Glomerular hyperfiltration predicts the onset of chronic kidney disease in humanized sickle cell mice
Authors: Kasztan Malgorzata , Speed Joshua S. , Pollock David M. 
Published: June 2021

Kidney disease occurs in 68% of adults with sickle cell disease (SCD), and accounts for 30% mortality. Although a high prevalence of hyperfiltration occurs in SCD, its role as a direct determinant of chronic kidney disease remains unknown. Further, while potential sex‐dependent protective mechanisms of chronic SCD complications have been reported, whether sex differences exist in SCD‐associated kidney disease is unknown. The aim of the study was to perform a longitudinal study to determine the course of renal phenotype and examine potential predictors of long‐term renal outcomes in humanized sickle cell mice (HbSS). Time course analysis of structural and functional markers of kidney injury were performed in 4‐week intervals for 24 weeks starting at 8 weeks of age in male and female HbSS and genetic controls (HbAA) mice. An early and rapid hyperfiltration occurring at 12 weeks of age in male HbSS vs. HbAA mice (GFR: 262±9 vs. 225±3 μl/min; p<0.05) was followed by a progressive decline of renal function (GFR: 139±7 vs. 229±4 μl/min; p<0.0001), and proteinuria (3.62±0.28 vs. 1.46±0.24 mg/24h; p<0.0001). Unlike male, female HbSS mice had a diffuse hyperfiltration pattern with a peak at 20 weeks of age (GFR: 229±18 μl/min), followed by mild decline in kidney function (177±7 μl/min) and proteinuria (1.70±0.33 mg/24h) at 32 weeks of age. Following hyperfiltration male HbSS mice developed progressive glomerular damage presented with albuminuria (319±22 μg/24h) and glomerulopathy, including glomerular sclerosis, congestion, hypertrophy, basement membrane of Bowman's capsule thickening, and glomerular loss. Female HbSS mice manifested with mild albuminuria (51±9 μg/24h) and a minor degree of glomerular injury. Male HbSS mice had more severe podocyte damage subsequent to hyperfiltration when compared to age‐matched females. Interestingly, elevated levels of urinary kidney injury marker 1 (at 8 weeks of age), a gradual brush border loss, progressive extension of interstitial fibrosis and tubular iron deposition were observed in both sexes of HbSS mice throughout the study course, suggesting that early tubular dysfunction preceded the onset of glomerular damage in these mice. Moreover, female HbSS mice had significantly lower mRNA expression of hypoxia inducible factor 1α when compared to males. In male HbSS mice, hyperfiltration strongly correlated with proteinuria (R2=0.57, p<0.0003), albuminuria (R2=0.4, p<0.003), decreased GFR (R2=0.44, p<0.004), and elevated plasma creatinine (R2=0.27, p<0.03) at 32 weeks of age. Additionally, the magnitude of hyperfiltration greater than 60 μl/min was associated with the greater degree of kidney damage in male HbSS mice. Unlike male, female HbSS mice did not demonstrate with a significant loss of renal function nor severe kidney damage during the time course of the study. These data suggest that hyperfiltration predicts the development of nephropathy in male HbSS mice, while protective mechanisms existing in female HbSS mice, may delay the onset of SCD nephropathy.Support or Funding InformationSupport provided by an NIH‐funded U01 HL117684 to D.M.P, R00 HL127178 to J.S.S and ASN Ben J. Lipps Research Fellowship for M.K.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.