The nature of brain edema in dialysis disequilibrium syndrome (DDS) was investigated by diffusion-weighted magnetic resonance imaging (DWI). DWI was performed on normal or bilaterally nephrectomized rats before, and immediately after, hemodialysis. Hemodialysis was performed with a custom-made dialyzer (surface area 150 cm2) against a bicarbonate-buffered bath for 90 min with or without 70 mM urea. Hemodialysis with non-urea bath decreased plasma urea by 21 mM, and plasma osmolality by 22 mosmol/kg H2O, and increased brain water content by 8.0% (all < 0.05), while hemodialysis with urea bath did not affect plasma urea, osmolality, or brain water content. Three sets of axial DWI images of the brain were obtained at different gradient weighing factors with an in-plane resolution of 0.39 mm2. The apparent diffusion coefficient (Dapp) of the brain water was not affected by bilateral nephrectomy, or by hemodialysis in normal rats. In nephrectomized rats, brain Dapp was significantly increased after dialysis with non-urea bath (1.15 +/- 0.08 vs 0.89 +/- 0.07 x 10(-9)m2/sec, P < 0.01). No significant changes of brain water Dapp could be observed after dialysis with urea bath. The increased Dapp associated with DDS indicates that brain extracellular water increases and/or intracellular water decreases after hemodialysis. Our results strongly suggest that the brain edema induced by hemodialysis in uremic rats is due to interstitial edema rather than cytotoxic edema. Furthermore, our results support a primary role for the "reverse urea effect" in the pathogenesis of brain edema in DDS.DWI may be a useful diagnostic tool for DDS in patients with end-stage renal disease.