Renal Effects of Iodixanol in Experimental Animals

Abstract

The effects of the new nonionic dimeric hexa-iodinated contrast medium (CM) iodixanol on renal function and morphology were investigated in 7 independent studies in rats, rabbits and monkeys and compared with other iodinated CM.

No significant effect on serum creatinine levels was seen at doses up to and including 5 g I/kg in rats and 10.5 g I/kg in rabbits. An immediate and transient increase in proteinuria was found in rabbits when 10.5 g I/kg was administered as a bolus, and when 12.5 g I/kg was administered as a slow infusion in a comparative study with several CM. Increased serum elimination half-life was shown by measuring serum iodine concentrations after the infusion of 12.5 g I/kg. The effect of a high dose of iodixanol on proteinuria and elimination half-life were in this study in the same range as those of the monomeric nonionic CM, but less pronounced than those of the monomeric ionic CM. Reduced renal capacity was induced in male rats by performing unilateral nephrectomy 4 weeks before i.v. injection of iodixanol or iopamidol (2 g I/kg). The administration of CM did not affect renal function monitored as serum concentrations of creatinine and urea. The vacuolation of renal proximal tubular cells and kidney iodine retention were investigated in rats 48 hours after administration of different doses of iodixanol or iotrolan. The no-effect level for vacuolation was 0.5 g I/kg for both CM. Iodine retention was higher in male than female rats, and was higher for iodixanol than iotrolan at the 2 highest dose levels (3 and 5 g I/kg). No difference in iodine retention was found at the other dose levels (0.25–1 g I/kg). The reversibility of renal proximal tubular vacuolation after administration of iodixanol was studied in male rats (1.2 g I/kg) and monkeys (1.2 and 3.6 g I/kg). The vacuolation was more pronounced in rats than in monkeys. Vacuolation was completely reversed in all rats 3 weeks after dosing, and in 2 of 3 monkeys 3 days after a dose of 1.2 g I/kg. The degree of vacuolation evident in renal percutaneous biopsy specimens from monkeys 14 days after i.v. administration of iodixanol at a dose of 3.6 g I/kg was not significantly different to that in control animals.

In conclusion, iodixanol affected renal function to the same degree as did the nonionic monomeric and dimeric comparative media, but to a lesser degree than the ionic monomers. The degree of renal proximal tubular cell vacuolation induced by iodixanol seems to be species-dependent, being less pronounced and more quickly reversed in monkeys than rats.