Figure 1: Lithium transport in kidney cells. In proximal tubule cells (top panel) and principal cells of the collecting duct (lower panel) lithium may substitute for sodium and be transported via sodium-transporting systems. Lithium is transported into proximal tubule cells and principal cells through NHE and ENaC, respectively. Other pathways for entry of lithium are less likely and may include: the sodium-glucose cotransporter, the sodium-phosphate transporter and the sodium-amino acids cotransporter. These pathways may be particularly active during states of dehydration and volume depletion. Extrusion of lithium to the blood may occur through SSE or Na+/K+-ATPase. Lithium inhibits GSK-3 leading to increased COX-2 expression and PGE2 synthesis. This results in diminished vasopressin activity and decreased AQP2 levels on apical membrane of principal cells, which leads to increased urination. Abbreviations: AQP, aquaporin; COX-2, cyclooxygenase 2; ENaC, epithelial sodium channel; GSK-3, glycogen synthase kinase 3; NHE, sodium-hydrogen exchanger; SSE, sodium-sodium exchanger; PGE2 , Prostaglandin E2 ; SGC, sodium-glucose cotransporter; SPT, sodium-phosphate transporter.
Alla Shnaider1 Abed N Azab2,3*1Nephrology Department, Soroka University Medical Center, Beer-Sheva, Israel
2Department of Nursing, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
3Department of Clinical Biochemistry and Pharmacology–Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
*Corresponding author: Abed N Azab, Department of Nursing, Faculty of Health Sciences, BenGurion University of the Negev, P.O.B 653, Beer-Sheva 84105, Israel, Tel: (972) 8-6479880; Fax: (972) 8-6477683; E-mail: firstname.lastname@example.org
Lithium is a useful treatment for bipolar disorder; it attenuates the recurrence of affective episodes and reduces the risk of suicide among bipolar patients. Nevertheless, lithium has a plethora of side effects some of which are serious and may be irreversible. Among the most troubling side effects of lithium is its nephrotoxicity. Herein we report a case of a bipolar patient who developed signs of lithium-induced nephrotoxicity including overt polyuria after 18 years of lithium treatment. Due to concerns that his renal function will continue to deteriorate, two trials to switch him to other psychotropic drugs were done following which he committed two aggressive suicidal attempts. As a result, a joint decision was reached between the patient, his family, psychiatrist and nephrologist that lithium is a “life-saving” treatment for him and lithium was never stopped again. To date, at 68 years old and after nearly 40 years of lithium treatment the patient is mentally stable and reasonably functional. His kidney function continued to deteriorate slowly through the years and he is now a candidate for hemodialysis. This case report emphasizes the need to balance between concerns regarding the damage to the kidney which is a result of long-term lithium treatment to the significant therapeutic benefit of lithium as a mood stabilizer and anti-suicidal drug.
Bipolar disorder; Creatinine; Lithium; Polyuria; Suicide
Lithium is the gold standard treatment for bipolar disorder [1,2]. It attenuates the recurrence of affective episodes [1,2] and reduces suicidal attempts and suicidal death among bipolar patients [3,4]. However, despite its established therapeutic efficacy, long-term lithium treatment is complicated by two limitations: (i) lithium has a narrow therapeutic index and increased risk of intoxication, and, (ii) lithium has several side effects, some of which are severe and occasionally irreversible [5-7].
Lithium is a simple chemical that does not undergo hepatic metabolism. Nevertheless, addressing its therapeutic and toxicological profiles necessitates acknowledgement of the variability among patients in their response to the drug. The therapeutic response and the toxicological profile of lithium may greatly differ among patients even at similar plasma levels, due to inter-individual variations in sensitivity to the drug and differences in renal excretion [2,5,6,8].Patients can differ in their response to lithium due to different age, gender, ethnic background, comorbidities, interaction with other medications and genetic variations [2,5,6,8]. Plasma levels do not always predict the severity of lithium intoxication despite being a principal factor that guides the clinical assessment of patients. Some patients develop signs of lithium toxicity while having plasma concentrations that are within the recommended therapeutic range . Thus, assessment of a patient’s situation must mainly rely on the clinical presentation and severity of symptoms . Several factors may affect plasma lithium levels and the risk for toxicity. Impaired renal function is one of the major factors that may lead to lithium intoxication due to decreased elimination and accumulation of the drug [10-12]. Many drugs may influence lithium clearance by altering renal blood flow, glomerular filtration rate (GFR) and sodium balance. For example,
Non-steroidal Anti-inflammatory Drugs (NSAIDs) are known to reduce lithium clearance, resulting in elevated plasma concentrations of the drug [10-12]. These drugs inhibit the Enzyme Cyclooxygenase (COX) and thereby diminish prostaglandins (PGs) production. Inhibition of PGs synthesis reduces renal blood flow and GFR, the result of which is enhancement of lithium reabsorption [10-12]. The interaction between lithium and NSAIDs occurs with classical NSAIDs as well as selective COX-2 inhibitors. However, this interaction seems to be less frequent with aspirin than other NSAIDs [11,12]. Angiotensin Converting Enzyme (ACE) inhibitors may increase the risk for toxicity because they reduce glomerular perfusion pressure (due to dilatation of efferent arterioles) and decrease lithium glomerular filtration [10-12]. Furthermore, medical conditions that are associated with volume depletion and diminished renal blood flow such as diarrhea and sepsis may reduce GFR and increase the risk of lithium toxicity.
