Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss.
Fabry disease
chronic kidney disease
pathology
podocyte
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
15
05
2019
accepted:
06
01
2020
pubmed:
5
3
2020
medline:
11
11
2020
entrez:
5
3
2020
Statut:
ppublish
Résumé
In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding In this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases. Podocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion-a strong prognosticator of adverse renal outcomes in Fabry disease-as well as with decreasing GFR. Given the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.
Sections du résumé
BACKGROUND
In males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding
METHODS
In this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases.
RESULTS
Podocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion-a strong prognosticator of adverse renal outcomes in Fabry disease-as well as with decreasing GFR.
CONCLUSIONS
Given the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.
Identifiants
pubmed: 32127409
pii: ASN.2019050497
doi: 10.1681/ASN.2019050497
pmc: PMC7191924
doi:
Substances chimiques
Trihexosylceramides
0
globotriaosylceramide
71965-57-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
865-875Subventions
Organisme : NINDS NIH HHS
ID : U54 NS065768
Pays : United States
Informations de copyright
Copyright © 2020 by the American Society of Nephrology.
Références
J Am Soc Nephrol. 2005 Oct;16(10):2953-66
pubmed: 16120818
J Am Soc Nephrol. 2015 Dec;26(12):3162-78
pubmed: 26038526
J Cell Biol. 2015 Apr 27;209(2):199-210
pubmed: 25918223
J Med Genet. 2016 Jul;53(7):495-502
pubmed: 26993266
J Clin Med. 2018 Nov 02;7(11):
pubmed: 30400144
Nephrol Dial Transplant. 2003 Aug;18 Suppl 6:vi39-44
pubmed: 12953041
Clin Biochem. 2012 Oct;45(15):1233-8
pubmed: 22569598
J Am Soc Nephrol. 2019 Jun;30(6):1049-1059
pubmed: 31152118
Clin Pediatr (Phila). 1986 Nov;25(11):569-72
pubmed: 3769373
Cell Tissue Res. 2017 Jul;369(1):53-62
pubmed: 28401309
PLoS One. 2014 Nov 11;9(11):e112188
pubmed: 25386848
Clin J Am Soc Nephrol. 2017 Sep 7;12(9):1470-1479
pubmed: 28625968
Heart. 2015 Jun;101(12):961-6
pubmed: 25655062
Kidney Int. 2002 Dec;62(6):1933-46
pubmed: 12427118
Ann Intern Med. 2007 Jan 16;146(2):77-86
pubmed: 17179052
Nephrol Dial Transplant. 2010 Jul;25(7):2168-77
pubmed: 19833663
Nefrologia. 2019 Mar - Apr;39(2):177-183
pubmed: 30139698
J Med Genet. 2001 Nov;38(11):750-60
pubmed: 11694547
Diabetes. 2007 Aug;56(8):2155-60
pubmed: 17536064
Pflugers Arch. 2011 Jul;462(1):75-87
pubmed: 21437600
Hum Mutat. 2016 Jun;37(6):564-9
pubmed: 26931183
J Lab Clin Med. 1973 Feb;81(2):157-71
pubmed: 4683418
Orphanet J Rare Dis. 2010 Nov 22;5:30
pubmed: 21092187
J Med Genet. 2017 Nov;54(11):781-786
pubmed: 28756410
Kidney Int. 2011 Mar;79(6):663-670
pubmed: 21160462
J Am Soc Nephrol. 2017 Oct;28(10):2931-2945
pubmed: 28720684
PLoS One. 2016 Apr 15;11(4):e0152812
pubmed: 27081853
Kidney Int. 2005 Feb;67(2):404-19
pubmed: 15673288
J Nephrol. 2016 Dec;29(6):791-797
pubmed: 26842625
Kidney Int. 2015 Nov;88(5):999-1012
pubmed: 25993321
Virchows Arch. 2006 Mar;448(3):337-43
pubmed: 16315019
Hum Mol Genet. 2015 Oct 15;24(20):5720-32
pubmed: 26206887
J Am Soc Nephrol. 2007 May;18(5):1547-57
pubmed: 17409312
Am J Pathol. 2013 Nov;183(5):1364-1374
pubmed: 24007883
PLoS One. 2016 Dec 16;11(12):e0168346
pubmed: 27992580
Ann Intern Med. 2009 May 5;150(9):604-12
pubmed: 19414839
Mol Genet Metab. 2019 May;127(1):86-94
pubmed: 30987917
J Microsc. 1985 May;138(Pt 2):127-42
pubmed: 4020857
Nephrol Dial Transplant. 2012 Mar;27(3):1042-9
pubmed: 21804088
Clin J Am Soc Nephrol. 2010 Dec;5(12):2220-8
pubmed: 20813854
Nephrol Dial Transplant. 2017 May 1;32(5):807-813
pubmed: 27190352