Fluctuation of Cystatin C Concentration during Deferasirox Treatment in Thalassemic Patients May Reflect Hemodynamic Changes

Deferasirox (Exjade^®, ICL670) is an once-daily, oral iron chelator for the treatment of transfusional iron overload and its efficacy and tolerability have been established in adults and children with a range of transfusion-dependent anemias, such as thalassemia. We observed alterations in cystatin C plasma concentration during longterm treatment of thalassemia patients with deferasirox. Cystatin-C is a non-glycosylated protein that belongs to the cystatin superfamily of cysteine protease inhibitors. Plasma cystatin-C has been suggested to be an ideal endogenous marker of glomerular filtration rate (GFR). We aimed to investigate if these changes in cystatin C concentration were solely due to deferasirox treatment, or whether other factors contribute to these changes. 150 b-thalassemia patients treated with deferasirox at doses between 20–40 mg/Kg/day were followed longitudinally. Cystatin C concentrations were measured by an immunonephelometric technique (Dade Behring, Siemens Healthcare Diagnostics) at regular monthly intervals (5–12 monthly serial measurements per patient), while GFR was calculated according to the recently proposed cystatin C–based prediction equation using only its concentration in mg/L: GFR [mL/min/1.73m²] = 76.7 x Cystatin C^−1.18. To further evaluate the effect of deferasirox on renal function we measured: a) plasma levels of Neutrophil-Gelatinase-Associated-Lipocalin (NGAL) (R&D Systems) a protein expressed on tubular cells and which production is markedly increased in response to harmful stimuli, such as ischemia or toxicity, b) N-terminal pro-B-type natriuretic peptide (NT-proBNP) (Roche Diagnostics), in order to correlate cystatin C fluctuation with left ventricular ejection fraction (LVEF) and c) ferritin level, as a marker of iron overload/mobilization. The main results of the study showed that cystatin C concentration fluctuated during deferasirox treatment (ANOVA repeat measures p>0.850). Baseline mean values were 0.97±0.27 mg/L and reached a maximum of 1.01±0.29 mg/L at 4 months of treatment. According to the guidelines and as no significant increase of creatinine levels was observed, the drug dose was not reduced. Analysis of data showed that: a) there is no correlation between cystatin C fluctuation and NGAL levels, p > 0.6745, evidence that the tubuloglomerular feedback is not activated b) cystatin C and NT-proBNP levels correlated positively with a binomial equation (p<0.004) and c) cystatin C and ferritin levels correlated positively with also a binomial equation (p<0.001). These findings suggest that cystatin C fluctuation during deferasirox treatment do not reflect renal injury. Hemodynamic signals, LVEF alterations and iron mobilization seem to play central role on changes of cystatin C.