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PubMed1987

Immunohistochemical localization of albumin and in situ hybridization of albumin mRNA.

Hepatocytes actively involved in albumin synthesis were identified by immunohistochemical method. In sections of perioidate-lysine-2 per cent (w/v) paraformaldehyde fixed normal rat liver, albumin was detected in all hepatocytes. At the ultrastructural level, albumin was localized in the rough endoplasmic reticulum and in Golgi complexes located near the nucleus in only a small subpopulation of hepatocytes, while all other hepatocytes contained albumin only in Golgi complexes located near the bile canaliculi. Stimulation of albumin synthesis by puromycin aminonucleoside-induced nephrosis resulted in an altered intracellular distribution of albumin at the light microscopic level. When examined at the ultrastructural level, albumin was localized in the rough endoplasmic reticulum as well as in Golgi complexes located near the nucleus in nearly all these hepatocytes. Hepatocytes with the potential to synthesize albumin were identified by in situ hybridization of albumin mRNA. In sections of 0.1 per cent (v/v) glutaraldehyde perfusion fixed normal rat liver, albumin mRNA was detected in the cytoplasm of only a few hepatocytes scattered throughout the lobule. Following stimulation of albumin synthesis by the induction of nephrosis, albumin mRNA was detected in the cytoplasm of the hepatocytes. The source of albumin in those hepatocytes which lacked albumin mRNA was identified in analbuminemic rats injected with rat albumin. At 6 h post injection, the light microscopic distribution of albumin in the liver of these animals was virtually indistinguishable from that in normal rat liver. At the ultrastructural level, injected albumin was localized in lysosomes and in Golgi complexes located near the bile canaliculi.

Animals↗
PubMed2002

Exogenous albumin peptides influence the processing of albumin during renal passage.

UNLABELLED: Exogenous albumin peptides influence the processing of albumin during renal passage. BACKGROUND/AIMS: This study investigates the hypothesis that there will be peptide regions in albumin that will effectively compete for the receptors associated with the renal processing of albumin. METHODS: We employ albumin peptides prepared from albumin by trypsin digestion. The presentation of the exogenous peptides along with intact [(3)H]albumin to the kidney was made by intravenous injection into rats. The excretion rate and integrity of urinary [(3)H]albumin was measured. Similar experiments were performed with the use of gelatin peptides produced by trypsin digestion as controls. The formation of [(3)H]albumin derived fragments by extrarenal sources was also examined in rats with nonfiltering kidneys. RESULTS: In the presence of exogenous albumin-derived peptides there was a significant increase in the proportion of larger [(3)H]albumin fragments in the urine. This is a reversible effect. There was no significant change when gelatin peptides were used. The albumin peptides also increase the fractional clearance of [(3)H]albumin. There were no [(3)H]albumin-derived fragments produced in plasma over a 4-hour circulation period in rats with nonfiltering kidneys. CONCLUSIONS: This study demonstrates that albumin fragments, which are produced by the kidney and not by extrarenal sources, are exclusively excreted in the urine. Exogenous albumin peptides were able to specifically exert a competitive effect on the renal enzyme cleavage of intact albumin.

Animals↗
PubMed1989

The albumin receptor effect may be due to a surface-induced conformational change in albumin.

To determine whether equilibrium binding between albumin and hepatocytes involves a cell surface receptor for albumin, we incubated freshly isolated rat hepatocytes with 125I-albumin and determined the amount of albumin associated with the cells as a function of the total albumin concentration. The resulting two-phase binding curve showed the rat albumin-hepatocyte interaction to consist of a saturable binding interaction with a dissociation constant of 1.1 microM and 2 X 10(6) sites/cell in addition to a weak, nonsaturable binding interaction. However, the saturable binding of albumin to hepatocytes did not appear to result from the presence of an albumin receptor on the cell surface; the interaction was the same for different species of albumin, for chemically modified albumins, and for fragments of albumin representing mutually exclusive domains of the molecule. The saturable binding was, instead, found to involve a subpopulation of albumin with an enhanced affinity for the cell surface. We show that this subpopulation of albumin is generated upon contact with either solid surfaces or cell surfaces and can be transferred from one surface to another. We propose that the two-phase Scatchard binding curve and the "albumin receptor effect" reflect two populations of albumin that bind to the cell surface with different affinities rather than one population of albumin that binds to two classes of binding sites.

