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REVIEW

Management and treatment of - induced nephrogenic

Christopher K Finch†, Lithium is a well documented cause of nephrogenic diabetes insipidus, with as Tyson WA Brooks, many as 10 to 15% of patients taking lithium developing this condition. Clinicians have Peggy Yam & Kristi W Kelley been well aware of lithium for many years; however, the treatment of this drug- induced condition has generally been remedied by discontinuation of the or a †Author for correspondence Methodist University reduction in dose. For those patients unresponsive to traditional treatment measures, Hospital, Department several pharmacotherapeutic regimens have been documented as being effective for the of Pharmacy, University of management of lithium-induced diabetes insipidus including , Tennessee, College of Pharmacy, 1265 Union Ave., , indomethacin, and correction of serum lithium levels. Memphis, TN 38104, USA Tel.: +1 901 516 2954 Fax: +1 901 516 8178 [email protected] is well known for its wide use associated with a mutation(s) of in bipolar disorders due to its mood stabilizing receptors. Acquired causes are tubulointerstitial properties. It is also employed in aggression dis- disease (e.g., sickle cell disease, amyloidosis, orders, post-traumatic stress disorders, conduct obstructive uropathy), disorders (e.g., disorders and even as adjunctive therapy in hypokalemia and hypercalcemia), , or . Lithium has many well documented conditions induced by a drug (e.g., lithium, adverse effects as well as a relatively narrow ther- , amphotericin B and apeutic range of 0.4 to 0.8 mmol/l. Clinically vincristine) [3,4]. Lithium is the most common significant adverse effects include , mus- cause of drug-induced nephrogenic DI [5]. cle weakness, weight loss, , , sei- The development of nephrogenic DI follow- zures, incontinence of and feces, ing lithium administration likely involves multi- and electrocardiographic changes. ple mechanisms. Abnormalities in the medullary Of major concern are lithium’s adverse effects osmotic gradient directed by hor- on the kidneys, specifically causing diabetes mone (ADH) or vasopressin (AVP) and insipidus (DI) and a decreased glomerular filtra- inhibition of the action of ADH on the renal tion rate. Lithium-induced DI may occur in tubules are both thought to be mechanisms by 10 to 15% of patients receiving lithium, espe- which lithium induces DI. The lack of response cially those who have received long-term therapy to ADH is due to the inhibition of adenylate (greater than 15 years) [1,2]. Given this potentially cyclase and resultant decreased formation of irreversible side effect, long-term therapy with cyclic cAMP [6]. cAMP serves as a second mes- lithium has been questioned, especially in elderly senger to kinase A and the fusion of and renally impaired patients. The exact mecha- storage vesicles to the luminal cell nism behind lithium-induced DI is not fully wall, which in turn allows the collecting ducts to understood and a definitive treatment has never become permeable and reabsorb . Ulti- been outlined for practitioners. This review will mately a patient with lithium-induced DI loses cover the pathophysiology and diagnosis of lith- the ability to reabsorb water, in essence due to a ium-induced DI as well as the different therapeu- loss of cAMP. Even after the administration of tic treatment options available, including how to exogenous ADH, lithium has been shown to monitor, interpret and manage lithium levels. have continued effects, suggesting lithium has Keywords: amiloride, desmopressin, diabetes additional mechanisms by which it inhibits the insipidus, lithium, Pathophysiology ability to retain water [6]. This renal insensitivity indomethacin, polyuria, Nephrogenic DI was first reported in 1892 [3]. In to ADH may be dependent on the dosage as well most cases of nephrogenic DI, solute as the duration of lithium therapy [7]. and renal filtration are normal but urine is hypo- In addition to the development of DI, lithium tonic and there is a characteristic resistance to also adversely affects the kidneys by inducing the antidiuretic effects of endogenous vaso- renal tubular acidosis, chronic interstitial nephritis Future Drugs Ltd pressin. Congenital nephrogenic DI is typically and nephrotic syndrome. Lithium is filtered in the

