Lithium-Induced Nephropathies

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Chapter 17

LITHIUM-INDUCED NEPHROPATHIES

Thomas J. Raedler1,2 1Dept. of Psychiatry, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada 2Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

ABSTRACT

More than 50 years after the introduction of lithium into clinical practice, lithium, an alkali metal, remains the treatment of choice for many subjects with bipolar disorder. Despite the introduction of multiple novel pharmacological treatment options for bipolar disorder, lithium remains unsurpassed in efficacy and tolerability for many subjects with bipolar disorder. However, long-term treatment with lithium carries the potential to cause thyroid and renal dysfunction. Treatment with lithium frequently causes nephrogenic diabetes insipidus, characterised by polydipsia, polyuria and an inability to concentrate the urine. About 20 % of subjects experience a decrease in GFR (glomerular filtration rate) after long term treatment with lithium. A smaller number of subjects go on to develop potentially irreversible renal insufficiency under long term treatment with lithium. Concerns about renal side-effects have led to a decrease in the use of lithium over the past decades. So far, no diagnostic tools exist to help with the early identification of subjects at risk of lithium-induced nephropathies. This review focuses on the pathomechanism of lithium-induced nephropathies as well as recommendations for the monitoring of subjects under treatment with lithium.

Keywords: Lithium, bipolar disorder, nephrogenic diabetes insipidus, renal insufficiency, GFR, creatinine

 E-mail: [email protected]. Fax: +1.403.210.9114. Phone: +1.403.210.6899. 528 Thomas J. Raedler

ABBREVIATIONS

ADH Antidiuretic hormone AQP2 Aquaporin 2 CKD Chronic kindey disease COX2 Cyclooxygenase 2 eGFR Estimated glomerular filtration rate ENaC Epithelial sodium channel ESRD End-stage renal disease GFR Glomerular filtration rate GSK-3β Glycogen synthase kinase-3β NDI Nephrogenic diabetes insipidus NKCC Na-K-Cl cotransporter NSAID Non-steroidal anti-inflammatory drug PG Prostaglandin PKC Protein kinase C UT Urea transporter

INTRODUCTION

Bipolar disorder is a severe psychiatric disorder that is characterised by episodes of mania and depression [1]. In the United States, the lifetime prevalence of bipolar disorder spectrum is estimated to be as high as 4.5% [2]. Bipolar disorder is frequently associated with other psychiatric disorders including anxiety disorders as well as alcohol- and substance- abuse [2]. Bipolar disorder frequently takes a chronic course and imposes a considerable toll on affected individuals, their families and public health services world-wide [3]. Bipolar disorder is one of the leading causes of disability and is associated with premature death [4]. Suicide-attempts and completed suicides occur frequently in subjects suffering from bipolar disorder [5;6]. More than 50 years ago, lithium was shown to be an effective pharmacological agent for the treatment of mania and maintenance treatment of bipolar disorder [7]. Since then, different antiepileptics (e.g. carbamazepine, valproic acid and lamotrigine) and antipsychotics (e.g. olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole) have been approved for the treatment of bipolar disorder. Despite recent advances in the pharmacotherapy of bipolar disorder, lithium is still considered a first-line agent for the pharmacological treatment of bipolar disorder [8;9]. Lithium has well documented acute antimanic effects as well as prophylactic antimanic effects in bipolar disorder. Lithium is less effective in preventing depressive episodes in bipolar disorder [10;11]. Long-term treatment with lithium also results in a marked reduction in suicidal behaviour and overall mortality in bipolar disorder [12;13]. Responders to lithium may constitute a subgroup bipolar disorder. Differences between lithium-responders and lithium-nonresponders extend to their offspring and there is evidence that children with bipolar disorder respond to the same mood-stabiliser as their bipolar parent [14]. Lithium-Induced Nephropathies 529

The mechanism of action of lithium remains unclear. Possible mechanisms of action include a lithium-induced inhibition of the enzyme glycogen synthase kinase-3 (GSK-3) [15], an inhibition of of protein kinase C (PKC) [16] and a significant reduction of inositol-levels [17]. Lithium also has neurotrophic and neuroprotective effects [18] and may lead to the neurogenesis through a stimulation of neural stem cells [19]. Due to concerns about somatic side-effects, including effects of lithium on thyroid and kidney [20], the use of lithium has declined over the past years. This manuscript will review the effects of pharmacological treatment with lithium on renal function with a special focus on lithium-induce nephrogenic diabetes insipidus and renal insufficiency.

Renal Effects of Lithium

Lithium is an alkali metal. Under physiological conditions, lithium is present in the body only in trace amounts. Under pharmacological treatment, lithium plasma-concentrations are usually maintained in the range of 0.6 – 0.8 mmol/l [21]. Lithium is excreted through the kidneys. Lithium is not bound to plasma-proteins and is freely filtered by the renal glomeruli. 65 – 75% of the filtered lithium is reabsorbed in the proximal tubule with additional reabsorption of lithium occurring along the thick ascending limb of Henle’s loop [22]. Lithium-ions use the amiloride-sensitive Na+-channel (ENaC) for their transport through the apical membrane of the collecting duct cells of the distal nephron. The EnaC has a higher permeability for lithium than for sodium [23]. Lithium accumulates in principal cells of the collecting duct to reach potentially cytotoxic concentrations that inhibit intracellular signalling pathways involving GSK-3β [24]. Treatment with lithium also reduces the regulatory effects of aldosterone on the ENaC, which helps to explain the sodium wasting associated with treatment with lithium [25]. Different observations from animal studies imply that treatment with pharmacological doses of lithium exerts effects on the kidneys. In rats, treatment with lithium results in changes in the cellular composition of the collecting duct [26;27] as well as changes in the levels of different kidney and urine metabolites, suggesting lithium-induced renal cell stress or injury [28]. In a proteomic analysis, treatment with lithium affected predominantly proteins involved in cell death, apopotosis, cell proliferation and morphology [29].

