Background: A wide spectrum of glomerular lesions has been described in patients with Sickle Cell Disease (SCD). The most frequently identified morphologic lesion associated with SCD is perihilar Focal Segmental Glomerulosclerosis (FSGS). Glomerular ischemia leads to a compensatory increase in renal blood flow and glomerular filtration rate (GFR); such hyperfiltration, combined with glomerular hypertrophy, probably contributes to glomerulosclerosis. As glomerulosclerosis becomes more extensive, GFR starts to decrease. The glomerular biomarker suPAR is the circulating form of a glycosyl-phosphatidylinositol-anchored three domain membrane protein that is expressed on a variety of cells, including immunologically active cells, endothelial cells, and podocytes. suPAR has been implicated in the pathogenesis of kidney disease, specifically FSGS, through interference with podocyte migration and apoptosis. Recently, suPAR was associated also with subsequent acute kidney injury. We aimed to investigate a possible link between suPAR serum levels and renal function decline for the first time in Caucasian patients with compound heterozygosity for HbS and β-thalassemia (HbS/βthal). Patients and Methods: Ιn the study were included 138 Caucasian adult patients with HbS/βthal at steady phase, and 20 healthy individuals of similar age and gender who served as controls. suPAR concentration was measured with an immunoenzymatic assay (ViroGates, Denmark) along with a series of other blood chemistry markers of erythropoiesis, renal, endothelial and cardiac function, such as: Neutrophil Gelatinase Associated Lipocalin (NGAL), Interleukin-18 (IL-18), Retinol Binding Protein-4 (RBP-4), Fatty Acid Binding Protein-4 (FABP-4), von Willebrand factor antigen (VWF:antigen), D-Dimers, Α Disintegrin and Metalloproteinase with Thrombospondin Type 1 Motif 13 (ADAMTS-13), hs-Troponin-T (hs-TnT), Placental Growth Factor (PlGF) and Growth Differentiation Factor-15 (GDF-15), measured with immunoenzymatic and electrochemiluminescence immunoassays. eGFR values were calculated using the CKD-EPI (Cystatin C and/or Creatinine equations. Results: We found that: a) suPAR levels were higher in patients with HbS/βthal compared to controls, 4.2±2.7pg/mL (1.2-18.2pg/mL) vs 1.9±0.4pg/mL (1.0-2.4pg/mL), p<0.001; b) No correlation was found with hydroxycarbamide treatment (p>0.1), while a weak correlation was found between suPAR levels and HbS/βthal genotype (r=-0.256, p=0.012). c) suPAR levels correlated significantly with eGFR values r=-0.657,p<0.001 and CKD stage (ANOVA p<0.001); 70% of the patients with hyperfiltration and stage-1 CKD had increased suPAR levels; d) suPAR levels correlated significantly with patients’ values of age r=0.477, p<0.001, Hb r= -0.493, p<0.001, Reticulocyte production Index r=0.367, p=0.002, ferritin r=0.459, p<0.001 and uric acid r=0.215, p<0.01, while no correlation was found with LDH r=0.149, p>0.1. e) Comparing the diagnostic significance of suPAR with other parameters of tubular-glomerular activation such as NGAL, IL-18, RBP-4, FABP-4, GDF-15, only the tubular marker NGAL has slightly superior significance, while none of these renal markers was increased in patients with hyperfiltration. f) Nevertheless, suPAR levels may reflect defects to more systems as correlated significance with markers of endothelial dysfunction-hemostatic system: vWF:antigen r=0.466, p<0.001, D-dimer r=0.344, p<0.001), ADAMTS-13/VWF ratio r=-0.485, p<0.001, cardiac injury and stress: hs-troponin-T r=0.519, p<0.001 and GDF-15 r=0.453, p<0.001) and angiogenesis: PlGF r=0.429, p<0.001 was found. Conclusions: To our knowledge this is the first report of the evaluation of a glomelurar biomarker such as suPAR in Caucasian patients with HbS/βthal, showing higher levels in these patients due to possible destruction of podocytes. As more than 70% of patients with hyperfiltration and stage-1 CKD, had increased suPAR levels, we suggest that suPAR could be a prognostic marker of renal injuries in patients with SCD particular in those patients with hyperfiltration and stage-1 CKD. However, this biomarker should be more investigated in order to determine its clinical significance.