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Mechanisms of Proteinuria in Kidney

Dr W.D. Comper

Our work on kidney ultrafiltration over the last few years has demonstrated that albumin is processed by being filtered on the basis of its size and that the relatively large amount of albumin that is transported across the filter is returned to the blood supply, undegraded, by a rapid and specific high capacity pathway associated with intracellular trafficking in proximal tubular cells.

The high capacity of this pathway makes it the likely focus for the etiology of albuminuria in most renal diseases. This means that discussion of the molecular mechanisms of albuminuria must recognise that glomerular negative charge and the status of glomerular heparan sulfate, and alterations in the size selectivity of the glomerular capillary wall, are not the major parameters governing the etiology of albuminuria. This represents a totally new understanding of the renal processing of albumin and now presents exciting new opportunities to explore new and old aspects of glomerular ultrafiltration, particularly in disease.

The general aim of this project is to continue to develop our understanding of this new mechanism and to carefully reanalyse the currently accepted mechanism of albuminuria. This will include the development of more sensitive techniques with which to measure the transtubular pathway in vivo and to study the influence of varying hemodynamic conditions on the magnitude of the pathway. We intend to identify the peptide in albumin that binds to the albumin receptor that is associated with the rapid transtubular pathway and use it diagnostically. We will further investigate the heteroporous model and test the hypothesis that it is an artifact associated with the use of dextrans that are taken up by cells during renal passage. We will then examine a rat model of human minimal change disease to demonstrate that the albuminuria is due to inhibition of the transtubular pathway and that glomerular size selectivity as measured with a panel of high molecular proteins does not significantly change. The specific projects are the following:

Project areas (Dr W. D. Comper)

  1. To develop simpler methods to examine the postglomerular rapid transtubular pathway.
  2. To determine the active peptide in the primary structure of albumin that binds to the albumin binding receptor in the proximal tubule cell.
  3. To test the heteroporosity model of the glomerular capillary wall in vivo (a model that is commonly used to explain glomerular albuminuria).
  4. To test the inhibition of tubular uptake and the lack of glomerular proteinuria in rats with experimental albuminuria