Histopathological Renal Changes in Subjects under Treatment with Lithium

Renal biopsies are rarely performed in subjects under treatment with lithium. Renal biopsies in subjects under treatment with lithium therefore constitute only a small fraction of all renal biopsies performed for clinical purposes. A variety of histopathological changes, including tubular atrophy, interstitial fibrosis, cysts and glomerular changes have been described after long-term treatment with lithium [30;31]. Histopathological changes after long-term treatment with lithium were first described several years after the introduction of lithium into clinical practice [32]. All subjects with renal impairment after long-term treatment with lithium, had abnormal renal morphology with cortical fibrosis as well as dilated tubules and microcyts consistent with the development of tubulointerstitial nephritis [33]. Renal biopsies taken from patients currently taking lithium show characteristic lesions 530 Thomas J. Raedler of the distal convulated tubules and collecting ducts. These lesions were no longer present in patients, who discontinued lithium [34;35]. Long-term treatment with lithium results in significantly more sclerotic glomeruli and interstitial fibrosis than in healthy controls [35]. The degree of interstitial fibrosis correlates with the duration of lithium treatment as well as the cumulative dose of lithium [36]. Sclerotic glomeruli and atrophic tubuli are more prevalent after long-term treatment with lithium if lithium is taken several times per day [37]. These observations suggest that long-term treatment with lithium causes structural renal changes in humans.

Lithium-Intoxication

Lithium has a narrow therapeutic range and lithium-overdose results in severe and potentially life-threatening toxicity. Lithium-intoxication can occur either following an intentional overdose or due to other mechanisms despite maintenance of a normal dosing- schedule. Predisposing conditions include co-medication with a variety of different medications (in particular ACE inhibitors, thiazide diuretics and NSAIDs) that can result in an increase in plasma lithium-concentrations [38]. Concurrent illnesses (e.g. gastroenteritis) that result in decreased circulating volume as well as disorders of the water and electrolyte balance are additional risk-factors for lithium-intoxication. Sodium-restriction results in increased reabsorption of lithium, creating yet another risk-factor for lithium-intoxication [23]. Acute lithium-intoxication affects different organs including CNS, kidneys, GI-tract and heart [39]. Lithium-intoxications are potentially life-threatening and put individuals at risk of irreversible neurological and renal complications [40]. Hemodialysis has been used in severe cases of lithium-intoxication [41], although a clear benefit of hemodialysis in the management of lithium-intoxication has been questioned [42]. In many affected subjects, the kidney function does not fully recover after an acute episode of lithium-intoxication. Lithium- intoxication therefore constitutes a risk-factor for long-term kidney damage [39].

Nephrogenic Diabetes Insipidus (NDI)

Nephrogenic diabetes insipidus is characterized by polydipsia, polyuria and an inability to concentrate the urine. Nephrogenic diabetes insipidus results from an unresponsiveness of the kidney to the effects of antidiuretic hormone (ADH). Nephrogenic diabetes insipidus is a frequent complication of pharmacological treatment with lithium as lithium is among the most frequent causes of reversible nephrogenic diabetes insipidus [43]. At the same time, lithium is the most frequent cause of medication-induced nephrogenic diabetes insipidus [44]. First signs of nephrogenic diabetes insipidus can be detected shortly after starting treatment with lithium. In severe cases, lithium-induced nephrogenic diabetes insipidus may require the discontinuation of lithium [44]. However, lithium-induced nephrogenic diabetes insipidus may persist even after discontinuation of lithium [45]. Several studies have assessed the frequency of nephrogenic diabetes insipidus as a complication of treatment with lithium. Polyuria (defined as a 24 hour urine volume of > 3 liters) was found in 70% of subjects under long-term treatment with lithium and was frequently associated with impairment in work and daily routine [46]. In another study the Lithium-Induced Nephropathies 531

prevalence of polyuria among long-term users of lithium was 37% and was more frequent among subjects with concomitant use of serotonergic antidepressants [47]. In an older study of the renal function in over 1000 patients chronically treated with lithium, an impairment of the urine concentrating ability was present in over 50% of the subjects. Overt polyuria and polydipsia were observed in 19% of the subjects [48]. Multiple daily doses of lithium have been associated with higher rates of polyuria [49]. Higher age may also predispose subjects to higher rates of impaired urine concentrating ability with 73% of lithium-treated subjects over age 65 showing a significant urine concentrating defect [50]. Different mechanisms, including transporter proteins (e.g. Na-Cl co-transporter, chloride channel and urea transporter) as well as aquaporins are involved in the regulation of urine- concentration. Over the past few years, the molecular mechanisms underlying lithium- induced nephrogenic diabetes insipidus have been studied extensively [22;51]. A special focus has been on the effects of lithium on aquaporins. Aquaporins (AQP) are proteins that are inserted into the membrane of the collecting tubules and thus facilitate the reabsorption of water from the collecting tubules [52]. In healthy volunteers a single dose of lithium had no immediate effects on AQP2 concentration [53]. After four weeks of treatment, lithium resulted in a decrease in the urinary concentrating ability as well as a decrease of the urinary AQP2 excretion in healthy volunteers [54]. While only few studies have been performed in humans, more is known from animal- studies about the effects of lithium on aquaporins. In rats, treatment with lithium results in a dramatic reduction in the levels of renal aquaporins (especially AQP2 and AQP3) as well as urea transporters (UT-A1 and UT-A3) [55-57]. While the concentrations of urea transporters normalise shortly after discontinuation of lithium, the expression of AQP2 fails to return to normal levels [55]. Concomitant use of amiloride reverses the reduction of AQP2- and UT- A1-levels in lithium-treated rats [58]. These effects of lithium on AQP2 are linked to an intact sodium channel. In genetically modified mice, the absence of ENaC protects mice from developing reduced AQP2 levels as well as NDI under treatment with lithium [59]. The molecular mechanisms responsible for the effects of lithium on renal aquaporins are now starting to become clear. Lithium inhibits the ADH-stimulated translocation of cytoplasmic AQP2 to the apical membrane [60]. Treatment with lithium results in a decreased mRNA expression of AQP2 [61] as well as a dose-dependent reduction of AQP2 protein expression [62]. Treatment with lithium also induces reversible changes in cellular organization [27] as well as the cell proliferation in the collecting ducts, which were associated with a decreased expression of AQP2 [26]. Beyond aquaporins, additional mechanisms also play a role in lithium-induced nephrogenic diabetes insipidus. Urinary PGE2-levels are increased in lithium-induced nephrogenic diabetes insipidus [63]. Treatment with lithium results in an increased renal cyclooxygenase 2 (COX2) expression, that is mediated via an inhibition of GSK-3β (glycogen synthase kinase-3β) activity [64]. Concomitant treatment with a COX-2 inhibitor in lithium treated rats leads to decreased polyuria and increased expression of AQP2 and NKCC2 [63]. At the same time, mice lacking a prostaglandin isomerase failed to develop polyuria as well as decreased levels of AQP2 and NKCC2 under treatment with lithium [65]. The increased production of renal PGE2 under treatment with lithium involves enhanced purinergic signalling [66]. Different treatment-strategies have been used to ameliorate nephrogenic diabetes insipidus in subjects under treatment with lithium. As with other psychiatric disorders 532 Thomas J. Raedler affecting the water homeostasis, subjects should be encouraged to balance their fluid-intake [67]. Concomitant use of amiloride increases urinary concentrating ability and urinary excretion of AQP2 [68;69]. Amiloride blocks the entry of lithium into kidney cells by blocking the ENaC [70]. The diuretic hydrochlorothiazide as well as the NSAID indometacin have been used successfully to improve lithium-induced polyuria [71]. COX-2 inhibitors decrease symptoms of lithium-induced NDI in rats [63], but have not been systematically evaluated in humans. However, it should be pointed out that NSAID and selective COX-2 inhibitors can increase serum lithium concentrations and put subjects at increased risk of lithium intoxication [72]. Careful monitoring of lithium-levels is therefore warranted when using these agents.

