TY - JOUR
T1 - Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy
AU - Saraf, Santosh L.
AU - Zhang, Xu
AU - Shah, Binal
AU - Kanias, Tamir
AU - Gudehithlu, Krishnamurthy P.
AU - Kittles, Rick
AU - Machado, Roberto F.
AU - Arruda, Jose A.L.
AU - Gladwin, Mark T.
AU - Singh, Ashok K.
AU - Gordeuk, Victor R.
N1 - Publisher Copyright:
© 2015 Ferrata Storti Foundation.
PY - 2015/10/2
Y1 - 2015/10/2
N2 - Intravascular hemolysis and hemoglobinuria are associated with sickle cell nephropathy. ApoLl is involved in cell-free hemoglobin scavenging through association with haptoglobin-related protein. APOL1 G1/G2 variants are the strongest genetic predictors of kidney disease in the general African-American population. A single report associated APOL1 G1/G2 with sickle cell nephropathy. In 22l patients with sickle cell disease at the University of Illinois at Chicago, we replicated the finding of an association of APOLI G1/G2 with proteinuria, specifically with urine albumin concentration (β=1.1, P=0.003), observed an even stronger association with hemoglobinuria (OR=2.5, P=4.3x10-6), and also replicated the finding of an association with hemoglobinuria in 487 patients from the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy study (OR=2.6, P=0.003). In 25 University of Illinois sickle cell disease patients, concentrations of urine kidney injury molecule-1 correlated with urine cell-free hemoglobin concentrations (r=0.59, P=0.002). Exposing human proximal tubular cells to increasing cell-free hemoglobin led to increasing concentrations of supernatant kidney injury molecule-1 (P=0.01), reduced viability (P=0.01) and induction of HMOXI and SOD2. HMOXI rs743811 associated with chronic kidney disease stage (OR=3.0, P=0.0001) in the University of Illinois cohort and end-stage renal disease (OR=10.0, P=0.0003) in the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy cohort. Longer HMOX1 GT-tandem repeats (>25) were associated with lower estimated glomerular filtration rate in the University of Illinois cohort (P=0.01). Our findings point to an association of APOL1 G1/G2 with kidney disease in sickle cell disease, possibly through increased risk of hemoglobinuria, and associations of HMOX1 variants with kidney disease, possibly through reduced protection of the kidney from hemoglobin-mediated toxicity.
AB - Intravascular hemolysis and hemoglobinuria are associated with sickle cell nephropathy. ApoLl is involved in cell-free hemoglobin scavenging through association with haptoglobin-related protein. APOL1 G1/G2 variants are the strongest genetic predictors of kidney disease in the general African-American population. A single report associated APOL1 G1/G2 with sickle cell nephropathy. In 22l patients with sickle cell disease at the University of Illinois at Chicago, we replicated the finding of an association of APOLI G1/G2 with proteinuria, specifically with urine albumin concentration (β=1.1, P=0.003), observed an even stronger association with hemoglobinuria (OR=2.5, P=4.3x10-6), and also replicated the finding of an association with hemoglobinuria in 487 patients from the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy study (OR=2.6, P=0.003). In 25 University of Illinois sickle cell disease patients, concentrations of urine kidney injury molecule-1 correlated with urine cell-free hemoglobin concentrations (r=0.59, P=0.002). Exposing human proximal tubular cells to increasing cell-free hemoglobin led to increasing concentrations of supernatant kidney injury molecule-1 (P=0.01), reduced viability (P=0.01) and induction of HMOXI and SOD2. HMOXI rs743811 associated with chronic kidney disease stage (OR=3.0, P=0.0001) in the University of Illinois cohort and end-stage renal disease (OR=10.0, P=0.0003) in the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy cohort. Longer HMOX1 GT-tandem repeats (>25) were associated with lower estimated glomerular filtration rate in the University of Illinois cohort (P=0.01). Our findings point to an association of APOL1 G1/G2 with kidney disease in sickle cell disease, possibly through increased risk of hemoglobinuria, and associations of HMOX1 variants with kidney disease, possibly through reduced protection of the kidney from hemoglobin-mediated toxicity.
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U2 - 10.3324/haematol.2015.124875
DO - 10.3324/haematol.2015.124875
M3 - Article
C2 - 26206798
AN - SCOPUS:84943255363
SN - 0390-6078
VL - 100
SP - 1275
EP - 1284
JO - Haematologica
JF - Haematologica
IS - 10
ER -