KIM‐1 as a new biomarker for glomerular hyperfiltration and chronic kidney disease in humanized sickle cell disease mice

Abstract

Sickle cell disease is associated with increased prevalence of nephropathy and approximately 30% mortality from chronic kidney disease and renal failure. The spectrum of renal manifestations includes hyperfiltration as well as subsequent glomerulopathies, and tubulopathies. Although hyperfiltration has been widely reported in sickle cell disease, its role as a direct precursor and determinant of glomerulopathy and progression of chronic kidney disease remains unknown. Moreover, novel risk factors and biomarkers are needed for early diagnosis and/or modification of disease progression. The aim of the current study was to evaluate the trajectory of glomerular filtration rate (GFR) in humanized sickle cell mice and investigate predictors of loss of renal function in this disease model. Experiments utilized male humanized sickle cell mice (HbSS) and age‐matched genetic controls (HbAA). Analysis of urinary renal biomarkers and time course GFR studies in 4‐week intervals for 24 weeks starting at 8 weeks of age were performed. At 8 weeks of age no differences were observed in GFR or protein excretion in HbSS and HbAA mice (GFR: 199±11 vs. 205±7 μl/min; p>0.99; proteinuria: 1.82±0.13 vs. 1.18±0.12 mg/24h; p=0.45). Glomerular hyperfiltration and increased proteinuria were observed at 12 weeks of age in HbSS vs. HbAA mice (GFR: 262±9 vs. 225±3 μl/min; p<0.05; proteinuria: 3.62±0.28 vs. 1.46±0.24 mg/24h; p<0.0001). In HbSS mice, GFR was also significantly elevated at 12 weeks compared to 8 weeks of age. Progressive loss of renal function was subsequently observed in HbSS mice following hyperfiltration, and at 32 weeks of age GFR was significantly lower and protein excretion was significantly higher in HbSS compared to HbAA (GFR: 139±7 vs. 229±4 μl/min; p<0.0001; proteinuria: 3.8±0.23 vs. 0.80±0.16 mg/24h; p<0.0001). Interestingly, the degree of the rise in GFR from 8 weeks to 12 weeks of age, within individual HbSS mice, was significantly associated with the magnitude of proteinuria at 32 weeks of age (R2=0.35; p=0.0097), suggesting that the level of hyperfiltration is associated with the degree of subsequent renal injury. The rate of decline in GFR in HbSS was modeled using linear regression to evaluate markers that may predict the rate of loss of renal function. Surprisingly, neither the degree of albuminuria nor nephrinuria were associated with the slope of decline in GFR in HbSS mice (albuminuria: R2=0.0029; p=0.9097; nephrinuria: R2=0.16; p=0.369). However, the tubular injury marker (KIM‐1), was significantly positively associated with the slope of decline in GFR in HbSS mice (R2=0.5835; p=0.0456). None of the measured parameters were altered in HbAA mice. These data support the hypothesis that glomerular hyperfiltration predicts the development of nephropathy and suggest that KIM‐1 may represent a novel predictor of the onset of nephopathy in sickle cell disease.Support or Funding InformationSupport provided by an NIH‐funded U01 HL117684 to D.M.P, F30 DK107194 to B.M.F, K99HL127178 to J.S.S and ASN Ben J. Lipps Research Fellowship for M.K.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.