Circulating antithyroid antibodies contribute to the decrease of glomerular filtration rate in lithium-treated patients: a longitudinal study
Bocchetta et al. Int J Bipolar Disord
Circulating antithyroid antibodies contribute to the decrease of glomerular filtration rate in lithium-treated patients: a longitudinal study
Alberto Bocchetta 0 2
Luca Ambrosiani 0
Gioia Baggiani 0
Claudia Pisanu 0
Caterina Chillotti 2
Raffaella Ardau 2
Fernanda Velluzzi 1
Doloretta Piras 3
Andrea Loviselli 1
Antonello Pani 3
0 Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari , Via Ospedale 54, 09124 Cagliari , Italy
1 Department of Medical Sciences and Public Health, University of Cagliari , Cagliari , Italy
2 Unit of Clinical Pharmacology, Cagliari University Hospital , Cagliari , Italy
3 Nephrology, Dialysis and Transplantation Unit, 'Giuseppe Brotzu' Hospital , Cagliari , Italy
Background: Concerns about the adverse effects of long-term treatment with lithium include reduced renal function. In the present study, we examined comorbidities which may be associated with chronic kidney disease in a cohort of patients treated with lithium for up to 41 years. Methods: We studied 394 patients who were treated with lithium for ≥ 5 years. The potential role of comorbidities (diabetes, concurrent antihypertensive medication, treatment with l -thyroxine, and presence of antithyroid peroxidase/microsomes, anti-thyroglobulin, and/or anti-thyrotropin-receptor antibodies) was analysed. We focused on the categories of patients with an estimated glomerular filtration rate (eGFR) lower than 60 or 45 mL/min/1.73 m2 as calculated from serum creatinine according to the Modification of Diet in Renal Disease Study Group. We applied multivariate regression analysis and Cox survival analysis to study the effects exerted by sex, age, duration of lithium treatment, and comorbidities using eGFR categories as the dependent variable. Kaplan-Meier curves were generated to measure the time to decline to an eGFR lower than 45 mL/min/1.73 m2 in patients with positive or negative thyroid antibodies. Results: Age was associated with a decline to an eGFR lower than 60 mL/min/1.73 m2 after controlling for sex, duration of lithium treatment, and comorbidities. Circulating thyroid antibodies were associated with a decline to an eGFR lower than 45 mL/min/1.73 m2. Conclusions: The present study is the first to suggest a potential role of circulating thyroid antibodies in the severe decline of eGFR in lithium-treated patients.
Lithium; Renal insufficiency; Chronic; Glomerular filtration rate; Thyroid microsomal antibodies; Antithyroglobulin
Adverse renal effects of lithium have long been known,
varying from very frequent reversible polyuria
to irreversible kidney damage
(Hestbech et al.
1977; Aurell et al. 1981)
. New studies have raised
concern especially for patients treated for many years (Bendz
et al. 2010) and the debate has been revived in 2012 by
a review and meta-analysis of the lithium toxicity profile
(McKnight et al. 2012)
. Thereafter, several studies based
on various kinds of data sources have addressed the
potential risk factors for chronic kidney disease (CKD)
in lithium-treated patients. Principal factors under
study include sex, age, duration of lithium treatment,
concurrent medications, and comorbidities that are
already known to predispose to CKD.
In an initial study of 139 patients from our lithium
clinic, we found a positive correlation between the
duration of lithium treatment and reduced estimated
glomerular filtration rate (eGFR)
(Bocchetta et al. 2013)
Subsequently, we extended the study to 953 patients
treated for at least one year and found that eGFR was
lower in women, in older patients, and in patients with
longer duration of lithium treatment
(Bocchetta et al.
