Cadmium-induced Renal Dysfunction Research Articles

Urinary proteins and enzymes as early indicators of renal dysfunction in chronic exposure to cadmium

We tested the diagnostic sensitivity of various urinary analytes for detecting cadmium-induced nephropathy at an early stage. We investigated 73 healthy persons (control group 1) and individuals exposed to cadmium, either environmentally (n = 36, risk group 2) or occupationally (n = 62, exposed group 3). All data were related to limits of the central 95% reference intervals of the control group. The serum creatinine and ribonuclease values, indicators of the glomerular filtration rate, were not different in the three groups. In the exposed persons (group 3), proximal tubular indicators (low-M(r) proteins lysozyme, ribonuclease, retinol-binding protein, and alpha 1-microglobulin) were more often increased than the glomerular indices (higher-M(r) proteins transferrin, IgG, and albumin). Both the low-M(r) proteins and tubular enzymes were differently altered in their excretion rates. Alanine aminopeptidase, alkaline phosphatase, and N-acetyl-beta-D-glucosaminidase increased even in the risk group 2. alpha 1-Microglobulin was increased in the exposed persons whose cadmium excretion was < 5 mumol/mol creatinine. The combined determination of alpha 1-microglobulin and N-acetyl-beta-D-glucosaminidase exceeded the corresponding upper reference limits in 30% of group 2 and 39% of group 3. We recommend screening for these two analytes to detect cadmium-induced renal dysfunction at an early stage.

Urinary Protein Excretion and the Diagnosis of Cadmium-Induced Renal Dysfunction

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Effects of zinc, selenium, and calcium on the nephrotoxicity of cadmium in primary cultures of rat renal proximal epithelial cells

The influence of essential metals, like zinc, selenium, and calcium, on the nephrotoxicity of cadmium was studied in primary cultures of rat proximal tubular cells. Damage to kidney cells was assessed by measuring the release of lactate dehydrogenase (LDH), γ-glutamyltranspeptidase (GTP), and β-N-acetylglucosaminidase (NAG) from cells into the medium and the cellular concentration of protein. Incubation with 200 μM cadmium in the presence of equivalent molar or lower concentrations of zinc and selenium showed greater release of LDH and NAG than cadmium alone, indicating an enhanced effect. However, metallothionein (MT) induced by pretreatment with a nontoxic concentration of zinc decreased significantly the release of enzyme from cells and elevated cellular protein levels in response to MT levels. MT provided partial protection against the nephrotoxicity of cadmium. Decreased calcium levels in the incubation medium also resulted in markedly increased release of LDH and NAG from cells exposed to cadmium and reduced cellular protein levels. These findings suggest that variations in zinc and calcium intake may affect the development of cadmium-induced renal dysfunction.

Abnormalities of calcium, phosphorous and vitamin D metabolism with proximal renal tubular dysfunction in subjects environmentally exposed to cadmium

Calcium, phosphorus and vitamin D metabolism were examined in 21 male and 13 female subjects with renal tubular dysfunction in the cadmium-polluted Jinzu River basin in Toyama prefecture, Japan. Multiple proximal renal tubular dysfunction was detected in all subjects showing increased FE beta 2-m and FFua, generalized aminoaciduria and renal glucosuria. Reduced ability of tubular reabsorption of phosphate resulted in hypophosphatemia in 31% of the women. Despite decreased tubular reabsorption of calcium, the level of serum calcium remained normal in all subjects. Serum 1,25-dihydroxyvitamin-D [1,25(OH)2D], which is produced in the proximal tubules through 1 alpha-hydroxylation from 25-hydroxyvitamin-D [25OHD], was normal or increased to more than 60pg/ml. The serum level of 1,25(OH)2D was inversely related to creatinine clearance in both the men (p < 0.05) and women (p < 0.01). Serum iPTH was slightly increased to more than 0.9 mg/ml, whereas the levels of other hormones, including 25OHD, calcitonin, thyroxine (T4) and triiodothyronine (T3) were normal. The serum alkaline phosphatase activity and serum osteocalcin concentration were significantly increased compared to those of controls in both sexes. Bone loss detected by the measurement of bone density was prominent in female subjects. These results support the hypothesis that the serum phosphate concentration is more important than the serum concentration of 1,25(OH)2D for abnormalities of bone metabolism in cadmium-induced renal tubular dysfunction.

