Risk of chronic kidney disease in individuals on lithium therapy in Iceland: a nationwide retrospective cohort study.

Background: The association between lithium use and chronic kidney disease, and the effect of comorbidities on this association are poorly understood. Our aim was to examine the risk of developing stage 3 or higher chronic kidney disease among people receiving lithium therapy.

Methods: This was a retrospective, population-based cohort study of all adults (aged ≥18 years) in Iceland treated with lithium for a mood disorder who had two or more serum creatinine measurements available in the years 2008-17, irrespective of duration of lithium therapy, identified from the Prescription Medicines Register of the Directorate of Health, or through blood lithium measurements. The control group comprised all eligible outpatients with mood disorders (ICD-10 codes F30-F39) who had not been prescribed lithium and who had attended the national tertiary referral centre in 2014-16. Individuals with chronic kidney disease (identified by ICD codes or an estimated glomerular filtration rate [eGFR] <60 mL/min per 1·73 m) before Jan 1, 2008, or those with glomerular disease, genetic or congenital kidney disease, or small kidneys diagnosed before or after 2008 were excluded. Chronic kidney disease stages 3 and higher were defined according to the 2012 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, and the eGFR was calculated from serum creatinine; all ICD-10 and ICD-9 diagnosis codes, serum creatinine and blood lithium concentrations, and urine albumin-to-creatinine ratios were obtained from health-care institutions and laboratories. Risk of developing stage 3 or higher chronic kidney disease between Jan 1, 2008, and Dec 31, 2017, was assessed using time-to-event regression analysis, accounting for competing risk of death. People with lived experience were not involved in the design or conduct of this study.

Findings: We identified 4310 individuals (2695 who had received lithium and 1615 control participants), of whom 3198 were included in the study. 2025 (75·1%) individuals in the lithium group (1165 [57·5%] female and 860 [42·5%] male) and 1173 (72·6%) in the control group (737 [62·8%] female and 436 [37·2%] male) were included in the study at end of follow-up. The mean age of the study sample at the end of follow-up was 46·6 years (SD 16·4; range 18·5-98·9). Ethnicity data were not available. In the lithium group, 211 (10·4%) of 2025 individuals developed stage 3 or higher chronic kidney disease, compared with 35 (3·0%) of 1173 individuals in the control group (hazard ratio [HR] 1·90, 95% CI 1·32-2·75 after adjusting for sex, age, and comorbid conditions). Compared with control participants, the risk of stage 3 or higher chronic kidney disease was significantly increased for subgroups with a mean blood lithium concentration of 0·60-0·79 mmol/L (HR 2·93, 95% CI 1·97-4·36) or 0·80-0·99 mmol/L (4·31, 2·66-6·99), but not for the subgroup with a mean blood lithium concentration of 0·30-0·59 mmol/L (1·22, 0·78-1·90). Analyses also showed that age, initial eGFR, diabetes, and history of acute kidney injury were significant risk factors for developing stage 3 or higher chronic kidney disease.

Interpretation: Individuals with mood disorders receiving lithium treatment had an increased risk of developing stage 3 or higher chronic kidney disease in a blood concentration-dependent manner. We also found that other factors, including age, initial eGFR, and comorbidities were associated with increased risk of for developing stage 3 or higher chronic kidney disease. Overall, our findings suggest that in addition to considering other risk factors (eg, age or clinical comorbidities), careful monitoring of blood lithium concentrations and use of the lowest effective lithium dose for adequate mood stabilisation is recommended for helping to mitigate the risk of chronic kidney disease.

Funding: Akureyri Hospital Research Fund and Landspitali University Hospital Science Fund.