Lithium-induced nephrogenic diabetes insipidus: New clinical and experimental findings

Abstract

Lithium (Li+) salts are widely used to treat bipolar mood disorders. Recent trials suggest a potential efficacy also in the treatment of amyotrophic lateral sclerosis and Alzheimer's disease. Li+ is freely filtered by the glomerulus and mainly reabsorbed in the proximal convoluted tubule. Reabsorption in the distal nephron becomes significant under sodium-restricted conditions. Nevertheless, the distal nephron is greatly affected by Li+ even under normal sodium intake. Polyuria, renal tubular acidosis and finally chronic renal failure are the most frequent adverse effects. The occurrence of an overt nephrogenic diabetes insipidus (NDI) limits Li+ usage and imposes suspension. The molecular mechanisms of Li+-related urinary concentration defect involve a dysregulation of the aquaporin system in principal cells of the collecting duct. ENaC is crucial as the entry route for intracellular Li+ accumulation. The basolateral exit route is not clearly identified, but some evidence suggests Na+/H+ exchanger 1 (NHE1) as a potential candidate. Li+ promotes polyuria mainly counteracting the intracellular vasopressin signaling. An additional role of the inner medullary interstitial cells and PGE-2 pathway has to be considered. The GSK3ß cascade is also regulated by Li+. GSK3ß inhibition could lead not only to the polyuria, but also to the Li+-dependent proliferative effect on principal cells. Cellular reorganization of the collecting duct and microcysts are the main pathological findings during Li+ treatment. Their relationship with the urinary concentration defect and an eventual Li+-induced ciliopathy has to been investigated. Li+-induced NDI has been a matter of investigation since the early 1970s. This manuscript reports the latest clinical and experimental findings in combination with the older fundamental results.

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In t r o d u c t I o n
Lithium (Li+) salts are the first-line therapy for bipolar mood
disorders (1). Li+ has been widely used for mood disorders
since 1970. The development of novel narcoleptics has
decreased the use of Li+ salts. Today a new potential effi-
cacy of lithium in lowering the progression of amyotrophic
lateral sclerosis (2) and Alzheimer’s disease (3) is attract-
ing the attention of clinicians and researchers.
About 50% of patients under lithium treatment experi-
ence urinary concentration defects (4). Therefore, it has
been reported that long-term lithium therapy (more than
10-20 years) can induce chronic kidney failure promot-
ing a tubulointerstitial nephritis with a slow progression to
end-stage renal disease (5). This condition is irreversible.
Other reports showed an incomplete form of renal tubular
acidosis in patients taking lithium (6).
Several experimental models showed that dysregulation of
aquaporins in the collecting duct (CD) is a crucial mecha-
nism for the development of Li+-dependent nephrogenic di-
abetes insipidus (NDI). Li+ affects many regulatory pathways
counteracting the vasopressin-dependent cellular signaling
and also rearranging the entire cellular structure of the CD.
Although Li+ is a very efficacious drug for psychiatrics, re-
nal adverse effects are a limiting problem. This manuscript
reviews the latest clinical and experimental studies on the
Li+-induced urinary concentration impairment.
re n a l h a n d l I n g o f l I t h I u m
Li+ is a monovalent cation that shares some features with
more abundant cations present in the body (Na+ and Mg++).
Li+ can take the place of Mg++, competitively, inhibiting the
activity of GSK3β (7). In addition, in vitro evidence shows
that Li+ can compete with Na+ for the amiloride-sensitive
epithelial Na+ channel (ENaC), Na+/H+ exchanger 3 (NHE3)
and Na+/K+/2Cl- (NKCC2) cotransporter (8, 9).
ab s t r a c t
Lithium (Li+) salts are widely used to treat bipolar mood
disorders. Recent trials suggest a potential efficacy also
in the treatment of amyotrophic lateral sclerosis and Al-
zheimer’s disease. Li+ is freely filtered by the glomerulus
and mainly reabsorbed in the proximal convoluted tu-
bule. Reabsorption in the distal nephron becomes signif-
icant under sodium-restricted conditions. Nevertheless,
the distal nephron is greatly affected by Li+ even under
normal sodium intake. Polyuria, renal tubular acidosis
and finally chronic renal failure are the most frequent ad-
verse effects. The occurrence of an overt nephrogenic
diabetes insipidus (NDI) limits Li+ usage and imposes
suspension. The molecular mechanisms of Li+-related
urinary concentration defect involve a dysregulation of
the aquaporin system in principal cells of the collecting
duct. ENaC is crucial as the entry route for intracellular
Li+ accumulation. The basolateral exit route is not clearly
identified, but some evidence suggests Na+/H+ exchang-
er 1 (NHE1) as a potential candidate.
