Nephrology Dialysis Transplantation, Vol 13, Issue 11 2781-2798, Copyright © 1998 by Oxford University Press
W Kriz, H Hosser, B Hahnel, N Gretz and A Provoost
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 tubulointerstitial
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 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.
Conclusion: 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. Key
words: Chronic renal disease; glomerulosclerosis; interstitial
fibrosis; misdirected filtration; renal histopathology
ORIGINAL ARTICLES
From segmental glomerulosclerosis to total nephron degeneration and interstitial fibrosis: a histopathological study in rat models and human glomerulopathies
Institut fur Anatomie und Zellbiologie, Universitat Heidelberg, Im Neuenheimer Feld 307, D-69120 Heidelberg, Germany; Zentrum fur medizinische Forschung, Universitatsklinikum Mannheim der Universitat Heidelberg, Mannheim, Germany; Department of Pediatric Surgery, Laboratory for Surgery, Erasmus University, Rotterdam, The Netherlands; Corresponding author
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