The early stages of sickle cell nephropathy manifest in children with sickle cell anemia as hyperfiltration and proteinuria. The physiological conditions of the renovascular system are amongst the most conducive to Hemoglobin S polymerisation in the body and will magnify small changes in red cell volume thus crucially modulating intracellular concentrations of Hemoglobin S. This large cross-sectional study of children with sickle cell anemia measured glomerular filtration rates and microalbuminuria to report prevalence, clinical correlates and uniquely, association with key red cell cation transport mechanisms. One hundred and twelve patients (mean age 10.7 ± 4.1) were recruited. The prevalence of hyperfiltration and microalbuminuria was 98% and 15.1% respectively. Glomerular filtration rates did not vary with age, but proteinuria became more prevalent with increasing age. Both features associated with markers of hemolysis, whilst elevated hemoglobin F was protective, but no association was seen with systolic or diastolic blood pressure. In multivariate analysis, both Gardos channel (beta=0.476, p<0.001) and KCC (beta=-0.216, p=0.009) activity, alongside age (beta=0.237, p=0.004), remained independently predictive for microalbuminuria. Increased activity of Gardos channel and Psickle positively associated with microalbuminuria, whilst increased KCC activity associated with a reduction in microalbuminuria. This study demonstrates a direct link between the abnormally active red cell cation transport systems in sickle cell disease and sickle organopathy. Small variations in the activity of these transport mechanisms predict for sickle cell nephropathy and measurement of them may help identify those at risk, whilst pharmaceutical manipulation of these excessively active systems may ameliorate their risk.