Biologic indicators of cadmium nephrotoxicity in persons with low-level cadmium exposure.

The relationship between abnormal urinary findings and renal function was investigated for 33 Itai-Itai patients, 17 suspected patients, 235 subjects exposed to Cd and 41 subjects not exposed to Cd pollution. High correlation coefficients were observed between urinary findings and renal function in advanced cases of chronic cadmium poisoning, and multiple correlation coefficients between them are as high as 0.73 to 0.86. beta 2-microglobulin in urine also correlated closely with renal function and age in slight to moderate cases of cadmium poisoning. It is concluded that urinary findings such as proteinuria, glucosuria and low molecular weight proteinuria are good indicators of renal dysfunction in moderate to severe cases of chronic cadmium poisoning. In slight to moderate cases beta 2-microglobulin in urine has a close relation with renal dysfunction.


Introduction
It is well known that environmental cadmium exposure can cause renal damage. There are many cadmium-polluted areas in Japan, and inhabitants living in some of the cadmium-polluted areas suffer from renal damage (1). Renal damage is manifested by abnormal urinary findings, such as low molecular weight proteinuria, glucosuria and aminoaciduria. Renal function tests also reveal both tubular and glomerular dysfunctions (2,3). Abnormal urinary findings are usually used as indicators of renal damage caused by environmental cadmium exposure because urine specimens are easy to collect from large numbers of people. It is reported that the prevalence of abnormal urinary findings is significantly higher in cadmium-polluted areas than in nonpolluted areas (1).
However, the significance of such urinary findings is not yet completely clear, and there is some controversy regarding the early signs of renal damage. 02-microglobulin in urine is considered to be one of the early signs of renal tubular damage caused by cadmium exposure. However, 02-microglobulin level in urine is also said to *Department of Hygiene, Kanazawa Medical University, Uchinada, Ishikawa 920-02, Japan.
increase with age and to be independent of renal dysfunction.
The purpose of the present study is to elucidate the significance of urinary findings which are observed in cadmium-polluted areas by comparing urinary findings and renal function tests. In the first part of this paper, the relationships between urinary findings and renal function tests on Itai-Itai patients as well as suspected patients who were considered as the most severe cases of chronic cadmium poisoning are reported. In the second part, results obtained on people living in cadmium-polluted area and showing abnormal urinary findings are examined and compared with values from people living in a nonpolluted area. The effect of age on excretion of 02-microglobulin in urine was of special interest.

Materials and Methods
In 1976 and 1977, 41 Itai-Itai patients and 17 suspected patients, all female, were admitted to The Kanazawa Medical University Hospital and received a detailed medical examination. Morning urine specimens were collected from them.
The following urinary parameters were analyzed by the methods reported earlier: 02-microglobulin (p2-mg), retinol binding protein (RBP), lysozyme, glucose, total protein, amino acid, proline, creati- For the second part of the study, 84 male and Table 1 presents urinary findings and renal 151 female inhabitants in the cadmium-polluted function parameters of 50 subjects examined in Kakehashi River basin in Ishikawa Prefecture The University Hospital. Urinary values were were selected from inhabitants over 50 years of expressed as values per weight creatinine. The age by performing urine examination for glucose, ranges of urinary values and renal function patotal protein, amino acid and 2-mg. The subjects rameters were very wide, indicating that condiselected showed an abnormal value for at least tions of subjects were almost normal to very seone of the urinary parameters mentioned above.
vere. The mean age was 70 years old. A simple Morning urine specimens were collected from the correlation matrix between various biological paselected subjects and analyzed for 02-mg by ra-rameters in urine is shown in Table 2. Most of the dioimmunoassay method (Phadebas 02-mg test, parameters, except for cadmium, showed signifi-Pharmacia). Ccr and %TRP were used as indica-cant correlation. Correlation coefficients between tive of renal function. The inhabitants gathered total protein and three kinds of low molecular at their community centers early in the morning.
weight protein were 0.70-0.85. However, signifi-   Table 3 shows a simple correlation matrix between different renal function tests. All of the correlation coefficients were significantly high. Correlation coefficients between urinary parameters and renal function tests are shown in Table 4. All correlation coefficients between low molecular weight protein, total protein and renal function tests were significant (r = -0.39 to -0.67). Glucose showed a significant correlation to %TRP and bicarbonate.
Significant correlations were observed between proline and all renal function tests except CPAH. Amino acid showed a significant correlation only to %TRP. No significant correlation were observed between cadmium and renal function tests. Table 5 shows multiple correlation coefficients between renal function tests and biological parameters in urine. All of the multiple correlation coefficients were significantly high, ranging from 0.73 to 0.84. ,32-mg and age of subjects from polluted areas and control subjects. The renal functions were significantly lower in subjects from the Cd-polluted areas than in the controls. Correlations between 132mg in urine and Ccr or %TRP in for both sets of subjects are presented in Figures 1 and 2. 02-mg is expressed on a logarithmic scale.