Preliminary study on serum levels of 1, 25-dihydroxyvitamin D and 25-hydroxyvitamin D in cadmium-induced renal tubular dysfunction

Serum 1, 25-dihydroxyvitamin D [1, 25(OH) 2D] and 25-hydroxyvitamin D [25(OH)D] were measured in 7 women living in a cadmium-polluted area in Toyama, Japan. Despite the fact that these subjects had severe proximal renal tubular dysfunction showing increased fractional excretion of β 2-microglobulin (FEβ 2-m) ranging from 9.7–49.1% with a mean of 30.75%, the levels of serum 1, 25(OH) 2D, which is produced in the proximal tubules, were within the normal range in 6 subjects. Significant correlations were found between 1, 25(OH) 2D and creatinine clearance ( r=0.802, P < 0.05), and FEβ 2-m ( r= −0.829, P < 0.05), respectively. These results suggest that renal production of 1, 25(OH) 2D decreases with progression of cadmium-induced renal tubular dysfunction.

Association between Cadmium-Induced Renal Dysfunction and Mortality: Further Evidence.

Our previous follow-up study, carried out from 1979 to 1989, on 256 residents of Sasu, a cadmium (Cd)-polluted area located on Tsushima Island, Nagasaki Prefecture, Japan, showed a significant relationship between urinary beta 2-microglobulin (beta 2-m) excretion and mortality in men. To investigate the association between Cd-induced renal dysfunction and mortality more precisely, 275 residents in the same area aged 40-92 years, who had participated in a health survey conducted in May 1982, were followed to February 1989. The expected number of deaths was calculated on the basis of the sex- and 5-year-age-specific mortality rates for Tsushima Island in 1985. In both men and women with urinary beta 2-m concentrations greater than 1,000 micrograms/g creatinine, observed deaths were greater than the expected. However, the P value of the difference was less than 0.05 only in women. Analysis by the Cox proportional hazards model showed that, in both men and women, serum beta 2-m and creatinine, as well as urinary total protein and beta 2-m were significantly or marginally significantly related to mortality independent of age. In men, serum beta 2-m was more strongly related to mortality than urinary beta 2-m. The results provide further evidence for the causal association between Cd-induced renal dysfunction and mortality. The present report also discusses the role played by decreased glomerular filtration rate in the excess mortality of subjects with Cd-induced renal dysfunction.

Prevalence of metallothioneinuria among the population living in the Kakehashi river basin in Japan — an epidemiological study

An epidemiological study to evaluate cadmium-induced renal dysfunction by urinary metallothionein levels was carried out in an environmentally-exposed Japanese population. the study population consisted of 3168 men and women from a cadmium-polluted area who were 50 years and older and 291 individuals from a non-polluted area. The mean metallothionein levels in urine of the control population were 138.2 ± 2.1 and 198.6 ±1.9 μg/g creatinine for men and women, respectively. The corresponding values for the cadmium-exposed population were 157.8 ± 2.2 and 248.0 ± 2.2. The 97.5% upper limits for men in the control population was determined to be 638 and for women 693 μg MT/g creatinine. Based on these values as the cut-off levels, the prevalence of metallothioneinuria was calculated to be 4.6% in men and 8.4% in women from the cadmium-polluted area. Further selection of the population, based on life-time residence in the polluted area accompanied with the consumption of cadmium-containing rice, showed an even greater prevalence of metallothioneinuria: 5.4% in men and 10.9% in women of all ages. The prevalence of metallothioneinurial increased with age and duration of residence in the polluted area. These results suggest that metallothioneinuria can be used as an indicator of renal dysfunction due to environmental cadmium exposure.

Long-Term Observation of Serum Creatinine and Arterial Blood pH in Persons with Cadmium-Induced Renal Dysfunction

Twenty-one subjects who had cadmium (Cd)-induced renal dysfunction and who lived in a Cd-polluted area in Japan were investigated to determine changes in their renal function. Since 1974, serum creatinine and arterial blood pH were measured annually during the autumn months for 9-14 y. Mean serum creatinine was significantly increased during this period, i.e., from 1.19 +/- 1.28 mg/100 ml to 1.68 +/- 1.56 mg/100 ml. Even after cadmium exposure ceased, significant deterioration of glomerular filtration was found. Eleven subjects showed a greater than 20% serum creatinine increase during this period. The most severe case had a serum creatinine value of 4.4 mg/100 ml at the most recent examination and experienced generalized edema, which suggests a clinical diagnosis of renal failure. The mean arterial blood pH values decreased significantly in all subjects, i.e., from 7.400 +/- 0.023 to 7.361 +/- 0.034. The 11 subjects cited above also showed a significant decrease and progression of tubular dysfunction after Cd exposure ceased. Our findings suggest that Cd-induced renal tubular dysfunction and decreased glomerular filtration are aggravated even after cessation of environmental Cd exposure, and in some cases this renal dysfunction may progress to renal failure.

Evaluation of qualitative and quantitative tests for proteinuria and glucosuria as screening tests for cadmium-induced renal tubular dysfunction.

