eMedicine Specialties > Nephrology > Drug- and Nephrotoxin-Associated Kidney Disorders

Lithium Nephropathy

Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine; Interim Chief of Nephrology; Director of Nephrology Training Program; Director, Metabolic Stone Clinic; Director of Outpatient Clinics, Kidney Disease Program, University of Louisville School of Medicine
Clifford C Dacso, MD, MPH, MBA, John S Dunn Sr Research Chair, The Methodist Hospital Research Institute; Distinguished Research Professor, University of Houston; Mark DT Tran, MD, Staff Physician, Department of Internal Medicine, Baylor College of Medicine

Updated: Aug 8, 2009

Introduction

Background

The medicinal use of lithium has a long and illustrious history. Galen recommended bathing in alkaline mineral waters, which might have contained lithium, for the treatment of mania as early as 200 AD.

In the mid-1800s, lithium was proposed as a treatment of uric acid calculi and gout, as uric acid crystals are highly soluble in solutions containing lithium carbonate. This therapy proved ineffective, but lithium was noted to be a highly effective treatment of psychiatric disorders in the late nineteenth century. Unfortunately, the toxicity of lithium severely limited its widespread acceptance at that point. Lithium was used as a substitute and added to the soft drink 7 Up in the early twentieth century; toxicity again leading to its withdrawal.

However, in 1949, the Australian psychiatrist John Cade reported on the successful use of lithium for mania. Since then, multiple studies have been performed demonstrating the efficacy of lithium in patients with mood disorders, such as depression, manic depression, and melancholia. Simultaneously, renal effects associated with lithium administration, including polyuria and nocturia, were increasingly reported.

In the 1950s and for several decades following, intensive studies on lithium nephrotoxicity were spurred by the wide acceptance of lithium administration in psychiatric practice as an effective treatment of and prophylaxis for unipolar and bipolar affective disorders. For the past 2 decades, alternative psychiatric agents have been adopted for the treatment of these disorders in large part because of the growing recognition of lithium nephrotoxicity.

Pathophysiology

Lithium can affect renal function in several ways. Acutely and chronically, lithium salts produce a natriuresis that is associated with an impaired regulation of the expression of the epithelial sodium channel in the cortical collecting tubule.^1,2 Specifically, lithium use partially inhibits the ability of aldosterone to increase apical membrane ENaC expression, resulting in inappropriate sodium losses.³

The most common complication of chronic lithium therapy is nephrogenic diabetes insipidus.^4,5,6 At the cellular level, antidiuretic hormone (ADH) is released from the posterior pituitary in response to increases in serum osmolarity or decreases in effective circulating volume, and this hormone acts on V2 receptors in the basolateral membrane of the principal cells in the cortical and medullary collecting tubules. The net result of the cascade involving a G protein (guanyl-nucleotide regulatory protein) and adenylate cyclase is an increase in the intracellular cyclic adenosine monophosphate (cAMP) level, which can play a dual role in antidiuresis regulation. cAMP acutely stimulates protein kinase A, which facilitates the insertion of aquaporin-2 (AQP2) water channels. These water channels are preformed and stored in cytoplasmic vesicles in the apical plasma membrane of the principal cells. This process leads to increased water permeability and, thus,antidiuresis.

Over extended periods of time, increased cAMP levels also increase the production of AQP2 water channels at the genetic level by promoting a 5' untranslated region of the AQP2 gene.⁷ Lithium impairs the ADH stimulatory effect on adenylate cyclase, thereby decreasing cAMP levels.⁸ Li and colleagues have also performed studies suggesting that the ability of lithium to produce nephrogenic diabetes insipidus may be independent of its effect on cAMP generation and related to decreased AQP2 mRNA levels.⁹ Thus, lithium most likely impairs water permeability in the principal cells by inhibiting water channel delivery and, over a prolonged period of time, by suppressing channel production.^1,10,11

A minority of reports, however, propose that lithium-induced partial central diabetes insipidus may play a role in the polyuria that may develop in patients who show a modest response to exogenous ADH. Other studies show that ADH levels in patients treated with lithium are normal or elevated.

