Incidence of primary graft dysfunction after lung transplantation is altered by timing of allograft implantation

Abstract

The importance of circadian factors in managing patients is poorly understood. We present two retrospective cohort studies showing that lungs reperfused between 4 and 8 AM have a higher incidence (OR 1.12; 95% CI 1.03 to 1.21; p=0.01) of primary graft dysfunction (PGD) in the first 72 hours after transplantation. Cooling of the donor lung, occurring during organ preservation, shifts the donor circadian clock causing desynchrony with the recipient. The clock protein REV-ERBα directly regulates PGD biomarkers explaining this circadian regulation while also allowing them to be manipulated with synthetic REV-ERB ligands.

Keywords: lung transplantation; macrophage biology.

Figure 1

Lungs transplanted between 4 and 8 AM have a higher incidence of PGD. Results from a retrospective cohort study showed that lungs reperfused between 4 and 8 AM had a higher incidence of PGD grades 2 and 3 after transplantation (p=0.01, univariate logistic regression) (A). A similar effect was seen for the severest form of PGD, grade 3, however, this was not significant (p=0.15, univariate logistic regression) (B). No difference was seen in surrogate markers of human performance between the two time points (C). Analysis of double lung transplant recipients from the same cohort controlling for circadian factors revealed that PGD incidence oscillated in a sinusoidal manner 24 hours after the operation (p=0.03, EU circwave) (D). A number of other covariates were also measured in our cohort (E), the effect of reperfusion time was still seen after controlling for these in the multivariate logistic regression model. BMI, body mass index; COPD, chronic obstructive pulmonary disease; PGD, primary graft dysfunction; TLC, total lung capacity.

Figure 2

PGD biomarkers are direct targets of the cellular clock whose phase is altered by organ preservation. Lungs were either kept at 37°C or rapidly cooled and rewarmed mimicking organ preservation. Assessment of circadian phase revealed that circadian oscillations were altered in lungs exposed to temperature alterations (A). Alveolar macrophages from transplant recipients were exposed to two synthetic compounds acting as agonists for the key clock protein, REV-ERBα. 2667 repressed all seven PGD biomarkers (*p<0.05, t-test) (B). PGD, primary graft dysfunction.