Lithium ER Twice Daily Dosing and Kidney Function
Once-daily lithium dosing appears to be less harmful to the kidneys than divided (twice or thrice daily) dosing, based on evidence showing that continuous lithium exposure may be more nephrotoxic than allowing periods of lower serum concentrations.
Evidence for Once-Daily Dosing Advantage
The most relevant study directly comparing dosing schedules found that patients receiving lithium in divided doses (2-3 times daily) had more pronounced structural kidney changes and functional impairment compared to those receiving once-daily dosing 1. The proposed mechanism is that regenerative kidney processes may only occur during periods of lower lithium concentrations, which are more likely with once-daily dosing that creates greater fluctuations in serum levels 1.
General Nephrotoxicity Risk with Lithium
Regardless of dosing frequency, lithium carries inherent renal risks that require vigilant monitoring:
- Lithium is nephrotoxic and may cause renal tubular dysfunction with prolonged use, even at therapeutic levels 2
- Large epidemiological studies confirm that lithium treatment elevates the risk of chronic kidney disease and renal failure 3
- Approximately one-third of patients treated for 10-29 years develop signs of chronic renal failure, though only 5% reach severe categories 4
- Both glomerular and tubular function are affected, with reduced glomerular filtration rate in 21% and reduced maximum urinary concentrating capacity in 44% of long-term users 5
Monitoring Requirements
GFR, electrolytes, and lithium levels should be monitored every 6 months or more frequently if dose changes or acute illness occurs 2. The FDA label emphasizes that progressive or sudden changes in renal function, even within the normal range, indicate the need for treatment reevaluation 6.
Specific monitoring should include:
- Baseline and ongoing assessment of tubular function (urine specific gravity, osmolality, 24-hour urine volume) 6
- Glomerular function (serum creatinine, creatinine clearance) 6
- Serum lithium levels, as toxicity is closely related to serum concentrations 6
Risk Mitigation Strategies
- Maintain hydration during intercurrent illness to avoid lithium retention and toxicity 2
- Avoid concomitant NSAIDs, which increase nephrotoxicity risk 2
- Target lower lithium plasma levels (0.6-0.8 mmol/L) for long-term maintenance to reduce severe nephrotoxicity risk 3, 7
- Temporarily discontinue lithium during serious intercurrent illness that increases AKI risk in patients with GFR <60 mL/min/1.73 m² 2
Important Caveats
The improved renal outcomes in more recent studies (post-1980) compared to earlier decades suggest that proper monitoring and adherence to recommended serum levels significantly reduce end-stage renal disease risk 4, 7. However, even with modern therapeutic principles, a substantial proportion of patients develop renal functional impairment after a decade or more of treatment 4.
The relationship between morphologic kidney changes and lithium therapy remains incompletely established, as similar changes have been observed in bipolar patients never exposed to lithium 6.