To evaluate the screening tests for cadmium-induced renal tubular dysfunction, qualitative and quantitative tests for urinary protein and glucose have been done in 146 urine samples obtained from subjects who had lived in the cadmium-polluted Jinzu River basin in Toyama Prefecture, Japan. The subjects consisted of 66 men and 80 women aged 55 to 71 years with beta 2-microglobulinuria exceeding 1,000 micrograms/g creatinine. The results obtained from this study were as follows; 1) The positive reaction (above 1+) for protein by the dipstick method was seen in 19.7% of men and 20.0% of women, and for glucose using Tes-tape in 48.5% of men and 33.8% of women. 2) The geometric means of protein and glucose concentrations in urine were 16.4 mg/dl and 12.7 mg/dl in men, and 14.2 mg/dl and 6.8 mg/dl in women, respectively. 3) The criteria of the primary screening in the health survey system for the residents in cadmium-contaminated areas conducted by the Japan Environment Agency were a proteinuria level exceeding 10 mg/dl and a glucosuria above (+/-) with Tes-tape. Nearly all subjects with urinary beta 2-microglobulin exceeding 30 mg/g creatinine were screened by these criteria in both sexes, whereas only 52.9% of men and 30.0% of women who had urinary beta 2-microglobulin between 10 to 30 mg/g creatinine could be screened in this manner. These results indicate that semiquantitative tests are insufficient as initial tests for screening cadmium-induced renal tubular dysfunction.

カドミウム腎障害における酸塩基平衡異常

カドミウム腎障害における酸塩基平衡異常

カドミウムによる腎障害の暴露軽減後の予後に関する追跡調査

カドミウムによる腎障害の暴露軽減後の予後に関する追跡調査

Kidney changes in multiparous mice fed a nutrient-sufficient diet containing cadmium

Female mice were given nutrient-sufficient, purified diets containing cadmium at either 0.25, 5, or 50 ppm, as described in the accompanying publication [1]. One-half of the females were bred for 6 consecutive 42-day rounds of pregnancy/lactation (PL mice); remaining females were non-pregnant controls (NP mice). PL mice and NP controls were sacrified after 1, 2, 4, or 6 consecutive rounds of pregnancy/lactation. At all levels of dietary cadmium and after all reproductive rounds, kidney cadmium concentrations were 2–5-fold higher in PL than NP mice. After 6 rounds of reproduction, the mean concentration of cadmium in the kidneys of PL mice exposed to dietary cadmium at 50 ppm was 115 μg Cd/g kidney, close to the critical concentration for cadmium-induced renal damage (200 μg/g). No consistent increases in the concentrations of amino acids, protein, or cadmium in urine were observed in the NP or PL mice in our study, indicating that cadmium-induced renal dysfunction had not yet appeared. Very small increases in kidney concentrations of zinc and copper were observed with large increases in kidney cadmium concentrations. Threshold cadmium concentrations below which the concentrations of zinc and copper were relatively constant and independent of cadmium concentration were identified; they were 7.2 μg Cd/g kidney for zinc and 13 μg Cd/g kidney for copper. In this study, cadmium-induced decreases in bone-mineral content occurred in the PL mice exposed to cadmium at 5 and 50 ppm (see accompanying publication). Data presented here indicate that the latter bone changes occurred in the absence of cadmium-induced renal dysfunction of the type that results in increased aminoaciduria/proteinuria. They suggest that the bone disease of Itai-Ital patients may also have started prior to the onset of this type of renal dysfunction.

Progress of renal dysfunction in inhabitants environmentally exposed to cadmium.

The reversibility of beta 2-microglobulinuria, glucosuria, and aminoaciduria was examined in 74 inhabitants (32 males and 42 females) over 50 yr of age, who lived in a cadmium-polluted area. The subjects participated in two examinations conducted just after the cessation of cadmium exposure and 5 yr later. All urinary parameters did not show reversible changes. During the 5 yr the geometric mean concentrations of beta 2-microglobulinuria, glucosuria, and aminoaciduria indicated significant increases in excretion. In cases where greater than 1,000 micrograms/g creatinine of beta 2-microglobulinuria was observed (at the time cadmium exposure ended), almost all individuals exposed to cadmium showed deterioration of beta 2-microglobulinuria, whereas in the case of less than 1,000 micrograms/g creatinine of beta 2-microglobulinuria, no significant changes were observed. The present study indicates that cadmium-induced renal dysfunction in individuals environmentally exposed to cadmium is irreversible.