Animals↗
PubMed2001

Albumin thiolate anion is an intermediate in the formation of albumin-S-S-homocysteine.

An elevated concentration of plasma total homocysteine is an independent risk factor for cardiovascular disease. Greater than 80% of circulating homocysteine is covalently bound to plasma protein by disulfide bonds. It is known that albumin combines with cysteine in circulation to form albumin-Cys(34)-S-S-Cys. Studies are now presented to show that the formation of albumin-bound homocysteine proceeds through the generation of an albumin thiolate anion. Incubation of human plasma with l-(35)S-homocysteine results in the association of >90% of the protein-bound (35)S-homocysteine with albumin as shown by nonreduced SDS-polyacrylamide gel electrophoresis. Treatment of the complex with beta-mercaptoethanol results in near quantitative release of the bound l-(35)S-homocysteine, demonstrating that the binding of homocysteine to albumin is through a disulfide bond. Furthermore, using an in vitro model system to study the mechanisms of this disulfide bond formation, we show that homocysteine binds to albumin in two steps. In the first step homocysteine rapidly displaces cysteine from albumin-Cys(34)-S-S-Cys, forming albumin-Cys(34) thiolate anion and homocysteine-cysteine mixed disulfide. In the second step, albumin thiolate anion attacks homocysteine-cysteine mixed disulfide to yield primarily albumin-Cys(34)-S-S-Hcy and to a much lesser extent albumin-Cys(34)-S-S-Cys. The results clearly suggest that when reduced homocysteine enters circulation, it attacks albumin-Cys(34)-S-S-Cys to form albumin-Cys(34) thiolate anion, which in turn, reacts with homocysteine-cysteine mixed disulfide or homocystine to form albumin-bound homocysteine.

Albumins↗
PubMed2001

Albumin uptake and transcytosis in endothelial cells in vivo induced by albumin-binding protein.

The 60-kDa endothelial cell surface albumin-binding glycoprotein (gp60) is postulated to be a docking site for albumin that mediates the uptake of albumin and its transport in cultured microvessel endothelial cells. In the present study, we used an isolated Krebs-perfused rat lung preparation to address the in vivo role of gp60 in mediating albumin uptake and transport. Addition of primary anti-gp60 antibody to the perfusate followed by the secondary antibody to cross-link gp60 increased the vessel wall (125)I-albumin permeability-surface area (PS) product 2.5-fold without affecting the capillary filtration coefficient (K(f,c;) a measure of liquid permeability). In contrast, EDTA (5 mM), which induces interendothelial gap formation, produced parallel increases in both K(f,c) and (125)I-albumin PS product. Increasing perfusate albumin concentration to >1 g/100 ml (EC(50) 1.2 g/100 ml) was sufficient to block (125)I-albumin PS product, indicating that the perfusate albumin competed with tracer albumin for transendothelial albumin transport. Cross-linking of gp60 in lungs perfused with saturating concentration of albumin resulted in a greater increase in (125)I-albumin PS product, indicating that gp60 function was capable of being modulated. These results show that activation of gp60 in pulmonary microvessels induces albumin uptake and its transport through a non-hydraulic pathway that fits with a model of albumin permeability via the transcellular pathway.

Albumins↗
PubMed1991

Effects of airway luminal concentration of albumin on histamine-induced mucosal exudation of radio-iodine labelled albumin.

