Low levels of HDL cholesterol and its major apoprotein constituents apoA-I and apoA-II are common in patients who have ESRD and are undergoing hemodialysis (HD), but the metabolic basis for the low HDL is poorly understood. This study aimed to investigate in vivo metabolism of apoA-I and apoA-II in five normotriglyceridemic ESRD-HD patients and compared it with five control subjects using endogenous stable isotope labeling methods coupled with a multicompartmental modeling. HDL cholesterol, apoA-I, and apoA-II levels were markedly decreased in the ESRD-HD patients by 39, 30, and 44%, respectively, in comparison with the control subjects. Fractional catabolic rate of apoA-I was found to be significantly increased by 59% to 0.360 +/- 0.084/d in ESRD-HD patients as compared with control subjects of 0.227 +/- 0.076/d (P = 0.028), whereas the production rates remained unchanged. Conversely, the apoA-II production rate significantly decreased by 31% to 1.50 +/- 0.61 mg/kg per d in the ESRD-HD patients in comparison with control subjects of 2.17 +/- 0.40 mg/kg per d (P = 0.047) with apoA-II fractional catabolic rate unchanged. These results revealed that the decreased levels of apoA-I are due solely to the increased rate of catabolism, whereas the reduced apoA-II levels are due primarily to the decreased rate of production in ESRD-HD patients. This differential regulation of apoA-I and apoA-II further supports the concept that apoA-I and apoA-II have distinct metabolic pathways.