Evolution Of The Structural Changes Of Diabetic Nephropathy
The sequence of structural changes in DN can be considered along either chronological or functional time scales. The functional alterations are expressed as the evolution of events related to clinical findings such as progression from normoalbuminuria to
From: Contemporary Diabetes: The Diabetic Kidney Edited by: P. Cortes and C. E. Mogensen © Humana Press Inc., Totowa, NJ
microalbuminuria and to proteinuria or from hyperfiltration to progressive glomerular filtration rate (GFR) decline and end-stage renal disease (ESRD). The functional sequence is not always progressive and studies show that patients can regress from microalbuminuria to normoalbuminuria (1). Thus, the consideration of structural changes could be more meaningful if evaluated along with functional alterations. The first structural change that can be quantified by stereological methods is thickening of glomerular basement membrane (GBM) (2). Tubular basement membrane (TBM) thickening develops in parallel to GBM thickening (see below) (3,4). Exudative lesions of DN include arteriolar hyalinosis, glomerular capillary subendothelial hyaline accumulation (hyaline caps), and capsular drops (hyaline material between the parietal epithelium and Bowman's capsule). Arteriolar hyalinosis can be seen within 3-5 yr after onset of diabetes or following transplantation of a normal kidney into the diabetic patient (5). Experimental and human studies suggest these lesions may trigger inflammatory cascades through complement fixation (6). Increases in the fractional volume of mesangium per glomerulus [Vv(Mes/glom)] can be documented 4-5 yr after the onset of type 1 diabetes (2). Increased fractional volume of mesangial matrix per glomerulus [Vv(MM/glom)] precedes increased Vv(Mes/glom) and represents the main component of glomerular mesangial expansion in diabetic glomerulopathy (7). The relative contribution of cell number vs cell size to the expansion of the cellular component of the mesangium is currently unknown. Late finding of increased Vv(Mes/glom) compared with GBM thickening can be the result of more interglomerular variability of this parameter among normal subjects (8) or nonlinearity of the relationship of mesangial expansion to diabetes duration, with more rapid development after 15 yr of diabetes (9). The fractional volume of interstitium per renal cortex [Vv(Int/cortex)] initially decreases
(10). This, perhaps, is owing to hypertrophy of tubules, which make up to 85% or more of the renal cortex and are the main contributor to kidney enlargement in early diabetes, reducing the relative volume of interstitium to the volume of the renal cortex. Initial expansion of cortical interstitium is primarily owing to an increase in its cellular component
(11), whereas increased fractional volume of interstitium occupied by extracellular matrix (ECM) fibrillar collagen is measurable only in later stages when GFR has already declined (11). Diffuse diabetic glomerulosclerosis is defined as widespread mesangial expansion within and among glomeruli, whereas nodular glomerulosclerosis (Kimmelstiel-Wilson [K-W] nodules) represents marked segmental expansion of mesangium appearing as round fibrillar nodules, with palisading of mesangial nuclei around the periphery often surrounded by compressed appearing capillary loops. Glomerular capillary wall detachment from mesangial anchoring points (mesangiolysis), leading to microaneurysm formation (12,13) (see also glomerulotubular junction abnormalities) has been proposed as underlying mechanism of these lesions. Generally, K-W nodules are primarily restricted to proteinuric patients with established diabetic glomerulopathy. However, occasional findings of nodular lesions in some patients with little or no diffuse mesangial expansion or albuminuria suggests that these two forms of diabetic mesangial expansion may, at least in part, have different pathogenesis.
The accumulation of different ECM components of mesangium, GBM, and TBM in DN does not occur proportionally. For instance, densities of a3 and a4 chains of type-IV collagen increase in the GBM, whereas those of a1 and a2 chains decrease in the mesangium and the subendothelial space of patients with DN (14,15). Quantitative immunogold electron microscopic studies have shown that densities of types-IV (15) and -VI collagen (16) were decreased in the mesangial matrix of patients with advanced mesangial expansion. However, given the marked increased amount of Vv(MM/glom), the absolute amount of these components per glomerulus was increased. Progression of DN toward renal insufficiency is accompanied by progressive global glomerulosclerosis. Expression of scar collagen can be found in globally sclerosed glomeruli or in advanced nodular glomerulosclerosis (14,17). Globally sclerosed glomeruli are more often than by chance oriented in the plane vertical to the renal capsule in diabetic patients, suggesting a vaso-occlusive pathophysiology (18). Moreover, more severe arteriolar hyali-nosis is associated with increased number of globally sclerosed glomeruli (19). Mesangial expansion and global glomerular sclerosis are correlated in type 1 diabetic patients (19,20), whereas heterogeneity of renal lesions in type 2 diabetes may disturb this correlation.
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