Renal Function Parameters for Kakehashi River Basin Inhabitants
In subjects from the polluted area, f2-mg in urine increased with a decrease of Ccr or %TRP. However, control subjects did not show such a tendency. Table 7 indicates correlation coefficients for 12-mg in urine, Ccr, %TRP and age in both sets of subjects. All of the correlation coefficients were significantly high among the male and female subjects from the polluted area. In control subjects, correlations were significant only between Ccr and age or %TRP in the female. Table 8 shows partial correlation coefficients for 12-mg in urine, Ccr, %TRP and age in both sets of subjects. The correlations were significant between P2-mg and C,. or %TRP when age was fixed in the subjects from the polluted area. Significant correlations were also observed between 132-mg and age when Ccr and %TRP were fixed. However, no significant partial correlations were found in control subjects.

Discussion
Renal damage in residents of the Cd-polluted areas was shown by the existence of abnormal urinary findings and decreased renal function. Abnormal urinary findings included increased excretion of total protein, glucose, amino acids, enzyme and low molecular weight protein such as 132-mg, RBP or lysozyme. Increased urinary excretion of these substances was more frequently observed in residents of Cd-polluted areas than of nonpolluted areas (1). Therefore, these urinary   findings are considered to indicate the existence dysfunction. There was a significantly high correof renal damage caused by environmental cad-lation among urinary findings except cadmium. mium exposure. However, the clinical signifi-Renal function tests also showed a significant cance of the abnormal urinary findings remains a high correlation with each other, indicating that question, specifically in relation to clinical renal in advanced cases of chronic cadmium poisoning tubular dysfunction.
the urinary parameters and renal functions para-Increased excretion of 02-mg in urine at an llel each other. It should be noted that age had no early stage of cadmium exposure is considered to close association with urinary or renal function be a more sensitive parameter than other abnorparameters. The high correlation coefficients bemal urinary findings. However, some reports indicate a close association between increase of 02- Table 7. Simple correlation matrix between various mg in urine and age (4,5). Therefore, an increase biological parameters in subjects from polluted areas   04 * tween urinary findings and renal function demonstrated that urinary findings have a close relationship with renal function. The multiple correlation coefficients between renal function tests and urinary findings were as high as 0.73 to 0.84. This means that renal functions could be estimated from the urinary parameters.
In the second part of this study, the significance of early urinary findings of chronic cadmium poisoning were examined. p2-mg was used as an early urinary sign, and the target group was the inhabitants of a Cd-polluted area who showed at least one positive urinary finding, such as proteinuria, glucosuria or P2-microglobulinuria.
Renal function of the residents of the Cd-polluted area was better than that of Itai-Itai patients; however, a significant decrease of renal function was observed compared with control subjects. Therefore the renal functions of the residents of the Cd-polluted area were better than those of Itai-Itai patients and poorer than those of the control subjects.
Correlations between 32-mg and Ccr, %TRP or age were significant in the residents of the Cdpolluted area. Partial correlations for these subjects were also significant between p2-mg and renal function or between 032-mg and age when age or renal function was fixed. The control subjects did not show such significant partial correlations. It is reasonable to say from these facts that p2-mg in urine has a significant relation to renal dysfunction and age in the early stage of chronic cadmium poisoning. However, the influence of age on p2-mg in urine of polluted subjects must be much less than that of renal dysfunction. In general, age has two aspects, namely, as a physiological factor and as a measure length of exposure to cadmium. It is usually difficult to separate these two to clarify the influence of age on urinary excretion of 02-mg. We believe that the influence ofphysiological factors was much less than that of duration of long-term exposure to cadmium for 2mg in urine. In the early stages of cadmium exposure both factors may have an effect on the excretion of 02-mg into urine.
In conclusion, the present study indicates that urinary findings are good indicators ofrenal function in advanced cases of chronic cadmium poisoning. 32-mg in urine has also significant meaning in evaluating renal function in the early stage of chronic cadmium poisoning.