High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury

Abstract

PurposeLung 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.MethodsWe 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.ResultsAKI 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%.ConclusionsAfter 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.What this study adds:• 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. Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-017-2204-8) contains supplementary material, which is available to authorized users.

Effect of CYP3A4, CYP3A5, and ABCB1 Polymorphisms on Intravenous Tacrolimus Exposure and Adverse Events in Adult Allogeneic Stem Cell Transplant Patients

“…No patients had subtherapeutic concentrations at the time of the first steady-state blood draw. However, nearly three-fourths of all patients had steadystate concentrations above the recommended therapeutic window, which could predispose patients to developing tacrolimus-related toxicities as demonstrated in prior studies [4][5][6][7]. Based on this finding it may seem prudent to initiate i.v.…”

“…dose of .03 mg/kg/day [3,4]. Current evidence suggests that tacrolimus blood concentrations less than 5 ng/mL portend a high risk for GVHD, whereas blood concentrations above 15 ng/mL are associated with tacrolimus-related toxicities such as nephrotoxicity and neurotoxicity [4][5][6][7]. Given the balance between drug efficacy and toxicity, therapeutic drug monitoring is routinely performed in clinical practice, particularly during the early period after SCT to maintain steady-state concentrations within the recommended therapeutic window of 5 to 15 ng/mL [8].…”

The association of post–lung transplant acute kidney injury with mortality is independent of primary graft dysfunction: A cohort study

“…We did not have detailed data on dosage, duration, and whether such medications were held prior to transplantation, limiting the ability to draw conclusions about possible mechanisms. CF has been noted as a post–lung transplant AKI risk factor in only one other study to date . Patients with CF frequently use inhaled or intravenous aminoglycoside and other nephrotoxic medications that may prime their kidneys for further injury .…”

Clinical Pharmacokinetics and Impact of Hematocrit on Monitoring and Dosing of Tacrolimus Early After Heart and Lung Transplantation

“…Although tacrolimus is known to be effective, heart and lung transplantation patients often show signs of toxicity and rejection [5][6][7][8]. Toxicity and rejection both have major consequences for the outcome of heart and lung transplantation, with a higher risk for morbidity and mortality [5,[9][10][11].…”

“…Acute kidney injury often evolves into chronic kidney disease and appears in approximately half of the patients during the first weeks after thoracic organ transplantation [5,6]. The occurrence of acute kidney injury has been associated with supratherapeutic (> 15 ng/mL) whole-blood tacrolimus trough concentrations in the first week after thoracic organ transplantation [7,8], and an increasing tacrolimus concentration has been associated with higher AKI risk and severity [12]. Furthermore, a higher rejection rate has been associated with a high variability in whole-blood concentrations after heart and lung transplantation [13,14].…”