MECHANISM OF HYPOALBUMINEMIA Mechanism of hypoalbuminemia in rodents

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 compex (MHC)-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 carbon-14 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 (b2m) 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 as there was no comparable increase in the plasma elimination rate of Ficoll (hydrodynamic radius range 36-85 Å) or negatively charged Ficoll (50-80 Å). In contrast, hypoalbuminemic states in b2m and FcRn KO mice were associated with decreases in excretion of both albumin and albumin-derived fragments. This demonstrates that the mechanism of hypoalbuminemia consists of at least of two distinct forms: one specifically associated with the renal handling of albumin and the other mediated by systemic processes. MECHANISM OF HYPOALBUMINEMIA 4 Albumin a 66 kDa protein is a critical and major component in the circulation. It provides the dominant colloid osmotic properties of blood but also acts as a carrier to many different types of ligands (23). The steady state levels of albumin in the circulation are governed by its synthesis rate in the liver and its elimination rate from the plasma. The elimination rate of albumin in humans corresponds to approximately 0.233 g.kg-1 day-1 or around 16-17 g.day-1 (27), whereas in rats values in the range of 4.5-7.9 mg per 100g body wt per hour have been obtained (12, 16, 17). Endogenous albumin catabolism has been assumed to be responsible for plasma albumin elimination once corrected for the portion of albumin that is eliminated in the urine. The major sites of albumin catabolism have been demonstrated to be liver, kidney, muscle (29, …