**2.1 The relationship of sodium to volume**

Traditionally, sodium content of the body and extracellular volume are equivalent concepts. Sodium concentration is a function of osmotic regulation while total sodium content is a function volume regulation. In renal, hepatic, or cardiac impairment, excess sodium cannot be adequately offloaded, leading to extracellular fluid accumulation in the form of peripheral and pulmonary edema, and ascites. Dialysis offers a means of volume regulation in the form of ultrafiltration. Hydrostatic gradients generated across the dialysis membrane are used to remove (relatively) isotonic fluid from the vascular space. Intradialytic weight gain (IDWG) is a function of the salt and water intake between dialysis sessions. Increased IDWG is attributed to dietary non-compliance; conversely, decreased IDWG reflects excellent dietary compliance or can be a harbinger of poor nutritional status as low salt intake can parallel inadequate protein-calorie intake (Sarkar et al., 2006). These mutually confounding factors must always be recognized when designing or evaluating outcomes research evaluating IDWG. An occult source of sodium can offset even the most compliant diet: hypertonic dialysate. While the programmed hydrostatic gradient moves sodium (volume) out of the patient in the form of ultrafiltrate, osmotic gradients can move sodium in or out of the patient by diffusion.

### **2.2 Defining the sodium space**

When dialyzing against hypertonic sodium, patient's sodium rises – but not so much that causes adverse osmotic sequelae. Problems arise by utilizing the osmotic utility of elevated interdialytic serum sodium without weighing the volume implications. When using profiling techniques, serum sodium concentration only increased from a predialysis average of 138.6 +/- 0.2 to 141.0 +/- 0.1 when dialyzing against an average dialysate sodium of 147mEq/L (Song et al., 2002). This change is an increase in of 2.4mEq/L; multiplying by the volume of distribution of sodium in a 70kg male patient results in 33meq of sodium transferred by diffusion. Once the set-point serum osmolality is restored by oral fluid intake, this represents just a little more than 200cc of normal saline (NS). As an osmotic agent, however, sodium's effects are distributed beyond the extracellular fluid. A change in serum sodium reflects a change in total body osmolality, or "total body cation" (Charra & Chazot, 2003; Gotch et al., 1980). When the extracellular sodium concentration rises, intracellular water will diffuse into the extracellular space reaching a new equilibrium: the predominant intracellular cation, potassium, would rise similarly to the extracellular sodium. Using the data presented by Song et al. (2002), an increase in serum sodium of 2.4mEq/L could be multiplied across the total body water; in a 70kg person this would result in a net diffusion of 100mEq of sodium, equivalent to 650cc of NS. Based on these calculations, the increase in IDWG should be between 0.20kg (ΔNa+ ≈ Δextracellular volume) and 0.65kg (Δsodium ≈ Δtotal body cation). The measured increase in IDWG, however, was greater than either calculated value. IDWG increased by 1.20kg. It is clear that the "osmolar space" is greater than the total body water. The body must be able to store sodium/osmoles outside the osmolar pool.

#### **2.3 Non-Osmotic sodium**

Increasing serum osmolality causes increased thirst leading to rapid re-accumulation of volume. As demonstrated above, this cannot account for all the sodium/volume transfer of hypertonic dialysate. Hypertonic dialysate causes sodium to accumulate in the extracellular

Traditionally, sodium content of the body and extracellular volume are equivalent concepts. Sodium concentration is a function of osmotic regulation while total sodium content is a function volume regulation. In renal, hepatic, or cardiac impairment, excess sodium cannot be adequately offloaded, leading to extracellular fluid accumulation in the form of peripheral and pulmonary edema, and ascites. Dialysis offers a means of volume regulation in the form of ultrafiltration. Hydrostatic gradients generated across the dialysis membrane are used to remove (relatively) isotonic fluid from the vascular space. Intradialytic weight gain (IDWG) is a function of the salt and water intake between dialysis sessions. Increased IDWG is attributed to dietary non-compliance; conversely, decreased IDWG reflects excellent dietary compliance or can be a harbinger of poor nutritional status as low salt intake can parallel inadequate protein-calorie intake (Sarkar et al., 2006). These mutually confounding factors must always be recognized when designing or evaluating outcomes research evaluating IDWG. An occult source of sodium can offset even the most compliant diet: hypertonic dialysate. While the programmed hydrostatic gradient moves sodium (volume) out of the patient in the form of

ultrafiltrate, osmotic gradients can move sodium in or out of the patient by diffusion.

