Retention of albumin in the circulation is governed by saturable renal cell-mediated processes

Objective: To examine the role of renal processing in the turnover of circulating albumin in the model of reversible overload proteinuria. Specifically, this study determines whether proteinuria due to hyperalbuminemia may be attributed to saturation of renal cell processing of albumin or alterations in diffusive/convective transport of albumin across the glomerular capillary wall. Methods: Overload proteinuria was induced in male Wistar rats by daily intraperitoneal injections of 1.5 g bovine serum albumin (BSA; endotoxin free) for 3 days. Plasma concentration and urinary excretion of total protein and rat serum albumin ( RSA) were determined by the biuret assay and radioimmunoassay, respectively. Glomerular size selectivity was assessed by examining the fractional clearance (FC) of neutral [H-3]Ficoll using a short-term, steady-state approach. Cellular processing was examined by size exclusion chromatography analysis of urinary [C-14]albumin and [C-14]transferrin structural integrity. Results: Total protein excretion (n = 4-15) increased 7-fold in BSA-treated rats (58 +/- 26 mg/24 h at baseline vs. 417 +/- 259 mg/24 h at day 3), while intact RSA excretion (n = 4-6) increased 200-fold (0.27 +/- 0.15 mg/24 h vs. 53 +/- 26 mg/24 h) despite a significant decrease in its plasma concentration. Total protein and albumin excretion returned to basal levels by day 7 (82 +/- 16 mg/24 h and 0.93 +/- 0.42 mg/24 h, respectively). FC of [H-3]Ficoll of equivalent size to albumin did not change in BSA-treated rats as compared to vehicle controls. Tubular lysosomal processing of proteins was altered at peak proteinuria, as determined by changes in the structural integrity of urinary [C-14]albumin, as well as [C-14]transferrin, but returned to normal by day 7. Conclusions: This study demonstrates the lack of proportionality between changes in plasma concentration and urinary excretion of albumin, as well as the lack of change in the glomerular size selectivity to albumin. The profound but reversible changes in the amount and integrity of excreted protein suggest that cell-mediated processes are saturated by albumin concentrations, leading to the development of proteinuria in this model.