In an in vivo study of guinea-pig airway barriers we have examined the effects of the luminal concentration of albumin on exudation (outward) and absorption (inward) permeabilities to radio-iodine labelled albumin. Previously validated techniques for superfusion of solutes onto the tracheobronchial mucosal surface and for subsequent tracheal lavage were employed. [125I]albumin was administered intravenously as plasma tracer and [131I]albumin was superfused topically as absorption tracer. Histamine (5.0 nmol) was superfused onto the mucosal surface together with the absorption tracer and in the presence of different albumin concentrations (0.3, 3.0 and 30 mg ml-1). The experiment was terminated 10 minutes after the tracheal mucosal superfusion and samples of plasma and tracheal lavage fluid were collected. The mucosal exudation response was calculated from the detection of [125I]albumin in the airway lumen. The absorption ability of the mucosa was determined by the detection of [131I]albumin in circulating plasma. Histamine induced a significant mucosal exudation of [125I]albumin. This effect was unaffected by the level of albumin on the mucosal surface. There was a small but significant absorption of [131I]albumin in the presence of 0.3 and 3.0 mg ml-1 of albumin in the luminal liquid. An albumin concentration of 30 mg ml-1 markedly increased the rate of absorption of [131I]albumin. However, the absorption rate was not affected by the histamine-induced mucosal exudation process at any level of luminal albumin. The present data further demonstrates that plasma exudation and mucosal absorption are independent processes. The data are in keeping with the view that an increased subepithelial hydrostatic pressure moves the plasma exudate across the mucosa as a distinct outward process.

Absorption↗
PubMed2004

Albumin infusion for low serum albumin in preterm newborn infants.

BACKGROUND: Intravenous albumin infusion to treat hypoalbuminaemia is used in intensive care nurseries. Hypoalbuminaemia occurs in a number of clinical situations including prematurity, the acutely unwell infant, respiratory distress syndrome (RDS), chronic lung disease (CLD), necrotising enterocolitis (NEC), intracranial haemorrhage, hydrops fetalis and oedema. Fluid overload is a potential side effect of albumin administration. Albumin is a blood product and therefore carries the potential risk of infection and adverse reactions. Albumin is also a scarce and expensive resource. OBJECTIVES: The primary objective was to assess whether albumin infusions, in preterm neonates with low serum albumin, reduces mortality and morbidity. A secondary objective was to assess whether albumin infusion is associated with significant side effects. SEARCH STRATEGY: Searches were made of MEDLINE from 1966 to April 2004, CINAHL from 1982 to April 2004 and the current Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library issue 1, 2004). Previous reviews (including cross references) and abstracts were also searched. SELECTION CRITERIA: All randomised controlled trials in which individual patients were allocated to albumin infusion versus control were included. Cross-over studies were excluded. Quasi randomised trials were excluded. Participants were preterm infants who had hypoalbuminaemia. Types of interventions included albumin infusion versus placebo (e.g. crystalloid) or no treatment. DATA COLLECTION AND ANALYSIS: The reviewers worked independently to search for trials for inclusion and to assess methodological quality. Studies were assessed using the following key criteria: blinding of randomisation, blinding of intervention, completeness of follow up and blinding of outcome measurement. MAIN RESULTS: Only two small studies were found for inclusion in this review and only one reported clinically relevant outcomes - it found no significant differences for our primary outcome measure of death (RR 1.5 [95% confidence interval 0.3 - 7.43]) or secondary outcome measures of intraventricular haemorrhage, patent ductus arteriosus, necrotising enterocolitis, bronchopulmonary dysplasia, duration of mechanical ventilation and duration of oxygen therapy. REVIEWERS' CONCLUSIONS: There is a lack of evidence from randomised trials to determine whether the routine use of albumin infusion, in preterm neonates with low serum albumin, reduces mortality or morbidity, and no evidence to assess whether albumin infusion is associated with significant side effects. There is a need for good quality, double-blind randomised controlled trials to assess the safety and efficacy of albumin infusions in preterm neonates with low serum albumin.

Albumins↗
PubMed2006

Ischemia-modified albumin concentrations should be interpreted with caution in patients with low serum albumin concentrations.

OBJECTIVE: Ischemia-modified albumin (IMA((R))) is a novel marker for assessing cardiac ischaemia. We assessed the relationship between total albumin concentrations and IMA in serum to investigate whether interpretation of IMA was albumin-dependent. SUBJECTS AND METHODS: 298 serum samples were assayed for total albumin (albumin), using bromcresol purple, and IMA, using an indirect colorimetric assay. Correlations were investigated for the whole data set and for two subgroups, those samples with low albumin (< or =34 g/l) and those with albumin within the reference interval. RESULTS: There was a significant (r = -0.888, p < 0.0001) negative correlation between IMA and albumin both over the entire range of albumin concentrations and in the low albumin concentration subgroup (r = -0.85, p < 0.0001); however, there was less significant correlation in the subgroup with albumin within the reference interval (r = -0.37, p < 0.0001). CONCLUSION: A negative correlation exists between IMA and albumin concentrations; however, there is less significant correlation when albumin is within the reference interval. IMA concentrations determined in patients with albumin concentrations < or =34 g/l should be interpreted with some caution.

