Cyclosporine is associated with endothelial dysfunction but not with platelet activation in renal transplantation.
BACKGROUND
Cyclosporine (CsA) is associated with thrombotic micro-angiopathy and endothelial dysfunction. Markers of endothelial dysfunction may serve to identify patients at risk for development of vascular injury. In this study we measured von Willebrand Factor (vWF) and sP-selectin as possible markers for endothelial dysfunction in renal transplant recipients at different concentrations of CsA. Because sP-selectin can also be derived from platelets an additional in vitro study was performed to study the potential effect of CsA on the expression of P-selectin on platelet surface, while the effects of CsA on the interaction of platelets with Endothelial Cell Matrix (ECM) were studied under flow conditions in a perfusion chamber model.


METHODS
CsA was stepwisely replaced by mycophenolate mofetil (MMF) in 15 renal transplant recipients (more than 6 months after transplantation). VWF and sP-selectin were measured at normal CsA (median trough level 130 microg/l), low CsA (trough level 45 microg/l) and after stopping CsA. MMF 2 g daily was added while lowering and stopping CsA. Platelet activation was investigated by measurement of P-selectin on platelet surface by flow-cytometry (FACS), after incubation with CsA (0, 2, 20 and 200 mg/l) in vitro and after perfusion of whole blood over ECM with CsA (0 or 2 mg/l, peak levels).


RESULTS
Stepwise withdrawal of CsA gave a dose-related decrease of both vWF and sP-selectin, suggesting reversible endothelial dysfunction. FACS showed no expression of P-selectin on platelets by CsA. Also perfusion studies over ECM demonstrated no platelet activation by CsA but even inhibition of platelet adhesion and aggregation.


CONCLUSIONS
The use of CsA is not accompanied by platelet activation. However endothelial dysfunction induced by CsA does occur as reflected by increased vWF and sP-selectin. (See Editorial p. 1).
Schrama
Y C
YC
Department of Nephrology, University Medical Centre Utrecht, Utrecht, The Netherlands.
van Dam
T
T
Fijnheer
R
R
Hené
R J
RJ
de Groot
P
P
Rabelink
T J
TJ
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000032:analysis; D016572:Cyclosporine / Q000009:adverse effects* / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects; D011446:Prospective Studies; D019087:Selectins / Q000032:analysis*; D018709:Statistics, Nonparametric; D014841:von Willebrand Factor / Q000032:analysis*
D015415:Biomarkers; D007166:Immunosuppressive Agents; D019087:Selectins; D014841:von Willebrand Factor; D016572:Cyclosporine