Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parameters
Tondo et al. Int J Bipolar Disord
Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parameters
Leonardo Tondo 0
Cynthia V. Calkin
Philipp Ritter Jr.
Janusz K. Rybakowski
Gustavo H. Vázquez 0
Ross J. Baldessarini 0
0 The International Consortium for Mood & Psychotic Disorders Research , MRC 306 , McLean Hospital , 115 Mill Street, Belmont, MA 02478‐9106 , USA
Background: 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. Methods: 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. Results: Overall, 29.5% of subjects experienced at least one low value of eGFR (<60 mL/min/1.73 m2), 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/m2. 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. Limitations: Control data for age‑ matched subjects not exposed to lithium were lacking. Conclusions: 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.
Blood urea nitrogen; Body‑ mass index; Creatinine; eGFR; Glomerular filtration rate; Glucose; Lithium; Staging of renal function; White blood cell count
Decades of widespread international clinical use of
lithium salts with controlled dosing, as well as
extensive therapeutic research, support the value of lithium
as a cornerstone of long-term, prophylactic treatment
of patients diagnosed with bipolar disorder
(Bauer et al.
2006; Baldessarini 2013; Severus et al. 2014; Bauer and
. Nevertheless, an adverse effect of major
concern associated with long-term lithium treatment is
the risk of developing chronic kidney disease (CKD). This
outcome usually is defined as a decrease of glomerular
filtration rate (GFR) to <60 mL/min per 1.73 m2 observed
at least twice in not less than 3 months (Azab et al. 2015).
Severe loss of renal function and end-stage renal disease
(ESRD) are uncommon with lithium treatment, with a
prevalence of approximately 1.5%, but 7-folds higher than
the general population
(Aiff et al. 2015)
. Risk of renal
dysfunction is believed to be associated with longer exposure
to lithium as well as with advancing age with or
without lithium, and appears to have changed little over the
(Aiff et al. 2015; Jonczyk-Potoczna et al.
. Pathological renal changes associated with long
exposure to lithium in clinical doses have included the
presence of macrocysts, microcysts, glomerulosclerosis,
proximal tubular atrophy, and chronic interstitial
(Albrecht et al. 1980; Oliveira et al. 2010; Alsady et al.
2016; Jonczyk-Potoczna et al. 2016)
mechanisms associated with such dysfunction appear to be
multiple and complex. Based mainly on preclinical
models, they include alterations in calcium signaling,
inositol monophosphate and phosphodiesterase activities,
prostaglandins, sodium-solute transport,
G-protein-coupled receptors, nitric oxide, vasopressin aquaporin, and
(Rej et al. 2016)
. However, it is
unclear why only some patients develop nephropathy in
association with lithium treatment, regardless of age or
At least 20 findings related to renal dysfunction have
emerged from studies of patients treated long term with
(Azab et al. 2015)
. They include (Table 1) (a)
significant increase of serum creatinine concentration, not
associated with age, in 99 lithium-treated patients
followed for up to 10 years
(Depaulo et al. 1981)
; (b) no
difference in eGFR among 30 patients aged 55, treated
with lithium for 6.2 years and 30 others not exposed to
(Hullin et al. 1979)
; (c) no difference in eGFR
among 32 patients aged 49 years, treated with lithium for
5.7 years and 32 matched controls
; (d) more
Age (years) Lithium exposure (years)
Hullin et al. (1979)
Depaulo et al. (1981)
Bendz et al. (1996)
Coşkunol et al. (1997)
Turan et al. (2002)
Bendz et al. (2010)
Rybakowski et al. (2012)
Bocchetta et al. (2013)
Minay et al. (2013)
Aiff et al. (2014)
Aprahamian et al. (2014)
Close et al. (2014)
Aiff et al. (2015)
Bocchetta et al. (2015)
Clos et al. (2015)
Shine et al. (2015)
Castro et al. (2016)
Hayes et al. (2016)
Kessing et al. (2015)
N = 20 studies
Abnormal renal functioning was associated with longer exposure to lithium in these studies (15.3 ± 9.54 vs. 5.00 ± 0.91 years, respectively [t = 2.37, p = 0.035])
No difference in eGFR
Creatinine increased with Li
No difference in eGFR
eGFR fell with Li
No difference in eGFR
eGFR fell with long‑term Li
ESRD 6.5‑fold more often with Li
eGFR < 60: 22.5%; 2.4‑times more in men
eGFR < 60: 4.8‑fold more often with Li
eGFR < 60: similar with/without Li
ESRD 7.8‑fold more often with Li
No difference in renal function
eGFR < 60: 3.25‑times less with Li
eGFR < 60: 32%; ESRD: 4.5‑fold more with Li
eGFR < 50: 12% in 10, 50% in 25 yrs of Li
No difference in eGFR
eGFR < 60: 1.21‑fold more often with Li
eGFR < 60: 25.7% lower with multiple doses/day
eGFR < 60: ~twofold higher HR with Li
Clinical CKD 3.6‑times more with Li
Function decreased in 15/20 reports (75.0%)
prevalent low eGFR in 13 patients (mean age, 59 years)
treated with lithium for 18 years (5/13) than that in
13 matched controls never exposed to lithium (0/13;
χ2 = 6.19, p = 0.01)
(Bendz et al. 1996)
; (e) no difference
in eGFR in 107 patients aged 39 treated with lithium for
4.5 years (eGFR = 86.5 [CI 82.4–90.6]) compared with 29
matched controls (83.9 [76.1–91.7] units) (Coşkunol et al.
