HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype.
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 (HDL(CKD)), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL(CKD) 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.
Nephrology Unit, Great Ormond Street Hospital for Children, London, United Kingdom; Vascular Physiology Unit, University College London Institute of Child Health, London, United Kingdom; Rukshana.Shroff@gosh.nhs.uk.
Rukshana
R
Shroff
Department of Internal Medicine, Nephrology, and Hypertension, Saarland University Medical Centre, Homburg, Saar, Germany;
Thimoteus
T
Speer
French Institute of Health and Medical Research Joint Research Unit 1011, European Genomic Institute for Diabetes, Lille Pasteur Institute, Lille 2 University, Lille, France;
Sophie
S
Colin
Vascular Physiology Unit, University College London Institute of Child Health, London, United Kingdom;
Marietta
M
Charakida
Department of Internal Medicine, Nephrology, and Hypertension, Saarland University Medical Centre, Homburg, Saar, Germany;
Stephen
S
Zewinger
French Institute of Health and Medical Research Joint Research Unit 1011, European Genomic Institute for Diabetes, Lille Pasteur Institute, Lille 2 University, Lille, France;
Bart
B
Staels
French Institute of Health and Medical Research Joint Research Unit 1011, European Genomic Institute for Diabetes, Lille Pasteur Institute, Lille 2 University, Lille, France;
Giulia
G
Chinetti-Gbaguidi
Department of Internal Medicine, Nephrology, and Hypertension, Saarland University Medical Centre, Homburg, Saar, Germany;
Inga
I
Hettrich
Institute of Clinical Chemistry and.
Lucia
L
Rohrer
Vascular Physiology Unit, University College London Institute of Child Health, London, United Kingdom;
Francis
F
O'Neill
Vascular Physiology Unit, University College London Institute of Child Health, London, United Kingdom;
Eve
E
McLoughlin
Nephrology Unit, Great Ormond Street Hospital for Children, London, United Kingdom;
David
D
Long
Cardiovascular Division, King's College London, London, United Kingdom.
Catherine M
CM
Shanahan
Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland; and.
Ulf
U
Landmesser
Department of Internal Medicine, Nephrology, and Hypertension, Saarland University Medical Centre, Homburg, Saar, Germany;
Danilo
D
Fliser
Vascular Physiology Unit, University College London Institute of Child Health, London, United Kingdom;
John E
JE
Deanfield
D000293:Adolescent; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002648:Child; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D016030:Kidney Transplantation / Q000401:mortality; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D006435:Renal Dialysis / Q000401:mortality; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000401:mortality* / Q000601:surgery; D014280:Triglycerides / Q000097:blood; D014652:Vascular Diseases / Q000097:blood* / Q000401:mortality* / Q000601:surgery
D015415:Biomarkers; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; D001120:Arginine