Immunosuppressive therapy regimen and platelet activation in renal transplant patients.
BACKGROUND
Increased platelet activation caused by an immunosuppressive therapy regimen may contribute to the high incidence of death from cardiovascular disease in renal transplant patients. Cyclosporine (INN, ciclosporin) and azathioprine are reported to activate platelets, but data are rare and controversial for tacrolimus and mycophenolate mofetil.


METHODS
This cross-sectional study assessed markers of platelet degranulation (P-selectin; CD62), the activated glycoprotein IIb/IIIa receptor (PAC1, indicating the fibrinogen binding site), platelet aggregation, and secretion of platelet-derived growth factor (PDGF(AB)) in renal transplant patients treated with 4 different therapy regimens. Immunosuppression was based on low-dose steroids (5 mg/d prednisone) in combination with a single agent: (1) cyclosporine (n = 16), (2) azathioprine (n = 18), (3) tacrolimus (n = 17), or (4) mycophenolate mofetil (n = 13). Effects were compared with those in an age-matched control group of patients with hypertension (n = 11).


RESULTS
In all renal transplant patient groups, unactivated platelets exhibited an increased expression of CD62. When stimulated with 2-micromol/L thrombin receptor-activating peptide, CD62 expression in platelets from patients treated with azathioprine (63% +/- 17%; P <.05), cyclosporine (51% +/- 23%; P <.05), and tacrolimus (50% +/- 22%; P <.05) was elevated compared with control subjects (33% +/- 19%). PAC1 expression was significantly increased in the patient groups that received azathioprine and cyclosporine. PDGF(AB) secretion was elevated in patients treated with azathioprine only (51 +/- 24 ng/10(9) platelets [versus 35 +/- 17 ng/10(9) platelets for control subjects]; P <.05). Platelet aggregation in response to collagen (0.5 microg/mL) was decreased in patients treated with tacrolimus (49% +/- 29%; P <.05) and mycophenolate mofetil (55% +/- 32%; P <.05) compared with control subjects (73% +/- 25%).


CONCLUSIONS
This is the first study to compare the effects on platelet function of different immunosuppressive regimens that are based on monotherapy. All renal transplant patients showed preactivated platelets compared with those of patients with hypertension. However, the "newer" immunosuppressive agents tacrolimus and mycophenolate mofetil seemed to have fewer unfavorable effects on platelet CD62 expression and PAC1 expression and aggregation. Whether this finding is accompanied by fewer cardiovascular events remains to be elucidated.
Graff
Jochen
J
pharmazentrum frankfurt, Institute of Clinical Pharmacology, Funktionsbereich Nephrologie, Medizinische Klinik IV, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. graff@em.uni-frankfurt.de
Klinkhardt
Ute
U
Harder
Sebastian
S
Wegert
Wolfgang
W
Lenz
Tomas
T
Scheuermann
Ernst-Heinrich
EH
Gossmann
Jan
J
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D003430:Cross-Sectional Studies; D005260:Female; D006084:Graft Rejection / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000096:biosynthesis / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism
D007166:Immunosuppressive Agents; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010982:Platelet-Derived Growth Factor; C095477:platelet-derived growth factor AB