title: Long-term mTOR inhibitors administration evokes altered calcium homeostasis and platelet dysfunction in kidney transplant patients.
abstract: The use of the mammal target of rapamycin (mTOR) inhibitors has been consolidated as the therapy of election for preventing graft rejection in kidney transplant patients, despite their immunosuppressive activity is less strong than anti-calcineurin agents like tacrolimus and cyclosporine A. Furthermore, as mTOR is widely expressed, rapamycin (a macrolide antibiotic produced by Streptomyces hygroscopicus) is recommended in patients presenting neoplasia due to its antiproliferative actions. Hence, we have investigated whether rapamycin presents side effects in the physiology of other cell types different from leucocytes, such as platelets. Blood samples were drawn from healthy volunteers and kidney transplant patients long-term medicated with rapamycin: sirolimus and everolimus. Platelets were either loaded with fura-2 or directly stimulated, and immunoassayed or fixed with Laemmli's buffer to perform the subsequent analysis of platelet physiology. Our results indicate that rapamycin evokes a biphasic time-dependent alteration in calcium homeostasis and function in platelets from kidney transplant patients under rapamycin regime, as demonstrated by the reduction in granule secretion observed and subsequent impairment of platelet aggregation in these patients compared with healthy volunteers. Platelet count was also reduced in these patients, thus 41% of patients presented thrombocytopenia. All together our results show that long-term administration of rapamycin to kidney transplant patients evokes alteration in platelet function.
authors.affiliation: Cell Physiology Research Group, Department of Physiology, University of Extremadura, Cáceres, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: López
authors.forename: Alejandro
authors.initials: A
authors.lastname: Berna-Erro
authors.forename: Nuria
authors.initials: N
authors.lastname: Bermejo
authors.forename: José María
authors.initials: JM
authors.lastname: Brull
authors.forename: Rocío
authors.initials: R
authors.lastname: Martinez
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Garcia Pino
authors.forename: Raul
authors.initials: R
authors.lastname: Alvarado
authors.forename: Ginés María
authors.initials: GM
authors.lastname: Salido
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Rosado
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Cubero
authors.forename: Pedro Cosme
authors.initials: PC
authors.lastname: Redondo
mesh_terms: D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D003710:Demography; D004789:Enzyme Activation / Q000187:drug effects; D000068338:Everolimus; D005260:Female; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: D047428:Protein Kinase Inhibitors; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002118:Calcium; D020123:Sirolimus