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Lithium-Induced Nephrogenic Diabetes Insipidus Treated with Indomethacin

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Title: Lithium-Induced Nephrogenic Diabetes Insipidus Treated with Indomethacin
Authors: Martinez, Enrique J.; Sinnott IV, MD, John T.; Rodriguez-Paz, MD, George; Oehler, Richard L.
Publisher: Southern Medical Journal
Date Published: August 01, 1993
Reference Number: 127
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Abstract • Article • Translation
NDI occurs in 5% to 20% of patients receiving long-term lithium therapy. The associated polyuria usually resolves within 3 weeks of lithium discontinuance but can persist beyond a year. For such patients, hydrochlorothiazide and amiloride therapy has been hampered by the delayed effect and intrinsic side effects of these agents. We have described the case of a 66-year-old man with a history of bipolar disorder treated with lithium who was transferred to the intensive care unit with coma. Indomethacin therapy, at a dose of 50 mg every 8 hours, was begun and improvement of the NDI state was observed within 3 hours of lithium administration. There was complete normalization of mental status and laboratory studies after 36 hours. A complete 3-week course of indomethacin was required to keep the patient free of symptoms of NDI. We have also discussed the role of indomethacin in reversing lithium-induced NDI and reviewed pertinent prior reports in the literature.
Reprinted by permission from the SOUTHERN MEDICAL JOURNAL, 1993 Aug;86(8):971-3. No part of this article may be reproduced in any way without permission in writing from the publisher.


CASE REPORT

A 66-year-old white man was transferred to the intensive care unit because of coma. The patient had a 7-year history of bipolar psychiatric disorder treated with lithium carbonate, 500 mg per day. In the 3 days before transfer to the intensive care unit, he was treated with aggressive enteral fluid support, and lithium therapy had been discontinued.

Physical examination afterward showed a blood pressure of 90/60 mm Hg, pulse of 115/min, dry oral mucosa, flat neck veins, and skin tenting. Neurologic examination revealed no focal deficits in a comatose patient. Laboratory studies disclosed the following values: sodium, 151 mOsmol/L; chloride, 119 mOsmol/L; serum osmolality, 315 mOsmol/L; urine osmolality, 177 mOsmol/l; serum creatinine, 62 ?ol/L; and serum lithium, 0.28 mmol/L. After treatment was begun with D5 ? normal saline and a single 5 mg dose of amiloride, the patient improved and became stuporous. The following day vasopressin, 2.5 units, was administered subcutaneously in addition to the intravenous fluids. Subsequent laboratory studies showed modest improvement with the following values: sodium, 149 mmol/L; chloride, 115 mmol/L; serum osmolality, 316 mOsmol/L; and urine osmolality, 218 mOsmol/L. Urinary output continued in excess of 6 L a day. Indomethacin therapy, 50 mg by nasogastric tube every 8 hours, was begun. Within 3 hours of initiation, urinary output decreased from 227 mL/hr to 82 mL/hr. Laboratory studies at this time showed improvement as well; values included sodium, 146 mmol/L; chloride, 113 mmol/L; serum osmolality, 307 mOsmol/L; urine osmolality, 368 mOsmol/L; and serum creatinine, 62 ?mol/L. After 36 hours of indomethacin therapy, the patient returned to his original mental status; laboratory values were sodium, 139 mmol/L; chloride, 104 mmol/L; serum osmolality, 288 mOsmol/L; urine osmolality, 377 mOsmol/L; and serum creatinine, 62 ?mol/L. Indomethacin therapy was continued for a total of 3 days. Twenty-four hours afterward urinary output increased dramatically, with serum osmolality increasing to 316 mOsmol/L and urinary osmolality decreasing to 258 mOsmol/L. Indomethacin, 25 mg every 8 hours, was reinitiated for a 3-week course. Carbamazepine therapy, 300 mg per day, was begun to control the patient's bipolar psychiatric disease.

DISCUSSION

Adverse renal effects are commonly encountered in patients receiving lithium carbonate therapy. Numerous studies have shown that in up to 70% of patients taking lithium, complaints of increased thirst can develop, and in up to 40%, overt polyuria of greater than 3 L per day will develop.2.3.12.13 Lithium-induced NDI occurs in 5% to 20% of all patients receiving lithium therapy.4,5 It generally resolves within 3 weeks of lithium discontinuance, but the effect can persist for up to a year.4,5 Lithium is believed to inhibit both proximal and distal vasopressin-induced cAMP production in the collecting tubule cells that normally modulate water resorption.4,5,7

