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APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis

  • Original Article
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Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging.

Methods

In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes.

Results

Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features.

Conclusions

While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

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Data Availability

Data are available upon request through communication with corresponding authors.

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Download references

Members of the Nephrotic Syndrome Study Network (NEPTUNE):

NEPTUNE Enrolling Centers

Cleveland Clinic, Cleveland, OH: K Dell*, J Sedor**, M Schachere#, J Negrey#

Children’s Hospital, Los Angeles, CA: K Lemley*, E Lim#

Children’s Mercy Hospital, Kansas City, MO: T Srivastava*, A Garrett#

Cohen Children’s Hospital, New Hyde Park, NY: C Sethna*, K Laurent #

Columbia University, New York, NY: P Canetta*, A Pradhan#

Emory University, Atlanta, GA: L Greenbaum*, C Wang**, C Kang#

Harbor-University of California Los Angeles Medical Center: S Adler*, J LaPage#

John H. Stroger Jr. Hospital of Cook County, Chicago, IL: A Athavale*, M Itteera

Johns Hopkins Medicine, Baltimore, MD: M Atkinson*, S Boynton#

Mayo Clinic, Rochester, MN: F Fervenza*, M Hogan**, J Lieske*, V Chernitskiy#

Montefiore Medical Center, Bronx, NY: F Kaskel*, M Ross*, P Flynn#

NIDDK Intramural, Bethesda MD: J Kopp*, J Blake#

New York University Medical Center, New York, NY: H Trachtman*, O Zhdanova**, F Modersitzki#, S Vento#

Stanford University, Stanford, CA: R Lafayette*, K Mehta#

Temple University, Philadelphia, PA: C Gadegbeku*, S Quinn-Boyle#

University Health Network Toronto: M Hladunewich**, H Reich**, P Ling#, M Romano#

University of Miami, Miami, FL: A Fornoni*, C Bidot#

University of Michigan, Ann Arbor, MI: M Kretzler*, D Gipson*, A Williams#, J LaVigne#

University of North Carolina, Chapel Hill, NC: V Derebail*, K Gibson*, E Cole#, J Ormond-Foster#

University of Pennsylvania, Philadelphia, PA: L Holzman*, K Meyers**, K Kallem#, A Swenson#

University of Texas Southwestern, Dallas, TX: K Sambandam*, Z Wang#, M Rogers#

University of Washington, Seattle, WA: A Jefferson*, S Hingorani**, K Tuttle**§, M Bray #, M Kelton#, A Cooper#§

Wake Forest University Baptist Health, Winston-Salem, NC: JJ Lin*, Stefanie Baker#

Data Analysis and Coordinating Center: M Kretzler, L Barisoni, J Bixler, H Desmond, S Eddy, D Fermin, C Gadegbeku, B Gillespie, D Gipson, L Holzman, V Kurtz, M Larkina, J Lavigne, S Li, S Li, CC Lienczewski, J Liu, T Mainieri, L Mariani, M Sampson, J Sedor, A Smith, A Williams, J Zee.

Digital Pathology Committee: Carmen Avila-Casado (University Health Network, Toronto), Serena Bagnasco (Johns Hopkins University), Joseph Gaut (Washington University in St Louis), Stephen Hewitt (National Cancer Institute), Jeff Hodgin (University of Michigan), Kevin Lemley (Children’s Hospital of Los Angeles), Laura Mariani (University of Michigan), Matthew Palmer (University of Pennsylvania), Avi Rosenberg (Johns Hopkins University), Virginie Royal (University of Montreal), David Thomas (University of Miami), Jarcy Zee (University of Pennsylvania) Co-Chairs: Laura Barisoni (Duke University) and Cynthia Nast (Cedar Sinai).

*Principal Investigator; **Co-investigator; #Study Coordinator

§Providence Medical Research Center, Spokane, WA

Funding

This study was supported by a grant from the National Institute of Diabetes, Digestive, and Kidney Diseases to MGS (NIDDK R01-DK108805). Support for JBK was provided by the NIDDK Intramural Research Program. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences and the National Institute of Diabetes, Digestive, and Kidney Diseases. Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International and the Halpin Foundation.

Author information

Authors and Affiliations

  1. Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia, 423 Guardian Drive, Philadelphia, PA, 19104, USA

    Jarcy Zee

  2. Division of Pediatric Nephrology, Boston Children’s Hospital, Enders 509 (Mail Stop BCH3100), 300 Longwood Ave, Boston, MA, 02115, USA

    Michelle T. McNulty & Matthew G. Sampson

  3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Jeffrey B. Hodgin

  4. Division of Nephrology, New York University Langone Health, New York, NY, USA

    Olga Zhdanova

  5. Department of Pediatrics, University of Washington and Division of Nephrology, Seattle Children’s, Seattle, WA, USA

    Sangeeta Hingorani

  6. Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA

    Jonathan Ashley Jefferson

  7. University of North Carolina Kidney Center at Chapel Hill, Chapel Hill, NC, USA

    Keisha L. Gibson, Dhruti Chen & Vimal K. Derebail

  8. Division of Nephrology, Department of Pediatrics, New York University Langone Health, New York, NY, USA

    Howard Trachtman & Suzanne Vento

  9. Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA

    Alessia Fornoni

  10. Department of Pediatrics, Cleveland Clinic Children’s, Cleveland, OH, USA

    Katherine M. Dell & Raed Bou Matar

  11. Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON, USA

    Heather N. Reich

  12. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Serena Bagnasco

  13. Division of Pediatric Nephrology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Larry A. Greenbaum & Chia-Shi Wang

  14. Division of Nephrology, Department of Medicine, Stanford University, Stanford, CA, USA

    Richard A. Lafayette

  15. Division of Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

    Debbie S. Gipson

  16. Division of Nephrology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA

    Elizabeth Brown

  17. Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Matthias Kretzler

  18. Division of Nephrology at Columbia University Medical Center, New York, NY, USA

    Gerald Appel

  19. Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    Kamalanathan K. Sambandam & Jiten Patel

  20. Providence Medical Research Center, Providence Health Care, Spokane, WA, USA

    Katherine R. Tuttle

  21. Kidney Research Institute, Nephrology Division, and Institute for Translational Health Sciences, University of Washington, Seattle, WA, USA

    Katherine R. Tuttle

  22. Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Meredith A. Atkinson

  23. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA

    Marie C. Hogan, John C. Lieske & Fernando C. Fervenza

  24. Division of Nephrology, Department of Pediatrics, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, USA

    Frederick J. Kaskel

  25. Division of Nephrology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Kevin E. Meyers

  26. Department of Nephrology, Cleveland Clinic, Cleveland, OH, USA

    John O’Toole

  27. Section of Nephrology, Children’s Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA

    Tarak Srivastava

  28. Pediatric Nephrology, Cohen Children’s Medical Center of New York, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA

    Christine B. Sethna & Pamela Singer

  29. Division of Nephrology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, USA

    Michelle A. Hladunewich

  30. Division of Pediatric Nephrology, Brenner Children’s Hospital, Wake Forest University, Winston Salem, NC, USA

    JJ Lin

  31. Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Cynthia C. Nast

  32. Renal-Electrolyte & Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Lawrence B. Holzman & Jonathan J. Hogan

  33. Division of Nephrology, Core Faculty, Internal Medicine Residency Program, Cook County Health, Chicago, IL, USA

    Ambarish M. Athavale

  34. Division of Nephrology and Hypertension, Lundquist Research Institute at Harbor-UCLA, Torrance, CA, USA

    Sharon G. Adler

  35. Department of Pediatrics, USC Keck School of Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Kevin V. Lemley

  36. Division of Nephrology, Temple University School of Medicine, Philadelphia, PA, USA

    Crystal A. Gadegbeku

  37. Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA

    Raed Bou Matar

  38. Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA

    Jeffrey B. Kopp

  39. Department of Pathology, Duke University, Durham, NC, USA

    Laura Barisoni

  40. Harvard Medical School, Boston, MA, USA

    Matthew G. Sampson

  41. Broad Institute, Cambridge, MA, USA

    Matthew G. Sampson

Authors
  1. Jarcy Zee
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  2. Michelle T. McNulty
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  3. Jeffrey B. Hodgin
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  4. Olga Zhdanova
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  5. Sangeeta Hingorani
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  6. Jonathan Ashley Jefferson
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  7. Keisha L. Gibson
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  8. Howard Trachtman
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  9. Alessia Fornoni
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  10. Katherine M. Dell
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  11. Heather N. Reich
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  12. Serena Bagnasco
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  13. Larry A. Greenbaum
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  14. Richard A. Lafayette
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  15. Debbie S. Gipson
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  16. Elizabeth Brown
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  17. Matthias Kretzler
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  18. Gerald Appel
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  19. Kamalanathan K. Sambandam
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  20. Katherine R. Tuttle
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  21. Dhruti Chen
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  22. Meredith A. Atkinson
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  23. Marie C. Hogan
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  24. Frederick J. Kaskel
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  25. Kevin E. Meyers
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  26. John O’Toole
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  27. Tarak Srivastava
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  28. Christine B. Sethna
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  29. Michelle A. Hladunewich
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  30. JJ Lin
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  31. Cynthia C. Nast
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  32. Vimal K. Derebail
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  33. Jiten Patel
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  34. Suzanne Vento
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  35. Lawrence B. Holzman
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  36. Ambarish M. Athavale
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  37. Sharon G. Adler
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  38. Kevin V. Lemley
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  39. John C. Lieske
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  40. Jonathan J. Hogan
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  41. Crystal A. Gadegbeku
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  42. Fernando C. Fervenza
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Corresponding authors

Correspondence to Jarcy Zee or Matthew G. Sampson.

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Zee, J., McNulty, M.T., Hodgin, J.B. et al. APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis. Pediatr Nephrol 36, 2747–2757 (2021). https://doi.org/10.1007/s00467-021-04990-4

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