HDL in Children with CKD Promotes Endothelial Dysfunction... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

HDL in Children with CKD Promotes Endothelial Dysfunction and an Abnormal Vascular Phenotype

Shroff, Rukshana*,†; Speer, Thimoteus‡; Colin, Sophie§; Charakida, Marietta†; Zewinger, Stephen‡; Staels, Bart§; Chinetti-Gbaguidi, Giulia§; Hettrich, Inga‡; Rohrer, Lucia‖; O’Neill, Francis†; McLoughlin, Eve†; Long, David*; Shanahan, Catherine M.¶; Landmesser, Ulf**; Fliser, Danilo‡; Deanfield, John E.†

*Nephrology Unit, Great Ormond Street Hospital for Children, London, United Kingdom;

†Vascular Physiology Unit, University College London Institute of Child Health, London, United Kingdom;

‡Department of Internal Medicine, Nephrology, and Hypertension, Saarland University Medical Centre, Homburg, Saar, Germany;

§French Institute of Health and Medical Research Joint Research Unit 1011, European Genomic Institute for Diabetes, Lille Pasteur Institute, Lille 2 University, Lille, France;

‖Institute of Clinical Chemistry and

**Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland; and

¶Cardiovascular Division, King’s College London, London, United Kingdom

Correspondence: Dr. Rukshana Shroff, Nephrology Unit, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK. Email: [email protected]

R.S. and T.S. contributed equally to this work.

Received November 20, 2013

Accepted March 14, 2014

Abstract

Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2–5 (HDLCKD), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDLCKD strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation.