Glomerular permselectivity factors are not responsible for the increase in fractional clearance of albumin in rat glomerulonephritis.

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 approximately -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.

Immuno-unreactive albumin excretion increases in streptozotocin diabetic rats.

We previously showed that albumin is fragmented (>90%) during renal passage to low-molecular-weight (<10 kd) peptides. The aim of the present study was to document the renal handling of albumin in experimental diabetes. Tritium-labeled albumin was infused into control and streptozotocin (STZ) diabetic rats during 7 days. Urinary radioactivity, assessed by size exclusion chromatography, revealed a major peak corresponding to low-molecular-weight, albumin-derived fragments and a minor peak corresponding to intact albumin or high-molecular-weight, albumin-derived protein. The fractional clearance of albumin, calculated from total radioactivity measurements, was at least 100-fold greater than the fractional clearance of albumin determined by radioimmunoassay (RIA) for control and diabetic rats. This result was mainly because low-molecular-weight, albumin-derived fragments were not detected by RIA. The fractional clearance of high-molecular-weight, albumin-derived protein was 2- to 10-fold greater than the fractional clearance determined by RIA. The immuno-unreactive high-molecular-weight, albumin-derived protein (called ghost albumin), characterized by size exclusion chromatography and high-performance liquid chromatography, was present in control and diabetic rat urine. Ghost albumin excretion rate was enhanced 11-fold after 8 weeks of STZ diabetes as compared with aged-matched controls. This study shows that renal modification resulting in low-molecular-weight and high-molecular-weight components of albumin is a major contributor to the renal handling of albumin. The results indicate that excretion of modified albumin is increased in STZ rats as compared with albumin detected by conventional RIA. Long-term studies are necessary to evaluate the potential of ghost albumin as a new marker for the assessment of urinary albumin in diabetes.