How does podocyte damage result in tubular damage?

Abstract

Severe podocyte damage including detachment from the GBM leads to adhesion of the glomerular tuft to Bowman's capsule, thus to a local loss of the separation of the tuft from the interstitium. Perfused capillaries contained in the tuft adhesion deliver their filtrate no longer into Bowman's space but into the interstitium. In response, interstitial fibroblasts create a cellular cover around the focus of misdirected filtration, interpreted teleologically, aiming at preventing the entry of this fluid into the interstitium. This results in the formation of a crescent-shaped, fluid-filled paraglomerular space overarching the segmental glomerular lesion. Extension of this space over the entire glomerulus leads to global sclerosis; extension of this space via the urinary pole onto the outer aspect of the corresponding tubule leads to the degeneration of the tubule. Since, as we postulate, such misdirected filtration and filtrate spreading is the crucial mechanism of damage progression in 'classic' focal segmental glomerulosclerosis (FSGS), the most characteristic structural injury of FSGS is the merger of the tuft with the interstitium, represented by a tuft adhesion, later a synechia. Therefore, histopathologically, 'classic' FSGS is best defined by an adhesion/synechia of the tuft to Bowman's capsule.