Restoration of Renal Function Does Not Correct Impairment of Uremic HDL Properties

Abstract

Cardiovascular disease remains the leading cause of death in renal transplant recipients, but the underlying causative mechanisms for this important problem remain elusive. Recent work has indicated that qualitative alterations of HDL affect its functional and compositional properties in ESRD. Here, we systematically analyzed HDL from stable renal transplant recipients, according to graft function, and from patients with ESRD to determine whether structural and functional properties of HDL remain dysfunctional after renal transplantation. Cholesterol acceptor capacity and antioxidative activity, representing two key cardioprotective mechanisms of HDL, were profoundly suppressed in kidney transplant recipients independent of graft function and were comparable with levels in patients with ESRD. Using a mass spectroscopy approach, we identified specific remodeling of transplant HDL with highly enriched proteins, including a-1 microglobulin/bikunin precursor, pigment epithelium-derived factor, surfactant protein B, and serum amyloid A. In conclusion, this study demonstrates that HDL from kidney recipients is uniquely altered at the molecular and functional levels, indicating a direct pathologic role of HDL that could contribute to the substantial cardiovascular risk in the transplant population.

Effect of chronic kidney disease on macrophage cholesterol efflux

“…No change in serum CAC was seen in our transplant patients which may be related to normalization of their apoA-I levels. Unlike our data Kopecky et al [34] showed moderately reduced cholesterol efflux to isolated HDL in transplant patients. The patients in these studies were about twenty years older than the young adults studied here and about 10 years older than their controls.…”

“…Our finding of unchanged CAC of isolated HDL in hemodialysis patients is consistent with a recent study [34] but differs from data by Holzer et al, who reported reduced CAC of HDL [22]. This discrepancy could at least in part be explained by exclusion of diabetic patients in our study, by the use of a human rather than a mouse macrophage Fig.…”

HDL Cholesterol Efflux Predicts Graft Failure in Renal Transplant Recipients

“…27 Previously, the cholesterol acceptor capacity of HDL was indicated to be reduced in RTRs. 28 Consistently, also with our efflux assay conditions, we observed a significant decrease in the cholesterol acceptor capacities of HDL from RTRs when compared with controls matched for age, sex, and BMI (Supplemental Figure 3). Whether this reduction is a reflection of the reduced kidney function in RTRs or is caused by the immunosuppressive medication or represents a feature of the preexisting kidney disease that transplantation fails to correct remains to be determined in future studies.…”

Molecular mechanisms of disorders of lipid metabolism in chronic kidney disease

“…Hence, elevated serum HDL cholesterol concentrations are not necessarily associated with improved outcomes in patients with CKD (121). This combined with the fact that HDL from patients with CKD/ESRD on maintenance hemodialysis has been shown to have impaired reverse cholesterol transport capabilities that can lead to HDL dysfunction and account for the paradoxical associations of serum HDL level with outcomes noted in epidemiologic studies (124,125).…”