. 2021 Sep;36(9):2747-2757.

doi: 10.1007/s00467-021-04990-4. Epub 2021 Mar 1.

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

Jarcy Zee¹, Michelle T McNulty², Jeffrey B Hodgin³, Olga Zhdanova⁴, Sangeeta Hingorani⁵, Jonathan Ashley Jefferson⁶, Keisha L Gibson⁷, Howard Trachtman⁸, Alessia Fornoni⁹, Katherine M Dell¹⁰, Heather N Reich¹¹, Serena Bagnasco¹², Larry A Greenbaum¹³, Richard A Lafayette¹⁴, Debbie S Gipson¹⁵, Elizabeth Brown¹⁶, Matthias Kretzler¹⁷, Gerald Appel¹⁸, Kamalanathan K Sambandam¹⁹, Katherine R Tuttle^{20

21}, Dhruti Chen⁷, Meredith A Atkinson²², Marie C Hogan²³, Frederick J Kaskel²⁴, Kevin E Meyers²⁵, John O'Toole²⁶, Tarak Srivastava²⁷, Christine B Sethna²⁸, Michelle A Hladunewich²⁹, J J Lin³⁰, Cynthia C Nast³¹, Vimal K Derebail⁷, Jiten Patel¹⁹, Suzanne Vento⁸, Lawrence B Holzman³², Ambarish M Athavale³³, Sharon G Adler³⁴, Kevin V Lemley³⁵, John C Lieske²³, Jonathan J Hogan³², Crystal A Gadegbeku³⁶, Fernando C Fervenza²³, Chia-Shi Wang¹³, Raed Bou Matar^{10

37}, Pamela Singer²⁸, Jeffrey B Kopp³⁸, Laura Barisoni³⁹, Matthew G Sampson^{40

41

42}

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@Pennmedicine.upenn.edu.
² Division of Pediatric Nephrology, Boston Children's Hospital, Enders 509 (Mail Stop BCH3100), 300 Longwood Ave, Boston, MA, 02115, USA.
³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁴ Division of Nephrology, New York University Langone Health, New York, NY, USA.
⁵ Department of Pediatrics, University of Washington and Division of Nephrology, Seattle Children's, Seattle, WA, USA.
⁶ Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA.
⁷ University of North Carolina Kidney Center at Chapel Hill, Chapel Hill, NC, USA.
⁸ Division of Nephrology, Department of Pediatrics, New York University Langone Health, New York, NY, USA.
⁹ Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
¹⁰ Department of Pediatrics, Cleveland Clinic Children's, Cleveland, OH, USA.
¹¹ Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON, USA.
¹² Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Division of Pediatric Nephrology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹⁴ Division of Nephrology, Department of Medicine, Stanford University, Stanford, CA, USA.
¹⁵ Division of Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Division of Nephrology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA.
¹⁷ Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Division of Nephrology at Columbia University Medical Center, New York, NY, USA.
¹⁹ Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
²⁰ Providence Medical Research Center, Providence Health Care, Spokane, WA, USA.
²¹ Kidney Research Institute, Nephrology Division, and Institute for Translational Health Sciences, University of Washington, Seattle, WA, USA.
²² Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²³ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
²⁴ Division of Nephrology, Department of Pediatrics, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, USA.
²⁵ Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁶ Department of Nephrology, Cleveland Clinic, Cleveland, OH, USA.
²⁷ Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA.
²⁸ Pediatric Nephrology, Cohen Children's Medical Center of New York, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
²⁹ Division of Nephrology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, USA.
³⁰ Division of Pediatric Nephrology, Brenner Children's Hospital, Wake Forest University, Winston Salem, NC, USA.
³¹ Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³² Renal-Electrolyte & Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³³ Division of Nephrology, Core Faculty, Internal Medicine Residency Program, Cook County Health, Chicago, IL, USA.
³⁴ Division of Nephrology and Hypertension, Lundquist Research Institute at Harbor-UCLA, Torrance, CA, USA.
³⁵ Department of Pediatrics, USC Keck School of Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.
³⁶ Division of Nephrology, Temple University School of Medicine, Philadelphia, PA, USA.
³⁷ Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
³⁸ Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
³⁹ Department of Pathology, Duke University, Durham, NC, USA.
⁴⁰ Division of Pediatric Nephrology, Boston Children's Hospital, Enders 509 (Mail Stop BCH3100), 300 Longwood Ave, Boston, MA, 02115, USA. matthew.sampson@childrens.harvard.edu.
⁴¹ Harvard Medical School, Boston, MA, USA. matthew.sampson@childrens.harvard.edu.
⁴² Broad Institute, Cambridge, MA, USA. matthew.sampson@childrens.harvard.edu.

PMID: 33646395
PMCID: PMC8524347
DOI: 10.1007/s00467-021-04990-4

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

Jarcy Zee et al. Pediatr Nephrol. 2021 Sep.

. 2021 Sep;36(9):2747-2757.

doi: 10.1007/s00467-021-04990-4. Epub 2021 Mar 1.

