title: From segmental glomerulosclerosis to total nephron degeneration and interstitial fibrosis: a histopathological study in rat models and human glomerulopathies.
abstract: BACKGROUND
  Focal segmental glomerulosclerosis (FSGS) is consistently associated with tubular degeneration and interstitial fibrosis, altogether, accounting for the progressive decline in renal function. The mechanisms which link glomerular injury to tubulo-interstitial fibrosis are controversial. The present study describes the step-by-step sequence of histopathological events, i.e. the evolution of the injury from the initial lesion in the glomerulus to total nephron destruction.
  
  
  METHODS
  The investigation was performed in male hypertensive Fawn-hooded rats (6-, 9-, and 12-month-old) and 14-month-old Milan normotensive rats. The kidneys were fixed by in vivo perfusion and processed for structural investigation. Autopsy materials from human cases of focal segmental glomerulosclerosis and diabetic nephropathy were also examined.
  
  
  RESULTS
  FSGS as seen in rat models consists of collapsed and hyalinized capillaries and mesangial portions which are included within a synechia between the glomerular tuft and Bowman's capsule. In addition, a synechia generally contains glomerular capillaries which are perfused and continue to filter with the filtrate being delivered into the interstitium rather than into Bowman's capsular space. Such filtration creates a paraglomerular space on the outer aspect of the parietal epithelium. This space becomes separated from the interstitium by a dense layer of sheet-like fibroblast processes. Associated with the progression to global sclerosis, this space spreads around the entire circumference of a glomerulus; all 'sclerotic' tuft portions are eventually contained in this space. Starting from the urinary pole this process also involves the proximal tubule, initially by expanding the tubular basement membrane (TBM) and later, by separating the TBM from its epithelium, thus creating a peritubular space by misdirected filtrate spreading. Similar to the situation observed at the glomerulus this space becomes separated from the interstitium by a layer of fibroblast processes. The final degeneration of the nephron occurs via two pathways. Pathway I whereby development to global sclerosis is dominant or develops concurrently with tubular degeneration, eventually terminating in global and cylindrical remnants of extracellular matrix surrounded by abundant fibrous tissue. Pathway II where the degeneration of the tubule is ahead of damage progression in the glomerulus leading to atubular glomerular cysts.
  
  
  CONCLUSIONS
  The present study suggests that severely injured glomeruli may continue to filter with the filtrate spreading along interstitial routes. Fluid added locally to the interstitium from such 'extraterritorial' glomerular capillaries probably is quite different in quantity and composition compared to that from interstitial capillaries. We propose that this kind of abnormal addition of fluid to the interstitium is the essential mechanism accounting for interstitial progression of the disease. Similar histopathological phenomena in human kidneys with focal segmental glomerulosclerosis suggest that the pathogenetic pathways defined in the rat models operate in human disease as well.
authors.affiliation: Institut für Anatomie und Zellbiologie, Universität Heidelberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Kriz
authors.forename: H
authors.initials: H
authors.lastname: Hosser
authors.forename: B
authors.initials: B
authors.lastname: Hähnel
authors.forename: N
authors.initials: N
authors.lastname: Gretz
authors.forename: A P
authors.initials: AP
authors.lastname: Provoost
mesh_terms: D000818:Animals; D001344:Autopsy; D001706:Biopsy; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology*; D006801:Humans; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D009399:Nephrons / Q000473:pathology*; D051381:Rats