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

Abstract

Itai-itai disease is a condition caused by long-term 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 iron-binding capacity, serum ferritin level, serum erythropoietin level, creatinine clearance, fractional excretion of beta 2-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.

Latest status of cadmium accumulation and its effects on kidneys, bone, and erythropoiesis in inhabitants of the formerly cadmium-polluted Jinzu River Basin in Toyama, Japan, after restoration of rice paddies

“…Additionally, the serum EPO level remained low (25.4 mIU/ml) despite the very low Hb level (8.8 g/dl), which would have been much higher in the absence of renal injury (Erslev et al 1980). These results indicate that she suVered from renal anemia, one of the major clinical manifestations of itai-itai disease (Horiguchi et al 1994). …”

“…These patients experience bone fractures, pseudofractures, and deformed spines, and complain of severe generalized pain due to osteomalacia (itai means "ouch"). They also often suVer from anemia due to insuYcient renal production of erythropoietin (EPO), an erythroid-speciWc glycoprotein hormone that promotes erythrocyte production (Ebert and Bunn 1999)-in short, renal anemia (Horiguchi et al 1994;Nordberg et al 2007). Nearly 200 patients with itai-itai disease have been identiWed so far, most of whom are middle-aged to old women who have had multiple births.…”

Suppression of erythropoietin gene expression by cadmium depends on inhibition of HIF-1, not stimulation of GATA-2

“…The characteristic clinical features of this disease include renal tubular dysfunction, osteomalacia, and anemia (Kasuya et al 1992). A clinical report demonstrated that the anemia observed in patients with Itai-itai disease is caused primarily by the impaired production of erythropoietin (Epo) (Horiguchi et al 1994). In addition, long-term exposure of rats to cadmium (Cd) resulted in the marked suppression of Epo mRNA expression in the kidneys, and the development of severe anemia (Horiguchi et al 1996).…”

A comparative evaluation of the biological effects of environmental cadmium-contaminated control diet and laboratory-cadmium supplemented test diet

“…In order to provide a clear understanding of the biochemical changes that precipitates the disease and other associated effects controlled laboratory experiments have been done (Horiguchi et al 1994(Horiguchi et al , 1996. In such experiments, the control animals are supposedly maintained on cadmium-free water and diet, while the test animals are maintained on cadmium supplemented water and/or diet.…”