In the meantime, several studies began to be published
exploring population-based health records, mostly
European, to identify factors which are potentially associated
with CKD in lithium-treated cohorts. According to three
large studies based on thousands of subjects from UK
and Denmark, it can be concluded that long-term
exposure to lithium is associated with increased rates of CKD
(Close et al. 2014; Kessing et al. 2015; Hayes et al. 2016)
Diabetes and the use of antihypertensive diuretic drugs
were found among potential risk factors for CKD
et al. 2014)
. On the contrary, a Scottish population-based
cohort study including 305 patients exposed to lithium
has come up with the different conclusion that there is
no effect of stable lithium maintenance therapy on the
rate of change in eGFR over time
(Clos et al. 2015)
However, it must be noted that the mean duration of
exposure to lithium was only for 55 months. In the Scottish
study, significant predictors for eGFR decline included
age, baseline eGFR, comorbidities, co-prescriptions of
nephrotoxic drugs, and episodes of lithium toxicity
et al. 2015)
More recently, we took part in a survey from 12
collaborating international sites including 312 patients treated
in the lithium clinics for at least 8 years
(Tondo et al.
. Medical comorbidities were found among risk
factors for low eGFR, but were not examined in the details.
Aims of the study
As we are in possession of the detailed clinical data
regarding patients on maintenance lithium treatment
over the last four decades, the aims of this study were to
determine whether comorbidities (hypertension,
diabetes, thyroid function, and presence of circulating thyroid
antibodies) or their treatments were associated with
Clinical records of the patients in the database of the Unit
of Clinical Pharmacology, Azienda
Ospedaliero-Universitaria, Cagliari, were examined. Our unit has been one of
the reference centres for lithium monitoring in the
Cagliari area since its introduction in the 1970s.
Lithium monitoring was in line with the international
guidelines. Our current therapeutic range for lithium
maintenance is 0.50–0.80 mmol/L, after it had been
lowered from the range 0.60–1.0 mmol/L which was used up
to the 1990s
The subjects included in this study were all the
consecutive patients from the database who had been followed
at the lithium clinic between 1976 and 2016 for at least
5 years and whose thyroid-antibody status was known.
For the purpose of this study, we extracted the
following variables from the charts of the patients:
demographic characteristics, age of onset of lithium treatment,
duration of lithium treatment, concurrent
antihypertensive medications, diagnosis of diabetes, data on renal and
Serum creatinine concentrations were taken from the
panel of laboratory tests requested on an annual basis.
We used the traditional standardisation method for
serum creatinine. The estimated glomerular filtration
rate (eGFR) was calculated from serum creatinine
values using the equation proposed by the Modification of
Diet in Renal Disease (MDRD) Study Group
(Levey et al.
2009; Earley et al. 2012)
, with the ‘186’ correction factor,
which takes age, sex and ethnicity into account. The
following categories of eGFR were considered: higher than
90 mL/min/1.73 m2 (G1); 60–89 mL/min/1.73 m2 (G2);
45–59 mL/min/1.73 m2 (G3a); 30–44 mL/min/1.73 m2
(G3b); 15–29 mL/min/1.73 m2 (G4); lower than 15 mL/
min/1.73 m2 (G5). The abbreviations and ranges recall
those used by Kidney Disease Improving Global
Outcomes (KDIGO) 2012 Clinical Practice Guidelines for the
Evaluation and Management of Chronic Kidney Disease
(CKD) (2012), but it must be noted that KDIGO CKD
stages are also based on albuminuria categories, which
were not included in the present study.
Concomitant medical conditions and related treatments
We studied the following conditions potentially
predisposing to CKD:
a. Long-term treatment with any antihypertensive
agent before declining to an eGFR lower than 60 mL/
b. Long-term treatment with oral hypoglycemic agents
or insulin, or dietary treatment after receiving an
established diagnosis of diabetes.
c. Long-term treatment with l-thyroxine or antithyroid
d. Presence of one or more of the following
circulating antibodies: anti-thyroid peroxidase (AbTPO),
anti-thyroid microsomes (AbM), anti-thyroglobulin
(AbTG), anti-thyrotropin receptors (TRAb). The
laboratory tests varied over the decades. The
antibodies were considered positive when they exceeded
the upper end of the laboratory range in use at
that time. For example, the cut-off was an AbM or
AbTG titre ≥ 1:100 in the 1990s or an AbTPO ≥ 20
or ≥ 35 IU/mL (depending on the laboratory) in the
more recent tests.
