Mechanism of Lithium-Induced Nephrogenic Diabetes Insipidus
Lithium causes nephrogenic diabetes insipidus by interfering with the kidney's ability to respond to antidiuretic hormone (ADH/vasopressin), specifically by disrupting intracellular cyclic adenosine monophosphate (cAMP) signaling in the collecting duct cells. 1
Primary Molecular Mechanism
Lithium blocks the normal ADH signaling cascade by reducing intracellular cAMP levels in the collecting duct epithelial cells, which prevents the insertion of aquaporin-2 water channels into the apical membrane 1
Without functional aquaporin-2 channels in the collecting duct membrane, water cannot be reabsorbed from the tubular fluid back into the bloodstream, resulting in the excretion of large volumes of dilute urine 1
This mechanism explains why patients develop polyuria (excessive urination) and polydipsia (excessive thirst) while maintaining inappropriately dilute urine despite elevated serum osmolality 2
Chronic Structural Changes
Prolonged lithium exposure causes morphologic kidney damage including glomerular and interstitial fibrosis and nephron atrophy, which can contribute to persistent concentrating defects even after lithium discontinuation 3
The FDA drug label specifically warns that chronic lithium therapy is associated with diminished renal concentrating ability, occasionally presenting as nephrogenic diabetes insipidus 3
These structural changes can result in permanent nephrogenic diabetes insipidus that persists years after stopping lithium—cases have been reported with persistent defects up to 8 years after discontinuation 1
Clinical Prevalence and Risk
Lithium-induced nephrogenic diabetes insipidus occurs in approximately 20-40% of patients on long-term lithium therapy 1, 4
The condition results from chronic renal exposure to lithium, leading to significant polyuria, dehydration, and hypernatremia 5
The FDA warns that lithium toxicity is closely related to serum lithium levels and can occur at doses close to therapeutic levels, making monitoring essential 3
Important Clinical Caveat
While nephrogenic diabetes insipidus is the predominant mechanism, rare cases of central diabetes insipidus have also been reported with lithium use, though the pathophysiology remains unclear 4
The exact mechanism of persistent concentrating defects after lithium discontinuation is unknown, though it is associated with the pathologic structural changes described above 1