Environmental exposure to cadmium and effects on human health. Part 2. Bone and mineral metabolism in inhabitants of the cadmium-polluted Jinzu River basin in Toyama Prefecture

Serum calcium and phosphorus concentrations, alkaline phosphatase activity and the metacarpal bone mass were measured in 85 female inhabitants of the cadmium-polluted Jinzu River basin aged 55-71 years who had various concentrations of β2-microglobulin (β2-m) in urine. The relationship between cadmium-induced renal tubular dysfunction and abnormalities of calcium and phosphorus metabolism was studied.1) Most of the values for serum calcium were within the normal range. However, fractional calcium excretion (FEca) was increased in 81 subjects (95.3%). The correlation coefficient between urinary excretion of β2-m and FEca was significant (r=0.352, p<0.005).2) Serum phosphorus concentration averaged 3.16±0.48ml/dl and the values found in 28 subjects (32.9%) were below the normal lower limit (3.0mg/dl). There was a significant correlation between serum phosphorus level and TmP/GFR (r=0.797, p<0.001). These observations show that hypophosphatemia is due to excessive renal phosphate excretion.3) Serum alkaline phosphatase activity was definitely elevated in 29 subjects (34.1%). A significant positive correlation of alkaline phosphatase activity and urinary β2-m level was present (r=0.346, p<0.005).4) The metacarpal index (MCI) and ΣGS/D of the second right metacarpal bone were measured by the quantitative microdensitometric method. A significant negative correlation of the urinary β2-m level with MCI and ΣGS/D was present (p<0.01). This result suggested that the degree of renal tubular dysfunction was related to the bone mass.5) This study showed that the inhabitants with severe renal tubular dysfunction had hypophosphatemia due to excessive renal phosphate excretion, increased urinary excretion of calcium, elevated activity of serum alkaline phosphatase and decreased bone mass. We proposed that these cases be diagnosed as latent renal tubular osteomalacia.

Cumulative blood-cadmium and tubular proteinuria: a dose-response relationship.

Biological monitoring, i.e. using individual measures of exposure such as cadmium in blood, is supposed to reflect the real dose better than the more commonly used external measures such as air-cadmium. In order to investigate this, cumulative cadmium doses were estimated individually for 440 workers in a battery factory. Cumulative air-cadmium dose as well as two different cumulative blood-cadmium doses were computed for each study individual. Forty workers had evidence of tubular proteinuria and a clear dose-response relationship was found for each of the dose estimates. Our results suggest that cumulative blood-cadmium is a more sensitive indicator of cadmium-induced renal dysfunction than cumulative air-cadmium.

A suggestion on how to use measurements of cadmium in blood as a cumulative dose estimate.

The individual cumulative cadmium dose was estimated for 44 smelter workers in a cadmium-copper alloy plant. Two different principles were used: cumulative respiratory dose and cumulative average annual blood-cadmium dose. Out of eight workers with a cumulative respiratory dose exceeding 500 mg Cd . h/m3, two of them (25%) had signs of a cadmium-induced renal dysfunction. These two men were the only workers that had a cumulative average annual blood cadmium dose exceeding 200 micrograms Cd . year/l. Our results suggest that measurements of cadmium in the blood can be used as an indicator of the cadmium exposure of each individual and that, in order to prevent renal dysfunction, the average blood-cadmium concentration should not exceed 10 micrograms Cd/l over periods of many years (decades).

Use of high-resolution proton nuclear magnetic resonance spectroscopy for rapid multi-component analysis of urine.

Numerous low-Mr metabolites--including creatinine, citrate, hippurate, glucose, ketone bodies, and various amino acids--have been identified in 400- and 500-MHz proton nuclear magnetic resonance (1H NMR) spectra of intact human urine. The presence of many of these was related to the specific condition of the donors: humans in different physiological states (resting, fasting, or post-exercise) and pathological conditions (e.g., diabetes mellitus, cadmium-induced renal dysfunction). We have also monitored the metabolism of simple nonendogenous compounds (methanol and ethanol) and of acetaminophen. The pH-dependencies of the NMR chemical shifts of some urine components are reported. Our studies show that high-resolution 1H NMR spectroscopy provides a fast, simple method for "fingerprint" identification of urinary compounds. In some cases, analytes can be quantified by standard additions or by comparing integrated peak areas for the metabolites with those for creatinine. Determinations of creatinine by 1H NMR spectroscopy compared well with those by an independent chemical assay based on the Jaffé reaction.

Evolution of cadmium-induced renal dysfunction in workers removed from exposure.

A retrospective examination of the medical records gathered during several surveys carried out among cadmium workers has permitted the identification of a group of 19 workers who had been examined before and after removal from cadmium exposure. All the workers had been exposed for more than 15 a (range 15.6-41.7 a). Their last examination took place from 0.3 to 7.9 a after the date of removal from cadmium exposure. At that time, all the workers exhibited sign(s) of cadmium-induced renal dysfunction. Comparison of the renal function parameters (serum creatinine, total proteinuria, aminoaciduria, albuminuria, beta 2-microglobulinuria, and the urinary excretion of retinol-binding protein) before and after the cessation of exposure indicated that cadmium-induced renal lesions, albeit of slow progression, are not reversible when exposure ceases.