Authors

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@Pennmedicine.upenn.edu.
² Division of Pediatric Nephrology, Boston Children's Hospital, Enders 509 (Mail Stop BCH3100), 300 Longwood Ave, Boston, MA, 02115, USA.
³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁴ Division of Nephrology, New York University Langone Health, New York, NY, USA.
⁵ Department of Pediatrics, University of Washington and Division of Nephrology, Seattle Children's, Seattle, WA, USA.
⁶ Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA.
⁷ University of North Carolina Kidney Center at Chapel Hill, Chapel Hill, NC, USA.
⁸ Division of Nephrology, Department of Pediatrics, New York University Langone Health, New York, NY, USA.
⁹ Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
¹⁰ Department of Pediatrics, Cleveland Clinic Children's, Cleveland, OH, USA.
¹¹ Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON, USA.
¹² Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Division of Pediatric Nephrology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹⁴ Division of Nephrology, Department of Medicine, Stanford University, Stanford, CA, USA.
¹⁵ Division of Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Division of Nephrology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA.
¹⁷ Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Division of Nephrology at Columbia University Medical Center, New York, NY, USA.
¹⁹ Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
²⁰ Providence Medical Research Center, Providence Health Care, Spokane, WA, USA.
²¹ Kidney Research Institute, Nephrology Division, and Institute for Translational Health Sciences, University of Washington, Seattle, WA, USA.
²² Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²³ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
²⁴ Division of Nephrology, Department of Pediatrics, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, USA.
²⁵ Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁶ Department of Nephrology, Cleveland Clinic, Cleveland, OH, USA.
²⁷ Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA.
²⁸ Pediatric Nephrology, Cohen Children's Medical Center of New York, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
²⁹ Division of Nephrology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, USA.
³⁰ Division of Pediatric Nephrology, Brenner Children's Hospital, Wake Forest University, Winston Salem, NC, USA.
³¹ Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³² Renal-Electrolyte & Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³³ Division of Nephrology, Core Faculty, Internal Medicine Residency Program, Cook County Health, Chicago, IL, USA.
³⁴ Division of Nephrology and Hypertension, Lundquist Research Institute at Harbor-UCLA, Torrance, CA, USA.
³⁵ Department of Pediatrics, USC Keck School of Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.
³⁶ Division of Nephrology, Temple University School of Medicine, Philadelphia, PA, USA.
³⁷ Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
³⁸ Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
³⁹ Department of Pathology, Duke University, Durham, NC, USA.
⁴⁰ Division of Pediatric Nephrology, Boston Children's Hospital, Enders 509 (Mail Stop BCH3100), 300 Longwood Ave, Boston, MA, 02115, USA. matthew.sampson@childrens.harvard.edu.
⁴¹ Harvard Medical School, Boston, MA, USA. matthew.sampson@childrens.harvard.edu.
⁴² Broad Institute, Cambridge, MA, USA. matthew.sampson@childrens.harvard.edu.

PMID: 33646395
PMCID: PMC8524347
DOI: 10.1007/s00467-021-04990-4

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.

Keywords: APOL1; Focal segmental glomerulosclerosis; Minimal change disease; Morphology; Pediatric.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest/Competing interests: No authors have any conflict of interest or competing interests relevant to this manuscript

Figures

**Fig 1**
Glomerular *APOL1* expression as measured by log2 transformed mRNA level increases with increasing number of *APOL1* risk alleles.

**Fig 2**
Morphologic descriptors associated with the *APOL1* high-risk genotype (a) presence of tubular microcysts (yes/no), (b) semi-quantitative amount of condensation of the actin cytoskeleton, (c) percent of global mesangial hypercellularity

**Fig 3**
Representative examples of (a) tubular microcysts, (b) condensation of the actin cytoskeleton, and (c) global mesangial hypercellularity from the NEPTUNE cohort. a) Tubular microcysts: The tubules are enlarged and have an irregular shape. They contain eosinophilic smooth proteinaceous material forming intratubular casts with scalloping of the edges of the casts. (Hematoxylin and Eosin stain); b) Condensation of the cytoskeleton: The cytoskeleton in podocytes with complete effacement is reorganized and condensed against the abluminal side of the podocytes facing the glomerular basement membranes (white arrow); c) Global mesangial cell hyperplasia: These 2 glomeruli reveal increased number of nuclei in the mesangium that is present in all glomerular lobules. The number of mesangial cell nuclei is 4 or more in each lobule. (Periodic Acid Schiff stain)

See this image and copyright information in PMC

References

1. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329:841–845. - PMC - PubMed
1. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, Bekele E, Bradman N, Wasser WG, Behar DM, Skorecki K (2010) Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet 128:345–350. - PMC - PubMed
1. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, Friedman D, Briggs W, Dart R, Korbet S, Mokrzycki MH, Kimmel PL, Limou S, Ahuja TS, Berns JS, Fryc J, Simon EE, Smith MC, Trachtman H, Michel DM, Schelling JR, Vlahov D, Pollak M, Winkler CA (2011) APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 22:2129–2137. - PMC - PubMed
1. Ng DK, Robertson CC, Woroniecki RP, Limou S, Gillies CE, Reidy KJ, Winkler CA, Hingorani S, Gibson KL, Hjorten R, Sethna CB, Kopp JB, Moxey-Mims M, Furth SL, Warady BA, Kretzler M, Sedor JR, Kaskel FJ, Sampson MG (2017) APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts. Nephrol Dial Transplant 32:983–990. - PMC - PubMed
1. Sampson MG, Robertson CC, Martini S, Mariani LH, Lemley KV, Gillies CE, Otto EA, Kopp JB, Randolph A, Vega-Warner V, Eichinger F, Nair V, Gipson DS, Cattran DC, Johnstone DB, O’Toole JF, Bagnasco SM, Song PX, Barisoni L, Troost JP, Kretzler M, Sedor JR, Nephrotic Syndrome Study N (2016) Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects. J Am Soc Nephrol 27:814–823. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Molecular Biology Databases
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous