Lithium-Induced NDI

Author: Bichet, Daniel G.

Researchers understand how lithium causes NDI (see preceding question), but they cannot as yet explain how lithium-induced NDI sometimes continues after a person discontinues lithium. It may be that lithium causes pathologic lesions in the kidney, but the evidence is not conclusive. Clinicians do know that a person can recover from lithium-induced NDI, though it may take many weeks, months, or in some cases, years for the kidneys to regain their full urine-concentratingpowers and for the symptoms of polyuria and polydipsia to resolve. Kurt Stone, MD reports in his article, Lithium-induced Nephrogenic Diabetes Insipidus of one woman still experiencing NDI eight years after discontinuing lithium use. It is important to remember, however, that many patients do recover from lithium-induced NDI, and in some of those who do not, their symptoms are mild enough to not require treatment.

For those who do require treatment to manage their polydipsia and polyuria, there are treatments available. Clinicians generally prescribe thiazide diuretics or amiloride, a potassium-sparing diuretic. Lithium concentration in the blood should be measured after the introduction of diuretic compounds because there is a risk of increased lithium reabsorption by the kidney. Sometimes clinicians prescribe a combination of both of these medicines. These diuretics take a little while to begin working. In emergency situations, clinicians may administer indomethacin, a prostaglandin synthesis inhibitor. It is not, however, recommended for long-term use.

Author: Bichet, Daniel G.

Lithium reduces the ability of the kidneys to reabsorb body water flowing through the kidney collecting ducts. This unabsorbed body water is voided as dilute urine. So much body water is voided in this manner that the patient would suffer from dehydration if he or she did not have ready access to drinking water. To better understand how lithiuminterferes with the water reabsorption (and resulting urine concentration) process it helps to know the molecular sequence that underlies it.

First, the antidiuretic hormone, arginine vasopressin (AVP) binds with its vasopressin-2 receptors located in the basolateral membranes of the principal cells of the kidney collecting ducts. This bond stimulates the enzyme, adenylyl cyclase (AC). AC, in turn, elevates the levels of cyclic adenosine monophosphate (cAMP) inside the principal cells. cAMP activates protein kinase A (PKA) which, through a series of steps that are not yet entirely clear, induces aquaporin-2s (AQP2s) to travel to the principal cell’s apical membrane. Once the AQP2s are inserted into the apical membrane, they act as channels through which much more water can cross the apical membrane than usual. The insertion of AQP2s is what allows the kidney to reabsorb the water flowing through the collecting ducts. When AVP absents itself from the cell, the AQP2s are removed from the apical membrane, brought back inside the cell, and the apical membranereturns to its normal level of low water permeability.

Lithium causes a dramatic decrease in the numbers of AQP2 expressed in the principal cells. This decrease is paralleled by a progressive development of severe polyuria. Of the few AQP2s that do get expressed in the presence of lithium, very few are able to travel to the apical membrane where they must be if they are to perform their function of letting water flow across the membrane. Lithium has been shown to impair the production of cAMP in CD cells, and it is likely that reduced cAMP is, in part, responsible for the reduced numbers of AQP2 found in patients with lithium-induced NDI.

Animal studies have shown that lithium decreases cAMP concentration by blocking the activation of adenylyl cyclase. Lithium may also decrease cAMP levels by increasing its destruction by phosphodiesterase. Lithium has been shown to increase the ability of AVP to produce prostaglandin E2 in the kidney medulla. This also results in increased urination.