Sodium is a finely regulated electrolyte for which homeostasis is crucial in order to maintain an effective extracellular osmolality (number of milliosmoles of solutes per kilogram of solvent, measured in mOsm/Kg) and therefore intracellular volume ¹. Single or combined disturbances in the external balances of water, sodium, and potassium result in dysnatremias². Hyponatremia is defined as a serum sodium concentration below the usual target value of 135 mmol/l (the range being 130 to 137 mmol/l)², and is either acute (<48h) or chronic (≥48h)³. Hyponatremia can be associated with osmotic cell swelling, osmotic cell shrinking, or no change in the intracellular volume. Hypotonic hyponatremia induces osmotic swelling of cells (true hyponatremia) and is typically associated with a low serum osmolality (<275 mOsm/kg). However, hypotonic hyponatremia may be associated with normal or high serum osmolality in uremic patients with low sodium values but excessive loads of seric urea solute⁴. Hypertonic (or translocational) hyponatremia results from an excess of solutes with extracellular distribution, other than sodium salts (e.g. glucose or mannitol), causing osmotic exit of fluid from the intracellular compartment, hyponatremia, and elevated serum tonicity and osmolality (>290 mOsm/kg) (4). Isotonic hyponatremia with normal cell volume (artifactual hyponatremia) is encountered when low sodium values are reported by methods requiring pre-measurement dilution of the serum sample, and plasma solid content is abnormally high due to hyperlipidemia or hyperproteinemia; and sodium measured by the direct ion-specific electrode is within the normal range ¹;⁴.

Hyponatremia is the most common disorder of body fluid and electrolyte balance encountered in clinical practice ⁵. In the PD population, hyponatremia is also frequent. Its prevalence would range from about 5% up to 75%, depending on its definition. However, most data suggest an approximate prevalence around 10% to 25% in PD ⁶. No data are available regarding the cause-specific prevalence of hyponatremia in PD patients.

In PD patients, the etiological workup of hyponatremia can be cumbersome. In this article, we review the clinical manifestations as well as the pathophysiology and the etiologies of hyponatremia in PD patients, and we propose a diagnostic algorithm.

Hyponatremia has been reported as a risk factor for all-cause mortality in PD patients (7), although the pathophysiological mechanisms by which hyponatremia increases the risk for mortality in patients with CKD are not well-understood.

Hyponatremia is recognized as an independent marker of survival, in particular in specific subgroups of patients, namely, hypoalbuminemic patients, deeply anemic patients with higher baseline levels of GFR and C-reactive protein, and faster peritoneal solute transport rates. Other factors potentially reinforcing the prognostic significance of hyponatremia include lower lean body mass levels, nonprescription of renin-angiotensin-aldosterone system antagonists, and use of icodextrin-based PD solution ⁸. Hyponatremia is associated with a low residual renal function and excessive weight (probably fluid) gains.

In the PD population, hyponatremia increases the risk for several adverse outcomes, such as hospitalization for infections ⁹, protein-energy malnutrition ¹⁰, and poor peritonitis outcomes ¹¹, in addition to a higher incidence of new cardiovascular events ⁷;¹².

Risk factors for the development of hyponatremia include lower glomerular filtration rate, female gender, lean body weight, race other than African American, diabetes mellitus, and hypoalbuminemia (⁷). Use of icodextrin is another inverse correlate of serum sodium, and the only consistent predictor of a decline of natremia, once PD was started.

The severity of symptoms in patients with acute hyponatremia generally reflects the severity of cerebral overhydration, which is related to the degree of hyponatremia ¹².

Symptoms of acute hyponatremia can vary from mild and non-specific (fatigue, nausea, confusion, headache) to severe and life-threatening (vomiting, cardiorespiratory distress due to noncardiogenic pulmonary edema and/or hypercapnic respiratory failure, abnormal and deep somnolence, seizures, coma, cerebral herniation). The depth, rapidity of development, and duration of hyponatremia determine its severity ⁴. Severe symptoms of hyponatremia are caused by increased intracranial pressure due to brain edema. As water shifts from the extracellular to the intracellular compartment due to the difference in effective tonicity between brain and plasma, brain cells (mainly astrocytes) begin to swell. This usually occurs when hyponatremia rapidly progresses, the brain having too little time to adapt to its hypotonic environment. Over time, brain cells reduce the number of osmotically active particles within themselves (mostly potassium and organic solutes) in an attempt to restore the brain volume. This process takes around 24 to 48 hours, hence the reason for using the 48h threshold to distinguish acute (<48 h) from chronic (≥48 h) hyponatremia.

Chronic hyponatremia can present with more subtle symptoms. Such abnormalities include gait disturbances, falls, concentration and cognitive deficits ¹⁴. In patients with advanced CKD, the neurological manifestations of uremia can be confounded with the manifestations of dysnatremias. In fact, there are few studies focusing on clinical manifestations of hyponatremia in CKD patients. One study reported an altered mental state in patients on PD with hyponatremia ¹⁵.

Patients suffering from chronic hyponatremia are at higher risk of osteoporosis, sustaining more bone fractures than normonatremic people due to an osteoclastic activation causing higher calcemia and suppressed parathyroid hormone levels ¹⁶;¹⁷;¹⁸. These findings were confirmed by a study on US incident/prevalent PD patients, which showed that higher parathyroid hormone levels were associated with a lower likelihood of having a low sodium ⁷. Furthermore, there are emerging data on a probable direct link between hyponatremia and impaired immunity ¹⁹.

The pathophysiology of hyponatremia in CKD patients and more specifically in PD patients usually results in a single or combined disturbances. Here we review the pathophysiological mechanisms and the etiologies of hyponatremia in PD patients and propose a diagnostic algorithm for PD-related hyponatremias.