Urea for Treatment of Hyponatremia in Patients With SIAD Unresponsive to Fluid Restriction

Official title

Efficacy of Oral Urea Supplementation in Patients With SIAD Not Adequately Controlled With Fluid Restriction

Overview

Hyponatremia due to SIAD is frequently insufficiently corrected by fluid restriction alone, which remains the first-line therapy but is often poorly tolerated. Urea supplementation is recommended as second-line therapy. This prospective study evaluates the effectiveness of oral urea supplementation in patients with chronic SIAD and persistent hyponatremia despite fluid restriction.

Detailed description

Hyponatremia (serum sodium, s-Na \<135 mmol/L) is the most common electrolyte disorder in hospitalized patients, with prevalence increasing with length of hospital stay. Among hypotonic euvolemic hyponatremias, the syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause and is characterized by impaired free water excretion. SIAD may result from central nervous system disorders, pulmonary diseases, malignancies, or medications, and remains a diagnosis of exclusion.

When possible, treating the underlying cause can resolve the syndrome; however, in many cases the cause remains unknown and therapeutic options are limited. First-line treatment is fluid restriction, which is often insufficient and difficult to maintain in the long term. AVP receptor antagonists, such as tolvaptan, are effective but expensive and may carry a risk of overly rapid correction of serum sodium.

Second-line therapy recommended by current guidelines is urea supplementation, which has shown safety and efficacy in normalizing serum sodium. However, most available evidence derives from retrospective studies, and prospective data are limited.

This study aims to evaluate the effectiveness of urea supplementation in patients with chronic, mildly symptomatic SIAD-related hyponatremia not adequately controlled by fluid restriction (≤1500 mL/day), and to explore its effects on neuroendocrine adaptation, body fluid composition, and bone metabolism.

Interventions

• Dietary supplement urea
  Patients with persistent hyponatremia (sodium corrected for glucose \<135 mmol/L) after ≥1 week of fluid restriction (≤1500 mL/day) will receive urea 30 g/day (2 sachets; 1 in the morning and 1 in the evening) dissolved in water, while maintaining fluid restriction ≤1500 mL/day. Blood and urine evaluations will be performed at day 1, day 21±4 and day 42±4, with additional assessments (Montreal Cognitive Assessment \[MoCA\] questionnaire and bioelectrical impedance vector analysis \[BIVA\]) at s

Primary outcome measures

• Change in serum sodium levels [Time frame: Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation]

Secondary outcome measures (5)

• Changes in copeptin, NT-proBNP, and MR-proADM levels [Time frame: Baseline, day 42±4, and 10±2 days post-therapy]
• Bioimpedance adaptation [Time frame: Baseline, day 42±4, and 10±2 days post-therapy]
• Bone turnover markers [Time frame: Baseline, day 42±4, and 10±2 days post-therapy]
• Cognitive performance [Time frame: Baseline and day 42±4]
• Variation in other Serum and Urinary Analytes [Time frame: Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation]

Eligibility criteria

Inclusion criteria

• Confirmed diagnosis of SIAD established prior to study inclusion, defined as:
• Plasma sodium concentration <135 mmol/L
• Plasma osmolality <300 mOsm/kg
• Urine osmolality >100 mOsm/kg
• Urine sodium concentration >30 mmol/L
• Intact adrenal and thyroidal function and no use of diuretics in the last 4 weeks
• Clinical euvolemia, defined as an absence of signs of hypovolemia (orthostasis, tachycardia, decreased skin turgor, dry mucous membranes) or hypervolemia (edema, ascites)

Fulfillment of all diagnostic criteria at baseline (day 0) was not mandatory, as the diagnosis of SIAD had already been established prior to study inclusion based on overall clinical assessment.

\- Written informed consent obtained

Exclusion criteria

• Chronic hypotonic hyponatremia secondary to another etiology
• Presence of moderate to severe symptoms attributable to plasma hypotonicity
• Severe hypotonic hyponatremia (serum sodium <120 mmol/L)
• Another ongoing drug treatment for hyponatremia (including vaptans and salt tablets)
• Severe hepatic insufficiency
• eGFR <45 mL/min/1.73 m²
• Pregnancy or breastfeeding
• Known allergy or intolerance to urea
• Patient refusal or inability to provide written informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 1 center

• AOU Città della Salute e della Scienza — Turin

Publications

• Rondon-Berrios H, Tandukar S, Mor MK, Ray EC, Bender FH, Kleyman TR, Weisbord SD. Urea for the Treatment of Hyponatremia. Clin J Am Soc Nephrol. 2018 Nov 7;13(11):1627-1632. doi: 10.2215/CJN.04020318. Epub 2018 Sep 4. PMID 30181129
• Perello-Camacho E, Pomares-Gomez FJ, Lopez-Penabad L, Mirete-Lopez RM, Pinedo-Esteban MR, Dominguez-Escribano JR. Clinical efficacy of urea treatment in syndrome of inappropriate antidiuretic hormone secretion. Sci Rep. 2022 Jun 17;12(1):10266. doi: 10.1038/s41598-022-14387-4. PMID 35715573
• Decaux G, Brimioulle S, Genette F, Mockel J. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med. 1980 Jul;69(1):99-106. doi: 10.1016/0002-9343(80)90506-9. PMID 7386514
• Soupart A, Coffernils M, Couturier B, Gankam-Kengne F, Decaux G. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol. 2012 May;7(5):742-7. doi: 10.2215/CJN.06990711. Epub 2012 Mar 8. PMID 22403276
• Woudstra J, de Boer MP, Hempenius L, van Roon EN. Urea for hyponatraemia due to the syndrome of inappropriate antidiuretic hormone secretion. Neth J Med. 2020 Apr;78(3):125-131. PMID 32332187
• Hammonds WM, Keating EA, Smetana ME, Smetana KS, Bond MM. Safety and Efficacy of Urea for Hyponatremia. Hosp Pharm. 2022 Jun;57(3):365-369. doi: 10.1177/00185787211037548. Epub 2021 Aug 5. PMID 35615479
• Lockett J, Berkman KE, Dimeski G, Russell AW, Inder WJ. Urea treatment in fluid restriction-refractory hyponatraemia. Clin Endocrinol (Oxf). 2019 Apr;90(4):630-636. doi: 10.1111/cen.13930. Epub 2019 Jan 25. PMID 30614552
• Nervo A, D'Angelo V, Rosso D, Castellana E, Cattel F, Arvat E, Grossi E. Urea in cancer patients with chronic SIAD-induced hyponatremia: Old drug, new evidence. Clin Endocrinol (Oxf). 2019 Jun;90(6):842-848. doi: 10.1111/cen.13966. Epub 2019 Mar 29. PMID 30868608

Identifiers

NCT: NCT07528365 · UREA-BIVA-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