Lithium‐associated nephrotoxicity: role of GDF15‐mediated collecting duct cells proliferation

Abstract

Lithium (Li+) salts are the most effective treatment of bipolar disorder (BD), affecting 1 to 4% of the population worldwide. However, this efficacy is counterbalanced by adverse long‐term events, mostly renal effects. Lithium treatment discontinuation is usually not an option as it substantially increases suicidal risk. Understanding the sequence of events in the kidneys might thus improve therapeutic strategies while maintaining this treatment.Li+‐induced nephrogenic diabetes insipidus (NDI) is the earliest and the most frequent side effect of chronic lithium use, leading to polyuria and polydipsia. Li+ treatment decreases AQP2 expression both in vivo and in vitro. Li+ treatment also induces a microcystic tubulointerstitial nephropathy eventually leading to end‐stage kidney disease. The mechanisms of tubular toxicity and microcyst formation have been related to a proliferative effect of Li+. The time course, the site and the mechanisms of this proliferation are still a matter of debate.Previous studies from our lab have shown that acidosis‐induced collecting duct cell proliferation depended on the overexpression of GDF15 by principal cells, especially in the early phase of linear proliferation along the tubular axis.Our objective during this project is to determine the pathways leading to planar and cystic proliferation of collecting duct cells, in particular GDF15 signaling, and their role in lithium nephrotoxicity, and to identify potential biomarkers that could help to predict the course of Li‐induced nephropathy.We have established a rat and a mouse experimental model treated with therapeutic concentrations of Li+, displaying as expected polyuria and polydipsia, with microcystic tubular dilations and a global proliferation of collecting duct cells (both principal and intercalated) on kidney slices and on microdissected collecting ducts, with an increase in the intercalated/principal cells ratio (figure). We examined the effect of Li+ in GDF15‐/‐ and wild type (WT) mice and found significantly lower polyuria and polydipsia in GDF15‐/‐ mice, along with a higher urine osmolality, and decreased intercalated/principal cell ratio compared to WT mice (figure).As collecting duct cell proliferation is mediated by GDF15, we studied urinary GDF15 levels (GDF ELISA kit) in Li+‐treated patients with proven diabetes insipidus and found them significantly increased compared to control patients (p<0.01) (figure).In conclusion, these results suggest a direct relationship between lithium‐induced proliferation signals, collecting duct cell dysfunction and GDF15 expression. Further investigation is needed to determine if GDF15 signaling might represent a therapeutic target in Li+‐induced nephrotoxicity.