• 1.

    Verbalis JG, et al.. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. Am J Med 2013; 126 (10 Suppl 1):S1S42. doi: 10.1016/j.amjmed.2013.07.006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Rondon-Berrios H. Urea for chronic hyponatremia. Blood Purif 2020; 49:212218. doi: 10.1159/000503773

  • 3.

    Sterns RH, et al.. Urea for hyponatremia? Kidney Int 2015; 87:268270. doi: 10.1038/ki.2014.320

  • 4.

    Crawford H, McIntosh JF. The use of urea as a diuretic in heart failure. Arch Intern Med (Chic) 1925; 36:530541. doi:10.1001/archinte.1925.00120160088004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Decaux G, et al.. Hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. Rapid correction with urea, sodium chloride, and water restriction therapy. JAMA 1982; 247:471474. doi: 10.1001/jama.1982.03320290017021

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Spasovski G, et al.. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Intensive Care Med 2014; 40:320331. doi: 10.1007/s00134-014-3210-2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Rondon-Berrios H, et al.. Urea for the treatment of hyponatremia. Clin J Am Soc Nephrol 2018; 13:16271632. doi: 10.2215/CJN.04020318

  • 8.

    Decaux G, et al.. Treatment of euvolemic hyponatremia in the intensive care unit by urea. Crit Care 2010; 14:R184. doi: 10.1186/cc9292

  • 9.

    Nervo A, et al.. Urea in cancer patients with chronic SIAD-induced hyponatremia: Old drug, new evidence. Clin Endocrinol (Oxf) 2019; 90:842848. doi: 10.1111/cen.13966

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Soupart A, et al.. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol 2012; 7:742747. doi: 10.2215/CJN.06990711

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Lockett J, et al.. Urea treatment in fluid restriction refractory hyponatremia. Clin Endocrinol (Oxf) 2019; 90:630636. doi: 10.1111/cen.13930

  • 12.

    Soupart A, et al.. Azotemia (48 h) decreases the risk of brain damage in rats after correction of chronic hyponatremia. Brain Res 2000; 852:167172. doi: 10.1016/s0006-8993(99)02259-3

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Pierrakos C, et al.. Urea for treatment of acute SIADH in patients with subarachnoid hemorrhage: A single-center experience. Ann Intensive Care 2012; 2:13. doi: 10.1186/2110-5820-2-13

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Gankam Kengne F, et al.. Urea minimizes brain complications following rapid correction of hyponatremia compared with vasopressin antagonist or hypertonic saline. Kidney Int 2015; 87:323331. doi: 10.1038/ki.2014.273

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Rondon-Berrios H. Urea for chronic hyponatremia. ClinicalTrials.gov: NCT04588207. https://clinicaltrials.gov/ct2/show/NCT04588207?cond=urea+hyponatremia&draw=2&rank=1

    • Search Google Scholar
    • Export Citation

Urea for the Treatment of Hyponatremia: An Old Treatment Offers Fresh Hope

  • 1 Edgar Lerma, MD, is Clinical Professor of Medicine and Educational Coordinator for the Section of Nephrology at the University of Illinois at Chicago/Advocate Christ Medical Center, Oak Lawn, IL. Helbert Rondon-Berrios, MD, is Associate Professor of Medicine and Program Director of the Nephrology Fellowship Program in the Renal-Electrolyte Division at the University of Pittsburgh School of Medicine, PA.
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The conventional first-line therapy for any patient presenting with hypotonic hyponatremia due to SIAD (syndrome of inappropriate antidiuresis) is that of fluid restriction. However, we recognize that fluid restriction alone does not always work. The Expert Panel Recommendations on Diagnosis, Evaluation, and Treatment of Hyponatremia, published in 2013, identified certain criteria that are predictive of which patients are less likely to respond to fluid restriction alone (1). These include a urine-to-plasma electrolyte ratio ([urine Na + urine K]/plasma sodium [PNa]) >1 or a high urine osmolality (>500 mOsm/kg H2O).

It has been suggested that those patients who are unlikely to respond to fluid restriction alone may be effectively treated with oral urea in combination with fluid restriction (2).

Historically, urea was first used as a diuretic in 1892 (3). Three decades later, Crawford et al. (4) reported on its use in advanced heart failure. With the recognition of its beneficial effects on brain swelling and water excretion, in 1982, Decaux et al. (5) published their paper, which highlighted the “use of urea for the treatment of symptomatic hyponatremia in SIAD.”

For many decades, oral urea has been used for the treatment of SIAD. In fact, in 2014, the European Hyponatraemia Guideline Development Group published the clinical practice guideline on diagnosis and treatment of hyponatraemia, which stated that “In moderate or profound hyponatraemia, we suggest the following can be considered equal second line treatments: increasing solute intake with 0.25–0.50 g/kg per day of urea or a combination of low-dose loop diuretics and oral sodium chloride (2D)” (6).

Urea became commercially available in the United States in 2016. Unlike prescription drugs, it is regulated differently, as it does not require a prescription, and it is recommended to be used under the care of a healthcare provider. Current available formulations in the United States include ure-Na (https://www.ure-na.com/) and UreaAide (https://www.kidneyaide.com/about-ureaaide.html#/).

