Exogenous albumin peptides influence the processing of albumin during renal passage

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.     

Detection of urinary albumin

Microalbuminuria is an important clinical marker in patients with diabetes and cardiovascular disease. The concentration of albumin in urine has traditionally been measured by semiquantitative dipsticks or by various quantitative immunochemical methods such as immunonephelometry, immunoturbidimetry, and radioimmunoassay. However, until recently, urinary albumin not reabsorbed by proximal tubular cells was assumed to be excreted intact. Studies have now revealed that the nature of urinary albumin is complex and is excreted as a mixture of intact albumin, albumin-derived peptides that are not detected by routine dipstick and antibody-based tests, and a species of intact albumin (immunounreactive albumin), also not detected by dipstick and antibody-based tests. A new test, Accumin, based on high-performance liquid chromatography analysis, is able to detect all the immunoreactive intact albumin and immunounreactive intact albumin (total intact albumin) in urine. The advantage in the use of Accumin over a conventional dipstick test or antibody-based laboratory method for detecting microalbuminuria is that false negatives are reduced and a relatively earlier diagnosis of incipient kidney disease can be achieved. The introduction of Accumin has, therefore, highlighted the need for a global standard in the detection and measurement of microalbuminuria. By detecting all of the immunoreactive and immunounreactive intact albumin in urine, Accumin has virtually invalidated the use of dye and immunologically-based dipstick tests and immunologically-based laboratory methods in screening for microalbuminuria in diabetic patients and in identifying microalbuminuria as a risk factor for cardiovascular disease.     

The return of glomerular filtered albumin to the rat renal vein--the albumin retrieval pathway

BACKGROUND: Recent studies have demonstrated that the normal glomerular capillary wall (GCW) is not charge selective to albumin. This means that albumin flux across the GCW is high. This has been confirmed in studies where albumin uptake by the tubules has been inhibited. Therefore, there must be a high capacity postglomerular retrieval pathway in normal kidneys that returns filtered albumin back to the blood supply. METHODS: This study identifies the presence of glomerular filtered albumin in the renal vein from the analysis of the decrease of radioactivity in the venous effluent after the injection of a pulse of tritium labeled albumin into the renal artery in vivo and in the isolated perfused kidney (IPK). RESULTS: The glomerular filtered albumin is returned to the blood supply by a high capacity pathway that transports this albumin at a rate of 1830+/-292 microg/min rat kidney (n= 14) (mean+/-SEM). This pathway has been identified under physiological conditions in vivo and in the IPK. The pathway is specific for albumin as it does not occur for horseradish peroxidase (HRP). The pathway is inhibited in a non-filtering kidney. The pathway is also inhibited by NH4Cl, an inhibitor of protein uptake. CONCLUSIONS: The high capacity retrieval pathway for albumin is most likely associated with transtubular cell transport. It is also apparent that most albuminuric states could be accounted for by the malfunctioning of this pathway without resorting to any change in glomerular permselectivity.     

Pooled human albumin primes neutrophils

Human pooled albumin has traditionally been used both to pacify the artificial surfaces in a cardiopulmonary bypass circuit and also for volume repletion following surgery. In evaluating the routine use of albumin in multiple phases of cardiac surgery, conscientious surgical teams must assess both the physiological and financial price of albumin. Albumin indiscriminately binds many plasma proteins and lipids. In this series of experiments, we explored the influence of highly purified albumin devoid of bound lipids and globulins on both receptor-dependent (FMLP) and receptor-independent (PMA) priming/activation of human neutrophils. We believe that it is important to distinguish the direct influence of albumin from the albumin-bound proteins and lipids. We, therefore, also examined the effect of clinically accessible human pooled albumin on human neutrophils. We observed a dose-dependent priming/activation (elastase release) of human neutrophils by both pooled and purified albumin. We conclude that it is increasingly difficult to justify the routine use of albumin in cardiac surgical patients.     

