Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parameters

Leonardo Tondo, Maria Abramowicz, Martin Alda, Michael Bauer, Alberto Bocchetta, Lorenza Bolzani, Cynthia V. Calkin, Caterina Chillotti, Diego Hidalgo-Mazzei, Mirko Manchia, Bruno Müller-Oerlinghausen, Andrea Murru, Giulio Perugi, Marco Pinna, Giuseppe Quaranta, Daniela Reginaldi, Andreas Reif, Philipp Ritter, Janusz K. Rybakowski, David Saiger, Gabriele Sani, Valerio Selle, Thomas Stamm, Gustavo H. Vázquez, Julia Veeh, Eduard Vieta, Ross J. Baldessarini

Concerns about potential adverse effects of long-term exposure to lithium as a mood-stabilizing treatment notably include altered renal function. However, the incidence of severe renal dysfunction; rate of decline over time; effects of lithium dose, serum concentration, and duration of treatment; relative effects of lithium exposure vs. aging; and contributions of sex and other factors all remain unclear. Accordingly, we acquired data from 12 collaborating international sites and 312 bipolar disorder patients (6142 person-years, 2669 assays) treated with lithium carbonate for 8-48 (mean 18) years and aged 20-89 (mean 56) years. We evaluated changes of estimated glomerular filtration rate (eGFR) as well as serum creatinine, urea-nitrogen, and glucose concentrations, white blood cell count, and body-mass index, and tested associations of eGFR with selected factors, using standard bivariate contrasts and regression modeling. Overall, 29.5% of subjects experienced at least one low value of eGFR (<60 mL/min/1.73 m(2)), most after ≥15 years of treatment and age > 55; risk of ≥2 low values was 18.1%; none experienced end-stage renal failure. eGFR declined by 0.71%/year of age and 0.92%/year of treatment, both by 19% more among women than men. Mean serum creatinine increased from 0.87 to 1.17 mg/dL, BUN from 23.7 to 33.1 mg/dL, glucose from 88 to 122 mg/dL, and BMI from 25.9 to 26.6 kg/m(2). By multivariate regression, risk factors for declining eGFR ranked: longer lithium treatment, lower lithium dose, higher serum lithium concentration, older age, and medical comorbidity. Later low eGFR was also predicted by lower initial eGFR, and starting lithium at age ≥ 40 years. Control data for age-matched subjects not exposed to lithium were lacking. Long-term lithium treatment was associated with gradual decline of renal functioning (eGFR) by about 30% more than that was associated with aging alone. Risk of subnormal eGFR was from 18.1% (≥2 low values) to 29.5% (≥1 low value), requiring about 30 years of exposure. Additional risk factors for low eGFR were higher serum lithium level, longer lithium treatment, lower initial eGFR, and medical comorbidity, as well as older age.