Chronic lithium therapy and urine concentrating ability in individuals with bipolar disorder: association between daily dose and resistance to vasopressin and polyuria

Background and objectives Chronic lithium treatment in individuals with bipolar disorder can induce nephrogenic diabetes insipidus. However, the prevalence, kinetics and mechanisms of such complication are poorly known. We aimed at evaluating patterns of urine concentrating ability and the correlates of 24-hour urine output in individuals treated with lithium. Design, setting, participants and measurements Prospective single center observational study of 217 consecutive individuals treated with lithium carbonate and referred to the renal unit. All individuals collected 24-hour urine the day before admission and underwent a desmopressin (DDAVP) concentrating test, fasting plasma vasopressin measurement (copeptin measurement in a subset of individuals, n=119), and measured GFR (mGFR) using urinary 99 Tc-DTPA clearance. Maximal urine osmolality (Max Uosm) was defined as the highest level during the DDAVP test. Results 21% of individuals displayed polyuria (> 3l/day), but 55% displayed elevated fasting vasopressin level (> 5 pg/ml). During the DDAVP test, Uosm was significantly lower, and urinary output and free water clearance were significantly higher in the highest treatment duration tertile (> 10 years) whereas no difference was observed between the first two tertiles (600 mOsm/KgH 2 O) (n=128), 51% displayed elevated vasopressin levels, which was associated with higher lithium daily doses (950 [750- 1200] versus 800 [500- 1000] mg/d, p<0.001), and 100% of patients with lithium daily dose ≥1400 mg/d had high vasopressin levels. In multivariable analysis, 24-hour urine output was associated with higher lithium daily dose (β 0.49 ± 0.17, p=0.005), female sex (β -359 ± 123, p=0.004), daily osmolar intake (β 2.21 ± 0.24, p<0.001), maximal urine osmolality (β -2.89 ± 0.35, p<0.001) and plasma vasopressin level (β 10.17 ± 4.76, p=0.03), but not with lithium formulation. Conclusions Higher lithium daily dose was associated with higher vasopressin levels and higher urine output, independently of other factors. Daily osmolar intake was also associated with higher 24-hour urine output. These results suggest that controlled salt and protein intake and lithium dose might reduce renal resistance to vasopressin in these patients.