Preoperative Plasma Club (Clara) Cell Secretory Protein Levels Are Associated With Primary Graft Dysfunction After Lung Transplantation

Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC‐16, sRAGE, ICAM‐1, IL‐8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC‐16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p < 0.001). CC‐16 was associated with PGD in nonidiopathic pulmonary fibrosis (non‐IPF) subjects (OR for highest quartile of CC‐16: 2.87, 95% CI: 1.37, 6.00, p = 0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p = 0.59). After adjustment, preoperative CC‐16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p = 0.013) in non‐IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients. The authors demonstrate a relationship between perioperative CC‐16 blood levels and an increased risk of primary lung allograft dysfunction, particularly in those without idiopathic pulmonary fibrosis as a pretransplant diagnosis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102697/1/ajt12541.pd

Advancing donor management research: design and implementation of a large, randomized, placebo-controlled trial

BACKGROUND:Given the persistent shortage of organs for transplantation, new donor management strategies to improve both organ utilization and quality of procured organs are needed. Current management protocols for the care of the deceased donor before organ procurement are based on physiological rationale, experiential reasoning, and retrospective studies without rigorous testing. Although many factors contribute to the lack of controlled clinical trials in donor management, a major factor is the unique challenges posed by research in the brain-dead organ donor.METHODS AND RESULTS:This article describes the study design and the challenges faced during implementation of the Beta-agonists for Oxygenation in Lung Donors (BOLD) study, a randomized, placebo-controlled clinical trial of nebulized albuterol vs. placebo in 500 organ donors. The study design and implementation are described with emphasis on aspects of the study that are unique to research in brain-dead organ donors.CONCLUSIONS:Experience gained during the design and implementation of the BOLD study should be useful for investigators planning future clinical trials in the brain-dead donor population and for intensivists who are involved in the care of the brain-dead organ donor.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation

Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP&lt;40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables

Plasma and bronchoalveolar lavage samples in acute lung allograft rejection: the potential role of cytokines as diagnostic markers

The role of differential cytology patterns in peripheral blood and bronchoalveolar lavage samples is increasingly investigated as a potential adjunct to diagnose acute and chronic allograft dysfunction after lung transplantation. While these profiles might facilitate the diagnosis of acute cellular rejection, low sensitivity and specificity of these patterns limit direct translation in a clinical setting. In this context, the identification of other biomarkers is needed. This review article gives an overview of cytokine profiles of plasma and bronchoalveolar lavage samples during acute cellular rejection. The value of these cytokines in supporting the diagnosis of acute cellular rejection is discussed. Current findings on the topic are highlighted and experimental settings for future research projects are identified

Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP

The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p &lt; 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis