β2-Microglobulin Levels in Serum and Urine of Cadmium Exposed Rabbits

Abstract: Male rabbits were exposed to cadmium during 16 weeks by subcutaneous injections of either 0.25 mg or 0.5 mg Cd as cadmium chloride per kg body weight 3 times per week. β₂-microglobulin (β₂-m) and creatinine in serum, cadmium in blood, as well as total protein, creatinine, β₂-m and cadmium in urine were determined before exposure and after 3 and 7 weeks of exposure. Measurements were also made at 19 weeks, 3 weeks after the last exposure. During exposure, there was a slight increase in the serum β₂-m/creatinine ratio among rabbits with the highest exposure, while no effect of the cadmium burden could be observed once exposure had ceased. Urinary excretion of β₂-m was related to urinary pH, which appeared to be the case also for excretion of total protein. In the high exposure group, a significant increase in urinary β₂-m excretion, indicative of renal tubular dysfunction was seen after 7 weeks of exposure. This was, however, not related to serum β₂-m levels. It was concluded that before renal damage has occurred even heavy cadmium exposure has very little influence on serum β₂-m levels.     

The relationships of urinary metallothionein with other indicators of renal dysfunction in people living in a cadmium-polluted area in Japan

An epidemiologic investigation was carried out to study the significance of urinary excretion of metallothionein (MT) in people aged 50 years and over living in a cadmium (Cd)-polluted area in Japan. The urinary level of MT was compared with various parameters (age, urinary alpha 1-microglobulin (alpha 1-MG), beta 2-microglobulin (beta 2-MG), total protein, Cd, copper (Cu), and zinc (Zn), and relative clearances to creatinine of alpha 1-MG, beta 2-MG, phosphate and uric acid). It was found that the urinary excretion of MT is closely associated with Cd and the indices of renal dysfunction listed above. This observation was more remarkable in women than men. When subjects with signs of renal dysfunction were compared as a group to those with normal renal functions, the excreted amount of MT in the former is significantly greater. The results support the notion that the urinary excretion of MT reflects not only Cd exposure levels but also renal dysfunction caused by long-term Cd exposure.     

Renal handling of humanβ 2-microglobulin in normal and cadmium-poisoned rats

The renal handling of human beta 2-microglobulin (beta 2-m) was investigated in normal rat and in rat with cadmium-induced renal damage. Cadmium was administered either in drinking water at a concentration of 100 ppm for up to 16 months or by i.p. injection of 1 mg Cd/kg, five times a week for up to 4 months. When renal dysfunction has developed, namely after 2 and 10 months of the i.p. and oral treatment respectively, unlabelled human beta 2-m was injected intravenously and its disappearance in serum and its urinary excretion were studied by means of a sensitive immunoassay. In serum, the level of beta 2-m drops by about 90% during the 10 first min, then declines more slowly with a half life around 20 min. Serum disappearance curves of beta 2-m in normal and cadmium-treated rats did not differ markedly. The amount of beta 2-m recovered in urine during the 4 h following the injection averaged 0.03% of the injected dose in normal rats. It increased on the average to 10% in rats treated i.p. with 1 mg Cd/kg for 3 months. However, in rats given 100 ppm Cd per os for 10 months, this amount averaged only 0.14%. A similar value was observed 5 months later, although at that stage, the critical level of cadmium in kidney cortex had been reached for 6-7 months. These data which were in accordance with the disturbances of the other renal parameters measured in cadmium-treated rats indicate that: 1) human beta 2-m is reabsorbed by rat kidney at a similar rate as by human kidney; 2) if the occurrence of cadmium tubulopathy is concomitant with the saturation of cadmium-binding sites in kidney, its severity depends greatly on the rate at which cadmium reaches the saturated kidneys.     

Biological monitoring for occupational cadmium exposure: the urinary metallothionein

The relationship between urinary metallothionein and kidney and liver cadmium levels was examined in 68 active and retired smelter workers. Metallothionein was analyzed by a radioimmunoassay and liver and kidney cadmium levels were determined by in vivo neutron activation. Four workers suffered from severe renal dysfunction and excreted high amounts of total protein and beta 2-microglobulin and greater than 1 mg metallothionein/g creatinine. In the remaining 64 workers the urinary metallothionein levels correlated significantly with the cadmium levels in both liver and kidney. Similarly, in these individuals urinary metallothionein was significantly related to cadmium in blood and urine. These results demonstrate that urinary metallothionein is a sensitive biological indicator of cadmium exposure and body burden, before the onset of severe renal dysfunction.     