Adolescent↗
PubMed1992

Albumin gene expression is down-regulated by albumin or macromolecule infusion in the rat.

A novel feedback regulatory mechanism operating on transcription of the albumin gene is described in the rat. In 1946, it was proposed that circulating colloids, including serum albumin, may affect the synthesis and/or secretion of albumin in the liver. The molecular basis for this proposed regulation has now been investigated by adding oncotically active macromolecules to the circulation of normal or genetically albumin-deficient Nagase analbuminemic rats (NAR) and analyzing the hepatic expression of genes, including albumin after 24 h. The transcription rate of the albumin gene was higher in NAR than in normal rats and was dramatically reduced by raising serum albumin to 1.6 g/dl. Intravenous infusion of albumin into normal rats also decreased transcriptional activity of the albumin gene by 50-60%, and this decrease correlated with changes in serum colloid osmotic pressure after albumin infusion. Inhibition of albumin gene transcription was also observed upon intravenous infusion of other protein or nonprotein macromolecules, such as gamma-globulin and dextran. This down-regulation appears to control the steady-state level of albumin mRNA in the liver. Aside from a concomitant decrease in apo E gene transcription after albumin or macromolecule infusion, there was no change in the transcription rate of other genes, including those exhibiting liver-preferred or -specific expression (e.g., tyrosine amino-transferase, cytochrome P-450, alpha 1-antitrypsin, apolipoproteins A-I and B, and transferrin) or general cellular expression (e.g., alpha-tubulin, pro alpha 2 collagen, and beta-actin). Feedback regulation of albumin gene expression by serum colloids may serve as a specific homeostatic mechanism to maintain the steady-state level of total protein in the circulation.

Animals↗
PubMed1989

High protein diets stimulate albumin synthesis at the site of albumin mRNA transcription.

High dietary protein intake directly stimulates albumin synthesis ald albuminuria in rats with Heymann nephritis. Increased albumin synthetic rate might be due to the presence of increased amino acids available for protein synthesis causing more efficient translation of preformed albumin mRNA, or instead might be linked to increased steady state albumin mRNA levels in the liver. Albumin synthesis, hepatic albumin mRNA content, and albumin mRNA relative to beta actin mRNA (as an internal control) (Alb/beta Act), were measured in rats with Heymann nephritis fed either 8.5% protein (LP), or after protein intake was increased to 40% for 4 days (HP). enalapril (E) was used to modulate the proteinuric effect of HP, yielding four experimental groups, LPN (8.5% protein nephrotic, no enalapril), LPE (8.5% protein, enalapril treated), HPN (40% protein nephrotic, no enalapril), and HPE (40% protein, enalapril treated). Dietary protein augmentation increased the rate of albumin synthesis, steady-state albumin mRNA levels, and Alb/beta Act in both HPN and HPE, compared to either LPH or LPE, even though serum albumin concentration was greater in HPE than in either of the groups fed LP. Both albumin mRNA and Alb/beta Act correlated with the rate of albumin synthesis (r = 0.531, P less than 0.05; and 0.553, P less than 0.01 respectively). Nuclear run-on assays were performed using nuclei isolated from the livers of LPN or HPN to determine whether increased albumin mRNA resulted from an increase in the rate of albumin mRNA transcription.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed2000

Urinary albumin excretion and transcapillary escape rate of albumin in malignancies.

