Lithium is currently a drug of choice for treating persons with bipolar depression and is widely used in this population. Approximately 0.1% of the US population is undergoing lithium treatment for psychiatric problems. Approximately 30% of patients taking lithium experience at least one episode of lithium toxicity.
Lithium toxicity can be acute, acute-on-chronic, or chronic.[1] The acute lithium nephrotoxicity picture is dominated by evidence of volume depletion, obtundation, and the potential for cardiovascular collapse. The chronic lithium nephrotoxicity picture is dominated by polyuria and evidence of chronic kidney disease. See Presentation.
Treatment of acute toxicity involves correction of electrolyte abnormalities, volume repletion followed by forced diuresis, and dialysis in severe cases. In patients with chronic toxicity, polyuria can be treated with medication and the chronic renal insufficiency can be treated with the measures routinely used for chronic kidney disease. See Treatment.
The medicinal use of lithium has a long and illustrious history. Galen recommended bathing in alkaline mineral waters, which might have contained lithium, for the treatment of mania as early as 200 AD.
In the mid-1800s, lithium was proposed as a treatment of uric acid calculi and gout, as uric acid crystals are highly soluble in solutions containing lithium carbonate. This therapy proved ineffective, but lithium was noted to be a highly effective treatment of psychiatric disorders in the late nineteenth century. Unfortunately, the toxicity of lithium severely limited its widespread acceptance at that point. Lithium was used as a substitute and added to the soft drink 7 Up in the early twentieth century; toxicity again leading to its withdrawal.
However, in 1949, the Australian psychiatrist John Cade reported on the successful use of lithium for mania. Since then, multiple studies have been performed demonstrating the efficacy of lithium in patients with mood disorders, such as depression, manic depression, and melancholia. Simultaneously, renal effects associated with lithium administration, including polyuria and nocturia, were increasingly reported.
In the 1950s and for several decades following, intensive studies on lithium nephrotoxicity were spurred by the wide acceptance of lithium administration in psychiatric practice as an effective treatment of and prophylaxis for unipolar and bipolar affective disorders.Those studies documented slowly progressive nephrotoxicity, rarely progressing to end-stage renal disease, in patients receiving long-term lithium.13033 For the past 2 decades, alternative psychiatric agents have been adopted for the treatment of these disorders, in large part because of the growing recognition of lithium nephrotoxicity.
Lithium is a univalent cation of the white metal series, closely related to both sodium and potassium, but having no known role in human physiology. Lithium is completely absorbed by the GI tract. The drug is not protein bound and is completely filtered at the glomerulus. The majority of the filtered load is reabsorbed by the proximal tubule, but significant amounts are also absorbed in the loop of Henle and the early distal nephron. Up to 90% of the filtered load is reabsorbed by the nephron, 60% in the proximal tubule, and the remainder in the thick ascending limb of the loop of Henle, the connecting tubule, and the cortical collecting duct. Lithium can substitute for sodium in several sodium channels, particularly the sodium-hydrogen exchanger in the proximal tubule (NHE3), the sodium/potassium/2chloride exchanger in the thick ascending limb of the loop of Henle (NKCC2), and the epithelial channel of the cortical collecting tubule (ENaC).
Lithium can affect renal function in several ways. Acutely and chronically, lithium salts produce a natriuresis that is associated with an impaired regulation of the expression of the epithelial sodium channel in the cortical collecting tubule.[2, 3] Specifically, lithium use partially inhibits the ability of aldosterone to increase apical membrane ENaC expression, resulting in inappropriate sodium losses.[4]
The most common complication of long-term lithium therapy is nephrogenic diabetes insipidus.[5, 6, 7] At the cellular level, antidiuretic hormone (ADH) is released from the posterior pituitary in response to increases in serum osmolarity or decreases in effective circulating volume, and this hormone acts on V2 receptors in the basolateral membrane of the principal cells in the cortical and medullary collecting tubules. The net result of the cascade involving a G protein (guanyl-nucleotide regulatory protein) and adenylate cyclase is an increase in the intracellular cyclic adenosine monophosphate (cAMP) level, which can play a dual role in antidiuresis regulation. cAMP acutely stimulates protein kinase A, which facilitates the insertion of aquaporin-2 (AQP2) water channels. These water channels are preformed and stored in cytoplasmic vesicles in the apical plasma membrane of the principal cells. This process leads to increased water permeability and, thus,antidiuresis.
