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.
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