10.1586/14750708.2.4.669 © 2005 Future Drugs Ltd ISSN 1475-0708 Therapy (2005) 2(4), 669–675 669 REVIEW – Finch, Brooks, Yam & Kelley

glomerulus and reabsorbed at several sites within concentrations, which in turn affect serum the renal tubules and is also concentrated at the osmolality and water , are under the renal medulla. Due to the extensive nature by control of mechanisms, ADH and the kid- which lithium is processed by the kidneys, the neys [10]. Serum sodium concentrations are often possible renal adverse effects of lithium are logical. used to determine a patient’s water balance. Hyper- is reported in up to 40% of patients natremia is a state in which the body’s water stores receiving lithium and polyuria in up to 20%; are in deficit compared with sodium stores and is a however, the severity of these adverse effects typi- common electrolyte abnormality whose cause is cally does not justify the cessation of therapy [5]. often unknown. Thus, using a serum sodium con- Progression to end-stage renal disease (ESRD) is centration alone is rather nonspecific in diagnosing rare and slowly progressive, representing only DI. When interpreting serum sodium concentra- 0.22% of all ESRD cases and occurring after an tions, there are several different categories into average of 20 years of lithium therapy [8]. which a patient may be placed based on their signs, symptoms and fluid balance, in addition to the Diagnosis serum sodium concentration. In the case of neph- A thorough physical examination and laboratory rogenic DI, serum sodium concentrations will be work up is essential to properly diagnose and deter- elevated. In these patients, there will be absolute mine the cause of nephrogenic DI. Patients with free water loss as opposed to other syndromes that DI usually have a constellation of polyuria, urine may be causing hypotonic fluid loss. osmolality below 200 mOsm/kg, and urine specific A water deprivation test is helpful in diagnosing gravity less than 1.005. In patients who are not DI and allows for the differentiation between fluid restricted, serum osmolality usually remains nephrogenic versus central DI. [9,11,12]. Differing within normal limits (280–290 mOsm/kg). Often responses to water deprivation tests due to differ- laboratory values as well as other diagnostic tests ent abnormalities in water homeostasis can be are examined together [7,9]. seen in Figure 1. To determine whether the DI is of Patients with DI who lack adequate water intake nephrogenic origin, a single five-unit dose of sub- are at risk of developing a hyperosmotic state where cutaneous desmopressin may be administered serum sodium concentrations are elevated. Serum after the patient has been deprived of water for at least 4 to 18 hours. Adequate water deprivation is noted by a weight loss of 3 to 5 lbs or two consec- Figure 1. Response to exogenous administration of arginine utive urine osmolality values, checked hourly, that vasopressin in different types of diabetes insipidus [11]. differ by less than 30 mOsm/kg [9,12]. A final measure of urine osmolality is obtained 1 h after administration of the desmopressin. In lithium- 1200 induced nephrogenic DI, the urine often remains dilute with lower urine osmolality levels of less 1000 than 200 mmol/l, even after administration of exogenous AVP. When the cause is central DI, 800 urine osmolality should typically increase in corre- 600 lation with a decrease in urine output, serum sodium concentrations and serum 400 osmolality [5,9,11]. Urine output in nephrogenic

Urine osmolality (mOsm) DI can reach 10 to 18 l/day in severe cases and 3 200 to 6l/day in milder cases. Plasma osmolality is 0 typically greater than 290 mOsmol/kg in patients 0 2 4 6 8 10 11 12 14 who have been placed in fluid restriction [11]. Hours of water deprivation Finally, in nephrogenic DI, arginine vasopressin levels are often normal or elevated. Refer to Table 1 for a review of common laboratory abnormalities Normal Central DI observed with nephrogenic DI. Partial central DI Nephrogenic DI Signs & symptoms The complications observed in patients with Adapted with kind permission from Cecil's textbook of Medicine, 19th Edition, lithium-induced DI are subsequent to the devel- Dennis VW (Ed). WB Saunders Publishers, PA, USA, 495, (1992). opment of and . In

