Background Sickle cell disease (SCD) is an inherited disorder of red blood cell hemoglobin. Sickle nephropathy (SN) (one of the most serious complications of SCA) is characterized by insufficient angiogenesis due to the imbalance between proangiogenic and antiangiogenic process. As the disease progresses, nephrotic syndrome and ESRD develop. The risk factors for the sickle nephropathy include the duration of the sickle disease, the severity of the anemia, iron overload, infection, number of crises, splenic status and genetic factors. Both microalbuminuria and lactate dehyrogenase are considered of the earliest markers of kidney damage. Vascular endothelial growth factor (VEGF) is a protein with antiapoptotic, mitogenic, and permeability-increasing activities specific for vascular endothelium. Soluble FMS like tyrosine kinase-1 (sFLT-1) is a member of the vascular endothelial growth factor receptor (VEGFR) family. In SCD patients sFLT-1 production is increased due to misregulation of FMS like tyrosine kinase in the endothelial cells resulting in over expression of the soluble splice variant of FLT-1 in the plasma. Insufficient angiogenesis observed in sickle nephropathy results from sequestration and inhibition of VEGF by sFLT-1 which is a potent antagonist to it. Aim of The Work The aim of this study was to determine the prevalence of sickle cell nephropathy in Egyptian SCD patients who attended the Hematology Clinic, New Cairo University Children Hospital (NCUCH). Also to determine the risk factors for sickle cell nephropathy. Finally to evaluate the association of sFLT-1 with other conventional biomarkers of renal damage in SCD patients and evaluate the association of s FLT-1 with measures of hemolysis and inflammation to identify a novel renal biomarker for early diagnosis of sickle nephropathy.Subjects and Methods A case control study was carried out on 47 SCD patients who attended the Hematology Clinic, NCUCH. Subjects were screened for the presence of microalbuminuria with first morning sample. Blood samples for measuring complete blood picture, reticulocytic count, serum ferritin, indirect serum bilirubin, lactate dehydrogenase, biomarkers of renal functions (creatinine, blood urea nitrogen, estimated glomerular filtration rate and serum FMS like tyrosine kinase-1). Medical records were reviewed for demographic data and clinical events. Results Our study revealed that the level of sFLT-1 was higher in patients with SCD compared to control subjects [192 pg/ml (110 - 1350) vs. 132 pg/ml (75 - 450) respectively] (p=0.001). sFLT-1 showed statistically significant positive correlation with severity index, TLC, ANC, ISB, LDH, microalbuminuria and albumin/creatinine (r = 0.342, 0.319, 0.285, 0.531, 0.364, 0.391, 0.482 and 0.427 respectively) and (p = 0.031, 0.029, 0.058, < 0.001, 0.032, 0.007 and 0.001 respectively). sFLT-1 showed statistically significant negative correlation with height SDS (r = - 0.298, p = 0.042). The sensitivity of sFLT in early detection of renal affection in SCD was 93.6 %, while the specificity was 68.6 %, and the cutoff value above which most patients lie was > 137 pg/ml. MA was statistically significantly higher in splenectomatized patients if compared to sFLT-1 (p = 0.033, 0.699 respectively). Both MA and sFLT-1 were statistically significant higher in SCD patients with abnormal grade I echogenicity in renal findings in abdominal ultrasound (p = 0.006, <0.001 respectively). MA showed statistically significant positive correlation with age of the patients, severity index, frequency of hospital admission, onset of hydroxyurea, AMC, platelet count, ISB, LDH and sFLT-1 (r = 0.407, 0.385, 0.305, 0.499, 0.291, 0.378, 0.311, 0.339 and 0.391 respectively), (p = 0.005, 0.007, 0.037, 0.001, 0.053, 0.009, 0.033, 0.020 and 0.007 respectively). LDH showed statistically significant positive correlation with ISB, sFLT-1, microalbuminuria (r = 0.451, 0.364 and 0.353 respectively) and (p = 0.001, 0.032 and 0.015 respectively). LDH showed statistically significant negative correlation with weight SDS (r = -0.311, p = 0.033). The multiple regression revealed that the indirect serum bilirubin was the independent factor that significantly correlate better with sFLT-1 (p = 0.004), followed by height SDS (p = 0.045), followed by absolute neutrophilic count (p = 0.026) and finally albumin/creatinine (p = 0.05). Also, the multiple regression revealed that the weight SDS was the independent factor that significantly correlate better with LDH (p = 0.050), followed by ISB (p = 0.023).Conclusion Our findings strongly suggest that excess sFLT-1 may constitute a novel renal biomarker that can predict sickle nephropathy, enabling early diagnosis and effective therapeutic interventions.