CHOICE OF TESTS IN THE BIOCHEMICAL ASSESSMENT OF NEPHROTOXICITY IN DOGS AND RATS - A STUDY WITH MALEIC-ACID

Urinalysis represents a useful tool in the evaluation of new pharmaceu tical agents acting on the kidney, during preclinical toxcological stu dies. In the present study, we studied the response of urinary creatin ine, LDH, AAP, ALP, beta-GAL, GGT, NAG and protein excretion to a sing le intravenous dose of maleic acid (25 mg/kg for dogs and 100 mg/kg fo r rats). Enzymes were selected based on their association with renal t oxicity and their localisation within the renal tubule. They included lysosomal, brush border and cytosolic enzymes. In male dogs, increases in enzyme excretion occurred within 2 h of maleic acid administration , peaked 3 h after dosing, and returned towards, or to, predose value at 24 h. Marked increases in enzyme levels occurred only for LDH and G GT (10-fold or more). Additionally, there was a marked increase in tot al protein excretion whereas creatinine excretion decreased. In male r ats, the only major difference from control was a higher 0-24 h protei n excretion rate (approximately 2-fold). Moderate increases were also present for ALP, GGT and LDH ( < 2-fold). In female rats, there was a marked increase in urinary excretion of proteins and LDH, GGT, NAG and ALP (8-13-fold when compared to controls). There were only moderate i ncreases (2-fold or less) in beta-GAL and AAP. Creatinine was unaffect ed by the treatment. Histopathological examination of the kidney revea led moderate to severe proximal tubular necrosis in dogs and minimal t o moderate tubular necrosis in rats. Overall, urinary GGT, LDH, total protein and creatinine concentrations are the most sensitive biochemic al indicators of maleic acid nephrotoxicity in dogs. For rats, in addi tion to LDH excretion, total proteins, NAG, GGT and ALP can be conside red to be sensitive markers of renal injury. In the light of these res ults and those reported in literature, it was concluded that the respo nse of urinary markers of nephrotoxicity is heavily dependent on the n ephrotoxic agent, the dose, species, sex and study design. Consequentl y, a range of markers should be examined in order to identify the most useful.