Renal toxicity of lithium

INTRODUCTION — Chronic lithium ingestion in patients with bipolar (manic depressive) illness has been associated with several different forms of kidney injury [1]. Arginine vasopressin resistance (AVP-R, previously called nephrogenic diabetes insipidus) is the most common kidney side effect of lithium therapy [2,3].

The predominant form of chronic kidney disease associated with lithium therapy is a chronic tubulointerstitial nephropathy [4]. Although the majority of studies show infrequent and relatively mild kidney function impairment attributable to lithium therapy, end-stage kidney disease (ESKD) secondary to lithium-associated chronic tubulointerstitial nephropathy does occur in a small percentage of patients [3,5-8]. Relatively less is known about potential glomerular toxicity of lithium, particularly the nephrotic syndrome. Additional kidney manifestations of lithium exposure include renal tubular acidosis and hypercalcemia. (See "Lithium poisoning".)

ARGININE VASOPRESSIN RESISTANCE (NEPHROGENIC DIABETES INSIPIDUS) — Normally, water permeability of principal cells in the collecting tubule is regulated by antidiuretic hormone (ADH). Aquaporin-2 water channels (AQP2), which normally reside in the endosomes of principal cells, move to and fuse with the luminal membrane under the influence of ADH, thereby allowing water to be reabsorbed down the favorable concentration gradient. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Regulation of plasma tonicity'.)

Chronic lithium ingestion can lead to resistance to ADH, resulting in polyuria and polydipsia in up to 20 to 40 percent of patients [4,9]. Lithium enters the principal cells of the collecting duct through epithelial sodium channels in the luminal membrane [9,10]. It then accumulates in these cells and interferes with the ability of ADH to increase water permeability. Several possible mechanisms may be involved [2,9,11-14].

Lithium may increase expression of cyclooxygenase-2 and therefore increase urinary prostaglandin E2 excretion by medullary interstitial cells [13]. These prostaglandins then act on principal cells to induce lysosomal degradation of AQP2 water channels and a decline in urine concentrating ability:

●Lithium may reduce AQP2 gene transcription, an effect that is prostaglandin independent, leading to a further decrease in concentrating ability [13].

●Lithium induces collecting duct remodeling characterized by a decreased population of principal cells relative to the number of intercalated cells, a phenomenon that was previously presumed to be due to apoptosis [11,12]. However, lithium may actually lead to proliferation of principal cells, which then undergo cell cycle arrest [15]. This may also be responsible for the development of interstitial nephritis and renal fibrosis.

With chronic use in humans, arginine vasopressin resistance (AVP-R, previously called nephrogenic diabetes insipidus) often becomes irreversible. In one study, patients who had been on the drug for more than 18 years invariably had an irreversible defect [12].

Acute onset of nocturia is an important clue to the presence of AVP-R. The urine is normally most concentrated in the morning due to lack of fluid ingestion overnight; as a result, the first manifestation of a loss of concentrating ability is often nocturia.

It should not be assumed that polyuria in a patient taking lithium is due to AVP-R. Both arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) and primary polydipsia have also been described in patients treated with lithium; they may be induced by lithium or reflect underlying psychiatric disease, particularly the use of psychotropic medications, which induce a dry mouth, thereby stimulating thirst and producing a picture of primary polydipsia [4,16,17].

Thus, a water restriction test may be helpful in establishing the correct diagnosis since the treatment of these disorders is different. (See "Evaluation of patients with polyuria" and "Causes of hypotonic hyponatremia in adults", section on 'Primary polydipsia due to psychosis'.)

Treatment — Although usually at least partially reversible [18], the lithium-induced concentrating defect may be permanent after prolonged therapy [4,19]. When lithium-induced AVP-R is diagnosed, discontinuation of the drug may be appropriate. However, in many cases, the benefits of lithium on mood stabilization and suicide prevention outweigh the risks [20,21]. For those patients who continue lithium therapy, we recommend the concomitant use of the potassium-sparing diuretic, amiloride.

Amiloride inhibits the epithelial sodium channels in collecting tubule cells (figure 1) and therefore should minimize further accumulation of lithium (if lithium therapy is continued). The following data support the use of amiloride in patients with AVP-R who continue to use lithium:

●Amiloride was given to nine patients who continued to take lithium despite the development of AVP-R [10]. After three to four weeks of therapy, mean urine volume fell significantly (from 4.7 to 3.1 liters per day), and urine osmolality increased significantly (from 228 to 331 mosm/kg). This effect persisted for at least six months.

●In a placebo-controlled crossover study, 11 patients with lithium-induced AVP-R were treated with 10 mg/day of amiloride or placebo in random order for six weeks [22]. Amiloride therapy significantly increased the responsiveness of the urine osmolality to exogenous arginine vasopressin (165 percent increase in urine osmolality); no change in responsiveness to arginine vasopressin was seen with placebo.