Lithium-Induced Renal Insufficiency

The issue of a possible relationship between treatment with lithium and renal insufficiency has been discussed controversially over the past decades. Initial studies failed to find a significant effect of treatment with lithium on renal function [73-76]. These initial studies led Walker to claim that there is very little evidence that stable maintenance treatment with lithium is associated with a reduction of glomerular filtration rate [77]. However, as the wide-spread use of lithium as a pharmacotherapy for bipolar disorder did not become common until the 1970ies, these initial studies were based on shorter durations of treatment with lithium. A different trend has emerged over the past decades. A significant decline in creatinine clearance as a measure of renal function can be present as early as one year after the initiation of treatment with lithium [78]. The creatinine clearance is significantly lower after prolonged treatment with lithium than after short-term treatment with lithium [79] and is inversely correlated with the duration of treatment with lithium [36]. Several studies found a significant deleterious effect of long-term treatment with lithium on renal function. An older study in over 1000 patients chronically treated with lithium found a mild reduction in GFR in 15% of the subjects [48]. In subjects who had taken lithium for a minimum of 15 years, reductions of GFR (21%) and urinary concentrating capacity (44%) were present in a significant number of subjects. [80]. In a follow-up study, the longer duration of treatment with lithium increased both the rate of subjects with decreased GFR as well as the rate of subjects with impaired urinary concentrating capacity [81]. More recently, Lepkifker examined the effects of long-term treatment with lithium on renal function. In a cohort of 114 subjects who were chronically treated with lithium (mean duration of treatment 16.8 years), 21% developed signs of renal insufficiency as indicated by an elevated creatinine on at least two separate measurements. The majority of cases of renal insufficiency occurred during the second decade of treatment. In patients with renal insufficiency, creatinine levels increased progressively over time. Patients with renal insufficiency also suffered from more episodes of acute lithium toxicity. However, almost 80% of subjects under long-term treatment with lithium remained free of signs of renal insufficiency [82]. These findings were confirmed by several recent studies. Tredget et al. followed a sample of 61 subjects who had been treated with lithium for a mean of 15.6 years. Over a period of 11.5 years, treatment with lithium caused a modest decline in renal function that was higher Lithium-Induced Nephropathies 533

than in a control-group [83]. Bendz et al. assessed the rates of lithium-induced renal failure in a sample of 2.7 million people from Sweden. Compared to the general population, chronic treatment with lithium resulted in a six-fold increase in the prevalence of end-stage renal disease with duration of treatment with lithium as the main risk factor [84]. Bassilios evaluated the rate of lithium-induced chronic kidney disease using data from a clinical laboratory in Paris. The prevalence of reduced eGFR was much higher in subjects treated with lithium than in the general population. 5% of the subjects treated with lithium between the ages of 40 to 69 years were found to be in CKD stage 4 (eGFR 20 – 39ml/min/1.73 m2) [85]. In a sample from Britain, Khatami obtained a follow-up eGFR measurement in lithium- treated subjects who had presented with a decreased eGFR at baseline. Over a period of three years 4% of the lithium-treated subjects with a decreased eGFR at baseline progressed to CKD stage 4 and 5 [86]. Several studies have provided follow-up on subjects, who discontinued lithium. Bendz followed 13 subjects who discontinued treatment with lithium after a mean duration of treatment of 18 years. While the GFR improved overall after the discontinuation of lithium, the urinary concentrating ability remained impaired. Still, some of these subjects progressed to ESRD despite discontinuation of lithium [87]. These findings were confirmed in another study from France, in which a small proportion of subjects continued to progress to ESRD after discontinuation of lithium. Some of these subjects eventually required dialysis [36]. In a survey among dialysis centers in France, 0.22% of all dialysis patients had a lithium-induced nephropathy [36]. The frequency of toxic nephropathies as the primary cause for end-stage renal disease may differ between different regions of the world. The highest rates of lithium- induced ESRD were reported from Australia and New Zealand [88]. However, there is still a paucity of data on the frequency of lithium-treated subjects among subjects with ESRD. As pointed out above, long-term treatment with lithium can negatively affect renal function in a small subgroup of subjects. Some subgroups, e.g. individuals with intellectual disability [89], may be at an even higher risk of an adverse effect of lithium on renal function. Higher age of subjects may be another risk-factor [50]. Despite the data presented above, it should be pointed out that some authors do not see a clear clinical relevance of a lithium- induced increase in serum creatinine [90].

Monitoring of Renal Function under Treatment with Lithium

There is a lack of clear guidelines on how to monitor kidney function in lithium-treated patients [91]. Traditionally serum creatinine has been used as a marker of renal function. eGFR (estimated GFR) corrects serum creatinine for age, gender and race. While eGFR is not the ideal tool to assess renal function either [92], eGFR is nowadays widely used as a laboratory test to monitor renal function. Based on recommendations from the National Strategic Framework for Renal Services, Morriss and Benjamin recommended the use of estimated glomerular filtration rate (eGFR) as a better marker of renal function in subjects under treatment with lithium. Morriss and Benjamin specifically recommended to use serial eGFR measurements to monitor renal function under treatment with lithium [93]. Using eGFR as a measurement of renal function, Kripalani et al. offer more specific guidelines on how to assess kidney function before starting lithium as well as during treatment with lithium [94]. They recommend a referral to a nephrologist if the eGFR is moderately or severely 534 Thomas J. Raedler impaired [94]. However, the recommended standards for monitoring of subjects under treatment with lithium are frequently not being followed in clinical practice [95].

DISCUSSION

More than 50 years after being introduced for the treatment of bipolar disorder, lithium remains a first-line agent for the pharmacological treatment of this disorder. Lithium is the treatment of choice for a subgroup of subjects with bipolar disorder, who respond preferentially to this medication. Partially due to concerns about somatic side-effects, lithium has been used less frequently over the past years. Many of these concerns focus around potentially deleterious effects of lithium on kidney-function. As outlined above, at least 50% of subjects under treatment with lithium develop polydipsia and polyuria as well as, less frequently, nephrogenic diabetes insipidus. The effects of these conditions range from bothersome to potentially life-threatening and can have a significant effect on quality of life as well as level of functioning. Polyuria also puts subjects at increased risk of lithium-intoxication under conditions of dehydration. The molecular mechanisms underlying lithium-induced NDI are starting to be elucidated and include an inhibitory effect of lithium on the expression of aquaporins (water-transporting proteins of the collecting ducts). Amiloride and indometacin have been used successfully to ameliorate symptoms of lithium-induced nephrogenic diabetes insipidus. Indometacin, however, carries the risk of elevating blood-levels of lithium, which puts subjects at increased risk of lithium-intoxication. The situation is less clear with regards to lithium-induced renal insufficiency. About 80% of subjects show no signs of decreased renal function even after decades of treatment with lithium. On the other side, about 15 – 20% of subjects start to develop an increase in creatinine and a decrease in GFR after about a decade of using lithium. A smaller proportion of subjects taking lithium experience a further decrease in renal function that can ultimately result in the need for hemodialysis. While only a small proportion of subjects taking lithium experiences severe renal problems, the risk of CKD under treatment of lithium is significantly increased when compared to the general population. The scenario of an initial decline in renal function under successful treatment with lithium can lead to very complex therapeutic situations. Some subjects respond preferentially to lithium and are at risk of insufficient symptom-control after discontinuation of lithium. This situation is further complicated by the fact that the sudden discontinuation of lithium puts subjects at much higher risk of relapse of their symptoms of bipolar disorder [96]. The care of subjects under treatment with lithium needs to be optimised in several areas that are relevant for this manuscript. So far, only little is known about conditions that predispose subjects to develop CKD under treatment with lithium. Acute lithium-intoxication frequently results in permanent renal damage and therefore needs to be prevented. The potential effects of additional medical conditions, in particular diabetes mellitus, have not been well studied. Subjects with bipolar disorder are at increased risk of developing diabetes mellitus [97]. In addition, atypical antipsychotics are being increasingly recommended as first line agents for the pharmacological treatment of bipolar disorder [9;98;99]. This trend is of particular concern in the context of this manuscript as atypical antipsychotics increase the risk Lithium-Induced Nephropathies 535 of diabetes mellitus [100]. It is also not known in how far bipolar disorder by itself may predispose subjects to develop renal problems. There are no clear guidelines on how to optimise monitoring renal function under treatment with lithium. Current guidelines recommend regular monitoring of creatinine levels and eGFR. Creatinine clearance based on 24-hour urine sampling may add more specific information. However, 24-hour urine sampling can be cumbersome and frequently leads to incorrect results due to incomplete sampling. Unfortunately the recommendations for regular monitoring are only followed in a small proportion of subjects under treatment with lithium [95]. A variety of different biomarkers are currently being developed to improve the monitoring of renal function [101]. Plasma Cystatin C-estimated glomerular filtration rate has been suggested as a more sensitive marker of renal function. However, in the only study to date, Cystatin C showed no advantage over creatinine in subjects under treatment with lithium [102]. The next few years will hopefully bring new and more accurate markers to monitor renal function. Currently, there are also no tools available to identify subjects at increased risk of lithium-induced nephropathies at an early stage of treatment. Using a proteomics-based approach, we found abnormal protein patterns in a subgroup of subjects chronically treated with lithium [103]. Microcysts in the kidneys can be detected using MR-imaging of the kidneys [104;105]. So far, however, it is not known if protein-patterns or structural microcysts carry prognostic relevance. Over the next few years we may find markers to reliably identify those subjects who are at significant risk of somatic side-effects from lithium. At the same time, only little is known about potential interventions to reduce the risk of subjects to develop renal damage under treatment with lithium. Early studies suggested a significant association between the dose of lithium and impaired renal concentrating ability for regular preparations of lithium, but not for slow release preparations of lithium [106]. Lithium is typically administered several times per day. This mode of administration leads to more stable plasma concentrations of lithium. However, the optimal mode of administration for lithium has not determined [107]. Single day administration of lithium may improve compliance and has been associated with a reduced risk of polyuria and renal damage [107- 109]. A single daily dose of lithium also results in less frequent histopathological changes than taking lithium multiple times per day [37]. More than a decade ago, Gatlin had suggested the following recommendations for the safe use of lithium [110]:

