WHERE AND HOW IS SODIUM STORED?

 

WHERE AND HOW IS SODIUM STORED?

It is now clear that sodium (Na+) is stored in at least four locations:

1. Osmotically active in the extracellular fluid such as plasma. This is the Na+ concentration that is reported in clinical laboratory results and is normally between 135 to 145 mmol/L.
2. Inside cells, at a concentration of around 10 mmol/L.
3. In bones and connective tissue. This compartment shows very little turnover.
4. In skin and muscle—more specifically, in the room between cells, the so-called interstitial space. This compartment is highly dynamic.

5. Originally, it was thought that sodium storage in the skin is a passive process, but recently it became clear that it is regulated by several intricate physiological mechanisms. Studies have shown that high-salt feeding can increase the content of particularly negatively charged GAG species in the skin and thus increase its Na+ binding capacity.7 Also, a high-salt diet increases the osmolarity in the skin, and this is sensed by local immune cells that "patrol" the interstitium, primarily macrophages. In response to increased osmolarity, the vascular endothelial growth factor C (VEGF-C) is released. VEGF-C is the primary lymphatic vessel growth factor, and its release results in hyperplasia of the lymph capillary network that facilitates Na+ (and chloride) clearance from the interstitium.8

   HOW SODIUM DRIVES INFLAMMATION

   Tissue Na+ also affects the immune system in several ways.9,10 First, a high-salt diet reduces the activation of innate immune cells that attenuate tissue inflammation. These cells are called alternatively activated (M2) macrophages. 

6. THE CATABOLIC EFFECTS OF SODIUM

   Sodium loading decreases aldosterone levels and increases the production of cortisol, a steroid hormone. 

   WHY IS THIS ALL RELEVANT FOR KIDNEY PATIENTS?

   Patients with kidney disease, especially those on dialysis, are particularly prone to the untoward effects of salt because they have a reduced ability, or no ability, to excrete salt by their failing kidneys. In patients without residual kidney function, the only way to remove salt is through dialysis. Importantly, hemodialysis can sometimes load the patients with salt, especially in situations where the dialysate sodium concentration exceeds that in the patient's plasma. In addition, patients may receive salt during hemodialysis—e.g., saline used for priming and rinsing or in the event of muscle cramps or hypotension.

7. Through a series of steps, these hormonal changes result in an increased production of urea in the liver, whereby some of the substrates required for urea generation come from muscle breakdown. In other words, the increased urea production in the liver occurs at the expense of muscle catabolism. The goal of the increased urea production is to enhance the water retention by the kidneys and avoid excessive water loss following salt intake. In addition, the increased muscle metabolism results in increased water production in liver and muscle mitochondria.11 RRI's hypothesis is that this increased water production in patients with kidney failure may contribute to the hyponatremia seen in some of them.

8. Based on physiological reasoning, it is likely ideal that the sodium ingested between hemodialysis sessions should be removed. This goal can be achieved by adjusting the dialysate sodium level in such a way that it parallels the patient's plasma Na+ level using a novel technology called electrolyte balancing control.12,13 This technology measures the conductivity, a proxy of sodium concentration, in the dialysate inlet and outlet streams, and adjusts dialysate inlet concentration so that diffusive sodium loading is avoided (Figure 2). This technology, developed by Fresenius Medical Care, also opens the way to a personalized removal of sodium, for example in patients with high sodium intake or in those with hyponatremia.

   FIGURE 2 | The electrolyte balancing control. Conductivity is measured by meters in the dialysate inflow and outflow streams. The data are sent to the central processor unit, where this information is used to calculate the dialysate sodium concentration.

   A major and fundamental problem is the quantitation of tissue sodium, since the only currently available noninvasive way to do so is by 23Na magnetic resonance imaging (23NaMRI).14,15  23NaMRI scans are only done in a few centers in the United States, are expensive, and are logistically challenging. Because of these limitations, the Renal Research Institute is currently exploring alternative methods, including novel measurement technologies. The vision is to make measurement of skin Na+ available to patients even beyond those on dialysis and to have this information become part of the routine clinical decision-making process.