Over extended periods of time, increased cAMP levels also increase the production of AQP2 water channels at the genetic level by promoting a 5' untranslated region of the AQP2 gene.[8] Lithium impairs the ADH stimulatory effect on adenylate cyclase, thereby decreasing cAMP levels.[9] Li and colleagues have also performed studies suggesting that the ability of lithium to produce nephrogenic diabetes insipidus may be independent of its effect on cAMP generation and related to decreased AQP2 mRNA levels.[10] Thus, lithium most likely impairs water permeability in the principal cells by inhibiting water channel delivery and, over a prolonged period of time, by suppressing channel production.[2, 11, 12]
A minority of reports, however, propose that lithium-induced partial central diabetes insipidus may play a role in the polyuria that may develop in patients who show a modest response to exogenous ADH. Other studies show that ADH levels in patients treated with lithium are normal or elevated.
Over 30 case reports of lithium-induced nephrogenic diabetes insipidus appear in the medical literature.[5] Patients with urine-concentrating defects resulting from lithium treatment usually take weeks to months to recover following discontinuation of the drug; in rare situations, the problem can persist for years. Early reports in psychiatric patients suggested that this persistent concentrating impairment may be linked to underlying renal histological damage and may be worse with neuroleptic use and prolonged lithium therapy. In a 1987 review, Boton and colleagues showed a 54% correlation between impaired urine-concentrating ability and the duration and total dosage of lithium treatment.[13]
Lithium may also be responsible for a distal tubular acidification defect. The defect is believed to be a variant of incomplete distal renal tubular acidosis, whereby the effect is exerted from the luminal side, requiring lithium cell entry. Patients taking lithium have normal phosphate and ammonia excretion. Lithium is not known to cause significant hyperkalemia.
The role of lithium in the production of acute renal failure is well accepted. The cause is generally due to severe dehydration and volume depletion due to the combination of natriuresis and water diuresis accompanied by elevated lithium levels, altered mental status, and subsequent poor oral intake. Acute renal failure has also been described as a result of lithium-induced neuroleptic malignant syndrome.[14] However, controversy still exists over its role in chronic renal failure. Boton and colleagues estimated (from an analysis of more than 1000 patients) that 85% of patients on long-term lithium therapy had normal glomerular filtration rates (GFRs); the remaining 15% had GFRs of more than 2 standard deviations below the age-corrected normal values, but very few patients had values less than 60 mL/min.[13]
Extensive reviews in 1988 and 1989 suggested that monitored long-term lithium treatment does not adversely affect the GFR, despite other reports of concurrent histological damage. Prospective studies of patients taking stable lithium also failed to show a decline in GFR in the absence of acute lithium intoxication. Although a minimal increase in the protein excretion rate has been reported in some patients who were taking lithium for at least 2 years, overt proteinuria is not a common complication. A rare association between minimal-change nephrotic syndrome and lithium administration has also been described.
Lithium does not appear to adversely affect proximal tubular function.
Lithium toxicity tends to occur in the context of suicide attempts or an intervening illness in an otherwise stable patient leading to poor intake, volume depletion, and subsequent increase in lithium levels. Alternatively, if the patient does not have elevated lithium level, then the practitioner should look for other causes of diabetes insipidus.
For central diabetes insipidus, other etologic possibilities are as follows:
For nephrogenic diabetes insipidus, etiologic possibilities include other renal causes, systemic disorders, drugs, dietary factors, and pregnancy.
Other renal causes include the following:
Systemic disorders include the following:
Drugs include the following:
Dietary factors include polydipsia, a low-protein diet, or a low-sodium diet.
Lithium is currently a drug of choice for treating persons with bipolar depression and is widely used in this population. Approximately 0.1% of the US population is undergoing lithium treatment for psychiatric problems. Approximately 20-54% of these patients have symptoms of urine-concentrating defects during and after lithium use. Up to 12% develop frank diabetes insipidus, and some continue to have this problem for years after discontinuing lithium. One case report describes patients who still had diabetes insipidus 8 years later. In another report of a small subset of patients, up to 63% had persistent defects 1 year after stopping lithium.[6, 15]
Of note, approximately 30% of patients taking lithium experience at least one episode of lithium toxicity, correlating with a decrease in glomerular filtration rate. Researchers continue to debate the incidence and pathophysiology of long-term lithium nephropathy.
Because of the frequent use and high incidence of associated urine-concentrating defects, lithium has been cited as the most common cause of nephrogenic diabetes insipidus. This complication is a major source of electrolyte disturbances and associated morbidity. The very narrow therapeutic window for this drug contributes substantially to the frequency of acute and chronic toxicity.
