Silver SM
Cerebral edema after rapid dialysis is not caused by an increase in brain organic osmolytes

J Am Soc Nephrol (Dec) 6:1600-1606 1995

Neurologic deterioration including seizures, coma, and cerebral edema developing toward the end of dialysis is called the dialysis disequilibrium syndrome (DDS). DDS was initially hypothesized to be caused by slow removal of urea from the brain, establishing a brain to plasma urea gradient that promoted osmotically driven movement of water into the brain ('reverse urea effect'). However, initial studies by Arieff in rapidly dialyzed uremic dogs found an increased brain to plasma osmolality ratio (Kidney Int 4:177, 1973). This led to the suggestion that cerebral edema was caused by formation of 'idiogenic osmoles' during dialysis. However, Arieff measured tissue osmolality by freezing-point depression, which is now recognized to have limited accuracy. These idiogenic osmoles are now known as organic osmolytes, and are found in regions of the body exposed to osmotic stress (especially the renal medulla and brain). Osmolytes change in an adaptive manner in response to changes in plasma tonicity, allowing cells to survive osmotic stress. The major brain osmolytes are glutamine, glutamate, taurine, and myoinositol. Brain osmolytes are increased during chronic hyponatremia; however, the response is gradual over several days. In contrast, Arieff hypothesized that these compounds increase rapidly, and in a maladaptive direction (since plasma osmolality falls during dialysis). Arieff's hypothesis has now been tested by several groups.

In a previous study, Dr. Silver found that a large brain to plasma urea gradient developed during dialysis that could account for the cerebral edema. However, since osmolytes were not measured, they could not rule out the concomitant formation of idiogenic osmoles. In this study, rats were made uremic by ureteral ligation. After 42 hrs, Dr. Silver directly measured plasma and brain water, electrolytes, urea and osmolytes in uremic rats, and uremic rats subjected to dialysis. Dialysis increased brain water, and increased the brain to plasma urea ratio (0.65 to 1.32), without altering the brain content of sodium, potassium or urea. There was no change in any of the major brain osmolytes. Finally, the retention of brain urea could quantitatively account for the increase in brain water. He concluded that the cerebral edema in this model of DDS was caused by a large brain to plasma urea gradient (reverse urea effect) and not due to the formation of organic osmolytes (idiogenic osmoles). These findings agree with his previous study, and preliminary study by Zhou et al (JASN 4: 899, 1994), who also did not find changes in brain osmoles.

The other interesting conclusion is that urea moves very slowly across the blood brain barrier. This is supported by the findings that 1) brain urea is 65% of plasma urea pre-dialysis, and 2) brain urea content falls slightly (but not significantly) during dialysis. Other studies have shown that 8 hrs are needed for urea to reach a steady state in the brain after IV injection. Thus, in contrast to generally accepted beliefs, urea moves very slowly across the blood brain barrier. This explains why dialysis with an iso-osmolar urea bath prevents cerebral edema, and why exponential decreases in dialysate sodium (sodium modeling) reduces the frequency of DDS, despite the advent of faster high efficiency and high flux dialysis membranes. (Star)

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Basic hemodialysis : Complications (acute)