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In drug-induced diabetes insipidus, urine cannot be concentrated despite adequate secretion of antidiuretic hormone
(vasopressin). Lithium used for the treatment of affective disorders is the most common cause of this serious adverse
effect, which can lead to dehydration and aggravation of lithium intoxication. Other classes of drug, such as
antibacterials and antineoplastics, are also associated with this condition. Treatment includes eliminating the
causative agent and controlling water balance. In severe cases, urinary output can be reduced using diuretics or
NSAIDs. The risks associated with lithium-induced diabetes insipidus can be reduced by keeping doses as low as
possible and informing patients about the condition.
Drug-induced diabetes insipidus is a nephrogenic (rather than neurogenic) condition in which the kidneys become
unresponsive to the action of antidiuretic hormone. The condition is characterised by polydipsia and excessive
excretion of urine that is inappropriately dilute relative to body fluid hypertonicity. Patients generally remain clinically
stable unless they are unable to maintain adequate spontaneous fluid intake. However, if polyuria becomes severe,
amounting to more than 4 to 6 L/day, dehydration can occur, with reflex tachycardia, orthostatic hypotension,
lethargy and confusion, and possibly seizures, coma or even death.
[1,2]
Drug-induced diabetes insipidus is an uncommon condition other than in patients receiving lithium.
[1]
There is wide
variability in the reported prevalence of lithium-induced diabetes insipidus. One analysis found the prevalence to be
approximately 15% among patients treated with lithium for > years,
[3]
whereas other estimates have been higher and
exceedingly variable (15 to 87%).
[2,4]
Lithium is freely filtered through the glomerulus and reabsorbed in the proximal
tubule concomitant with sodium and water. Even small doses of lithium may cause diabetes insipidus. Nevertheless,
lithium-induced diabetes insipidus is dose-dependent.
[1]
There is an increased risk of developing diabetes insipidus
with long term lithium treatment and with severe and treatment-resistant affective disorders.
[1]
When induced by drugs other than lithium, diabetes insipidus usually appears in patients who are critically ill in
intensive care units. These other drugs are a varied group, dominated by antimicrobials and antineoplastics (table 1).
After lithium, foscarnet and clozapine were the next most commonly reported causes of drug-induced diabetes
insipidus reported to the adverse effect database of the World Health Organization according to a recent search.
[1]
Milder forms of drug-induced diabetes insipidus (urine volumes of about 3 to 4 L/day) need no special treatment apart
from correcting deficits in extracellular fluid volume by maintaining adequate water intake. Oral fluid therapy can be
administered to alert patients, whereas intravenous normal saline is required for patients with seizures or coma.
[1,2]
Patients with more serious forms of polyuria (urine volumes of more than 4 L/day) may require treatment with
diuretics such as thiazides and amiloride in conjunction with sodium restriction.
[1,2]
Amiloride administered to patients with lithium-induced polyuria has been found to diminish polyuria and increase
osmolality.
[5]
Amiloride is regarded as safer than thiazide diuretics since it also blocks the entrance of lithium into
the cells of the distal tubule, and therefore may help to keep serum lithium concentrations below toxic levels.
Thiazide treatment also reduces renal water output (via an increase in proximal sodium reabsorption secondary to
increased urinary sodium excretion), but may be counterproductive since it can increase lithium retention and can
lead to complications such as hypokalaemia and hypercalcaemia.
[1,2]
Hypokalaemia may, in turn, exacerbate the
nephrogenic diabetes insipidus.
[1]
NSAIDs, for example indomethacin, can also reduce urine volume and are often used in intensive care units for
treating nephrogenic diabetes insipidus.
[1]
However, these agents should not be considered as 'standard treatment'
for drug-induced diabetes insipidus as they may have negative effects on kidney perfusion and glomerular filtration,
Drug-Induced Diabetes Insipidus: Has Its Importance Been
Diluted?
Drug Ther Perspect. 2001;17(10)
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especially in critically ill patients. In patients receiving lithium therapy, NSAIDs may lead to lithium intoxication by
decreasing renal excretion of lithium.
[1]
A reduction in lithium dosage can help to control lithium-induced diabetes insipidus. Combining lithium with an
anticonvulsant (carbamazepine or valproic acid) may allow for further reduction in lithium dosage.
[1]
In severely
polyuric patients at risk for dehydration and electrolyte imbalance, lithium should be discontinued altogether and
replaced with an alternative mood-stabilising agent.
[1,2]
In some patients, drug-induced diabetes insipidus can persist after discontinuation of lithium. Chronic renal failure
from interstitial nephritis may occur with long term lithium therapy, although the incidence of uraemia with lithium
appears to be very low. As ACE inhibitors can retard the progression of renal disease,
[6,7]
patients with lithium-
associated nephropathy may benefit from this therapy. ACE inhibitor therapy should be started cautiously after the
discontinuation of lithium. Urea nitrogen, creatinine and electrolytes should be closely monitored to ensure there is no
initial worsening of renal function.
[1,2]
The prevention of diabetes insipidus induced by drugs other than lithium is difficult because the condition often occurs
in critically ill patients and in difficult treatment conditions.
[1]
Patients receiving lithium treatment should be administered the lowest possible dose.
[1]
12-hour trough values of
serum lithium concentrations should be from 0.4 to 0.6 mmol/L and no higher than 1.0 mmol/L. In order to monitor the
presence and severity of polyuria, urine volume needs to be regularly measured. Alternative treatment should be
considered when urinary volume exceeds 4 L/day.
In some cases it may not be possible to prevent lithium-induced diabetes insipidus, particularly in those at high risk
of developing the condition. Amiloride should be considered as a preventative agent in patients who develop
progressive polyuria, particularly in those at high risk of lithium-induced diabetes insipidus.
[3]
Awareness of the potential for lithium-induced diabetes insipidus must be increased so that the condition can be
detected and treated as early as possible. Water and electrolyte balance, how lithium is processed and the causes
and symptoms of lithium intoxication should be taught to and regularly discussed with patients. Psychiatrists and
other physicians and healthcare professionals also require education on the existence, hazards and prevention of
lithium-induced diabetes insipidus.
[1]
References
1. Bendz H, Aurell M. Drug-induced diabetes insipidus: incidence, prevention and management. Drug Saf 1999;
21 (6): 449-56
2. Siegel AJ, Baldessarini RJ, Klepser MB, et al. Primary and drug-induced disorders of water homeostasis in
psychiatric patients: principles of diagnosis and management. Harv Rev Psych 1998; 6: 190-200
3. Bendz H, Aurell M, Balldin J, et al. Kidney damage in long-term lithium patients: a cross-sectional study of
patients with 15 years or more on lithium. Nephrol Dial Transplant 1994; 9: 1250-4
4. Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis and treatment of renal dysfunction associated with
chronic lithium therapy. Am J Kidney Dis 1987; 10: 329-45
5. Batlle DC, von Riotte AB, Gaviria M, et al. Amelioration of polyuria by amiloride in patients receiving long-term
lithium therapy. N Engl J Med 1985; 312: 408-14
6. Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of
nondiabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med 1997; 127: 337-45
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Drug Ther Perspect. 2001;17(10) 2001 Adis Data Information BV
7. Blayney-Chandramouli J, Stokes JB. Use of ACE inhibitors in diabetic and nondiabetic patients with renal
disease. Formulary 1998; 33: 318-40

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