When dialyzing against hypertonic sodium, patient's sodium rises – but not so much that causes adverse osmotic sequelae. Problems arise by utilizing the osmotic utility of elevated interdialytic serum sodium without weighing the volume implications. When using profiling techniques, serum sodium concentration only increased from a predialysis average of 138.6 +/- 0.2 to 141.0 +/- 0.1 when dialyzing against an average dialysate sodium of 147mEq/L (Song et al., 2002). This change is an increase in of 2.4mEq/L; multiplying by the volume of distribution of sodium in a 70kg male patient results in 33meq of sodium transferred by diffusion. Once the set-point serum osmolality is restored by oral fluid intake, this represents just a little more than 200cc of normal saline (NS). As an osmotic agent, however, sodium's effects are distributed beyond the extracellular fluid. A change in serum sodium reflects a change in total body osmolality, or "total body cation" (Charra & Chazot, 2003; Gotch et al., 1980). When the extracellular sodium concentration rises, intracellular water will diffuse into the extracellular space reaching a new equilibrium: the predominant intracellular cation, potassium, would rise similarly to the extracellular sodium. Using the data presented by Song et al. (2002), an increase in serum sodium of 2.4mEq/L could be multiplied across the total body water; in a 70kg person this would result in a net diffusion of 100mEq of sodium, equivalent to 650cc of NS. Based on these calculations, the increase in IDWG should be between 0.20kg (ΔNa+ ≈ Δextracellular volume) and 0.65kg (Δsodium ≈ Δtotal body cation). The measured increase in IDWG, however, was greater than either calculated value. IDWG increased by 1.20kg. It is clear that the "osmolar space" is greater than the total body water. The body must be able to store sodium/osmoles outside the

Increasing serum osmolality causes increased thirst leading to rapid re-accumulation of volume. As demonstrated above, this cannot account for all the sodium/volume transfer of hypertonic dialysate. Hypertonic dialysate causes sodium to accumulate in the extracellular

**2. Theoretical framework for consideration of dialysate sodium** 

**2.1 The relationship of sodium to volume** 

**2.2 Defining the sodium space** 

osmolar pool.

**2.3 Non-Osmotic sodium** 

matrix in a concentration dependent, non-osmotic fashion. In a now classic experiment, Saul Farber, Maxwell Schubert, and Nancy Schuster demonstrated how sodium behaves in connective tissue (Farber et al., 1957). Completely ionized chondroitin sulfate can complex with "countercations" at a ratio of 1:100. Every mol of chondroitin can associate with 100 mols of sodium- thereby reducing soluble (osmotically active) sodium. The proportion of sodium complexed with chondroitin is positively correlated to the concentration of sodium in the surrounding solution. In addition to chondroitin sulfate, hyaluronic acid and other mucopolysaccharides can interact with multiple sodium ions (Dunstone, 1959; Schubert, 1964). Given relative equal binding capacity of chondroitin sulfate for most cations (Na+, K+, Mg2+, Ca2+, Sr2+, Ba2+), the relative concentration will determine the quantity of ion bound to the polyanion (Woodbury, 1956). Therefore, when the serum sodium concentration is increased (such as when dialyzing against a high sodium dialysate), it follows that the sodium content of the mucopolysaccharides will also increase. As each ion of sodium complexes with a polyanion, it leaves the osmotic pool, leaving a lower serum sodium concentration - restoring the dialysate:serum sodium gradient. Sodium will continue to diffuse into the patient until the polyanions are saturated while the patient osmolality will not rise appreciably. Thus, the net transfer of sodium into the patient will be much more than simply the difference between the predialysis and postdialysis serum sodium as demonstrated by the calculations in paragraph 2.2. When dialysis is complete, water intake will eventually restore serum sodium to the set-point determined by the hypothalamic osmostat. The mucopolysaccharide sodium reservoir will release sodium into the osmotic pool, stimulating thirst and driving extracellular volume expansion.

Polyanions are ubiquitously distributed: bone (Woodbury, 1956), cartilage (Dunstone, 1959), blood vessels (Tobain et al., 1961), liver, intestine, brain, kidney (Law, 1984), lung and skin (Titze et al., 2003). Given this distribution, it should not be surprising that extracellular, soluble sodium makes up approximately 75% of total body sodium (Bergstrom, 1955). Therefore, 25% of total body sodium is sequestered out of the extracellular osmotic pool. The amplitude of the effect of non-osmotic sodium reservoirs should be significant.

