title: Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial.
abstract: Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone.
authors.affiliation: Kidney Disease Section, jbkopp@nih.gov.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland;
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.affiliation: Biostatistics Core, and.
authors.forename: Xiongce
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Quantitative Heath Sciences, Cleveland Clinic, Cleveland, Ohio;
authors.forename: Milena K
authors.initials: MK
authors.lastname: Radeva
authors.affiliation: Department of Quantitative Heath Sciences, Cleveland Clinic, Cleveland, Ohio;
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Gassman
authors.affiliation: Department of Pathology, Columbia University Medical Center, New York, New York;
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.affiliation: Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California;
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Nast
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois;
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois;
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: Center for Translational Science, Children's National Health System, Washington, DC;
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Guay-Woodford
authors.affiliation: Beth Israel Deaconess Medical Center and.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
authors.affiliation: Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts;
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.affiliation: Division of Kidney, Urology and Hematology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
authors.forename: Marva
authors.initials: M
authors.lastname: Moxey-Mims
authors.affiliation: Department of Pediatrics and Communicable Disease, University of Michigan, Ann Arbor, Michigan;
authors.forename: Debbie S
authors.initials: DS
authors.lastname: Gipson
authors.affiliation: Department of Pediatrics, New York University School of Medicine, New York, New York;
authors.forename: Howard
authors.initials: H
authors.lastname: Trachtman
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota; and.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Friedman
authors.affiliation: Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Kaskel
mesh_terms: D000293:Adolescent; D000328:Adult; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D002648:Child; D003524:Cyclosporins / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D005838:Genotype; D005923:Glomerulosclerosis, Focal Segmental / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D007677:Kidney Function Tests; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011446:Prospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D003524:Cyclosporins; D008075:Lipoproteins, HDL; D003907:Dexamethasone; D009173:Mycophenolic Acid
keywords: FSGS; cyclosporin; genetic renal disease