Atorvastatin for the Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus
Condition: Lithium Use, Nephrogenic Diabetes Insipidus
MeSH terms: Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Mellitus
Study type: Interventional
Phase: Phase 2

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.
    


Intervention name(s): Atorvastatin
Intervention type(s): Drug
Intervention description(s): Member of drug class called statins, primarily used as a lipid-lowering agent and the prevention of events associated with cardiovascular disease
Other intervention name(s): Lipitor
Intervention MeSH terms: Atorvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment