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

Lithium Nephropathy: Differential Diagnoses & Workup

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
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; Mark DT Tran, MD, Staff Physician, Department of Internal Medicine, Baylor College of Medicine
Contributor Information and Disclosures

Updated: Aug 8, 2009

Differential Diagnoses

Adrenal Crisis
Diabetic Ketoacidosis
Diabetes Insipidus
Hypernatremia
Diabetes Mellitus, Type 1
Hyperosmolar Coma
Diabetes Mellitus, Type 2
Lead Nephropathy

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.

More on Lithium Nephropathy

Overview: Lithium Nephropathy
Differential Diagnoses & Workup: Lithium Nephropathy
Treatment & Medication: Lithium Nephropathy
Follow-up: Lithium Nephropathy
References
Further Reading
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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.

  29. Walker RG. Lithium nephrotoxicity. Kidney Int Suppl. Jul 1993;42:S93-8. [Medline].

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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

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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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