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Nephrogenic diabetes insipidus in a lethargic lithium-treated patient
Netherlands Journal of Medicine 50 Ž1997. 105–109
Brief report
Nephrogenic diabetes insipidus in a lethargic lithium-treated patient J.R. Meinardi ) , S.H.J. Donders Department of Internal Medicine, Martini Ziekenhuis (Locatie Õan Swieten), Van Swietenlaan 4, 9700 RM Groningen, Netherlands Received 13 May 1996; revised 29 September 1996; accepted 15 October 1996
Abstract We report on a patient who developed severe lithium-induced nephrogenic diabetes insipidus ŽNDI. and neurotoxicity, despite recommended serum lithium levels. Hydrochlorothiazide and indomethacin appeared effective antipolyuric drugs, which led to a normalization of serum osmolality. After re-initiating lithium therapy, with lithium levels around 0.3 mmolrl, recurrence of NDI or neurotoxicity was not observed, despite discontinuation of indomethacin and hydrochlorothiazide. Together with hypothyroidism, NDI and neurotoxicity must be considered in lethargic lithium-treated patients. Keywords: Lithium; Nephrogenic diabetes insipidus; Neurotoxicity
1. Introduction Lithium treatment is widely used in patients with bipolar affective disorders. In 1979 it was estimated that 0.1% of the United States population was taking lithium w1x. Of patients receiving long-term lithium therapy, 30–90% develop a urinary concentrating defect, 2–35% polyuria Ž) 3 lr24 h. and 4.5–20% nephrogenic diabetes insipidus ŽNDI. w2–4x. The latter might be present despite therapeutic serum lithium concentrations w4x. Predominantly due to the widespread use of lithium carbonate, lithium has become the most common cause of diabetes insipidus. We describe a patient who developed a severe )
Corresponding author: Interne Kliniek, Afdeling Haemostase Thrombose en Rheologie, Academisch Ziekenhuis Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands. Fax q31 50 3611790.
diabetes insipidus and the clinical picture of neurotoxicity, despite recommended serum lithium levels. He had been taking lithium carbonate for 31 years, without a history of lithium toxicity.
2. Case report A 82-year-old man was admitted to our hospital because of a 1-week history of apathy, drowsiness and incontinence of urine. Two days before admission he was unable to drink or eat, due to his lethargy. Polydipsia was present for many years, but no polyuria. He had a long history of a rapid cycling bipolar affective disorder, treated with lithium carbonate for 31 years. The current dosage was 600 mg daily. In the previous 4 years, psychiatric treatment also included carbamazepine 300 t.i.d, haloperidol 50 mg given every 2 weeks i.m. and fluvoxamine 50 mg b.d. Lithium levels had never exceeded therapeu-
0300-2977r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. PII S 0 3 0 0 - 2 9 7 7 Ž 9 6 . 0 0 0 8 2 - 4
106
J.R. Meinardi, S.H.J. Dondersr Netherlands Journal of Medicine 50 (1997) 105–109