However, amiloride is likely to be effective only when there is a mild to moderate concentrating defect that is potentially reversible. The experience with amiloride has been disappointing in patients with severe disease (maximum urine osmolality below 200 mosmol/kg). In these patients, the tubular damage is often permanent, even if lithium is discontinued [4,19]; as a result, diminishing lithium entry into the collecting tubular cells cannot improve concentrating ability.

If amiloride therapy is given, serum lithium concentrations must be carefully monitored since diuretic-induced volume depletion may increase proximal sodium and lithium reabsorption. The ensuing fall in lithium excretion may then require a reduction in drug dose.

Other therapeutic options to manage polyuria in lithium-induced AVP-R are similar to those in other causes of AVP-R: a thiazide diuretic (to diminish distal water delivery or upregulate aquaporin receptors [23]) and a nonsteroidal antiinflammatory drug (NSAID; to decrease the synthesis of prostaglandins) [16]. (See "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment".)

Another well-accepted regimen is the use of the combination of low-sodium diet and thiazide diuretics. Thiazides decrease urine volume and increase urine osmolality by producing a state of mild sodium depletion; this reduces distal tubule delivery of sodium and increases fractional water reabsorption in the collecting duct. As with the use of amiloride, serum lithium concentrations must be closely monitored after initiation of therapy with a thiazide diuretic. (See "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment".)

Since most patients have only partial resistance to ADH, it is also possible that attaining supraphysiologic levels of ADH (by administering desmopressin [1-deamino,8-D arginine-vasopressin; dDAVP]) will attenuate the polyuria. The likelihood of success may be increased by combining desmopressin with an NSAID [24]. NSAID therapy alone also may be effective in selected patients [25]. (See "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment".)

The risk of hypernatremia and its complications is also considerable in these patients. This is particularly true in settings in which fluid intake is curtailed, during an acute illness, or when inadequate fluid resuscitation is given in those undergoing surgery.

RENAL TUBULAR ACIDOSIS — The tubular defect in the distal nephron can also impair the ability to maximally acidify the urine. This is most often manifested as the incomplete form of type 1 (distal) renal tubular acidosis, in which the urine pH is persistently above 5.3 but the extracellular pH and bicarbonate concentration are within the normal range [4]. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis" and "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

NEPHROTIC SYNDROME — Lithium has infrequently been associated with the nephrotic syndrome. Most cases are due to minimal change disease [26,27], but focal segmental glomerulosclerosis (FSGS) has also been described (picture 1 and picture 2) [6,28].

The mechanism by which lithium leads to glomerular injury is not completely understood, but the course is highly suggestive of an etiologic role for lithium (ie, epithelial toxicity). Proteinuria generally begins within 1.5 to 10 months after the onset of therapy and, in minimal change disease, completely or partially resolves in most patients one to four weeks after lithium is discontinued [26]. In several patients, reinstitution of lithium led to recurrent nephrosis [26,27]. Corticosteroids have occasionally been required to induce remission; it is possible that the minimal change disease in such cases was unrelated to lithium [26].

The relationship to FSGS is less clear. In three patients, for example, cessation of lithium did not lead to resolution of the disease [28], suggesting either no relation to lithium or possible secondary FSGS due to tubular injury induced by chronic lithium therapy. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Drugs and toxins'.)

Edema during the manic phase — Occasionally, lithium-treated patients become edematous in the absence of overt kidney, hepatic, or cardiac disease [29-31]. How this occurs is not well understood, but two factors may contribute: a marked increase in sodium intake that may be induced in part by mania and perhaps a lithium-induced reduction in maximum sodium excretory capacity that is of no importance when sodium intake is relatively normal. Affected patients present with the unusual combination of edema plus high rates of urinary sodium excretion that can exceed 200 mEq/day [30,31]. Serum lithium concentrations may also fall below the therapeutic range at this time due to enhanced urinary lithium excretion. Volume expansion appropriately decreases the proximal reabsorption of sodium; lithium reabsorption also falls since it is reabsorbed via the same transporters as sodium [4].

CHRONIC INTERSTITIAL NEPHRITIS AND KIDNEY FUNCTION IMPAIRMENT — Long-term lithium use is associated with chronic kidney disease that occasionally progresses to end-stage kidney disease (ESKD) [6-8,32-39]. As an example, in a large, retrospective, case-control study of Swedish adults, 1.8 percent of patients receiving kidney replacement therapy (KRT) for ESKD had a history of lithium exposure compared with 0.2 percent of patients without ESKD (odds ratio 7.8, 95% CI 5.4-11.1) [40].