Li+ promotes polyuria mainly counteracting the intracel-
lular vasopressin signaling. An additional role of the inner
medullary interstitial cells and PGE-2 pathway has to be
considered. The GSK3β cascade is also regulated by Li+.
GSK3β inhibition could lead not only to the polyuria, but
also to the Li+-dependent proliferative effect on principal
cells. Cellular reorganization of the collecting duct and
microcysts are the main pathological findings during Li+
treatment. Their relationship with the urinary concentra-
tion defect and an eventual Li+-induced ciliopathy has to
been investigated. Li+-induced NDI has been a matter
of investigation since the early 1970s. This manuscript
reports the latest clinical and experimental findings in
combination with the older fundamental results.
Key words: Lithium, Nephrogenic diabetes insipidus,
Collecting duct
Department of Anatomy, The Water and Salt Research
Center, Aarhus University, Aarhus C - Denmark
Francesco Trepiccione, Birgitte Mønster Christensen
Lithium-induced nephrogenic diabetes insipidus:
new clinical and experimental findings
ACID-BASE BALANCE: BASIC ASPECTS

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Trepiccione and Mønster Christensen: Lithium-induced urinary concentrating defect
Endogenous level of Li+ in healthy humans are quite low,
ranging around 0.2 μmol/L (10). Renal handling of Li+, in
the therapeutic range, is similar to the sodium (Fig. 1). Li+
does not have a high affinity to serum proteins, and it is
freely filtered by the glomerulus. Micropuncture studies
have shown that 65%-75% of the filtered amount is reab-
sorbed along the proximal tubule (PT) mainly in a paracel-
lular transport. One third of this transport occurs in the
straight part of the PT. Proximal Li+ and Na+ reabsorption
are proportional (11). Neither a significant distal absorp-
tion nor tubular secretion mechanisms are described un-
der normal sodium intake in humans. These features made
Li+ clearance an easy tool for estimating sodium and water
reabsorption in the proximal tubule under normal sodium
intake (12). However, clinical (13) and experimental (14)
studies have shown that Li+ is reabsorbed mainly through
a transepithelial route along the thick ascending limb. This
mechanism accounts for about the 20% of the Li+ filtered
amount in salt-depleted subjects (13).
Experimental studies illustrated that a low-sodium diet in-
duces distal Li+ reabsorption (15). Amiloride (16) but not
thiazides (17) can revert this phenomenon, pointing to the
CD as the crucial segment of Li+ distal reabsorption. Recent
Fig. 1 - Renal handling of lithium along the nephron: 65%-
75% of the filtered amount is reabsorbed along the proximal
tubule, mainly in the straight part (large gray arrow). This
reabsorption is paracellular. In salt-depleted status, Li reab-
sorption along the thick ascending limb of Henle’s loop is es-
timated around 20% (small arrow). In rats, a small amount of
lithium is taken up along the amiloride-sensitive distal part of
the nephron (arrowhead).
studies showed that Li+ is taken up from the ENaC to the
same extent as Na+, and this could be relevant for the Li+-
induced urinary concentrating defect.
lI+-I n d u c e d n e p h r o g e n I c d I a b e t e s I n s I p I d u s :
c l I n I c a l d a t a
Li+ therapy can progressively reduce urinary concentration
ability according to the length of the exposure and the dos-
ing. A single dose (600 mg) of Li+-carbonate impairs the an-
tidiuretic response of hypertonic saline infusion in healthy
subjects (18). One month of Li+ treatment reduces both
urinary osmolality and aquaporin 2 excretion in healthy vol-
unteers (19). Longer treatment can progressively induce a
more severe impairment of the urinary concentration ability
up to an overt polyuria (about 10 l/day). Patients with Li+-
induced polyuria have higher levels of circulating vasopres-
sin than healthy controls (20). Finally, Li+-associated polyu-
ria does not respond to deamino-D-vasopressin (dDAVP)
administration (21). This shows a picture of a Li+-induced
NDI. The therapeutic range of lithium is quite narrow. Li+-
related renal adverse effects are also relative to dosages. A
recent review illustrates that a single daily dose is associ-
ated with a lower incidence of renal adverse effects than a
multiple daily dose (22).
