Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:


Subscribers log in here


Renal toxicity of lithium

INTRODUCTION

Chronic lithium ingestion in patients with bipolar (manic-depressive) illness has been associated with several different forms of renal injury. Nephrogenic diabetes insipidus (NDI) is the most common renal side effect of lithium therapy [1,2].

The predominant form of chronic renal disease associated with lithium therapy is a chronic tubulointerstitial nephropathy [3]. Although the majority of studies show infrequent and relatively mild renal insufficiency attributable to lithium therapy, end-stage renal disease (ESRD) secondary to lithium-associated chronic tubulointerstitial nephropathy does occur in a small percentage of patients [2,4-7]. Relatively less is known about potential glomerular toxicity of lithium, particularly the nephrotic syndrome. Additional kidney manifestations of lithium exposure include renal tubular acidosis and hypercalcemia. (See "Lithium poisoning".)

NEPHROGENIC DIABETES INSIPIDUS

Normally, water permeability of principal cells in the collecting tubule is regulated by antidiuretic hormone (ADH). Aquaporin-2 water channels (AQP2), which normally reside in the endosomes of principal cells, move to and fuse with the luminal membrane under the influence of ADH, thereby allowing water to be reabsorbed down the favorable concentration gradient. (See "Chapter 6B: Antidiuretic hormone and water balance", section on 'Actions'.)

Chronic lithium ingestion can lead to resistance to ADH, resulting in polyuria and polydipsia in up to 20 to 40 percent of patients [3,8]. Lithium enters the principal cells of the collecting duct through epithelial sodium channels in the luminal membrane [8,9]. It then accumulates in these cells and interferes with the ability of ADH to increase water permeability. Several possible mechanisms may be involved [1,8,10-13]:

Lithium may increase expression of cyclooxegenase-2 and therefore increase urinary prostaglandin E2 excretion by medullary interstitial cells [12]. These prostaglandins then act on principal cells to induce lysosomal degradation of AQP2 water channels and a decline in urine concentrating ability.

         

