FROM SEGMENTAL GLOMERULOSCLEROSIS TO TOTAL NEPHRON DEGENERATION AND INTERSTITIAL FIBROSIS - A HISTOPATHOLOGICAL STUDY IN RAT MODELS AND HUMAN GLOMERULOPATHIES

Background. Focal segmental glomerulosclerosis (FSGS) is consistently associated with tubular degeneration and interstitial fibrosis, altoge ther, accounting for the progressive decline in renal function. The me chanisms which link glomerular injury to tubulointerstitial fibrosis a re controversial. The present study describes the step-by-step sequenc e of histopathological events, i.e, the evolution of the injury from t he initial lesion in the glomerulus to total nephron destruction. Meth ods. The investigation was performed in male hypertensive Fawn-hooded rats (6-, 9-, and 12-month-old) and 14-month-old Milan normotensive ra ts. The kidneys were fixed by in vivo perfusion and processed for stru ctural investigation. Autopsy materials from human cases of focal segm ental glomerulosclerosis and diabetic nephropathy were also examined. Results. FSGS as seen in rat models consists of collapsed and hyaliniz ed capillaries and mesangial portions which are included within a syne chia 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 inte rstitium rather than into Bowman's capsular space. Such filtration cre ates a paraglomerular space on the outer aspect of the parietal epithe lium. This space becomes separated from the interstitium by a dense la yer of sheet-like fibroblast processes. Associated with the progressio n to global sclerosis, this space spreads around the entire circumfere nce of a glomerulus; all 'sclerotic' tuft portions are eventually cont ained in this space. Starting from the urinary pole this process also involves the proximal tubule, initially by expanding the tubular basem ent membrane (TBM) and later, by separating the TBM from its epitheliu m, thus creating a peritubular space by misdirected filtrate spreading . Similar to the situation observed at the glomerulus this space becom es separated from the interstitium by a layer of fibroblast processes. The final degeneration of the nephron occurs via two pathways. Pathwa y I whereby development to global sclerosis is dominant or develops co ncurrently with tubular degeneration, eventually terminating in global and cylindrical remnants of extracellular matrix surrounded by abunda nt fibrous tissue. Pathway II where the degeneration of the tubule is ahead of damage progression in the glomerulus leading to atubular glom erular cysts. Conclusion. The present study suggests that severely inj ured glomeruli may continue to filter with the filtrate spreading alon g interstitial routes. Fluid added locally to the interstitium from su ch 'extraterritorial' glomerular capillaries probably is quite differe nt in quantity and composition compared to that from interstitial capi llaries. We propose that this kind of abnormal addition of fluid to th e interstitium is the essential mechanism accounting for interstitial progression of the disease. Similar histopathological phenomena in hum an kidneys with focal segmental glomerulosclerosis suggest that the pa thogenetic pathways defined in the rat models operate in human disease as well.