We used Student’s t test to compare mean and Fisher’s
exact test to analyse contingency tables. We applied
multivariate regression analysis to study the effect exerted by
demographic and clinical variables on renal function,
using the eGFR category as the dependent variable. The
independent variables which were analysed include: sex,
age, duration of lithium treatment, diabetes, treatment
with antihypertensive medication, treatment with l
-thyroxine, and presence of thyroid antibodies. We used Cox
survival analysis to study the effects exerted by sex, age,
duration of lithium treatment, and comorbidities on
renal function. Kaplan–Meier curves were generated to
measure the time taken to enter stage G3b in the
subgroups of the patients with positive or negative
circulating thyroid antibodies. The Log-rank (Mantel–Cox) test
was used to compare the survival distributions of the
subgroups with positive or negative circulating thyroid
Statistical analysis was performed using the SPSS
statistical software package v20 (SPSS, Inc., USA).
Psychiatric diagnoses according to ICD-10 were the
following: bipolar affective disorder (F31), N = 280
(bipolar I, 198; bipolar II, 82); schizoaffective disorder (F25),
N = 33 (manic type, 20; depressive type, 13); recurrent
depressive disorder (F33) N = 81.
Table 1 shows demographic and clinical
characteristics of the 394 patients studied. Men had started lithium
treatment earlier than women and were younger when
studied. Duration of lithium treatment did not differ
significantly between the sexes.
Similar proportions of women and men were taking
long-term antihypertensive drugs before declining to an
eGFR lower than 60 mL/min/1.73 m2.
Diabetes was diagnosed in 89 (23%) patients: when
last observed, 14 patients (9 women, 5 men) were being
treated with insulin, 34 (21 women, 13 men) with oral
hypoglycemic agents, and 41 (33 women, 8 men) with
Only four patients (1%) had been treated with
methimazole for hyperthyroidism, whereas treatment with
L-thyroxine regarded as many as 125 (32%) patients.
More women than men were taking treatment with
Prevalence of circulating thyroid antibodies was
significantly higher in women. Antibodies were principally
represented by AbTPO (or AbM in older tests prior to the
identification of TPO as the specific thyroid microsomal
antigen) alone or associated with AbTG (79% of cases).
AbTG without AbTPO/AbM were found in 18 women
and 1 man. We found only two cases of TRAb with no
other circulating antibodies. However, it must be noted
that TRAb is not in the panel of first instance thyroid
Antibody-positive women were taking l-thyroxine
more frequently (54/90 = 60%) compared to the
antibody-negative (60/199 = 30%) (P = 0.0001).
Table 2 shows demographic and clinical
characteristics of patients by their final eGFR category. Overall,
84 patients had declined to an eGFR lower than 45 mL/
min/1.73 m2 (CKD3b). A greater proportion of patients
in the G3b subgroup had been treated with
antihypertensive agents before the diagnosis of CKD compared to the
In the regression analysis using three different eGFR
categories (G1/G2; G3a; G3b) as the dependent variable,
age was the only independent variable with significant
effects (Table 3). When the regression analysis was
limited to the severest stage (G3b), the effect of circulating
Total sample (N = 394)
Women (N = 289)
Men (N = 105)
Superscripts a–o are used to indicate significant between-group differences
G1–G2, eGFR ≥ 60 mL/min/1.73 m2
G3a, eGFR = 45–59 mL/min/1.73 m2
G3b, eGFR < 45 mL/min/1.73 m2
thyroid antibodies was the only significant variable
The presence of circulating antibodies was the only
significant variable in the Log-rank test or Cox survival
analysis (Table 5).