1) Careful avoidance of lithium intoxication 2) Regular monitoring of blood-levels of lithium with the goal of using lowest effective concentration 3) Regular monitoring of creatinine levels 4) (Possibly) administering lithium once a day

With the exception of using eGFR instead of creatinine levels, these recommendations remain valid. Over the next few years, further research will hopefully result in better ways of identifying subjects at risk of lithium-induced nephropathies at an early stage of treatment and to prevent their progression into end-stage renal disease. A closer collaboration between 536 Thomas J. Raedler psychiatrists and nephrologists may help to improve the outcome of this vulnerable population.

FINANCIAL DISCLOSURE

Dr. Raedler has received honoraria, grants and/or travel funds from different pharmaceutical companies

REFERENCES

[1] Belmaker RH: Bipolar disorder. N. Engl.J. Med. 2004, 351:476-486. [2] Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, Kessler RC: Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch.Gen.Psychiatry 2007, 64:543-552. [3] Andlin-Sobocki P, Wittchen HU: Cost of affective disorders in Europe. Eur.J.Neurol. 2005, 12 Suppl 1:34-38. [4] Frye MA: Clinical practice. Bipolar disorder--a focus on depression. N.Engl.J.Med. 2011, 364:51-59. [5] Bostwick JM, Pankratz VS: Affective disorders and suicide risk: a reexamination. Am.J.Psychiatry 2000, 157:1925-1932. [6] Novick DM, Swartz HA, Frank E: Suicide attempts in bipolar I and bipolar II disorder: a review and meta-analysis of the evidence. Bipolar.Disord. 2010, 12:1-9. [7] Schou M: Forty years of lithium treatment. Arch.Gen.Psychiatry 1997, 54:9-13. [8] Hirschowitz J, Kolevzon A, Garakani A: The pharmacological treatment of bipolar disorder: the question of modern advances. Harv.Rev.Psychiatry 2010, 18:266-278. [9] Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, Goodwin GM, Geddes JR: Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011. [10] Nivoli AM, Murru A, Vieta E: Lithium: still a cornerstone in the long-term treatment in bipolar disorder? Neuropsychobiology 2010, 62:27-35. [11] Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM: Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am.J.Psychiatry 2004, 161:217-222. [12] Tondo L, Baldessarini RJ: Long-term lithium treatment in the prevention of suicidal behavior in bipolar disorder patients. Epidemiol.Psichiatr.Soc. 2009, 18:179-183. [13] Cipriani A, Pretty H, Hawton K, Geddes JR: Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am.J.Psychiatry 2005, 162:1805-1819. [14] Grof P, Duffy A, Alda M, Hajek T: Lithium response across generations. Acta. Psychiatr.Scand. 2009, 120:378-385. [15] Gould TD, Manji HK: Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology 2005, 30:1223-1237. Lithium-Induced Nephropathies 537

[16] Zarate CA, Manji HK: Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs 2009, 23:569-582. [17] Moore GJ, Bebchuk JM, Parrish JK, Faulk MW, Arfken CL, Strahl-Bevacqua J, Manji HK: Temporal dissociation between lithium-induced changes in frontal lobe myo- inositol and clinical response in manic-depressive illness. Am.J.Psychiatry 1999, 156:1902-1908. [18] Quiroz JA, Machado-Vieira R, Zarate CA, Jr., Manji HK: Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology 2010, 62:50-60. [19] Hashimoto R, Senatorov V, Kanai H, Leeds P, Chuang DM: Lithium stimulates progenitor proliferation in cultured brain neurons. Neuroscience 2003, 117:55-61. [20] Raedler TJ, Wiedemann K: Lithium-induced nephropathies. Psychopharmacol.Bull. 2007, 40:134-149. [21] Grandjean EM, Aubry JM: Lithium: updated human knowledge using an evidence- based approach. Part II: Clinical pharmacology and therapeutic monitoring. CNS Drugs 2009, 23:331-349. [22] Trepiccione F, Christensen BM: Lithium-induced nephrogenic diabetes insipidus: new clinical and experimental findings. J.Nephrol. 2010, 23 Suppl 16:S43-S48. [23] Thomsen K, Shirley DG: A hypothesis linking sodium and lithium reabsorption in the distal nephron. Nephrol.Dial.Transplant. 2006, 21:869-880. [24] Grunfeld JP, Rossier BC: Lithium nephrotoxicity revisited. Nat.Rev.Nephrol. 2009, 5:270-276. [25] Nielsen J, Kwon TH, Frokiaer J, Knepper MA, Nielsen S: Lithium-induced NDI in rats is associated with loss of alpha-ENaC regulation by aldosterone in CCD. Am.J.Physiol. Renal Physiol. 2006, 290:F1222-F1233. [26] Christensen BM, Kim YH, Kwon TH, Nielsen S: Lithium treatment induces a marked proliferation of primarily principal cells in rat kidney inner medullary collecting duct. Am.J.Physiol. Renal Physiol. 2006, 291:F39-F48. [27] Christensen BM, Marples D, Kim YH, Wang W, Frokiaer J, Nielsen S: Changes in cellular composition of kidney collecting duct cells in rats with lithium-induced NDI. Am.J.Physiol. Cell Physiol. 2004, 286:C952-C964. [28] Hwang GS, Yang JY, Ryu dH, Kwon TH: Metabolic profiling of kidney and urine in rats with lithium-induced nephrogenic diabetes insipidus by (1)H-NMR-based metabonomics. Am.J.Physiol. Renal Physiol. 2010, 298:F461-F470. [29] Nielsen J, Hoffert JD, Knepper MA, Agre P, Nielsen S, Fenton RA: Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down- regulation and cellular proliferation. Proc.Natl.Acad.Sci.U.S.A 2008, 105:3634-3639. [30] Markowitz GS, Radhakrishnan J, Kambham N, Valeri AM, Hines WH, D'Agati VD: Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J.Am.Soc.Nephrol. 2000, 11:1439-1448. [31] Hestbech J, Hansen HE, Amdisen A, Olsen S: Chronic renal lesions following long- term treatment with lithium. Kidney Int. 1977, 12:205-213. [32] Hansen HE, Hestbech J, Olsen S, Amdisen A: Renal function and renal pathology in patients with lithium-induced impairment of renal concentrating ability. Proc.Eur.Dial.Transplant.Assoc. 1977, 14:518-527. 538 Thomas J. Raedler