tically accepted values. His medical history was unremarkable. We saw an unresponsive, drowsy, dehydrated man with a Glasgow Coma Scale of 8, blood pressure 170r105, pulse rate 78rmin Žregular, equal., axillary temperature 37.88C. No other striking findings were present. Neurological examination revealed small pupils, increased muscle tone in neck, upper and lower extremities, with hyperreflexia. Cogwheeling was present in the upper extremities. Sensory deficits were not found. Initial laboratory studies showed a Hb of 10.4 mmolrl, Hct 0.51 lrl, WBC 21.3 = 10 9 with predominantly neutrophilia, serum sodium 172 mmolrl, potassium 4.0 mmolrl, chloride 127 mmolrl, calcium 2.17 mmolrl, blood urea nitrogen 16.3 mmolrl, creatinine 197 mmolrl. Serum osmolality revealed 362 mosmrkg. Lithium and carbamazepine levels were within normal range Ž0.7 mmolrl and 2.8 mgrl, respectively.. Repeated measurements of urine osmolality were 480 and 248 mosmrkg, respectively. Urine sodium was 35 mmolrl. Urine sediment showed protein, leucocytes, and erythrocytes. Urine culture revealed an enterococcus species and a coagulase-negative staphylococcus. The proteinuria was 1.19r24 h, the creatine clearance 34 mlrmin. Two blood cultures were negative. Thyroid function test results and serum cortisol levels were normal. After 3 weeks admission the results of the initial serum ADH showed an elevated value of 12 pmolrl. Because of the presence of hypernatraemia, hypotonic polyuria despite elevated plasma osmolality and a long-term history of lithium use, a diagnosis of lithium-induced NDI was considered. Hence, lithium carbonate and haloperidol were lowered and stopped. Since the dehydration and severe hypernatraemia, dextrose 5% solution with potassium chloride was administered i.v., at an infusion rate up to 4 lrh, whereas urine output reached 5 lr24 h. Nutrition was given by nasoenteric tube Ž1.5 lr24 h in total.. For treatment of the urinary tract infection, cefuroxime i.v. was administered, which after 4 days was changed to amoxicillinrclavulan acid i.v., based on urine culture results. As expected, vasopressin 10 mg daily, given nasally, did not induce any antipolyuric effect nor did doubling of the dosage. Indomethacin 25 mg t.i.d. was given, which led to an initial decrease in
urine output to 2 lr24 h. Serum sodium levels remained slightly elevated. Hydrochlorothiazide 25 mg daily was added to the therapy, leading to normalization of serum sodium levels and serum osmolality. Fig. 1 shows the course of urine output and serum sodium level during this antipolyuric treatment. The laboratory values are outlined in Table 1. Despite the slow and gradual correction of the dehydration and hypernatraemia, the patient remained lethargic. To rule out neurological disorders, cranial computed tomography was performed, which showed no abnormalities. Neurotoxicity due to the psychiatric drugs was suspected because of the concomitant presence of lethargy, pronounced extrapyramidal symptoms, weakness, and fine intention tremor. After discontinuation of lithium therapy, the patient’s mental state improved, as did the extrapyramidal symptoms. However, he developed maniac behaviour, so that it was decided to reintroduce lithium carbonate in a lowered dosage of 400 mg daily, despite the presence of NDI. During lithium therapy and continuation of hydrochlorothiazide and indomethacin, urine output did not to exceed 2700 mlr24 h. Serum sodium and osmalality values remained within normal range, whereas the creatinine clearance increased to 43 mlrmin and the proteinuria was
Fig. 1. Course of serum sodium concentrations and urine volume during antipolyuric therapy.
J.R. Meinardi, S.H.J. Dondersr Netherlands Journal of Medicine 50 (1997) 105–109
107
Table 1 Laboratory values
Sodium Žmmolrl. K Žmmolrl. BUN Žmmolrl. Creatinine Žmmolrl. Hb Žmmolrl. P osmolal Žmmolrl. U osmolal Žmosmrkg. Lithium Žmmolrl.
Admission
Day 4
Day 26
Day 40
Day 71
172 4.0 16.3 197 10.4 362 480 0.7
156 4.4 11.7 132 8.5 322 248
148 4.0 9.1 110 7.3 301 216 0.0
145 4.2 6.7 106 6.2 284 222 0.6
147 3.4 4.5 96 6.6 295 263 0.3
reduced to a trace. Urine osmalality values remained subnormal. On the day of discharge, the patient was sitting in a wheelchair. Due to weakness of the lower extremities he was unable to walk without help. He could eat and drink by himself and communicated in a meaningful fashion. Four weeks after discharge, he again became lethargic and unresponsive, so that he was readmitted. On initial examination, striking neurological symptoms included small pupils, pronounced rigidity of head and extremities, unresponsiveness, and cogwheeling. No signs of dehydration were present and serum sodium was 147 mmolrl. Serum lithium level, however, was increased to 1.3 mmolrl. Thyroid function tests were normal. All medication was stopped on the day of admission. Because of psychotic symptoms, lithium was resumed after 5 days, but in a lowered dosage of 300 mg daily. Within 10 days, our patient showed a marked clinical improvement. Considering this, together with the proven lithium intoxication, extensive neurological investigations were not repeated. At the time of discharge his clinical state was comparable with that on the previous discharge. Remarkably, no polyuria was observed during this second admission, despite discontinuation of indomethacin and hydrochlorothiazide. Furthermore, the serum and urine osmolality returned to normal values Žsee Table 1., so that even the urinary concentrating defect seemed to be restored. Lithium level, twice measured during this period, was 0.3 mmolrl. 3. Discussion The way in which lithium exerts polyuria has been extensively investigated, in both animal and
human studies. Impaired urinary concentrating ability, which is resistant to vasopressin administration, has been shown to be the underlying cause of the lithium-induced polyuria w4,5x. Lithium causes an urinary concentrating defect, by interfering with the ADH-mediated production of cAMP in the epithelium of the medullary and papillary collecting duct w6x. This results in a rise of serum ADH level, as found in our patient. Lithium exerts its inhibitory effect on cAMP production, partially by elevating prostaglandin levels, predominantly of PGE 2 . In animal studies, administration of lithium induced an inclined urinary excretion of PGE 2 w7x. A recently published animal study reported a downregulating aquaporin-2 ŽAQ-P2. channel expression in collecting duct cells by lithium salts w8x. AQ-P2 channels belong to a large family of homologous membrane proteins that function as highly selective water channels w9x. Hence, by downregulating the AQ-P2 channels, water absorption at the level of the collecting ducts will be impaired. The lithium-induced decrease of AQ-P2 channels appears to be only partially reversible by water deprivation, vasopressin administration or discontinuation of lithium administration w8x. This indicates an irreversible defect of the urinary-concentrating ability, which might be due to underlying kidney disease w10,11x. Indeed, focal interstitial nephropathy, characterized by interstitial fibrosis, tubular atrophy and glomerulosclerosis, has been reported to occur frequently in patients receiving long-term lithium therapy w2,10x. Interestingly, patients with a bipolar affective disorder not treated with lithium salts showed comparable tubulo-interstitial changes on renal biopsy, as found in their lithium-treated counterparts w12,13x. This could indicate a predisposition of pa-
108
J.R. Meinardi, S.H.J. Dondersr Netherlands Journal of Medicine 50 (1997) 105–109
tients with affective disorders to the development of interstitial nephropathy. A characteristic lithium-induced renal lesion, however, has been found, including distal tubular dilatation with formation of microcysts w11,13,14x. The slight proteinuria found in our patient was probably caused by interstitial tubulopathy. A renal biopsy was not performed because of its minor therapeutic effects. Several reports have mentioned a favorable response of lithium-induced diabetes insipidus to indomethacin therapy w15,16x. Inhibition of prostaglandin synthesis seems to be an important factor in reduction of urine output w6x. The urinary excretion of PgE 2 declines after administration of indomethacin in rats with lithium-induced polyuria w7x. Decrease of tubular prostaglandin levels would enhance ADH-induced cAMP generation and hence fluid reabsorption. Indomethacin, however, might decrease lithium excretion and can provoke lithium toxicity w16x. In our patient renal function remained stable during indomethacin therapy and even showed a slight improvement. Another possibility for antipolyuric therapy is hydrochlorothiazide. Thiazide diuretics decrease extracellular fluid volume, stimulate fluid Žand lithium. reabsorption in the proximal tubule, and thus decrease fluid delivery to the distal nephron w3x. However, lithium toxicity is of special concern in thiazide diuretic therapy since depletion of extracellular fluid and serum sodium will enhance the renal retention of lithium w3,17,18x. In our patient, addition of hydrochlorothiazide led to normalization of serum sodium and a further decline of urine output. Possibly, hydrochlorothiazide may have contributed to the increased lithium level seen at the second admission. Since our patient remained lethargic in the initial 10-day period, despite correcting the hypernatraemia and dehydration, lithium-induced neurotoxicity was considered. The striking neurological findings of tardive dyskinesia, muscle weakness and fine intention tremor supported this diagnosis w19x. Lithium may cause severe neurotoxicity, despite normal serum lithium levels w2,19,20x. He was prone to develop neurotoxicity because of the concomitant use of lithium, haloperidol and carbamazepine w20,21x. The neurological symptoms responded well after lowering lithium dosage and stopping haloperidol and carbamazepine.
In conclusion, we describe a patient who developed severe lithium-induced NDI and symptoms of neurotoxicity, despite serum lithium levels within the therapeutic range. Indomethacin and hydrochlorothiazide proved to be effective antipolyuric drugs and restored serum osmolality to normal values. After reinitiating lithium therapy, with lithium levels around 0.3 mmolrl, recurrence of NDI or neurotoxicity was not seen, despite discontinuation of indomethacin and hydrochlorothiazide therapy. We therefore recommend lower lithium levels in the elderly, since they are at risk for development of lithium intoxication. Together with hypothyroidism, NDI and neurotoxicity must be considered in lethargic lithium-treated patients.
References w1 x Walker RG. Lithium nephrotoxicity. Kidney Int 1993;44;S42:S93–S98. w2x Simard M, Gumbiner B, Lee A, Lewis H, Norman D. Lithium carbonate intoxication. Arch Intern Med 1989;149:36–46. w3x Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 1987;10:329–345. w4x Baylis PH, Heath DA. Water disturbances in patients treated with oral lithium carbonate. Ann Intern Med 1978;88:607– 609. w5x Martinez-Maldonado M, Opava-Stitzer S. Distal nephron function of the rat during lithium chloride infusion. Kidney Int 1977;12:17–22. w6x Christensen S, Kusano E, Yusufi ANK, Murayama N, Dousa TP. Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats. J Clin Invest 1985;75:1869–1879. w7x Sugawara M, Hashimoto K, Ota Z. Involvement of prostaglandin E 2 , cAMP and vasopressin in lithium-induced polyuria. Am J Physiol 1988;254:R863–R869. w8x Marples D, Christensen S, Christensen EI, Ottosen PD, Nielsen S. Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla. J Clin Invest 1995;95:1838–1845. w9x Connolly DL, Shanahan CM, Weissberg PL. Water channels in health and disease. Lancet 1996;347:210–212. w10x Hestbech J, Hansen HE, Amdisen A, Olsen S. Chronic renal lesions following long-term treatment with lithium. Kidney Int 1977;12:205–213. w11x Kling MA, Fox JG, Johnston SM, Tolkoff-Rubin NE, Rubin RH, Colvin RB. Effects of long term lithium administration
J.R. Meinardi, S.H.J. Dondersr Netherlands Journal of Medicine 50 (1997) 105–109
w12x
w13x
w14x
w15x
on renal structure and functions in rats. A distinctive tubular lesion. Lab Invest 1984;50:526–535. Kincaid-Smith P, Burrows GD, Davies BM, Holwill B, Walter M, Walker RG. Renal biopsy findings in lithium and prelithium patients. Lancet 1979;2:700–701. Walker RG, Bennett WM, Davies BM, Kincaid-Smith P. Structural and functional effects of long-term lithium therapy. Kidney Int 1982;21;S11;S13–S19. Walker RG, Dowling JP, Alcorn D, Ryan GB, Kincaid-Smith P. Renal pathology associated with lithium therapy. Pathology 1983;15:403–411. Allen HM, Jackson RL, Winchester MD, Deck LV, Allon M. Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus. Arch Intern Med 1989;149:123– 1126.
