Drug-induced diabetes insipidus is almost always of the. nephrogenic type. genic diabetes insipidus and managed her with intra …
Age and Ageing 2001; 30: 347350
2001, British Geriatrics Society
CASE REPORT
Lithium-induced nephrogenic diabetes insipidus in older people
DIPTARUP MUKHOPADHYAY, LINGESAN GOKULKRISHNAN, KANTHAYA MOHANARUBAN
Department of Integrated Medicine, Withybush General Hospital, Haverfordwest SA61 2PZ, UK Address correspondence to: K Mohanaruban Fax: q44 1437 773328 Email: mdipta@aolcom
Abstract
Presentation: we report two patients The rst is a 68-year-old woman who presented with a 2-day history of vomiting She was hypernatraemic and her elevated serum sodium concentration did not improve initially, despite adequate uid replacement She subsequently developed polyuria and polydipsia The second patient, a 77-year-old woman, presented with delirium and severe hypernatraemia after being treated for a chest infection 1 week earlier Both patients were on long-term lithium treatment Investigation: in both the cases, a supervised water-deprivation test done after normalization of the blood biochemistry showed partial nephrogenic diabetes insipidus Outcome: lithium was discontinued Conclusion: older people on lithiumÐespecially those requiring supportive careÐare at risk of severe
hypernatraemia after an acute illness or if their uid intake is restricted
Keywords: hypernatraemia, lithium, nephrogenic diabetes insipidus
Introduction
Drug-induced diabetes insipidus is almost always of the nephrogenic type Lithium is the commonest drug implicated [1] We report two cases of lithium-induced nephrogenic diabetes insipidus which highlight a relatively common but under-appreciated problem occurring in some older people who take this medication
Case reports
Case 1
A 68-year-old woman was admitted with a 2-day history of vomiting after eating pork She had been taking lithium for the last 8 years for recurrent depression The clinical examination was unremarkable, apart from signs of moderate dehydration Investigations revealed hypernatraemia sodium 149 mmol/l, pre-renal azotaemia urea 303 mmol/l, creatinine 306 mmol/l, normal serum potassium, glucose and calcium, and normal plasma lithium level -02 mmol/l We made a diagnosis of food poisoning and she was treated with intravenous 5 dextrose The vomiting did
not improve The serum urea rose, despite adequate uid replacement via a central venous line with monitoring of the central venous pressure On the third day,
endoscopy revealed the presence of a paraoesophageal hernia Three litres of uid were aspirated from the stomach She was given nothing by mouth and was subsequently managed with nasogastric suction and intravenous dextrose saline infusion However, nasogastric suction yielded only 300350 ml of uid per day Her vomiting improved gradually with conservative management She was discharged after 2 weeks with a diagnosis of a spontaneously resolved gastric volvulus and oesophageal hiatus hernia On discharge, her blood urea and electrolytes were normal At follow-up 2 weeks later, she complained of polyuria and excessive thirst In view of her lithium treatment, we considered the possibility of nephrogenic diabetes insipidus A review of her inpatient record showed her serum sodium had been persistently elevated 144149 mmol/l despite adequate hydration 445 l/day She had an urine output of between 22 and 34 l/day over the same period She was re-admitted for a supervised waterdeprivation test Table 1, which suggested a diagnosis of partial nephrogenic diabetes insipidus After consultation with the consultant psychiatrist, lithium was stopped She is now under regular follow-up
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Table 1 Water-deprivation test results
Osmolality mosmol/kg Pre-test Case 1 295 Case 2 302
After dehydration Urine 605 587 305 307
After desmopressin Plasma 306 304 Urine 598 543
Plasma Urine Plasma 460 518
Case 2
A 77-year-old woman from a residential home was admitted with delirium She had been treated for chest infection a week earlier by her general practitioner She had a long history of manic depressive illness and had been on lithium for the past 10 years On admission, she was severely hypernatraemic sodium 163 mmol/l with pre-renal azotaemia urea 25 mmol/l, creatinine 253 mmol/l Her blood potassium, glucose and calcium concentrations were normal Her lithium level was 14 mmol/l Her serum osmolality was 358 mosmol/kg and a simultaneous urine osmolality was 513 mosmol/kg We made a diagnosis of lithium-induced nephrogenic diabetes insipidus and managed her with intravenous uid replacement 5 dextrose via a central line After normalization of renal function and sodium level, we carried out a supervised water-deprivation test Table 1 This showed a picture suggestive of partial nephrogenic diabetes insipidus The lithium was stopped She was discharged
and continues outpatient follow-up
Discussion
