Hyponatremia Due to Reset Osmostat: Uncovering the Clues

Hyponatremia, a condition affecting 1 in 3 hospitalized adult patients, is a prevalent and significant electrolyte abnormality (1). It is defined as serum sodium <135 mEq/L, and within its broad differential lies a subtle, often underrecognized etiology: reset osmostat (RO).

Under normal conditions, the osmostat maintains serum sodium within a tight therapeutic range (140-145 mEq/L) by regulating water retention when osmolality rises above 285-295 mOsm/kg and promoting water excretion when osmolality falls below this range. In patients with reset osmostat (RO), the osmostat threshold is lowered to a new set point, typically below 280 mOsm/kg. This adjustment results in stable, chronic hyponatremia, usually in the range of 125-134 mEq/L. Unlike most other causes of hyponatremia, where antidiuretic hormone (ADH) secretion is either appropriately altered (e.g., due to volume changes) or inappropriately elevated (e.g., SIADH), ADH secretion in RO patients remains normal but is aligned with their new osmostat set point.

The pathophysiology of RO involves a recalibration of the hypothalamic osmoreceptors that control ADH release. While the exact mechanisms remain incompletely understood, this reset creates a new homeostatic balance that the body actively maintains, resulting in stable, mild-to-moderate hyponatremia that typically doesn't worsen over time and improves if the underlying problem resolves. RO has been associated with various clinical conditions, including malnutrition, tuberculosis, advanced age, psychosis, and certain malignancies (2). 

RO remains unrecognized for several compelling reasons. Its clinical presentation and biochemical profile may appear remarkably similar to SIADH, leading to an inappropriate classification of RO as a subtype of SIADH (type C SIADH). Many clinicians lack familiarity with diagnosing this condition, leading to misclassification under other broader hyponatremia categories. Some studies have suggested that 1 in 3 patients diagnosed as SIADH actually have RO (3). Although some astute clinicians may suspect this condition due to the clinical presentation, confirming the diagnosis involves water loading (15- 20 ml/kg of free water PO or D5W IV in 0.5-1 hr.) with subsequent close monitoring due to the risk of worsening hyponatremia or fluid overload (1). The time and resources needed to perform this test may make it impractical in many clinical settings, discouraging clinicians from looking for RO as the cause. 

Figure 1. Water loading test to differentiate reset osmostat from other causes of euvolemic hyponatremia

The consequences of this underdiagnosis are significant. Patients may undergo unnecessary and potentially harmful treatments to correct a sodium level their body is programmed to maintain at a lower setpoint. Fluid restriction, salt supplementation, and medications like vaptans not only prove ineffective but may cause adverse effects without addressing the underlying physiological adaptation.

The fractional excretion of uric acid (FeUA) provides a simpler method for differentiating RO from conditions like volume depletion, overload, or SIADH(1,4). In RO, FeUA remains normal (4-11%), while it is low (<4%) with volume changes and high (>12%) in SIADH or renal salt-wasting syndromes.

Under normal conditions, about 99% of filtered uric acid is reabsorbed in the proximal tubule via the URAT1 transporter, indirectly coupled to sodium transport through an electroneutral anion exchanger. Reabsorbed uric acid exits into circulation via GLUT9 on the basolateral membrane. Additionally, uric acid is secreted from blood to tubular cells via OAT1/OAT3 transporters and into the lumen via MRP4, NPT1, and NPT4, with less than 10% ultimately excreted in urine after post-secretory reabsorption(5). The normal FeUA range remains at 4-11%.

Although somewhat speculative, in mildly volume-expanded states such as SIADH, hypouricemia results not only from volume expansion but also from vasopressin V1A receptor activation on the basolateral side of the proximal tubular cell. This receptor activation downregulates GLUT9 and enhances uric acid excretion via apical transporters, leading to hyperuricosuria (FeUA >12%) (6).  Conversely, in conditions where ADH is appropriately elevated, low effective arteriolar volume and V2 receptor activation dominate, increasing sodium, urate, and water reabsorption, resulting in hypouricosuria (FeUA <4%).RO patients, however, maintain a stable FeUA (4-11%), making this test a reliable tool for distinguishing RO from SIADH and other volume-related hyponatremia, provided adrenal, thyroid, and renal functions are intact, psychogenic polydipsia is ruled out by history, and thiazide diuretics are not in use.

Figure 2. Steps involved in uric acid transport in the proximal tubule of the kidney and the role of V1A receptor in patients with SIADH. Figure 2A outlines the different uric acid transporters involved in the reabsorption and excretion of uric acid, and Figure 2B outlines the four-step process in uric acid transport.

Clinicians should maintain a high index of suspicion for reset osmostat (RO) in patients with mild to moderate hyponatremia (typically 125-134 mEq/L) that does not respond to standard therapy. Recognizing hyponatremia due to RO as a distinct physiological adaptation rather than a disorder will help clinicians provide more appropriate care, avoiding ineffective or potentially harmful interventions. While mild to moderate hyponatremia has been associated with subtle neurological and cognitive symptoms, there is currently no evidence linking these symptoms specifically to RO, highlighting the need for further research.

References:

1. Rigueto, L. G.; Santiago, H. M.; Hadad, D. J.; Seguro, A. C.; Girardi, A. C. C.; Luchi, W. M. The “New Normal” Osmotic Threshold: Osmostat Reset. Clin. Nephrol. Case Stud. 2022, 10 (2196–5293), 11–15.Taniguchi, K.; Tamura, Y.; Kumagai, T.; Shibata, S.; Uchida, S. Stimulation of V1a Receptor Increases Renal Uric Acid Clearance via Urate Transporters: Insight into Pathogenesis of Hypouricemia in SIADH. Clin. Exp. Nephrol. 2016, 20 (6), 845–852.

2. Feder, J.; Gomez, J. M.; Serra-Aguirre, F.; Musso, C. G. Reset Osmostat: Facts and Controversies. Indian J. Nephrol. 2019, 29 (4), 232–234.

3. Zerbe, R.; Stropes, L.; Robertson, G. Vasopressin Function in the Syndrome of Inappropriate Antidiuresis. Annu. Rev. Med. 1980, 31 (1), 315–327.

4. Assadi, F.; Mazaheri, M. Differentiating Syndrome of Inappropriate ADH, Reset Osmostat, Cerebral/Renal Salt Wasting Using Fractional Urate Excretion. J. Pediatr. Endocrinol. Metab. 2021, 34 (1), 137–140.

5. Hediger, M. A.; Johnson, R. J.; Miyazaki, H.; Endou, H. Molecular Physiology of Urate Transport. Physiology (Bethesda) 2005, 20 (2), 125–133.

6. Taniguchi, K.; Tamura, Y.; Kumagai, T.; Shibata, S.; Uchida, S. Stimulation of V1a Receptor Increases Renal Uric Acid Clearance via Urate Transporters: Insight into Pathogenesis of Hypouricemia in SIADH. Clin. Exp. Nephrol. 2016, 20 (6), 845–852.