title: Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy.
abstract: Intravascular hemolysis and hemoglobinuria are associated with sickle cell nephropathy. ApoL1 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 221 patients with sickle cell disease at the University of Illinois at Chicago, we replicated the finding of an association of APOL1 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=4.3×10(-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 HMOX1 and SOD2. HMOX1 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.
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, IL ssaraf@uic.edu vgordeuk@uic.edu.
authors.forename: Santosh L
authors.initials: SL
authors.lastname: Saraf
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, IL.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, IL.
authors.forename: Binal
authors.initials: B
authors.lastname: Shah
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh, PA.
authors.forename: Tamir
authors.initials: T
authors.lastname: Kanias
authors.affiliation: Division of Nephrology, Department of Medicine, John H. Stroger, Jr Hospital of Cook County, Chicago, IL.
authors.forename: Krishnamurthy P
authors.initials: KP
authors.lastname: Gudehithlu
authors.affiliation: Department of Surgery, University of Arizona, Tucson, AZ.
authors.forename: Rick
authors.initials: R
authors.lastname: Kittles
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Illinois at Chicago, IL.
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.affiliation: Division of Nephrology, Department of Medicine, University of Illinois at Chicago, IL, USA.
authors.forename: Jose A L
authors.initials: JA
authors.lastname: Arruda
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh, PA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.affiliation: Division of Nephrology, Department of Medicine, John H. Stroger, Jr Hospital of Cook County, Chicago, IL.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, IL ssaraf@uic.edu vgordeuk@uic.edu.
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics*; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics; D002460:Cell Line; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006454:Hemoglobins / Q000235:genetics* / Q000378:metabolism*; D006456:Hemoglobinuria; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000652:urine; D008875:Middle Aged; D011991:Receptors, Virus / Q000235:genetics
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; C491143:HAVCR1 protein, human; D006454:Hemoglobins; D000072596:Hepatitis A Virus Cellular Receptor 1; D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1