Cadmium induces osteomalacia mediated by proximal tubular atrophy and disturbances of phosphate reabsorption. A study of 11 autopsies.

Osteomalacia of cadmium (Cd) poisoning (Itai-Itai disease) is induced by renal tubular dysfunction; however, the precise pathological changes and mechanisms have not been adequately elucidated. Of the 25 inhabitants in a Cd-polluted area who developed chronic tubular proteinuria, 22 individuals died over a 16-year period. Autopsies were performed in 11 cases and osteomalacia was detected in 9 cases (mean age at death 82.2 +/- 7.8 years; 1 man and 8 women). Histologically, osteomalacia occurred coincidentally with diffuse atrophy of the proximal tubules, moderate thickening of the tubular basement membrane and mild interstitial fibrosis in the renal cortex. Ultrastructurally, mitochondria in the proximal tubules were decreased in number and showed abnormal structure, while membrane enzymes, such as 5'-nucleotidase and ALPase, were still well preserved in their brush border. Glomeruli and distal tubules were minimally damaged. Severity of osteomalacia correlated with the damage of the proximal tubules as well as reduced serum calcium (Ca), serum Ca x phosphorus (P) and hematocrit, increased urine beta2-microglobulin, lysozymes, N-acetyl-b-D-glucosaminidase, retinol binding protein, creatinine, and reduced percent tubular reabsorption of phosphate. Multiple regression analysis showed that among these factors, serum Ca x P was an independent factor for predicting the severity of osteomalacia. Our findings suggest that osteomalacia by Cd poisoning causes degenerative changes in the proximal tubules, especially in mitochondria, which might affect the disturbance of the intracellular active transport energy system for calcium and phosphorus, resulting in osteomalacia.