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2014. | This topic last updated: Sep 25, 2013.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Trepiccione F, Christensen BM. Lithium-induced nephrogenic diabetes insipidus: new clinical and experimental findings. J Nephrol 2010; 23 Suppl 16:S43.
  2. McKnight RF, Adida M, Budge K, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012; 379:721.
  3. 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.
  4. Aurell M, Hestbech J. Lithium-induced uraemia. Lancet 1979; 1:882.
  5. Markowitz GS, Radhakrishnan J, Kambham N, et al. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 2000; 11:1439.
  6. Presne C, Fakhouri F, Noël LH, et al. Lithium-induced nephropathy: Rate of progression and prognostic factors. Kidney Int 2003; 64:585.
  7. Bendz H, Schön S, Attman PO, Aurell M. Renal failure occurs in chronic lithium treatment but is uncommon. Kidney Int 2010; 77:219.
  8. Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009; 5:270.
  9. Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med 1985; 312:408.
  10. Ecelbarger CA. Lithium treatment and remodeling of the collecting duct. Am J Physiol Renal Physiol 2006; 291:F37.
  11. Christensen BM, Kim YH, Kwon TH, Nielsen S. Lithium treatment induces a marked proliferation of primarily principal cells in rat kidney inner medullary collecting duct. Am J Physiol Renal Physiol 2006; 291:F39.
  12. Kortenoeven ML, Schweer H, Cox R, et al. Lithium reduces aquaporin-2 transcription independent of prostaglandins. Am J Physiol Cell Physiol 2012; 302:C131.
  13. 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; 17:1063.
  14. 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.
  15. Movig KL, Baumgarten R, Leufkens HG, et al. Risk factors for the development of lithium-induced polyuria. Br J Psychiatry 2003; 182:319.
  16. Garofeanu CG, Weir M, Rosas-Arellano MP, et al. Causes of reversible nephrogenic diabetes insipidus: a systematic review. Am J Kidney Dis 2005; 45:626.
  17. Shaikh BS, Nicholas GG, Miller FJ. Persistent nephrogenic diabetes insipidus after lithium carbonate. Ann Intern Med 1977; 86:446.
  18. Bedford JJ, Weggery S, Ellis G, et al. Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. Clin J Am Soc Nephrol 2008; 3:1324.
  19. Kim GH, Lee JW, Oh YK, et al. Antidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channel. J Am Soc Nephrol 2004; 15:2836.
  20. Stasior DS, Kikeri D, Duel B, Seifter JL. Nephrogenic diabetes insipidus responsive to indomethacin plus dDAVP. N Engl J Med 1991; 324:850.
  21. Allen HM, Jackson RL, Winchester MD, et al. Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus. Arch Intern Med 1989; 149:1123.
  22. Wood IK, Parmelee DX, Foreman JW. Lithium-induced nephrotic syndrome. Am J Psychiatry 1989; 146:84.
  23. Alexander F, Martin J. Nephrotic syndrome associated with lithium therapy. Clin Nephrol 1981; 15:267.
  24. Santella RN, Rimmer JM, MacPherson BR. Focal segmental glomerulosclerosis in patients receiving lithium carbonate. Am J Med 1988; 84:951.
  25. Vestergaard P, Amdisen A, Schou M. Clinically significant side effects of lithium treatment. A survey of 237 patients in long-term treatment. Acta Psychiatr Scand 1980; 62:193.
  26. Demers R, Heninger G. Pretibial edema and sodium retention during lithium carbonate treatment. JAMA 1970; 214:1845.
  27. Rose BD. An unusual disorder of salt and water balance. Kidney Int Suppl 1997; 59:S111.
  28. Kripalani M, Shawcross J, Reilly J, Main J. Lithium and chronic kidney disease. BMJ 2009; 339:b2452.
  29. Waller DG, Edwards JG, Papasthatis-Papayanni S. A longitudinal assessment of renal function during treatment with lithium. Q J Med 1988; 68:553.
  30. Walker RG, Escott M, Birchall I, et al. Chronic progressive renal lesions induced by lithium. Kidney Int 1986; 29:875.
  31. Hansen HE, Hestbech J, Sørensen JL, et al. Chronic interstitial nephropathy in patients on long-term lithium treatment. Q J Med 1979; 48:577.
  32. Farres MT, Ronco P, Saadoun D, et al. Chronic lithium nephropathy: MR imaging for diagnosis. Radiology 2003; 229:570.
  33. Sloand JA, Shelly MA. Normalization of lithium-induced hypercalcemia and hyperparathyroidism with cinacalcet hydrochloride. Am J Kidney Dis 2006; 48:832.
  34. Spiegel AM, Rudorfer MV, Marx SJ, Linnoila M. The effect of short term lithium administration on suppressibility of parathyroid hormone secretion by calcium in vivo. J Clin Endocrinol Metab 1984; 59:354.
  35. Bendz H, Sjödin I, Toss G, Berglund K. Hyperparathyroidism and long-term lithium therapy--a cross-sectional study and the effect of lithium withdrawal. J Intern Med 1996; 240:357.
  36. Gregoor PS, de Jong GM. Lithium hypercalcemia, hyperparathyroidism, and cinacalcet. Kidney Int 2007; 71:470.
  37. Sajid-Crockett S, Singer FR, Hershman JM. Cinacalcet for the treatment of primary hyperparathyroidism. Metabolism 2008; 57:517.
  38. Lehmann K, Ritz E. Angiotensin-converting enzyme inhibitors may cause renal dysfunction in patients on long-term lithium treatment. Am J Kidney Dis 1995; 25:82.
  39. Juurlink DN, Mamdani MM, Kopp A, et al. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc 2004; 52:794.
  40. Oktem F, Ozguner F, Sulak O, et al. Lithium-induced renal toxicity in rats: protection by a novel antioxidant caffeic acid phenethyl ester. Mol Cell Biochem 2005; 277:109.
  41. Efrati S, Averbukh M, Berman S, et al. N-Acetylcysteine ameliorates lithium-induced renal failure in rats. Nephrol Dial Transplant 2005; 20:65.