Major risk factors for nephrotoxicity appear to be the duration of lithium exposure and the cumulative dose [7,32,41]. Other risk factors include episodes of acute intoxication, increased age [35,41], other comorbid illnesses (eg, hypertension, diabetes mellitus, hyperparathyroidism, and hyperuricemia), and concomitant use of other antipsychotic medications. The degree of kidney function impairment is variable [16,35,36,41,42].

Chronic interstitial nephritis usually presents as the insidious development of kidney function impairment, with normal to only a mild degree of proteinuria, often in the setting of arginine vasopressin resistance (AVP-R). The degree of interstitial fibrosis on kidney biopsy may be directly related to the duration and cumulative dose of lithium [7,41]. Additional histologic lesions may be suggestive of chronic interstitial nephritis due to lithium:

●In experimental animals fed with lithium, there is a predominance of tubular lesions (ie, dilatation of tubules in the distal segments and collecting ducts); glomerulosclerosis tends to be a late event [43].

●In humans, the presence of tubular cysts, which have been demonstrated to be of distal and collecting tubular origin, probably correspond to these tubular lesions [6,44].

Such microcysts have also been demonstrated on magnetic resonance imaging and ultrasonographic studies [45,46].

It has been suggested that 15 to 25 percent of patients develop a slowly progressive decline in glomerular filtration rate, which usually does not fall below 40 to 60 mL/min [4,7,16,32]. Progressive kidney failure with a serum creatinine concentration above 2 mg/dL (176 micromol/L) due solely to lithium is uncommon [42] but can occur if lithium is continued after otherwise unexplained kidney function impairment has developed [35,36]. In a review of 74 patients with lithium-induced kidney function impairment from France, the mean loss of creatinine clearance was 2.3 mL/min per year, and, by age 65 years, 12 reached ESKD [7]. The average latent period between the onset of lithium therapy and ESKD was 20 years.

The course of the kidney disease after discontinuation of lithium is unpredictable. There may be some recovery of kidney function, particularly with correction of hypovolemia. Progressive kidney failure can occur among patients with significant kidney function impairment as is shown in the following studies:

●In one study, seven out of nine patients with lithium nephrotoxicity and a serum creatinine concentration of >2.5 mg/dL (221 micromol/L) progressed to ESKD even after stopping lithium [6]. Among 10 patients who had an initial serum creatinine less than 2.5 mg/dL (221 micromol/L), only one developed ESKD.

●Another study identified 18 patients with ESKD among 3369 lithium-treated patients in two regions of Sweden, a sixfold higher prevalence of disease than in the general population [8]. Of these, 13 had discontinued lithium for at least two years prior to starting dialysis. Eleven patients had serum creatinine concentrations greater than 1.4 mg/dL (125 micromol/L) at the time that lithium was discontinued; two patients had initial serum creatinine concentrations less than 1.1 mg/dL (100 micromol/L). However, both patients had even lower creatinine concentrations (less than 0.7 mg/dL [65 micromol/L]) when lithium was started, suggesting that a decline in kidney function had occurred with lithium.

Progressive kidney function impairment after cessation of lithium may be due to secondary factors, such as systemic and intraglomerular hypertension, possibly resulting in secondary glomerulosclerosis [6]. (See "Secondary factors and progression of chronic kidney disease".)

HYPERPARATHYROIDISM AND HYPERCALCEMIA — Another complication of long-term therapy with lithium carbonate is hyperparathyroidism, with associated hypercalcemia and hypocalciuria [47].

There are several mechanisms by which lithium may increase serum calcium levels:

●Increasing the threshold for the calcium-sensing mechanism within the parathyroid gland [48]. Thus, parathyroid hormone (PTH) secretion continues despite the presence of hypercalcemia.

●Inducing PTH overproduction via inhibiting the action of glycogen synthase kinase 3b (GSK-3b).

●Inhibiting calcium transport (influx) across cell membranes.

As hypercalcemia develops, it is further confounded by kidney failure and its progression, which leads to decreased urinary calcium excretion (hypocalciuria). Other findings associated with lithium-induced hypercalcemia/hyperparathyroidism include a normal serum phosphorus level and an elevated serum magnesium level.

There is a higher proportion of patients (33 percent) who develop parathyroid hyperplasia in those with lithium-induced hyperparathyroidism compared with the proportion of hyperparathyroidism affecting the general population [47]. This is probably the reason why acute withdrawal of lithium does not necessarily translate into any significant change in serum calcium levels [49]. Because simple discontinuation of lithium carbonate therapy does not always lead to normalization of serum-intact PTH and calcium levels, surgical parathyroidectomy has been a common option in those patients.

Case reports have been published in which the use of cinacalcet [47], a calcimimetic, decreased or normalized the serum calcium, with some reduction of serum-intact PTH levels, similar to its effect in patients with primary hyperparathyroidism [50,51], thereby averting the need for surgical treatment. It is believed that cinacalcet can neutralize the effects of lithium on the calcium-sensing receptor of the parathyroid gland. However, the mechanisms that underlie this effect remain undefined.

POSSIBLE INTERACTION WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITORS — Some evidence suggests that there may be an adverse interaction between lithium and angiotensin-converting enzyme (ACE) inhibitors, leading to renal insufficiency that may be associated with lithium accumulation toxicity [52,53]. Although it is unclear whether this interaction is real, the serum creatinine concentration and lithium levels must be closely monitored if a patient on lithium is begun on an ACE inhibitor.

EXPERIMENTAL INVESTIGATIONS OF ALTERNATIVE TREATMENT OPTIONS — Caffeic acid phenethyl ester (CAPE), a known component of honeybee propolis, was protective against oxidative stress induced by reactive oxygen species (ROS), commonly observed in ischemia-reperfusion and toxic injuries. Used in experimental rat models, CAPE was shown to be protective against lithium-induced tubular damage and oxidative stress [54].

N-acetylcysteine (NAC) has been demonstrated to be renoprotective and effective in preventing hypoperfusion and radiocontrast-induced nephropathy. Experimental Sprague-Dawley rats given NAC with lithium had significantly lower percentages of tubular necrosis and tubular lumen obstruction [55].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Chronic lithium ingestion in patients with bipolar (manic depressive) illness has been associated with a variety of kidney diseases, particularly arginine vasopressin resistance (AVP-R, previously called nephrogenic diabetes insipidus) and, less frequently, chronic tubulointerstitial nephropathy. (See 'Introduction' above.)

●Approximately 20 to 40 percent of patients who chronically take lithium develop polyuria and polydipsia. In such patients, a water restriction test should be performed to establish the presence of AVP-R since patients with bipolar illness may also develop arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) and primary polydipsia. AVP-R appears to result from lithium accumulation in collecting tubule cells, which interferes with the ability of antidiuretic hormone (ADH) to increase water permeability. (See 'Arginine vasopressin resistance (nephrogenic diabetes insipidus)' above.)

●In patients who develop AVP-R, lithium therapy should be discontinued, if possible. However, for those patients in whom lithium therapy is absolutely necessary despite its kidney effects, concomitant amiloride therapy to minimize lithium accumulation in collecting tubule cells is recommended. Amiloride is likely to be effective only when there is a mild to moderate concentrating defect that is potentially reversible. (See 'Treatment' above.)

●Therapy of the polyuria in lithium-induced disease is similar to that in other causes of AVP-R: a thiazide diuretic (to diminish distal water delivery or upregulate aquaporin receptors), a nonsteroidal antiinflammatory drug (NSAID; to decrease the synthesis of prostaglandins) provided kidney function is preserved, and a low-sodium diet. (See 'Treatment' above.)

●Since most patients have only partial resistance to ADH, it is also possible that attaining supraphysiologic levels of ADH (by administering desmopressin [1-deamino,8-D arginine-vasopressin; dDAVP]) will attenuate the polyuria. (See 'Treatment' above.)

●Long-term lithium use is associated with the insidious onset of chronic kidney disease due to chronic interstitial nephritis in up to 15 to 20 percent of patients. Major risk factors for nephrotoxicity appear to be the duration of lithium exposure, the cumulative dose, and advanced age. The degree of kidney function impairment is generally relatively mild but may occasionally progress to end-stage kidney disease (ESKD). (See 'Chronic interstitial nephritis and kidney function impairment' above.)

●The course of the kidney disease after discontinuation of lithium is unpredictable. There may be some recovery of kidney function, particularly with correction of hypovolemia. However, progression of chronic kidney disease can occur. (See 'Chronic interstitial nephritis and kidney function impairment' above.)

●Long-term therapy with lithium may lead to hyperparathyroidism, hypercalcemia, and hypocalciuria. Discontinuation of lithium therapy does not always lead to normalization of parathyroid hormone (PTH) and calcium levels; thus, surgical parathyroidectomy is a common option in such patients. Cinacalcet, a calcimimetic, may also reduce PTH levels and a return the serum calcium to normal, thereby averting the need for surgical treatment. (See 'Hyperparathyroidism and hypercalcemia' above.)

●Less commonly, lithium therapy can be associated with distal renal tubular acidosis, minimal change disease, focal segmental glomerulosclerosis (FSGS), and edema during episodes of mania. (See 'Renal tubular acidosis' above and 'Nephrotic syndrome' above and 'Edema during the manic phase' above.)