Role of albumin and its modifications in glomerular injury.

Albuminuria is both a characteristic hallmark and a known risk factor for progressive glomerular disease. Although the molecular basis for a potential causative role for albuminuria in progressive chronic kidney disease remains poorly understood, there have been several recent advances in our understanding of the role of albumin, and its molecular modifications, in the development and progression of glomerular disease. This review discusses recent findings related to the ability of albumin and its associated factors to directly induce podocyte and glomerular injury. Additional recent studies confirming the ability and mechanisms by which podocytes endocytose albumin are also discussed. Lastly, we present several known molecular modifications in the albumin molecule itself, as well as substances bound to it, which may be important and potentially clinically relevant mediators of albumin-induced glomerular injury. These recent findings may create entirely new opportunities to develop novel future therapies directed at albumin that could potentially help reduce podocyte and renal tubular injury and slow the progression of chronic glomerular disease.

Albumin contributes to kidney disease progression in Alport syndrome.

Alport syndrome is a familial kidney disease caused by defects in the collagen type IV network of the glomerular basement membrane. Lack of collagen-α3α4α5(IV) changes the glomerular basement membrane morphologically and functionally, rendering it leaky to albumin and other plasma proteins. Filtered albumin has been suggested to be a cause of the glomerular and tubular injuries observed at advanced stages of Alport syndrome. To directly investigate the role that albumin plays in the progression of disease in Alport syndrome, we generated albumin knockout (Alb(-/-)) mice to use as a tool for removing albuminuria as a component of kidney disease. Mice lacking albumin were healthy and indistinguishable from control littermates, although they developed hypertriglyceridemia. Dyslipidemia was observed in Alb(+/-) mice, which displayed half the normal plasma albumin concentration. Alb mutant mice were bred to collagen-α3(IV) knockout (Col4a3(-/-)) mice, which are a model for human Alport syndrome. Lack of circulating and filtered albumin in Col4a3(-/-);Alb(-/-) mice resulted in dramatically improved kidney disease outcomes, as these mice lived 64% longer than did Col4a3(-/-);Alb(+/+) and Col4a3(-/-);Alb(+/-) mice, despite similar blood pressures and serum triglyceride levels. Further investigations showed that the absence of albumin correlated with reduced transforming growth factor-ß1 signaling as well as reduced tubulointerstitial, glomerular, and podocyte pathology. We conclude that filtered albumin is injurious to kidney cells in Alport syndrome and perhaps in other proteinuric kidney diseases, including diabetic nephropathy.

Reduced protein availability by albumen removal during chicken embryogenesis decreases body weight and induces hormonal changes.

NEW FINDINGS: What is the central question of this study? Prenatal protein undernutrition by albumen removal in an avian model of fetal programming leads to long-term programming effects, but when do these effects first appear and are these programming effects regulated by the same candidate genes as in mammals? What is the main finding and its importance? The present results indicate that prenatal protein undernutrition by albumen removal induces phenotypical and hormonal changes in the early posthatch period, when the mismatch between the prenatal and postnatal environment first arises, but these changes are not accompanied by an altered gene expression of the selected candidate genes. Studies of the chicken offer a unique model for investigation of the direct effects of reduced prenatal protein availability by the partial replacement of albumen with saline in eggs at embryonic day 1 (albumen-deprived group). The results were compared with mock-treated sham chicks and non-treated control chicks. Although no differences in hatch weight were found, body weight and growth were reduced in the albumen-deprived chicks until 3 weeks of age. The feed intake of the albumen-deprived chicks, however, was increased compared with the control (day 13-21) and the sham chicks (day 16-18). In the albumen-deprived chicks, the ratio of thyroxine to 3,5,3'-triiodothyronine in the plasma was increased compared with the control chicks, whereas the plasma corticosterone level was increased only at day 7 compared with both other groups. The plasma glucose concentration and glucose tolerance were not affected by treatment. Several candidate genes previously associated with effects of prenatal protein deprivation in mammals were examined in the liver of newly hatched chicks. Gene expression of glycogen synthase 2, glycogen phosphorylase 1, peroxisome proliferator-activated receptor α and γ and glucocorticoid receptor was not affected by the treatment. In conclusion, reduction of prenatal protein availability led to differences in body weight and influenced hormones involved in metabolism and growth. Gene expression of the selected candidate genes was not altered, in contrast to mammals.

The effect of albumen removal before incubation (embryonic protein under-nutrition) on the post-hatch performance, regulators of protein translation activation and proteolysis in neonatal broilers.

Albumen was removed from broiler eggs before the start of incubation to induce prenatal protein under-nutrition in chicken embryos. With this method, the direct effect of protein deficiency was investigated, differing from mammalian models manipulating the maternal diet where indirect, hormonal effects can interfere. Based on the estimated albumen/egg weight ratio, 10 % of albumen was removed with an 18G needle, after making a hole at the sharp end of the egg with another 18G needle. Eggs were taped thereafter. The sham group underwent the same procedure, except that no albumen was removed. Control eggs did not receive any treatment. The removal of albumen decreased both embryonic and post-hatch body weight up to day 7 compared with the control group. On embryonic day 18, embryos from the albumen-deprived group had higher plasma uric acid levels compared with the sham (P= 0·016) and control (P= 0·009) groups. Moreover, a lower plasma amino acid concentration was observed at hatch compared with the sham (P= 0·038) and control (P= 0·152) groups. These findings indicate an altered protein metabolism. At hatch, a higher mRNA expression of muscle ring finger-1 (MuRF1), a gene related to proteolysis, was observed in albumen-deprived chicks compared with the control and sham chicks, together with an up-regulated expression of atrogin-1 (another atrogene) at this time point in the male protein-deficient chicks. These findings suggest that muscle proteolysis is transiently increased by the removal of albumen before the start of incubation. No evidence was found for altered protein synthesis capacity and translational efficiency in albumen-deprived chicks.

Psychosocial and biochemical interactions in aging: preliminary results from an Italian old sample of "Zincage" project.

The study of the interactions among biological factors and psychosocial conditions is a very innovative field, because data are lacking in the scientific literature. Among biological aspects, zinc is an essential element in the elderly, especially in relation to one of the proteins, such as albumin, involved in zinc transport into the cells. In this study, the aim is the assessment of the interrelationship between albumin value (used as an index of the body zinc status) and some psychosocial dimensions in elderly Italian sample recruited for ZINCAGE project, supported by the European Commission in the "Sixth Framework Programme". Some tests and questionnaires were administered to older people included in the trial: the "life-style questionnaire"; the mini mental state examination (MMSE); the geriatric depression scale (GDS-15 items). On the basis of the Senieur Protocol for gerontological studies, a sample of 291 Italian healthy old subjects has been recruited in Central Italy and divided into 3 age groups: (a) 125 subjects aged from 65 to 74 years, (b) 89 subjects aged from 75 to 84 years, (c) 77 subjects aged >or=85 years (classified like successful old people). No cognitive impairment assessed by MMSE was observed in 67.5% of the sample; 64.0% had GDS score less than 5, indicating no depression, whereas the prevalence of biological albumin deficiency (<3.5 g/dl) found in Italian old people was 21.0%. Sixty one percent of subjects with albumin deficiency displayed higher values of GDS (>or=5). These preliminary results showed an interrelationship among serum albumin value and psychosocial aspects in Italian old population, suggesting that low albumin values may be involved in impaired psychological dimensions.

Predictors of severe outcomes in patients with Clostridium difficile infection from a Hispanic population.

BACKGROUND: Factors associated with complicated Clostridium difficile infection (CDI) may vary among populations, and predictors of severe outcomes in CDI have not been studied in Hispanic patients. The aim of this study was to identify factors associated with a higher risk of colectomy, all-cause mortality, and CDI-associated mortality in a Hispanic population. METHODS: We performed a retrospective study of all hospitalized patients with a diagnosis of CDI between January 1, 2011 and September 30, 2015 in a 450-bed teaching hospital in Monterrey, northeast Mexico. Three main outcomes were defined: fulminant colitis with subsequent colectomy, all-cause mortality within 30 days of diagnosis, and CDI-attributable mortality. RESULTS: Of 261 patients with diarrhea, 176 were diagnosed with CDI. For colectomy, Charlson comorbidity index, ICU stay and mechanical ventilation prior to CDI diagnosis, days with diarrhea prior to treatment, total days of hospital stay and days after CDI diagnosis, elevated ATLAS score, days of diarrhea post CDI treatment, and treatment failure significantly predicted the necessity of surgical treatment with colectomy. CONCLUSION: Treatment failure, persistent diarrhea, and a high ATLAS score were identified as risk factors for severe outcomes of CDI. A low albumin concentration and high creatinine were associated with higher overall mortality.

