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TBM thickening is an early abnormality in type 1 diabetes that parallels GBM thickening and can be detected in normoalbuminuric patients using stereological methods (4). TBM width correlates with GBM width and Vv(Mes/glom) and more specifically with Vv(MM/glom), consistent with the idea that the TBM changes are part of a broad accumulation of basement membrane ECM material in the diabetic kidney (8) and arguing against the hypothesis that glomerular hemodynamic abnormalities are causally related to the development of the early lesions of diabetic glomerulopathy (60). This accumulation of ECM material can be owing to increased matrix production, decreased matrix removal (suggested by increased expression of Plasminogen active inhibitor-1 [PAI-1] in glomeruli of diabetic patients [61] or both). Both nephrocenteric and diffuse tubular atrophy can be seen in DN. Nephrocentric tubular atrophy usually precedes appearance of diffuse tubular atrophy. As mentioned above, nephrocentric tubular atrophy is initiated by TBCA, mostly involves proximal tubules and manifests as focal profiles of atrophic tubules around segmentally or globally sclerosed glomeruli (Fig. 1). Interstitial expansion is accentuated around these atrophic tubules and is often accompanied by lymphocytic infiltration. Our observations, based on serial sectioning studies of atrophic tubules attached to glomeruli with glomerulotubular junction abnormalities, indicates that the atrophic segment of these tubules is covered by flat cells, overlying a basement membrane that is detached from an outer TBM. The space between these two layers of TBM is filled with an amorphous material, which proximally is continuous with the space between the layers of reduplicated Bowman's capsule associated with TBCA (33). Transition of this atrophic segment to a normal-appearing tubule is usually abrupt and happens at the point where the two layers of reduplicated TBM fuse together. We hypothesize that para-glomerular filtration originating from TBCA infiltrates into the Bowman's capsule and TBM and dissects them into two layers or results in the production of a second layer. This process, if it progresses distally, could lead to progressive nephrocentric tubular atrophy and/or detachment of the atrophic tubule from glomerulotubular junction and development of atubular glomeruli, and thus contributes to GFR loss in proteinuric patients.

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