In 2018, a retrospective study was published, involving an inpatient population of 58 patients, whereby it compared the change in PNa between a subgroup of patients who included those with SIAD receiving urea as the “only” medication for hyponatremia, and a matched group of patients being treated for SIAD who did not receive urea (7). In the 12 patients who received “urea only,” PNa increased from 125 to 131 (p < 0.001) with 33% achieving normal PNa (vs. 8%, p = 0.08). The study concluded that this formulation of oral urea appears to be safe and efficacious in the treatment of hyponatremia.

Other studies showed the efficacy of urea in the treatment of hyponatremia in the intensive care unit (ICU) setting (8), as well as in cancer-induced SIAD (9).

Another notable study showed that the efficacy of urea was similar to that of vasopressin antagonists for treatment of chronic SIAD, whereas tolerability was good for both agents (10).

Common side effects observed with urea include distaste, nausea, vomiting, diarrhea, and headaches (3, 9, 11). There is always a concern with rapid correction of PNa with any therapy used in hyponatremia, including fluid restriction. Two studies describe overly rapid correction associated with urea (8, 13); however, no cases of osmotic demyelination syndrome (ODS) have been reported, and there is experimental data suggesting that urea may be protective in ODS (12, 14). The main indication for urea is SIAD, and there is very limited data on its use in patients with hyponatremia associated with heart failure and cirrhosis.

With the consideration of all of the limitations of current studies on urea for treatment of chronic hyponatremia due to SIAD, are randomized controlled trials on the horizon?

Well, in fact, a pilot study (NCT04588207) at the University of Pittsburgh, led by Dr. Rondon-Berrios, is currently in the works (15). The study plans to 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 a 10-day washout period, participants initially randomized to no-drug therapy will receive urea, and those initially treated with urea will receive no-drug therapy for another 42 days. In addition to measuring serum sodium at baseline and after urea therapy, participants will undergo neurocognitive and posture-stability measurements. This pilot study 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.

Helbert Rondon-Berrios is funded by exploratory/developmental research grant R21DK122023 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

References

  • 1.

    Verbalis JG, et al.. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. Am J Med 2013; 126 (10 Suppl 1):S1S42. doi: 10.1016/j.amjmed.2013.07.006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Rondon-Berrios H. Urea for chronic hyponatremia. Blood Purif 2020; 49:212218. doi: 10.1159/000503773

  • 3.

    Sterns RH, et al.. Urea for hyponatremia? Kidney Int 2015; 87:268270. doi: 10.1038/ki.2014.320

  • 4.

    Crawford H, McIntosh JF. The use of urea as a diuretic in heart failure. Arch Intern Med (Chic) 1925; 36:530541. doi:10.1001/archinte.1925.00120160088004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Decaux G, et al.. Hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. Rapid correction with urea, sodium chloride, and water restriction therapy. JAMA 1982; 247:471474. doi: 10.1001/jama.1982.03320290017021

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Spasovski G, et al.. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Intensive Care Med 2014; 40:320331. doi: 10.1007/s00134-014-3210-2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Rondon-Berrios H, et al.. Urea for the treatment of hyponatremia. Clin J Am Soc Nephrol 2018; 13:16271632. doi: 10.2215/CJN.04020318

  • 8.

    Decaux G, et al.. Treatment of euvolemic hyponatremia in the intensive care unit by urea. Crit Care 2010; 14:R184. doi: 10.1186/cc9292

  • 9.

    Nervo A, et al.. Urea in cancer patients with chronic SIAD-induced hyponatremia: Old drug, new evidence. Clin Endocrinol (Oxf) 2019; 90:842848. doi: 10.1111/cen.13966

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Soupart A, et al.. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol 2012; 7:742747. doi: 10.2215/CJN.06990711

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Lockett J, et al.. Urea treatment in fluid restriction refractory hyponatremia. Clin Endocrinol (Oxf) 2019; 90:630636. doi: 10.1111/cen.13930

  • 12.

    Soupart A, et al.. Azotemia (48 h) decreases the risk of brain damage in rats after correction of chronic hyponatremia. Brain Res 2000; 852:167172. doi: 10.1016/s0006-8993(99)02259-3

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Pierrakos C, et al.. Urea for treatment of acute SIADH in patients with subarachnoid hemorrhage: A single-center experience. Ann Intensive Care 2012; 2:13. doi: 10.1186/2110-5820-2-13

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Gankam Kengne F, et al.. Urea minimizes brain complications following rapid correction of hyponatremia compared with vasopressin antagonist or hypertonic saline. Kidney Int 2015; 87:323331. doi: 10.1038/ki.2014.273

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Rondon-Berrios H. Urea for chronic hyponatremia. ClinicalTrials.gov: NCT04588207. https://clinicaltrials.gov/ct2/show/NCT04588207?cond=urea+hyponatremia&draw=2&rank=1

    • Search Google Scholar
    • Export Citation
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