Biochemical monitoring of mTOR inhibitor-based immunosuppression following kidney transplantation: a novel approach for tailored immunosuppressive therapy.
BACKGROUND
Immunosuppressive therapy with the mammalian target of rapamycin (mTOR) inhibitors requires a fine balance between allograft maintenance and drug-related side effects.


METHODS
In this study we examined the feasibility of monitoring TOR inhibitor-based immunosuppression by assessment of the phosphorylation status at the Thr(389) site of the p70S6 kinase in peripheral blood mononuclear cells (PBMCs). At total of 36 patients with renal transplants and 8 healthy controls were enrolled.


RESULTS
We found that sirolimus treatment was associated with a pronounced inhibition of p70S6 kinase phosphorylation, as compared to healthy donors or otherwise immunosuppressed patients. In sirolimus-treated patients, phosphorylation of the p70S6 kinase was significantly inhibited when sirolimus trough levels were > 6 ng/mL. In contrast, for trough levels <6 ng/mL, the degree of inhibition of p70S6 kinase phosphorylation showed a high degree of interindividual variability. We recorded a total of five clinical relevant rejection episodes in this patient category. Intriguingly, rejecters uniformly maintained a high degree of phosphorylation independent of the sirolimus trough level whereas non-rejecters showed a significant inhibition of phosphorylation.


CONCLUSIONS
Therefore, the phosphorylation status of the p70S6 kinase appears to provide more relevant information on the desired effect of sirolimus in target cells as compared to trough level measurements. Moreover, this assay provides an opportunity to safely titer down sirolimus levels to avoid overimmunosuppression and, on the other hand, to identify patients with insufficient TOR inhibitor therapy that are at risk for rejection.
Hartmann
Bertram
B
Department of Nephrology, Medical Clinic I, University Hospital Munich-Grosshadern, Munich, Germany.
Schmid
Gerald
G
Graeb
Christian
C
Bruns
Christiane J
CJ
Fischereder
Michael
M
Jauch
Karl-Walter
KW
Heeschen
Christopher
C
Guba
Markus
M
D000328:Adult; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases
D007166:Immunosuppressive Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus