On Measurement

Duval et al. (Clin Chem 1989;35: 963-6) recently confirmed our findings of greater concentrations of free apelipoprotein (ape) A-I (also known as pre-f3 high-density lipoprotein) in the serum of patients with severe renal failure than in healthy controls (1). However, the concentrations they report are considerably greater than those in healthy subjects (2-4) or in our study of renal-failure patients (1). This difference can be explained by their use of the ultracentrifuge to measure the free ape A-I concentration in serum. Their method relies on the assumption that the ape A-I present in the d >1.21 ultracentrifugal fraction represents the free ape A-I present in vivo. This is unlikely, because, during ultracentrifugation, as much as half of the ape A-I in HDL can be dissociated into the d >1.21 zone (5). Apparently Duval et al. were measuring both the in vivo free ape A-I and the portion of lipid-poor ape A-I dissociated from HDL during ultracentriftigation, so that they overestimated the free ape A-I concentration in serum. To support their findings, they suggested that an increased concentration of free ape A-I would be expected in renal failure because ape A-I is degraded in the kidney. However, there is no evidence that this occurs in humans. Consequently, their other hypothesis-that ape A-I is more easily dissociated from HDL in renal failure-cannot be excluded. Duval et al. claim that the presence of free ape A-I in increased concentrations in serum of renal-failure patients explains why the ratio of IIDLcholesterol to total ape A-I in serum is relatively low. This explanation may not be valid if they have overestimated the concentration of free ape A-I. Indeed, when we analyzed our own data, we found that the free ape A-I concentrations were insufficient to explain this decreased ratio. Thus, altered composition of HDL, with triglyceride enrichment and cholesterol depletion, remains the most likely reason for this finding (6). Duval et al. also stated that, in our earlier report (1), we found an association between free apo A-I and triglyceride concentrations in serum in renal failure. This was not the case and, indeed, our results are in agreement with their own. However, we did find a significant positive correlation between these two measurements in patients with primary hyperlipidemias (4), although in these patients the hypertriglyceridemia was much greater than we observed in our renal failure patients. Duval et al. also stated that HDL2 is the preferred substrate for lecithin:cholesterol acyltransferase (LCAT), and suggest that a decreased HDLcholesterol/ape A-I ratio could account for the decreased activity of this enzyme. However, small, protein-rich HDL3 particles are a better substrate for LCAT (7, 8). Further, as has recently been shown (9), LCAT activity is present in a complex with HDL of pre-/3 electrophoretic mobility (free ape A-I). Therefore, it is unlikely that increased concentrations of ape A-I could cause decreased LCAT activity. Pre-3 HDL has also been shown to be important for the initial stages of uptake of cholesterol from cells in vitro (10). Perhaps the increased concentration of these particles in renal failure reflects a defect in their normal metabolism. This may help explain why these patients are especially prone to develop coronary heart disease.