The most important result from this study was that plasma RAGE levels 4 hours after lung allograft reperfusion predicted the duration of mechanical ventilation and ICU length of stay, even after adjusting for allograft ischemia time. In contrast, markers of alveolar type II cell injury, endothelial injury, and acute inflammation were not predictive of these outcomes. Further, in this small sample, plasma RAGE had better prognostic value for these short-term outcomes than the clinical diagnosis of PGD.
This prospective study is the first to specifically examine these biomarkers of lung epithelial and endothelial injury, which are well-validated in patients with ALI/ARDS, in the setting of lung transplantation. Levels of RAGE in lung transplant patients in this study were in fact similar to levels in patients with ALI that we recently published and higher than those in normal controls in that previous study as well.(11
) In addition, this study is the first to compare the predictive ability of biomarkers of lung injury to those of clinical predictors like PGD and to demonstrate that RAGE has prognostic value for short-term patient outcomes in this setting.
Why might RAGE be a better predictor of short-term outcomes in this study than a clinical scoring system like PGD? The current classification system for PGD was developed primarily to standardize diagnostic criteria so as to improve the uniformity and generalizability of future research. As such, it encompasses a wide range of organ dysfunction and may be an overly broad instrument for predicting specific clinical outcomes. Similarly, the consensus definition developed for acute lung injury,(21
) which has been extremely useful for the purposes of clinical research, has not proven to be a good predictive instrument.(22
) By more directly quantifying lung epithelial cell injury, plasma RAGE may provide a more sensitive measure of actual allograft tissue damage that can predict short-term outcomes with greater precision. Alternatively, it may be that our small sample size limited our ability to detect the prognostic value of the PGD scoring system, which has been well-demonstrated in other studies.(3
The finding that plasma RAGE (a marker of alveolar type I cell injury) was of greater prognostic value than plasma KL-6 (a marker of alveolar type II cell injury) is intriguing and has at least four potential explanations. Alveolar type I cells constitute 95% of the alveolar epithelium, so it may be that their greater quantity translates to a more sensitive marker of injury. Alternatively, it may be that injury to the type I cell is more deleterious to the function of the lung epithelium, particularly in light of the new data confirming the critical role of the type I cell in alveolar fluid transport and the resolution of alveolar edema.(12
) A third possibility is that our small sample size prevented us from detecting a relationship between KL-6 and short-term outcomes.
A fourth possibility is that plasma RAGE levels in this study may reflect conditions other than alveolar epithelial cell injury. While RAGE has been recently implicated as a marker of alveolar type I epithelial cell injury(11
) and is most abundant in the lung,(23
) it is not specific for alveolar type I cells; RAGE has also been demonstrated in vascular endothelium,(24
) nervous tissues,(25
) and other cell types in the lung(26
) and is involved in systemic inflammatory responses such as sepsis.(27
) Thus, it is possible that the prognostic value of RAGE in this sample reflects its role in systemic inflammation rather than its role as a marker of alveolar type I cell injury. This possibility, however, should not diminish the potential value of RAGE as a biomarker with prognostic value in the post-transplant setting. Other biomarkers reflective of potentially systemic phenomena such as PAI-1 have been demonstrated to have prognostic value in both the ALI(9
) and post-transplant(16
Our study has some limitations. First, it is a small, single-center study; as such, it lacks the power needed to study longer-term outcomes such as mortality and to adjust for all potential confounders. Thus, it is possible that biomarkers may have particular prognostic value in certain subsets of patients—for instance, that results may differ in single vs. bilateral lung transplantation—or that the etiology of the recipient's lung disease may impact the results. Likewise, as in all small studies, results may be significantly impacted by outlier values; however, we used non-parametric analyses for the biomarker data throughout to mitigate this concern. The small sample size also makes the study underpowered to generate conclusions about negative associations; therefore, the negative correlations in this study should be interpreted with caution. Second, we only studied plasma data from the first 4 hours after reperfusion; repeating the analysis of these markers at later time points may be more informative or generate different results, although early blood sampling will certainly be of more practical value for prognostic purposes. Third, we collected information on PGD only at T0, within 6 hours of allograft reperfusion; PGD scores at 24, 48, and 72 hours may be more useful. Finally, we are unable to differentiate between RAGE generated in the allograft donor and that generated in the allograft recipient. A larger study may be able to study a broader range of both donor and recipient clinical characteristics to examine whether particular characteristics of either are highly associated with plasma RAGE levels.
In summary, plasma RAGE, a marker of alveolar type I cell injury, was associated with longer duration of mechanical ventilation and ICU length of stay in patients undergoing lung transplantation, even after adjusting for allograft ischemia time. Furthermore, in this small sample, plasma RAGE measured within 4 hours of allograft reperfusion had better prognostic value for these short-term outcomes than did the clinical diagnosis of PGD. Further studies are needed to replicate these results in larger and broader populations, to examine the role of biomarkers in predicting important longer-term outcomes like BOS and mortality, and to determine whether RAGE has additive value when combined with established clinical predictors of outcomes.(28