Monitoring biological action of rapamycin in renal transplantation.
BACKGROUND
Inhibition of P70S6 kinase (P70(S6K)) phosphorylation in activated T cells is 1 of the major mechanisms by which rapamycin exerts its immunosuppressive action.


METHODS
Observational cohort study.


METHODS
2 different groups of kidney transplant recipients at a single center: 30 transplant recipients converted from mycophenolic acid and low-dose prednisone plus cyclosporine A to mycophenolic acid and low-dose prednisone plus rapamycin therapy for chronic allograft nephropathy (group 1) and 16 recipients of suboptimal organs converted from tacrolimus plus rapamycin to rapamycin therapy alone after 3 months (group 2).


METHODS
Exposure to rapamycin therapy and rapamycin trough levels.


METHODS
Basal and stimulated phosphorylation of P70(S6K) was measured by using Western blotting in patients' peripheral-blood mononuclear cells before and 6 to 11 months after conversion to rapamycin-based therapy. Kinase activation was attained in vivo by means of intravenous insulin injection.


RESULTS
The potency of rapamycin inhibition of P70(S6K) phosphorylation varied among patients (RAPA blood concentration required to achieve 50% inhibition of P70(S6K) activation for mitogen-activated kinase, 3.14 to 12.14 ng/mL) and failed to correlate with drug trough levels. The combination of tacrolimus and rapamycin limited the inhibitory effect of the latter drug on P70(S6K) activation.


CONCLUSIONS
Need for additional studies exploring the relationship between P70(S6K) activity and kidney graft outcome. Exclusion of patients with diabetes.


CONCLUSIONS
Long-term rapamycin treatment inhibits P70(S6K) phosphorylation in peripheral-blood mononuclear cells without significant correlation with rapamycin trough levels. By measuring in vivo the biological action of rapamycin, the assay may provide potentially relevant information for the clinical management of rapamycin-treated patients.
Leogrande
Domenica
D
Department of Emergency and Organ Transplants, Division of Nephrology, Dialysis and Transplantation, University of Bari, Policlinico, Bari.
Teutonico
Annalisa
A
Ranieri
Elena
E
Saldarelli
Marilisa
M
Gesualdo
Loreto
L
Schena
F Paolo
FP
Di Paolo
Salvatore
S
D000328:Adult; D015331:Cohort Studies; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000097:blood; D020123:Sirolimus / Q000097:blood* / Q000627:therapeutic use*
D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus