title: Glomerular Aging and Focal Global Glomerulosclerosis: A Podometric Perspective.
abstract: Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasing renal function, and exponentially increasing ESRD prevalence. In model systems, podocyte depletion causes glomerulosclerosis, suggesting age-associated glomerulosclerosis could be caused by a similar mechanism. We measured podocyte number, size, density, and glomerular volume in 89 normal kidney samples from living and deceased kidney donors and normal poles of nephrectomies. Podocyte nuclear density decreased with age due to a combination of decreased podocyte number per glomerulus and increased glomerular volume. Compensatory podocyte cell hypertrophy prevented a change in the proportion of tuft volume occupied by podocytes. Young kidneys had high podocyte reserve (podocyte density >300 per 10(6) µm(3)), but by 70-80 years of age, average podocyte nuclear density decreased to, <100 per 10(6) µm(3), with corresponding podocyte hypertrophy. In older age podocyte detachment rate (urine podocin mRNA-to-creatinine ratio) was higher than at younger ages and podocytes were stressed (increased urine podocin-to-nephrin mRNA ratio). Moreover, in older kidneys, proteinaceous material accumulated in the Bowman space of glomeruli with low podocyte density. In a subset of these glomeruli, mass podocyte detachment events occurred in association with podocytes becoming binucleate (mitotic podocyte catastrophe) and subsequent wrinkling of glomerular capillaries, tuft collapse, and periglomerular fibrosis. In kidneys of young patients with underlying glomerular diseases similar pathologic events were identified in association with focal global glomerulosclerosis. Podocyte density reduction with age may therefore directly lead to focal global glomerulosclerosis, and all progressive glomerular diseases can be considered superimposed accelerators of this underlying process.
authors.affiliation: Departments of Pathology.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Hodgin
authors.affiliation: Internal Medicine, and.
authors.forename: Markus
authors.initials: M
authors.lastname: Bitzer
authors.affiliation: Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
authors.forename: Larysa
authors.initials: L
authors.lastname: Wickman
authors.affiliation: Internal Medicine, and.
authors.forename: Farsad
authors.initials: F
authors.lastname: Afshinnia
authors.affiliation: Internal Medicine, and.
authors.forename: Su Q
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: Departments of Pathology, Internal Medicine, and.
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Connor
authors.affiliation: Internal Medicine, and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
authors.forename: Chrysta
authors.initials: C
authors.lastname: Meadowbrooke
authors.affiliation: Internal Medicine, and.
authors.forename: Mahboob
authors.initials: M
authors.lastname: Chowdhury
authors.affiliation: Internal Medicine, and.
authors.forename: Masao
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Internal Medicine, and.
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Wiggins
authors.affiliation: Internal Medicine, and rwiggins@umich.edu.
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiggins
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D002452:Cell Count; D002467:Cell Nucleus / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology*; D006801:Humans; D006984:Hypertrophy / Q000473:pathology; D008875:Middle Aged; D009929:Organ Size; D050199:Podocytes / Q000473:pathology*; D055815:Young Adult
keywords: aging; glomerulosclerosis; podocyte