Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.

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We would like to acknowledge the members of the Emory Biobank Team, Emory Clinical Cardiovascular Research Institute (ECCRI) and Atlanta Clinical and Translational Science Institute for the recruitment of participants, compilation of data and preparation of samples. Specifically, we would like to acknowledge M. Awad, T. Varghese, W. Schultz, J. Patrick, M. Namara and A. Samman Tahhan (Emory University Department of Medicine) for assisting in data collection. We also appreciate A. Arnaout and B. Adair for the discussion of APOL1 and suPAR interaction. We are grateful to A.P. Mazar for providing anti-suPAR antibody ATN615. We thank R. Shemer, (Technion, Israel Institute of Technology) and A. Ofir (Rambam Medical Center, Haifa, Israel) for discussions and technical help.

Author information

Author notes

    • Salim S Hayek
    • , Kwi Hye Koh
    • , Morgan E Grams
    •  & Changli Wei

    These authors contributed equally to this work.


  1. Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Salim S Hayek
    •  & Arshed A Quyyumi
  2. Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.

    • Kwi Hye Koh
    • , Changli Wei
    • , Jing Li
    • , Beata Samelko
    • , Ranadheer R Dande
    • , Ha Won Lee
    • , Eunsil Hahm
    • , Vasil Peev
    • , Melissa Tracy
    • , Nicholas J Tardi
    • , Vineet Gupta
    • , Mehmet M Altintas
    •  & Jochen Reiser
  3. Welch Center for Prevention and Johns Hopkins Bloomberg School of Public Health, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.

    • Morgan E Grams
    • , Adrienne Tin
    •  & Josef Coresh
  4. Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, USA.

    • Yi-An Ko
  5. Center for Biomolecular Science and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA.

    • Hyun Lee
  6. Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.

    • Garrett Garborcauskas
    • , Nikolina Stojanovic
    •  & Sanja Sever
  7. Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA.

    • Cheryl A Winkler
  8. Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC, USA.

    • Michael S Lipkowitz
  9. Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.

    • Lesley A Inker
    •  & Andrew S Levey
  10. Division of Nephrology, Ruprecht Karls University, Heidelberg, Germany.

    • Martin Zeier
  11. Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Barry I Freedman
  12. Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Jeffrey B Kopp
  13. Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Rambam Health Care Campus, Haifa, Israel.

    • Karl Skorecki


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S.S.H., K.H.K. and C.W. designed and performed experiments, and wrote the paper; M.E.G. and Y.-A.K. contributed to data analysis; J.L., B.S., H.L., R.R.D., H.W.L., E.H., V.P., M.T., N.J.T., G.G. and N.S. contributed to experiments; K.S. participated in formulating aspects of study design relating to suPAR–APOL1 interaction and developing novel enabling reagents, and collaborated in the writing of the manuscript; V.G., M.M.A., C.A.W., M.S.L., A.T., L.A.I., A.S.L., M.Z., B.I.F., J.B.K. and J.C. contributed to the interpretation of data and manuscript revision; A.A.Q. established the Emory Cardiovascular Biobank that contributed all clinical samples and assisted in manuscript preparation; J.R. and S.S. designed and supervised the study, and wrote the paper. J.R. is supported by grants 5R01DK101350-03 (NIDDK) and 1R01DK106051 (NIDDK). A.A.Q. is supported by grants 5P01HL101398-02, 1P20HL113451-01, 1R56HL126558-01, 1RF1AG051633-01, R01 NS064162-01, R01 HL89650-01, HL095479-01, 1U10HL110302-01, 1DP3DK094346-01, 2P01HL086773-06A1 (NIH). M.E.G., J.C., A.S.L., L.A.I. and A.T. are supported by grants R01DK108803 (NIH) and U01DK085689 (NIDDK). J.C., A.S.L. and L.A.I. are supported by grant R01DK087961 (NIH). E.H. was supported by grant 1RO1 DK106051. Funding for the collection and management of samples was received from the Robert W. Woodruff Health Sciences Center Fund (Atlanta, GA), Emory Heart and Vascular Center (Atlanta, GA), Katz Family Foundation Preventive Cardiology Grant (Atlanta, GA), and National Institutes of Health (NIH) Grants UL1 RR025008 from the Clinical and Translational Science Award program and the Intramural Research Programs of NCI and NIDDK, NIH. This project has also been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Competing interests

J.R. and S.S. are cofounders of the biotech TRISAQ, and hold patents and stock in the space of proteinuric kidney disease. C.W. has a pending patent on suPAR in diabetic kidney disease. J.R., S.S., C.W. and E.H. are inventors on pending and issued patents related to anti-proteinuric therapies. They stand to gain royalties from present and future commercialization. J.C., A.S.L. and L.I. have a patent pending on GFR estimation and a collaboration agreement with Metabolon. Wake Forest University Health Sciences and B.F have filed for a patent related to APOL1 genetic testing. B.F receives research support from Novartis Pharmaceuticals and is a consultant for Ionis and AstraZeneca Pharmaceuticals.

Corresponding authors

Correspondence to Sanja Sever or Jochen Reiser.

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