One of the most worrisome side effects of lithium is impairment of kidney function. Potential deleterious effects of lithium on renal function include a decrease in urinary concentrating capacity and a reduction in glomerular filtration rate, among other complications [5-7,13-20]. The most common renal side effect of lithium is Nephrogenic Diabetes Insipidus (NDI) [5,7]. Important factors that contribute to the development of lithium-induced NDI are: increased blood lithium levels, long duration of treatment and high incidence of lithium intoxication episodes [5- 7,13-20]. Importantly, NDI may appear even after lithium cessation  and withdrawal of lithium does not necessarily reverse the impairment in urinary concentrating ability [7,16,17,22]. This article presents a case of a patient who suffered several episodes of lithium-induced NDI and gradually developed a chronic kidney disease. Thereafter, it discusses the pathophysiological mechanism(s) underlying lithium-induced NDI.
A male patient started to receive lithium at the age of 28 years after being diagnosed as having bipolar disorder. Lithium treatment was continued for nearly 18 years during which plasma lithium concentrations where within the therapeutic range (0.6-1.2 mEq/L) and no documentation of lithium intoxication episodes. At age 46 years the patient was referred to a nephrologist (A.S.) due to complaints on dry mouth, polydipsia, polyuria and deterioration in renal function. His clinical assessment at the nephrology clinic revealed the following findings: blood pressure was normal; plasma creatinine =1.4 mg/dl, urea =34 mg/dl, sodium =139 mEq/L; eGFR =57 ml/min; urine output =8 L/day, without proteinuria, glucosuria, red blood cells or casts; kidney ultrasound was normal. After an initial examination, a water deprivation test was performed revealing the following results: before the test – plasma osmolality =283 mOsm/ kg, urine osmolality =164 mOsm/kg; 6 hours after water deprivation – plasma osmolality =298 mOsm/kg, urine osmolality =165 mOsm/kg; after administration of vasopressin – urine osmolality =174 mOsm/kg. After the test, a diagnosis of lithium-induced NDI was made and lithium was stopped and the patient was switched to other psychotropic drugs (such as valproate, carbamazepine, antipsychotics). The cessation of lithium did not alleviate the symptoms of NDI and after 2 months the patient attempted suicide and was hospitalized for several weeks. During hospitalization lithium was reinstated and the patient became affectively stable (euthymic) and resumed his job. After 5 years (age~51 years), lithium was stopped due to further deterioration in kidney function (plasma creatinine =1.7 mg/dl, eGFR =47 ml/min). The patient was treated with other mood stabilizers for few months after which he committed a suicide attempt once again and was hospitalized. A joint meeting was conducted between the treating psychiatrist, nephrologist, patient and his family – and it was decided to reinstate lithium despite the possibility of further deterioration in NDI and renal function. It was also agreed upon that lithium is a “lifesaving” treatment for the patient and that it will not be stopped again even if it will lead to renal replacement therapy. Today, after nearly 40 years of treatment with lithium (excluding two pauses of few months) and 21 years of a nephrologist follow-up, the patient is mentally stable and reasonably functional. The dose of lithium is adjusted according to its plasma concentration. His renal data is as follows: plasma creatinine =4.1 mg/dl, eGFR =16 ml/min; urine output =6-7 L/day, proteinuria =800 mg/ day; renal ultrasound – echogenic kidney with decreased corticomedullar differentiation and cortical cysts; the patient is on the waiting list for hemodialysis.