1997); (f ) lower eGFR among 10 patients/group of
average age 35, exposed to lithium for 6.7 years (72.8 [50.7–
94.9]) compared to those exposed for 1.3 years (150
[129–172]) or no exposure (125 [112–138] units)
et al. 2002)
; (g) a risk of ESRD of 0.53% among 3369
subjects of average age 65 exposed to lithium for 23 years,
compared to 0.082% of the general Swedish population—
a 6.5-fold difference (χ2 = 82.5, p < 0.0001)
(Bendz et al.
; (h) eGFR < 60 units in 23.0% of 80 patients treated
with lithium up to 38 (mean, 17) years, and more often
among men (38%) than women (16%; p = 0.04)
(Rybakowski et al. 2012)
; (i) eGFR values were lower in 27.3%
of 139 lithium-treated patients of mean age 54, exposed
to lithium for ≥1 year, compared to 5.71% among 70
psychiatric controls—a difference of 4.8-fold (χ2 = 9.66,
p < 0.002), and were more likely among older patients
(Bocchetta et al. 2013)
; (j) mean GFR 8.0%
lower among 330 general practice patients taking
lithium compared with 659 matched controls, with
similar prevalence of eGFR values ≤60 units in both groups
(17.0 vs. 13.1%; χ2 = 2.75, p = 0.10)
(Minay et al. 2013)
(k) the rate of dialysis treatment or renal transplantation
in the Swedish general population was 0.019%, compared
to a 7.8-fold higher rate of 1.5% among 1995
lithiumtreated patients of age 66 years given lithium for 27 years
(χ2 = 176, p < 0.0001)
(Aiff et al. 2014)
; (l) no difference
in renal function in a 2-year randomized control trial
(RCT) for patients given lithium >4 years
et al. 2014)
; (m) eGFR < 60 units in 12.3% of 2496 general
practice patients given lithium for undefined times,
compared to a 3.25-fold lower risk of 3.78% in 3864 bipolar
disorder patients not given lithium, all of average age 49
(χ2 = 165, p < 0.0001)
(Close et al. 2014)
; (n) values of
eGFR < 60 units were encountered in 32% of 630 subjects
aged 66 years treated with lithium ≥10 years, and 4.5%
developed ESRD (stage 4 or 5; eGFR < 30 units), with
little sex-difference in either outcome
(Aiff et al. 2015)
eGFR < 60 units was found in 12% of 953 patients given
lithium for 10 years and in 50% by 25 years
et al. 2015)
; (p) no significant difference in the annual
decline of eGFR in a case–control study: 305 patients
aged 43 given lithium for an average of 4.6 years and
815 controls given other treatments (1.3 vs. 0.9 units)
after adjustment for age, baseline eGFR, comorbidities,
exposure to nephrotoxic drugs, and episodes of acute
(Clos et al. 2015)
; (q) eGFR < 60 units
was 1.21-times more prevalent among 4678
lithiumtreated subjects than among 689,228 controls of mean
age 52 treated for up to 28 years, after adjustment for
age, sex, and diabetes (estimates: 62.3 vs. 51.4%; χ2 = 118,
p < 0.0001)
(Shine et al. 2015)
; (r) risk for eGFR < 60 units
among 3850 patients, aged 54 years, treated with lithium
for an average of 1.4 years was 25.7%, and was higher
with multiple daily doses, higher serum concentrations,
and co-treatment with first-generation neuroleptics
(Castro et al. 2016)
; [s] eGFR < 60 units was about
twofold more prevalent among 2148 lithium-treated patients
than among those treated with valproate (n = 1670),
olanzapine (n = 1477), or quetiapine (n = 1376)
et al. 2016)
; (t) in a nationwide population study,
clinically diagnosed CKD was increased by up to 3.6-fold
with longer exposure to lithium, and associated with use
of anticonvulsants (with risk of confounding by selective
avoidance of lithium with renal failure), but not
antidepressants or antipsychotics
(Kessing et al. 2015)
summarize, all these studies point out that lower eGFR is
associated with older age and longer exposure to lithium
In addition to changes in renal functioning, the
presence of macrocysts or microcysts as possible precursors
of loss of kidney function has been reported in
several renal-imaging studies following long-term lithium
(Tuazon et al. 2008; Slaughter et al. 2010;
Farshchian et al. 2013; Karaosmanoglu et al. 2013;
Jonczyk-Potoczna et al. 2016)
. Also, an increase of renal
neoplasia during long-term treatment with lithium has
(Zaidan et al. 2014)
, but not supported by
(Baldessarini and Tondo 2014; Licht
et al. 2014; Pottegård et al. 2016)
To extend the preceding findings, we evaluated effects
of lithium on GFR and other metabolic parameters in a
composite sample of 312 bipolar disorder patients
followed for 8–48 years in 12 international specialized
mood-disorder clinics with extensive experience in the
clinical use of lithium.