Pharmacokinetics of oltipraz in mutant Nagase analbuminemic rats.

Pharmacokinetic parameters of oltipraz were compared after intravenous (10 mg/kg) and oral (50 mg/kg) administration to control male Sprague-Dawely rats and mutant Nagase analbuminemic rats (NARs). In NARs, the expression and mRNA level of CYP1A2 increased, and oltipraz was mainly metabolized via CYP1A1/2, 2B1/2, 2C11, 201, and 3A1/2 in male rats. Hence, it may be expected that the CL of oltipraz would be significantly faster in NARs. This was proven by the following results. After intravenous administration, the CL of oltipraz was significantly faster in NARs (125% increase) than controls due to significantly greater free fractions (unbound to plasma proteins) of oltipraz (197% increase) and significantly faster CL(int) for the disappearance of oltipraz (11.4% increase) in NARs, since oltipraz is an intermediate hepatic extraction ratio drug in rats. The V(ss) was significantly larger in NARs (109% increase) and this could be due to significant increase in free fractions of oltipraz in NARs. After oral administration, the AUC of oltipraz was also significantly smaller in NARs (61.9% decrease). This could also be due to significant increase in free fractions of oltipraz and significantly faster CL(int) in NARs. However, this was not due to decrease in absorption in NARs.

Differential Expression of Genes and DNA Methylation associated with Prenatal Protein Undernutrition by Albumen Removal in an avian model.

Previously, long-term effects on body weight and reproductive performance have been demonstrated in the chicken model of prenatal protein undernutrition by albumen removal. Introduction of such persistent alterations in phenotype suggests stable changes in gene expression. Therefore, a genome-wide screening of the hepatic transcriptome by RNA-Seq was performed in adult hens. The albumen-deprived hens were created by partial removal of the albumen from eggs and replacement with saline early during embryonic development. Results were compared to sham-manipulated hens and non-manipulated hens. Grouping of the differentially expressed (DE) genes according to biological functions revealed the involvement of processes such as 'embryonic and organismal development' and 'reproductive system development and function'. Molecular pathways that were altered were 'amino acid metabolism', 'carbohydrate metabolism' and 'protein synthesis'. Three key central genes interacting with many DE genes were identified: UBC, NR3C1, and ELAVL1. The DNA methylation of 9 DE genes and 3 key central genes was examined by MeDIP-qPCR. The DNA methylation of a fragment (UBC_3) of the UBC gene was increased in the albumen-deprived hens compared to the non-manipulated hens. In conclusion, these results demonstrated that prenatal protein undernutrition by albumen removal leads to long-term alterations of the hepatic transcriptome in the chicken.

Effects of nutritional programing on growth and metabolism caused by albumen removal in an avian model.

In mammalian models of prenatal undernutrition the maternal diet is manipulated, exerting both nutritional and hormonal effects on the offspring. In contrast, in the chicken, strictly nutritional effects can be applied. Prenatal protein undernutrition in chickens was induced by partial replacement of albumen with saline during early embryonic development (albumen-deprived group) and results were compared with a sham-manipulated and a non-manipulated group. Body weight of the albumen-deprived hens was reduced throughout the entire experimental period (0-55 weeks). The reproductive capacity was diminished in the albumen-deprived hens as reflected in the reduced number of eggs and lower egg weight. The plasma triiodothyronine levels were increased in the albumen-deprived group compared with the non-manipulated hens, but not the sham-manipulated hens. An oral glucose tolerance test (OGTT) at 10 weeks of age revealed a decreased glucose tolerance in the albumen-deprived hens. During adulthood, an age-related loss of glucose tolerance was observed in the hens, leading to disappearance of treatment differences in the OGTT. The offspring of the albumen-deprived hens (PA chicks) had reduced body weight until at least 3 weeks of age. In addition, the PA chicks had a decreased relative residual yolk weight at hatching. An insulin tolerance test revealed increased sensitivity to insulin for the PA chicks compared with the offspring of the non-manipulated (PN) and sham-manipulated hens (PS). In conclusion, prenatal protein undernutrition by albumen removal caused long-term effects on body weight, reproductive performance, and physiology.