Alterations in urinary concentration usually occur after 8
weeks of therapy (23). A drug washout progressively im-
proves the symptoms; they revert progressively up to 8
weeks from after the Li+ withdrawal has started (24). This
reversal seems to be dependent on the time of Li+ exposure,
and is lacking in subjects exposed for more than 15 years
(25). More evidence is necessary to clarify when and how
the NDI symptoms become irreversible with Li+ withdrawal.
Many studies from the 1970s have investigated the histolog-
ical features of patients under Li+ therapy. The distal tubule
and CD are dilated, and their cells show a glycogen-con-
taining PAS-positive material (26). The severity of the tubular
abnormalities positively correlate with urinary concentration
impairment (27). Li+ treatment also induces microcyst gen-
eration. They are easily detected by magnetic resonance
imaging (MRI) scan to be located in the cortex and medulla
and usually ranging around 1-2 mm in diameter (28). Micro-
cysts correlate with the duration of Li+ therapy (26).
Reduction or suspension of treatment are the first steps in
controlling the polyuria; nevertheless, some drugs are ef-
ficacious. Amiloride has been used for a long time in the
treatment of Li+-induced NDI. It was first introduced for
the prevention of the potassium loss associated with an
overt polyuria. Amiloride improves the concentrating ability
of Li+ NDI patients regardless of any significant changes

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JN 2010; 23 (S16): S43-S48
in serum Li+ concentration (29). A recent study has shown
that amiloride treatment increases the response to dDAVP
in terms of urinary osmolality, and AQP2 excretion (30). In-
domethacin and other nonsteroidal antiinflammatory drugs
(NSAIDs) have been used for the management of severe
Li+-induced polyuria (31). Short-time usage of NSAIDs is ef-
fective in decreasing the urinary output, but more exhaus-
tive data are necessary on their renal safety in long-term
trials. Whether the pharmacological therapy also has a role
in improving the Li+-induced morphological changes has to
be investigated.
lI+-I n d u c e d n e p h r o g e n I c d I a b e t e s I n s I p I d u s :
e x p e r I m e n t a l d a t a
In vitro and in vivo studies showed that Li+ decreases AQP2
expression (Fig. 2). The vasopressin-regulated water chan-
nel AQP3 is also down-regulated by Li+ treatment (32). Li+
determines a vasopressin nonresponding form of diabetes
insipidus down-regulating luminal AQP2 expression and ba-
solateral AQP3 in principal cells.
The ENaC is the entry route of Li+ in principal cells. Li+ fails to
induce NDI in mice lacking ENaCs in CDs (33). In addition,
amiloride treatment significantly reduces the Li+-induced
polyuria (34). No clear evidence exists for the exit pathways
of Li+. NHE1 in erythrocytes is crucial for Na-Li countertrans-
port (35); this protein could play a similar role in CDs.
Many intracellular pathways can be involved in this process.
Impairment of protein kinases A (PKA) cascade has been
considered the main mechanism of Li+ action. Li+ inhibits
both basal and dDAVP-stimulated activity of adenylate cy-
clase enzyme, thereby reducing the 3’-5’ cyclic adenosine
monophosphate (cAMP) production in isolated CDs from
Li+-treated rats (36). It is controversial whether this mecha-
nism is directly related to AQP2 down-regulation. Mpk-CCD
cells treated with Li+ showed a non-cAMP-dependent down-
regulation of AQP2 (37). A recent study depicts another sce-
nario. Selective GSK3β deletion in CDs is associated with
a lower activity of adenylate cyclase and lower cAMP level,
suggesting a GSK3β-dependent regulation of adenylate cy-
clase (38).
Besides cAMP-dependent pathways, several other key
enzymes are regulated by Li+. Phospho-proteomic analy-
sis on inner medullary CDs from long-term Li+-treated rats
showed Li+ activates PKB/Akt and MAPK kinases and in-
hibits GSK3β kinase (39). Akt is an upstream regulator of
GSK3β. Among several functions, this pathway regulates
the proapoptotic signals. Li+ activates Akt by promoting its
phosphorylation at S473 and T308. Therefore Akt inhibits
GSK3β through phosphorylation at S9. GSK3β inhibition is
associated with an accumulation of β-catenin in principal
cells. This latter protein is mainly involved in cadherin-me-
diated cell adhesion, and it plays a role as transcriptional
coregulator of cell growth genes. This regulatory pathway
Fig. 2 - The collecting duct’s principal cells.