This international collaborative study involved data
provided by 12 sites in Argentina, Canada, Germany, Italy,
Poland, Spain, and Switzerland (Table 2). Subjects were
adults meeting DSM-IV diagnostic criteria for
bipolar I or II disorder. Participation was based on meeting
local institutional requirements for the ethical conduct
of research. Measurements considered included age;
sex; years of exposure to lithium treatment; mean daily
dose of lithium carbonate and mean daily trough serum
concentration of lithium; body-mass index (BMI), white
blood cell counts (WBC), and assays of serum
concentrations of glucose, blood urea nitrogen (BUN), and
Years on Lic
19.4 ± 7.41
17.2 ± 8.12
15.1 ± 5.93
17.5 ± 8.61
24.1 ± 8.86
20.3 ± 9.49
11.9 ± 3.97
18.2 ± 9.45
11.7 ± 6.29
23.1 ± 8.59
18.4 ± 9.47
6.80 ± 7.94
Total exposure = 6142 person-years
Across the 12 sites, among 312 subjects: at = 1.55, p = 0.007; bt = 1.70, p = 0.001; ct = 1.13, p = 0.24
creatinine, with estimated GFR (eGFR, in units of mL/
min/1.73 m ) computed according to the chronic
kidney disease (CKD)-epidemiology collaboration
(CKDEPI) formulas for Caucasian (as all study subjects were)
women and men
(Levey et al. 2009)
females : 141 × ([creatinine]/0.7)−0.329
× ([creatinine]/0.7)−1.209 × 0.993age × 1.018;
males : 141 × ([creatinine]/0.9)−0.411
× ([creatinine]/0.9)−1.209 × 0.993age × 1.018.
Metabolic measures at baseline were compared over
times of exposure to lithium treatment, ranging from 8 to
48 years, using ANOVA methods (t-scores). Additional
analyses focused on the prevalence of renal dysfunction
based on low eGFR (<60 mL/min/1.73 m ), and
considered standard functional staging, as: Stage 1 normal
functioning (GFR ≥ 90); Stage 2 mildly decreased
functioning (GFR = 60–89); Stage 3 moderate dysfunction
(GFR = 30–59); Stage 4 severe dysfunction (GFR = 15–
29); and Stage 5 kidney failure (GFR < 15 or needing
(American National Kidney Foundation, NKF 2002,
. Low eGFR included Stages 3 and 4.
We addressed the prevalence of low values of eGFR across
study sites, and changes with time and in association with
selected measures, including ages (at onset, at lithium start
and at the last follow up visit), sex, co-occurring medical
illnesses, and exposure to lithium (by daily dose, mean serum
concentration, and time) as well as to other psychotropic
drugs (anticonvulsants, antidepressants, antipsychotics).
Associations of potential risk factors were tested by
comparing subjects meeting the criterion of at least one low
value of eGFR (<60 units) or not, in bivariate comparisons
using ANOVA methods (t-scores) for continuous
measures and contingency tables (χ2) for categorical measures,
followed by multivariable logistic regression modeling. In
order to differentiate effects on eGFR of age and lithium
exposure, we also sampled subjects matched for long-term
lithium exposure (20–25 years), but starting treatment at
ages <40 vs. ≥40 years. Data are shown as mean ± standard
deviation (SD) or with 95% confidence interval (CI), unless
stated otherwise. Analyses employed commercial software:
Statview.5 (SAS Institute, Cary, NC, USA; for spreadsheets),
and Stata.12 (StataCorp, College Station, TX, USA).
The pooled study sample consisted of 312 adult,
bipolar disorder subjects, treated with lithium
carbonate for 8–48 (mean 17.9 ± 8.62) years (with or without
other treatments), representing a total exposure of 6142
person-years. Selected characteristics of subjects from
each site (subject count, age at entry to study site, age
at last contact, and years treated with lithium) are
summarized in Table 2. The proportion of women/men was
57.7/42.3%; age at study site intake averaged 37.9 ± 12.9
(range 11–76) years, and last age averaged 55.8 ± 14.2
(range 20–89) years. Diagnoses were 78.2% bipolar I and
21.8% bipolar II, with an average age at illness-onset of
28.5 ± 11.1 years.
Metabolic parameters at baseline and during lithium treatment
Summary data for average measures and their status
across years of treatment with lithium are based on 2669
assays (Table 3). They include: lithium carbonate dose
(833 ± 311 mg/day), mean daily trough serum
concentrations of lithium (0.656 ± 0.184 mEq/L), body-mass
index (BMI, 27.0 ± 4.86 kg/m ), serum glucose
concentration (97.3 ± 28.4 mg/dL), blood urea nitrogen (BUN,
26.1 ± 12.9 mg/dL), serum creatinine concentration
(0.92 ± 0.24 mg/dL), and estimated glomerular filtration
rate (eGFR; 83.3 ± 21.8 mL/min/1.73 m ). In addition,
white blood cell count ([WBC] not shown) was initially
7.29 and finally 7.59 × 10−3/µL, without appreciable
change over years of lithium treatment.