The pathophysiological mechanisms underlying lithium-induced NDI are not clearly understood. Understanding the physiological processes involving renal sodium and water homeostasis is a key point. In the kidney, on the apical membrane of proximal tubules and principal cells of the collecting duct the major proteins that transport lithium into cells are the sodium-hydrogen exchanger (NHE) and the epithelial sodium channel (ENaC), respectively (Figure 1) [10,23-25]. It is established that lithium can substitute for sodium and enter cells through sodium-transporting systems [10,23-25] particularly during states of dehydration and volume depletion. There are other transporting systems that may transfer lithium into tubular cells such as the sodium-phosphate cotransporter(Figure 1) [10,23-25], however, their relevance to the entry of lithium into kidney cells is still unknown. On the basolateral side of proximal and distal tubules, the most likely possibility for lithium to be extruded out of cells (to the blood) is through the sodium-sodium exchanger (Figure 1) [10,23-25].
The transport of water into renal tubular cells is mediated through the water channel protein aquaporin (AQP) (Figure 1) . AQP1 is abundantly expressed in the proximal tubule and descending loop of Henle where it is localized to the apical and basolateral membranes . In the collecting duct, the transport of water into principal cells is mediated mainly by AQP2 (Figure 1) . The exit of water occurs through AQP3 and AQP4. Normally, water permeability of principal cells is regulated by vasopressin. Vasopressin activates V2 receptors and increases intracellular cyclic adenosine monophosphate (cAMP), leading to translocation of AQP2 from intracellular vesicles to the apical membrane [27,28]. Prostaglandins also play a role in the regulation of sodium and water reabsorption . PGE2 is the main prostaglandin synthesized in the kidney  and its effect on renal function seems to be site-specific [29- 31]. For example, in the collecting duct, PGE2 attenuates the antidiuretic effect of vasopressin .
Lithium decreases the antidiuretic effect of vasopressin after short as well as long-term treatment duration [32,33]. The mechanisms by which chronic lithium therapy may reduce the antidiuretic effect of vasopressin are: First, lithium enhances PGE2 production, which decreases vasopressin-induced cAMP synthesis . Induction of COX-2 is a crucial mechanism by which medullary interstitial cells adapt successfully to the rapid shifts in ambient tonicity normally occurring in renal medulla . These adaptive mechanisms are partially regulated by the enzyme glycogen synthase kinase 3β (GSK-3β), which is regarded as an up-stream modulator of COX-2 expression . Lithium inhibits GSK-3β [35,36], which results in increased expression of COX-2 (i.e., GSK-3β negatively regulates COX-2 expression) . Thus, the regulation of renal sodium and water homeostasis by the GSK-3β-COX-2 pathway may be summarized as follows: (i) PGE2 increases urination by attenuating the antidiuretic action of vasopressin; (ii) GSK-3β enhances the antidiuretic action of vasopressin by decreasing COX-2 expression and reducing PGE2 synthesis; (iii) lithium inhibits GSK-3β leading to increased COX-2 expression and PGE2 synthesis the result of which is diminished vasopressin activity and increased urination (Figure 1). These understandings were probably the basis for using NSAIDs and COX-2 inhibitors as a treatment against lithium-induced NDI [27,37,38]. Second, lithium reduces AQP2 gene transcription through a PG-independent mechanism, leading to further decrease in urinary concentrating ability . Third, lithium induces remodeling of collecting duct which characterized by a decrease in the number of principal cells and an increase in the number of intercalated cells . Fourth, lithium was found to decrease the ratio between principal and intercalated cells in mice collecting duct due to G2 (cell cycle) arrest in principal cells . The decrease in principal/intercalated cell ratio was accompanied with features of NDI.
The management and treatment of a patient with lithium-induced NDI should take into account several important factors including: severity of NDI, risk of affective deterioration if lithium is stopped, stage of tubulointerstitial damage (if the damage is irreversible the patient will not necessarily benefit from the cessation of lithium), and, availability and feasibility of treatment options (for example, if a severe NDI develops due to acute lithium intoxication, hemodialysis should be immediately considered to minimize the damage to the kidney). Several pharmacological interventions have been suggested as a treatment for lithium-induced NDI. The potassium-sparing diuretic amiloride is one of the established options [15,42,43]. Other options are thiazide diuretics and vasopressin; however, their efficacy and safety remain to be ascertained. Classical NSAIDs and selective COX-2 inhibitors have also been tried [33,37,38] but these drugs increase the risk of lithium toxicity and may not be the best choice for additive therapy.
