title: Podocyte Depletion in Thin GBM and Alport Syndrome.
abstract: The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 collagen IV chains resulting in abnormal glomerular basement membrane (GBM) structure/function. We previously reported that podocyte detachment rate measured in urine is increased in AS, suggesting that podocyte depletion could play a role in causing progressive loss of kidney function. To test this hypothesis podometric parameters were measured in 26 kidney biopsies from 21 patients aged 2-17 years with a clinic-pathologic diagnosis including both classic Alport Syndrome with thin and thick GBM segments and lamellated lamina densa [n = 15] and Thin GBM cases [n = 6]. Protocol biopsies from deceased donor kidneys were used as age-matched controls. Podocyte depletion was present in AS biopsies prior to detectable histologic abnormalities. No abnormality was detected by light microscopy at <30% podocyte depletion, minor pathologic changes (mesangial expansion and adhesions to Bowman's capsule) were present at 30-50% podocyte depletion, and FSGS was progressively present above 50% podocyte depletion. eGFR did not change measurably until >70% podocyte depletion. Low level proteinuria was an early event at about 25% podocyte depletion and increased in proportion to podocyte depletion. These quantitative data parallel those from model systems where podocyte depletion is the causative event. This result supports a hypothesis that in AS podocyte adherence to the GBM is defective resulting in accelerated podocyte detachment causing progressive podocyte depletion leading to FSGS-like pathologic changes and eventual End Stage Kidney Disease. Early intervention to reduce podocyte depletion is projected to prolong kidney survival in AS.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Larysa
authors.initials: L
authors.lastname: Wickman
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Hodgin
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Su Q
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Farsad
authors.initials: F
authors.lastname: Afshinnia
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Kershaw
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiggins
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D050533:Glomerular Basement Membrane / Q000473:pathology*; D006801:Humans; D009394:Nephritis, Hereditary / Q000473:pathology*; D050199:Podocytes / Q000473:pathology*