109
w16x Grindlinger GA, Boylan MJ. Amelioration by indomethacin of lithium-induced polyuria. Crit Care Med 1987;15:538–539. w17x Himmelhoch JM, Forrest J, Neil JF, Detre TP. Thiazide– lithium synergy in refractory mood swings. Am J Psychiatry 1977;134:149–152. w18x Hurtig HI, Dyson WL. Lithium toxicity enhanced by diuresis. N Engl J Med 1974;290:748–749. w19x Newman PK, Saunders M. Lithium neurotoxicity. Postgrad Med J 1979;55:701–703. w20x Spring G, Frankel M. New data on lithium and haloperidol incompatibility. Am J Psychiatry 1981;138:818–821. w21x Shukla S, Godwin CD, Long LEB, Miller MG. Lithium– carbamazepine neurotoxicity and risk factors. Am J Psychiatry 1984;141:1604–1606.
Brief report
Nephrogenic diabetes insipidus in a lethargic lithium-treated patient J.R. Meinardi ) , S.H.J. Donders Department of Internal Medicine, Martini Ziekenhuis (Locatie Õan Swieten), Van Swietenlaan 4, 9700 RM Groningen, Netherlands Received 13 May 1996; revised 29 September 1996; accepted 15 October 1996
Abstract We report on a patient who developed severe lithium-induced nephrogenic diabetes insipidus ŽNDI. and neurotoxicity, despite recommended serum lithium levels. Hydrochlorothiazide and indomethacin appeared effective antipolyuric drugs, which led to a normalization of serum osmolality. After re-initiating lithium therapy, with lithium levels around 0.3 mmolrl, recurrence of NDI or neurotoxicity was not observed, despite discontinuation of indomethacin and hydrochlorothiazide. Together with hypothyroidism, NDI and neurotoxicity must be considered in lethargic lithium-treated patients. Keywords: Lithium; Nephrogenic diabetes insipidus; Neurotoxicity
1. Introduction Lithium treatment is widely used in patients with bipolar affective disorders. In 1979 it was estimated that 0.1% of the United States population was taking lithium w1x. Of patients receiving long-term lithium therapy, 30–90% develop a urinary concentrating defect, 2–35% polyuria Ž) 3 lr24 h. and 4.5–20% nephrogenic diabetes insipidus ŽNDI. w2–4x. The latter might be present despite therapeutic serum lithium concentrations w4x. Predominantly due to the widespread use of lithium carbonate, lithium has become the most common cause of diabetes insipidus. We describe a patient who developed a severe )
Corresponding author: Interne Kliniek, Afdeling Haemostase Thrombose en Rheologie, Academisch Ziekenhuis Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands. Fax q31 50 3611790.
diabetes insipidus and the clinical picture of neurotoxicity, despite recommended serum lithium levels. He had been taking lithium carbonate for 31 years, without a history of lithium toxicity.
2. Case report A 82-year-old man was admitted to our hospital because of a 1-week history of apathy, drowsiness and incontinence of urine. Two days before admission he was unable to drink or eat, due to his lethargy. Polydipsia was present for many years, but no polyuria. He had a long history of a rapid cycling bipolar affective disorder, treated with lithium carbonate for 31 years. The current dosage was 600 mg daily. In the previous 4 years, psychiatric treatment also included carbamazepine 300 t.i.d, haloperidol 50 mg given every 2 weeks i.m. and fluvoxamine 50 mg b.d. Lithium levels had never exceeded therapeu-
0300-2977r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. PII S 0 3 0 0 - 2 9 7 7 Ž 9 6 . 0 0 0 8 2 - 4
106
J.R. Meinardi, S.H.J. Dondersr Netherlands Journal of Medicine 50 (1997) 105–109
