We propose to use novel methods to characterize the evolution of early diabetic glomerular injury (DGI) in 70 Pima Indians with NIDDM and microalbuminuria. They will be entered into a randomized, controlled trial of losartan vs placebo lasting 60-84 months. GFR, its hemodynamic determinants and albuminuria, will be monitored annually. More elaborate physiological studies, an analysis of glomeruli obtained by biopsy and mathematical modelling of filtration properties of glomeruli will be performed after 60 months. We wish to test the following four hypotheses. The first hypothesis is that evolution from micro- to macroalbuminuria is a consequence of impairment of a size-selective filtration barrier. We propose to compute the effective radii of functional pores from sieving coefficients of polydisperse ficoll, a rigid and spherical polymer of sucrose that replicates the molecular configuration of proteins. Confocal immunomicroscopy of podocytes will seek a structural basis for protein-permeable pores. The second hypothesis is that podocyte injury and deformation lowers glomerular hydraulic permeability (k) and is the principal determinant of a decline in GFR from elevated to normal levels as DGI becomes overt (macroalbuminuria). Morphometric analysis of glomeruli will examine podocyte density and foot process, slit diaphragm, GBM, and endothelial fenestral dimensions. A novel hydrodynamic model of viscous flow will be used to compute k from these quantities, and single nephron Kf from k and filtration surface area(s). The third hypothesis is that podocyte injury is a consequence of specific changes in epithelial cell-cell and cell-substrate interactions. We will accordingly use confocal immunomicroscopy to examine for alterations in the distribution of adhesion and tight junction molecules in the podocyte cell membrane and slit diaphragm. The fourth hypothesis is that blockade of the renin-angiotensin system will confer renoprotection by conserving podocyte function and structure, as judged by less impairment of barrier function and computed k in losartan than placebo-treated individuals. Because GFR remains constant for up to 5 years after detection of microalbuminuria, it is our hope that structural determinants of computed k and SNKf will provide alternative outcome measures for demonstrating effective renoprotection by angiotensin blockade early in the course of DGI.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Meyers, Catherine M
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Lemley, Kevin V (2008) Diabetes and chronic kidney disease: lessons from the Pima Indians. Pediatr Nephrol 23:1933-40
Lemley, Kevin V; Boothroyd, Derek B; Blouch, Kristina L et al. (2005) Modeling GFR trajectories in diabetic nephropathy. Am J Physiol Renal Physiol 289:F863-70
Vogelmann, Stefanie U; Nelson, W James; Myers, Bryan D et al. (2003) Urinary excretion of viable podocytes in health and renal disease. Am J Physiol Renal Physiol 285:F40-8
Lemley, Kevin V (2003) A basis for accelerated progression of diabetic nephropathy in Pima Indians. Kidney Int Suppl :S38-42
Lemley, K V; Abdullah, I; Myers, B D et al. (2000) Evolution of incipient nephropathy in type 2 diabetes mellitus. Kidney Int 58:1228-37
Andersen, S; Blouch, K; Bialek, J et al. (2000) Glomerular permselectivity in early stages of overt diabetic nephropathy. Kidney Int 58:2129-37
Lemley, K V; Blouch, K; Abdullah, I et al. (2000) Glomerular permselectivity at the onset of nephropathy in type 2 diabetes mellitus. J Am Soc Nephrol 11:2095-105