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Lithium isotopes: differential effects on renal function and histology

Authors


Corresponding author: Peter M Stoll, MA, Pharmaceutical Development, Clinical Operations, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. Fax: +1 973 235 6505; e-mail: peter.stoll@roche.com

Abstract

Objectives: Reduction in renal concentrating ability has been reported in patients undergoing chronic lithium treatment. Prior work has demonstrated differences in physiological effects of the stable lithium isotopes, 6Li and 7Li. Here, we measured the degree of polyuria, polydipsia and kidney histological changes induced in rats by equimolar amounts of 6LiCl, 7LiCl and the commercially available mixture of both isotopes.

Methods: Rats were given 1.0 mEq/kg of either 6LiCl, 7LiCl or ‘nLiCl’ (isotope mixture, 93% 7LiCl) by subcutaneous injection twice daily for up to 49 days. Twenty-four-hour urine volume and water intake were measured daily. Kidneys from rats treated for 7 days with 1.5 mEq/kg 6LiCl, 7LiCl and vehicle were examined under light microscopy and histopathologic changes graded on a 4-point scale of severity.

Results: All rats showed loss in renal concentrating ability manifested by increasing urine volume and water intake. Peak effects occurred after 9–13 days treatment, then declined to stable levels at two to three times pre-treatment level. Mean peak effect was significantly greater for 6LiCl than for 7LiCl. Chronic effects of 6LiCl (weeks 3–7 of treatment) on polyuria and polydipsia were persistently higher than that of 7LiCl. nLiCl effect was intermediate. Kidneys from rats treated for 7 days with 6LiCl showed more frequently severe lesions in renal tubules than did 7LiCl-treated rats.

Conclusions: Our current data and prior studies suggest that elimination or reduction of 6Li from pharmaceutical preparations may merit further evaluation as a possibly less potentially nephrotoxic form of lithium treatment.

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