The uremic retention solute p-cresyl sulfate and markers of endothelial damage.
BACKGROUND
Cardiovascular disease is highly prevalent in patients with chronic kidney disease. In hemodialysis patients, the protein-bound uremic retention solute p-cresol is independently associated with cardiovascular disease. The underlying mechanisms have not been elucidated.


METHODS
(1) Prospective observational study of humans and (2) in vitro study in human umbilical vein endothelial cells.


METHODS
Hemodialysis patients.


METHODS
p-Cresol and its main derivative p-cresyl sulfate.


RESULTS
Endothelial dysfunction.


METHODS
We studied: (1) the relation between p-cresol and blood markers of endothelial dysfunction, including soluble P-selectin and endothelial microparticles; and (2) direct effects of p-cresol and p-cresyl sulfate on endothelial cell cultures.


RESULTS
(1) In a cohort of 100 maintenance hemodialysis patients, free serum p-cresol concentrations (median, 11.7 micromol/L; interquartile range, 15.2) were directly associated with circulating endothelial microparticles (P = 0.007), but not with soluble P-selectin (mean, 37.7 +/- 14.4 [SD] pg/mL). Other independent determinants of the degree of circulating microparticles were greater serum phosphorus (mean, 4.8 +/- 1.5 mg/dL; P = 0.008) and serum calcium concentrations (mean, 9.3 +/- 0.8 mg/dL; P = 0.03), whereas treatment with active vitamin D (P = 0.008) and vintage (median, 25 months; P = 0.04) were inversely associated. (2) In vitro, p-cresyl sulfate induced a dose-dependent increase in the shedding of endothelial microparticles (P < 0.001) by human umbilical vein endothelial cells. Shedding was reduced, but not completely aborted, in the presence of albumin, whereas the selective Rho kinase inhibitor Y-27632 abrogated the p-cresyl sulfate-induced generation of endothelial microparticles.


CONCLUSIONS
The relationship between p-cresyl sulfate and shedding of endothelial microparticles in vivo was not mechanistically explored.


CONCLUSIONS
p-Cresyl sulfate induces shedding of endothelial microparticles in the absence of overt endothelial damage in vitro and is independently associated with the number of endothelial microparticles in hemodialysis patients. These findings suggest that p-cresyl sulfate alters endothelial function in hemodialysis patients.
Meijers
Björn K I
BK
Department of Medicine, Division of Nephrology, University Hospitals Leuven, Leuven, Belgium.
Van Kerckhoven
Soetkin
S
Verbeke
Kristin
K
Dehaen
Wim
W
Vanrenterghem
Yves
Y
Hoylaerts
Marc F
MF
Evenepoel
Pieter
P
D000368:Aged; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D002908:Chronic Disease; D003408:Cresols / Q000097:blood / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014511:Uremia / Q000097:blood / Q000378:metabolism*
D015415:Biomarkers; D003408:Cresols; C032538:4-cresol