Albumin and collagen mRNA expression in normal and analbuminemic rodent liver: analysis by in situ hybridization using biotinylated probes.

We used in situ nucleic acid hybridization cytochemistry to examine cell types and subcellular sites expressing albumin (alb) or pro alpha 2 collagen (col) mRNA in livers from normal and analbuminemic rodents. Biotinylated cDNA or RNA probes were applied to aldehyde-fixed, non-frozen sections and the resulting DNA-RNA or RNA-RNA hybrids were subsequently visualized by enzymatic detection of either peroxidase or alkaline phosphatase conjugated to anti-biotin IgG or streptavidin. In normal rat liver, alb mRNA was expressed in all hepatocytes and was localized to discrete subcellular structures distributed as aggregates in the cytoplasm and in specific structures encircling the nucleus; these subcellular structures most likely represent the endoplasmic reticulum and nuclear envelope. In mouse liver, pro alpha 2 col mRNA was identified in a subpopulation of sinusoidal lining cells which have the morphological appearance of lipocytes. In liver from analbuminemic rats, a small number of hepatocytes, distributed throughout the hepatic lobule, expressed alb mRNA at high levels; the subcellular distribution of this alb mRNA was essentially identical to that observed in normal rat hepatocytes. Since non-radioactive in situ hybridization detected mRNA within the boundaries of individual cells and showed its precise subcellular location under conditions in which there was excellent preservation of tissue morphology, this procedure should be useful for a wide variety of histopathologic studies.

Absence of albumin in tissues of analbuminemic rats.

Nagase analbuminemic rats (NAR) are deficient in serum albumin. Extravascular regions of the tissues of NAR were tested for rat serum albumin by the immunofluorescence staining technique. Albumin was not detectable in any of the tissues of NAR tested (liver, kidney, muscle, skin, and small intestine), whereas it was clearly demonstrated in all these tissues of normal rats. Furthermore, extracts of NAR tissues, including the liver, contained no albumin detectable by the single radial immunodiffusion method. These findings indicate that albumin is not present in either the serum or extravascular regions of tissues of NAR, and suggest that the deficiency of serum albumin in NAR is not due to impaired albumin secretion from the liver or alteration of the tissue distribution of albumin in certain tissues, but to the absence of its synthesis in the liver.

Penetration of bilirubin into the brain in albumin-deficient and jaundiced rats (AJR) and Nagase analbuminemic rats (NAR).

An albumin-deficient and jaundiced strain of rats (AJR) was established by crossing Nagase analbuminemic rats (NAR) with jaundiced Gunn rats. AJR have no serum albumin and die with kernicterus within 3 weeks after birth. Their serum bilirubin level was 25 per cent (20 micrograms/ml) of that of Gunn rats at 1-2 weeks of age, while their brain bilirubin content was 1.2-2.7 times (4-5 micrograms/g brain) that of Gunn rats. Binding of bilirubin to NAR plasma proteins was examined. The bilirubin binding protein in NAR plasma was found to be lipoprotein, showing an association constant of 6.7 X 10(6) M-1. Bilirubin-transport into the brain of postnatal NAR was investigated by intravenous infusion of bilirubin with taurocholate. The brain bilirubin level of NAR infused with free bilirubin was 1.6 times that of normal rats. In NAR, the brain level on infusion of lipoprotein-bound bilirubin was similar to that on infusion of free bilirubin, but albumin-bound bilirubin scarcely entered the brain. These findings suggest that lipoprotein-bound bilirubin can diffuse across the blood-brain barrier into the brain.

The effect of prenatal hypoxia and malnutrition on memory consolidation in the chick.

