Histopathology of Diabetic Nephropathy
Section snippets
Morphometric Analysis and Structural-Functional Relationships
The relationships between structural abnormalities and kidney function are best defined using light and electron microscopic morphometric analysis. The critical lesion in T1DM is mesangial expansion, morphometrically termed mesangial fractional volume (Vv [Mes/glom]) (the fraction of the cross-sectional area of the glomerular tuft made up by mesangium); this is the electron microscopically estimated structural parameter that best correlates with all functional parameters in T1DM.9, 17 Indeed, a
Role of Podocytes in DN
The glomerular filtration barrier is composed of fenestrated endothelium, GBM, podocyte foot processes, and slit diaphragms. Compromise of one or more elements of this filtration complex leads to proteinuria.41 Podocyte detachment from GBM, from apoptosis, necrosis, or loss of adhesive interaction may play a central role in the pathogenesis of several proteinuric diseases; in fact proteinuria in glomerular disorders ultimately is associated with foot process effacement, flattening, and
Risk Factors for DN
Although it is clear that genetic factors modulate DN risk and that some patients escape this complication despite decades of poor glycemic control, it also is clear that hyperglycemia is a necessary precondition for DN lesions and renal functional disturbances to develop. Important support for this concept derives from research kidney biopsy studies in identical twins discordant for T1DM. The kidneys of all of the nondiabetic members of these twin pairs were normal structurally, and in each
Reversibility of DN Lesions
Pancreas transplantation offers the opportunity to test the effects of long-term normoglycemia to prevent, halt, or reverse DN lesions. Pancreas transplantation, performed at the time of renal transplant or within a few years after kidney transplant, prevents or slows the development of early diabetic glomerulopathy lesions in the renal allograft.71, 72, 73
The possibility of diabetic renal lesion reversal was addressed by long-term studies of the native kidneys of T1DM recipients of pancreas
Acknowledgments
The authors thank Patricia L. Erickson for assistance in manuscript preparation.
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The natural history studies discussed here also were supported by the Juvenile Diabetes Research Foundation. Many of the other studies reported here were supported by National Institutes of Health grant awards (PO1-DK13083, RO1-DK054638, and RO1-DK51975).
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Dr. Fioretto was a Juvenile Diabetes Research Foundation Fellow and Career Development Award recipient while performing some of the research reviewed herein.