Pathomorphological Sequence of Nephron Loss in Diabetic Nephropathy.

Following our reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN)(25,34) we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulo-interstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerge from two defects: First, an increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium. Second, a defect of glomerular vessels consisting of an increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of the accumulated worn-out GBM-material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally healthy podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulo-tubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myo-fibroblasts resulting in interstitial fibrosis.