tically accepted values. His medical history was unremarkable. We saw an unresponsive, drowsy, dehydrated man with a Glasgow Coma Scale of 8, blood pressure 170r105, pulse rate 78rmin Žregular, equal., axillary temperature 37.88C. No other striking findings were present. Neurological examination revealed small pupils, increased muscle tone in neck, upper and lower extremities, with hyperreflexia. Cogwheeling was present in the upper extremities. Sensory deficits were not found. Initial laboratory studies showed a Hb of 10.4 mmolrl, Hct 0.51 lrl, WBC 21.3 = 10 9 with predominantly neutrophilia, serum sodium 172 mmolrl, potassium 4.0 mmolrl, chloride 127 mmolrl, calcium 2.17 mmolrl, blood urea nitrogen 16.3 mmolrl, creatinine 197 mmolrl. Serum osmolality revealed 362 mosmrkg. Lithium and carbamazepine levels were within normal range Ž0.7 mmolrl and 2.8 mgrl, respectively.. Repeated measurements of urine osmolality were 480 and 248 mosmrkg, respectively. Urine sodium was 35 mmolrl. Urine sediment showed protein, leucocytes, and erythrocytes. Urine culture revealed an enterococcus species and a coagulase-negative staphylococcus. The proteinuria was 1.19r24 h, the creatine clearance 34 mlrmin. Two blood cultures were negative. Thyroid function test results and serum cortisol levels were normal. After 3 weeks admission the results of the initial serum ADH showed an elevated value of 12 pmolrl. Because of the presence of hypernatraemia, hypotonic polyuria despite elevated plasma osmolality and a long-term history of lithium use, a diagnosis of lithium-induced NDI was considered. Hence, lithium carbonate and haloperidol were lowered and stopped. Since the dehydration and severe hypernatraemia, dextrose 5% solution with potassium chloride was administered i.v., at an infusion rate up to 4 lrh, whereas urine output reached 5 lr24 h. Nutrition was given by nasoenteric tube Ž1.5 lr24 h in total.. For treatment of the urinary tract infection, cefuroxime i.v. was administered, which after 4 days was changed to amoxicillinrclavulan acid i.v., based on urine culture results. As expected, vasopressin 10 mg daily, given nasally, did not induce any antipolyuric effect nor did doubling of the dosage. Indomethacin 25 mg t.i.d. was given, which led to an initial decrease in
urine output to 2 lr24 h. Serum sodium levels remained slightly elevated. Hydrochlorothiazide 25 mg daily was added to the therapy, leading to normalization of serum sodium levels and serum osmolality. Fig. 1 shows the course of urine output and serum sodium level during this antipolyuric treatment. The laboratory values are outlined in Table 1. Despite the slow and gradual correction of the dehydration and hypernatraemia, the patient remained lethargic. To rule out neurological disorders, cranial computed tomography was performed, which showed no abnormalities. Neurotoxicity due to the psychiatric drugs was suspected because of the concomitant presence of lethargy, pronounced extrapyramidal symptoms, weakness, and fine intention tremor. After discontinuation of lithium therapy, the patient’s mental state improved, as did the extrapyramidal symptoms. However, he developed maniac behaviour, so that it was decided to reintroduce lithium carbonate in a lowered dosage of 400 mg daily, despite the presence of NDI. During lithium therapy and continuation of hydrochlorothiazide and indomethacin, urine output did not to exceed 2700 mlr24 h. Serum sodium and osmalality values remained within normal range, whereas the creatinine clearance increased to 43 mlrmin and the proteinuria was
Fig. 1. Course of serum sodium concentrations and urine volume during antipolyuric therapy.
J.R. Meinardi, S.H.J. Dondersr Netherlands Journal of Medicine 50 (1997) 105–109
107
Table 1 Laboratory values
Sodium Žmmolrl. K Žmmolrl. BUN Žmmolrl. Creatinine Žmmolrl. Hb Žmmolrl. P osmolal Žmmolrl. U osmolal Žmosmrkg. Lithium Žmmolrl.
