On the Mechanism of Lithium-Induced Diabetes Insipidus in Man and the Rat

Abstract

A B S.T R A C T The mechanism of lithium-induced diabetes insipidus was investigated in 96 patients and in a rat model. Polydipsia was reported by 40% and polyuria (more than 3 liter/day) by 12% of patients receiving lithium. Maximum concentrating ability after dehydration and vasopressin was markedly impaired in 10 polyuric patients and was reduced in 7 of 10 nonpolyuric patients studied before and during lithium therapy. Severe polyuria (more than 6 liter/day) was unresponsive to trials of vasopressin and chlorpropamide, but improved on chlorothiazide. Rats receiving lithium (3-4 meq/kg/day) developed massive polyuria that was resistant to vasopressin, in comparison to rats with comparable polyuria induced by drinking glucose. Analysis of renal tissue in rats with lithium polyuria showed progressive increase in the concentration of lithium from cortex to papilla with a 2.9-fold corticopapillary gradient for lithium. The normal corticopapillary gradient for sodium was not reduced by lithium treatment. The polyuria was not interrupted by brief intravenous doses of vasopressin (5-10 mU/kg) or dibutyryl cyclic AMP (10-15 mg/kg) capable of reversing water diuresis in normal and hypothalamic diabetes insipidus rats (Brattleboro strain). The present studies suggest that nephrogenic diabetes insipidus is a common finding after lithium treatment and results

Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity

“…Together, we believe that these and our mpkCCD cell line data strongly indicate that lithium-induced downregulation of AQP2 and thus lithium-induced NDI occur independent from adenylate cyclase activity. Our findings are in line with the finding that in rats that were treated for only 7 d with lithium, their lithium-induced polyuria was not interrupted by low doses of AVP but also not by cAMP (37).…”

Lithium and the antidiuretic hormone.

“…The latter is well recognised in the literature (Thomsen, 1970;Singer et al, 1972;Forrest et al, 1974).…”

“…These subjects did not show polyuria. Similarly Forrest et al, (1974) found that all of the ten polyuric patients he studied had concentrating defects, but only seven of the ten non-polyuric patients had abnormal renal concentrating ability. Viol, Grof & Diagle (1975) found no evidence of renal concentrating defects in any of the ten patients receiving lithium whom they studied.…”

“…Lithium can produce a reversible nephrogenic diabetes insipidus in rats and man (Thomsen, 1970;Singer, Rotenberg & Puschett, 1972;Forrest, Cohen, Torretti, Himmelhoch & Epstein, 1974; Harris & Jenner, 1972). This is probably due in part to the inhibition of the renal vasopressin-sensitive adenyl cyclase (Dousa & Hechter, 1970), but there also seems to be evidence for the inhibition of the antidiuretic action of cyclic AMP (Harris & Jenner, 1972;Forrest et aL, 1974), and for an effect of lithium on sodium distribution in the kidney (Jenner & MacNeil, in press).…”

Effects of Lithium on the Hypothalamo-Pituitary-Adrenal Axis.

“…Lithium not only induces a vasopressin-resistant polyuria, i.e. nephrogenic diabetes insipidus (Singer et al, 1972;Forrest et al, 1974), but it also modulates the action of several hormones and neurotransmitters (Bakker., 1982;Newman et al, 1983;Waller et al, 1983). An elevated level of plasma corticosterone was observed in lithium-administered rats (Jacobs et al, 1978) and the stimulatory effect of lithium on ACTH secretion was suggested in vivo (Vatal et al, 1983) and in vitro (Zatz et al, 1985).…”