Renal transplant recipients experience increased cardiovascular morbidity and mortality largely unaffected by therapeutic measures such as statins: here we studied molecular composition and functionality of High-Density Lipoprotein (HDL) to explore the principal mechanisms of this excessive cardiovascular risk.

HDL from fresh human plasma of stable renal transplant (CKD I-IV) and end-stage renal disease (ESRD) patients as well as matched healthy controls was isolated by one-step density gradient ultracentrifugation. Changes in protein composition were identified by immunoblot and ELISA. Functional HDL modifications were determined by measurement of cholesterol-efflux, the membrane cholesterol concentration in peripheral blood mononuclear cells and by analyzing pro- versus anti-inflammatory cytokine production of human monocytes.

We found that distinct proteins like surfactant protein B (SP-B), serum amyloid A (SAA), apolipoprotein-CII and Α-1 microglobulin/bikunin precursor (AMBP) were enriched in HDL of renal transplant patients similar to ESRD patients indicating a characteristic disease-specific HDL proteome. Of note, alterations of HDL were virtually identical between patients with CKD I-II and III-IV and independent of transplant vintage and both were similar to ESRD patients. Furthermore, transplant HDL displayed decreased cholesterol acceptor capacity, but substantially increased free cholesterol in PBMCs of the patients. Finally, impaired anti-inflammatory HDL function could be demonstrated by increased expression of inflammatory cytokines including IL-6, IL-12p40 and TNF-Α in monocytes compared to healthy HDL.

In conclusion, we demonstrate unique alterations of HDL from renal transplant recipients at the molecular and functional level. Importantly, remodeling of HDL including enrichment of distinct proteins previously identified from uremic HDL was also observed in patients with excellent graft function independent of the transplant vintage. These data may therefore not only help to unravel the causes of the excessive cardiovascular risk in renal transplant patients, but may also pave the way for novel diagnostic and innovative therapeutic directions.

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