Admission
Day 4
Day 26
Day 40
Day 71
172 4.0 16.3 197 10.4 362 480 0.7
156 4.4 11.7 132 8.5 322 248
148 4.0 9.1 110 7.3 301 216 0.0
145 4.2 6.7 106 6.2 284 222 0.6
147 3.4 4.5 96 6.6 295 263 0.3
reduced to a trace. Urine osmalality values remained subnormal. On the day of discharge, the patient was sitting in a wheelchair. Due to weakness of the lower extremities he was unable to walk without help. He could eat and drink by himself and communicated in a meaningful fashion. Four weeks after discharge, he again became lethargic and unresponsive, so that he was readmitted. On initial examination, striking neurological symptoms included small pupils, pronounced rigidity of head and extremities, unresponsiveness, and cogwheeling. No signs of dehydration were present and serum sodium was 147 mmolrl. Serum lithium level, however, was increased to 1.3 mmolrl. Thyroid function tests were normal. All medication was stopped on the day of admission. Because of psychotic symptoms, lithium was resumed after 5 days, but in a lowered dosage of 300 mg daily. Within 10 days, our patient showed a marked clinical improvement. Considering this, together with the proven lithium intoxication, extensive neurological investigations were not repeated. At the time of discharge his clinical state was comparable with that on the previous discharge. Remarkably, no polyuria was observed during this second admission, despite discontinuation of indomethacin and hydrochlorothiazide. Furthermore, the serum and urine osmolality returned to normal values Žsee Table 1., so that even the urinary concentrating defect seemed to be restored. Lithium level, twice measured during this period, was 0.3 mmolrl. 3. Discussion The way in which lithium exerts polyuria has been extensively investigated, in both animal and
human studies. Impaired urinary concentrating ability, which is resistant to vasopressin administration, has been shown to be the underlying cause of the lithium-induced polyuria w4,5x. Lithium causes an urinary concentrating defect, by interfering with the ADH-mediated production of cAMP in the epithelium of the medullary and papillary collecting duct w6x. This results in a rise of serum ADH level, as found in our patient. Lithium exerts its inhibitory effect on cAMP production, partially by elevating prostaglandin levels, predominantly of PGE 2 . In animal studies, administration of lithium induced an inclined urinary excretion of PGE 2 w7x. A recently published animal study reported a downregulating aquaporin-2 ŽAQ-P2. channel expression in collecting duct cells by lithium salts w8x. AQ-P2 channels belong to a large family of homologous membrane proteins that function as highly selective water channels w9x. Hence, by downregulating the AQ-P2 channels, water absorption at the level of the collecting ducts will be impaired. The lithium-induced decrease of AQ-P2 channels appears to be only partially reversible by water deprivation, vasopressin administration or discontinuation of lithium administration w8x. This indicates an irreversible defect of the urinary-concentrating ability, which might be due to underlying kidney disease w10,11x. Indeed, focal interstitial nephropathy, characterized by interstitial fibrosis, tubular atrophy and glomerulosclerosis, has been reported to occur frequently in patients receiving long-term lithium therapy w2,10x. Interestingly, patients with a bipolar affective disorder not treated with lithium salts showed comparable tubulo-interstitial changes on renal biopsy, as found in their lithium-treated counterparts w12,13x. This could indicate a predisposition of pa-
108
J.R. Meinardi, S.H.J. Dondersr Netherlands Journal of Medicine 50 (1997) 105–109
tients with affective disorders to the development of interstitial nephropathy. A characteristic lithium-induced renal lesion, however, has been found, including distal tubular dilatation with formation of microcysts w11,13,14x. The slight proteinuria found in our patient was probably caused by interstitial tubulopathy. A renal biopsy was not performed because of its minor therapeutic effects. Several reports have mentioned a favorable response of lithium-induced diabetes insipidus to indomethacin therapy w15,16x. Inhibition of prostaglandin synthesis seems to be an important factor in reduction of urine output w6x. The urinary excretion of PgE 2 declines after administration of indomethacin in rats with lithium-induced polyuria w7x. Decrease of tubular prostaglandin levels would enhance ADH-induced cAMP generation and hence fluid reabsorption. Indomethacin, however, might decrease lithium excretion and can provoke lithium toxicity w16x. In our patient renal function remained stable during indomethacin therapy and even showed a slight improvement. Another possibility for antipolyuric therapy is hydrochlorothiazide. Thiazide diuretics decrease extracellular fluid volume, stimulate fluid Žand lithium. reabsorption in the proximal tubule, and thus decrease fluid delivery to the distal nephron w3x. However, lithium toxicity is of special concern in thiazide diuretic therapy since depletion of extracellular fluid and serum sodium will enhance the renal retention of lithium w3,17,18x. In our patient, addition of hydrochlorothiazide led to normalization of serum sodium and a further decline of urine output. Possibly, hydrochlorothiazide may have contributed to the increased lithium level seen at the second admission. Since our patient remained lethargic in the initial 10-day period, despite correcting the hypernatraemia and dehydration, lithium-induced neurotoxicity was considered. The striking neurological findings of tardive dyskinesia, muscle weakness and fine intention tremor supported this diagnosis w19x. Lithium may cause severe neurotoxicity, despite normal serum lithium levels w2,19,20x. He was prone to develop neurotoxicity because of the concomitant use of lithium, haloperidol and carbamazepine w20,21x. The neurological symptoms responded well after lowering lithium dosage and stopping haloperidol and carbamazepine.