The dose of lithium carbonate declined significantly
over the years (0.78%/year) whereas serum lithium
concentrations remained stable over time, reflecting
dosing adjustments as lithium clearance decreased with
advancing age (Table 3). BMI increased slightly, from
25.9 initially to a final mean value of 26.6 kg/m2, at a rate
of 0.16%/year, and did not differ significantly between
those given psychotropic drugs other than lithium or not
(27.0 ± 5.36 vs. 26.3 ± 3.72 kg/m2; t = 1.36, p = 0.18).
Serum glucose concentration also rose significantly over
years of treatment and with advancing age, at 0.79%/year.
BUN increased appreciably (from 23.7 to 33.1 mg/dL), at
a rate of 1.4%/year, and creatinine rose at about half the
rate of BUN, from 0.87 to 1.17 mg/dL, at 0.72%/year.
The metabolic measure of particular interest, eGFR,
declined from a mean at intake of 94.2, to a final
average of 62.2 mL/min/1.73 m2, at an average rate of decline
of 0.915%/year (Table 3). Times to first-observed
significant increases in various measures vs. baseline included:
BMI, just after the first year; glucose, from years 6–10;
creatinine, years 16–20; and BUN, years 21–30. Decline
of eGFR was noted starting from years 6–10, with a
projected decline to the lower limit of normal (60 units) after
30 or more years of exposure to lithium (Table 3).
Staging of renal deficiency
We considered changes in the prevalence of stages of
renal function based on standard values
National Kidney Foundation, NKF 2002, 2014)
vs. years of lithium treatment (Fig. 1). The prevalence of
normal or Stage I eGFR (≥90 mL/min/1.73 m2) declined
over years of lithium exposure (and advancing age), from
48.3% at intake to 9.80% after 31–48 years of exposure,
whereas Stage 2 (60–89 units) declined slightly (from
50.8 to 44.1% of subjects), and the prevalence of
abnormal eGFR Stages 3 and 4 eGFR (15–59 units) increased
from 0.85 to 46.1%. No subject reached end-stage renal
failure (Stage 5). The relative risk of each stage by sex
(women/men) was: Stage 1, 0.72 (more in men); Stage
2, 1.11; Stage 3, 1.68; and Stage 4, 9.29 (all three more
in women); these sex-differences were highly significant
(overall χ2 [df = 3] = 51.3, p < 0.0001).
Comparison of subjects with low vs. normal eGFR
A total of 92 (29.5%) of the 312 subjects had at least
one estimate of eGFR below the lower limit of normal
(<60 mL/min/1.73 m2). Based on the widely accepted
criterion of ≥2 low values
(Azab et al. 2015)
, the risk of
eGFR < 60 units was 18.1% [CI 13.9–22.7].
Characteristics of subjects with vs. without low eGFR values were
Data are based on means of N measurements (of a total of 2669) for 312 subjects over stated exposures to lithium treatment
Not shown are data for white blood cell counts (WBC), which did not change appreciably (initital: 7.29, final: 7.59 × 10–3 per µL)
BMI (body-mass index [kg/m2]), BUN (blood urea nitrogen [mg/dL]), creatinine [mg/dL], eGFR (estimated glomerular filtration rate for creatinine [mL/min/1.73 m2]),
glucose (not necessarily fasting [mg/dL]), WBC (white blood cell count [thousands/µL])
a Values differ significantly from baseline measure, based on Tukey–Kramer post hoc tests comparing each exposure-interval to baseline values
compared in initial bivariate comparisons (Tables 4, 5).
