The syndrome of inappropriate antidiuresis (SIAD) can be treated with oral urea; however, compliance is impaired by its poor palatability.

To investigate whether dietary proteins could increase plasma sodium levels through urea-induced osmotic diuresis.

An open-label, proof-of-concept trial.

University Hospital of Basel, Switzerland, between October 2021 and February 2023.

Outpatients with chronic SIAD.

Ninety grams of protein daily for 7 days in the form of protein powder, followed by 30 g of oral urea daily for 7 days after a wash-out period of ≥1 week.

The increase in sodium levels from baseline to the end of the 7-day protein supplementation.

Seventeen patients were included. After 7 days of 90 g daily protein supplementation (n = 17), plasma sodium levels increased from 131 (129-133) to 133 (132-137), that is, by a median of 3 mmol L-1 (0-5) (P = .01). Plasma urea levels increased by 3 mmol L-1 (1.7-4.9) (P < .01), and urine urea to creatinine ratio increased by 21.2 mmol mmol-1 (6.2-29.1) (P < .01). After 7 days of 30 g oral urea (n = 10), plasma sodium levels increased from 132 (130-133) to 134 (131-136), that is, by a median of 2 mmol L-1 (1-3) (P = .06). Plasma urea levels increased by 5.8 mmol L-1 (2.7-9.2) (P < .01), and urine urea to creatinine ratio increased by 31.0 mmol mmol-1 (18.7-45.1) (P < .01).

Our findings suggest that protein powder increases plasma sodium levels in patients with chronic SIAD through protein-induced ureagenesis and osmotic diuresis. The effects are comparable with oral urea.