Recipient, donor, and surgical factors leading to primary graft dysfunction after lung transplant.

Background: Primary graft dysfunction is a major cause of early mortality following lung transplantation. The International Society for Heart and Lung Transplantation subdivides it into 4 grades of increasing severity. Methods: A retrospective review of the institutional lung transplant database from March 2018 to September 2021 was performed. Patients were stratified into three groups: primary graft dysfunction grade 0 patients, grade 1 or 2 patients, and grade 3 patients. Recipient, donor, and surgical variables were analyzed by logistic regression analysis to identify risk factors for primary graft dysfunction grade 1 or 2 and grade 3. Results: Primary graft dysfunction grade 1 to 3 occurred in 45.0% of the cohort (n=68) of whom 33.3% (n=23) had primary graft dysfunction grade 3. Longer operative time was more common in primary graft dysfunction grade 1 to 3 patients (P<0.001). The 1-year survival of the patients with primary graft dysfunction grade 3 was lower than the others (grade 0-2 vs. 3, 93.7% vs. 65.2%, P=0.0006). Univariate analysis showed that acute respiratory distress syndrome, operative time, and intraoperative veno-arterial extracorporeal membrane oxygenation use were risk factors for primary graft dysfunction grades 1 or 2 and grade 3. Multivariate analysis identified that intraoperative veno-arterial extracorporeal membrane oxygenation use was an independent risk factor of primary graft dysfunction grade 1 or 2. Patients with an operative time of more than 8.18 hours had significantly higher incidence of primary graft dysfunction grade 3, acute kidney injury, and digital ischemia. Conclusions: The calculated predictors of primary graft dysfunction grade 1 or 2 were similar to those of primary graft dysfunction grade 3.

Primary graft dysfunction grade correlates with acute kidney injury stage after lung transplantation.

Background: Primary graft dysfunction (PGD) and acute kidney injury (AKI) are major early complications of lung transplantation and are associated with increased mortality. Lung injury after PGD can contribute to renal dysfunction; however, the association between PGD and AKI severity has not been thoroughly investigated. We analyzed the association between PGD grading and AKI staging, and the impact of AKI on subsequent changes to chronic kidney disease (CKD), including glomerular filtration rate (GFR), over time. Methods: This was a retrospective review of a single-center lung transplantation database between January 2018 and June 2022. AKI and GFR categories were classified according to the Kidney Disease: Improving Global Outcomes criteria. Spearman's and Kaplan-Meier tests were used to compare disease severity and assess survival. Results: In a total of 206 patients: 119 (57.8%), 25 (12.1%), 34 (16.5%), and 28 (13.6%) had PGD grades 0, 1, 2, and 3, respectively; 96 (46.6%), 47 (22.8%), 27 (13.1%), and 36 (17.5%) had AKI stages 0, 1, 2, and 3, respectively. Twenty-one of the 28 patients (75.0%) with PGD grade 3 had AKI stage 3. There was a significant correlation between PGD grade and AKI stage (P<0.001). There was also a significant correlation between AKI stage and GFR category of CKD at 3, 6, 9, and 12 months after lung transplantation (all P<0.001). For all AKI stages, GFR categories worsened with postoperative time. Conclusions: PGD grade was significantly correlated with AKI stage, and AKI stage was correlated with GFR categories of CKD.

IL-1ß-dependent extravasation of preexisting lung-restricted autoantibodies during lung transplantation activates complement and mediates primary graft dysfunction.

Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin in recipient mice failed to rescue lung function. LRA-mediated injury was localized to the transplanted lung and dependent on IL-1ß-mediated permeabilization of pulmonary vascular endothelium, which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL-1R in the donor lungs prevented LRA-induced graft injury. In humans, preexisting LRAs were an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that preexisting LRAs can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective.