Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

• Published in: Haematologica (Roma) Vol. 100; no. 10; pp. 1275 - 1284
• Main Authors: Saraf, S. L., Zhang, X., Shah, B., Kanias, T., Gudehithlu, K. P., Kittles, R., Machado, R. F., Arruda, J. A. L., Gladwin, M. T., Singh, A. K., Gordeuk, V. R.
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.10.2015
• Subjects: Adult; Anemia, Sickle Cell - complications; Anemia, Sickle Cell - genetics; Apolipoprotein L1; Apolipoproteins - genetics; Cell Line; Cohort Studies; Female; Gene Expression; Genetic Predisposition to Disease; Genetic Variation; Genotype; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hemoglobins - genetics; Hemoglobins - metabolism; Hemoglobinuria; Hepatitis A Virus Cellular Receptor 1; Humans; Kidney Diseases - etiology; Kidney Diseases - metabolism; Kidney Tubules, Proximal - metabolism; Lipoproteins, HDL - genetics; Male; Membrane Glycoproteins - genetics; Membrane Glycoproteins - urine; Middle Aged; Receptors, Virus - genetics
• DOI: 10.3324/haematol.2015.124875
• ISSN: 0390-6078

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.