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Lithium-induced Nephrogenic Diabetes Insipidus: Renal Effects of Amiloride

Jennifer J. Bedford^*, Susan Weggery^*, Gaye Ellis^*, Fiona J. McDonald, Peter R. Joyce, John P. Leader^*, and Robert J. Walker^*

Departments of ^* Medical and Surgical Sciences and Physiology, University of Otago, Dunedin, New Zealand; and Department of Psychological Medicine, University of Otago, Christchurch, New Zealand

Correspondence: Prof. Robert J. Walker, Department of Medical & Surgical Sciences, University of Otago, PO Box 913, Dunedin, New Zealand. Phone: (643) 474 0999, 8045; Fax: (643) 474 7641; E-mail: rob.walker{at}stonebow.otago.ac.nz

Background and objectives: Polyuria, polydipsia, and nephrogenic diabetes insipidus have been associated with use of psychotropic medications, especially lithium.

Design, setting, participants, & measurements: The impact of psychotropic medications on urinary concentrating ability and urinary aquaporin 2 (AQP2) excretion was investigated after overnight fluid deprivation, and over 6 h after 40 µg of desmopressin (dDAVP), in patients on lithium (n = 45), compared with those on alternate psychotropic medications (n = 42).

Results: Those not on lithium demonstrated normal urinary concentrating ability (958 ± 51 mOsm/kg) and increased urinary excretion of AQP2 (98 ± 21 fmol/µmol creatinine) and cAMP (410 ± 15 pmol/µmol creatinine). Participants taking lithium were divided into tertiles according to urinary concentrating ability: normal, >750 mOsm/kg; partial nephrogenic diabetes insipidus (NDI), 750 to 300 mOsm/kg; full NDI, <300 mOsm/kg. Urinary AQP2 concentrations were 70.9 ± 13.6 fmol/µmol creatinine (normal), 76.5 ± 10.4 fmol/µmol creatinine (partial NDI), and 27.3 fmol/µmol creatinine (full NDI). Impaired urinary concentrating ability and reduced urinary AQP2, cAMP excretion correlated with duration of lithium therapy. Other psychotropic agents did not impair urinary concentrating ability. Eleven patients on lithium were enrolled in a randomized placebo-controlled crossover trial investigating the actions of amiloride (10 mg daily for 6 wk) on dDAVP-stimulated urinary concentrating ability and AQP2 excretion. Amiloride increased maximal urinary osmolality and AQP2 excretion.

Conclusions: By inference, amiloride-induced reduction of lithium uptake in the principal cells of the collecting duct improves responsiveness to AVP-stimulated translocation of AQP2 to the apical membrane of the principal cells.