Submitted on June 19, 2007
Accepted on July 30, 2007
THE DIFFERENTIAL EFFECTS OF DIALYSIS AND ULTRAFILTRATE FROM INDIVIDUALS WITH CKD, WITH OR WITHOUT DIABETES, ON PLATELET PHOSPHATIDYLSERINE EXTERNALISATION.
Yingjie Wang1, Werner Beck2, Reinhold Deppisch2, Sally M. Marshall3, Nicholas A Hoenich3, and Michael G Thompson1*
1 Clinical Laboratory Sciences, Newcastle University, Newcastle-upon-Tyne, Tyne and Wear, United Kingdom
2 Clinical Research, Gambro Dialysatoren GmbH, 72379 Hechingen, Germany
3 Clinical Medical Sciences, Newcastle University, Newcastle-upon-Tyne, Tyne and Wear, United Kingdom
* To whom correspondence should be addressed. E-mail: m.g.thompson{at}ncl.ac.uk.
Individuals with chronic kidney disease (CKD) and/or diabetes mellitus (DM) are at increased risk of cardiovascular events and have elevated externalisation of phosphatidylserine (PS), (which propagates thrombus formation), in a small, sub-population of platelets. The aim of this study was to examine the effect of (i) removing uraemic toxins by hemodialysis on PS externalisation in patients with either CKD or CKD and DM and (ii) ultrafiltrate (UF) from these individuals on PS externalisation in healthy platelets. PS externalisation was quantified by a fluorescence-activated cell sorter using Annexin V in platelet rich plasma. PS externalisation was elevated 3-fold in CKD patients and returned to basal values during 3 hrs hemodialysis. In contrast, it was elevated 5-fold in individuals with CKD and DM and was still 3-fold above control after 3 hrs treatment. UF significantly increased PS externalisation in a small, sub-population 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 Cδ (PKCδ) inhibitor, rottlerin, and the 5-hydroxytryptamine (5-HT)2A/2C receptor antagonist, ritanserin. The data suggest that uremic toxins present in UF mediate PS externalisation in a small, sub-population of platelets, at least in part, via the 5-HT2A/2C receptor and PKCδ and demonstrate that DM further enhances platelet PS externalisation 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.
