Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Halls C&D
In this exploratory biomarker sub-study, a comprehensive combined targeted/ non-targeted metabolomics and targeted proteomics approach was used to assess potential differences between the everolimus+ low-dose tacrolimus and the MMF+ standard dose tacrolimus treatment arms in the Novartis CRAD001AUS92 multicenter trial in de novo kidney transplant patients, including sensitive kidney function, anti-allograft response, inflammation, oxidative stress, bioactive lipids and vascular endothelial function biomarkers.
Samples were collected longitudinally (baseline, 1, 2, 4 and 6 months) from 120 de novo kidney transplant patients. A targeted/ non-targeted metabolomics approach based on a set of quantitative multi-analyte LC-MS/MS assays (targeted pathway assessment, TAPAS) that assessed 609 metabolites in plasma and urine was used in combination with a custom targeted proteomics array of 28 proteins that are known allo-immune reaction, inflammation and kidney function markers in serum.
The results showed two drug-related effects:
* Activation of the pyrimidine synthesis pathway in mycophenolate mofetil (MMF)-treated patients, potentially a compensatory response to the inhibition of purine synthesis by mycophenolate.
* Inhibition of the synthesis of the pro-inflammatory and vasoconstrictive bioactive lipid 20-HETE in the everolimus-treated patients, potentially due to mTOR-mediated reduction of arachidonic acid conversion by cytochrome P4504-enzymes.
There were no significant differences in any of the other more than 600 evaluated parameters between the two treatment arms, including serum protein kidney function, immune response and inflammation biomarkers, plasma vascular endothelial dysfunction markers, amino acid profiles, oxidative stress markers, fatty acid patterns in enriched blood cells, and urine metabolite kidney function markers, as well as plasma and urine metabolomics profiles.
Except the effects directly associated with mycophenolic acid and everolimus mechanisms of action, there was no evidence for differences in immune, inflammation, vascular and kidney dysfunction markers between the two treatment arms.
CITATION INFORMATION: Klepacki J, Klawitter J, Klawitter J, Karimpour-fard A, Anderson E, Ingle G, Patel D, Johnson K, Cibrik D, Christians U. A Comprehensive Biomarker Study to Compare Tacrolimus and Mycophenolic Acid versus Half-Dose Tacrolimus and Everolimus in De Novo Kidney Transplant Patients in the Novartis US92 Study. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Klepacki J, Klawitter J, Klawitter J, Karimpour-fard A, Anderson E, Ingle G, Patel D, Johnson K, Cibrik D, Christians U. A Comprehensive Biomarker Study to Compare Tacrolimus and Mycophenolic Acid versus Half-Dose Tacrolimus and Everolimus in De Novo Kidney Transplant Patients in the Novartis US92 Study. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/a-comprehensive-biomarker-study-to-compare-tacrolimus-and-mycophenolic-acid-versus-half-dose-tacrolimus-and-everolimus-in-de-novo-kidney-transplant-patients-in-the-novartis-us92-study/. Accessed May 29, 2020.
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