Increased atherogenicity of low-density lipoprotein in heavy proteinuria

Background: Heavy proteinuria is associated with marked abnormalities of lipoprotein metabolism and increased risk of atherogenesis. It is possible that qualitative as well as quantitative changes occur in lipoproteins to contribute to increased cardiovascular risk; for example, it is known that LDL exhibits heterogeneity, with small, dense LDL III particles being more atherogenic. Methods: We investigated LDL subfractions (measured by density gradient ultracentrifugation), VLDL subfractions, and post-heparin lipases in 12 patients with primary glomerular disease and 24-h albuminuria >2.5 g. These were compared to 23 age- and sex-matched controls. Results: Total LDL concentrations were similar in proteinuric patients and controls; however, there was a shift in subfraction distribution. The larger LDL I and LDL II particles were lower in the proteinuric group (29±24 vs 62±26 mg/dl P=0.011 and 121±80 vs 197±74 mg/dl P=0.028), whereas the concentration of atherogenic LDL III (small dense) was higher (135±64 vs 75±71 mg/dl P=0.0016). The concentration of total VLDL and both its subfractions were increased in the patients with proteinuria. Post-heparin hepatic and lipoprotein lipase levels were similar to normal. Conclusions: These findings suggest that the atherogenicity of LDL is increased in patients with heavy proteinuria because of the redistribution towards smaller denser particles. Since small, dense LDL has a lower affinity for the LDL receptor, the altered nature of the lipoprotein in proteinuria may decrease its clearance by the receptor-mediated pathway and contribute to the reduced clearance of LDL observed in this population. This may contribute to progression of renal failure or the accelerated vascular disease found in patients with heavy proteinuria.