Monitoring of cadmium toxicity in a Thai population with high-level environmental exposure

This study evaluated the utility of single and combined measurements of cadmium toxicity markers for surveillance purposes, using a sample of 224 individuals, 30-87 years of age, who were residents of cadmium polluted area in Mae Sot District, Tak Province, Thailand. Urinary cadmium levels excreted by them ranged between 1 and 58 microg/g creatinine with geometric mean of 8.2 microg/g creatinine which was 16-fold greater than the average for the general Thai population of 0.5 microg/g creatinine. The urinary markers evaluated were total protein, albumin, N-acetyl-beta-D-glucosaminidase (NAG), lysozyme, beta2-microglobulin (beta2-MG) and alpha1-microglobulin (alpha1-MG). Among these markers, only NAG showed a positive correlation with urinary cadmium in both male and female subjects with and without disease (r=0.43-0.71). Further, the prevalence rates for urinary NAG above 8 units/g creatinine (NAG-uria) increased with exposure levels in a dose dependent manner (p=0.05) among subjects with disease. In contrast, however, increased prevalence of beta2-MG above 0.4 mg/g creatinine (beta2-MG-uria) was associated with cadmium above 5 microg/g creatinine only in those without disease (POR=10.6 and 7.8 for 6-10 and >10 microg/g creatinine). Prevalence rates for abnormal excretion of all other markers, except albumin, were markedly increased among those having beta2-MG-uria with and without disease (chi2-test, p相似文献   

Urinary alpha 1-microglobulin as an indicator protein of renal tubular dysfunction caused by environmental cadmium exposure

An epidemiologic investigation was carried out to clarify the significance of the urinary excretion of alpha 1-microglobulin (alpha 1-MG) in people aged 50 years and over living in a Cd-polluted area in Japan. Approximately 80% of the population participated in the health examination. The urinary and serum levels and the relative clearance of alpha 1-MG to creatinine clearance were compared with various parameters (age, urinary beta 2-microglobulin (beta 2-MG), total protein, Cd, Cu and Zn, serum beta 2-MG, creatinine and blood urea nitrogen and relative clearances of alpha 1-MG, beta 2-MG, inorganic phosphate and uric acid). It was found that the urinary excretion of alpha 1-MG is closely associated with the urinary Cd and Cu and with the indices of renal dysfunction listed above. These results suggest that the urinary alpha 1-MG level markedly reflects a degree of proximal tubular dysfunction and that it may be useful as one of the screening measures for proximal tubular dysfunction caused by environmental Cd exposure.     

Determination of rat beta 2-microglobulin in urine and in serum. II. Application of its urinary measurement to selected nephrotoxicity models

beta 2-microglobulin (beta 2-m) was measured in the urine of rats by a specific immunoassay based on latex particles agglutination. The excretion of this protein was compared to the excretion of the enzyme beta-N-acetyl-D-glucosaminidase (NAG), albumin and amino acids in rats treated with either a single dose of sodium chromate (5 and 10 mg kg-1), repeated doses of gentamicin (5 and 20 mg kg-1), or cadmium (1 mg kg-1), and in aging rats (from 2 to 20 months). All treatments resulted in an early increased excretion of beta 2-m indicative of functional alterations of the proximal tubular cells. An increased NAG excretion was observed only at the highest dose of chromate and in the cadmium model but the relative increases of beta 2-m were much larger (up to 200 times the control values against four times the control values for NAG). From 2 to 20 months of age, urinary beta 2-m increases by a factor of four. Aminoacids excretion showed little sensitivity in the various models. Albumin showed little variations in purely tubular or in the tubular phase of renal injury but the chronic progressive nephrosis of aging rats caused a 40-fold increase in its excretion between 2 and 20 months of age. Therefore urinary beta 2-m, albumin and albumin/beta 2-m ratio provide useful tools in the assessment of nephrotoxicity and of its mechanisms in various experimental models.     

Alpha 1-microglobulin in urine as an indicator of renal tubular damage caused by environmental cadmium exposure

Alpha1-Microglobulin (alpha 1-m) was determined in the urine of both the cadmium-exposed and nonexposed subjects and was compared with those of other urinary parameters such as beta 2-microglobulin (beta 2-m), glucose, total protein or amino acids. Large amounts of alpha 1-m were detected in the urine of cadmium-exposed subjects. There were significant correlations between alpha 1-m and other urinary parameters. The sensitivity and specificity of both alpha 1-m and beta 2-m as indices of tubular dysfunction caused by cadmium was similar. It was concluded that alpha 1-m in urine seemed to be a useful indicator of renal tubular dysfunction caused by cadmium.     