Subjects with significantly lower eGFR were (a) more
often women than men; (b) older at illness-onset, at
starting lithium, and at final observation; (c) significantly
less likely to be given co-treatments with anticonvulsants
p-value [χ2 or
Age at assay 62.7 [61.4–64.0]
Medical comor‑ 83.5
Years treated 19.6 [18.5–20.7]
Mean dose 588 [554–622]
Mean serum 0.65 [0.63–0.68]
BUN 36.7 [34.3–39.1]
[Glucose] 108 [103–112]
BMI 28.5 [26.2–30.8]
or antipsychotics; and (d) having significantly lower
initial values of eGFR (Table 4). In addition, measures
associated with low eGFR based on all assays, included
(e) older at the time of assays; (f ) more likely to have
medical comorbidities (mainly cardiovascular diseases,
diabetes, hypercholesterolemia, hypertension,
hypertriglyceridemia, hypothyroidism, or respiratory diseases);
(g) longer exposure to lithium; (h) lower average doses
of lithium carbonate; (i) without differences in mean
serum lithium concentrations; (j) higher mean BUN; (k)
higher serum glucose concentration; and (l) higher BMI
(Table 5). Factors not associated with low eGFR included
(a) diagnosis; (b) educational level; (c) metabolic
syndrome; (d) abuse of alcohol or drugs; (e) cigarette
smoking; (f ) lifetime suicidal behavior, and (g) serum TSH
Of note, antipsychotic drugs (59.2% of all subjects)
were given with lithium more than either anticonvulsants
(38.6%) or antidepressants (33.1%). Based on multiple
variable logistic regression modeling, adjusted for age
and sex (not shown), mood-altering anticonvulsants were
associated with shorter exposure to lithium and lower
serum concentrations. Use of antipsychotics was
significantly greater among subjects diagnosed with bipolar
I than II disorder, as well as shorter exposure to lithium
Means are with 95% CI. Serum lithium concentration is in mEq/L; dose is of
lithium carbonate is total mg/day. Additional factors not associated with low
eGFR: (1) diagnosis (bipolar I vs. bipolar II), (2) education, (3) metabolic syndrome
(overall risk = 30.4%), (4) any substance abuse, (5) alcohol abuse, (6) smoking,
(7) any suicidal act, (8) serum TSH. Medical illnesses include cardiovascular and
a Low eGFR: subjects with at least one value <60 mL/min/1.73 m2; the observed
rate of such subjects was 92/312 (29.5%), but 312/2669 assays (11.3%)
but at higher doses and serum concentrations.
Antidepressants were given more often to bipolar II than bipolar
I disorder subjects.
Declining eGFR with age and exposure to lithium
As expected, advancing age and years of lithium
treatment were associated with low values for eGFR
(<60 mL/min/1.73 m2), with corresponding increases
in rates of elevated serum creatinine concentration
(defined as >1.2 mg/dL, based on the lower standard
value for women rather than that of 1.5 mg/dL for men)
(Fig. 2; Table 3). The rate of decline (slope function as
%/year) averaged 0.710%/year of age, with a
nonsignificantly steeper decline among women than men (0.756
vs. 0.631%/year), and 0.915%/year of lithium exposure,
with a significantly greater (non-overlapping CIs) rate
of decline among women than men (0.934 vs. 0.785%/
year of lithium; Table 6). The overall observed rate of
decline of eGFR was 28.9% greater for years of lithium
treatment than for years of age (0.915 vs. 0.710%/year;
For comparison with subjects not exposed to lithium,
we obtained data from a study by Rule et al. (2004) who
measured the effect of age in 365 healthy subjects on
eGFR estimated as in the present study. These data
indicate a nonsignificantly lower rate of decline with age
without than with lithium treatment (0.637 vs. 0.710%/
year), as well as a slightly larger decreases among women
than men (Table 6). In addition, the rate of decline of
eGFR was significantly greater with years of exposure
Lithium-treated subjects are from the present study. Data for healthy adults are adapted from Rule et al. (2004) for clearance of iothalamate. Rates of GFR decrease
as %/year are computed as [initial eGFR − observed eGFR]/[initial eGFR] × 100 with 95% confidence intervals and number (n) of subjects (eGFR is in units of mL/
Years of lithium
0.915 [0.822–1.08] (312)
0.785 [0.546–0.717] (132)
0.934 [0.815–1.05] (180)
to lithium (0.915%/year) than with age in subjects not
exposed to lithium (0.637%/year; Table 6).
Renal effects of age at starting lithium treatment
Given the uncertain relative contributions of aging and
exposure to lithium on declining eGFR, we considered
a restricted sample of 610 assays, matched for
longterm treatment with lithium for 20–25 years (mean for
both = 22 years), but starting treatment at ages <40
vs. ≥40 years (Table 7). Mean eGFR was highly
significantly lower among participants starting lithium at
age ≥ 40 years. Moreover, risk of low values of eGFR was
nearly twice as high (1.94-times) among the older
subjects, despite similar exposure to lithium.
Multivariable regression modeling
Finally, we carried out multivariable logistic regression
modeling of factors associated with low eGFR (<60 mL/
min/1.73 m2). Factors remaining independently and
significantly associated ranked: (a) longer treatment with
lithium, (b) lower mean daily dose of lithium carbonate,
(c) higher mean serum lithium concentration, (d) older
age at the time of assays, (e) co-occurring medical illness
(Table 8). Not significantly associated with low eGFR in
such modeling were sex, BMI, and co-treatment with an
anticonvulsant, antipsychotic, or antidepressant drugs.
Of note, serum concentration was associated with low
eGFR only when adjusted for age, dose, and duration
of exposure (Table 8), but not without such adjustment
(Tables 4, 5).