[33] Aurell M, Svalander C, Wallin L, Alling C: Renal function and biopsy findings in patients on long-term lithium treatment. Kidney Int. 1981, 20:663-670. [34] Walker RG, Bennett WM, Davies BM, Kincaid-Smith P: Structural and functional effects of long-term lithium therapy. Kidney Int.Suppl. 1982, 11:S13-S19. [35] Walker RG, Dowling JP, Alcorn D, Ryan GB, Kincaid-Smith P: Renal pathology associated with lithium therapy. Pathology 1983, 15:403-411. [36] Presne C, Fakhouri F, Noel LH, Stengel B, Even C, Kreis H, Mignon F, Grunfeld JP: Lithium-induced nephropathy: Rate of progression and prognostic factors. Kidney Int. 2003, 64:585-592. [37] Hetmar O, Brun C, Clemmesen L, Ladefoged J, Larsen S, Rafaelsen OJ: Lithium: long- term effects on the kidney--II. Structural changes. J.Psychiatr.Res. 1987, 21:279-288. [38] Thomsen K, Schou M: Avoidance of lithium intoxication: advice based on knowledge about the renal lithium clearance under various circumstances. Pharmacopsychiatry 1999, 32:83-86. [39] Hansen HE, Amdisen A: Lithium intoxication. (Report of 23 cases and review of 100 cases from the literature). Q.J.Med. 1978, 47:123-144. [40] Goddard J, Bloom SR, Frackowiak RS, Pusey CD, MacDermot J, Liddle PF: Lithium intoxication. BMJ 1991, 302:1267-1269. [41] Eyer F, Pfab R, Felgenhauer N, Lutz J, Heemann U, Steimer W, Zondler S, Fichtl B, Zilker T: Lithium poisoning: pharmacokinetics and clearance during different therapeutic measures. J.Clin.Psychopharmacol. 2006, 26:325-330. [42] Bailey B, McGuigan M: Comparison of patients hemodialyzed for lithium poisoning and those for whom dialysis was recommended by PCC but not done: what lesson can we learn? Clin.Nephrol. 2000, 54:388-392. [43] Garofeanu CG, Weir M, Rosas-Arellano MP, Henson G, Garg AX, Clark WF: Causes of reversible nephrogenic diabetes insipidus: a systematic review. Am.J.Kidney Dis. 2005, 45:626-637. [44] Bendz H, Aurell M: Drug-induced diabetes insipidus: incidence, prevention and management. Drug Saf. 1999, 21:449-456. [45] Stone KA: Lithium-induced nephrogenic diabetes insipidus. J.Am.Board Fam.Pract. 1999, 12:43-47. [46] Pradhan BK, Chakrabarti S, Irpati AS, Bhardwaj R: Distress due to lithium-induced polyuria: exploratory study. Psychiatry Clin.Neurosci. 2011, 65:386-388. [47] Movig KL, Baumgarten R, Leufkens HG, van Laarhoven JH, Egberts AC: Risk factors for the development of lithium-induced polyuria. Br.J.Psychiatry 2003, 182:319-323. [48] 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. [49] Bowen RC, Grof P, Grof E: Less frequent lithium administration and lower urine volume. Am.J.Psychiatry 1991, 148:189-192. [50] van Melick EJ, Meinders AE, Hoffman TO, Egberts TC: Renal effects of long-term lithium therapy in the elderly: a cross-sectional study. Int.J.Geriatr.Psychiatry 2008, 23:685-692. [51] Nielsen J, Kwon TH, Christensen BM, Frokiaer J, Nielsen S: Dysregulation of renal aquaporins and epithelial sodium channel in lithium-induced nephrogenic diabetes insipidus. Semin.Nephrol. 2008, 28:227-244. Lithium-Induced Nephropathies 539