Cadmium-induced renal dysfunction and mortality in two cohorts: disappearance of the association in a generation born later

The association between exposure to environmental cadmium and mortality was investigated in two cohorts. The study population consisted of 275 (cohort I) and 329 (cohort II) residents (aged >or=40 years) in a cadmium-polluted area, Nagasaki Prefecture, Japan, who had participated in health surveys conducted in 1982 and 1992, respectively. The follow-up period extended from 1982 or 1992 to 2005. In the study area, the dietary cadmium intake had decreased after 1980-1983 because of the restoration of cadmium-polluted paddy fields. In cohort I, the mortality rate among those with urinary beta2-microglobulin (beta2-MG) concentration >or=1000 microg/g creatinine (cr.) was 1.41 times higher than the regional reference rate (95% confidence interval [CI] 1.07-1.83). After adjusting for age and other variables, in men, urinary N-acetyl-beta-D-glucosaminidase, and in women, serum creatinine, beta2-MG clearance, and urinary beta2-MG were significantly associated with increased mortality. However, in cohort II, urinary beta2-MG or total protein was not significantly associated with survival. These findings indicate that cadmium-induced renal dysfunction was a significant predictor of mortality, but that such an association is disappearing, probably because of the selective loss of advanced cases and reduced exposure and body burden.     

alpha 1-Microglobulin determination in urine for the early detection of renal tubular dysfunctions caused by exposure to cadmium

The determination of alpha 1-microglobulin (alpha 1-m) in urine was compared with that of beta 2-microglobulin (beta 2-m) for the detection of renal tubular dysfunctions caused by exposure to cadmium. alpha 1-m In urine is stable down to pH 4.5, whereas beta 2-m degrades below pH 5.5. The relationship between the urinary pH and alpha 1-m or beta 2-m in urine showed that alpha 1-m was independent of urinary pH, whereas beta 2-m-concentration decreased as urinary pH fell to a pH level below 6. Without a pH effect, alpha 1-m was highly correlated with beta 2-m in urine (N = 174, r = 0.96) from Cd-polluted subjects with renal dysfunctions. Due to the greater stability of alpha 1-m in urine, alpha 1-m seemed to be more advantageous than beta 2-m for the detection of renal tubular dysfunctions caused by Cd.     

Urinary beta 2-microglobulin and retinol binding protein: individual fluctuations in cadmium-exposed workers

Urinary retinol binding protein (RBP) and beta 2-microglobulin (beta 2-m) were compared in apparently healthy population groups with and without occupational exposure to cadmium (Cd). The relationship observed in neutral urine was: RBP (micrograms/mmol creatinine) = 0.786 + 0.814 beta 2-m (micrograms/mmol creatinine). This relationship was similar to that reported for patients with various renal diseases [13]. Analysis of urine samples collected weekly from workers exposed occupationally to Cd revealed marked fluctuations, not only in the concentration of the acid-labile beta 2-m but also in the level of the pre-analytically more stable RBP. Therefore, repeated sampling and urine analyses are suggested as means to obtain more reliable data when monitoring Cd-exposed personnel.     

Increased endothelin excretion in rats with renal failure induced by partial nephrectomy.

1. Six weeks following partial nephrectomy in rats, significant increases in serum urea nitrogen and serum creatinine concentration and a significant decrease in creatinine clearance were observed. 2. Measurement of systolic blood pressure by tail plethysmography indicated that animals that had undergone partial nephrectomy were hypertensive. 3. Compared to sham-operated animals, there were 4 fold increases in both urinary protein excretion and urinary endothelin excretion. 4. There was a significant correlation between urinary protein and urinary endothelin excretion (r = 0.77). There was also a correlation (r = 0.65) between urinary endothelin excretion and systolic blood pressure. 5. Plasma endothelin concentrations were not different in sham-operated and partially nephrectomized rats. 6. The data indicate that there is an increased renal endothelin production in rats with chronic renal failure.     

