Neutrophil Gelatinase-Associated Lipocalin Levels in Patients with Thalassemia Intermedia: Lack of Association with Erythropoiesis, Iron Metabolism, Renal Dysfunction and Inflammation.

Abstract

Neutrophil Gelatinase-Associated Lipocalin (NGAL, 24p3, SIP24, lipocalin-2 or siderocalin) is a novel iron-carrier protein exerting pleiotropic properties. The physiological role of NGAL is not fully elucidated though a few pivotal functions, such as regulation of apoptosis of leukocytes have been described recently. It has also been demonstrated that NGAL is abundantly expressed in erythroid progenitor cells inducing apoptosis and inhibiting their differentiation. NGAL is reduced in the erythroid cells of mice with acute anemia and injection of recombinant lipocalin-2 delayed the recovery of red blood cells suggesting a negative effect of NGAL in accelerating erythropoiesis. The recently reported functions of NGAL on erythroid progenitor cells and its relation to iron transport prompted us to study the pattern of NGAL levels in Thalassemia Intermedia (TI), which is characterized by erythroid progenitor cells hyperactivity and irregularities in iron metabolism (especially iron transport). To this end we measured NGAL levels in 30 patients with TI and in 20 apparently healthy controls matched for age. We also evaluated other parameters that could be possibly related to NGAL’s functions as: soluble transferrin receptor (sTfR) for eythroid marrow activity; NTBI concentration for non-transferrin-bound mediate iron delivery pathway; creatinine, cystatin C and β2-microglobulin for renal dysfunction and CRP and IL-6 for low grade inflammation. The main results of the showed that: a) NGAL levels were significantly higher in patients with TI compared to controls (139.1±86.1 vs 51.2±11.8 μg/L, p<0.0001), while 4 patients presented with NGAL levels within normal range, b) in patients with TI no correlation was found between NGAL and the erythropoiesis’ parameters Hb, Hb F and sTfR, (p>0.66, p>0.67 and p>0.81 respectively), the parameters of iron metabolism, ferritin and NTBI (p>0.90 and p>0.95 respectively) the markers of renal dysfunction and/or those of low-grade inflammation (p>0.50). The increased NGAL levels observed in TI patients in this study are in agreement with the elevated expression of NGAL observed in experimental models of thalassemia. We postulate that the induction of NGAL in these patients may represent either a response facilitating the survival of the less damaged thalassemic erythroid precursors, or a consequence due to the abnormal iron regulation in patients with TI.