Prior studies have shown limited usefulness of hydrochlorothiazide in management of lithium-induced NDI. Hydrochlorothiazide is thought to produce a natriuresis with negative body salt balance, which in turn decreases intravascular fluid volume and glomerular filtration rate, triggering increased proximal tubular water reabsorption.6,14-16 The reduced intravascular fluid volume from hydrochlorothiazide use causes an increased proximal nephron reabsorption of both sodium and lithium that potentially can lead to the toxic accumulation of lithium.16-18 In addition, hydrochlorothiazide usage leads to potassium depletion, which can further aggravate lithium's potassium-wasting effect.19

Amiloride, a potassium-sparing diuretic, produces only a mild antidiuretic effect. In animal models, it has been shown to block the entrance of lithium into collecting duct cells.20,21 While this agent blocks lithium's effects on cAMP, the clinical response is modest and is seen only after 4 days of therapy. Up to several weeks of therapy must be used before its full benefit can be achieved.7,8 Some authors have postulated that the initial effect of amiloride may be attributed to a mild natriuresis. Thus, amiloride acts in a fashion similar to hydrochlorothiazide but without producing its potassium-depleting effect.7,8

Indomethacin's major advantage is its ability to inhibit the mediators of lithium-induced NDI directly. In the kidney, antidiuretic hormone (ADH) concurrently stimulates adenyl cyclase production in the distal and collecting tubules, leading to increased cAMP levels. It also increases prostaglandin E2 production in the renal medulla.22-24 Adenyl cyclase activates a protein kinase that increases the permeability of the distal and collecting tubules. Renal prostaglandin E2 production serves as a local hormone that limits ADH-mediated water conservation by stimulating vasodilation, natriuresis, and diuresis in the kidney. Furthermore, it has been hypothesized that it interferes directly with the ADH receptor-guanine nucleotide complex that normally stimulates cAMP production.23,25,26

Lithium creates an imbalance in this system by increasing prostaglandin E2 levels. Lithium is believed to decrease cAMP levels not only by blocking the ADH activation of adenyl cyclase but perhaps also by accelerating phosphodiesterase-mediated destruction of cAMP.22,23 In addition, lithium has been shown to augment the ability of ADH to produce renal prostaglandin E2, further leading to a local abundance of PGE2.27-29

Indomethacin's therapeutic effect lies in its interference with lithium-induced renal dysfunction at several levels. Given indomethacin's strong antiprostaglandin effect, it can be postulated that excess prostaglandin production can be curtailed easily with subsequent increased renal cAMP generation, and both animal and human studies have confirmed this.23,30 The more intriguing effect, however, is that indomethacin appears to actually promote water resorption in subjects who do not have lithium-induced NDI by preventing prostaglandin-mediated sodium loss in the ascending loop of Henle, thus effectively increasing sodium resorption and secondarily passive water absorption.24,31,32 In fact, nonsteroidal agents have been noted in the literature for their ability to precipitate renal failure by destroying the normal prostaglandin-mediated effective glomerular filtration pressure.33

Our report illustrates several key points that were not apparent in the three previous reports of indomethacin therapy for lithium-induced NDI.9-11 First, indomethacin in a single 50 mg oral dose causes an immediate and safe improvement of the NDI state; our patient's serum osmolality decreased from 316 to 307 mOsmol/L as urinary output decreased from 227 mL/hr to 82 mL/hr in a 4-hour period, with complete normalization of serum osmolality and sodium levels by 36 hours, when he was treated with indomethacin, 50 mg, every 8 hours. Second, prolonged usage does not induce tolerance; our patient had a serum osmolality value of 288 mOsmol/L and a serum sodium value of 138 mmol/L after completion of 3 weeks' therapy. Finally, 3 weeks of usage did not alter renal function; the serum creatinine level (0.7 mg/dL) remained within normal limits throughout the course of therapy. This is in contrast to a previous report.11

Indomethacin is a safe acute and chronic treatment modality for lithium-induced NDI. Its effect is mediated by altering prostaglandin levels in the kidneys that are elevated by lithium usage. No adverse renal effects were noted in our patient after 3 weeks of indomethacin therapy. It is apparent that indomethacin offers the internist an immediate therapy for reversing the life-threatening electrolyte disturbances in patients with NDI.

SUMMARY

NDI occurs in 5% to 20% of patients receiving long-term lithium therapy. The associated polyuria usually resolves within 3 weeks of lithium discontinuance but can persist beyond a year. For such patients, hydrochlorothiazide and amiloride therapy has been hampered by the delayed effect and intrinsic side effects of these agents. We have described the case of a 66-year-old man with a history of bipolar disorder treated with lithium who was transferred to the intensive care unit with coma. Indomethacin therapy, at a dose of 50 mg every 8 hours, was begun and improvement of the NDI state was observed within 3 hours of lithium administration. There was complete normalization of mental status and laboratory studies after 36 hours. A complete 3-week course of indomethacin was required to keep the patient free of symptoms of NDI. We have also discussed the role of indomethacin in reversing lithium-induced NDI and reviewed pertinent prior reports in the literature.