Lithium is the recommended treatment for the prophylaxis of bipolar affective disorder It is also used in the prophylactic treatment of recurrent uni-polar depression, short-term treatment of mania and to augment antidepressant drugs in cases of resistant depression [2] About one in 1000 of the general population is on lithium treatment [3] and about 20 of these patients are over 65 [4] Over the age of 65 years the point prevalence of lithium therapy is 027 [5] Lithium can cause major disturbance in water balance, manifested by polyuria and secondary polydipsia This is because of decreased urinary concentrating abilityÐa consequence of impaired responsiveness of the distal nephron to the anti-diuretic action of arginine vasopressin [6] nephrogenic diabetes insipidus Lithium interferes with arginine vasopressinmediated activation of adenylate cyclase in the principal cells of the distal tubule and collecting duct of the kidney, thereby decreasing intracellular cyclic AMP generation and protein kinase A stimulation, and reducing the abundance of water channels in the apical membrane of the cells and subsequent water transport [7,
8]
Aquaporin-2 is the vasopressin-regulated water channel It is found only in the collecting duct In the experimental rat model, immunoblotting reveals that lithium treatment has been associated with marked downregulation of aquaporin-2 expression to 318 after 10 days and to 41 after 25 days of treatment, coincident with development of severe polyuria, which only partially reversed by cessation of therapy [9] In most cases, there is a correlation between impaired urinary concentrating ability and duration of lithium therapy or total lithium dose [7] Chronic lithium administration may cause focal interstitial nephritis, distal renal tubular dilatation and microcyst formation Patients developing these lesions can be identied clinically by impaired urinary concentrating ability, which progresses with the duration of lithium treatment [7, 10] The current practice is to maintain the serum lithium level between 05 and 08 mmol/l The incidence and severity of adverse effects are greater at higher serum concentrations [2] Between 20 and 40 of patients currently taking lithium have a moderate increase in urine volume 25 l/day as a result of the concentrating defect Up to 12 have frank
nephrogenic diabetes insipidus characterized by polyuria urine volume 3 l/day, excessive thirst, nocturia, delirium, tachycardia, hypotension, hypernatraemia and even hyperosmolar coma [8, 11] Lithium-induced nephrogenic diabetes insipidus is usually reversible on stopping therapy but a few patients remain symptomatic long after the lithium has been discontinued [12] a case of persistent nephrogenic diabetes insipidus has been reported 8 years after discontinuation of lithium [13] These patients are at risk of severe hypernatraemia if their uid intake is restricted, if they receive inadequate intravenous uid peri-operatively or during episodes of vomiting or diarrhoea or during acute illness [13, 14] This is particularly important in institutionalized older people who require supportive care with feeding Furthermore, the patients are at increased risk if the importance of current or past lithium use is under-estimated In the rst case, the onset of vomiting led to inadequate replenishment of excreted water and the patient presented with hypernatraemia and severe dehydration Subsequently, although volume-depleted, she never had a tendency to conserve body water The acute illness
unmasked lithium-induced nephrogenic diabetes insipidus That lithium might be contributory to her biochemical derangement was considered only at outpatient follow-up During her hospital stay, polyuric data were overlooked because of a normal serum lithium level on presentation In the second case, the patient was care-dependent and a recent chest infection led to restriction of oral uid intake Perhaps the carers were not aware of her need for increased hydration It is likely that in both cases, urinary concentrating ability was progressively impaired as a consequence of long-term maintenance
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Lithium-induced diabetes insipidus in older people
Table 2 Studies of the water-deprivation test in healthy older people
Study population Mean age years
Results after test Test duration h Osmolality Plasma
Authors
Li et al, 1984 [18] Faull et al, 1993 [19] Jian et al, 1995 [20] Men Women
n
Urine
Serum AVP level
765 68
30 21
14 9
30723 mosmol/l 29305 mosmol/kg
441160 mosmol/l 50847 mosmol/kg
3114 mU/ml 0501 pmol/l
652 658
26 18
25 25
NA NA
88791 mmol/l 888127 mmol/l
Not done Not done
AVP, arginine vasopressin; NA, not available
therapy with lithium 8 years and 10
years respectively and was at a critical level before the onset of an acute illness It is possible that an acute illness alone may produce similar hypernatraemia in older people [15, 16] but urine output will always be low in that situation Nephrogenic diabetes insipidus in adults is usually partial with mild symptoms [17] Usually the serum sodium is normal or mildly elevated, the plasma osmolality is within normal range, the urine osmolality is low -300 mosmol/kg and the urine volume is between 25 and 60 l/day [8, 17] However, when patients are uid-depleted, there is a marked rise in serum sodium, a rise in plasma osmolality and a urine osmolality that may exceed that of plasma [8] The water-deprivation test is useful in diagnosis: the urine osmolality is usually -300 mosmol/kg after dehydration with no further or a minimal -9 rise after desmopressin In partial nephrogenic diabetes insipidus, the urine osmolality is between 300 and 750 mosmol/kg after dehydration and is -750 mosmol/kg after desmopressin [8, 17] To nd out the result of water-deprivation tests in healthy older people, we conducted a Medline search between the years 1984 and 2000 keyword: water deprivation test The
