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

Santosh L. Saraf, Xu Zhang, Binal Shah, Tamir Kanias, Krishnamurthy P. Gudehithlu, Rick Kittles, Roberto Machado, Jose A.L. Arruda, Mark T. Gladwin, Ashok K. Singh, Victor R. Gordeuk

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1275-1284
Number of pages10
JournalHaematologica
Volume100
Issue number10
DOIs
StatePublished - Oct 2 2015
Externally publishedYes

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Hemoglobinuria
Sickle Cell Anemia
Hemoglobins
Kidney Diseases
Urine
Kidney
Pulmonary Hypertension
Tandem Repeat Sequences
Haptoglobins
Wounds and Injuries
Therapeutics
Hemolysis
Glomerular Filtration Rate
Chronic Renal Insufficiency
Proteinuria
African Americans
Chronic Kidney Failure
Albumins
Population
Proteins

ASJC Scopus subject areas

  • Hematology

Cite this

Saraf, S. L., Zhang, X., Shah, B., Kanias, T., Gudehithlu, K. P., Kittles, R., ... Gordeuk, V. R. (2015). Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy. Haematologica, 100(10), 1275-1284. https://doi.org/10.3324/haematol.2015.124875

Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy. / Saraf, Santosh L.; Zhang, Xu; Shah, Binal; Kanias, Tamir; Gudehithlu, Krishnamurthy P.; Kittles, Rick; Machado, Roberto; Arruda, Jose A.L.; Gladwin, Mark T.; Singh, Ashok K.; Gordeuk, Victor R.

In: Haematologica, Vol. 100, No. 10, 02.10.2015, p. 1275-1284.

Research output: Contribution to journalArticle

Saraf, SL, Zhang, X, Shah, B, Kanias, T, Gudehithlu, KP, Kittles, R, Machado, R, Arruda, JAL, Gladwin, MT, Singh, AK & Gordeuk, VR 2015, 'Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy', Haematologica, vol. 100, no. 10, pp. 1275-1284. https://doi.org/10.3324/haematol.2015.124875
Saraf SL, Zhang X, Shah B, Kanias T, Gudehithlu KP, Kittles R et al. Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy. Haematologica. 2015 Oct 2;100(10):1275-1284. https://doi.org/10.3324/haematol.2015.124875
Saraf, Santosh L. ; Zhang, Xu ; Shah, Binal ; Kanias, Tamir ; Gudehithlu, Krishnamurthy P. ; Kittles, Rick ; Machado, Roberto ; Arruda, Jose A.L. ; Gladwin, Mark T. ; Singh, Ashok K. ; Gordeuk, Victor R. / Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy. In: Haematologica. 2015 ; Vol. 100, No. 10. pp. 1275-1284.
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