Structuralfunctional Relationships In Diabetic Nephropathy

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Mesangial expansion is the major hallmark of nephropathy in type 1 diabetic patients (42) and is, more or less, related to all other renal structural or functional alterations of the disease. Increased Vv(Mes/glom) closely correlates with a decrease in peripheral GBM filtration surface density [Sv(PGBM/glom)]. On the other hand, total filtration surface per glomerulus [S(PGBM/glom)] is highly correlated with GFR across the spectrum from hyperfiltration to renal insufficiency in type 1 diabetes (42-45). Vv(Mes/glom) is also related to the AER (42,46) and high blood pressure (20,42). Similarly, but less strongly than for Vv(Mes/glom), GBM width is directly correlated with blood pressure and AER and inversely correlated with GFR (42,46). In fact, the rate of development of mesangial expansion and GBM thickening varies among patients (42,46). For example, relatively marked GBM thickening can be seen without remarkable mesangial expansion and vice versa, preventing a precise correlation between these parameters (42,47). Considering both Vv(Mes/glom) and GBM width as predictor variables, and using multiple regression analyses these structural variables explain 59% of the variability in AER in type 1 diabetic patients, with AER ranging from normo-albuminuria to proteinuria (46).

Percent global glomerulosclerosis (19) and interstitial expansion (48) along with glomerular structural changes are correlated with deterioration of renal function in type 1 diabetic patients with a wide spectrum of AER and GFR. However, sequential renal biopsies of normoalbuminuric and microalbuminuric patients showed that the increase in AER correlated with the increase in Vv(Mes/glom), whereas the Vv(Int/cortex) did not change during the 5-yr interval of the study (49). This suggests that the correlation of Vv(Int/cortex) with renal function may be in great part driven by the more advanced cases. In general, it appears that during most of the natural history of DN glomerular structural parameters are more important determinants of renal dysfunction, whereas Vv(Int/cortex) is a stronger determinant of the rate of progression from moderate to severe renal insufficiency (50).

The average GBM width and Vv(Mes/glom) is increased in normoalbuminuric patients with long-standing (20 yr) type 1 diabetes (46,51). However, individual values of these parameter within this group vary from the normal range to increased values that overlap those of patients with microalbuminuria and proteinuria (46,51). Although GBM width and Vv(Mes/glom) in patients with microalbuminuria are rarely in the normal range, overlap with values observed in normoalbuminuric (and protein-uric) patients exists (46,51). Studies of identical twin pairs discordant for type 1 diabetes showed, in every pair studied, that the diabetic twin had higher values for GBM and TBM width and Vv(Mes/glom) than the nondiabetic sibling, even if values for GBM width and Vv(Mes/glom) of the diabetic twin were within the normal range (3).These studies suggested that the metabolic abnormalities of diabetes are necessary for the development of glomerular abnormalities and that all type 1 diabetic patients develop diabetic glomerulopathy changes, albeit, some so slowly that their structural measures remain in the normal range despite many years of diabetes. Unpublished analyses of data from these same studies showed that glomerular structural parameters of the nondiabetic twins did not predict the rate of development of diabetic glomeru-lopathy lesions in the diabetic twins, indicating that genetic or environmental determinants of variability in these structural parameters before the onset of diabetes do not represent risk factors for DN.

Volume and number of glomeruli are shown to be related to nephropathy risk. Mean glomerular volumes were higher in type 1 diabetic patients developing DN after 25 yr of diabetes compared with a group that developed nephropathy after only 15 yr (52). This study suggested that glomerular size or the capacity for glomerular expansion may determine the rate of progressive deterioration of renal function in patients who develop DN. The number of glomeruli per kidney varies widely among normal individuals (53). The number of glomeruli were reportedly not different among type 1 and 2 diabetic patients with proteinuria but without advanced renal insufficiency and nondiabetic patients (54). This study showed that a subgroup of type 1 diabetic patients with severe renal dysfunction had less glomeruli compared with patients with mild or no glomerulopathy. This could be owing either to resorption of sclerotic glomeruli (54) or to greater susceptibility to glomerulopathy in patients with fewer glomeruli. However, the proteinuric type 1 diabetic patients in this study without advanced renal insufficiency had glomerular number no different from normal. This is concordant with the former hypothesis. Moreover, the rate of development of diabetic glomerulopathy lesions in type 1 diabetic patients with a single transplanted kidney is not different from native (two) kidneys of type 1 diabetic patients with duration of diabetes matched with the time after transplantation in the one kidney patients (Chang S, personal communication). These studies imply that reduced number of glomeruli does not accelerate the early lesions of diabetic glomerulopathy. Reduced number of glomeruli, however, could speed the rate of progression to ESRD in established DN.

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