nephrin and Anemia--Sickle-Cell

We previously reported that humanized sickle cell (HbSS) mice develop spontaneous nephropathy, a major cause of morbidity and mortality in sickle cell disease (SCD). Because sex-dependent protective mechanisms in SCD have been reported, we examined the course of nephropathy in male and female HbSS mice to determine contributors and/or predictors of disease severity. In male HbSS mice, glomerular filtration rate was characterized by a rapid onset of hyperfiltration and subsequent progressive decline of renal function over 20 weeks. Early tubular injury presented with increased excretion of kidney injury marker 1 (KIM-1), progressive loss of tubular brush border, and interstitial fibrosis that preceded the onset of glomerular damage, suggesting a tubuloglomerular mechanism of kidney injury in these mice. Additionally, we observed a strong association between the magnitude of hyperfiltration and the degree of long-term kidney injury in male HbSS mice. Unlike males, female HbSS mice did not demonstrate a significant loss of renal function or severe kidney damage during the time course of the study. These results suggest that magnitude of hyperfiltration predicts the onset of chronic kidney damage in male HbSS mice, whereas protective mechanisms in female HbSS mice delay the onset of SCD nephropathy.

Topics: Anemia, Sickle Cell; Animals; Disease Models, Animal; Female; Glomerular Filtration Rate; Hemoglobin, Sickle; Hepatitis A Virus Cellular Receptor 1; Humans; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Longitudinal Studies; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic

Glomerulopathy is an increasingly identified complication in young patients with sickle cell disease (SCD). Hyperfiltration and albuminuria followed by declining glomerular filtration rates and eventual end-stage renal disease (ESRD) is assumed to be the typical progression of glomerular disease. There are only a few reported biomarkers to identify early-stage renal disease in SCD.. We detail the renal profile of 101 children with SCD in Malawi and propose a novel urinary biomarker for the identification of early renal disease.. Among children with sickle cell anemia, 24.8% had a urine albumin-creatinine ratio of 30 mg/g or above. In univariate analysis, only patients with higher urinary nephrin, a urinary marker of glomerular injury, had significantly greater odds of having albuminuria. In multivariable analysis, nephrin remained significantly associated with albuminuria. A nephrin-creatinine ratio (NCR) cut-point of 622 ng/mg, the 50. These data suggest that a substantial number of children with SCD in Malawi have renal disease and could be at risk for worsening nephropathy and ESRD as they age. Our data suggest that urinary nephrin could be utilized as an early marker of glomerular disease in SCD.

Topics: Adolescent; Albuminuria; Anemia, Sickle Cell; Biomarkers; Child; Cross-Sectional Studies; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Function Tests; Malawi; Male; Membrane Proteins; Prognosis

Topics: Adolescent; Adult; Age Factors; Albuminuria; Anemia, Sickle Cell; Biomarkers; Disease Progression; Female; Glomerular Filtration Rate; Hepatitis A Virus Cellular Receptor 1; Humans; Hydroxyurea; Male; Membrane Glycoproteins; Membrane Proteins; Middle Aged; Receptors, Virus