Effects of deferasirox dose and decreasing serum ferritin concentrations on kidney function in paediatric patients: an analysis of clinical laboratory data from pooled clinical studies

Background Serious and fatal deferasirox-induced kidney injury has been reported in paediatric patients. This study aimed to investigate the effects of deferasirox dose and serum ferritin concentrations on kidney function and the effect of impaired kidney function on dose-normalised deferasirox minimum plasma concentration (C-min). Methods We did a case-control analysis using pooled data from ten clinical studies. We identified transfusion-dependent patients with thalassaemia, aged 2-15 years, who were receiving deferasirox and had available baseline and follow-up serum creatinine and ferritin measurements. Cases of acute kidney injury (AKI) were defined according to an estimated glomerular filtration rate (eGFR) threshold of 90 mL/min per 1.73 m(2) or less (if baseline eGFR was >= 100 mL/min per 1.73 m(2)), an eGFR of 60 mL/min per 1.73 m(2) or less (if baseline eGFR was <100 mL/min per 1.73 m(2)), or an eGFR decrease from baseline of at least 25%. Cases were matched to control visits (eGFR >= 120 mL/min per 1.73 m(2)) on age, sex, study site, and time since drug initiation. We calculated rate ratios for AKI using conditional logistic regression, and evaluated the effect of eGFR changes on C-min. Findings Among 1213 deferasirox-treated paediatric patients, 162 cases of AKI and 621 matched control visits were identified. Patients with AKI had a mean 50.2% (SD 15.5) decrease in eGFR from baseline, compared with a 6.9% (29.8) decrease in controls. A significantly increased risk for AKI (rate ratio 1.26, 95% CI 1.08-1.48, p=0.00418) was observed per 5 mg/kg per day increase in deferasirox dispersible tablet dose (equivalent to a 3.5 mg/kg per day dose of film-coated tablets or granules), above the typical starting dose (20 mg/kg per day). An increased risk (1.25, 1.01-1.56, p=0.0400) for AKI was also observed per 250 mu g/L decrease in serum ferritin, starting from 1250 mu g/L. High-dose deferasirox (dispersible tablet dose >30 mg/kg per day) resulted in an increased risk (4.47, 1.25-15.95, p=0.0209) for AKI when serum ferritin was less than 1000 mu g/L. Decreases in eGFR were associated with increased C-min. Interpretation Deferasirox can cause AKI in a dose-dependent manner. The increased AKI risk with high-dose deferasirox and lower serum ferritin concentration is consistent with overchelation as a causative factor. Small decreases in eGFR correlate with increased deferasirox C-min, especially in younger patients. Physicians should closely monitor renal function and serum ferritin, use the lowest effective dose to maintain acceptable body iron burden, and interrupt deferasirox treatment when AKI or volume depletion are suspected. Copyright (C) 2018 Elsevier Ltd. All rights reserved.