Medical Care

The treatment of lithium nephrotoxicity depends on the severity of the toxicity and chronicity as well as the presence of related abnormalities.^[32]

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 mL/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 diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs; see Medication).The potassium-sparing diuretic amiloride is the most established therapy for the polyuria associated with lithium use.^{[33, 17]}Amiloride is thought to block lithium uptake into the principal cells of the cortical collecting tubule through epithelial channels (ENaC), allowing the principal cells to regain responsiveness to antidiuretic hormone.

In an animal model of lithium-induced nephrogenic diabetes insipidus, acetazolamide reduced polyuria as effectively as hydrochlorothiazide plus amiloride. Case reports describe successful use of acetazolamide in patients with lithium-induced nephrogenic diabetes insipidus that had failed to respond to treatment with standard agents.^{[34, 35]}

In contrast, a study by de Groot et al in six patients with a lithium-induced urinary concentrating defect found evidence against the use of acetazolamide treatment. Two patients withdrew from the study because of adverse effects, and the remaining four showed no change in urine output or clinically relevant changes in maximal urine osmolality. Three of the four patients experienced an increase in serum creatinine levels, indicating a decreased glomerular filtration rate (GFR). The authors postulate that the reduction in polyuria in animal studies is the result of the decrease in GFR.^[36]

The chronic kidney insufficiency can be treated using therapy that would routinely be used for any cause of chronic kidney disease. Evidence of chronic kidney disease is an indication for discontinuation of the drug being administered and for consideration of alternative medications for treatment of the patient's psychiatric disorder.

Consultations

See the list below:

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

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Nielsen J, Kwon TH, Christensen BM, et al. Dysregulation of renal aquaporins and epithelial sodium channel in lithium-induced nephrogenic diabetes insipidus. Semin Nephrol. 2008 May. 28(3):227-44. [QxMD MEDLINE Link].
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. 1999 Jul. 438(2):159-64. [QxMD MEDLINE Link].
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. 2006 May. 290(5):F1222-33.
Garofeanu CG, Weir M, Rosas-Arellano MP, et al. Causes of reversible nephrogenic diabetes insipidus: a systematic review. Am J Kidney Dis. 2005 Apr. 45(4):626-37.
Stone KA. Lithium-induced nephrogenic diabetes insipidus. J Am Board Fam Pract. 1999 Jan-Feb. 12(1):43-7. [QxMD MEDLINE Link].
Thompson CJ, France AJ, Baylis PH. Persistent nephrogenic diabetes insipidus following lithium therapy. Scott Med J. 1997 Feb. 42(1):16-7.
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. 2005 Jun. 288(6):F1276-89.
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. 2005 Jan. 67(1):291-4.
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. 2006 Apr. 17(4):1063-72. [QxMD MEDLINE Link].
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. 2008 Mar 4. 105(9):3634-9. [QxMD MEDLINE Link]. [Full Text].
Marples D, Frokiaer J, Knepper MA, et al. Disordered water channel expression and distribution in acquired nephrogenic diabetes insipidus. Proc Assoc Am Physicians. 1998 Sep-Oct. 110(5):401-6. [QxMD MEDLINE Link].
Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis. 1987 Nov. 10(5):329-45. [QxMD MEDLINE Link].
Markowitz GS, Radhakrishnan J, Kambham N, et al. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol. 2000 Aug. 11(8):1439-48. [QxMD MEDLINE Link].
Gill J, Singh H, Nugent K. Acute lithium intoxication and neuroleptic malignant syndrome. Pharmacotherapy. 2003 Jun. 23(6):811-5.
Davis J, Desmond M, Berk M. Lithium and nephrotoxicity: a literature review of approaches to clinical management and risk stratification. BMC Nephrol. 2018 Nov 3. 19 (1):305. [QxMD MEDLINE Link]. [Full Text].
Paw H, Slingo ME, Tinker M. Late onset nephrogenic diabetes insipidus following cessation of lithium therapy. Anaesth Intensive Care. 2007 Apr. 35(2):278-80. [QxMD MEDLINE Link].
Van Alphen AM, Bosch TM, Kupka RW, Hoekstra R. Chronic kidney disease in lithium-treated patients, incidence and rate of decline. Int J Bipolar Disord. 2021 Jan 4. 9 (1):1. [QxMD MEDLINE Link]. [Full Text].
Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015 Aug 1. 386 (9992):461-8. [QxMD MEDLINE Link]. [Full Text].
Bocchetta A, Ardau R, Fanni T, Sardu C, Piras D, Pani A, et al. Renal function during long-term lithium treatment: a cross-sectional and longitudinal study. BMC Med. 2015 Jan 21. 13:12. [QxMD MEDLINE Link].
Clos S, Rauchhaus P, Severn A, Cochrane L, Donnan PT. Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study. Lancet Psychiatry. 2015 Dec. 2 (12):1075-83. [QxMD MEDLINE Link].
Aprahamian I, Santos FS, dos Santos B, Talib L, Diniz BS, Radanovic M, et al. Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension. J Clin Psychiatry. 2014 Jul. 75(7):e672-8. [QxMD MEDLINE Link].
Rej S, Herrmann N, Shulman K, Fischer HD, Fung K, Harel Z, et al. Lithium Use, but Not Valproate Use, Is Associated With a Higher Risk of Chronic Kidney Disease in Older Adults With Mental Illness. J Clin Psychiatry. 2017 Sep/Oct. 78 (8):e980-e985. [QxMD MEDLINE Link].
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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. 2007 Jul 2. 566(1-3):50-7. [QxMD MEDLINE Link].
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Author

Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, 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

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc.

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, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

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, National Kidney Foundation

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Interim Chair, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Anil Kumar Mandal, MD Clinical Professor, Department of Internal Medicine, Division of Nephrology, University of Florida College 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, Central Society for Clinical and Translational Research

Disclosure: Nothing to disclose.

Mark D T Tran, MD

Mark D T Tran, MD is a member of the following medical societies: American Academy of Family Physicians

Disclosure: Nothing to disclose.

Lithium Nephropathy Treatment & Management

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