Abstract: PUB316
Clinical Implications of Appropriate Molecular and Glomerular Models
Session Information
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Author
- Luke, Robert L., Maine Medical Center, Portland, Maine, United States
Background
Proteinuria is associated with deposition of immunoglobulin and complement because these proteins initiate damage to the glomerular capillary wall, particularly basement membrane, long considered the definitive layer because dextran accumulated before, but not after the lamina densa. Only a small percent of animals developed proteinuria after antigen/adjuvant challenge, however, and dextran had been unrealistically represented as impervious rigid spheres. In this study partial draining malleable dextran defines inherent glomerular dysfunction in two diseases that are devoid of immunoglobulin or complement, minimal change disease and diabetic nephropathy.
Methods
A flow dependent fiber formulation separates podocyte from basement membrane and a cylindrical glomerular tuft separates filtering basement membrane bordered by capillaries from non-filtering basement membrane bordered by mesangium. These models are introduced with the permeability of a1acidglycoprotein, albumin, transferrin, IgG, and a2macroglobulin in newly reported patients with primary glomerular disease and completed using hydrostatic pressures, vascular dimensions, and permeability of dextran, albumin, and IgG in similar patients obtained from the literature. Linear regression yields fiber density from slope and trans-epithelial shunt from intercept; glomerular volume is concomitantly apportioned between vascular and mesangial regions.
Results
Fiber density was similar in controls and patients; urinary protein was proportional to trans-epithelial shunts and mesangial volume. Dextran does not accumulate beneath slit pore because flow reduces its effective size. Most albumin is blocked by lamina densa, but significant amounts leak, is blocked by slit diaphragm, and must return locally to circulation to explain low proximal tubular albumin. Lower fiber densities revealed by proteins and large dextran are compatible with retrieval route that begins in lamina rara externa and continues back across lamina densa into mesangial channels that are indistinct in minimal change disease, but prominent in diabetic nephropathy, a flow path driven by periodic reversed hydraulic pressure.
Conclusion
Realistic macromolecular models trace a loop through glomerulus that is critical to protein homeostasis. Tubular reabsorption is overwhelmed if podocyte seal is compromised in minimal change disease or if mesangial recovery is compromised in diabetic nephropathy.