Assessment of Renal Function in Transfused b-Thalassemia Patients Based on Cystatin C Measurements and Equations.

Cystatin C is a non-glycosylated protein that belongs to the cystatin superfamily of cysteine protease inhibitors. Its low molecular weight (13.3kDa) and positive charge at physiological pH levels facilitates its glomerular filtration and subsequently it is reabsorbed and almost completely catabolized in the proximal renal tubules. Therefore and due to its constant rate of production, its serum concentration is determined by the rate of glomerular filtration (GFR). Cystatin C production in the body is a stable process that is not influenced by renal conditions, increased protein catabolism or dietary factors. Moreover, in contrary to creatinine, it does not change with age or muscle mass. For these reasons, serum cystatin C has been suggested to be an ideal endogenous marker of GFR. Studies on the renal function of patients with transfusion-dependent β-thalassemia are sparse. These studies suggested that the renal abnormalities observed in β-thalassemia are due to proximal tubular dysfunction and postulated that their severity is related with the degree of anemia. They were less severe in patients on hypertransfusion and appropriate desferrioxamine therapy suggesting that the damage might be caused by both anemia and increased oxidation induced by excess iron deposition. None of these studies have demonstrated renal insufficiency as reflected by decreased GFR. This was probably due to the fact that all estimations were based on creatinine measurements. In this study we estimated GFR in 195 transfused patients with β-thalassemia major by measuring cystatin C and calculating GFR according to the recently proposed cystatin C-based prediction equation using only concentration in mg/L and a prepubertal factor:¹GFR [mL/min/1.73m²] = 84.7 × cystatin C (mg/L)^−1.68 × 1.38* (*if a child <14 years). We found that 136 patients had normal cystatin C levels (0.66–1.03mg/L) and GFR values (80–170mL/min/1.73m²), 36 patients had mild renal insufficiency (cystatin C levels: 1.04–1.22mg/L and GFR values: 60–79mL/min/1.73m²), 21 patients had moderate renal insufficiency (cystatin C levels: 1.23–1.72mg/L and GFR values: 34–59mL/min/1.73m²), while 2 patients had severe renal insufficiency with cystatin C levels >2.5mg/L and GFR values <20mL/min/1.73m². We further determined plasma levels of Neutrophil gelatinase-associated lipocalin (NGAL) in 30 randomly selected patients. NGAL is a protein expressed on tubular cells of which the production is markedly increased in response to harmful stimuli, such as ischemia or toxicity. We found increased NGAL levels in 19 β-thalassemia patients (mean: 95.0±45.0mg/L compared to normal values of 51.2±11.8mg/L, p<0.0003). NGAL levels correlated significantly with cystatin C levels (r=0.740, p<0.0001), indicating that the renal impairment in these patients seems to be originated from tubular injury. The findings of this study indicate that renal insufficiency is present in a significant proportion of transfusion-dependent β-thalassemia patients. Further studies are warranted in order to identify predisposing factors that contribute to the renal damage in thalassemia and to establish appropriate guidelines for the evaluation and follow up of renal function in these patients. 1.