The problem of lithium-associated renal dysfunction has
recently been addressed by several research studies and
reviews. As already mentioned in the introduction, recent
large studies agree that long-term exposure to lithium is
associated with increased rates of CKD
(Close et al. 2014;
Bocchetta et al. 2015; Kessing et al. 2015; Hayes et al.
. Current interest has been devoted principally to
risk factors that are already known to predispose to CKD.
Results vary according to study setting, sample size,
duration of lithium exposure, quality of data on confounders,
and availability of a control group.
The purpose of the present study was to help clarify
the role of concomitant conditions which may have been
associated with CKD in our cohort of patients. From the
beginning of lithium treatment, we have recorded any
concurrent medication taken regularly in our clinical
charts, as well as laboratory tests which are requested
on an annual basis, and reports from consulting
cardiologists, endocrinologists, and nephrologists. The main
focus of the study was on antihypertensive treatment,
diabetes and thyroid function with particular regard to
thyroid antibodies. Although international guidelines
do not generally include circulating thyroid antibodies
a In the univariate analysis, three categories of age (< 45 years; 45–65 years; > 65 years) were used
among the routine laboratory tests for lithium patients,
we have started recommending the search for
antibodies since the late 1980s, when we first found evidence of
high prevalence of AbM and/or AbTG in our cohort of
(Bocchetta et al. 1991)
. Thereafter, as AbTPO
had been identified as the specific thyroid microsomal
(Mariotti et al. 1987)
, we switched from AbM to
AbTPO in our series of follow-up studies
(for a review,
see Bocchetta and Loviselli 2006)
Diabetes and hypertension
In the present study, we were not able to reveal the role
of diabetes and hypertension, that are already known to
predispose to CKD in the general population
and have also been associated with renal failure in
patients treated with lithium
(Close et al. 2014; Clos et al.
. It must be noted that we found only 14 cases of
type-I diabetes, whereas cases of type-II diabetes were
typically found in older patients and their effect was
perhaps included in the age-related decline of eGFR that we
already found in the entire cohort of patients treated with
lithium (Bocchetta et al. 2015). A similar conclusion can
also be made regarding the treatment with
antihypertensive agents, whose apparent role (as shown in Table 2)
vanished after controlling for age in the regression
analysis. Similar results were observed in the UK study of
the patients treated with lithium,
(Close et al. 2014)
reported that hypertension itself was not associated with
renal disease in fully adjusted models. Moreover,
hypertension may not only predispose to CKD, but may also
be a consequence of CKD (Sternlicht and Bakris 2017).
It must also be noted that certain agents (namely ACE
inhibitors and sartans) are prescribed to CKD patients
even in the absence of hypertension to prevent further
decline in eGFR
(Ruggenenti et al. 2012)
, and this might
influence results obtained by studies using the database
of antihypertensive prescriptions as a proxy of a
diagnosis of hypertension.
In the present study, we did not observe cases of
clinical hypothyroidism or hyperthyroidism because patients
were referred to the endocrinologist in case of abnormal
TSH concentrations. Therefore, we focused on treatment
with l-thyroxine or antithyroid agents as a measure of
thyroid dysfunction. It must be noted that the large
proportion of patients taking l-thyroxine in the present sam
ple (one-third) may be due to the over-surveillance bias
in patients treated with lithium as well as to the multiple
indications for treatment: hypothyroidism (lithium- and/
or autoimmunity-related), hormone replacement after
thyroidectomy (for goitre or cancer), and
TSH-suppressing therapy of nodular goitre. The apparent
association between treatment with l-thyroxine and stage G3b
(Table 2) vanished in the adjusted analyses (Tables 3 and
At variance with the present study which was based on
specific treatments, population-based surveys of renal
and thyroid function have focused on clinical or
subclinical hypothyroidism (increased TSH concentrations with
normal thyroid hormone concentrations).
