eMedicine Specialties > Nephrology > Drug- and Nephrotoxin-Associated Kidney Disorders
Lithium Nephropathy: Treatment & Medication
Updated: Aug 8, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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.
Adult
5 mg/d PO; may titrate to 20 mg/d PO
Pediatric
Not established
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
Documented hypersensitivity, hyperkalemia, potassium supplementation, renal impairment, potassium-sparing diuretics
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.
Adult
25-100 mg/d PO; not to exceed 200 mg/d
Pediatric
Not established
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
Documented hypersensitivity, anuria or renal decompensation
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.
Adult
25-50 mg PO bid/tid
75 mg SR PO bid; not to exceed 200 mg/d
Pediatric
Not established
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
Documented hypersensitivity, GI bleeding, or renal insufficiency
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)
More on Lithium Nephropathy |
| Overview: Lithium Nephropathy |
| Differential Diagnoses & Workup: Lithium Nephropathy |
 Treatment & Medication: Lithium Nephropathy |
| Follow-up: Lithium Nephropathy |
| References |
| Further Reading |
| « Previous Page | Next Page » |
References
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].
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].
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.
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.
Stone KA. Lithium-induced nephrogenic diabetes insipidus. J Am Board Fam Pract. Jan-Feb 1999;12(1):43-7. [Medline].
Thompson CJ, France AJ, Baylis PH. Persistent nephrogenic diabetes insipidus following lithium therapy. Scott Med J. Feb 1997;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. Jun 2005;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. Jan 2005;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. Apr 2006;17(4):1063-72. [Medline].
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].
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].
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].
Gill J, Singh H, Nugent K. Acute lithium intoxication and neuroleptic malignant syndrome. Pharmacotherapy. Jun 2003;23(6):811-5.
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].
Robertson GL. Differential diagnosis of polyuria. Annu Rev Med. 1988;39:425-42. [Medline].
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].
Farres MT, Ronco P, Saadoun D. Chronic lithium nephropathy: MR imaging for diagnosis. Radiology. 2003;229:570-4. [Medline]. [Full Text].
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].
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].
Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. May 2009;5(5):270-6. [Medline].
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.
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].
McIntyre RS, Mancini DA, Parikh S, Kennedy SH. Lithium revisited. Can J Psychiatry. May 2001;46(4):322-7.
No authors listed. Lithium nephropathy [editorial]. Lancet. Sep 22 1979;2(8143):619-20. [Medline].
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.
Schou M. Forty years of lithium treatment. Arch Gen Psychiatry. Jan 1997;54(1):9-13; discussion 14-5. [Medline].
Timmer RT, Sands JM. Lithium intoxication. J Am Soc Nephrol. Mar 1999;10(3):666-74. [Medline].
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.
Walker RG. Lithium nephrotoxicity. Kidney Int Suppl. Jul 1993;42:S93-8. [Medline].
Further Reading
Related eMedicine topics:
Acute Renal Failure
Chronic Renal Failure
Diabetes Insipidus [Endocrinology]
Diabetes Insipidus [Pediatrics: General Medicine]
Nephritis, Interstitial
Renal Failure, Acute
Toxicity, Lithium
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