Over 30 case reports of lithium-induced nephrogenic diabetes insipidus appear in the medical literature.⁴ Patients with urine-concentrating defects resulting from lithium treatment usually take weeks to months to recover following discontinuation of the drug; in rare situations, the problem can persist for years. Early reports in psychiatric patients suggested that this persistent concentrating impairment may be linked to underlying renal histological damage and may be worse with neuroleptic use and prolonged lithium therapy. In a 1987 review, Boton and colleagues showed a 54% correlation between impaired urine-concentrating ability and the duration and total dosage of lithium treatment.¹²

Lithium may also be responsible for a distal tubular acidification defect. The defect is believed to be a variant of incomplete distal renal tubular acidosis, whereby the effect is exerted from the luminal side, requiring lithium cell entry. Patients taking lithium have normal phosphate and ammonia excretion. Lithium is not known to cause significant hyperkalemia.

The role of lithium in the production of acute renal failure is well accepted. The cause is generally due to severe dehydration and volume depletion due to the combination of natriuresis and water diuresis accompanied by elevated lithium levels, altered mental status, and subsequent poor oral intake. Acute renal failure has also been described as a result of lithium-induced neuroleptic malignant syndrome.¹³ However, controversy still exists over its role in chronic renal failure. Boton and colleagues estimated (from an analysis of more than 1000 patients) that 85% of patients on long-term lithium therapy had normal glomerular filtration rates (GFRs); the remaining 15% had GFRs of more than 2 standard deviations below the age-corrected normal values, but very few patients had values less than 60 mL/min.¹²

Extensive reviews in 1988 and 1989 suggested that monitored long-term lithium treatment does not adversely affect the GFR, despite other reports of concurrent histological damage. Prospective studies of patients taking stable lithium also failed to show a decline in GFR in the absence of acute lithium intoxication. Although a minimal increase in the protein excretion rate has been reported in some patients who were taking lithium for at least 2 years, overt proteinuria is not a common complication. A rare association between minimal-change nephrotic syndrome and lithium administration has also been described.

Lithium does not appear to adversely affect proximal tubular function.

Frequency

United States

Lithium is currently a drug of choice for treating persons with bipolar depression and is widely used in this population. Approximately 0.1% of the US population is undergoing lithium treatment for psychiatric problems. Approximately 20-54% of these patients have symptoms of urine-concentrating defects during and after lithium use. Up to 12% develop frank diabetes insipidus, and some continue to have this problem for years after discontinuing lithium. One case report describes patients who still had diabetes insipidus 8 years later. In another report of a small subset of patients, up to 63% had persistent defects 1 year after stopping lithium.^5,14 Of note, approximately 30% of patients taking lithium experience at least one episode of lithium toxicity, correlating with a decrease in glomerular filtration rate. Researchers continue to debate the incidence and pathophysiology of long-term lithium nephropathy.

Mortality/Morbidity

Because of the frequent use and high incidence of associated urine-concentrating defects, lithium has been cited as the most common cause of nephrogenic diabetes insipidus. This complication is a major source of electrolyte disturbances and associated morbidity. The very narrow therapeutic window for this drug contributes substantially to the frequency of acute and chronic toxicity. There does not appear to be any documented gender or ethnic predisposition to the development of lithium toxicity, although some studies suggest that women may require less drug to achieve therapeutic serum levels than men.

Race

The available literature does not suggest a racial or gender predominance in lithium nephrotoxicity, although early pharmacokinetic studies suggest that young women may need a lesser dose of lithium to achieve therapeutic serum levels than men.

Clinical

History

Generally, lithium nephrotoxicity will occur within a month of onset of use of the drug, manifested predominantly by polyuria and polydipsia. The onset of these symptoms may also occur in the presence of accelerating dose regimens. Initially, these symptoms are reversible but may become permanent with long-term use and/or chronically high serum lithium levels. When acute renal failure occurs in the setting of lithium toxicity, the patients generally will exhibit other signs of lithium toxicity, such as obtundation.

• Polyuria
  • Polyuria, defined as a 24-hour urine output of greater than 3 L, is the most common complication in an otherwise asymptomatic patient who has a plasma lithium level consistent with therapeutic dosing.¹⁵ Patients may develop polydipsia. In a case report of persistent lithium-induced nephrogenic diabetes insipidus, the patient drank 20-40 glasses of water per day.
  • Nocturia can be a useful marker of polyuria. Up to 68% of patients report at least 1 urination episode per night.