Transcapillary escape rate of albumin was determined in 22 patients with different malignancies. In addition, urinary albumin excretion rate was measured in 24-h urine samples using a sensitive immunoassay. Increased urinary albumin excretion was defined as >/=20 microg/min according to conventional standards. Renal glomerular filtration and tubular function was estimated by 51Cr-EDTA plasma clearance and urinary beta 2-microglobulin, respectively. Median urinary albumin excretion rate was 15.0 microg/min (range 6-510 microg/min) and the frequency of increased urinary albumin excretion was 41%. This agrees with other studies showing increased albuminuria in several types of malignant diseases. Patients with advanced disease (tumour, node, metastasis (TNM) stage II-IV) had a significantly higher urinary albumin excretion rate than patients with localized disease (TNM stage I). Serum creatinine, glomerular filtration rate and urinary beta 2-microglobulin were all within normal limits. Median transcapillary escape rate of albumin was 5.5 %/h (range 2-8 %/h) and this level is comparable with values in healthy subjects. There was no significant difference in transcapillary escape rate between patients with elevated urinary albumin excretion and the normoalbuminuric group. Median value of the absolut outflux of albumin was 10.6 g/h with similar levels in patients with increased urinary albumin excretion and patients with normoalbuminuria. Our results indicate a high prevalence of minor glomerular dysfunction with a slightly elevated urinary albumin excretion in patients with malignancies. The normal endothelial function, as estimated by the transcapillary escape rate of albumin, suggests an overall unaffected capillary permeability and increased urinary albumin loss appears to be an isolated renal phenomenon in cancer patients.

Adult↗
PubMed2006

The pharmacokinetics of an albumin-binding Fab (AB.Fab) can be modulated as a function of affinity for albumin.

An AB.Fab (albumin-binding Fab) consists of a Fab and a phage-derived albumin-binding peptide. This molecule is capable of binding both antigen and albumin simultaneously. Using a Fab derived from Herceptin we generated a panel of AB.Fab variants with wide-ranging affinities for albumin. An assay that measured AB.Fab binding to albumin in solution was developed to most accurately reflect the binding affinity for albumin in vivo. Affinity varied depending upon the species of albumin tested. For rat and rabbit albumin, affinities ranged from 0.04 to 2.5 microM. Reduced affinity for albumin correlated with a reduced half-life and higher clearance rates in both species; the beta half-life ranged 6-fold while clearance ranged over 50-fold in rats and 20-fold in rabbits. To estimate the pharmacokinetic properties of an AB.Fab in humans, AB.Fab variants with similar affinities for rat and rabbit albumin were selected. Using their pharmacokinetic parameters and the principles of allometric scaling for albumin, we estimate an approximate beta half-life for an AB.Fab with 0.5 microM affinity for albumin of up to 4 days in humans with a clearance of 76 ml/h. These variants demonstrate the ability to modulate the clearance of a Fab fragment in vivo and help to establish guidelines for pharmacokinetic engineering of molecules through albumin binding.

Albumins↗
PubMed2005

Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces.

It is now understood that the nonclassical major histocompatibility complex-I molecule FcRn binds albumin and retrieves it from an intracellular degradative fate. Whether FcRn in the liver modulates albumin turnover through effects on biosynthesis and production is not known. Thus we quantified the appearance of biosynthetically labeled albumin in plasma after an intravenous bolus injection of [(3)H]leucine in FcRn-deficient mice. The production rates for both albumin (FcRn substrate) and transferrin (nonsubstrate) are increased by approximately 20% in FcRn-deficient mice compared with normal mice, likely compensating for the lowered plasma oncotic pressure caused by hypoalbuminemia in FcRn-deficient mice. Determining the magnitude of FcRn-mediated effects on albumin turnover, we then measured the steady-state plasma concentrations of biosynthetically labeled albumin and transferrin during [(3)H]leucine infusion. The concentration of albumin was approximately 40% lower in FcRn-deficient mice compared with normal mice. Furthermore, the approximately 40% lower plasma albumin concentration in FcRn-deficient mice along with the approximately 20% increase in albumin production indicate, by the mass-balance equation, that albumin degradation in FcRn-deficient mice is twice that of normal mice. These studies of biosynthetically labeled, and thus native, albumin support our previous finding that FcRn protects albumin from degradation. Permitting quantification of the magnitude of FcRn-mediated recycling, they further indicate that FcRn has extraordinary capacity: the amount of albumin saved from degradation by FcRn-mediated recycling is the same as that produced by the liver.

Albumins↗