Cadmium-metallothionein-induced nephropathy: a morphological and autoradiographic study of cadmium distribution, the development of tubular damage and subsequent cell regeneration.

A single intravenous dose of 0.8 mg thionein-bound cadmium (Cd) per kg body weight, as the isolated (Cd, Zn)-metallothionein (MT) from rat liver, in rats of the same strain is nephrotoxic, but not lethal. Apical vesiculation in epithelial cells of the renal proximal convoluted tubules is apparent within 1 h of dosing and, by 4 h, is extensive in some of these cells that surround the larger arteries in the cortex. The membranes of these cells appear undamaged. The lesion at first progresses with time; by 24 h, the initially affected cells show extensive necrosis and most proximal convoluted tubular epithelia in other regions of the cortex are hydropically or vacuolarly degenerated. The inner stripe of the outer zone of the medulla and other portions of the nephron (glomerulus, distal tubule and collecting duct), however, appear essentially unaffected. The necrotic changes are maximal at 48 h but, after this time, regeneration begins. By seven days, much of the cell debris has been eliminated and cells of the regenerating or regenerated epithelia are similar in morphology to those of the normal kidney. Electron microscopic autoradiography of kidney sections from rats after administration of 109Cd-metallothionein of high specific activity shows that Cd is not concentrated in endocytotic vesicles, lysosomes, or any other cellular organelle, even at early times after dosing, but is distributed evenly throughout the epithelial cell. Thus, although Cd-MT appears to be taken up endocytotically in the kidney tubules, it appears that liberation of Cd from the metalloprotein must occur very early in the reabsorptive process.