The present controversy over albumin

Albumin may, from a physiological point of view, be considered an ideal natural colloid. At the present time, however, the indications for its clinical use are being seriously questioned. Hypoalbuminaemia is a normal phenomenon in the critically ill patient. Therefore, serum albumin should be considered a non-specific marker of disease processes and reduced levels are mainly the result of pathological events not the cause of them. The clinical value of repeated serum albumin determinations may, consequently, be questioned. The effects of albumin administration on plasma volume expansion are not entirely predictable, especially in pathological states accompanied by leaky capillary membranes. Therefore, albumin is not an ideal plasma volume expander and its supplementation shows no benefit on many kinds of tissue oedema. Albumin supplementation for treatment of hypoalbuminaemia in critically ill patients will probably only exert transient effects on the serum level, but the supplementation may at the same time even include a risk of increased morbidity and mortality. There are at the present time no clear indications for albumin administration. It seems appropriate to review the use of human albumin in most clinical situations and especially in critically ill patients suffering from hypovolaemia, burns, and hypoalbuminaemia.     

Teicoplanin pharmacokinetics during albumin dialysis

Teicoplanin (TP) pharmacokinetics was assessed in a critically ill patient during albumin dialysis (AD), which was performed with the molecular adsorbent recirculating system. After a 1200-mg loading dose (24 mg/kg), doses of 1200 and 1000 mg (20 mg/kg) on day 2 and 3, respectively, were administered during two cycles of AD. The mean TP peak and trough concentrations amounted to 99.3 and 21.4 μg/mL, respectively, during AD. A mean half-life of 5.5 h, an apparent volume of distribution of 0.302 L/kg, and a mean total TP clearance of 39 mL/h/kg were calculated. Ninety minutes after the start of AD, the extracorporeal clearance was 3560 mL/h. Within 8 h of AD therapy, the serum concentrations decreased by about 75%. Despite a considerable elimination of TP by AD, therapeutic serum levels could be maintained during the entire treatment by administration of high doses and close monitoring of TP serum concentrations.     

Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients

BACKGROUND: The concentration of albumin in serum is maintained by its rates of synthesis, catabolism, and distribution between vascular and extravascular compartments. Albumin synthesis is suppressed when there is inflammation or inadequate protein intake. This study was conducted to establish whether a decline in serum albumin of >0.3 g/dL was accompanied by a change in albumin synthesis and if so whether these changes were associated with increased levels of acute phase proteins and/or with a decrease in equilibrated normalized protein catabolic rate (enPCR). METHODS: Seventy-nine patients in the National Institutes of Health (NIH)-sponsored HEMO Study had baseline measurements of albumin synthesis (measured kinetically as the disappearance of [125]I human serum albumin), the serum concentrations of albumin, transferrin, C-reactive protein (CRP), alpha1 acid glycoprotein (alpha1AG), ceruloplasmin, interleukin-6 (IL-6), plus monthly measurements of enPCR. The plasma levels of all proteins and enPCR were measured regularly over 2 years or until serum albumin decreased by >0.3 g/dL on two sequential measurements. Albumin synthesis was measured a second time when serum albumin declined by >0.3 g/dL or after 2 years. RESULTS: Fifty-nine patients [21 with a significant decrease in serum albumin (decliners) and 38 with stable values of serum albumin] had albumin synthesis measured twice. A decline in albumin concentration and synthesis was associated with an increase in alpha1AG when data from all patients were analyzed as a group. In decliners, albumin synthesis decreased significantly but was unchanged in stable. Likewise, in decliners, IL-6, CRP, alpha1AG, and ceruloplasmin increased significantly but were unchanged in stable. enPCR was unchanged in both groups and was not associated with either changes in albumin level or synthesis in the whole group. CONCLUSION: A decrease in serum albumin of >0.3 g/dL that persists for a period of 6 weeks is associated a decrease in albumin synthesis. This response is associated with evidence of activation of the acute phase response (inflammation) but not with changes in enPCR. In well-dialyzed patients, inflammation is the principal cause of a decrease in serum albumin while protein intake plays an insignificant role.     

Clinical renal preservation by cryoperfusion with an albumin perfusate: renal perfusion with albumin.

