Deferasirox Reduces Serum TNF-α but Impairs Renal Function in Patients with Thalassemia Major after 12 Months of Therapy

Abstract

Deferasirox is an oral iron chelator approved for the management of iron overload in thalassemia major (TM). However, there are some concerns for its effect on renal function. Cystatin C (Cys-C) is a cysteine protease inhibitor, which is considered as a sensitive marker of GFR. Inflammation process has been recently implicated in TM pathophysiology. The aim of this study was to evaluate the effect of deferasirox on renal function and inflammatory cytokines in 52 TM patients. Deferasirox was administered at a dose between 10–30 mg/kg/day for a 12-month period. Serum Cys-C, serum creatinine (Cr), clearance of Cr (Ccr), albuminuria and inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1α, IL-1β, IL-4, IL-10 and transforming growth factor (TGF)-β1 and β2, were measured at baseline and then after 6 and 12 months post-deferasirox therapy. Standard hematology and biochemistry was evaluated monthly. Serum Cys-C was measured using a latex particle-enhanced nephelometric immunoassay (Dade Behring, Liederbach, Germany). Serum levels of the above cytokines were determined using ELISA (R&D Systems, Minneapolis, MN, USA, for ILs, and Diaclone, Bensancon, France for TNF-α, TGF-β1 and TGF-β2). Ten healthy blood donors were also evaluated as control group. At baseline, TM patients had elevated values of Cys-C (p<0.0001) compared with controls. Specifically, 21/52 patients (40%) had higher Cys-C values than the upper normal limit according to manufacturer (0.95 mg/L), while no patient had increased levels of serum Cr (>1.4 mg/dl) and only 6 (11.5%) had low Ccr (<80 ml/min). Before deferasirox administration, TM patients had also increased levels of IL-6 (p=0.008), IL-1α (p=0.015), TGF-β2 (p=0.017), IL-10 (0.021), IL-4 (p=0.039), and a borderline increase of TNF-α (p=0.05) compared with controls (Table). Serum levels of Cys-C correlated strongly with Cr (r=0.657, p<0.0001), and Ccr (r=−0.625, p<0.0001) but also with IL-6 (r=0.441, r<0.001) and proteinuria (r=0.261, p=0.037). Il-1a correlated with Hb (r=−0.417, p<0.001) and IL-4 (r=0.474, p<0.001), while IL-6 correlated with TNF-α (r=0.37, p<0.01). After 6 and 12 months of therapy, deferasirox produced a dramatic reduction of ferritin, SGOT and SGPT compared with baseline values (p<0.0001), but concomitantly we observed an increase of Cys-C and Ccr during the same period (p<0.0001). In particular at the end of the study 32/52 patients (61.5%) had increased Cys-C values, while 10 (19.2%) had low Ccr and only one high serum Cr. Interestingly serum levels of TNF-α reduced post-deferasirox administration (p=0.01), while the levels of all other cytokines remained unchanged during therapy (Table). Our study suggests that deferasirox is an effective chelator in TM. However, its effect on renal function is not insignificant and needs further investigation. Inflammatory cytokines seem to have a role in the pathogenesis of TM but further studies are needed to fully elucidate this role as well as the effect of deferasirox, if any, on inflammation.Table 1. Characteristics of patients & controls (mean values ± SD)ParametersControls (n=10)Patients-baseline values (n=52)p-value (patientsvs.controls)Patients-12-month valuesp-value patients (baselinevs.12 m)Age(years)40.8±11.739.5±10.90.782Gender(Male/Female)4/622/300.346Hb(g/dL)14.8±2.68.8±1.4<0.00018.7±1.5AST(U/L)29.3±10.146.7±23.9<0.000135.5±19.2<0.0001ALT(U/L)23.8±12.550.7±28.6<0.000134.3±22.1<0.0001Ferritin(μg/L)88±34.22355±1380<0.00011516±1320<0.0001Serum Creatinine (mg/dL)0.8±0.10.7±0.10.8230.8±0.20.001Creatinine Clearance (ml/min/1.732)125.2±22.7126.5±29.90.227117.0±31.10.005Proteinuria(mg/24h)55.4±28.2322.9±461.6<0.0001323.4±417.00.976Cystatin-C (mg/L)0.76±0.110.93±0.26<0.00011.12±0.37<0.0001Inflammatory CytokinesIL-1α (pg/mL)0.08±0.190.65±0.800.0151.06±1.130.114IL-1β (pg/mL)2.30±2.541.68±2.370.4752.05±2.820.571IL-4 (pg/mL)ND0.78±1.830.0390.28±0.590.167IL-6 (pg/mL)0.09±0.212.50±4.420.0083.00±7.510.752TNF-α (pg/mL)1.13±2.053.85±7.480.050.46±1.400.015TGF-β1 (ng/mL)87.1±21.7107.5±53.60.180112.1±74.00.678TGF-β2 (pg/mL)5.62±10.519.5±26.40.01715.8±29.70.318