Mechanism of hypoalbuminemia in rodents

1 Department of Biochemistry and Molecular Biology, Monash University, and 2 Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia Submitted 9 August 2004 ; accepted in final form 10 November 2004 Normal albumin loss from the plasma is thought to be minimized by a number of mechanisms, including charge repulsion with the capillary wall and an intracellular rescue pathway involving the major histocompatibility complex-related Fc receptor (FcRn)-mediated mechanism. This study investigates how these factors may influence the mechanism of hypoalbuminemia. Hypoalbuminemia in rats was induced by treatment with puromycin aminonucleoside (PA). To test the effects of PA on capillary wall permeability, plasma elimination rates were determined for tritium-labeled tracers of different-sized Ficolls, negatively charged Ficolls, and 14 C-labeled tracer of albumin in control and PA-treated Sprague-Dawley rats. Urinary excretion and tissue uptake were also measured. Hypoalbuminemia was also examined in two strains of FcRn-deficient mice: 2 -microglobulin ( 2 M) knockout (KO) mice and FcRn -chain KO mice. The excretion rates of albumin and albumin-derived fragments were measured. PA-induced hypoalbuminemia was associated with a 2.5-fold increase in the plasma elimination rate of albumin. This increase could be completely accounted for by the increase in urinary albumin excretion. Changes in the permeability of the capillary wall were not apparent, inasmuch as there was no comparable increase in the plasma elimination rate of 36- to 85-Å Ficoll or negatively charged 50- to 80-Å Ficoll. In contrast, hypoalbuminemic states in 2 M and FcRn KO mice were associated with decreases in excretion of albumin and albumin-derived fragments. This demonstrates that the mechanism of hypoalbuminemia consists of at least two distinct forms: one specifically associated with the renal handling of albumin and the other mediated by systemic processes. albumin; capillary wall permeability; glomerular permeability; macromolecular transport probes; plasma elimination rate; 2 -microglobulin; Fc receptor Address for reprint requests and other correspondence: W. D. Comper, Dept. of Biochemistry and Molecular Biology, Monash Univ., Wellington Rd., Clayton, Victoria 3800, Australia (E-mail: wayne.comper{at}med.monash.edu.au )