results are shown in Table 2 [1820] The ndings of the three studies varied, possibly because of the different mean age of the study populations and the duration of water deprivation It seems that with increasing age there is a reduction in the maximal urinary concentrating ability during water deprivation In view of the nding of a lower concentration of arginine vasopressin after water deprivation as compared with healthy young adults, studies have suggested that the older people might be in a state similar to partial cranial diabetes insipidus [18, 19] However, in neither of our cases did the urine osmolality rise further after desmopressin administration, suggesting unresponsiveness of the distal nephron rather than a central cause Symptomatic stable patients with lithium-induced nephrogenic diabetes insipidus may respond to a reduction in lithium dosage or discontinuation of lithium [6, 21] If the urine volume exceeds 4 l/day, treatment with thiazides and amiloride has been advocated [1, 22]
Nonsteroidal anti-inammatory drugs such as indomethacin [23, 24] and intravenous ketorolac [25] may be used in severe refractory cases Preventive measures include education of patients and
their carers about maintaining adequate hydration The serum lithium level should be kept between 05 and 08 mmol/l Annual measurement of the 24-h urine volume is a simple and effective screening test [1] Physicians caring for older people should be aware of the development of lithium-induced nephrogenic diabetes insipidus and should consider it in the differential diagnosis of patients with unexplained hypernatraemia
Key points
Lithium is the commonest drug causing nephrogenic The prevalence of lithium therapy is higher in those Those taking lithium may develop severe hyper-
diabetes insipidus
over 65 years than in the general population
natraemia during acute illness or after uid deprivation Institutionalized dependent people are at increased risk if carers are not educated about the need to maintain adequate hydration Lithium must be considered in the differential diagnosis of patients with unexplained hypernatraemia
References
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patients receiving lithium treatment who require major surgery [letter] Br J Anaesth 1987; 59: 80910 4 Jefferson JW Lithium and affective disorder in the elderly Compr Psychiatry 1983; 24: 16678
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5 Head L, Dening T Lithium in the over-65s: who is taking it and who is monitoring it? A survey of older adults on lithium in the Cambridge Mental Health Services catchment area Int J Geriatr Psychiatry 1998; 13: 16471 6 Walker RG Lithium nephrotoxicity Kidney International 1993, 44 suppl 42: S938 7 Boton R, Gaviria M, Battle D Prevalence, pathogenesis and treatment of renal dysfunction associated with chronic lithium therapy Am J Kidney Dis 1987; 10:32945 8 Moses AM, Streeten DHP Disorders of the neurohypophysis In Fauci AS, Braunwald E, Isselbacher KJ et al eds Harrisons Principles of Internal Medicine, 14th ed New York: McGraw-Hill, 1998; 200312 9 Marples D, Christensen S, Christensen EI et al Lithiuminduced down-regulation of aquaporin-2 water channel expression in rat kidney medulla J Clin Invest 1995; 95: 183845 10 Hansen HE, Mogensen CE, Sorensen JL et al Chronic interstitial nephropathy in patients on long-term lithium treatment Queensland J Med 1979; 48:
57791 11 Hyperosmolar coma due to lithium-induced diabetes insipidus clinical conference Lancet 1995; 346: 41317 12 Bucht G, Wahlin A Renal concentrating capacity in longterm lithium treatment and after withdrawal of lithium Acta Medica Scandinavica 1980; 207: 30914 13 Stone KA Lithium-induced nephrogenic insipidus J Am Board Fam Pract 1999; 12:437 diabetes 16 Weinberg AD, Pals JK, Levesque PG et al Dehydration and death during febrile episodes in the nursing home J Am Geriatr Soc 1994; 42: 96871 17 Baylis PH Water and sodium homeostasis and their disorders In Weatherall DJ, Ledingham JGG, Warrell DA eds Oxford Textbook of Medicine, 3rd ed Oxford: Oxford University Press, 1996; 311626 18 Li CH, Hsieh SM, Nagai I The response of plasma arginine vasopressin to 14 h water deprivation in the elderly Acta Endocrinol 1984; 105: 3147 19 Faull CM, Holmes C, Baylis PH Water balance in elderly people: is there a deciency of vasopressin? Age Ageing 1993; 22: 11420 20 Jian Z, Han Z, Wu H et al A study on oliguric standard in the elderly Chin Med J 1995; 108: 8258 21 Martin A Clinical management of lithium-induced polyuria Hosp Comm Psychiatry 1993; 44: 4278 22 Kosten TR, Forrest JN Treatment
of severe lithium induced polyuria with amiloride Am J Psychiatry 1986; 143: 15638 23 Allen HM, Jackson RL, Winchester MD et al Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus Arch Int Med 1989; 149: 11236 24 Lam SS, Kjellstrand C Emergency treatment of lithiuminduced diabetes insipidus with nonsteroidal anti-inammatory drugs Ren Fail 1997; 19: 1838 25 Burke C, Fulda GJ, Castellano J Lithium-induced nephrogenic diabetes insipidus treated with intravenous ketorolac Crit Care Med 1995; 23: 19247
14 Johnson MA, Ogorman J, Golembiewski GH, Paluzzi MW Nephrogenic diabetes insipidus secondary to lithium therapy in the postoperative patient: a case report Am Surg 1994; 60: 8369 15 Mahowald JM, Himmelstein DU Hypernatraemia in the elderly: relation to infection and mortality J Am Geriatr Soc 1981; 29: 17780
Received 18 July 2000; accepted in revised form 15 January 2001
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