[52] Agre P, Nielsen S: The aquaporin family of water channels in kidney. Nephrologie 1996, 17:409-415. [53] Pedersen RS, Bentzen H, Bech JN, Pedersen EB: Effect of an acute oral lithium intake on urinary Aquaporin-2 in healthy humans with and without simultaneous stimulation with hypertonic saline infusion. Scand.J.Clin.Lab. Invest. 2003, 63:181-194. [54] Walker RJ, Weggery S, Bedford JJ, McDonald FJ, Ellis G, Leader JP: Lithium-induced reduction in urinary concentrating ability and urinary aquaporin 2 (AQP2) excretion in healthy volunteers. Kidney Int. 2005, 67:291-294. [55] Blount MA, Sim JH, Zhou R, Martin CF, Lu W, Sands JM, Klein JD: Expression of transporters involved in urine concentration recovers differently after cessation of lithium treatment. Am.J.Physiol. Renal Physiol. 2010, 298:F601-F608. [56] Kwon TH, Laursen UH, Marples D, Maunsbach AB, Knepper MA, Frokiaer J, Nielsen S: Altered expression of renal AQPs and Na(+) transporters in rats with lithium-induced NDI. Am.J.Physiol. Renal Physiol. 2000, 279:F552-F564. [57] Klein JD, Gunn RB, Roberts BR, Sands JM: Down-regulation of urea transporters in the renal inner medulla of lithium-fed rats. Kidney Int. 2002, 61:995-1002. [58] Bedford JJ, Leader JP, Jing R, Walker LJ, Klein JD, Sands JM, Walker RJ: Amiloride restores renal medullary osmolytes in lithium-induced nephrogenic diabetes insipidus. Am.J.Physiol. Renal Physiol. 2008, 294:F812-F820. [59] Christensen BM, Zuber AM, Loffing J, Stehle JC, Deen PM, Rossier BC, Hummler E: alphaENaC-mediated lithium absorption promotes nephrogenic diabetes insipidus. J.Am.Soc.Nephrol. 2011, 22:253-261. [60] Nielsen S, Frokiaer J, Marples D, Kwon TH, Agre P, Knepper MA: Aquaporins in the kidney: from molecules to medicine. Physiol. Rev. 2002, 82:205-244. [61] Laursen UH, Pihakaski-Maunsbach K, Kwon TH, Ostergaard JE, Nielsen S, Maunsbach AB: Changes of rat kidney AQP2 and Na,K-ATPase mRNA expression in lithium-induced nephrogenic diabetes insipidus. Nephron. Exp.Nephrol. 2004, 97:e1- 16. [62] Kazama I, Arata T, Michimata M, Hatano R, Suzuki M, Miyama N, Sanada S, Sato A, Satomi S, Ejima Y, Sasaki S, Matsubara M: Lithium effectively complements vasopressin V2 receptor antagonist in the treatment of hyponatraemia of SIADH rats. Nephrol.Dial.Transplant. 2007, 22:68-76. [63] Kim GH, Choi NW, Jung JY, Song JH, Lee CH, Kang CM, Knepper MA: Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2. Am.J.Physiol. Renal Physiol. 2008, 294:F702-F709. [64] Rao R, Zhang MZ, Zhao M, Cai H, Harris RC, Breyer MD, Hao CM: Lithium treatment inhibits renal GSK-3 activity and promotes cyclooxygenase 2-dependent polyuria. Am.J.Physiol. Renal Physiol. 2005, 288:F642-F649. [65] Jia Z, Wang H, Yang T: Mice lacking mPGES-1 are resistant to lithium-induced polyuria. Am.J.Physiol. Renal Physiol. 2009, 297:F1689-F1696. [66] Zhang Y, Nelson RD, Carlson NG, Kamerath CD, Kohan DE, Kishore BK: Potential role of purinergic signaling in lithium-induced nephrogenic diabetes insipidus. Am.J.Physiol. Renal Physiol. 2009, 296:F1194-F1201. 540 Thomas J. Raedler

[67] Siegel AJ, Baldessarini RJ, Klepser MB, McDonald JC: Primary and drug-induced disorders of water homeostasis in psychiatric patients: principles of diagnosis and management. Harv.Rev.Psychiatry 1998, 6:190-200. [68] Bedford JJ, Weggery S, Ellis G, McDonald FJ, Joyce PR, Leader JP, Walker RJ: Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. Clin.J.Am.Soc.Nephrol. 2008, 3:1324-1331. [69] Batlle DC, von Riotte AB, Gaviria M, Grupp M: Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N.Engl.J.Med. 1985, 312:408-414. [70] Kortenoeven ML, Li Y, Shaw S, Gaeggeler HP, Rossier BC, Wetzels JF, Deen PM: Amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant nephrogenic diabetes insipidus. Kidney Int. 2009, 76:44-53. [71] Jakobsson B, Berg U: Effect of hydrochlorothiazide and indomethacin treatment on renal function in nephrogenic diabetes insipidus. Acta Paediatr. 1994, 83:522-525. [72] Phelan KM, Mosholder AD, Lu S: Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J.Clin.Psychiatry 2003, 64:1328-1334. [73] Vestergaard P, Amdisen A, Hansen HE, Schou M: Lithium treatment and kidney function. A survey of 237 patients in long-term treatment. Acta Psychiatr.Scand. 1979, 60:504-520. [74] Johnson GF, Hunt GE, Duggin GG, Horvath JS, Tiller DJ: Renal function and lithium treatment: initial and follow-up tests in manic-depressive patients. J.Affect.Disord. 1984, 6:249-263. [75] Waller DG, Edwards JG, Papasthatis-Papayanni S: A longitudinal assessment of renal function during treatment with lithium. Q.J.Med. 1988, 68:553-558. [76] Vaamonde CA, Milian NE, Magrinat GS, Perez GO, Oster JR: Longitudinal evaluation of glomerular filtration rate during long-term lithium therapy. Am.J.Kidney Dis. 1986, 7:213-216. [77] Walker RG: Lithium nephrotoxicity. Kidney Int.Suppl 1993, 42:S93-S98. [78] Jorkasky DK, Amsterdam JD, Oler J, Braden G, Alvis R, Geheb M, Cox M: Lithium- induced renal disease: a prospective study. Clin.Nephrol. 1988, 30:293-302. [79] Turan T, Esel E, Tokgoz B, Aslan S, Sofuoglu S, Utas C, Kelestimur F: Effects of short- and long-term lithium treatment on kidney functioning in patients with bipolar mood disorder. Prog.Neuropsychopharmacol.Biol.Psychiatry 2002, 26:561-565. [80] Bendz H, Aurell M, Balldin J, Mathe AA, Sjodin I: Kidney damage in long-term lithium patients: a cross-sectional study of patients with 15 years or more on lithium. Nephrol.Dial.Transplant. 1994, 9:1250-1254. [81] Bendz H, Aurell M, Lanke J: A historical cohort study of kidney damage in long-term lithium patients: continued surveillance needed. Eur.Psychiatry 2001, 16:199-206. [82] Lepkifker E, Sverdlik A, Iancu I, Ziv R, Segev S, Kotler M: Renal insufficiency in long-term lithium treatment. J.Clin.Psychiatry 2004, 65:850-856. [83] Tredget J, Kirov A, Kirov G: Effects of chronic lithium treatment on renal function. J.Affect.Disord. 2010, 126:436-440. [84] Bendz H, Schon S, Attman PO, Aurell M: Renal failure occurs in chronic lithium treatment but is uncommon. Kidney Int. 2010, 77:219-224. Lithium-Induced Nephropathies 541