Urinary trehalase activity as an indicator of kidney injury due to environmental cadmium exposure

One hundred and seventy-eight subjects, patients with Itai-itai disease and their family members, aged 12–87 years living in a cadmium (Cd)-polluted area in the Jinzu River basin (Cd-exposed group) and 176 controls (control group) were examined. In the Cd-exposed group urinary trehalase increased with increasing age, urinary 2-microglobulin (2-m) and retinol-binding protein. Although urinary cadmium was higher in the Cd-exposed group, no particular correlation was found between urinary trehalase and urinary cadmium. Seventeen men and 11 women showed raised urinary trehalase activities despite normal values of urinary 2-m (<300 g/g.creatinine), suggesting that urinary trehalase increases earlier than urinary 2-m. In 19 patients with Itai-itai disease included in the Cd-exposed group, urinary trehalase decreased with decreasing reciprocal of serum creatinine, suggesting that urinary trehalase decreases in the most advanced cases of chronic cadmium nephropathy due to reduced tubular cell mass.     

Occupational exposure to cadmium: effect on metallothionein and other biological indices of exposure and renal function

The effect of duration of employment at a North American cadmium smelter on urinary metallothionein (MT), total protein, ₂-microglobulin (2-MG), glucose, cadmium, copper and zinc of 53 men was studied. The levels of all urinary parameters increased with the duration of employment. Smoking history did not affect any of the above parameters studied. Although age was responsible for some of the changes noted in protein, glucose and ₂-MG levels, its effect on MT and cadmium was insignificant. All urinary parameters were significantly related with each other. The relationship of elevated urinary MT levels with respect to renal dysfunction was also examined. Subjects with abnormal renal function excreted significantly higher amounts of MT than did those with normal renal function. The results confirm not only that occupational exposure to cadmium over long periods results in renal dysfunction but also that urinary MT could be used to monitor exposure and ultimately the appearance of the renal dysfunction.     

Effect of N-benzyl-D-glucamine dithiocarbamate on the renal toxicity produced by subacute exposure to cadmium in rats

The effect of N-benzyl-D-glucamine dithiocarbamate (BGD) on the renal toxicity produced by subacute exposure to cadmium in rats was studied. Rats were injected sc with CdCl2 (1.5 mg Cd/kg) daily for 26 days and thereafter they received 13 injections of BGD (400 mumol/kg) every other day. Urinary protein concentration and AST activity significantly increased after 20 days of cadmium treatment. The pattern of the increase in the urinary excretion of cadmium after cadmium treatment was consistent with that in the urinary excretion of protein and AST. Urinary excretion of amino acid increased gradually after the cessation of cadmium treatment. BGD treatment significantly decreased the urinary excretion of protein, aspartate aminotransferase (AST), and amino acid. Plasma AST activity was elevated 8 days after the beginning of cadmium treatment, indicating that the hepatic damage occurred prior to the renal damage. In addition, the microscopic examination of renal tissue from cadmium-treated rats revealed the necrosis of the proximal tubular cells. The cadmium concentrations in liver and kidney were significantly decreased by BGD treatment. The results of this study indicate that BGD treatment is effective in decreasing the cadmium concentrations in liver and kidney, resulting in the therapeutic effect on the cadmium-induced renal damage.     

Changes in urinary proximal tubule parameters in neonatal rats exposed to cadmium chloride during pregnancy.

Pregnant Sprague-Dawley rats were injected intraperitoneally with physiological saline solution (vehicle) or cadmium chloride (CdCl2) at 2.0 or 2.5 mg kg-1 on days 8, 10, 12 and 14 of gestation. On postnatal day (PND) 3, 12 or 49, the offspring were examined for 8- or 24-h urinary excretion of beta 2-microglobulin (beta 2-m), metallothionein (MT) and urinary activity of three proximal tubular enzymes: gammaglutamyl transferase (GGT), alkaline phosphatase (ALP) and N-acetyl-beta-glucosaminidase (NAG). Treatment with CdCl2 did not affect growth or survival of offspring. Significant decreases in the urinary excretion of GGT, ALP and NAG were observed on PND 3, at both doses. Exposure to 4 x 2.5 mg kg-1 resulted in functional deficit of the proximal tubule on PND 3, as evidenced by the significant increase in beta 2-m. Except for a slight but significant increase of beta 2-m in 49-day-old males, all the other urinary parameters returned to control values on PND 12. There was no effect on MT. Results from this study show that prenatal exposure to CdCl2 can induce significant changes in the kidney biochemistry of rats in the early postnatal period.     

Estimation of benchmark dose for pancreatic damage in cadmium-exposed smelters.

