Glomerular Permselectivity Factors Are Not Responsible for the Increase in Fractional Clearance of Albumin in Rat Glomerulonephritis

Abstract

The increased fractional clearance of albumin in nephrotic states has long been attributed to glomerular permselectivity dysfunction. Using radiolabeled rat serum albumin, transferrin, IgG, and polydisperse Ficoll, this study investigated the changes in their in vivo fractional clearance in puromycin aminonucleoside nephrosis and anti-glomerular basement membrane glomerulonephritis. In control rats the lack of charge selectivity was confirmed by the demonstration that carboxymethyl Ficoll (valence ϳ؊39) had the same fractional clearance as uncharged Ficoll. Both diseases exhibited similar effects on fractional clearance measurements suggesting an underlying common mechanism. In disease, there was good agreement between the fractional clearance of proteins determined by radioactivity as compared to those determined by radioimmunoassay. A small increase in the fractional clearance for IgG was evident in disease as compared to controls, which mirrored the change in the equivalent size Ficoll, suggesting that the increase is because of the development of a small proportion of large pores in the glomerular capillary wall. There was no increase, however, in the fractional clearance of Ficoll of equivalent size to albumin in either disease, yet the fractional clearance of the albumin increased by 12 to 14 times as determined by radioactivity and 4500 to 6600 times as determined by radioimmunoassay. This study demonstrates that glomerulonephritis is not a disease associated with changes in glomerular permeability to albumin but is because of alterations in albumin processing by cells distal to the glomerular basement membrane. It is also apparent that approaches to glomerular pathology and proteinuria as risk factors in renal disease must be reassessed. (Am J Pathol 2001, 159:1159 -1170)

Cell Biology of the Glomerular Podocyte

“…Low ionic strength increased the size selectivity, whereas it reduced the charge density, indicating that size and charge selectivity are influenced by ionic strength in an opposite manner (439). In contrast to the data reported in these studies, Greive et al (145) did not find a different fractional clearance of negatively charged carboxymethyl Ficoll versus uncharged Ficoll in rats, indicating a complete lack of charge selectivity of the glomerular filtration barrier. In agreement with the latter study, it has been shown that the sieving coefficients of Ficoll sulfate of the isolated GBM were not different from those of Ficoll at physiological ionic strength, although the values for Ficoll sulfate were depressed at low ionic strength (47).…”

Cultured Podocytes Establish a Size-Selective Barrier Regulated by Specific Signaling Pathways and Demonstrate Synchronized Barrier Assembly in a Calcium Switch Model of Junction Formation

“…However, attempts to define which component(s) of the glomerular capillary wall contributes to this selectivity remain inconclusive. Animal studies have produced conflicting results as a result of the inherent inability to separate the contribution of the endothelium, GBM, podocytes, and the tubular epithelium (32,33). Recently, Deen and colleagues (34,35) improved on this approach by stripping cells from the GBM (endothelial and epithelial) and measuring the hydraulic permeability and sieving coefficient of that layer alone.…”

Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients

“…The concept of abnormal charge permeability as a cause of albuminuria has been recently challenged, at least in severe proteinuric conditions (31). Furthermore, the significance of alterations in differential clearance of neutral and anionicdextrans as a marker of glomerular charge permselectivity has also been disputed (32).…”