Background:  The objective of this study was to determine if rats with subclinical renal injury (SRI) are more susceptible than healthy control animals to nephrotoxic metals that exert their effect on different nephron segments. 

Methods:  To induce SRI, rats were dosed with gentamicin (sc) for 3 days. Twenty-four hr after the third injection, SRI- and saline-pretreated rats were injected with a single NOAEL or LOAEL dose of chromium (sc), mercury (iv) or lithium (ip) salts, metals which typically exert effects on proximal convoluted tubules (S₁/S₂ segments), proximal straight tubules (S₃ segment), and distal tubules, respectively.  The following biomarkers were evaluated 24 hours after metal injection: blood urea nitrogen (BUN) and creatinine; urinary N-acetyl-ß-glucosaminidase (u-NAG), creatinine, and total protein (u-TP); and kidney levels of kidney injury molecule-1 (KIM-1) mRNA. 

Results:  BUN levels were increased by 1.5-, 1.4-, 1.7-fold and NAG/Cr levels were elevated by 3.4-, 5.7-, and 2.2-fold in SRI rats challenged with chromium, mercury, and lithium, respectively, compared to control rats challenged with these metals.  Kidney levels of KIM-1 mRNA were elevated due to gentamicin alone and elevated to a higher level in SRI rats treated with mercury, but not lithium and chromium.  

Conclusions:  SRI model rats demonstrated increased susceptibility to the effects of several nephrotoxic metals that target different nephron segments, thereby increasing the utility of the model for preclinical evaluation.  U-NAG appeared to be the most sensitive biomarker to these metals, and kidney KIM-1 expression was elevated only in mercury-treated rats but not chromium- or lithium-treated rats.