Terms] OR lung transplantation[Text Word]; “pharmacokinetics”[Subheading] OR “pharmacokinetics”[MeSH Terms] OR pharmacokinetics[Text Word]; “tacrolimus”[MeSH Terms] OR tacrolimus[Text Word]