Differential effects of dialysis and ultrafiltrate from individuals with CKD, with or without diabetes, on platelet phosphatidylserine externalization.
Individuals with chronic kidney disease (CKD) and/or diabetes mellitus (DM) are at increased risk of cardiovascular events and have elevated externalization of phosphatidylserine (PS; which propagates thrombus formation) in a small subpopulation of platelets. The purpose of this study was to examine the effect of 1) removing uremic toxins by hemodialysis on PS externalization in patients with either CKD or CKD and DM and 2) ultrafiltrate (UF) from these individuals on PS externalization in healthy platelets. PS externalization was quantified by a fluorescence-activated cell sorter using annexin V in platelet-rich plasma. PS externalization was elevated threefold in CKD patients and returned to basal values during 3-h hemodialysis. In contrast, it was elevated fivefold in individuals with CKD and DM and was still threefold above control after 3-h treatment. UF significantly increased PS externalization in a small subpopulation of platelets from healthy controls. The effect of UF from individuals with CKD and DM was significantly greater than that from patients with CKD alone, and the responses were partially inhibited by the protein kinase Cdelta (PKCdelta) inhibitor rottlerin and the 5-hydroxytryptamine (5-HT)(2A/2C) receptor antagonist ritanserin. The data suggest that uremic toxins present in UF mediate PS externalization in a small subpopulation of platelets, at least in part, via the 5-HT(2A/2C) receptor and PKCdelta and demonstrate that DM further enhances platelet PS externalization in CKD patients undergoing hemodialysis. This may explain, at least in part, the additional increase in vascular damage observed in CKD patients when DM is present.
Faculty of Medical Sciences, Newcastle University, Newcastle-Upon-Tyne, United Kingdom.
Yingjie
Y
Wang
Werner
W
Beck
Reinhold
R
Deppisch
Sally M
SM
Marshall
Nicholas A
NA
Hoenich
Michael G
MG
Thompson
D000098:Acetophenones / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001578:Benzopyrans / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D016022:Case-Control Studies; D002908:Chronic Disease; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D007674:Kidney Diseases / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010718:Phosphatidylserines / Q000097:blood*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors; D006435:Renal Dialysis; D016713:Ritanserin / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D010718:Phosphatidylserines; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D016713:Ritanserin; C085746:rottlerin; D051745:Protein Kinase C-delta