The available literature does not suggest a racial predominance in lithium nephrotoxicity. A United Kingdom study of patients taking lithium reported greater risk of development of renal disorders in women than in men, with women younger than 60 years at higher risk than older women. The adverse effects occurred early in treatment. Patients with lithium concentrations higher than median were also at greater risk.[16]
In an Italian study, cross-sectional evaluation showed that estimated glomerular filtration rate (eGFR) was lower in women (by 3.47 mL/min/1.73 m²), in older patients (0.73 mL/min/1.73 m² per year of age), and in patients with longer duration of lithium treatment (0.73 mL/min/1.73 m² per year). These authors found that renal dysfunction tends to appear after decades of lithium treatment and to progress slowly and irrespective of whether lithium is continued at previous doses, continued at reduced doses, or discontinued.[17]
A population-based cohort study that assessed the effect of lithium maintenance therapy on eFGR in patients with affective disorders found no significant difference in the decline in eGFR in 305 patients taking lithium compared with 815 patients taking other first-line drugs (quetiapine, olanzapine, and semisodium valproate). The researchers concluded that their results contradict the idea that long-term lithium therapy is associated with nephrotoxicity in the absence of episodes of acute intoxication.[18]
In a randomized, double-blind, placebo-controlled study in older adults who were receiving low doses of lithium for treatment of mild cognitive impairment (serum lithium range of 0.25 to 0.5 mEq/L), 4 years of treatment did not have any adverse effects on renal function. However, lithium treatment was associated with significant increases in the number of neutrophils, serum thyroid-stimulating hormone level, body weight, and more adverse events overall than placebo, and patients treated with lithium had higher rates of diabetes mellitus and arrhythmia.[19]
In a nested case-control study of Canadian mental health service users aged 66 years and older, lithium use ws independently associated with an almost 2-fold increase in risk of chronic kidney disease (CKD). The adjusted odds ratio (OR) in lithium users (n=529) was 1.76 (95% confidence index [CI], 1.41-2.1), In comparison, valproate users (n=498) were not at increased risk (adjusted OR = 1.03; 95% CI, 0.81-1.29).[20]
Generally, lithium nephrotoxicity will occur within a month of onset of use of the drug, manifested predominantly by polyuria and polydipsia. The onset of these symptoms may also occur in the presence of accelerating dose regimens. Initially, these symptoms are reversible but may become permanent with long-term use and/or chronically high serum lithium levels. When acute renal failure occurs in the setting of lithium toxicity, the patients generally will exhibit other signs of lithium toxicity, such as obtundation.
Polyuria, defined as a 24-hour urine output of greater than 3 L, is the most common complication in an otherwise asymptomatic patient who has a plasma lithium level consistent with therapeutic dosing.[21] Patients may develop polydipsia. In one case report of persistent lithium-induced nephrogenic diabetes insipidus, the patient drank 20-40 glasses of water per day.
Nocturia can be a useful marker of polyuria. Up to 68% of patients report at least 1 urination episode per night.
Patients with lithium nephrotoxicity may exhibit signs of modest volume depletion, including orthostatic hypotension, tachycardia, and dry mouth. With severe dehydration, patients will show evidence of hypernatremia, including altered mental status.
A chemistry panel may help identify electrolyte abnormalities that may be causing the patient's concentrating defect and natriuresis (ie, hypernatremia, hypokalemia, hypercalcemia, elevated BUN and creatinine). Uncontrolled diabetes mellitus may cause similar findings from osmotic diuresis; however, in that disorder, the serum glucose level will be elevated.
Urine and serum osmolality may help determine if the patient has a concentrating defect. Urine osmolality will be less than 100 mOsm/kg despite normal or higher-than-normal serum osmolality.
The prevalence of decreased urine osmolality was similar in adult and geriatric lithium users in a cross-sectional study of 100 patients (12.5% in geriatric patients and 17.9% in adult patients), but affected geriatric patients were significantly less likely to report urinary and thirst symptoms. Urine specific gravity less than 1.010 was correlated with urine osmolality of less than 300 mOsm/kg. Age, duration of lithium treatment, and serum lithium level were each independently associated with urine osmolality level.[22]
High urine output accompanied by elevated blood urea nitrogen (BUN) and serum creatinine levels[23] can be due to volume depletion with any polyuric syndrome, such as nephrogenic diabetes insipidus, central diabetes insipidus, or osmotic diuresis; the polyuric phase of acute renal failure; or chronic renal failure.
Assess the patient's lithium level: Check the plasma vasopressin level to rule out central diabetes insipidus.