Acknowledgment. We thank Chester Kokseng, MD, for his initial assistance with the care of this patient.

REFERENCES

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  3. Bendz H: Kidney function in lithium-treated patients. Acta Psychiatr Scand 1983; 68:303-324
  4. Price TRP, Beiswenger PJ: Persistent lithium-induced nephrogenic diabetes insipidus. Am J Psychiatry 1978; 135:1247-1248
  5. Bucht G, Wahlin A: Renal concentrating capacity in long term lithium treatment and after withdrawal of lithium. Acta Med Scand 1980; 207:309-314
  6. Constandis DD, Schriever HG: Severe lithium-induced diabetes insipidus in a surgical patient treated with hydrochlorothiazide. AM J Surg 1981; 141:741-743
  7. Kosten TR, Forrest JN: Treatment of severe lithium-induced polyuria by amiloride. Am J Psychiatry 1986; 143:1563-1568
  8. Batlle DC, von Riotte AB, Gaviria M, et al: Amelioration of polyuria in patients receiving long-term lithium therapy. N Engl J Med 1985; 312:408-414
  9. Rapoport J, Chaimowitz C, Alroy GG, et al: Lithium-induced nephrogenic diabetes insipidus studies of tubular function and pathogenesis. Ist J Med Sci 1979; 15:765-771
  10. Grindlinger GA, Boylan MJ: Amelioration by indomethacin of lithium-induced polyuria. Crit Care Med 1987; 15:538-539
  11. Allen HM, Jackson RL, Winchester MD, et al: Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus. Arch Intern Med 1989; 149:1123-1126
  12. Baylis PH, Heath DA: Water disturbances in patients treated with oral lithium carbonate. Ann Intern Med 1978; 88:607-609
  13. DePaulo JR: Lithium. Psychiatr Clin North Am 1984; 7:587-599
  14. Earley LE, Orloff J: The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin resistant diabetes insipidus. J Clin Invest 1962; 41:1988-1997
  15. Niaudet P, Dechaux M, Trivin C, et al: Nephrogenic diabetes insipidus: clinical and pathophysiological aspects. Adv Nephrol 1984; 13:247-260
  16. Himmelhoch JM, Proust RI, Mallinger AG, et al: Adjustment of lithium dose during lithium-chlorthiazide therapy. Clin Pharmacol Ther 1977; 22:225-227
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  28. Ausiello DA, Zusman RM: The role of calcium in the stimulation of prostaglandin synthesis by vasopressin in rabbit renal-medullary interstitial cells in culture. Biochm J 1984; 220:139-145
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  32. Stokes JB: Effects of prostaglandin E2 on chloride transport across the rabbit thick ascending loop of Henle: selective inhibition of the medullary portion. J Clin Invest 1979; 64:495-502
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Department of Medicine, University of South Florida, College of Medicine, Tampa. (E.J. Martinez, MD, J.T. Sinnott IV, MD, G. Rodriguez-Paz, MD, R.L. Oehler, BS)

1993, August

Address reprint requests to John T. Sinnott IV, MD, Tampa General Hospital, PO Box 1289, Tampa, FL 33601.


This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

Nephrogenic diabetes insipidus (NDI) can be induced in people by giving them lithium over a period of time. In fact, 5% to 20% of patients receiving lithium as part of their therapy develop NDI. NDI symptoms may disappear in as little as three weeks after lithium use is stopped, though it may take up to a year for the NDI symptoms to resolve. Martinez, et al., report of a case involving a 66-year-old white male suffering from lithium-induced NDI. The authors treated him with the drug, indomethacin, and within three hours the patient's excessive urination (associated with NDI) decreased dramatically. And there was a complete normalization of urine concentration and blood chemistry within 36 hours of indomethacin treatment.

Lithium is believed to inhibit the production of an important metabolic regulator called cAMP in the kidneys' collecting tubule cells. These cells normally help balance the kidneys' ability to reabsorb water. The antidiuretic hormone, vasopressin (VP) is instrumental in cAMP production. It also increases prostaglandin E2 (PGE2), which acts as a hormone that helps maintain a balanced kidney function by stimulating excretion of sodium in the urine and increasing the excretion of urine in general.

Lithium upsets balanced kidney function by increasing the PGE2 levels and decreasing cAMP levels. Indomethacin seems to curtail the production of PGE2, and this is followed by increased kidney cAMP production. Tests on people without NDI show indomethacin promotes sodium and water reabsorption by preventing prostaglandin-mediated sodium loss. The authors treated their patient with indomethacin for three weeks and found that indomethacin:

  1. caused an immediate and safe improvement of lithium-induced NDI beginning with the first 50 mg oral dose,
  2. could be used over a three-week period without losing its therapeutic ability, and
  3. produced no ill effects in the kidney.