This case report emphasizes the need to balance between concerns regarding the damage to the kidney which is a result of long-term lithium treatment to the significant therapeutic benefit of lithium as a mood stabilizer and anti-suicidal drug. Our patient committed suicide attempts at two occasions after lithium cessation due to concerns regarding deterioration in renal function and aggravation of NDI. One of those suicidal attempts (or others that lithium probably prevented) could “bear fruit” and kill the patient at an early age. Therefore, treating psychiatrists and nephrologists must perform a risk-benefit calculation before deciding to stop lithium in bipolar patients, particularly when the cessation of lithium is not expected to lead to improvement in kidney function. On the other hand, it is essential that clinicians pursue preventive strategies to minimize the risk of developing impairments in kidney function in lithium-treated patients. This may include: prescribing the lowest effective dose of lithium; rigorous monitoring of plasma lithium levels in order to avoid episodes of intoxication and acute nephrotoxicity; annual examination of creatinine clearance (GFR); avoid co-administration of other drugs that may increase plasma lithium levels such as NSAIDs, ACE inhibitors and diuretic drugs; and, assessment of other determinants of renal function, such as plasma calcium, proteinuria and peripheral edema.
This research received no specific grant from any funding agency.
Conflict of Interest
The authors declare that they have no conflict of interest.
This article does not contain data obtained from a study with human participants. This type of study did not require a formal informed consent.
- Belmaker RH (2004) Bipolar disorder. N Engl J Med 351: 476-486. [Ref.]
- Gershon S, Chengappa KN, Malhi GS (2009) Lithium specificity in bipolar illness: a classic agent for the classic disorder. Bipolar Disord 11: 34-44. [Ref.]
- Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, et al. (2003) Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA 290: 1467-1473. [Ref.]
- Baldessarini RJ, Tondo L (2009) Suicidal risks during treatment of bipolar disorder patients with lithium versus anticonvulsants. Pharmacopsychiatry 42: 72-75. [Ref.]
- McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM et al. (2012) Lithium toxicity profile: a systematic review and meta-analysis. Lancet 379: 721-728. [Ref.]
- Shine B, McKnight RF, Leaver L, Geddes JR (2015) Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet 386: 461-468. [Ref.]
- Azab AN, Shnaider A, Osher Y, Wang D, Bersudsky Y, et al. (2015) Lithium nephrotoxicity. Int J Bipolar Disord 3: 28. [Ref.]
- Belmaker RH, Bersudsky Y, Agam G (2012) Individual differences and evidence based psychopharmacology. BMC Medicine 27: 10-11. [Ref.]
- Grueneberger EC, Maria Rountree E, Baron Short E, Kahn DA (2009) Neurotoxicity with therapeutic lithium levels: a case report. J Psychiatr Pract 15: 60-63. [Ref.]
- Timmer RT, Sands JM (1999) Lithium intoxication. J Am Soc Nephrol 10: 666-674. [Ref.]
- Baldessarini RJ, Tarazi FI (2006) Pharmacotherapy of psychosis and mania. In: Brunton LL, Lazo JS, Parker KL (eds) Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th edition, The McGraw-Hill companies, New York 461-500. [Ref.]
- Kripalani M, Shawcross J, Reilly J, Main J (2009) Lithium and chronic kidney disease. BMJ 339: 166-169. [Ref.]
- Bucht G, Wahlin A (1980) Renal concentrating capacity in long-term lithium treatment and after withdrawal of lithium. Acta Med Scand 207: 309-314. [Ref.]
- Vestergaard P, Amdisen A (1981) Lithium treatment and kidney function. A follow-up study of 237 patients in long-term treatment. Acta Psychiatr Scand 63: 333-345. [Ref.]
- Boton R, Gaviria M, Batlle DC (1987) Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 10: 329-345. [Ref.]
- Markowitz GS, Radhakrishnan J, Kambham N, Valeri AM, Hines WH, et al. (2000) Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 11: 1439-1448.
- Walker RG (1993) Lithium nephrotoxicity. Kidney Int 42: 93-98. [Ref.]
- Bendz H, Aurell M, Lanke J (2001) A historical cohort study of kidney damage in long-term lithium patients: continued surveillance needed. Eur Psychiatry 16: 199-206. [Ref.]
- Lepkifker E, Sverdlik A, Iancu I, Ziv R, Segev S, et al. (2004) Renal insufficiency in long-term lithium treatment. J Clin Psychiatry 65: 850- 856. [Ref.]
- Presne C, Fakhouri F, Noël LH, Stengel B, Even C, et al. (2003) Lithium-induced nephropathy: Rate of progression and prognostic factors. Kidney Int 64: 585-592. [Ref.]
