Impact of CYP3A5, CYP3A4, and ABCB1 Genotypes on Lung Transplant Recipient Early Clinical Outcomes

Calabrese, Daniel R.; Boettger, Rebecca F.; Dewey, Katherine; Cai, Hui; Torgerson, Dara G.; Faust, H; Rajalingam, Rajesh; Hays, Steven R.; Singer, Jonathan P.; Shah, Rupal J.; Kukreja, Jasleen; Golden, Jeffrey A.; Greenland, John R.

doi:10.1016/j.healun.2017.01.397

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“…It is possible that variation in tacrolimus levels within the targets used early after lung transplantation has little impact on the risk of rejection. Consistent with this notion, we previously reported a plateau in the risk of acute rejection as a function of tacrolimus trough beyond a level of 8-10 ng/mL (25). Indeed, highly potent immunosuppression could even drive rejection though the increased innate immune signaling associated with airway infection.…”

Section: Discussionsupporting

confidence: 64%

Suppressed calcineurin-dependent gene expression identifies lung allograft recipients at increased risk of infection

Greenland

Chong

Wang

et al. 2018

American Journal of Transplantation

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ABSTRACT:Lung transplant immunosuppression regimens generally include the calcineurin inhibitor tacrolimus. We hypothesized that mean residual expression (MRE) of calcineurin-dependent genes assesses rejection and infection risk better than tacrolimus trough. We prospectively followed 44 lung allograft recipients 2 to 18 months post-transplant and measured changes in whole blood IL-2, interferon-, and GM-CSF gene expression following a tacrolimus dose. Posttransplant duration, immunosuppressive medication levels, and bronchoscopic rejection and infection assessments were compared with MRE using generalized-estimating equationadjusted models. Prednisolone effect on MRE was assessed ex vivo in blood samples from non-transplanted controls. Tacrolimus concentration inhibiting 50% of cytokine production (IC50) was measured in a pre-transplant subset. Results showed that MRE did not change with diagnosis of rejection, but that airway infection was associated with a 20% absolute decrease (95% CI 11% -29%). MRE increased with time following transplantation but was not associated with tacrolimus trough. Interestingly, MRE correlated inversely with corticosteroid dose in the study cohort and ex vivo. Pre-transplant tacrolimus IC50 depended on the cytokine measured and varied between individuals, suggesting a range in baseline responses to tacrolimus. We conclude that MRE identifies infection risk in lung allograft recipients, potentially integrating calcineurin inhibitor and steroid effects on lymphocyte effector function. INTRODUCTION:

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Section: Discussionsupporting

confidence: 64%