Physical

Patients with lithium nephrotoxicity may exhibit signs of modest volume depletion, including orthostatic hypotension, tachycardia, and dry mouth. With severe dehydration, patients will show evidence of hypernatremia, including altered mental status.

• Signs of volume depletion - Hypotension, orthostasis, tachycardia, and dry mouth
• Altered mental status.
• Occasional signs of hypothyroidism, including impaired reflexes and bradycardia
• Signs of cardiotoxicity, including cardiac conduction blockade, SA node dysfunction, T wave flattening and inversion, and cardiovascular collapse

Causes

• Central diabetes insipidus
  • Familial disorder
  • Trauma-induced
  • Postsurgical
  • Neoplastic
  • Ischemic
  • Infectious
  • Autoimmune
  • Granulomatous
  • Idiopathic
• Other causes of nephrogenic diabetes insipidus
  • Renal causes include chronic renal failure, the diuretic phase of acute renal failure, and obstructive uropathy.
  • Systemic disorders include familial X-linked syndrome, electrolyte disturbances (hypokalemia, hypercalcemia), sickle cell anemia (trait or disease), Sjögren syndrome, amyloidosis, or sarcoidosis.
  • Drugs include demeclocycline, loop diuretics, angiographic dyes, or anticancer agents.
  • Dietary abnormalities include polydipsia, low-protein diet, or low-sodium diet.
  • Pregnancy

Differential Diagnoses

Other Problems to Be Considered

See Causes.

Workup

Laboratory Studies

• A chemistry panel may help identify electrolyte abnormalities that may be causing the patient's concentrating defect and natriuresis (ie, hypernatremia, hypokalemia, hypercalcemia, elevated BUN and creatinine). Uncontrolled diabetes mellitus may cause similar findings from osmotic diuresis; however, in that disorder, the serum glucose level will be elevated.
• Urine and serum osmolality may help determine if the patient has a concentrating defect. Urine osmolality will be less than 100 mOsm/kg despite normal or higher-than-normal serum osmolality.
• High urine output accompanied by elevated BUN and serum creatinine levels¹⁶ can be due to volume depletion with any polyuric syndrome, such as nephrogenic diabetes insipidus, central diabetes insipidus, or osmotic diuresis; the polyuric phase of acute renal failure; or chronic renal failure.
• Assess the patient's lithium level: Check the plasma vasopressin level to rule out central diabetes insipidus.
• Perform full toxicology screen to exclude the possibility of multiple toxin ingestion, particularly in the case of suicide attempts.

Imaging Studies

• An MRI of the sella can be ordered for patients who have abnormal hormonal findings (ie, elevated prolactin) and if multiple endocrine disorders or masses that may be causing central diabetes insipidus are suggested.
• MRI examination of the kidneys, while not necessary for diagnosis, has demonstrated the presence of renal cysts in many patients. These are described as microcysts and can be quite numerous.¹⁷
• Renal ultrasound can be used to assess for suggested obstructive causes.

Other Tests

• Water deprivation test
  • This test documents if the patient has a concentrating defect.
  • First, baseline measurements of urine and serum osmolality and electrolytes are obtained.
  • Strict water deprivation is then imposed for 4-18 hours (usually 8 h).
  • Urine output and weight are carefully monitored before and after fluid deprivation.
  • Serum and urine osmolality and electrolyte levels are measured hourly after initiation of fluid deprivation.
  • A patient without a concentrating defect should have a 2- to 4-fold increase in urine osmolality.
• Vasopressin challenge¹⁸
  • This test differentiates central and nephrogenic diabetes insipidus.
  • Following the water deprivation test, 5 U of vasopressin is administered subcutaneously (ie, vasopressin as 5 U of aqueous arginine vasopressin or 1 mcg of desmopressin SC or 10 mcg of desmopressin by nasal spray).
  • Serum and urine osmolality are measured 1-2 hours later.
  • Patients with complete central diabetes insipidus fail to increase their urine osmolality after water deprivation (ie, concentrating defect), but they have more than a 50% increase in urine osmolality from baseline after vasopressin administration.
  • Patients with nephrogenic diabetes insipidus also fail to show an increase in urine osmolality after deprivation (ie, concentrating defect) but have less than a 10% increase in urine osmolality from baseline after vasopressin administration.
  • Reports have described patients with combined central and nephrogenic defects who show a 10-50% increase in urine osmolality.
• ECG: Look for evidence of cardiac conduction abnormalities, such as T wave flattening.
• Thyroid functions

Histologic Findings

In reports of small groups of patients, lithium use has been associated with many nonspecific renal lesions.