[85] Bassilios N, Martel P, Godard V, Froissart M, Grunfeld JP, Stengel B: Monitoring of glomerular filtration rate in lithium-treated outpatients--an ambulatory laboratory database surveillance. Nephrol.Dial.Transplant. 2008, 23:562-565. [86] Khatami Z, Handley G, Narayanan K, Weaver JU: Applicability of estimated glomerular filtration rate in stratifying chronic kidney disease. Scand.J.Clin.Lab. Invest. 2007, 67:297-305. [87] Bendz H, Sjodin I, Aurell M: Renal function on and off lithium in patients treated with lithium for 15 years or more. A controlled, prospective lithium-withdrawal study. Nephrol.Dial.Transplant. 1996, 11:457-460. [88] Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB, Wolfe RA, Jones E, Disney AP, Briggs D, McCredie M, Boyle P: Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study. Am.J.Kidney Dis. 2000, 35:157-165. [89] Janowsky DS, Soares J, Hatch JP, Zunta-Soares G, Hu Q, Davis JM: Lithium effect on renal glomerular function in individuals with intellectual disability. J.Clin.Psychopharmacol. 2009, 29:296-299. [90] Paul R, Minay J, Cardwell C, Fogarty D, Kelly C: Meta-analysis of the effects of lithium usage on serum creatinine levels. J.Psychopharmacol. 2010, 24:1425-1431. [91] Jefferson JW: A clinician's guide to monitoring kidney function in lithium-treated patients. J.Clin.Psychiatry 2010, 71:1153-1157. [92] Glassock RJ: Estimated glomerular filtration rate: time for a performance review? Kidney Int. 2009, 75:1001-1003. [93] Morriss R, Benjamin B: Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease. Br.J.Psychiatry 2008, 193:93-95. [94] Kripalani M, Shawcross J, Reilly J, Main J: Lithium and chronic kidney disease. BMJ 2009, 339:b2452. [95] Collins N, Barnes TR, Shingleton-Smith A, Gerrett D, Paton C: Standards of lithium monitoring in mental health Ttrusts in the UK. BMC.Psychiatry 2010, 10:80. [96] Faedda GL, Tondo L, Baldessarini RJ, Suppes T, Tohen M: Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Arch.Gen.Psychiatry 1993, 50:448-455. [97] McIntyre RS, Nguyen HT, Soczynska JK, Lourenco MT, Woldeyohannes HO, Konarski JZ: Medical and substance-related comorbidity in bipolar disorder: translational research and treatment opportunities. Dialogues.Clin.Neurosci. 2008, 10:203-213. [98] Yildiz A, Vieta E, Leucht S, Baldessarini RJ: Efficacy of antimanic treatments: meta- analysis of randomized, controlled trials. Neuropsychopharmacology 2011, 36:375-389. [99] Yatham LN, Kennedy SH, Schaffer A, Parikh SV, Beaulieu S, O'Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Young AH, Alda M, Milev R, Vieta E, Calabrese JR, Berk M, Ha K, Kapczinski F: Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar.Disord. 2009, 11:225-255. [100] Baker RA, Pikalov A, Tran QV, Kremenets T, Arani RB, Doraiswamy PM: Atypical Antipsychotic Drugs and Diabetes Mellitus in the US Food and Drug Administration 542 Thomas J. Raedler

Adverse Event Database: A Systematic Bayesian Signal Detection Analysis. Psychopharmacol.Bull. 2009, 42:11-31. [101] Ozer JS, Dieterle F, Troth S, Perentes E, Cordier A, Verdes P, Staedtler F, Mahl A, Grenet O, Roth DR, Wahl D, Legay F, Holder D, Erdos Z, Vlasakova K, Jin H, Yu Y, Muniappa N, Forest T, Clouse HK, Reynolds S, Bailey WJ, Thudium DT, Topper MJ, Skopek TR, Sina JF, Glaab WE, Vonderscher J, Maurer G, Chibout SD, Sistare FD, Gerhold DL: A panel of urinary biomarkers to monitor reversibility of renal injury and a serum marker with improved potential to assess renal function. Nat.Biotechnol. 2010, 28:486-494. [102] Olsson CL, Rippe B, Bendz H: A comparison of plasma cystatin C and plasma creatinine for the screening of renal function in lithium-treated patients. Clin.Nephrol. 2010, 74:132-140. [103] Raedler TJ, Wittke S, Jahn H, Koessler A, Mischak H, Wiedemann K: Capillary electrophoresis mass spectrometry as a potential tool to detect lithium-induced nephropathy: Preliminary results. Prog.Neuropsychopharmacol.Biol.Psychiatry 2008, 32:673-678. [104] Farres MT, Ronco P, Saadoun D, Remy P, Vincent F, Khalil A, Le Blanche AF: Chronic lithium nephropathy: MR imaging for diagnosis. Radiology 2003, 229:570- 574. [105] Roque A, Heredia V, Ramalho M, de CR, Ferreira A, Azevedo R, Semelka R: MR findings of lithium-related kidney disease: preliminary observations in four patients. Abdom.Imaging. 2011. [106] Miller AL, Bowden CL, Plewes J: Lithium and impairment of renal concentrating ability. J.Affect.Disord. 1985, 9:115-119. [107] Ljubicic D, Letica-Crepulja M, Vitezic D, Bistrovic IL, Ljubicic R: Lithium treatments: single and multiple daily dosing. Can.J.Psychiatry 2008, 53:323-331. [108] Malhi GS, Tanious M: Optimal frequency of lithium administration in the treatment of bipolar disorder: clinical and dosing considerations. CNS Drugs 2011, 25:289-298. [109] Hetmar O, Povlsen UJ, Ladefoged J, Bolwig TG: Lithium: long-term effects on the kidney. A prospective follow-up study ten years after kidney biopsy. Br.J.Psychiatry 1991, 158:53-58. [110] Gitlin M: Lithium and the kidney: an updated review. Drug Saf. 1999, 20:231-243.