670 Therapy (2005) 2(4) Lithium-induced nephrogenic diabetes insipidus – REVIEW

Table 1. Laboratory abnormalities. difficult to define given the number of other comorbidities that are often present in patients Laboratory Normal Abnormality seen in who experience symptomatic hypernatremia. nephrogenic diabetes insipidus Often the complications that arise from hyper- Urine osmolality 1000 mmol/l <100 mmol/l natremia are not due to the syndrome itself, but Urine output <3 l/day >3 l/day up to 18 l/day rather the inappropriate treatment. Plasma osmolality 275–290 >290 mOsmol/kg mOsmol/kg Treatment Arginine 0.9–4.6 pmol/l >4.6 pmol/l As with most drug-induced conditions that are vasopressin level fully or partially reversible, general treatment of Administration of Little to no rise in urine osmolality lithium-induced DI should begin with the dis- exogenous arginine continuation of lithium therapy. However, in vasopressin many patients, this may not always be feasible [16]. Even when the drug can be discon- most cases, findings of DI on physical examina- tinued, lithium-induced DI may take several tion are most related to CNS dysfunctions sec- weeks to correct and may not ever completely ondary to severe changes in serum sodium resolve [17,18]. Over 25% of patients who develop concentrations. In most outpatient cases of DI, polyuria while taking lithium will have a dimin- patients are either very young or elderly. In a ished ability to concentrate their urine 1 year majority of the reported cases of lithium- after stopping lithium [12]. induced DI, the patients were elderly and had Fluid restriction to reduce urine volume is not received lithium for chronic long-term recommended in lithium-induced DI as it may therapy [13–15]. As hypernatremia is an abnormal- lead to extreme hypernatremia and the potential ity likely to occur in the elderly, the safety of for hypertonic encephalopathy [12]. It is impor- long-term therapy with lithium in the elderly has tant to note that the diagnosis and differentia- been questioned. In younger infantile patients, tion of DI typically involves a water deprivation common signs and symptoms of hypernatremia test. In the case of lithium-induced DI, it may are hyperpnea, , insomnia, serve to detect a mixed picture where lithium- observed in cases of acute sodium loading and induced nephrogenic DI co-exists with either aggressive rehydration. Elderly patients are often or central DI. However, aside asymptomatic until sodium serum concentra- from the water deprivation test for diagnostic tions reach 160 mmol/l [10]. They may also expe- purposes, fluid restriction in lithium-induced DI rience intense thirst, decreased consciousness, is dangerous and should be avoided. muscle weakness, confusion and coma. In the in- If concurrent hypercalcemia and/or hypo- patient setting, hypernatremia affects patients of kalemia are present along with lithium-induced all ages and the signs and symptoms may be DI, these factors must also be corrected [19]. harder to detect due to pre-existing neurologic Either of these states may cause significant ADH dysfunctions. Patients with nephrogenic DI usu- resistance and reduced aquaporin-2 expression, ally intake adequate amounts of water but may leading to increased urinary water excretion and develop hypernatremia when fluid intake is loss of concentrating ability [3]. Once all of the restricted for any reason [13]. While lethargy, correctable contributing factors are resolved, coma and brain shrinkage is common, dural treatment with pharmacologic agents may be sinus thrombosis has been reported in at least required. Amiloride, thiazide diuretics, one case as a complication of hypernatremia sec- indomethacin and desmopressin have all been ondary to long-term lithium use. In this particu- used to successfully treat lithium-induced DI. lar case, the thombosis was hemorrhagic and As mentioned previously, correction of hyper- fatal [13]. In the management of chronic hyper- natremia associated with lithium-induced DI must natremia, it is important to slowly reduce serum be carried out slowly in order to avoid further wors- sodium concentrations to prevent cerebral ening of the neurologic status. Although a thor- edema and convulsions. In the case of lithium- ough discussion of the treatment of hypernatremia induced DI, these patients will have experienced is beyond the scope of this article, a common error prolonged hypernatremia and therefore should in the overall management of the disease is the use be treated with a more conservative method to of isotonic saline, which will not lower serum prevent further neurologic complications. Mor- sodium concentrations effectively. Conversely, bidity and mortality from hypernatremia itself is aggressive lowering of serum sodium by more than www.future-drugs.com 671 REVIEW – Finch, Brooks, Yam & Kelley