Table 8 Multivariate logistic regression model for factors
associated with low eGFR (<60 mL/min/1.73 m2)
Longer lithium treatment 1.07 [1.04–1.09] 5.92
Lower mean lithium dose (mg/ 1.003 [1.002–1.004] 5.42
Higher mean serum [Li+] 4.47 [4.36–43.5] 4.47
Older age at assay 1.04 [1.02–1.06] 4.32
Co‑ occurring medical illness 2.11 [1.28–3.49] 2.91
Among 312 adult bipolar disorder patients, treated for
8–48 years with lithium carbonate (6142 person-years
of exposure), from 12 international collaborating centers
we found an incidence of low eGFR (<60 units) of 18.1%
of subjects for ≥2 low values. The risk was 29.5% using
a broad criterion of one low value, for which the overall
female/male risk ratio was 1.76. Stage 1 eGFR (values
of ≥90 units) was 39% more prevalent among men than
women, whereas Stages 2 (60–89; by 11%), 3 (30–59;
68%), and 4 (15–29 units, by 9.3-fold) were more
frequent among women. No subject reached end-stage renal
dysfunction (ESRD), perhaps reflecting the source of
study data from specialized mood-disorder clinics where
close clinical follow-up would lead to suspension of
treatment before reaching ESRD. Close clinical monitoring
probably is also reflected in the lack of decline in average
serum concentrations of lithium over years of treatment,
despite a significant decline in total daily dose,
presumably adjusted to maintain stable blood levels.
A particularly important finding is that eGFR declined
with longer exposure to lithium treatment, but also with
corresponding increases in age (Fig. 2; Table 6). Both
factors were sustained as significant and independent
in multivariable modeling (Table 8). Effects of aging on
renal function are well established even among human
subjects without known disease or toxic factors
et al. 2004; Weinstein and Anderson 2010)
. Although we
did not have a comparison sample of patients followed
over time without lithium treatment, we could compare
rates of decline of eGFR as a function of age and of time
of exposure to lithium, and with reported rates of decline
in healthy subjects (Rule et al. 2004). Without lithium
treatment, the rate of decline in eGFR (%/year) vs. age in
normal subjects averaged 0.637 [CI 0.497–0.777]
et al. 2004)
, compared to 0.710 [0.653–0.767] for age in
lithium-treated subjects, and to 0.915 [0.822–1.08] for
years of lithium treatment (Table 6). These estimates
are similar, with overlapping confidence intervals for the
effect of aging, but a higher rate with lithium exposure.
Additional reported data indicate a rate of decline of
eGFR in healthy subjects of 0.708 [0.644–0.772] %/year
(American National Kidney Foundation, NKF 2014)
value even closer to that found in our study for age
among lithium-treated subjects. We also addressed the
relative contributions to declining eGFR by considering
a sample of subjects matched for long-term exposure to
lithium (22 years), but starting the treatment at ages <40
vs. ≥40 years (Table 7). Mean eGFR was significantly
higher among participants who started lithium at older
ages, and the risk of low values of eGFR was nearly twice
greater among the older subjects, despite similar
exposure to lithium. These findings indicate that effects of
aging were greater than the exposure to lithium.
Moreover, adverse effects of lithium on renal function may be
greater at older ages.
The rate of decline of eGFR averaged 0.92% per year of
lithium treatment, and was 19% higher among women
than men. The observed overall rate of decline is
consistent with most
(Bendz et al. 1996, 2010; Bocchetta et al.
2013, 2015; Close et al. 2014; Aiff et al. 2015; Shine et al.
2015; Kessing et al. 2015; Hayes et al. 2016)
, but not all
(Clos et al. 2015)
retrospective reports on the effects of
lithium on kidney function. In the study by Clos et al.
(2015), however, patients were exposed to lithium for
an average of 55 months, possibly too brief to support
detection of effects on kidney function
(Davis et al. 2015;
Bocchetta et al. 2016)
. Interestingly, however, a similar
lack of effect of lithium on renal function was found in
a 4-years prospective study in elderly patients with mild
cognitive impairment (Aprahamian et al. 2014). In the
present findings, average values of eGFR became
significantly lower than baseline levels by 6–10 years of
treatment, and a mean decline to the lower limit of normal
(60 units) required ≥30 years of exposure to lithium
(Table 3). Other reports of long-term lithium treatment
effects on renal function are consistent with this
(Bendz et al. 2010; Bocchetta et al. 2015; Shine et al.
. We also found that risk of later low values of eGFR
were strongly predicted by lower initial values (Table 4).
Exposure to lithium treatment needed to be at least
6–10 years to be associated with significant decreases of
eGFR (Table 3).
Our finding of greater risk of a decline in eGFR among
women is also consistent with some recent reports
(Bocchetta et al. 2015; Shine et al. 2015)
suggesting a higher
vulnerability of women to developing lithium-related
effects on kidney. Of note, however, other studies have
found greater risk of declining eGFR among men
(Rybakowski et al. 2012; Bocchetta et al. 2013)
or no sex
(Aiff et al. 2015)
Serum concentrations of urea (BUN) increased by
1.41%/year, glucose by 0.787%/year, and creatinine by
0.724%/year—all rising with longer exposure to
lithium and correspondingly advancing age. The observed
increase in serum glucose levels contrasts with a study
reporting a nonsignificant increase in glucose levels after
four years of treatment with lithium in elderly patients
(Aprahamian et al. 2014)
. Interestingly, studies in animals
evaluating the effects of lithium on glucose metabolism
also may be discordant with our findings
Pishdad 1980; Tabata et al. 1994)
. Indeed, whereas Shah and
Pishdad (1980) found that lithium induced the
hyperglycemia in rats, Tabata et al. (1994) found a markedly
increased sensitivity of glucose transport to insulin after
We also found that average BMI increased by 0.162%/
year of treatment with lithium, with a significant increase
over baseline values by the end of the first year of
exposure, but little more thereafter (Table 3). This finding
confirms that lithium may contribute to weight gain
(Mathew et al. 1989; Atmaca et al. 2002)
, although the
effect might reflect exposure to other weight-increasing
agents including antipsychotic drugs (Calkin et al. 2009).
