Although erythropoietin (EPO) derivatives improve anemic status in most end-stage renal disease patients, some EPO-resistant patients remain. Asialo-type EPO is as effective as is native EPO in vitro, but in vivo, it is quickly trapped by the hepatic asialo receptors. Alkaline phosphatase (ALP) also binds to the asialo receptor for degradation. We compared hematologic indices in 27 stable PD patients 1-3 months before and after the start of icodextrin solution. In selected patients, we also performed imaging with 99m-technetium-labeled galactosyl serum albumin (GSA) for asialo receptors. Resistance to EPO was defined as a hematocrit below 30% concurrent with EPO administration of more than 18,000 IU monthly. In 19 patients without EPO resistance started on icodextrin, the average hematocrit level did not change (-1.2%), and the average ALP activity increased 36%. But in 8 patients with EPO resistance, the average hematocrit level increased by 12% (p = 0.03 as compared with baseline), and ALP activity increased by 79% (p = 0.02 as compared to non EPO resistant cases) after icodextrin introduction. In the patients with marked elevation of ALP activity, GSA scintigraphy showed inhibition of tracer binding. These results indicate that improvement in EPO-resistant anemia and greater ALP activity with icodextrin administration are mediated through blockade of the asialo receptors on hepatocytes.