Eighty-six human kidneys have been preserved by cryoperfusion with an albumin-based perfusate for five to 50 hours prior to transplantation. Sixty-three of the kidneys were transplanted. The overall immediate function rate was 72% and was 100% (34/34) for kidneys with no warm ischemic damage transplanted into recipients without hypotension or prior sensitivity. The overall actuarial one-month kidney survival rate was 87%, the three-month survival was 73%, and the one-year survival rate was 65%. No kidney was discarded because of poor perfusion. Perfusion data, including flow, dastolic pressure, perfusion time, and lactate concentration were not predictive of immediate renal function. Light, electron, and immunofluorescence microscopic study of biopsy specimens showed no evidence of perfusion or immunologic damage to the kidneys. Perfusion of transplantable kidneys with albumin provides reliable preservation for up to 50 hours without producing either structural or immunologic damage to the organ.     

Normal serum albumin transfer from blood to small intestine and its role in albumin breakdown.

131I-albumin transfer into isolated segments of the small intestine has been determined following the intravenous injection of human 131I-albumin in 23 dogs. The importance of different intestinal segments in the normal degradation of albumin has been established. The slope of the serum disappearance curve was unaltered with proves that the applied technique had no damaging effect. Albumin leakage was not uniform in the whole length of the small intestine. It was highest in the duodenum (0.241 +/- 0.014 ml/10 cm intestine/hour). This was followed by the jejunum (0.142 +/- 0.022 ml/10 cm intestine/hour), and the smallest vally quantity of albumin leakage corresponded to a plasma volume of 14.49 ml in the duodenum, 27.16 ml in the jejunum, and to 23.76 ml in the ileum. The relationship of albumin leakage and catabolism revealed that protein bound activity (transferred and regained) in the dudodenum, in spite of the shortness of this section of the intestine, was responsible for 11.72 +/- 1.70% of total catabolism, that in the jejunum for 21.28 +/- 3.69%, and that in the ileum for 19.24 +/- 3.64%. The sum of the catabolism of the three intestinal segments yielded 52.26 +/- 6.65% of the total catabolism. After correction with a proteolytic factor, this value was 68.44%. Our examinations have established that the small intestine is the main region of normal albumin breakdown.     

Urinary albumin excretion in Spanish children

We measured urinary albumin excretion in 2,224 school-children (1,168 boys, 1,056 girls) aged 2–18 years, between 1989 and 1990 to establish reference values. We recorded all pathological antecedents and findings from physical examination, including anthropometric parameters and arterial blood pressure. The analytical study included serum total protein, albumin and creatinine. The second-morning urine and the nightly (rest) 10-h urine sample were collected and we determined the concentration of albumin and creatinine. We found a positive statistically significant correlation between the urinary albumin excretion (g/10 h) and age, height, weight and body surface area. We suggest that it would be useful to relate the urinary albumin excretion to body surface area. The mean value for albumin excretion was 3.49 g/ml in boys and 3.63 g/ml in girls. The urinary albumin/creatinine ratio showed a high correlation with the albumin excretion (r=0.958).The following members are co-authors of this report: N. Caballo, M. A. Arias, C. Serna, M. Ramirez and A. Cornejo     

Urinary albumin excretion after donor nephrectomy

Surgical ablation of renal tissue in animals leads to compensatory hyperfiltration, hypertension, and focal glomerular sclerosis in remnant nephrons, in association with albuminuria; the detection of slightly elevated urinary albumin (microalbuminuria) has been shown to predict later, more severe renal disease in diabetics. To determine whether unilateral nephrectomy in humans initiates a similar pathogenetic sequence, we measured urinary albumin excretion (UalbV), total protein excretion (UprotV), creatinine clearance (Ccreat) and blood pressure in 22 transplant donors before and at intervals up to 3 years after donor nephrectomy. Urinary albumin was determined using a sensitive enzyme immunoassay (ELISA). Mean Ccreat fell on average to 68% of prenephrectomy values at all times after nephrectomy, indicating a rise of 33% in average single nephron filtration rate. Mean absolute and fractional albumin excretion rates and UprotV values were transiently elevated one week postnephrectomy, but returned thereafter to values not significantly different from prenephrectomy values. Blood pressure rose slightly, but significantly, with time after nephrectomy. Average increases of 10 mm and 5 mm in systolic and diastolic pressures, respectively, were noted by 2 years after surgery. In this study, there was no evidence of glomerular injury from hyperfiltration in the 3 years following donor nephrectomy.