Urea for Chronic Hyponatremia
Urea for Chronic Hyponatremia
This study is examining how a dietary supplement called urea can be used to treat low blood
 sodium level. Low blood sodium level is a common problem and some studies show that many
 patients with low blood sodium level suffer from brain fog and/or loss of balance.
 Unfortunately, it is unknown at this point what the best treatment is for low blood sodium
 level. With this pilot research study, the investigators are hoping to learn more about
 whether urea is safe to take, whether patients can tolerate taking urea for several weeks,
 whether urea increases blood sodium level, and whether urea can help prevent the brain fog
 and/or loss of balance that some patients with low blood sodium level suffer from. The
 information obtained with this study is intended to be used to design a larger study in the
 future to get a definite answer whether urea is beneficial for patients with low blood sodium
 level.
Hyponatremia is the most common electrolyte disorder encountered clinically. While acute
 and/or severe hyponatremia is commonly associated with significant symptoms, milder and more
 chronic forms of hyponatremia remain clinically inconspicuous as the brain effectively adapts
 to the low extracellular osmolality. However, recent evidence suggests that even mild
 hyponatremia is associated with subtle neurocognitive deficits, gait disturbances, falls,
 fractures, and osteoporosis, as well as increased mortality. Current therapeutic
 interventions for hyponatremia, including fluid restriction and loop diuretics lack clinical
 trial data to support their efficacy and are commonly associated with poor adherence. The
 discovery of vasopressin antagonists (vaptans) provided a new drug class targeting the most
 common mechanism of hyponatremia, i.e., elevated vasopressin. Despite the demonstrated
 efficacy of vaptans in clinical trials, their use has been limited by high cost as well as
 safety concerns related to risk of liver injury and the potential for rapid correction of
 hyponatremia. Thus, despite the significant morbidity and mortality associated with chronic
 non-severe hyponatremia, there is a paucity of definitively effective, safe, well-tolerated,
 and reasonably priced treatments.

 Small European case series have suggested that oral urea is safe and effective for the
 treatment of hyponatremia. However, urea has not been available for the treatment of
 hyponatremia in the United States until very recently. This research group recently published
 the first and only study describing the effectiveness and safety of a new American
 formulation of oral urea among hospitalized patients with hyponatremia. However, the latter
 was a retrospective study limited to hospitalized patients. Data from large clinical trials
 on the efficacy of urea for the prevention of patient-centered outcomes in those with chronic
 hyponatremia are lacking. The current proposal is a pilot study that seeks to establish the
 feasibility of recruiting ambulatory patients with chronic hyponatremia into a study of urea,
 determine the acceptability of urea to patients, and explore the effect of this agent on
 plasma sodium level (PNa), neurocognitive function, and postural stability. The investigators
 will recruit 30 ambulatory patients with chronic non-severe hyponatremia and randomize them
 to oral urea or no drug treatment for a period of 42 days. Following this initial phase, all
 participants will have a 10-day washout period, followed by a 42-day period in which
 participants initially randomized to no drug therapy will receive urea and those initially
 treated with urea will receive no drug therapy. The investigators will collect data regarding
 the ease of recruitment, participant adherence to urea, and adverse events related to its
 use. The investigators will monitor participants' PNa, neurocognitive function, and postural
 stability over the course of the study. The feasibility, acceptability, and proof of
 concept/efficacy data from this pilot study will confirm the investigator's capacity to
 conduct, and will inform the design of a large clinical trial that will assess the efficacy
 of urea for the prevention of serious clinical outcomes of chronic non-severe hyponatremia.
Inclusion Criteria:

 -  Age ≥18 years

 -  Attended ≥1 visit at a University of Pittsburgh Medical Center (UPMC) outpatient
 clinic within the prior 12 months

 -  Chronic hyponatremia with a history of ≥ 2 sequential plasma sodium concentration
 (PNa) between 125 mmol/L and 132 mmol/L performed ≥ 30 days apart within the last 12
 months with most recent PNa ≤ 132 mmol/L prior to screening

 -  Patients are ambulatory without the need for any assist device (e.g., cane, walker)

 -  Mini-mental state examination (MMSE) score ≥ 27

 -  Diagnosis of SIADH established by the Bartter and Schwartz criteria as follows:

 1. Hyponatremia with a PNa between 125 mmol/L and 132 mmol/L

 2. Plasma osmolality < 275 mOsm/kg

 3. Clinical euvolemia

 4. Urine osmolality > 100 mosm/kg

 5. Urine Na > 30 mmol/L

 6. Intact adrenal function (i.e., morning plasma cortisol value ≥15 μg/dL, or
 negative corticotropin stimulation test)

 7. Normal thyroid stimulating hormone (TSH) level (i.e., TSH between 0.3 to 5
 μIU/mL)

 8. Normal kidney function (i.e., eGFR > 60 ml/min/1.73 m2)

 Exclusion Criteria:

 -  Cirrhosis and/or end-stage liver disease

 -  Heart failure on diuretics and/or with recorded left ventricular ejection fraction <40
 percent

 -  Chronic kidney disease with most recent estimated glomerular filtration rate <60
 ml/min/1.73m2

 -  Adrenal insufficiency

 -  Untreated hypothyroidism

 -  Urinary tract obstruction within the prior 2 months

 -  Uncontrolled hyperglycemia (most recent random plasma glucose ≥ 200 mg/dL)

 -  Ongoing drug treatment for hyponatremia with vaptans or combination of loop diuretics
 and salt tablets.

 -  Active malignancy

 -  Active infection

 -  Neurological disorders

 -  Pulmonary disorders

 -  Chronic pain or nausea

 -  Hypersensitivity to urea

 -  Women who are pregnant, breast feeding, or of childbearing potential who are not using
 contraception

 -  Patient is unable to consent for himself/herself