Hypothyroidism or increased TSH have been found associated with
lower eGFR or impaired kidney function in several
crosssectional surveys, mostly European
(Lo et al. 2005;
Chonchol et al. 2008; Targher et al. 2009; Asvold et al. 2011;
Ye et al. 2013; Meuwese et al. 2014; Rhee et al. 2015)
the other hand, results from prospective studies have not
been consistent. In fact, for example, an American and
a Chinese survey reported that elevated TSH were not
associated with the development of incident CKD
(Schultheiss et al. 2016; Huang et al. 2016)
a large South Korean study reported that high levels of
TSH were associated with an increased risk of incident
(Zhang et al. 2014)
, whereas the Rotterdam Study
reported that higher TSH levels were associated with
lower CKD incidence
(Chaker et al. 2016)
With regard to the role of thyroid antibodies, the absence
of control groups of either lithium naïve patients or
healthy individuals does not allow us to determine
whether the long-term exposure to lithium is a necessary
condition or thyroid antibodies may be nephrotoxic in
Thyroid function has been studied in the general
population or in clinical samples with various degrees of CKD
(for review, see Iglesias et al. 2017)
, but the inclusion of
antibodies in the panel of thyroid markers has been very
rare. To our knowledge, there are only two relevant but
(Targher et al. 2009; Schultheiss et al.
Targher et al. (2009) surveyed cross-sectionally the
database of a clinical chemistry laboratory in the north
of Italy and found an excess of AbTPO and/or AbTG
among individuals with an eGFR lower than 60 mL/
min/1.73 m2 (18/53 = 34%) compared to the
remaining individuals (195/862 = 23%). Age- and sex-adjusted
P value in logistic regression analysis was significant
(0.01). Data included 16 participants with an eGFR
lower than 45 mL/min/1.73 m . On the contrary, the
Atherosclerosis Risk in Communities study, a large
prospective study of middle-aged American adults
(Schultheiss et al. 2016)
found no association between
AbTPO and reduced kidney function. In their
prospective evaluation over a median follow-up time of
19.6 years, incidence of CKD (eGFR lower than 60 mL/
min/1.73 m ) did not differ between AbTPO-positive
and AbTPO-negative participants (odds ratio 0.79;
95% CI = 0.5–1.25; P = 0.32; total N of events = 1488)
(Schultheiss et al. 2016)
We first suspected that thyroid antibodies may play a
role in CKD of patients treated with lithium when we
collected the data for our recent collaboration study
et al. 2017)
. In fact, we contributed with 30 patients to
the study and we were impressed by the high prevalence
of circulating thyroid antibodies among the patients who
had eventually manifested severe CKD (7/14 = 50%). The
present study confirms that circulating thyroid antibodies
can contribute to the severe decline of eGFR in patients
treated with lithium.
We can only speculate about the potential mechanisms
involved in the excess of thyroid-antibody-related CKD
in our cohort of patients treated with lithium, because no
renal biopsy data were available.
Case reports have repeatedly associated nephropathy
with thyroid antibodies over the last four decades. In
some cases, deposition of immune complexes was
documented. For example,
Jordan et al. (1978
) reported a case
with immune complex glomerulonephritis and
hypothyroidism. Granular glomerular basement membrane and
mesangial staining were detected by indirect
immunofluorescence, with antibody specific for thyroglobulin and
thyroid microsomal antigen.
From the clinical point of view, the majority of the
cases reported to date were nephrotic syndrome rather
than reduced eGFR
(for review, see Santoro et al. 2017)
With regard to the relationship between pathological
and clinical findings, the most informative contribution
has been provided by Koçak et al. (2012) who reviewed
retrospectively 28 patients with Hashimoto’s
thyroiditis referred to their department because of unexplained
haematuria, proteinuria or renal impairment. They
concluded that glomerular pathologies associated with
Hashimoto’s thyroiditis are similar to those in the general
population. The most common lesions were membranous
glomerulonephritis, focal segmental glomerulosclerosis
and immunoglobulin A nephritis. Proteinuria and
glomerular filtration rate were found independent of thyroid
hormone concentrations and thyroid antibodies titres. Of
the 28 cases, 12 (43%) had an eGFR lower than 60 mL/
min/1.73 m2, whereas proteinuria was found in 24 (86%),
nephrotic range proteinuria in 11 (39%), and haematuria
in 11 (39%).
Data on prevalence of proteinuria and haematuria were
not available for the present study.
Besides the potential deposition of immune complexes,
other mechanisms have been involved in the various
diseases that have been found associated with circulating
thyroid antibodies. This does not necessarily mean that
thyroid antibodies play a direct role in all the observed
cases. As circulating thyroid antibodies are very
prevalent in the population, their concomitant occurrence
with other prevalent diseases may be a coincidence. For
example, a Sardinian survey found an overall prevalence
of AbTPO of 174/789 (22%) in women and 30/444 (7%)
(Loviselli et al. 1999)
. With regard to the
psychiatric presentation of the so-called Hashimoto’s
encephalopathy, we have suggested that it may be dependent
on a diffuse vasculitis
(Bocchetta et al. 2007, 2016)
turn, vasculitis may be due to concurrent antibodies: for
Yoneda et al. (2007
) have suggested that
antibodies against the amino terminal region of
alpha-enolase play a role in Hashimoto’s encephalopathy. Because
alpha-enolase is expressed in vascular endothelial cells,
autoantibodies against this enzyme may be associated
with vasculitis. Moreover, alpha-enolase has been
identified among intrinsic renal antigens that are targets of
nephritogenic antibodies. Indeed, in situ formation of
immune complexes is a well-recognised mechanism of
renal injury, as observed in systemic autoimmune
(Migliorini et al. 2002)
On the other hand, vasculitis or cross-reactivity
between antigens are among the mechanisms suggested
to explain the cases of glomerulopathies associated with
(Santoro et al. 2017)
Whatever the mechanism, the potential role of
thyroid antibodies in the decline of glomerular filtration in
patients with mood disorders is relevant, given their
Given the current uncertainty regarding the
potential role of thyroid antibodies in CKD due to the
paucity of studies on the general population and the lack of
a control group of patients with mood disorders never
treated with lithium in the present study, it is yet to be
established whether the long-term exposure to lithium
is a necessary condition to allow the manifestation of the
effects of thyroid antibodies or thyroid antibodies are
nephrotoxic in themselves.
If our finding will be confirmed, it might have some
clinical implications when discussing the role of lithium
with consultant nephrologists in cases of patients with
declining eGFR. We suggest the inclusion of thyroid
antibodies in the list of risk factors potentially associated
CI: confidence interval; CKD: chronic kidney disease; eGFR: estimated
glomerular filtration rate; AbTPO: anti-thyroid peroxidase antibodies; AbM: anti-thyroid
microsomes antibodies; AbTG: anti-thyroglobulin antibodies; TRAb:
antithyrotropin receptors; TSH: thyroid stimulating hormone; FT4: free thyroxine;
T3: triiodothyronine; FT3: free triiodothyronine.
AB devised the study, participated in its design and coordination, and drafted
the manuscript. RA and CC participated in the study design, literature search,
and data collection and interpretation. LA and GB participated in data
collection and interpretation. CP and DP participated in the study design,
performed statistical analysis, and participated in data interpretation. FV and
AL performed the assessment of thyroid function and participated in data
interpretation and drafting of the manuscript. DP and AP performed the
assessment of renal function and participated in data interpretation and
drafting of the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Availability of data and materials
The datasets used and/or analysed during the current study are available from
the corresponding author on reasonable request.
Consent for publication
All patients signed an informed consent for publication of anonymous and
aggregate data derived from their medical records.
Ethics approval and consent to participate
According to national laws, the local Ethics Committee does not require
any specific approval for non-interventional studies. All patients signed an
informed consent for use of anonymous and aggregate data derived from
their medical records.
This work was supported by a supplementary fund for research from the
University of Cagliari.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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