The typical acid/base cycle in hemodialysis patients amplify pathologic sodium binding & release of polyanions, especially those of bone. Approximately 25% of total body sodium is sequestered in the bone and cartilage (Harrison, 1936). Thirty to forty percent of skeletal sodium is exchangeable with circulating sodium every 24hrs (Kaltreider, 1941; Forbes & Perley, 1951; Forbes & Lewis, 1956). During acidosis, sodium is freed from the bone, the hydrogen ion displacing the sodium ion (Levitt, 1955; Bergstrom, 1955). This model approximates the interdialytic period. The inverse process occurs during dialysis; as pH rapidly corrects, H+ ions disassociate from bone easily leaving room for sodium – a process amplified by high dialysate sodium. After dialysis, pH begins to fall; hydrogen ions reaccumulate, displacing bound sodium back into the osmotically active sodium pool, driving volume expansion.

Polyanions are not a static quantity. A high sodium environment leads to increased glycosaminoglycans synthesis: the expression mRNA of various enzymes for the synthesis of glycosaminoglycans increases 120% to 210% during high sodium intake (Heer, 2009). Increased polyanion synthesis leads to an expansion of the non-osmotic sodium pool. Further, there is increasing evidence that hypertonic stress and sodium overload stimulate mononuclear phagocyte system cells to release vascular endothelial growth factor C (VEGF-C) promoting lymphangiogenesis (Titze & Machnik, 2010). Thus, hypertonic dialysate may stimulate the creation of reservoirs for further sodium storage.

Sodium and Hemodialysis 51

As seen in Table 2, we identified ten (10) prospective involving 165 patients evaluating the relationship between the dialysate sodium prescription and IDWG, BP control, intradialytic

Of the nine (9) prospective studies reporting data on IDWG, eight (8) showed statistically significant improvement in IDWG during dialysis on the lower sodium dialysate. The one study that did not show any change in IDWG compared the narrowest sodium difference (141mEq/L vs. 138 mEq/L), making it the most susceptible to beta error (Thein et al., 2007). This 8 month study did show a blunting of the expected seasonal increase in IDWG and BP (Argiles, 2004), perhaps due to the lower sodium dialysate used during the four months of

Six prospective studies demonstrate improvement in blood pressure control after switching patients to lower dialysate sodium. Blood pressure control is defined as reduction in predialysis blood pressure measures or reduction in number of prescribed antihypertensives. Three studies showed no change in blood pressure control. No study, however, showed worsening blood pressure on lower dialysate sodium. It seems certain that a modest reduction in dialysate sodium can have beneficial influence on blood pressure

Of the five studies reporting interdialytic hypotensive events, two demonstrated more frequent hypotension on the lower sodium dialysate. The first found, 9% fewer dialysis sessions complicated by hypotension using higher dialysate sodium (Cybulsky et al., 1985). Of note, the dialysate sodium used in the "low sodium" cohort was 133mEq/L, the second lowest in all of the studies reviewed. However, given the yearlong duration of this study, the results cannot be dismissed lightly. The other study showing worsening BP stability during dialysis had an increased incident rate of approxamately 10% as well (Song, 2002). These studies highlight the limitations of reducing sodium indefinitely. There is a lower limit on decreasing serum osmolality before fluid shifts into the interstitium enough to cause hypotension. Two studies showed no change in intradialytic hypotension. One had the narrowest range of dialysate sodium (Thein et al., 2007) while the other had nearly the largest (see table 2 and Daugirdas et al., 1985). One study actually demonstrated better hemodyanamic stability on lower sodium dialysate highlighting the sometimes paradoxical effects of high sodium (de Paula et al., 2004): As hypertonic dialysate drives higher IDWG, ultrafiltration must increase in order to maintain steady dry weight. If IDWG becomes great enough, removing this excess fluid will put the

Effect of dialysate sodium on thirst was quite variable. Thirst is probably most dependent

**3.2 Prospective studies** 

hypotension and thirst.

winter typically associated with higher IDWG.

**3.2.2 Blood pressure control** 

**3.2.3 Interdialytic hypotension** 

patient at risk for intradialytic hypotension.

on subjective patient factors than any other factor.

**3.2.1 IDWG** 

management.

**3.2.4 Thirst** 
