**Sodium and Hemodialysis**

Matthew Gembala and Satish Kumar

*University of Oklahoma USA* 

### **1. Introduction**

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Impact of biofeedback-induced cardiovascular stability on hemodialysis tolerance

The original dialysate sodium prescription was 126.5 mEq/L (Kolff, 1947). Before volumetric controlled ultrafiltration, sodium was removed primarily, slowly and most predictably by diffusion. With the development of high flux dialysis membranes, dialysate osmolality asserted a faster and more dramatic effect on serum osmolality. Hypotonic dialysate rapidly drops serum osmolality that leads to net fluid shift out of the vascular space, causing significant intradialytic symptoms (Stewart et al., 1972). Further, the duration of dialysis sessions was shortened as clearance of urea was improved, requiring an accelerated rate of ultrafiltration.

To counter symptoms of hypo-osmolarity and rapid ultrafiltration, dialysate sodium concentration was increased. In the early 1970s, Stewart demonstrated less cramping with sodium of 145 mEq/L than with 132 mEq/L (Stewart et al., 1972). In the early 1980s, Locatelli showed improved cardiovascular stability when sodium concentration was raised to 148 mEq/L from 142 mEq/L (Locatelli et al., 1982). As the sodium prescription increased, concerns about sodium overloading arose. In 1985, Cybulsky demonstrated worsening of hypertension in already hypertensive patients (Cybulsky et al., 1985); and Daugirdas showed increasing thirst and interdialytic weight gain (IDWG), in both level and modelled high sodium techniques (Daugirdas et al., 1985). Nevertheless, intradialytic hemodynamic stability remained a valid concern and the data were not always clear. For example, Barré showed no worsening of hypertension and pulmonary edema at [Na+] 145, 150 and 155 mEq/L (Barré, 1988). The technique of sodium modelling offered a theoretical means to attenuate the risk of sodium loading. By the early 1990s, Acchiardo advocated, "[s]odium modelling [149mEq/L dropping to 140 mEq/L] should always be used in patients being maintained on high flux dialysis" (Acchiardo & Hayden, 1991). This approach was widely practiced throughout the 1990s. After more than a decade of high sodium and sodium profiling dialysis, trends toward exacerbation of hypertension and interdialytic weight gain were becoming evident (Song, 2002).

Despite a growing body of literature on the effects of dialysis sodium, the sodium prescription is frequently overlooked or ineffectually utilized. Further, despite the increasing sophistication of dialysis delivery systems, the sodium prescription is often not adjusted to suit individual patient needs. First, we will erect a conceptual framework for understanding the dialysate sodium prescription. Second, we will review the primary literature regarding dialysate sodium and outcomes. Third, we will formulate recommendations on prescribing dialysate sodium. Finally, we will explore the technical and systems challenges to adjusting the actual sodium delivered to an individual patient.

Sodium and Hemodialysis 49

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

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 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,

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

The amplitude of the effect of non-osmotic sodium reservoirs should be significant.

pool, stimulating thirst and driving extracellular volume expansion.

stimulate the creation of reservoirs for further sodium storage.

driving volume expansion.
