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 m²) 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.

中文翻译：

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冰岛接受锂治疗个体患慢性肾病的风险：一项全国性回顾性队列研究

 背景

锂使用与慢性肾病之间的关联以及合并症对这种关联的影响知之甚少。我们的目的是检查接受锂治疗的人患 3 期或更高期慢性肾病的风险。

 方法

这是一项回顾性、基于人群的队列研究，针对冰岛所有接受锂治疗情绪障碍治疗的成年人（≥18 岁），他们在 2008-17 年有两次或两次以上的血清肌酐测量值，无论锂治疗的持续时间如何，从卫生局的处方药登记处确定，或通过血液锂测量确定。对照组包括所有符合条件的心境障碍门诊患者（ICD-10 代码 F30-F39），他们没有服用锂剂，并且在 2014-16 年参加了国家三级转诊中心。2008 年 1 月 1 日之前患有慢性肾病的个体（通过 ICD 代码或估计肾小球滤过率 [eGFR] <60 mL/min 每 1·73 m² 识别），或患有肾小球疾病、遗传性或先天性肾病，或 2008 年之前或之后诊断的小肾的个体被排除在外。根据 2012 年肾脏病：改善全球结局慢性肾脏病评估和管理临床实践指南定义 3 期及以上慢性肾脏病，eGFR 根据血清肌酐计算;所有 ICD-10 和 ICD-9 诊断代码、血清肌酐和血锂浓度以及尿白蛋白/肌酐比值均从卫生保健机构和实验室获得。使用 2008 年 1 月 1 日至 2017 年 12 月 31 日期间发展为 3 期或更高阶段慢性肾病的风险，使用事件时间回归分析进行评估，考虑竞争性死亡风险。有生活经验的人没有参与这项研究的设计或实施。

 发现

我们确定了 4310 名个体 （2695 名接受锂剂治疗和 1615 名对照参与者），其中 3198 人被纳入研究。锂组 2025 名 （75·1%） 个体（1165 名 [57·5%] 女性和 860 名 [42·5%] 男性）和对照组 1173 名 （72·6%） （737 [62·8%] 女性和 436 名 [37·2%] 男性）在随访结束时被纳入研究。随访结束时研究样本的平均年龄为 46·6 岁 （SD 16·4;范围 18·5–98·9）。种族数据不可用。在锂组中，2025 名个体中有 211 名 （10·4%） 发展为 3 期或更高阶段的慢性肾病，而对照组 1173 名个体中有 35 名 （3·0%） 发展为慢性肾病（风险比 [HR] 1·90,95% CI 1·32-2·75 调整性别、年龄和合并症后）。与对照组参与者相比，平均血锂浓度为 0·60–0·79 mmol/L（HR 2·93,95% CI 1·97–4·36）或 0·80–0·99 mmol/L（4·31,2·66–6·99）的亚组患 3 期或更高期慢性肾病的风险显著增加，但平均血锂浓度为 0·30–0·59 mmol/L（1·22， 0·78–1·90).分析还显示，年龄、初始 eGFR、糖尿病和急性肾损伤史是发展为 3 期或更高期慢性肾病的重要危险因素。

 解释

接受锂治疗的情绪障碍个体以血药浓度依赖性方式发展为 3 期或更高阶段慢性肾病的风险增加。我们还发现，其他因素，包括年龄、初始 eGFR 和合并症，与患 3 期或更高期慢性肾病的风险增加有关。总体而言，我们的研究结果表明，除了考虑其他风险因素（例如，年龄或临床合并症）外，还建议仔细监测血锂浓度并使用最低有效锂剂量来充分稳定情绪，以帮助降低慢性肾病的风险。

 资金

阿克雷里医院研究基金和 Landspitali 大学医院科学基金。