In conclusion, we describe a patient who developed severe lithium-induced NDI and symptoms of neurotoxicity, despite serum lithium levels within the therapeutic range. Indomethacin and hydrochlorothiazide proved to be effective antipolyuric drugs and restored serum osmolality to normal values. After reinitiating lithium therapy, with lithium levels around 0.3 mmolrl, recurrence of NDI or neurotoxicity was not seen, despite discontinuation of indomethacin and hydrochlorothiazide therapy. We therefore recommend lower lithium levels in the elderly, since they are at risk for development of lithium intoxication. Together with hypothyroidism, NDI and neurotoxicity must be considered in lethargic lithium-treated patients.
References w1 x Walker RG. Lithium nephrotoxicity. Kidney Int 1993;44;S42:S93–S98. w2x Simard M, Gumbiner B, Lee A, Lewis H, Norman D. Lithium carbonate intoxication. Arch Intern Med 1989;149:36–46. w3x Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 1987;10:329–345. w4x Baylis PH, Heath DA. Water disturbances in patients treated with oral lithium carbonate. Ann Intern Med 1978;88:607– 609. w5x Martinez-Maldonado M, Opava-Stitzer S. Distal nephron function of the rat during lithium chloride infusion. Kidney Int 1977;12:17–22. w6x Christensen S, Kusano E, Yusufi ANK, Murayama N, Dousa TP. Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats. J Clin Invest 1985;75:1869–1879. w7x Sugawara M, Hashimoto K, Ota Z. Involvement of prostaglandin E 2 , cAMP and vasopressin in lithium-induced polyuria. Am J Physiol 1988;254:R863–R869. w8x Marples D, Christensen S, Christensen EI, Ottosen PD, Nielsen S. Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla. J Clin Invest 1995;95:1838–1845. w9x Connolly DL, Shanahan CM, Weissberg PL. Water channels in health and disease. Lancet 1996;347:210–212. w10x Hestbech J, Hansen HE, Amdisen A, Olsen S. Chronic renal lesions following long-term treatment with lithium. Kidney Int 1977;12:205–213. w11x Kling MA, Fox JG, Johnston SM, Tolkoff-Rubin NE, Rubin RH, Colvin RB. Effects of long term lithium administration
J.R. Meinardi, S.H.J. Dondersr Netherlands Journal of Medicine 50 (1997) 105–109
w12x
w13x
w14x
w15x
on renal structure and functions in rats. A distinctive tubular lesion. Lab Invest 1984;50:526–535. Kincaid-Smith P, Burrows GD, Davies BM, Holwill B, Walter M, Walker RG. Renal biopsy findings in lithium and prelithium patients. Lancet 1979;2:700–701. Walker RG, Bennett WM, Davies BM, Kincaid-Smith P. Structural and functional effects of long-term lithium therapy. Kidney Int 1982;21;S11;S13–S19. Walker RG, Dowling JP, Alcorn D, Ryan GB, Kincaid-Smith P. Renal pathology associated with lithium therapy. Pathology 1983;15:403–411. Allen HM, Jackson RL, Winchester MD, Deck LV, Allon M. Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus. Arch Intern Med 1989;149:123– 1126.
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