The histology of acute renal lesions associated with lithium intoxication tends to involve the distal nephron and includes acute tubular necrosis with nonspecific changes such as distal tubular flattening, proximal tubular necrosis, and cytoplasmic vacuolation and cellular and nuclear polymorphism of the distal tubular epithelial cells. In 1978, Kincaid-Smith described a more specific acute lesion consisting of glycogen deposition in the swollen and vacuolated cytoplasm of the distal tubular epithelial cells. These lesions can reverse when lithium administration is stopped.

The development of chronic renal lesions with prolonged lithium use is controversial. Earlier studies have cited interstitial fibrosis, tubular atrophy, and glomerulosclerosis among the chronic changes attributed to lithium. Furthermore, studies suggested that these lesions correlated clinically with the duration of lithium use and concomitant neuroleptic treatments. The data, however, had several limiting factors. The biopsy samples were obtained from a subgroup that had a history of acute lithium toxicity, and many of the histological changes were also identified in the control group. Other more specific chronic lesions include distal tubular dilation and microcyst formation. No evidence indicates that chronic glomerular lesions persist after discontinuing lithium.

Animal studies that used toxic doses of lithium demonstrated epithelial degeneration and dilatation of the distal part of the nephron in dogs, and rats had degenerative changes in the proximal tubules. Rats exposed to levels corresponding to the therapeutic range in humans had ultrastructural lesions, including mitochondrial changes with bulging cytoplasm in tubular cells, liquefaction, karyolysis, and karyorrhexis of the distal tubule and collecting duct.

Treatment

Medical Care

The treatment of lithium nephrotoxicity is dependent upon the severity of the toxicity and chronicity as well as accompanying abnormalities.

• The acute lithium nephrotoxicity picture is dominated by evidence of volume depletion, obtundation, and the potential for cardiovascular collapse. These patients will frequently require close monitoring and aggressive fluid replacement even dialysis; therefore, the intensive care unit is the most appropriate site for these patients.
  • Correcting electrolyte abnormalities in patients with acute disease is critical. Treatment should be initiated with parenteral fluids to replete hypovolemia (normal saline at 200-250 cc/h), followed by administration of hypotonic fluid (0.5% normal saline). Once volume status is restored, then a forced diuresis should be initiated by the administration of parenteral furosemide or bumetanide accompanied by continued intravenous hypotonic fluid administration to maintain volume status.
  • For patients with lesser degrees of lithium toxicity, this therapy will be adequate to treat the condition. For patients with greater degrees of lithium toxicity, generally with lithium levels of greater than 4 mEq/L, dialysis is indicated. Dialysis may also be considered in patients with levels in the mid 2s but who are exhibiting evidence of instability.
• The chronic lithium nephrotoxicity picture is dominated by polyuria and evidence of chronic kidney disease.
  • Polyuria can be treated with medications, such as thiazide diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs; see Medication). Reports suggest that the drug amiloride may be particularly beneficial for the treatment of the polyuria associated with lithium use.^19,20  The mechanism for this effect is thought to be the ability of amiloride to block lithium uptake into the principal cells of the cortical collecting tubule through epithelial channels (ENaC), allowing the principal cell to regain responsiveness to ADH. 
  • The chronic renal insufficiency can be treated using therapy that would routinely be used for any cause of chronic renal disease. Evidence of chronic renal disease is an indication for discontinuation of the drug being administered and for consideration of alternative medications for psychiatric disorder treatment in the patient.

Consultations

• Endocrinology for evidence of thyroid dysfunction
• Nephrology for management of aggressive forced diuresis or potential hemodialysis for removal of drug
• Poison control for updates on the latest treatment guidelines
• Cardiology for evidence of cardiovascular collapse
• Psychiatry for evaluation of the ongoing need for lithium therapy or for evaluation of suicidal behavior if apparent

Medication

Diuretics and NSAIDs are used in the treatment of stable lithium-induced nephrogenic diabetes insipidus.

