Abstract / Summary
Abstract Background Lithium remains one of the most effective long-term treatments for bipolar disorder (BD). However, concerns about kidney function can make decisions about long-term treatment more difficult. The extent to which lithium exposure, BD, and sex contribute to changes in kidney function remains uncertain. Methods We conducted a retrospective longitudinal cohort study of 3,458 adults aged ≥18 years at their first lithium measurement and with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m², including 2,383 with BD and 1,075 without BD. Longitudinal eGFR trajectories were examined using mixed-effects models accounting for age, sex, BD status, cumulative lithium exposure, current and past lithium use, a history of serum lithium concentrations ≥1.2 mmol/L, and comorbidity burden. A secondary analysis examined change in eGFR between the first and last measurements in relation to changes in cumulative lithium exposure. Results Greater cumulative lithium exposure was consistently associated with lower eGFR across sex and BD groups. Overall, each additional year of lithium exposure was associated with a 1.14 mL/min/1.73 m² lower eGFR (95% CI, -1.29 to -1.00; p < .001). Current and past lithium use were also associated with lower eGFR compared with non-use. A history of lithium toxicity, defined as at least one serum lithium concentration ≥1.2 mmol/L, was associated with lower eGFR overall (-1.58; 95% CI, -2.19 to -0.97; p < .001), with a significant association among females but not males. In the secondary analysis, an increase in cumulative lithium exposure of >2 years was associated with greater eGFR decline across all sex and BD groups. However, interactions between lithium exposure change, sex, and BD status were not significant, providing no clear evidence that this association differed by sex or BD status. Conclusions Long-term kidney-function changes were more consistently associated with lithium exposure than with BD itself. Greater cumulative exposure and a history of lithium toxicity were associated with lower eGFR. These findings support continued monitoring of kidney function and lithium levels during long-term treatment while maintaining lithium’s important role in the management of BD.