Purpose of Study:

To demonstrate that profiling kidney transplant recipients (KTR) on Tacrolimus (Tac) based immunosuppression based on quantitative analysis of NFAT (nuclear factor of activated T-cells) regulated cytokine gene expression by real time PCR is safe and efficacious.

Methods:

Study population in this single center, randomized, controlled trial includes KTR who are on maintenance therapy with Tac, MMF, and prednisone. 40 patients with no prior rejection episodes who had a 6 month protocol biopsy showing no evidence of acute rejection will be randomized in 1:1 ratio. Patients in the intervention(INT) arm have Tac dose adjusted based on NFAT dependent gene expression. In the control (CTL) arm, Tac dose is adjusted based on trough levels. At enrollment, expression of 3 NFAT-dependent cytokines, IL2, IFNγ, and GM-CSF is measured by real time PCR at 2 time points, T0 (pre dose) and T1.5 (1.5 h after Tac dose). Residual expression of each gene is calculated as T1.5/T0 x 100. Mean residual expression (MRE) is the average of the 3 genes. In the INT arm, daily dose of Tac is reduced by 15% if MRE is <20% and increased by 15% if MRE is > 60%. In the INT arm, MRE levels are re -measured at 1 year and a second adjustment is made if indicated.

Results:

31 patients, 17 randomized to INT arm and 11 to CTL arm, were enrolled. There was no difference in MRE between the 2 arms at enrollment: 41.0% (CI 31.0-54.0) in the INT arm vs. 31.2% (CI 25.9-40.8) in CTL arm, p=0.24.There was no difference in median Tac levels at enrollment: 9.8 ¯o;g/L (CI 8.5-11.2) in the INT arm vs. 8.75 ¯o;g/L (CI 7.5-11.0) in the CTL arm, p=0.7. 12 patients, 7 (41.2 %) in the INT arm and 5 (35.7%) in the CTL arm, developed infections, p=0.8. Infections included viral gastroenteritis, upper respiratory infection, BK virus infection, CMV infection, urosepsis and vertebral osteomyelitis. The 2 groups did not differ significantly with respect to rate of hospitalization, 17.7% in the INT arm vs 14.3% in the CTL arm, p=0.8. No episodes of rejection occurred in either study arm and there were no cases of malignancy.

Conclusions:

Preliminary data from our trial suggest that therapeutic monitoring of tacrolimus based on NFAT regulated gene expression in KTR is a viable alternative to dose adjustment based on tacrolimus trough levels and provide clinical equipoise to undertake larger studies to assess strengths of this novel immune monitoring assay.

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