Osmotic diuresis in the treatment of hyponatremia

BACKGROUND Hyponatremia is the most common electrolyte disturbance and is associated with increased mortality and morbidity, including an increased risk for osteoporosis. Preclinical studies suggest an hyponatremia-mediated osteoclasts activation, whereas clinical studies rather
suggest osteoblasts downregulation, therefore the effect of hyponatremia correction on bone metabolism needs to be studied further. The most common cause of euvolemic hyponatremia and the main etiology addressed in this thesis is the syndrome of inappropriate antidiuresis
(SIAD). The different treatment options target the pathophysiological free water excess and include restricting fluid intake and/or increasing renal water excretion, either with AVP receptor antagonists or with osmotic diuresis. The latter can be achieved with sodium/glucose cotransporter 2 (SGLT2) inhibitors that induce glucosuria or with oral urea. Our group showed in two double-blind placebo controlled trials that SGLT2 inhibitors increased sodium levels in SIAD
Whether their chronic use prevents hyponatremia on hospital admission remained unknown Animal data suggest that the effect of urea could be achieved with a large quantity of dietary protein but whether this concept was applicable to humans was unknown.
OBJECTIVES This MD-PhD had 3 objectives; first, to investigate the effect of hyponatremia correction on bone metabolism; second, to investigate the potential of SGLT2 inhibitors in preventing hyponatremia on admission; and third, to investigate the therapeutic potential of a
high-protein supplementation in outpatients with chronic SIAD as compared to oral urea.
METHODS Manuscript 1 is a preplanned secondary analysis of a randomized, double-blind placebo-controlled, crossover trial investigating the effect of an increase in sodium levels on
serum bone markers in chronic SIAD. Manuscript 2 is a retrospective cross-sectional study aiming to compare the prevalence of hyponatremia on hospital admission in patients with diabetes mellitus type 2 (T2DM) treated with SGLT2 inhibitors as compared to matched T2DM control patients without SGLT2 inhibitors. Manuscript 3 is a proof-of-concept interventional controlled study investigating the effect of 90 g protein supplementation per day in the form of protein powder for 7 days, as compared to 30 g oral urea per day for 7 days, on plasma sodium levels of outpatients with chronic SIAD.
RESULTS First, an increase in plasma sodium levels in outpatients with hyponatremia due to chronic SIAD, even when mild, was associated with an increase in bone formation mirrored by an increase in a surrogate marker of osteoblast function. This was independent of empagliflozin treatment. Second, despite their effect in overt SIAD, SGLT2 inhibitors were not associated with a reduced hyponatremia prevalence in patients with T2DM. Third, a one-week high-protein
supplementation increased plasma sodium levels in patients with chronic SIAD through protein induced ureagenesis. The effects were achieved without additional fluid restriction and comparable to a one-week oral urea intake.
CONCLUSION Increasing sodium levels in chronic SIAD stimulates osteoblasts but the effect on bone mineral density needs further research. In chronic SIAD, plasma sodium can be increased with glucose-induced osmotic diuresis with an SGLT2 inhibitor or with urea-induced osmotic diuresis using a high-protein supplementation or oral urea. However, chronic treatment of T2DM with SGLT2 inhibitors does not prevent hyponatremia on hospital admission. Whether a long-term protein-rich diet is effective for SIAD and whether SGLT2 inhibitors are effective for hyponatremia causes other than SIAD should be investigated in future studies.