Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus
Status:
Completed
Trial end date:
2019-07-01
Target enrollment:
Participant gender:
Summary
Lithium remains the gold-standard treatment for bipolar disorder, with 30-40% of patients
with responding preferentially to this medication. Additionally, lithium is commonly used in
treatment-resistant depression, and other psychiatric disorders (e.g. schizoaffective
disorder). Lithium is especially valuable considering the great difficulty in achieving and
maintaining symptomatic remission, the high rates of disability, as well as tremendous
personal, family, and societal costs associated with bipolar disorder and treatment-resistant
depression. Despite this, clinicians are increasingly avoiding lithium, largely due to fear
of irreversible chronic kidney disease (CKD), particularly in North America.
It is well known that lithium exposure, even when dosed safely (<1.0mmol/L in adults 11 and
<0.8mmol/L in geriatric patients 12,13), can increase the risk of CKD by 3 times, in large
part through Nephrogenic Diabetes Insipidus (NDI) 14-19. NDI itself has also been associated
with acute kidney injury 20, and life-threatening hypernatremia, which is an electrolyte
imbalance characterized by high levels of blood sodium. Aside from hypertension, diabetes
mellitus, aging, and other nonspecific CKD risk factors.
NDI is characterized by excessive thirst (polydipsia) due to increased production of dilute
urine (polyuria). In NDI, lithium is believed to interact with the inositol monophosphate and
protein kinase C pathways, thereby affecting calcium-related intracellular signaling, cyclic
AMP (cAMP), inhibition of Glycogen Synthase Kinase-3 Beta (GSK3Beta), activation of MAP
Kinase and many other pathways.
NDI occurs commonly in lithium users: 50% of chronic lithium users have urinary concentrating
difficulties, with 12-19% have decreased urine osmolality (UOsm) <300mOsm/Kg).
To date, amiloride (5-20mg/day) is the only medication with prior evidence of therapeutic
effectiveness in NDI from randomized clinical trials. However as a potassium-sparing diuretic
31, amiloride can lead to lithium-level elevations, and can thereby theoretically increase
the risk of lithium-associated CNS and acute renal toxicity.
There is a need for novel, well-tolerated agents for the treatment of lithium-induced NDI.
We recently demonstrated that statins, which are well-tolerated and commonly used
medications, are associated with low lithium-induced NDI risk in the first and only previous
cross-sectional study examining statins and NDI in humans (n=71) 33. In this study we
examined current lithium users aged 20-95, who had a mean lithium duration and serum lithium
level of 10.6 years and 0.62mmol/L, respectively. Patients were assessed for UOsm following
10-hour water-restriction, a reliable measure of NDI. We found that 0% (0/17) of statin users
compared to 20.4% (11/54) on non-users had UOsm <300mOsm/Kg following 10-hour
water-restriction (Fisher's Exact p=0.055). The main statin prescribed in our previous study
was atorvastatin 10-40mg/day (n=10) 33, which is the most widely used statin for
cardiovascular disease. Atorvastatin and other statins are well-tolerated and have not been
found to have adverse effects on mood, cognition, or renal function.
The mechanism by which statins may treat NDI is not yet known, but two independent mice
studies have demonstrated the effectiveness of statins in treating genetic forms of NDI. In
those mice models of genetic NDI, prostaglandin and intracellular cytoskeleton proteins
pathways were thought to explain statins' activity on NDI.
In preparation for this project, our co-investigators Drs. Trepiccione and Christensen have
initiated a pilot study in mice to investigate whether atorvastatin treatment could improve
the lithium-induced NDI. NDI was induced in 10 mice by feeding mice with a LiCl-enriched diet
for 15 days. After induction of NDI, a group of mice received intraperitoneal injection of
atorvastatin (n=5) and a control group received vehicle (n=5) for additional 5 days in
parallel with continued lithium treatment. Although our small statistical sample do not allow
us to reach significance, (n=5 per group), the mice receiving atorvastatin showed a tendency
to reduce polyuria.
In line with this research, our present research protocol aims at conducting a randomized
controlled trial investigating a statin, such as atorvastatin, in the treatment of
lithium-induced NDI.