The contribution of hypoxia and malnutrition to cognitive impairments was investigated in chicks incubated in conditions of reduced gas exchange. Previous research has shown that reducing gas exchange during incubation by wrapping half the eggshell with an impermeable membrane results in impaired cognitive ability in young chicks. The results were interpreted within a three stage sequential model of memory using discriminated bead avoidance learning. Reducing gas exchange for 4 days from day 10 or 14, of the 21-day incubation, inhibits memory formation and consolidation into permanent storage. The nature of the cognitive deficit depended on the timing of the insult. Environmental hypoxia (14% oxygen), induced from days 10 to 14 and from days 14 to 18, replicated the memory deficits found previously when eggs were partially wrapped with a membrane. Oxygen is necessary to break down food and to provide energy to build tissue proteins, and therefore hypoxia (partial wrapping or environmental incubation) may indirectly cause malnutrition. Malnutrition, induced by removing 5%, 7.5% or 10% albumin from the egg prior to incubation, had no significant effect on memory consolidation. Raised corticosterone levels occurred in chicks malnourished by 5% and 7.5%, but brain sparing was only evident in chicks with 7.5% albumin removal. Hatch rates were very low in 10% malnourished chicks. Using the chick as a model of prenatal stress, we have been able to isolate the effects of hypoxia from contributing maternal factors.

Liver gene expression and increase in albumin synthesis by fetal hepatocytes transplanted into analbuminemic rats.

This report describes the evolution of hepatocytes isolated from 21-day fetuses and transplanted into spleens of Nagase analbuminemic rats which have negligible serum albumin levels due to a mutation affecting albumin mRNA processing. Albumin and alpha-fetoprotein expression, in addition to other parameters related to cellular proliferation status (thymidine kinase and proliferating cell nuclear antigen expression) were studied as indicative of the behavior and evolution of the cells. In recipient rats, only a few clusters of hepatocytes could be observed in the red pulp of the spleen 24 h after transplantation. The fetal hepatocytes migrated to the liver and could be seen in portal branches immediately after transplantation. Fifteen days later, albumin mRNA was detected in recipient livers and was expressed throughout the entire 3-month study. Alpha-fetoprotein was not detected. Cell proliferation was not relevant, although 3 months after transplantation, the proliferation rates appeared to show a tendency to increase. These data demonstrate that fetal hepatocytes transplanted into spleen migrate to liver, settle there and acquire an adult phenotype free of malignant transformation. Our study is a first step towards the thorough understanding of fetal hepatocyte transplantation. The next steps will involve in-depth studies of the possibilities of genetic manipulation to achieve a high degree of repopulation/expression, employing the least possible number of donor cells, and of how the cells reach the liver parenchyma, overcoming the endothelial barrier.

Inhibitory effect of resveratrol on proteinuria, hypoalbuminemia and hyperlipidemia in nephritic rats.

The effect of resveratrol, a polyphenolic compound present in grapes and other plants, on proteinuria, hypoalbuminemia and hyperlipidemia was studied in rats with glomerulonephritis. The nephritis was induced by an intravenous injection of anti-rat kidney glomerular basement membrane rabbit antiserum. Nephritic rats were given oral intubation of resveratrol (5 mg/day/100 g body weight) for 14 days, while control nephritic rats as well as normal ones were similarly given vehicle alone. By resveratrol treatment, enlargement in liver and kidney due to nephritis induction was significantly reduced, together with partial restoration of nephritis-induced reduction in body weight gain. Both proteinuria and hypoalbuminemia, characteristic symptoms to nephrotic syndrome, were significantly remedied, that is, urinary protein excretion was suppressed and serum albumin concentration was increased by resveratrol treatment. Resveratrol also suppressed significantly hyperlipidemia incident to nephritis, the hypotriglyceridemic action being more prominent than the hypocholesterolemic one. From these results, resveratrol is suggested to be a potent anti-glomerulonephritic food factor capable of suppressing proteinuria, hypoalbuminemia and hyperlipidemia at the same time.

Oncotic pressure, albumin and ileus: the effect of albumin replacement on postoperative ileus.

