Risk of adverse kidney-related events for patients on lithium is low but increases with greater exposure

1. For patients newly initiated on lithium or valproate, the absolute risks of chronic kidney disease (CKD) progression or acute kidney injury (AKI) were low and similar.

2. Higher cumulative exposure to lithium was associated with greater risk of CKD progression compared to valproate.

3. Higher median lithium levels were associated with increased risk of AKI in a dose-response relationship.

EvidEnce Rating Level: 2 (Good)

Study Rundown:  Lithium is used in the treatment of bipolar disorder, but has always been associated with concerns of nephrotoxicity, although the pathophysiology is not well understood. Currently, the evidence linking lithium to chronic kidney disease (CKD) is inconclusive, and its association with acute kidney injury (AKI) is based mostly on single-centre studies or case series. Therefore, this study aimed to evaluate the risk of CKD progression and AKI for patients on lithium compared to valproate, which is not generally associated with nephrotoxicity. This was a retrospective cohort study based in Stockholm, Sweden, which consisted of patients initiated on lithium or valproate therapy from 2007-2018. The study also analyzed the length of treatment and amount of drug exposure analyzed as well. Follow-up for outcomes was limited to 10 years. Overall, the study found that the absolute risks of CKD progression or AKI for patients on lithium versus valproate were similarly low. However, there was a dose-response relationship whereby higher lithium levels in long-term users had a tendency towards increased risk of CKD progression, and this was statistically significant for increased risk of AKI.

Click here to read the study in JAMA Network Open

Relevant Reading: Lithium toxicity profile: a systematic review and meta-analysis

In-Depth [retrospective cohort]: The study population consisted of adults in Stockholm, Sweden who were newly started on lithium or valproate between 2007 and 2018. The study employed intention-to-treat analysis based on first prescription. Furthermore, the medication exposure was calculated using the length of treatment and defined daily dosages (DDDs) for participants. Patients with use at 1 year following initiation were defined as having long-term use in this study. Outcomes evaluated were CKD progression, defined as either kidney replacement therapy (KRT) or a 30% or more eGFR decline from baseline. AKI was determined from diagnoses made, and inpatient or outpatient creatinine results. In total, there were 10,946 patients included, with 5308 initiated on lithium and 5638 on valproate. Over a median (IQR) follow-up of 4.5 (1.9-8.0) years, the incidence of CKD progression was 6.9 events per 1000 person-years for the lithium cohort and 8.9 events per 1000 person-years for the valproate cohort. There was no difference in risk of CKD progression for patients started on lithium compared to valproate (adjusted hazards ratio 1.11, 95% CI 0.86-1.45). For AKI events, there was also no difference in risk for lithium compared to valproate (weighted HR 0.88, 95% CI 0.70-1.10), though there was lower risk at 10 years for lithium (absolute risk difference -3.2%, 95% CI -5.6 to -1.1). In the cumulative use analysis, there was a 30% higher risk of CKD progression for every 500 DDDs of lithium (ratio of HRs 1.30, 95% CI 1.09-1.50) compared to valproate. Moreover, for long-term lithium users, there was a dose-response pattern where higher lithium levels was associated with a tendency toward increased risk of CKD, such as when comparing lithium levels >0.8 mmol/L (HR 1.03, 95% CI 0.36-2.91) and lithium levels >1.0 mmol/L (HR 2.86, 95% CI 0.97-8.45). This dose-response relationship was statistically significant for risk of AKI, such as for a median lithium level of >0.8 mmol/L (HR 2.56, 95% CI 1.67-3.92) and >1.0 mmol/L (HR 3.51, 95% CI 1.41-8.76). In conclusion, there was no overall increased risk of CKD progression or AKI when comparing lithium and valproate users, though longer cumulative use and higher lithium levels were associated with higher risk of adverse kidney-related events.

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