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Background: Long-term lithium treatment decreases kidney function. However, it remains unclear whether stopping lithium improves kidney function.

Objectives: To study kidney function in patients who stopped and subsequently restarted lithium treatment.

Methods: Mirror-image design using data from the LiSIE retrospective cohort study. The mirror was set to when lithium was stopped with a 5-year pre- and post-mirror period. Adult patients with bipolar, schizoaffective disorder or unipolar depression, who had lithium ≥4.5 years in the pre-mirror period, were included. Creatinine measurements were available from 1997 to 2017. The main outcome was the difference in mean annual change of the estimated glomerular filtration rate (eGFR) adjusted for sex, hypertension and diabetes mellitus.

Results: A total of 168 participants (94 women, 74 men) were included. Mean annual eGFR change was −1.58 (−1.87 to −1.28) mL/min/1.73 m²/year before and −0.023 (−0.49 to +0.44) mL/min/1.73 m²/year after lithium discontinuation (p < 0.0001 for difference). The improvement was 0.77 (0.35–1.20) mL/min/173 m²/year in participants with eGFR >60 mL/min/1.73 m², and 3.03 (2.15–3.92) mL/min/1.73 m²/year for participants with eGFR <30 mL/min/1.73 m². The effect was persistent over the 5-year post-mirror study period. For participants restarting lithium, the mean annual eGFR change was −1.71 (−2.26 to −1.16) mL/min/1.73 m²/year, a setback compared to their lithium-free post-mirror period (p < 0.0001). We did not see any difference compared to the pre-mirror period (p = 0.51).

Conclusions: Stopping lithium slowed down mean eGFR decline. This effect was more pronounced in participants with lower eGFR at the time of lithium discontinuation. In participants who restarted lithium, the annual decline of eGFR reverted to pre-lithium discontinuation levels.