Hidetoyo Teranishi

Hypoproduction of erythropoietin contributes to anemia in chronic cadmium intoxication: clinical study on Itai-itai disease in Japan

Itai-itai disease is a condition caused by longterm exposure of the inhabitants of Toyama prefecture, Japan, to cadmium intoxication. The characteristic clinical features of this disease include renal tubular dysfunction, osteomalacia, and anemia. In order to clarify the pathogenesis of the anemia, the red blood cell count, hemoglobin concentration, hematocrit, serum iron level, total ironbinding capacity, serum ferritin level, serum erythropoietin level, creatinine clearance, fractional excretion of β2-microglobulin, and bone marrow morphology were determined in ten patients with Itai-itai disease. Low serum iron or ferritin levels were not observed, and bone marrow aspiration did not reveal any specific hematological disorders. A close relationship was observed between the decrease in the hemoglobin level and the progression of renal dysfunction. Low serum erythropoietin levels were detected despite the presence of severe anemia. These results suggest an important role of renal damage in the anemia which develops in Itai-itai disease.

Assessment of bone metabolism in cadmium-induced renal tubular dysfunction by measurements of biochemical markers

Bone metabolism related to the severity of cadmium (Cd)-induced renal tubular dysfunction (RTD) was assessed by measuring several bone biochemical markers. Fifty-three female subjects with RTD aged 65-76 years (mean 70.0+/-3.3 years) and who lived in the Cd-polluted Jinzu River basin in Toyama, Japan were studied. Bone alkaline phosphatase (bone-ALP), intact bone Gla-protein (intact-BGP) and carboxy-terminal propeptide of type I collagen (PICP) in serum as bone formation markers and pyridinoline (Pyr) and deoxypyridinoline (Dpyr) in urine as bone resorption markers were measured. All markers of bone turnover were increased and significantly correlated with each other, suggesting that bone formation and resorption were coupled and increased in Cd-induced RTD. Fractional excretion of beta(2)-microglobulin (beta(2)-m, FE(beta 2-m)) as an index of severity of Cd-induced RTD was extremely varied ranging from 0.45 to 53%. There were no significant correlations between FE(beta 2-m) and each of the five bone biochemical markers. The bone turnover in Cd-induced RTD appeared to be determined by the glomerular filtration rate (GFR): in subjects with GFRs above 50 ml/min, the levels of bone-ALP or intact-BGP tended to be inversely related to the GFRs, whereas in subjects with GFRs below 40 ml/min, those levels tended to decrease. These results suggest that the bone turnover, in particular the bone formation, was influenced by renal tubular function as assessed by the levels of GFR in Cd-induced RTD.

Occupational Allergy to Adult Chironomid Midges among Environmental Researchers

A case of occupational allergy to chironomid midges in research work is described. A researcher was exposed to adult chironomid midges during his research and developed allergic rhinitis after 10 years of such exposure. Using the midge extract of adult Chironomus plumosus (CP) (Linnaeus, 1758), both immediate skin test and the ophthalmic challenge test gave positive results. IgE antibody against adult CP was also demonstrated by the radioallergosorbent test. Four of the five serum samples of the environmental researcher examined showed a positive radioallergosorbent test to at least one of the adult midges breeding around eutrophic Japanese lakes. Enzyme-linked immunosorbent assay inhibition test and immunoblot experiments indicated that the remaining hemoglobin is one of the major allergens of adult CP. These results demonstrate that the exposure to adult chironomid midges is an important occupational hazard among environmental researchers.

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 β2-microglobulin (β2-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 β2-m (<300 μg/g.creatinine), suggesting that urinary trehalase increases earlier than urinary β2-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.

Elevation of urinary trehalase activity in patients of itai-itai disease.

The elevation of urinary trehalase activity in patients of itai-itai disease was examined. Urinary trehalase was correlated with tubular reabsorption of phosphorus (%TRP): the lower the trehelase activity, the worse was %TRP. Furthermore, this activity was inversely correlated with urinary glucose and urinary total protein. In itai-itai disease, the excretion of β2-microglobulin seems to be maximal, and urinary trehelase activity was low in the latter stages of the disease. It is inferred that itai-itai disease produces extremely severe tubular damage as well as glomerular dysfunction.

Severity of tubular brush border damage in cadmium-polluted area (Jinzu River Basin): Clinical role of urinary trehalase

Urinary trehalase activity and leucine aminopeptidase activity were parabolically correlated with urinary beta 2-microglobulin, and these enzymes were observed to be biphasic in relation to urinary beta 2-microglobulin when the study populations included patients of Itai-itai disease and inhabitants of a cadmium-polluted area. Furthermore, urinary trehalase activity was parabolically correlated with urinary total protein and urinary glucose. From these results, it is inferred that by measuring both urinary trehalase and urinary beta 2-microglobulin, one can elucidate the degree of tubular damage.