The mood stabilizer Lithium is a well-established cause of Nephrogenic Diabetes Insipidus (NDI). Lithium is primarily used to manage bipolar disorder, but its use can lead to the kidneys becoming unresponsive to the body’s water-retaining signals. This results in Diabetes Insipidus (DI), a disorder characterized by the inability to concentrate urine, causing excessive urination and intense thirst. This adverse effect is a significant concern, with 10% to 15% of patients on long-term Lithium therapy developing full-blown NDI.
Understanding Nephrogenic Diabetes Insipidus
Nephrogenic Diabetes Insipidus (NDI) is a disorder where the kidneys fail to respond to antidiuretic hormone (ADH), also known as vasopressin. Normally, ADH signals the kidneys to reabsorb water back into the bloodstream, thereby concentrating the urine. In NDI, the kidney tubules are resistant to this signal, leading to the continuous excretion of large amounts of dilute urine.
The primary clinical features of NDI are polyuria (excessive urine production) and polydipsia (excessive thirst). Adults with NDI may produce more than 3 liters of urine per day, and output can reach 20 liters in severe cases. This constant fluid loss drives intense thirst as the body attempts to compensate and prevent dehydration.
How Lithium Interferes with Kidney Function
Lithium causes NDI by disrupting the signaling pathway within the kidney’s principal cells, located in the collecting ducts. These cells rely on antidiuretic hormone (ADH) for water regulation. When ADH binds to its receptors, it triggers a cascade that increases the production of a signaling molecule called cyclic AMP (cAMP).
The increase in cAMP directs aquaporin-2 (AQP2) water channels to the cell membrane, allowing water to be pulled out of the urine and back into the body. Lithium ions enter the principal cells through the same channels that reabsorb sodium. Once inside, they interfere with the ADH-stimulated cAMP production. This interference prevents the AQP2 water channels from being properly inserted into the membrane, making the cells resistant to ADH and disabling the kidney’s ability to reabsorb water.
Chronic exposure to Lithium may also lead to a decrease in the overall expression of AQP2 channels and structural changes within the collecting ducts. This long-term effect causes the concentrating defect to persist in some patients even after Lithium therapy is stopped.
Screening, Monitoring, and Treatment Strategies
Diagnosing Lithium-induced NDI begins with recognizing the symptoms of polyuria and polydipsia, often accompanied by nocturia (frequent nighttime urination). Diagnostic tests include monitoring serum Lithium levels and measuring urine specific gravity and osmolality, which will be abnormally low. A fluid deprivation test confirms the diagnosis by observing the kidney’s inability to concentrate urine under dehydration stress.
The initial management prioritizes patient safety and adjusting the Lithium regimen. Strategies include simplifying the dosing to a single daily dose, allowing the kidneys more time to clear the drug and potentially recover function. If the condition is severe or significantly impacts quality of life, discontinuing the medication entirely may be necessary.
Pharmacological interventions manage NDI symptoms while maintaining mood stabilization. The diuretic Amiloride is frequently used because it blocks Lithium entry into the principal cells of the collecting ducts, mitigating the drug’s damaging effects. Thiazide diuretics, such as hydrochlorothiazide, are also used to reduce urine volume. They achieve this by creating a mild state of volume depletion that enhances water reabsorption in a different part of the kidney.
Patients must be monitored routinely with blood tests to check serum Lithium levels and assess kidney function, typically every 6 to 12 months. Maintaining adequate fluid intake is crucial to prevent serious complications like hypernatremia. Nonsteroidal anti-inflammatory drugs (NSAIDs) like Indomethacin may be used alongside diuretics to help increase urine concentration.