Perform full toxicology screen to exclude the possibility of multiple toxin ingestion, particularly in the case of suicide attempts.
A magnetic resonance imaging (MRI) study of the sella can be ordered for patients who have abnormal hormonal findings (ie, elevated prolactin level) and if multiple endocrine disorders or masses that may be causing central diabetes insipidus are suggested.
MRI examination of the kidneys, while not necessary for diagnosis, has demonstrated the presence of renal cysts in many patients. These are described as microcysts and can be quite numerous.[24, 25]
Renal ultrasound can be used to assess for suggested obstructive causes.
Other tests that can be used in the diagnosis of lithium toxicity include the following:
This test documents whether the patient has a concentrating defect. First, baseline measurements of urine and serum osmolality and electrolytes are obtained. Strict water deprivation is then imposed for 4-18 hours (usually 8 h).
Urine output and weight are carefully monitored before and after fluid deprivation. Serum and urine osmolality and electrolyte levels are measured hourly after initiation of fluid deprivation. A patient without a concentrating defect should have a 2- to 4-fold increase in urine osmolality.
This test differentiates central and nephrogenic diabetes insipidus. Following the water deprivation test, 5 U of vasopressin is administered subcutaneously (ie, vasopressin as 5 U of aqueous arginine vasopressin or 1 mcg of desmopressin SC or 10 mcg of desmopressin by nasal spray). Serum and urine osmolality are measured 1-2 hours later.
Patients with complete central diabetes insipidus fail to increase their urine osmolality after water deprivation (ie, concentrating defect), but they have more than a 50% increase in urine osmolality from baseline after vasopressin administration. Patients with nephrogenic diabetes insipidus also fail to show an increase in urine osmolality after deprivation (ie, concentrating defect) but have less than a 10% increase in urine osmolality from baseline after vasopressin administration. Reports have described patients with combined central and nephrogenic defects who show a 10-50% increase in urine osmolality.
In reports of small groups of patients, lithium use has been associated with many nonspecific renal lesions.
The histology of acute renal lesions associated with lithium intoxication tends to involve the distal nephron and includes acute tubular necrosis with nonspecific changes such as distal tubular flattening, proximal tubular necrosis, and cytoplasmic vacuolation and cellular and nuclear polymorphism of the distal tubular epithelial cells. In 1978, Kincaid-Smith described a more specific acute lesion consisting of glycogen deposition in the swollen and vacuolated cytoplasm of the distal tubular epithelial cells. These lesions can reverse when lithium administration is stopped.
The development of chronic renal lesions with prolonged lithium use is controversial. Earlier studies have cited interstitial fibrosis, tubular atrophy, and glomerulosclerosis among the chronic changes attributed to lithium. Furthermore, studies suggested that these lesions correlated clinically with the duration of lithium use and concomitant neuroleptic treatments. The data, however, had several limiting factors. The biopsy samples were obtained from a subgroup that had a history of acute lithium toxicity, and many of the histological changes were also identified in the control group. Other more specific chronic lesions include distal tubular dilation and microcyst formation. No evidence indicates that chronic glomerular lesions persist after discontinuing lithium.
Animal studies that used toxic doses of lithium demonstrated epithelial degeneration and dilatation of the distal part of the nephron in dogs, and rats had degenerative changes in the proximal tubules. Rats exposed to levels corresponding to the therapeutic range in humans had ultrastructural lesions, including mitochondrial changes with bulging cytoplasm in tubular cells, liquefaction, karyolysis, and karyorrhexis of the distal tubule and collecting duct.
The treatment of lithium nephrotoxicity depends on the severity of the toxicity and chronicity as well as the presence of related abnormalities.[27]
The acute lithium nephrotoxicity picture is dominated by evidence of volume depletion, obtundation, and the potential for cardiovascular collapse. These patients will frequently require close monitoring and aggressive fluid replacement even dialysis; therefore, the intensive care unit is the most appropriate site for these patients.
Correcting electrolyte abnormalities in patients with acute disease is critical. Treatment should be initiated with parenteral fluids to replete hypovolemia (normal saline at 200-250 mL/h), followed by administration of hypotonic fluid (0.5% normal saline). Once volume status is restored, then a forced diuresis should be initiated by the administration of parenteral furosemide or bumetanide accompanied by continued intravenous hypotonic fluid administration to maintain volume status.
For patients with lesser degrees of lithium toxicity, this therapy will be adequate to treat the condition. For patients with greater degrees of lithium toxicity, generally with lithium levels of greater than 4 mEq/L, dialysis is indicated. Dialysis may also be considered in patients with levels in the mid 2s but who are exhibiting evidence of instability.
The chronic lithium nephrotoxicity picture is dominated by polyuria and evidence of chronic kidney disease.
Polyuria can be treated with medications, such as thiazide diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs; see Medication). Reports suggest that the potassium-sparing diuretic amiloride may be particularly beneficial for the treatment of the polyuria associated with lithium use.[28, 29] The mechanism for this effect is thought to be the ability of amiloride to block lithium uptake into the principal cells of the cortical collecting tubule through epithelial channels (ENaC), allowing the principal cells to regain responsiveness to antidiuretic hormone.
In an animal model of lithium-induced nephrogenic diabetes insipidus, acetazolamide reduced polyuria as effectively as hydrochlorothiazide plus amiloride. One case report describes successful use of acetazolamide in a patient with lithium-induced nephrogenic diabetes insipidus that had failed to respond to treatment with hydrochlorothiazide and desmopressin.[30]
In contrast, a study by de Groot et al in six patients with a lithium-induced urinary concentrating defect found evidence against the use of acetazolamide treatment. Two patients withdrew from the study because of adverse effects, and the remaining four showed no change in urine output or clinically relevant changes in maximal urine osmolality. Three of the four patients experienced an increase in serum creatinine levels, indicating a decreased GFR. The authors postulate that the reduction in polyuria in animal studies is the result of the decrease in GFR.[31]
The chronic renal insufficiency can be treated using therapy that would routinely be used for any cause of chronic renal disease. Evidence of chronic renal disease is an indication for discontinuation of the drug being administered and for consideration of alternative medications for treatment of the patient's psychiatric disorder.
See the list below:
Diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of stable lithium-induced nephrogenic diabetes insipidus.[32]
Clinical Context: Prevents uptake of lithium by epithelial cells. Has less potential for lithium toxicity because has a weak natriuretic effect and is less likely to increase lithium level by causing volume contraction. Has the advantage of being potassium-sparing; hypokalemia itself may potentiate a defect in concentrating ability. Also induces less extracellular fluid contraction than thiazides.
Clinical Context: Thiazides may require potassium supplementation; more often associated with lithium toxicity. Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions. Equivalent dosages of other thiazide preparations may be used. Use same dose range effective for treating hypertension.
Decrease extracellular fluid and promote proximal tubular resorption that is not ADH dependent. Ultimately, less free water is transmitted to distal collecting tubules, which is where the urine-concentrating defect is located; therefore, the polyuria decreases. However, extracellular fluid depletion can also increase the risk of lithium intoxication by enhancing lithium reabsorption at the proximal tubule. Diuretics have a gradual onset of action and are less useful in an acute setting.
Clinical Context: Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis. One case report exists of IV ketorolac used in acutely ill patient failing to respond to indomethacin.
Have an antiprostaglandin effect in rats. Inhibiting prostaglandin increases cAMP in the collecting tubules, which promotes water resorption (see Pathophysiology). NSAIDs also inhibit the production of prostaglandin that regulates glomerular blood flow and therefore decreases the GFR and urine flow to the distal tubules. Physicians do not recommend long-term NSAID therapy.
Some reports recommend testing the patient's renal-concentrating ability, 24-hour urinary volume, and creatinine clearance before initiating lithium therapy and at 1-year intervals.
Schou recommends regular measurements of serum lithium and creatinine every 2-6 months and obtaining serum thyroid-stimulating hormone determinations once a year.
Patients with severe cases of volume depletion with associated electrolyte abnormalities (ie, hypernatremia) may require ICU care.
Once aggressive diuresis is initiated or dialysis is performed for acute toxicity, lithium levels should be sequentially checked to ensure that rebound toxic levels and/or delayed gastrointestinal absorption leading to recurrent toxicity do not occur.
Lithium has a low therapeutic index; monitor levels closely to prevent acute lithium intoxication.
Some reports have linked acute renal failure to lithium intoxication. In these cases, however, researchers did not exclude decreased perfusion and other causes of volume depletion as possible contributing factors. Nevertheless, physicians must remember that lithium intoxication can cause volume depletion and vice versa.
Patients with urine-concentrating defects from lithium treatment usually take weeks to months to recover following discontinuation of lithium. In rare situations, the problem can persist for years.
Acute renal failure associated with lithium toxicity has an excellent prognosis.
Chronic renal failure associated with lithium use only uncommonly will completely resolve but generally will not progress if the medication is discontinued and other nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs or hypertension, are minimized.