However, the potential adverse risks associated with
long-term treatment with lithium need to be balanced
against major clinical benefits of treatment with lithium
(McKnight et al. 2012; Severus and Bauer 2013; Kessing
et al. 2015)
Several factors were associated with loss of eGFR
during long-term treatment with lithium (Tables 4, 5, 6, 7
and 8). Notably, declining eGFR was associated with
serum lithium concentrations only when adjusted for
age, dose of lithium, and duration of lithium exposure,
whereas total daily doses of lithium carbonate were
actually lower with low eGFR, in association with older age
(Tables 4, 5, and 8). These findings suggest that dose was
adjusted to maintain therapeutic serum levels in the face
of declining renal clearance of lithium and with age. We
also found that medical comorbidities (especially
diabetes and hypertension) were associated with declining
eGFR. In contrast, use of adjunctive treatments,
especially modern antipsychotic drugs and mood-altering
anticonvulsants, were associated with less risk of low
eGFR values (Tables 4, 5). These associations are not
readily explained. Patients with low eGFR were older, had
more general medical comorbidity, and were given fewer
psychotropic drugs of all kinds as well as lower doses of
lithium. Of note, there is suggestive evidence that
anticonvulsants and antipsychotics may themselves
contribute to risk of renal damage
(Hwang et al. 2014; Kessing
et al. 2015)
. Other findings implicate episodes of acute
lithium intoxication (possibly an indication of more
aggressive treatment) with declining renal function (Rej
et al. 2012).
There may be effects of once-daily vs. multiple daily
dosing with lithium on renal function
(Carter et al.
2013; Castro et al. 2016)
. Some evidence suggests less
renal toxicity with once-daily dosing, but the findings
are inconsistent, and may be confounded by likely use
of lower doses with once-daily regimens
(Schou et al.
1982; Carter et al. 2013)
. Moreover, the observed effects
pertain mainly to small reductions in 24-h urine
(Kusalic and Engelsmann 1996)
dosing is perhaps best reserved for young, vigorous patients
given moderate doses of lithium to limit the potentially
toxic impact of high, daily peak serum concentrations.
Reducing lithium dose might be expected to limit toxic
effects as was supported by present findings (Tables 4, 5,
assuming that dose was not lowered because of
declining renal function). Lithium dose can be reduced by use
of combinations with other agents with mood-stabilizing
effects, including some anticonvulsants or antipsychotics.
Consideration of these factors during appropriately
close, long-term clinical monitoring should help to limit
risks of renal impairment with long-term lithium
(Paul et al. 2010)
. In addition, there may be
benefits in monitoring serum concentrations of lithium levels
relatively frequently, especially in elderly patients. It has
been suggested that lithium levels should be monitored
every 3 months since even a single occurrence of a level
higher than 1.0 mEq/L may result in a modest but
significant decrease of the GFR lasting for at least 3 months
(Bauer et al. 2006; Van Beneden et al. 2011; Kirkham et al.
2014; Davis et al. 2015; Shine et al. 2015)
. In general, we
would emphasize the importance of appropriate selection
of patients for long-term lithium treatment, maintaining
them on minimum effective doses and daily trough serum
concentrations especially for older populations, and
regular monitoring to assess adherence to prescribed
treatment. These principles of safe practice are important to
emphasize, especially as many mood-disorder patients are
followed by primary-care clinicians and are not followed
in specialized programs directed by experts
(Müller-Oerlinghausen et al. 2012)
The present findings should be interpreted in the context
of some limitations. First, the study is retrospective in
nature. However, clinical data were collected
longitudinally in specialized mood-disorder clinics where patients
are followed up systematically and at regular intervals,
increasing the statistical accuracy of gathered
information. Second, the main measure of renal function in this
study was estimated GFR based on serum
concentrations of creatinine, and not on independently verified
clearance of an exogenous test molecule. The formulas
employed may not adequately reflect the rate of
glomerular filtration at very high concentrations of creatinine,
such as >1.75 mg/dL
(Levey et al. 2009; Stevens 2013)
Nevertheless, eGFR is widely employed measure of renal
function and is readily obtained for routine clinical use.
Finally, we lacked a comparison group without lithium
treatment, leaving the important question of effects of
aging vs. of lithium on eGFR unresolved.
