Pathophysiology of Lithium-Induced Nephrogenic Diabetes Insipidus
Core Mechanism
Lithium-induced nephrogenic diabetes insipidus (NDI) results from renal insensitivity to arginine vasopressin (AVP), preventing the kidneys from concentrating urine despite normal or elevated plasma AVP levels. 1 The fundamental defect occurs when lithium interferes with vasopressin signaling at a step distal to cyclic AMP formation in the collecting duct principal cells. 2
Cellular Entry and Accumulation
Lithium enters collecting duct principal cells primarily through the epithelial sodium channel (ENaC) located on apical membranes, which shows high selectivity for both sodium and lithium ions. 3 Once inside the kidney, lithium progressively accumulates along the corticopapillary axis, creating a 2.9-fold concentration gradient from cortex to papilla—meaning papillary cells experience the highest lithium exposure. 2
Molecular Disruption of Water Channels
The cellular damage manifests through two key molecular pathways:
Aquaporin-2 (AQP2) downregulation: Lithium directly reduces the abundance of AQP2 water channels, which are essential for water reabsorption in collecting duct principal cells. 4, 5 These misfolded AQP2 proteins become retained in the endoplasmic reticulum and fail to traffic to the apical membrane where they normally function. 1
Resistance to vasopressin: Even when vasopressin binds to V2 receptors and generates cyclic AMP, lithium blocks the downstream response, preventing AQP2 insertion into the apical membrane. 2 This explains why exogenous vasopressin or dibutyryl cyclic AMP cannot reverse lithium-induced polyuria. 2
Altered Cell Population Dynamics
Lithium initiates a paradoxical proliferative response in principal cells while simultaneously arresting them in the G2 phase of the cell cycle:
Lithium triggers principal cell proliferation, evidenced by increased PCNA expression in 30-40% of papillary principal cells. 5
However, a significant percentage of these proliferating cells express pHistone-H3, indicating arrest in late G2/M phase—double the rate seen during normal proliferation. 5
This G2 arrest explains the reduced ratio of principal cells to intercalated cells observed in chronic lithium therapy, despite increased proliferation signals. 5
The arrested cells likely contribute to the development of glomerular and interstitial fibrosis with nephron atrophy seen in long-term lithium users. 6, 5
Clinical Manifestation
The FDA label confirms that chronic lithium therapy causes diminution of renal concentrating ability, occasionally presenting as nephrogenic diabetes insipidus with polyuria and polydipsia. 6 Approximately 12-20% of lithium-treated patients develop frank polyuria (>3 liters/day), while 40% report polydipsia. 2 The condition results from chronic renal exposure to lithium, leading to significant polyuria, dehydration, and hypernatremia when fluid access is restricted. 7
Reversibility and Chronicity
The FDA notes this condition is "usually reversible when lithium is discontinued," 6 though the extent of recovery depends on duration of exposure and degree of structural damage. Morphologic changes including glomerular and interstitial fibrosis represent potentially irreversible injury. 6
Important Caveats
The normal corticopapillary sodium gradient remains intact during lithium-induced NDI, indicating lithium does not disrupt overall medullary hypertonicity—only the cellular response to vasopressin. 2
Serious intercurrent illnesses and medications affecting renal function can trigger acute worsening of NDI symptoms in patients with chronic lithium exposure. 8
Approximately 50% of adult patients with NDI develop chronic kidney disease stage ≥2, though the exact contribution of lithium versus the underlying disease process remains unclear. 9