In this pilot study, muscle interstitial urea concentrations during hemodialysis (HD) were determined with a microdialysis technique and the results were compared with plasma water urea concentrations. Three patients were investigated during a total of five treatments. Under predialysis steady-state conditions, no difference was observed. During treatment, the muscle interstitial urea concentration was on average 19% higher (range 13-28%, n=4) than the plasma urea concentration after 17+/-3 min, 29% higher (25-31%, n=3) after 53+/-10 min, 40% higher (26-50%, n=3) after 117+/-6 min, 31% higher (26-34%, n= 3) after 179+/-5 min, and 31% higher (27-36%, n=4) after 231+/-5 min. The gradient declined after the conclusion of HD, muscle interstitial concentrations being on average 16% (9-26%, n=4) higher than plasma urea concentrations 9+/-2 min after treatment, and 8% (6-10%, n=3) 25+/-3 min after treatment. Thus, a urea concentration gradient with a higher concentration in muscle interstitium than in plasma, developed during HD, and dissipated gradually after treatment. This is consistent with blood flow-dependent urea sequestration in muscle tissue, causing intercompartment disequilibrium of urea during HD, and its consequent redistribution after treatment contributing to postdialysis urea rebound.