Acute CdMT injection is not a good model to study chronic Cd nephropathy: comparison of chronic CdCl2 and CdMT exposure with acute CdMT injection in rats.

Kidney is the main target organ of Cd toxicity in humans. Cd-induced nephrotoxicity is thought to be caused by the Cd-metallothionein complex (CdMT) that "leaks" out of the liver and is taken up by the kidney. A single injection of CdMT has therefore been used as a model to study Cd nephropathy for the last 20 years. However, our recent studies reveal discrepancies between renal Cd concentration and nephrotoxic potencies of CdCl2 and CdMT. This study was further designed to critically evaluate whether a single injection of CdMT is an appropriate model to study the mechanism of chronic CdCl2 nephropathy. Age-matched rats were given multiple sc injections of either CdCl2 (0.8 and 1.2 mg Cd/kg) or CdMT (0.05 mg Cd/kg) daily, 6 days/week for 6 weeks, or a single injection of CdMT (0.2-0.6 mg Cd/kg i.p. for 24 h), and the nephrotoxicity was compared. Histologically, chronic CdCl2 or CdMT administration produced damage to the whole kidney, including tubular cell degeneration, apoptosis, and atrophy; interstitial inflammation; glomerular swelling; and sclerosis. In contrast, acute CdMT injection produced severe proximal tubule necrosis as the major feature of its toxicity. Biochemically, chronic exposure to Cd produced polyuria and calciuria, while proteinuria, glucosuria, and enzymuria were mild (2-5x). In contrast, acute CdMT nephrotoxicity was characterized by marked increases in urinary protein (13x), glucose (25x), N-acetyl-beta-d-glucosaminidase (28x), lactate dehydrogenase (100x), and gamma-glutamyltranspeptidase (160x). Serum levels of creatinine and blood urea nitrogen were unchanged following chronic Cd exposure but were markedly elevated (5x) after acute injection of CdMT. Chronic exposure to either CdCl2 or CdMT produced nephrotoxicity at renal Cd concentration of 85 to 110 micrograms/g kidney, while acute CdMT injection produced nephrotoxicity at only 5 to 7 micrograms/g kidney. In conclusion, the present study indicates that the features and mechanisms of renal injury from chronic Cd exposure are quite different from those produced by a single injection of CdMT. Therefore, it is proposed that acute CdMT injection is not an appropriate model for the study of chronic Cd-induced nephrotoxicity.