This multisite, international, long-term study found
significant changes in renal function and other metabolic
measures in association with very prolonged treatment
with lithium carbonate given to prevent recurrences
of bipolar disorder. It adds to evidence that long-term
lithium treatment is associated with a decline in renal
function as expressed by significant decreases of eGFR
over time. We found moderate decreases in eGFR after
prolonged exposure to lithium (at least 6–10 years) and
advancing age, along with increases in serum creatinine
and BUN concentrations, and small increases in glucose
levels and BMI. No cases of severe or end-stage renal
failure were encountered, probably owing to close
clinical monitoring and timely interventions in cases with
declining renal function. We found greater decreases in
eGFR among women than men, and following lower
initial values of eGFR, as well as when lithium treatment
was started at older ages. The study findings contribute to
clarifying relationships between long-term lithium
treatment and its metabolic safety profile. Overall, this study
and those summarized above (Table 1) indicate, with
some notable inconsistencies, that there were major risks
of declining eGFR with very prolonged treatment with
lithium salts, but that effects of advancing age also are
prominent and confound quantification of risk-by-time
specific to lithium exposure. Noteworthy risk factors
for low eGFR included female sex, higher serum lithium
level, longer lithium treatment, lower initial eGFR, and
medical comorbidity, as well as older age. A clinically
favorable conclusion is that emerging decreases in renal
function can be detected readily with regular metabolic
monitoring, and probably modified by timely
interventions that include an increasing number of apparently
effective treatment options to lithium.
All the authors contributed to this paper by providing data and discussing the
design and results of the study, and preparation of this report. All the authors
read and approved the final manuscript.
The authors offer their thanks to Kathleen Cairns, Julie Garnham, Terry McCa‑
rvill, and Claire Slaney for help with data collection. This study was supported
by the Aretaeus Foundation of Rome and by Angelini Corp. (LT); by Grant
64410 from the Canadian Institutes of Health Research (to MA); by the Spanish
Ministry of Economy and Competitiveness (PI12/00912; PN 2008–2011); by the
Grant/research support from Deutsche Forschungsgemeinschaft, European
Commission (FP7); by the American Foundation for Suicide Prevention, and
by the Bundesministerium für Bildung und Forschung (BMBF)(to MB); by a
German Excellence Initiative to the Graduate School of Life Sciences, University
of Wurzburg, and by the RTG 1256/2 “gk emotions” (to JV); Instituto de Salud
Carlos III, Subdirección General de Evaluación y Fomento de la Investigación,
Fondo Europeo de Desarrollo Regional, Unión Europea, “Una manera de hacer
Europa,” and by CIBERSAM and the Secretaria d’Universitats i Recerca del
Departament d’Economia i Coneixement (2014‑SGR‑398 to EV); by a German
Ministry of Education and Research Grant (01EE1404C; to AR); (to JKR); and
by a grant from the Bruce J. Anderson Foundation and the McLean Private
Donors Research Fund (to RJB).
Drs. Abramowicz, Alda, Bocchetta, Bolzani, Calkin, Chillotti, Hidalgo‑Mazzei,
Manchia, Müller‑ Oerlinghausen, Murru, Pinna, Quaranta, Reginaldi, Reiff,
Saiger, Selle, Vázquez, Veeh, and members of the immediate families of all
authors have no potential conflicts of interest to disclose, and their consulting
relationships to industry are reported above. Dr. Baldessarini is a consultant
to Britannia Pharmaceuticals, Ltd. and participates in continuing medical
education programs sponsored by Harvard Medical School, McLean Hospital,
and the New England Educational Institute. Dr. Bauer has been a consultant
for Ferrer Internacional, Janssen, Lilly, Lundbeck, Neuraxpharm, Otsuka, and
Servier Corporations, and has received speaker honoraria from AstraZeneca,
Lilly, Lundbeck, Otsuka and Pfizer Corporations. Dr. Rybakowski is a consultant
to Janssen‑ Cilag, Lundbeck, and Servier Corporations. Dr. Stamm has received
speaker honoraria from Lundbeck and BristolMyers Squibb and is a consultant
to Servier Corporation. Dr. Tondo is consultant for Angelini Corporation. Dr.
Vieta has received grants and served as consultant, advisor, or CME speaker
for the following entities: AB‑Biotics, Actavis, Allergan, AstraZeneca, Bristol‑
Myers Squibb, Dainippon Sumitomo Pharma, Ferrer, Forest Research Institute,
Gedeon Richter, Glaxo‑SmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche,
Sanofi‑Aventis, Servier, Shire, Sunovion, Takeda, and Telefónica Corporations,
the Brain and Behavior Foundation, the Spanish Ministry of Science and Inno‑
vation (CIBERSAM), the Seventh European Framework Programme (ENBREC),
and the Stanley Medical Research Institute.
Availability of data and materials
Data were made available by all participants/authors of the study.
Consent for publication
All patients signed an informed consent to publication of anonymous and
aggregate data derived from their medical records.
Ethics approval and consent to participate
The study has been approved by local Ethical Committee according to
national laws which allow the anonymous and aggregate use of human data if
not involved in any experimental designs.
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
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