MO502: Use of Lithium, Valproate and the Risk of Acute or Chronic Kidney Disease: An Observational Study From Routine Care Data
Authors: Bosi Alessandro , Laura Ceriani , Fu Edouard , Runesson Björn , M. Clase Catherine , Chang Zheng , Landen Mikael , Elinder Carl-Gustaf , Jesus Carrero Juan , Bellocco Rino 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Lithium is an established treatment for bipolar disorder and treatment-resistant depression. Despite awareness of potential kidney damage, there is a lack of research evidence to inform on the existence and magnitude of the risk. Observational studies to date show conflicting findings, possibly explained by inadequate control populations, prevalent user bias and a lack of information on kidney function or serum lithium levels.

METHOD
We conducted a cohort study to compare kidney outcomes in adults who started lithium or valproate therapy in Stockholm, Sweden, during 2007–18. Within lithium users, we also compared outcomes by average serum lithium concentrations during the first year of therapy. Kidney outcomes were CKD progression (composite of &gt;30% eGFR decline and kidney failure) and AKI (by diagnosis or KDIGO transient creatinine elevations). Propensity score weighted Cox regression was used to estimate hazard ratios with [95% confidence intervals (95% CI)] and balance 46 identified confounders. Complete collection of repeated dispensations at Swedish pharmacies allowed modelling of the time-dependent risk associated with cumulative lithium exposure. Sensitivity analyses included restricting to patients with a diagnosis of bipolar disorder, apply a 1-year lag, use of alternative weighting methods and evaluation of eGFR monitoring rates to ascertain surveillance bias between groups.

RESULTS
We included 16 645 individuals, of whom 5308 initiated lithium and 5638 valproate therapy. Their median age was 45 years (57% women) and median eGFR was 99 mL/min/1.73 m2. A total of 179 CKD progression events and 234 AKI were identified during a median of follow-up of 4.3 and 4.2 years, respectively. After propensity score weighting, the adjusted hazard ratio for the risk of CKD progression was 1.12 (95% CI 0.86–1.47) and for AKI 0.88 (95% CI 0.7–1.09). There was a weak, non-statistically significant association between cumulative exposure to lithium and the risk of CKD progression that was not observed for cumulative use of valproate. Results were consistent among patients with a bipolar disorder diagnosis and robust to 1-year lag or alternative weighing methods. A total of 3913 lithium users were on therapy for at least one year and underwent routine serum lithium monitoring. Compared with patients with average serum lithium levels &lt;1.0 mEq/L, those with serum lithium ≥1.0 mEq/L (n = 270) were at a higher risk of both CKD progression (HR: 2.18; 1.28–3.71) and AKI (HR: 1.37; 0.81–2.34).

CONCLUSION
In this analysis of patients from routine clinical practice, the risk of kidney outcomes associated with lithium therapy did not differ from that of valproate. Modest risk magnitudes need to be offset with the effectiveness and anti-suicidal benefits of lithium. However, elevated serum lithium levels strongly predicting kidney risk, emphasizing the need for close monitoring and lithium dose-adjustment.