“A”: principal cells are equipped with epi-
thelial Na+ channel (ENaC) on the luminal
side and Na+/H+ exchanger 1 (NHE-1) at
the basolateral side. They are considered
the entry and exit route of Li+ into and out
of the cell, respectively. “B”: Li+ impairs
the PKA pathways. Li+ inhibits adenylate
cyclase activity (AC) and cAMP genera-
tion. “C”: Li+ induces phosphorylation of
the Akt at S473 and T308. This leads to an
inhibition of GSK3β through phosphoryla-
tion at S9. The Akt-GSK pathway can in-
fluence the regulation of AQP2 at several
levels. Recent evidence showed a lower
activity of AC in mice with collecting duct
(CD)-selective knockout for GSK3β. “D”:
role of interstitial cells in AQP2 regulation.
Li+ inhibition of GSK3β activity in intersti-
tial cells stimulates COX2-PGE pathway
leading to AQP2 down-regulation in prin-
cipal cells.

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Trepiccione and Mønster Christensen: Lithium-induced urinary concentrating defect
could potentially lead to the high proliferation rate of prin-
cipal cells during long-term Li+ treatment (40). In addition, a
recent study showed a vasopressin-dependent regulation
of the phosphorylation status of β-catenin (41). Whether Li+
counteracts the vasopressin action also by modulating the
phosphorylation status of β-catenin is an interesting future
direction deserving a deeper investigation. Finally Li+-in-
duced NDI pathogenesis involves, at least partly, the med-
ullary interstitial cells. Li+ inhibits the GSK3β and increases
the expression of COX-2 in medullary interstitial cells. This
is associated with an increased urinary excretion of PGE-2
and to the diuretic effect. COX-2 inhibitors partially reverse
Li+-induced polyuria in rats (42). Higher sensitivity to puri-
nergic stimuli could be one of the driving forces of PGE-2
secretion (43).
Li+ remodels the entire structure of the CD. The usual ratio
between principal and intercalated cells (ICs) forming the
CD is subverted after long-term Li+ treatment along all of
the CD zones. The fraction of type A ICs is increased. Type
A ICs appear in the inner medulla, where they are usually
rare (44). Despite this cellular reorganization, principal cells
have a higher proliferation rate than type A ICs (40). Cellular
conversion of principal into type A ICs could be one of the
possible underlying mechanisms (unpublished data).
Both in humans and rats, Li+ treatment is associated with
microcyst formation. Many studies have shown that abnor-
mal renal cyst formation is related to ciliopathies (impair-
ment of primary cilium complex function). A recent study
illustrates that Li+ induces the elongation of the primary cil-
ium in fibroblast-like synoviocytes in a GSK3β not related
mechanism (45).
co n c l u s I o n a n d p e r s p e c t I v e s
Li+ salts are efficacious antipsychotic agents; however, NDI
is a frequent adverse effect that requires cessation of the
therapy. These renal consequences are mainly due to an
impairment of the aquaporin system in the CD. In patients
affected by Li+-dependent NDI, amiloride improves the uri-
nary concentration ability. Experimental data confirm the
crucial importance of the amiloride-sensitive ENaC as the
entry route for Li+ in the CD principal cells. However, de-
spite the fact that many key components have been iden-
tified, the complete picture is still lacking. The detection
of earlier targets involved in Li+-affected AQP2 pathways
will add new insights into aquaporin physiology and NDI
pathogenesis.
Li+ induces severe alterations of the morphology of the CD.
Human biopsies reveal several degrees of lesion from cell
swelling to necrosis and tubular interstitial nephritis. CDs of
Li+-treated rats show a dysregulation of the ratio between
principal and ICs, but how these pathological alterations
occur and what the underlying mechanisms are have still
been only poorly investigated.
Li+ effects on renal physiology have been investigated for
many years. And, although many points have been ad-
dressed, new intriguing questions have arisen and continue
to take the Li+ story forward.
Financial support: None.
Conflict of interest statement: None declared.
Address for correspondence:
Francesco Trepiccione
Department of Anatomy
The Water and Salt Research Center
Aarhus University
Wilhelm Meyers Allé 3
DK-8000 Aarhus C, Denmark
francesco.trepiccione@ana.au.dk
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