What is the risk of lithium-induced nephrotoxicity (kidney injury)?

From the Guidelines

Lithium can cause kidney injury, particularly with long-term use, and patients taking lithium should have regular kidney function monitoring, including serum creatinine, estimated glomerular filtration rate (eGFR), and urinalysis every 3-6 months. The most common kidney problems associated with lithium include nephrogenic diabetes insipidus (causing excessive urination and thirst), chronic tubulointerstitial nephropathy, and in severe cases, chronic kidney disease 1. Risk factors include higher lithium doses, longer duration of treatment, episodes of lithium toxicity, and pre-existing kidney disease. To minimize kidney damage, lithium levels should be maintained at the lowest effective dose (typically keeping serum levels between 0.6-0.8 mmol/L for maintenance therapy), avoiding dehydration, and using once-daily dosing with extended-release formulations when possible.

Key Recommendations

• Regular monitoring of GFR, electrolytes, and drug levels is recommended for patients taking lithium 1
• Maintaining hydration during intercurrent illness and avoiding concomitant NSAIDs can help minimize kidney damage 1
• If kidney function deteriorates significantly (persistent eGFR decline below 60 ml/min or proteinuria), consultation with both psychiatry and nephrology is recommended to consider alternative mood stabilizers such as valproate or lamotrigine.

Important Considerations

• Lithium shouldn't be abruptly discontinued due to risk of psychiatric relapse, and any medication changes should be gradual and supervised by healthcare providers
• The risk-benefit of lithium in specific situations must be weighed, considering the potential benefits of lithium treatment against the potential risks of kidney injury 1

From the FDA Drug Label

Chronic lithium therapy may be associated with diminution of renal concentrating ability, occasionally presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia Morphologic changes with glomerular and interstitial fibrosis and nephron-atrophy have been reported in patients on chronic lithium therapy The relationship between renal functional and morphologic changes and their association with lithium therapy has not been established.

The risk of lithium-induced nephrotoxicity (kidney injury) is a potential concern, as chronic lithium therapy may be associated with renal functional and morphologic changes, including:

• Diminution of renal concentrating ability
• Nephrogenic diabetes insipidus
• Glomerular and interstitial fibrosis
• Nephron-atrophy However, the relationship between these changes and lithium therapy has not been established 2.

From the Research

Risk of Lithium-Induced Nephrotoxicity

The risk of lithium-induced nephrotoxicity is a concern for patients undergoing long-term lithium treatment. Key findings from various studies include:

• A cross-sectional study of 142 patients with more than 15 years of lithium treatment found that 21% had reduced glomerular filtration rate (GFR) and 44% had reduced maximum urinary concentrating capacity (Umax) 3.
• A study of 120 patients with bipolar disorder found that those treated with lithium for 0.5 to 20 years had significantly decreased urine osmolality and urine-to-serum osmolality ratio compared to those not treated with lithium 4.
• A review of the literature found that nephrogenic diabetes insipidus (NDI) occurs in 20% of patients on long-term lithium treatment, and that progressive renal failure occurs in approximately 20% of patients on long-term lithium treatment 5.
• A study of 2169 patients who started long-term lithium treatment in three consecutive decades found that the risk for severe renal damage during the first decade of treatment is low, but has not changed over time 6.

Factors Associated with Lithium-Induced Nephrotoxicity

Several factors are associated with an increased risk of lithium-induced nephrotoxicity, including:

• Duration of lithium treatment: Longer treatment duration is associated with a higher risk of nephrotoxicity 3, 5.
• Cumulative lithium dose: Higher cumulative doses are associated with a higher risk of nephrotoxicity 3.
• Age: Older patients are at higher risk of nephrotoxicity 6.
• Serum creatinine concentration: Higher serum creatinine concentrations are associated with a higher risk of nephrotoxicity 6.
• Concomitant treatment with other psychotropic medications: Patients treated with lithium and other psychotropic medications are at higher risk of nephrotoxicity 3.

Monitoring and Prevention of Lithium-Induced Nephrotoxicity

To minimize the risk of lithium-induced nephrotoxicity, several strategies can be employed, including:

• Monitoring serum lithium concentrations to achieve optimal efficacy at the lowest possible concentrations 5.
• Monitoring serum creatinine levels at least annually 5.
• Avoiding acute episodes of renal toxicity 5.
• Considering alternative treatments or adjusting the lithium dose in patients with declining renal function 5, 6.