- Paw H, Slingo ME, Tinker M (2007) Late onset nephrogenic diabetes insipidus following cessation of lithium therapy. Anaesth Intensive Care 35: 278-280. [Ref.]
- Khairallah W, Fawaz A, Brown EM, El-Hajj Fuleihan G (2007) Hypercalcemia and diabetes insipidus in a patient previously treated with lithium. Nat Clin Pract Nephrol 3: 397-404. [Ref.]
- Greger R (1990) Possible sites of lithium transport in the nephron. Kidney Int Suppl 28: 26-30. [Ref.]
- Holstein-Rathlou NH (1990) Lithium transport across biological membranes. Kidney Int 28: 4-9. [Ref.]
- Grünfeld JP, Rossier BC (2009) Lithium nephrotoxicity revisited. Nat rev Nephrol 5: 270-276. [Ref.]
- Nielsen S, Smith BL, Christensen EI, Knepper MA, Agre P (1993) CHIP28 water channels are localized in constitutively water-permeable segments of the nephron. J Cell Biol 120: 371-383. [Ref.]
- Deen PM, Verdijk MA, Knoers NV, Wieringa B, Monnens LA, et al. (1994) Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 264: 92-95. [Ref.]
- Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK, et al. (1995) Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci USA 92: 1013-1017. [Ref.]
- Harris RC, Breyer MD (2001) Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol 281: 1-11. [Ref.]
- Kotnik P, Nielsen J, Kwon TH, Krzisnik C, Frøkiaer J, et al. (2005) Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus. Am J Physiol Renal Physiol 288: 1053-1068. [Ref.]
- Zelenina M, Christensen BM, Palmér J, Nairn AC, Nielsen S, et al. (2000) Prostaglandin E(2) interaction with AVP: effects on AQP2 phosphorylation and distribution. Am J Physiol Renal Physiol 278: 388-394. [Ref.]
- Singer I, Rotenberg D, Puschett JB (1972) Lithium-induced nephrogenic diabetes insipidus: in vivo and in vitro studies. J Clin Invest 51: 1081-1091. [Ref.]
- Sugawara M, Hashimoto K, Ota Z (1988) Involvement of prostaglandin E2, cAMP, and vasopressin in lithium-induced polyuria. Am J Physiol 254: 863-869. [Ref.]
- Rao R, Hao CM, Breyer MD (2004) Hypertonic stress activates glycogen synthase kinase 3beta-mediated apoptosis of renal medullary interstitial cells, suppressing an NFkappaB-driven cyclooxygenase-2- dependent survival pathway. J Biol Chem 279: 3949-3955. [Ref.]
- Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 93: 8455-8459. [Ref.]
- Stambolic V, Ruel L, Woodgett JR (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 6: 1664-1668. [Ref.]
- Kim GH, Choi NW, Jung JY, Song JH, Lee CH, et al. (2008) Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2. Am J Physiol Renal Physiol 294: 702-709. [Ref.]
- Allen HM, Jackson RL, Winchester MD, Deck LV, Allon M (1989). Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus. Arch Intern Med 149: 1123-1126. [Ref.]
- Kortenoeven ML, Li Y, Shaw S, Gaeggeler HP, Rossier BC, et al. (2009) Amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant nephrogenic diabetes insipidus. Kidney Int 76: 44-53. [Ref.]
- Ecelbarger CA (2006) Lithium treatment and remodeling of the collecting duct. Am J Physiol. Renal Physiol 291: 37-38. [Ref.]
- de Groot T, Alsady M, Jaklofsky M, Otte-Höller I, Baumgarten R, et al. (2014) Lithium causes G2 arrest of renal principal cells. J Am Soc Nephrol 25: 501-510. [Ref.]
- Bedford JJ, Leader JP, Jing R, Walker LJ, Klein JD, et al. (2008) Amiloride restores renal medullary osmolytes in lithium-induced nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 294: 812- 820. [Ref.]
- Bedford JJ, Weggery S, Ellis G, McDonald FJ, Joyce PR, et al. (2008) Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. Clin J Am Soc Nephrol 3: 1324-1331. [Ref.]
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Article Type: Case Report
Citation: Shnaider A, Azab AN (2015) Lithium-induced Nephrogenic Diabetes Insipidus – A Case Report and Discussion on the Pathophysiological Mechanism. Int J Nephrol Kidney Failure 1(3): doi http://dx.doi. org/10.16966/2380-5498.113
Copyright: © 2015 Shnaider A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.