Acute kidney injury (AKI), rapid loss of renal function over several days, occurs in up to 70% of lung transplant recipients postoperatively, far more common than after cardiac surgery despite a younger population with almost no pre-existing chronic kidney disease (CKD). While post-transplant AKI is associated with subsequent CKD and mortality, it is unclear if AKI impacts outcomes independently or is simply an epiphenomenon of lung allograft dysfunction and other early transplant complications. Knowledge of post-transplant AKI epidemiology is limited to relatively small, retrospective, single-center studies with limited assessment of AKI risk factors. Clarifying AKI?s independent impact on outcomes and identifying patients at high risk of AKI, particularly the severe forms more strongly linked to CKD and mortality, is critical since renal-protective strategies such as fluid administration carry risk to the allograft. Blood and urine biomarkers have shown predictive utility for AKI in critical illness and cardiac surgery populations but have not been studied in lung transplant patients. These predictive markers may also shed light on mechanisms underlying the high rate of AKI in this population. The Lung Transplant Outcomes Group (LTOG) is an NIH-funded multicenter prospective cohort started in 2002, coordinated by our institution and designed to study the clinical and molecular epidemiology of primary graft dysfunction (PGD), an acute lung allograft injury syndrome. With enrollment >2000, the LTOG is uniquely suited to support an ancillary, multicenter study of AKI epidemiology. We conducted pilot studies of clinical and plasma biomarker risk factors for AKI in a small group of LTOG subjects. Based on these studies and existing literature, we hypothesize that distinct clinical and molecular characteristics are associated with AKI after lung transplantation, with implications for AKI pathogenesis. We further hypothesize that these characteristics can be used to predict AKI risk to identify candidates for risk reduction strategies. Utilizing the robust multicenter structure of the LTOG to conduct a study 3 times the size of the largest to date, we propose the following aims in the lung transplant population: 1) Determine clinical risk factors for and outcomes of AKI, 2) Determine the association of established and novel plasma and urine biomarkers with AKI, and 3) Derive and validate predictive models for AKI. This proposal leverages the research investments already made in the LTOG in order to produce the first comprehensive study of AKI after lung transplant to establish the independent impact of AKI on outcomes, determine modifiable AKI risk factors, identify plasma and urine molecular markers associated with AKI, and enable AKI prediction. Completion of the aims will create a flexible infrastructure within the LTOG to support trials of current and novel renal-protective peri-transplant management strategies targeted to high-risk patients, with the ultimate goals of reducing CKD burden and maximizing the long-term success of lung transplant. In addition, our exploratory studies to identify novel AKI biomarkers may detect new predictors and point toward targetable AKI mechanisms for future study.
Lung transplantation is the only effective treatment option for many people with advanced lung diseases such as emphysema, pulmonary fibrosis, and cystic fibrosis, but the transplant operation is complicated by acute damage to the kidneys in up to 70% of patients. This acute kidney injury (AKI) may lead to chronic kidney disease, need for dialysis, and early death, but limited knowledge of AKI risk factors and outcomes in the lung transplant population is an obstacle to implementing kidney-protective strategies. The research outlined in this proposal will use a large, National Institutes of Health-funded multicenter lung transplant cohort to clarify the impact of AKI on transplant outcomes and to determine patient and peri-operative characteristics, as well as protein characteristics in blood and urine, that identify high-risk patients to target for AKI prevention and treatment strategies.
