Analyzing the Effects of Lithium Withdrawal on Renal Function

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CASE VIGNETTE

“Ms James” is a 58-year-old Caucasian female with a history of bipolar disorder with psychotic features and borderline intellectual function. She has been treated with clozapine 400 mg every night at bedtime and lithium 300 mg twice a day for more than 10 years, with good clinical response. Ms James has chronic kidney disease, with a current estimated glomerular filtration rate (eGFR) of 47 mL/min per 1.73 m2.

The patient and her sister (the patient’s primary caretaker) are well aware of the adverse effects of lithium on kidney function. However, Ms James has a history of exacerbation of psychosis, which required inpatient psychiatric hospitalization when she discontinued lithium in the past. Therefore she and her sister have requested to continue therapy. If Ms James were to discontinue lithium for an extended period of time, what is the likely impact on her renal function?

Lithium is related to risk of chronic kidney disease (CKD), with an estimated prevalence of 10% to 35%.¹ Fortunately, only a small percentage of chronic lithium users (maybe 0.5% to 1%) develop stage 4 or 5 CKD (requiring hemodialysis or transplant).

Data on the effects of discontinuing lithium on renal function are scarce and conflicting, and they are based on small samples.^2,3 However, a Danish cohort study found that continuing lithium after a diagnosis of CKD was not associated with an increased risk of developing end-stage CKD.⁴ Therefore, understanding the effects of lithium discontinuation on renal function is important for clinical decision-making.

The Current Study

Hoekstra and colleagues⁵ studied the trajectory of renal function after discontinuation of chronic lithium therapy. The authors investigated the laboratory database of the Antes Centre for Mental Health Care in Rotterdam, the Netherlands. They identified patients who stopped using lithium between 2000 and 2015.

They included patients with at least 2 creatinine values before and 1 value after stopping lithium, from which the eGFR was calculated. Another inclusion criterion was the availability of eGFR from at least 6 months before and 6 months after lithium discontinuation. The authors also identified a subset of patients who discontinued lithium at an eGFR of 60 mL/min or less.

Data were analyzed using linear mixed models. A linear trend in eGFR before and after lithium discontinuation was modeled by a linear spline, with a single knot at the point when lithium was stopped. The model was optimized using restricted maximum likelihood (REML). The difference in eGFR between patients with and without improvement in kidney function was compared using the Student t-test.

The authors identified 43 patients with data on eGFR available before and after discontinuation of lithium, primarily for bipolar or schizoaffective disorder. The mean age was 43 years, and 53% of patients were male. The mean duration of lithium therapy was 9.6 years. The most common reason for lithium discontinuation was adverse effects (37%), although decline in renal function was cited as the main reason for 14% of patients.

The eGFR increased in 67% (29 of 43) of patients. On average, it increased by 2.0 mL/min/year after discontinuation. In 8 patients (19%), eGFR continued to decline after discontinuation, but at a smaller rate. In the remaining 6 patients (14%), eGFR continued to decline at a similar or increased rate.

Thirteen patients had an eGFR of 60 mL/min or less when lithium was discontinued. Among these patients, eGFR increased in 7 and continued to decline in 6 patients. Among those with a continued decline, their mean eGFR at discontinuation was 32 mL/min and they had used lithium for an average of 8.6 years. Among the patients with an increase, their mean eGFR at discontinuation was 46 mL/min and they had used lithium for an average of 5.8 years.

Study Conclusions

The authors concluded that eGFR improved after lithium discontinuation. Furthermore, the vast majority of patients with CKD stage 3 or greater (eGFR, ≤ 60 mL/min) showed either increased eGFR or a decrease in the rate of decline after stopping lithium.

Study strengths included a relatively larger sample size than that of previous studies. Limitations are the small sample size of patients with CKD at the time of lithium discontinuation. Findings were nevertheless consistent with those of previous studies that showed a low risk of more severe CKD (stage 4 or 5) in this population.

The Bottom Line

In the majority of patients, lithium discontinuation results in improvement in renal function or less rapid deterioration.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times^TM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Nielsen RE, Kessing LV, Nolen WA, Licht RW. Lithium and renal impairment: a review on a still hot topic. Pharmacopsychiatry. 2018;51(5):200-205.

2. Bendz H. Kidney function in a selected lithium population: a prospective, controlled, lithium-withdrawal study. Acta Psychiatr Scand. 1985;72(5):451-463.

3. Bendz H, Sjödin I, Aurell M. Renal function on and off lithium in patients treated with lithium for 15 years or more: a controlled, prospective lithium-withdrawal study. Nephrol Dial Transplant. 1996;11(3):457-460.

4. Kessing LV, Feldt-Rasmussen B, Andersen PK, et al. Continuation of lithium after a diagnosis of chronic kidney disease. Acta Psychiatr Scand. 2017;136(6):615-622.

5. Hoekstra R, Lekkerkerker MN, Kuijper TM, et al. Renal function after withdrawal of lithium. Bipolar Disord. 2022;24(6):667-670.