Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride

Abstract

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 microg 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/micromol creatinine) and cAMP (410 +/- 15 pmol/micromol 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/micromol creatinine (normal), 76.5 +/- 10.4 fmol/micromol creatinine (partial NDI), and 27.3 fmol/micromol 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.

Figure 1.

Urine osmolality (A), cAMP excretion (B), and AQP2 excretion (C) of participants, grouped into tertiles according to their ability to concentrate urine, after overnight water deprivation and administration of desmopressin (dDAVP), 40 μg intranasally; n = 87. Data mean ± SEM. *P < 0.05, **P < 0.01 compared with the lithium-naive group. P < 0.001, difference between baseline and maximum in each case. n = 2 for >300 mOsm/kg tertile.

Figure 2.

Urinary osmolality, cAMP excretion, and AQP2 excretion of participants, grouped according to the length of exposure to lithium, after overnight water deprivation and administration of desmopressin (dDAVP), 40 μg intranasally; n = 87. Data mean ± SEM. *P < 0.05, **P < 0.01 compared with the lithium-naive group. P < 0.001, difference between baseline and maximum in each case.

Figure 3.

Maximum percentage change in urinary osmolality (A), AQP2 excretion (B), and cAMP excretion (C) of participants maintained on lithium, in a double-blind amiloride/placebo crossover trial; n = 11. Data mean ± SEM. **P < 0.05, compared with baseline.