0.5 mEq/h is detrimental and will increase the risk Currently, the most well established mecha- of cerebral edema [10]. Administration of fluids and nism to explain the efficacy of in lith- additional agents should be guided by frequent ium-induced DI relates to extracellular volume monitoring of laboratory values as well as hydra- contraction. Initially, thiazides reduce sodium tion status; however, if urine output exceeds reabsorption in the distal tubule and increase 4 l/day, additional therapies may be needed [14]. urinary sodium excretion [16]. This reduction in sodium reabsorption causes extracellular fluid Amiloride volume contraction and a reduction in glomeru- Multiple authors suggest that the potassium- lar filtration rate. Sodium and water reabsorp- sparing , amiloride, in doses of tion increase at the , which 5 to 20 mg daily, should be considered first-line diminishes dilute urine formation at distal sites therapy for the management of lithium-induced and decreases urine volume [16,20]. DI [9,20–23].Lithium is thought to inhibit vaso- Some authors believe that thiazide-mediated pressin-mediated opening of and inhibition of sodium reabsorption in the distal aquaporin expression in the collecting ducts. tubule cannot be solely responsible for the anti- Amiloride blocks the cellular uptake of lithium diuretic effect of thiazide agents [26–28]. In addi- from the distal tubules and collecting ducts [21]. tion to the extracellular volume contraction, By preventing lithium from entering these cells, thiazides may redistribute total body sodium and amiloride blunts lithium’s inhibition of water increase papillary osmolality [27]. It has also been reabsorption and ultimately decreases urine out- postulated that thiazides can increase water per- put [7]. Due to this direct mechanism, improve- meability in the collecting duct and enhance ment in symptoms can often be seen even in water reabsorption [28]. In a recent study, rats patients who cannot discontinue lithium with lithium-induced DI that were treated with therapy [21]. Some authors postulate that if ami- hydrochlorothiazide for 7 days were shown to loride directly blocks lithium uptake into have significantly increased aquaporin expression aquaporin-expressing tubular cells, then admin- and significantly decreased urine volume com- istering amiloride from the start of lithium ther- pared with nontreated controls [26].This suggests apy could theoretically prevent lithium-induced the possibility that thiazides may directly DI [7]. The clinical utility of this theory has never increase water permeability in the collecting duct been studied to our knowledge. via increased aquaporin expression. The use of amiloride in lithium-induced DI Unfortunately, the volume contraction has multiple advantages over alternative thera- induced by thiazides results in decreased lithium pies. Due to its , amiloride excretion and the potential for lithium may be a safer choice than thiazides or nonsteroi- toxicity [20]. Similar to sodium and water, lith- dal anti-inflammatory drugs (NSAIDs) as it is ium is also reabsorbed in the proximal tubules. less likely to increase serum-lithium concentra- Any treatment modality that increases the tions to toxic levels [23]. Secondly, amiloride use absorption of sodium in the proximal tubule will will not contribute to the development of cause a concurrent increase in lithium reabsorp- hypokalemia due to its potassium-sparing tion [7]. When lithium-induced DI is treated effects [9]. This obviates the need for potassium with thiazide diuretics, lithium levels may rise by supplementation, which is usually required when 25–40% [26,29]. Additionally, thiazides can cause treating lithium-induced DI with thiazides. hypokalemia that may not fully respond to the administration of [16]. Due to Thiazides this potential complication, close monitoring of The use of thiazide diuretics to treat DI has been potassium levels is necessary during thiazide documented since 1959 in animal models and as treatment and potassium supplementation is early as 1961 in humans [24,25].The use of thi- often required. The addition of amiloride to thi- azides in conjunction with a sodium-restricted azide therapy has an additive effect on urine vol- diet of less than 2 g/day has been shown to ume reduction while lessening the chances for decrease urine volume by 40 to 50% [17,19]. The thiazide induced hypokalemia and alkalosis [30]. paradoxical effect of using thiazide diuretics to treat lithium-induced DI has been studied exten- Indomethacin sively and multiple hypotheses regarding the Indomethacin, in doses of 100 to 150 mg mechanisms behind their beneficial effects have daily has been cited extensively as having ben- been described. eficial effects in nephrogenic DI and may be a

672 Therapy (2005) 2(4) Lithium-induced nephrogenic diabetes insipidus – REVIEW

useful adjunct in therapy due to potentiation Desmopressin of ADH activity [23,31,32]. In the kidneys, ade- By definition, nephrogenic DI is characterized by nyl cyclase production and subsequent open- normal plasma ADH levels and an inadequate ing of aquaporins is stimulated by vasopressin. response to ADH in the kidneys. Therefore, it Prostaglandin E2 inhibits adenyl cyclase, would be expected that exogenous administration which diminishes vasopressin-induced water of desmopressin would be of little use in lithium- permeability in the collecting ducts and causes induced nephrogenic DI. However, in one article, water to be excreted in the urine rather than the authors suggest that the use of a thiazide, reabsorbed [16]. Indomethacin blocks prostag- indomethacin, and desmopressin in combination, landin E2 activity and causes increased water may decrease urine output by up to 80% [17]. In reabsorption in the collecting ducts [20]. addition, in another case report, the administra- Additionally, indomethacin has been shown tion of large doses of desmopressin in patients to increase sodium reabsorption in the thick with lithium-induced DI was associated with ascending loop of Henle, which causes more decreased polyuria [34]. The addition of desmo- water to be reabsorbed rather than excreted in pressin to a treatment regimen can be useful in the urine [7]. However, this effect also leads to some patients with lithium-induced DI as they increased lithium reabsorption in the loop of may have a combination of lithium-induced Henle, and may precipitate lithium nephrogenic DI along with central DI from toxicity [23]. In a trial carried out by Frolich another cause that is responsive to desmopressin. and colleagues [33], lithium levels increased by There is also some evidence that desmopressin, 59% in psychiatric patients and 30% in but not endogenous vasopressin, can partially healthy volunteers who received 50 mg of reverse the lithium-induced decrease in aquaporin indomethacin three-times daily. Indomethacin expression in the collecting ducts [20,35]. may also severely disrupt perfusion pressure and lead to acute renal failure, espe- Management of lithium levels cially in the elderly [7]. Owing to these negative Of the many case reports involving lithium- effects, indomethacin should not be considered induced DI, not all cases demonstrated elevated as first-line therapy for lithium-induced DI. levels of lithium (normal 0.4–0.8 mmol/l). While