The aim of this study was to estimate the benchmark dose (BMD) for pancreas dysfunction caused by cadmium (Cd) exposure in smelters. Smelter workers who had been exposed to Cd for more than 1 year and matching nonoccupationally exposed subjects were asked to participate in this study. Urinary cadmium (UCd) was used as a biomarker for exposure, serum insulin and amylase were used as biomarkers for pancreatic effects. In this study, serum insulin and amylase were lower in the smelter workers than in the nonoccupationally exposed subjects. A significant dose-response relationship with UCd was displayed. BMDs in terms of urinary Cd corrected for creatinine were calculated by use of BMDS (version 1.3.2). The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. It was found that the BMDL10 for serum insulin and serum amylase was 3.7 and 5.3 microg/g Cr, respectively. Compared to the BMDL for renal damage caused by Cd exposure, identified by the effect biomarkers urinary beta2-microglobulin, urinary N-acetyl-beta-glucosaminidase, and urinary albumin (UALB), it was shown that BMDL10 for serum insulin is the lowest among all values and UALB gave the highest value (5.8 microg/g Cr). This study indicates that Cd exposure can result in pancreatic dysfunction and the effect appears at lower urinary Cd level than renal dysfunction. The endocrine function of the pancreas was affected at lower urinary levels of Cd, compared to the exocrine function, which was seen at higher urinary levels of Cd than those giving rise to renal tubular dysfunction.     

Biomarkers of renal effects in children and adults with low environmental exposure to heavy metals

The health effects of chronic exposure to heavy metals such as lead, cadmium, and mercury are widely documented, yet few data exist about the renal impact of low environmental exposure to these metals, particularly in children. The aim of this study was to assess renal parameters in children and adults living in an environment known for its past heavy metal contamination around two nonferrous smelters in northern France (Noyelles-Godault and Auby) and to compare their results with age and gender-matched controls living in neighboring municipalities with unpolluted soil (total: 400 children, 600 adults, sex ratio = 1). The integrity of renal function was assessed by measuring the urinary excretion levels of total protein, albumin, transferrin, beta(2)-microglobulin, retinol-binding protein, brush border antigen, and the enzyme N-acetyl-beta-D-glucosaminidase (NAG). The mean blood concentrations of lead (Pb-B, children 相似文献   

贝那普利联合硫唑嘌呤对IgA肾病的疗效观察

目的探讨贝那普利联合硫唑嘌呤对IgA。肾病的治疗疗效及安全性。方法收集我科2003年1月一2007年12月36例IgA。肾病患者,病理分级均采用LEE氏分级法,均在Ⅲ～V级之间,24h尿蛋白定量在1一3g之间。随机分为治疗组和对照组。其中治疗组20例,对照组16例。治疗组在病理诊断后以贝那普利联合硫唑嘌呤治疗,贝那普利10mg／d,硫唑嘌呤2mg／kg·d。对照组仅以贝那普利10mg／d治疗。观察9个月后临床评估患者血清肌酐水平、肝功能、血脂及24小时尿蛋白定量。结果经过9个月的治疗,贝那普利对照组患者的24小时蛋白尿从（1．82±1．23）g／L减少至（1．32±0．27）g／L;血清肌酐水平从（97．34±11．25）μmol／L上升至（126．34±13．43）μmol／L。而贝那普利联合硫唑嘌呤24小时蛋白尿从（1．78±1．11）g／L减少至（0．65±0．45）g／L,与对照组比较,差异有显著性（P〈0．05）;而治疗后血清肌酐水平为（106．34±11．27）μmol／L,与对照组比较,差异有显著性（P〈0．05）。两组在血脂水平方面,治疗前后均无明显差异（P〉0．05）。结论对IgA肾病病理分级在3级以上,24小时尿蛋白定量在1～3g之间的患者,贝那普利联合硫唑嘌呤能明显降低患者的尿蛋白及保护患者的肾功能。     

Significance of increase in urinary metallothionein of rats repeatedly exposed to cadmium

Cadmium chloride was injected subcutaneously (s.c.) into female Wistar rats at a dose of 1 mg Cd/kg body weight, 5 times a week up to 10 weeks. At specified intervals, 24-h urine was collected and the excreted amounts of metallothionein (MT), cadmium, copper, zinc and several indicators of renal damage were determined. Concentrations of cadmium and MT in the livers and kidneys of rats were also determined. Both cadmium and MT in the livers and kidneys were increased upon cadmium exposure. The urinary MT excretion started to increase within a week after the start of exposure. This increased excretion preceded those of enzymes and total protein as well as histopathological abnormalities in the proximal tubular cells. After the occurrence of tubular damage that disturbs reabsorption of MT, MT in urine was drastically increased. These results indicate that urinary MT levels may be an indicator not only of cadmium exposure but also of tubular damage.