Evidence map›Paper›PMID 26206798›Full record

ArticleHaematologica2015

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 F Machado, Jose A L Arruda, Mark T Gladwin, Ashok K Singh and 1 more

Registry-linked trialAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Haematologica, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07175051 (Targeting the Pathophysiology of Sickle Cell-Related Kidney Disease Using the SGLT2 Inhibitors, Empagliflozin), which is not on this map. Cited by 55 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
55citing papers in PubMed, 4 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT07175051 phase2recruitingnot on this mapstarted 2026, after this paper: background citation

Targeting the Pathophysiology of Sickle Cell-Related Kidney Disease Using the SGLT2 Inhibitors, Empagliflozin

TypeinterventionalSponsorUniversity of Illinois at ChicagoRan2026 to 2030Enrolled20ConditionsSickle Cell Anemia (HbSS, or HbSβ-thalassemia0), AlbuminuriaArmsEmpagliflozin (oral)
3 · Its place in the literature

Who cites it

55 citing papers in PubMed, 4 syntheses or guidelines pooled it.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. Review
  6. Review
  7. Review
  8. Article
  9. Article
  10. Observational
  11. Management of Kidney Disease with Sickle Cell Disease.Journal of the American Society of Nephrology : JASN · 2025
    Review
  12. Review
  13. Article
  14. Observational
  15. Article
  16. Sickle Cell Disease and CKD: An Update.American journal of nephrology · 2024
    Review
  17. Article
  18. Article
  19. Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Santosh L SarafDivision of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, IL ssaraf@uic.edu vgordeuk@uic.edu.
Xu ZhangDivision of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, IL.
Binal ShahDivision of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, IL.
Tamir KaniasDivision of Pulmonary, Allergy, and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh, PA.
Krishnamurthy P GudehithluDivision of Nephrology, Department of Medicine, John H. Stroger, Jr Hospital of Cook County, Chicago, IL.
Rick KittlesDepartment of Surgery, University of Arizona, Tucson, AZ.
Roberto F MachadoDivision of Pulmonary and Critical Care Medicine, Department of Medicine, University of Illinois at Chicago, IL.
Jose A L ArrudaDivision of Nephrology, Department of Medicine, University of Illinois at Chicago, IL, USA.
Mark T GladwinDivision of Pulmonary, Allergy, and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh, PA.
Ashok K SinghDivision of Nephrology, Department of Medicine, John H. Stroger, Jr Hospital of Cook County, Chicago, IL.
Victor R GordeukDivision of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, IL ssaraf@uic.edu vgordeuk@uic.edu.

Funding

Vascular Subphenotypes of Lung DiseaseP01HL103455 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GLADWIN, MARK T · 2011 to 2020
$26.1M
Storage Lesion in Banked Blood Due to Disruption of Nitric Oxide HomeostasisR01HL098032 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Mark T Gladwin · 2009 to 2026
$12.5M
Vascular Targeting Genomic & Genetic Strategies for Acute Chest SyndromeR01HL111656 · NHLBI · UNIVERSITY OF MARYLAND BALTIMORE · PI Roberto F. Machado · 2013 to 2026
$7.9M
Myoglobin as a Nitrite Reductase that Regulates Hypoxic Cardiac NO SignalingR01HL096973 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GLADWIN, MARK T, SHIVA, SRUTI · 2010 to 2013
$1.5M
Carbon monoxide therapy for severe pulmonary arterial hypertensionK23HL098454 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI MACHADO, ROBERTO F. · 2010 to 2014
$657k
Center for Clinical and Translational ScienceKL2TR000048 · NCATS · UNIVERSITY OF ILLINOIS AT CHICAGO · PI AZAR, DIMITRI T, MERMELSTEIN, ROBIN J. · 2012 to 2014
$559k
NCATS NIH HHS KL2 TR000048NCATS NIH HHS KL2TR000048NHLBI NIH HHS K23 HL098454NHLBI NIH HHS K23HL098454NHLBI NIH HHS P01 HL103455NHLBI NIH HHS P01HL103455NHLBI NIH HHS R01 HL096973NHLBI NIH HHS R01HL096973NHLBI NIH HHS R01 HL098032NHLBI NIH HHS R01HL098032NHLBI NIH HHS R01 HL111656NHLBI NIH HHS R01HL111656NIDDK NIH HHS L30 DK099990PHS HHS HHSN268200617182C
6 · The paper itself

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.

Indexed as

Genetic VariationAdultAnemia, Sickle CellApolipoprotein L1ApolipoproteinsCell LineCohort StudiesFemaleGene ExpressionGenetic Predisposition to DiseaseGenotypeHeme Oxygenase-1HemoglobinsHemoglobinuriaHepatitis A Virus Cellular Receptor 1HumansAPOL1 protein, humanApolipoprotein L1ApolipoproteinsHAVCR1 protein, humanHeme Oxygenase-1HemoglobinsHepatitis A Virus Cellular Receptor 1HMOX1 protein, humanLipoproteins, HDLMembrane GlycoproteinsReceptors, Virus

Identifiers

PMID26206798
PMCPMC4591759

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.