Lithium-induced Nephrogenic Diabetes Insipidus

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 g 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/ mol creatinine) and cAMP (410 ؎ 15 pmol/ mol 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/ mol creatinine (normal), 76.5 ؎ 10.4 fmol/ mol creatinine (partial NDI), and 27.3 fmol/ mol 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.

Nefrotoxicidade por lítio

“…This drug not only blocks sodium entry via ENaC, but also inhibits lithium entry into collecting duct principal cells. Amiloride partially restores the urinary concentrating ability, and this is associated with increased urinary AQP2 excretion 10 .…”

“…The most prevalent form of lithium-induced renal injury is impaired urinary concentrating ability 10 , which can be detected about eight weeks after lithium initiation 11 . In a study involving 1,172 patients on chronic lithium therapy, Boton et al 11 found that impairment of urinary concentrating ability was present in at least 54% of 1,105 unselected individuals.…”

“…Initially reversible after cessation of lithium, tubular dysfunction translates into overt and irreversible polyuria and polydipsia with continued treatment, affecting 20 to 40% of patients 12 . This is the typical clinical picture of nephrogenic diabetes insipidus, which is resistant to the action of arginine vasopressin (AVP) 10 .…”

“…The first factor is the generation of a hypertonic medullary interstitium and the second is the insertion of water channels, the aquaporins, into the apical (AQP2) and basolateral (AQP3 and AQP4) membranes of the collecting duct, allowing tubular water reabsorption through a concentration gradient between the collecting duct lumen and the hyperosmotic medullary interstitium 10,13,14 . In response to increased serum osmolality, AVP is released from the posterior pituitary, binds to V2 receptors in the basolateral membrane of collecting duct cells and, through the activation of adenylyl cyclase, triggers a series of intracellular events that culminate in the insertion of AQP2 molecules in the apical membrane, which is facing the tubular lumen.…”

Nephrogenic diabetes insipidus partially responsive to oral desmopressin in a subject with lithium-induced multiple endocrinopathy

“…Amiloride blocks ENaC-mediated Li entry into renal cells and ameliorates this effect. 6 Li-induced NDI may become irreversible in some subjects after treatment for more than 2-10 years.…”