Deferasirox nephrotoxicity—the knowns and unknowns

Abstract

In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.

Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes

“…55 Some of this promise is hindered by the nephrotoxicity frequently present in young and elderly patients after many years of therapy. 56 The finding of a proliferative effect in both cancer and normal cells, for undetermined reasons, further limits the application of deferasirox (or even BHPT) alone as an anticancer agent. This is a limitation not observed for the Ti(IV) complexes of the ligands, possibly because the proliferative effect of the ligands requires that they remain a free molecule and is independent of their metal binding capacity.…”

Chelation of dietary iron prevents iron accumulation and macrophage infiltration in the type I diabetic kidney

“…DFX is reported to have nephrotoxic effects, partially due to its depletion of circulating iron (Diaz-Garcia et al, 2014). Nephrotoxi-city might not be relevant in this study as there were no changes in hematocrit and hemoglobin levels and DFX decreased, rather than increased, macrophage infiltration and inflammatory marker expression.…”

Deferasirox pharmacokinetic and toxicity correlation in β-thalassaemia major treatment†

“…Particularly, nephrotoxicity is the most frequent DFX adverse effect; it can consist in an acute or chronic decrease in GFR. Nephrotoxicity is usually non‐progressive and/or reversible and rapid iron depletion is one of several risk factors, but its molecular mechanisms have not been well explained . In our analysis, a positive trend resulted considering creatinine evaluation and AUC, suggesting that in higher drug exposure represents a potential risk for kidney function.…”