The effect of decreased colloid oncotic pressure, as seen in hypoalbuminemia and hypoproteinemia, upon intestinal function has been well delineated in the surgical literature. Patients undergoing abdominal aortic aneurysm resection or aortoiliac or aortofemoral bypass grafts are almost uniformly hypoalbuminemic postoperatively; with these two facts in mind, a prospective, randomized clinical study was undertaken to identify the role of serum albumin concentration on the length of postoperative ileus in this population. The main hypothesis was that patients whose albumin levels dropped below 3.5 gm/dL would have a more prolonged postoperative hospital course as a result of delay in return of bowel function when compared with those patients in whom the low albumin levels were exogenously acutely replenished to > 3.5 gm/dL. Albumin was replaced to a level greater-than or equal to 3.5 g/dL in one group of 37 patients (AR), with a control group of 32 patients (NR) not receiving any albumin. Return of bowel function was measured by the postoperative day that flatus was documented, as well as the postoperative day oral intake was resumed. Mean values were determined for each group, and t tests did not reveal a significant difference in postoperative day of flatus (AR mean = 4.06 days, NR mean = 4.16 days) or postoperative day of oral intake (AR mean = 4.0, NR mean = 3.75). Additional comparisons between the groups involving the number of postoperative days until a regular diet was begun (AR mean = 6.06, NR mean = 5.48) and length of postoperative hospital stay (AR mean = 9.16, NR mean = 8.43) failed to reveal significant differences.(ABSTRACT TRUNCATED AT 250 WORDS)

The treatment of hypoalbuminemia in the critically ill patient.

Hypoalbuminemia is a common finding in critically ill patients. It has been well documented that hypoalbuminemic patients have a higher morbidity and mortality rate when compared with patients with a normal serum albumin. Consequently, hypoalbuminemic patients are commonly treated with exogenous albumin in the hope of improving their outcome. There is, however, very little evidence that this practice is of any benefit. In this article the physiology of albumin in health and disease is reviewed, and those clinical studies that have investigated the use of albumin in acutely ill hypoalbuminemic patients are evaluated.

[A novel adult case of acute necrotizing encephalopathy of childhood with bilateral symmetric thalamic lesions].

This report describes a 46-year-old Japanese woman with bilateral symmetric thalamic necrosis. The unusual radiologic findings are discussed in relation with acute necrotizing encephalopathy (ANE) of childhood, a rare disease proposed by Mizuguchi et al. ANE affects young children and the incidence is highest between 6 and 18 months of ages. There is only one report of an adult case. The acute stage pathology in ANE can be summarized as acute edema and necrosis involving both gray and white matter by local breakdown of the blood-brain barrier. The radiologic findings in our case were similar to those in ANE of childhood. Though the pathogenesis between our adult case and ANE of childhood might be different, severe hypoalbuminea in our case could cause the alteration of permeability of the thalamic vessels, which might accelerate breakdown of the blood-brain barrier in the thalamus.

[Cerebrospinal fluid proteins in the course of subacute sclerosing panencephalitis in children]. / Bialka plynu mózgowo-rdzeniowego w przebiegu podostrego stwardniajacego zapalenia mózgu u dzieci.

In cerebrospinal fluid samples obtained from lumbar tap from 31 children with subacute sclerosing panencephalitis the concentration of total protein was determined and electrophoretic separation of protein fractions on paper was carried out from 1 to 28 months after the onset of first clinical symptoms. Moreover, in 22 children the concentration of IgG was determined by electroimmunodiffusion. The reference group included 22 children without organic diseases of the central nervous system. In nearly half the samples of the cerebrospinal fluid obtained from these children a rise was observed in total protein level, and in most samples a significant fall of albumin proportion and an evident rise of this relative proportion of globulins (tau + gamma) and IgG immunoglobulins was observed. No correlation was demonstrated between changes in cerebrospinal proteins and the phase of the disease and its duration.

[The prognostic significance of microalbuminuria in cardiovascular events]. / Prognostyczne znaczenie mikroalbuminurii w incydentach sercowo-naczyniowych.

Microalbuminuria is a useful marker for progression of renal damage in patients with diabetes. Many population studies demonstrated that microalbuminuria is associated with many risk factors of cardiovascular damage. Microalbuminuria is more and more frequently appreciated as a marker not only of diabetic nephropathy but also as a marker of increased risk of ischemic heart disease, cardiovascular events, in both diabetic and non-diabetic patients. Results of some of the studies quoted in this article support hypothesis that microalbuminuria reflects general damage of cardiovascular system and can be a marker of early changes in arteries.