Table 2. Drug therapy for lithium-induced diabetes insipidus. Treatment Dose Comments Ref. Amiloride 5–20 mg daily; may be First line for lithium-induced DI; [8,20–23] divided b.i.d directly blocks Li+ uptake in kidney; less likely to increase Li+ levels; possible hyperkalemia with use Hydrochlorothiazide* 50–150 mg daily; may be Longest and most widely used [24–26,29] divided b.i.d/t.i.d agent in literature; multiple MOA’s; increase Li+ levels; possible hypokalemia with use Indomethacin 100–150 mg daily; divide Consider use as adjunct, not 1st [23,31–33] b.i.d/t.i.d# line therapy; may potentiate ADH activity; increase Li+ levels; potential for ARF, especially in elderly Desmopressin 10–40 µg intranasal daily; Little data to support use in Li+ [17,20,33, may divide b.i.d/t.i.d OR induced DI; may be useful in 35] 2–4 µg s.c/iv. daily; divide mixed Li+ induced DI with central b.i.d¶ DI component *Any thiazide diuretic may be substituted in equivalent doses. #Other NSAIDS have been used, but most of the literature describes indomethacin use ¶Doses used in treatment of central DI; no specific data for dosage in lithium-induced DI ADH: Anti-diuretic ; ARF: Acute renal failure; b.i.d: Twice daily; iv.: intravenously; MOA: Mechanism of action; s.c.: Subcutaneously; t.i.d: Three times a day.

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it has been suggested that these laboratories Finally, targeting a therapeutic range of 0.4 to should be monitored annually, more frequent 0.8 mmol/l is suggested; however, DI can still monitoring may be prudent in elderly patients occur within these therapeutic levels. as well as in those patients who will receive lithium long term. In a retrospective case Expert commentary review of 149 patients who received lithium In lithium-induced DI, underlying factors con- long term, a decreased glomerular-filtration tributing to the condition should be resolved rate was associated with the duration of lith- before any specific therapies are introduced. ium treatment and increased age [36]. In this This includes discontinuation of lithium ther- study, patients who were on lithium for a apy when possible and correction of electrolyte longer period of time were twice as likely to imbalances such as hypernatremia, hypercal- experience decreased urine-concentrating cemia and hypokalemia, if present. In patients capacity as well as decreased glomerular filtra- who continue to take lithium, it is recom- tion rate. In a case report of two patients with mended that trough levels less than 1 mmol/l be lithium-induced DI, 8 years and were also maintained along with attempting to maintain over the age of 65 years [14]. Only one of these urinary output at less than 4 l/day [7,8]. Dietary patients had an elevated level of lithium. Of sodium restriction of less than 2 g daily is neces- patients on lithium, approximately 20% are sary for the maintenance of the mild extracellu- over the age of 65 years. Given the association lar volume contraction required for the of lithium-induced DI with age and length of antidiuretic effect of thiazides [20]. Treatment therapy but not lithium level, patients should regimens (Table 2) involving amiloride or thi- be thoroughly educated about staying well- azides alone or in combination with each other hydrated in addition to frequent monitoring +/- indomethacin have all been shown to be suc- of urine output and renal function. Institu- cessful in the treatment of lithium-induced DI tionalized patients, who may or may not be and its symptoms. In certain patients with lith- able to let others know when they are thirsty ium-induced DI and an additional component and need fluids, should be monitored very of central DI, the addition of desmopressin may carefully and kept adequately hydrated. also be useful.

Highlights

• Lithium is the most common cause of nephrogenic diabetes insipidus (DI), which may occur in 10–15% of patient taking the medication. • Polydipsia and polyuria develop in up to 40 and 20% of patients, respectively. • The development of DI may be dependent on the dosage as well as the duration of lithium therapy. • Lithium promotes a lack of response to ADH through inhibition of cAMP formation which results in patients losing the ability to reabsorb water and polyuria. • Treatment regimens involving amiloride or thiazides alone or in combination with each other +/- indomethacin have all been shown to be successful in the treatment of lithium-induced DI and its symptoms. • Despmopressin alone may be of little use. • Target therapeutic rangefor lithium is 0.4 to 0.8 mmol/l; however, DI can still occur within these levels.

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