Diuretics

Decrease extracellular fluid and promote proximal tubular resorption that is not ADH dependent. Ultimately, less free water is transmitted to distal collecting tubules, which is where the urine-concentrating defect is located; therefore, the polyuria decreases. However, extracellular fluid depletion can also increase the risk of lithium intoxication by enhancing lithium reabsorption at the proximal tubule. Diuretics have a gradual onset of action and are less useful in an acute setting.

Amiloride (Midamor)

Prevents uptake of lithium by epithelial cells. Has less potential for lithium toxicity because has a weak natriuretic effect and is less likely to increase lithium level by causing volume contraction. Has the advantage of being potassium-sparing; hypokalemia itself may potentiate a defect in concentrating ability. Also induces less extracellular fluid contraction than thiazides.

Dosing

Adult

5 mg/d PO; may titrate to 20 mg/d PO

Pediatric

Not established

Interactions

Increases toxicity of amantadine and lithium; increased risk of hyperkalemia with ACE inhibitors, indomethacin, potassium supplements, spironolactone, and triamterene; additive effects with thiazides; decreased effect with NSAIDs

Contraindications

Documented hypersensitivity, hyperkalemia, potassium supplementation, renal impairment, potassium-sparing diuretics

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

States of extracellular fluid depletion can increase risk of lithium intoxication by enhancing lithium reabsorption at the proximal tubule; closely monitor lithium levels in the setting of diuretic use, diarrhea, vomiting, and other fluid loss (eg, sauna use, febrile illness)

Hydrochlorothiazide (Esidrix)

Thiazides may require potassium supplementation; more often associated with lithium toxicity. Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions. Equivalent dosages of other thiazide preparations may be used. Use same dose range effective for treating hypertension.

Dosing

Adult

25-100 mg/d PO; not to exceed 200 mg/d

Pediatric

Not established

Interactions

May decrease effects of anticoagulants, antigout agents, and sulfonylureas; thiazides may increase toxicity of allopurinol, anesthetics, antineoplastics, calcium salts, loop diuretics, lithium, diazoxide, digitalis, amphotericin B, and nondepolarizing muscle relaxants

Contraindications

Documented hypersensitivity, anuria or renal decompensation

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Some experts say pregnancy category D; caution in renal disease, hepatic disease, gout, diabetes mellitus, and erythematosus; states of extracellular fluid depletion can increase risk of lithium intoxication by enhancing lithium reabsorption at proximal tubule; closely monitor lithium levels in the setting of diuretic use, diarrhea, vomiting, and other fluid loss (eg, sauna use, febrile illness)

Nonsteroidal anti-inflammatory drugs

Have an antiprostaglandin effect in rats. Inhibiting prostaglandin increases cAMP in the collecting tubules, which promotes water resorption (see Pathophysiology). NSAIDs also inhibit the production of prostaglandin that regulates glomerular blood flow and therefore decreases the GFR and urine flow to the distal tubules. Physicians do not recommend long-term NSAID therapy.

Indomethacin (Indocin, Indochron ER)

Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis. One case report exists of IV ketorolac used in acutely ill patient failing to respond to indomethacin.

Dosing

Adult

25-50 mg PO bid/tid
75 mg SR PO bid; not to exceed 200 mg/d

Pediatric

Not established

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and possibly the toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity, GI bleeding, or renal insufficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in third trimester of pregnancy, acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia develops)

Follow-up

Further Inpatient Care

• Patients with severe cases of volume depletion with associated electrolyte abnormalities (ie, hypernatremia) may require ICU care.
• Once aggressive diuresis is initiated or dialysis is performed for acute toxicity, lithium levels should be sequentially checked to ensure that rebound toxic levels and/or delayed gastrointestinal absorption leading to recurrent toxicity do not occur.

Further Outpatient Care

• Some reports recommend testing the patient's renal-concentrating ability, 24-hour urinary volume, and creatinine clearance before initiating lithium therapy and at 1-year intervals.
• Schou recommends regular measurements of serum lithium and creatinine every 2-6 months and obtaining serum thyroid-stimulating hormone determinations once a year.

Inpatient & Outpatient Medications

• See Medication.

Deterrence/Prevention

• Lithium has a low therapeutic index; monitor levels closely to prevent acute lithium intoxication.

Complications

• Some reports have linked acute renal failure to lithium intoxication. In these cases, however, researchers did not exclude decreased perfusion and other causes of volume depletion as possible contributing factors. Nevertheless, physicians must remember that lithium intoxication can cause volume depletion and vice versa.

Prognosis

• Patients with urine-concentrating defects from lithium treatment usually take weeks to months to recover following discontinuation of lithium. In rare situations, the problem can persist for years.
• Acute renal failure associated with lithium toxicity has an excellent prognosis.
• Chronic renal failure associated with lithium use only uncommonly will completely resolve but generally will not progress if the medication is discontinued and other nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs or hypertension, are minimized.

Miscellaneous

Medicolegal Pitfalls

• Failure to assess the patient for signs of volume depletion
• Failure to realize that patients with severe cases of volume depletion with associated electrolyte abnormalities (ie, hypernatremia) may require ICU care
• Failure to correct electrolyte abnormalities in patients with acute disease
• Failure to realize that lithium has a low therapeutic index and to monitor levels closely to prevent acute lithium intoxication

References

1. Nielsen J, Kwon TH, Christensen BM, et al. Dysregulation of renal aquaporins and epithelial sodium channel in lithium-induced nephrogenic diabetes insipidus. Semin Nephrol. May 2008;28(3):227-44. [Medline].

2. Mu J, Johansson M, Hansson GC, et al. Lithium evokes a more pronounced natriuresis when administered orally than when given intravenously to salt-depleted rats. Pflugers Arch. Jul 1999;438(2):159-64. [Medline].

3. Nielsen J, Kwon TH, Frokiaer J, et al. Lithium-induced NDI in rats is associated with loss of alpha-ENaC regulation by aldosterone in CCD. Am J Physiol Renal Physiol. May 2006;290(5):F1222-33.

4. Garofeanu CG, Weir M, Rosas-Arellano MP, et al. Causes of reversible nephrogenic diabetes insipidus: a systematic review. Am J Kidney Dis. Apr 2005;45(4):626-37.

5. Stone KA. Lithium-induced nephrogenic diabetes insipidus. J Am Board Fam Pract. Jan-Feb 1999;12(1):43-7. [Medline].

6. Thompson CJ, France AJ, Baylis PH. Persistent nephrogenic diabetes insipidus following lithium therapy. Scott Med J. Feb 1997;42(1):16-7.

7. Rojek A, Nielsen J, Brooks HL, et al. Altered expression of selected genes in kidney of rats with lithium-induced NDI. Am J Physiol Renal Physiol. Jun 2005;288(6):F1276-89.

8. Walker RJ, Weggery S, Bedford JJ, et al. Lithium-induced reduction in urinary concentrating ability and urinary aquaporin 2 (AQP2) excretion in healthy volunteers. Kidney Int. Jan 2005;67(1):291-4.

9. Li Y, Shaw S, Kamsteeg EJ, et al. Development of lithium-induced nephrogenic diabetes insipidus is dissociated from adenylyl cyclase activity. J Am Soc Nephrol. Apr 2006;17(4):1063-72. [Medline].

10. Nielsen J, Hoffert JD, Knepper MA, et al. Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation. Proc Natl Acad Sci U S A. Mar 4 2008;105(9):3634-9. [Medline]. [Full Text].

11. Marples D, Frokiaer J, Knepper MA, et al. Disordered water channel expression and distribution in acquired nephrogenic diabetes insipidus. Proc Assoc Am Physicians. Sep-Oct 1998;110(5):401-6. [Medline].

12. Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis. Nov 1987;10(5):329-45. [Medline].

13. Gill J, Singh H, Nugent K. Acute lithium intoxication and neuroleptic malignant syndrome. Pharmacotherapy. Jun 2003;23(6):811-5.

14. Paw H, Slingo ME, Tinker M. Late onset nephrogenic diabetes insipidus following cessation of lithium therapy. Anaesth Intensive Care. Apr 2007;35(2):278-80. [Medline].

15. Robertson GL. Differential diagnosis of polyuria. Annu Rev Med. 1988;39:425-42. [Medline].

16. Janowsky DS, Soares J, Hatch JP, et al. Lithium effect on renal glomerular function in individuals with intellectual disability. J Clin Psychopharmacol. Jun 2009;29(3):296-9. [Medline].

17. Farres MT, Ronco P, Saadoun D. Chronic lithium nephropathy: MR imaging for diagnosis. Radiology. 2003;229:570-4. [Medline]. [Full Text].

18. Wilting I, Baumgarten R, Movig KL, et al. Urine osmolality, cyclic AMP and aquaporin-2 in urine of patients under lithium treatment in response to water loading followed by vasopressin administration. Eur J Pharmacol. Jul 2 2007;566(1-3):50-7. [Medline].

19. Bedford JJ, Weggery S, Ellis G, McDonald FJ, Joyce PR, Leader JP, et al. Lithium-induced Nephrogenic Diabetes Insipidus: Renal Effects of Amiloride. Clin J Am Soc Nephrol. 2008;epub ahead of print:[Medline]. [Full Text].

20. Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. May 2009;5(5):270-6. [Medline].

21. Bendz H, Aurell M, Lanke J. A historical cohort study of kidney damage in long-term lithium patients: continued surveillance needed. Eur Psychiatry. Jun 2001;16(4):199-206.

22. Markowitz GS, Radhakrishnan J, Kambham N, et al. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol. Aug 2000;11(8):1439-48. [Medline].

23. McIntyre RS, Mancini DA, Parikh S, Kennedy SH. Lithium revisited. Can J Psychiatry. May 2001;46(4):322-7.

24. No authors listed. Lithium nephropathy [editorial]. Lancet. Sep 22 1979;2(8143):619-20. [Medline].

25. Presne C, Fakhouri F, Noel LH, et al. Lithium-induced nephropathy: Rate of progression and prognostic factors. Kidney Int. Aug 2003;64(2):585-92.

26. Schou M. Forty years of lithium treatment. Arch Gen Psychiatry. Jan 1997;54(1):9-13; discussion 14-5. [Medline].

27. Timmer RT, Sands JM. Lithium intoxication. J Am Soc Nephrol. Mar 1999;10(3):666-74. [Medline].

28. Turan T, Esel E, Tokgoz B, et al. Effects of short- and long-term lithium treatment on kidney functioning in patients with bipolar mood disorder. Prog Neuropsychopharmacol Biol Psychiatry. Apr 2002;26(3):561-5.

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Keywords

lithium nephropathy, diabetes insipidus, insipidus, nephropathy, aquaporin, cyclic AMP, lithium intoxication, nephrogenic diabetes insipidus, aquaporins, lithium nephrotoxicity, adenosine monophosphate, cyclic adenosine monophosphate, distal tubular function, urine-concentrating defects, tubular acidification defect, renal tubular acidosis, renal failure, uric acid calculi, polyuria, nocturia, transient natriuresis, hypokalemia, hypercalcemia, antidiuretic hormone, ADH

Contributor Information and Disclosures

Author

Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine; Interim Chief of Nephrology; Director of Nephrology Training Program; Director, Metabolic Stone Clinic; Director of Outpatient Clinics, Kidney Disease Program, University of Louisville School of Medicine
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Clifford C Dacso, MD, MPH, MBA, John S Dunn Sr Research Chair, The Methodist Hospital Research Institute; Distinguished Research Professor, University of Houston
Clifford C Dacso, MD, MPH, MBA is a member of the following medical societies: American College of Physicians, American Medical Association, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Mark DT Tran, MD, Staff Physician, Department of Internal Medicine, Baylor College of Medicine
Mark DT Tran, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Medical Editor

Anil Kumar Mandal, MD, Clinical Professor, Department of Internal Medicine, Division of Nephrology, University of Florida School of Medicine
Anil Kumar Mandal, MD is a member of the following medical societies: American College of Clinical Pharmacology, American College of Physicians, American Society of Nephrology, and Central Society for Clinical Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

George R Aronoff, MD, Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine
George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation
Disclosure: Nothing to disclose.

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

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