Novel Pathological Study of Cadmium Nephropathy of Itai-itai Disease

Abstract

Itai-itai disease, the most severe form of chronic cadmium (Cd) poisoning, is caused by prolonged ingestion of Cd. It developed in numerous inhabitants of the Jinzu River basin in Toyama Prefecture, Japan, an area severely polluted by Cd. The target organ of Cd toxicity is the kidney, and in particular, it is known that this disease is characterized mainly by renal tubule disorder and subsequent renal osteomalacia, resulting from proximal tubular injury. This chapter is to clarify the pathogenesis of tubulopathy caused by Cd exposure in itai-itai disease kidney by novel pathological study.

Paraffin-embedded sections of renal tissues were obtained from a total of 98 autopsied cases of itai-itai disease in the University of Toyama. Thirty-six autopsy cases of other disease without Cd exposure as control group were selected. The extent of hyalinized nephron and interstitial fibrosis was assessed by Masson trichrome staining. In the immunohistochemical study, each antibody used was liver fatty acid-binding protein (LFABP) of the liver recognized to the proximal tubule, CD34 for perivascular capillaries, and D2-40 for lymphatic vessels. Immunohistovisualization was done by automated immunostainer. In morphometrical analysis, immunoreactive and staining areas were evaluated by morphometrical analysis.

The marked atrophy of proximal tubules was exhibited in the patient of itai-itai disease. Immunohistochemical study using LFABP revealed that the proximal tubular region was significantly reduced. On the other hand, with regard to nephron disorder, the global sclerosis of glomerulus was observed in the superficial nephron which is present in the outer layer of renal cortex. Interstitial fibrosis was recognized to repair the disordered region. Altitude disappearance of peritubular vascular network and dilation of the lymph duct was confirmed by immunohistochemical studies with CD34 and D2-40 antibody.

In this study we were able to elucidate the mechanism of various pathogenesis in itai-itai disease. These findings are important discovery to explain the clinical evidence of the polyuria in itai-itai disease. It was objectively reconfirmed that the main injured site in the kidney of this disease is mainly the proximal renal tubule, as instructed in previous histological studies. As a new finding, there is also a disability of nephron which has not attracted attention so far. Namely, it has been reported that the outer nephron was correlated with osmotic adjustment of urine from the physiologic studies. Therefore, it is supposed that the polyuria might appear by disturbance of the urine volume adjustment in the patients of itai-itai disease that these nephrons were impaired. Although the mechanism about the decrease of peritubular capillaries and the dilation of lymphatic vessels is unclear, these findings may explain the mechanism of tubular impairment. An additional study is needed. In conclusion, although there have been few previous reports on the disorder of nephrons in Cd nephropathy, this study demonstrated disorders of superficial nephrons were more specific for itai-itai disease than for other renal diseases. Furthermore, the abnormalities of peritubular capillaries and lymphatic vessels in conjunction with the superficial nephron may become the key to elucidate the mechanism of this disease.