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The Proceedings of the American Thoracic Society 6:39-46 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200808-082GO
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Primary Graft Dysfunction

James C. Lee1 and Jason D. Christie1,2

1 Division of Pulmonary, Allergy, and Critical Care Medicine, and 2 Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to James C. Lee, M.D., Instructor of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania School of Medicine, 826 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19104. E-mail: james.lee{at}uphs.upenn.edu

ABSTRACT

Primary graft dysfunction (PGD) is a severe form of ischemia/reperfusion acute lung injury that is a major cause of early morbidity and mortality after lung transplantation. Survivors of PGD have worse long-term lung function and an increased chance of developing bronchiolitis obliterans syndrome (BOS), the manifestation of chronic rejection. This review examines the current state of PGD research in the context of a recent consensus statement by the International Society for Heart and Lung Transplantation (ISHLT) designed to standardize the definition of PGD in clinical research efforts. This article will review this definition and issues surrounding it, outcome studies examining the long-term effects of PGD, and the established clinical risk factors for PGD. Translational studies exploring the pathogenesis of PGD will be highlighted, and the current state of PGD prevention and management will also be described. Finally, we will summarize efforts at finding genetic and molecular markers for PGD and discuss future directions for PGD research.

Key Words: primary graft dysfunction • lung transplantation

DEFINITION

Primary graft dysfunction (PGD) affects an estimated 10 to 25% of lung transplants and is the leading cause of early post-transplantation morbidity and mortality (1–9). Thirty-day mortality rates are up to eightfold higher in patients with severe PGD as compared with those without PGD. In addition, patients who survive to 12 months after severe PGD have significantly impaired physical function (5) and have an increased risk of bronchiolitis obliterans syndrome (BOS) (10).

To provide a framework for future research on this important clinical problem, the International Society for Heart and Lung Transplantation (ISHLT) Working Group on PGD proposed a standardized definition of PGD based on PaO2/FIO2 (P/F) ratio and chest infiltrates assessed at time points up to 72 hours: T(0 – within 6 hours of reperfusion, 24, 48, and 72 hours) (Table 1) (9). The time points at which to grade PGD were recommended to potentially discern different patterns of lung injury. As such, groups have employed varying time points for the determination of PGD, and different outcomes have been measured (3, 11, 12). For example, Prekker and coworkers have recently shown that the early trend in P/F can predict 90-day mortality after transplant (13). Other groups have suggested grading PGD at additional time points (T6 and T12 hours) (14). However, neither trends in P/F nor additional time points have yet to be directly compared with the suggested ISHLT time points for PGD grading as outcome definitions in clinical studies.


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  		TABLE 1. INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION PRIMARY GRAFT DYSFUNCTION GRADING SCHEMA

 
A growing area of interest is the difference in PGD grades between single and bilateral transplants. Oto and colleagues suggest that PGD in single and bilateral lung transplants be considered separately due to their findings that PGD grading varies with time and that the native lung may artificially lower P/F ratios early after transplant. The accuracy of PGD grading as a predictor of outcomes for single lung transplant procedures would then be decreased (14, 15). However, this has not yet been shown prospectively. In the future, the ISHLT guidelines will likely be refined as these and other studies are performed to best define PGD grading.

INCIDENCE AND OUTCOMES

As can be expected, studies published before the ISHLT guidelines are inconsistent in the reported incidences and outcomes of PGD due to differences in study definition of PGD (6). In studies using a definition of PGD similar to the definition of acute respiratory distress syndrome (ARDS) (Grade 3 PGD), the reported incidence of PGD ranges from 10 to 25%, with 30-day mortality close to 50% (1–3, 5, 16). If a less stringent definition of PGD is used, reported incidences of PGD increase to 50 to 57%, with no significant mortality differences between groups (17, 18). Several studies have been conducted looking at patient outcomes since the ISHLT guidelines were published. Burton and coworkers examined 180 consecutive patients who had undergone lung transplant and noted a correlation between severity of PGD and worse lung function and degree of histologic findings on pathology (19). The authors noted decreased short- and long-term survival with increased PGD severity; however, they conducted their subgroup analysis based on the degree of radiographic infiltrates. The University of Minnesota group has conducted important studies expanding the ISHLT PGD guidelines. In 2006, these researchers validated the ISHLT grading system by demonstrating that short- and long-term mortality and length of hospital stay were significantly associated with Grade 3 PGD, based on the worst P/F within the first 48 hours after transplant (20). The authors highlighted the discriminatory ability of PGD Grade 3 versus Grades 1–2 to predict mortality and other outcomes. In 2007, they expanded on this work and looked at early trends in P/F ratio, demonstrating that the highest 90-day mortality was in the patient group with the least amount of improvement in P/F in the first 12 hours after transplant (13). The number of deaths within the first 5 years after transplant was also the highest in this subgroup. Finally, Whitson and colleagues published a retrospective review of lung transplant recipients from 1992 to 2005, a total of 374 patients. PGD severity was graded over the first 48 hours after transplant. Overall survival rates were 51% at 5 years and 11% at 10 years in those patients with Grade 3 PGD. BOS-free survival was also lower in the severe PGD group, though this was seen only in the bilateral transplant group (21).

The link between PGD and BOS has been hypothesized before, but conflicting results have been published (22–26). A recent study by Daud and coworkers provided convincing data supporting an association between PGD and increased risk of BOS. In their retrospective cohort of 337 lung transplants, the risk of developing BOS stage 1 was directly related to worsening PGD grade immediately after transplant (10). Most interestingly, this association was independent of acute rejection, lymphocytic bronchiolitis, and community-acquired respiratory infections (Table 2) (10). These findings lend insight into the pathogenesis of BOS, potentially implicating early lung injury and PGD in the chronic alloimmune response of chronic rejection. Studies exploring potential mechanisms underlying this relationship will be highlighted below in PATHOGENESIS AND TRANSLATIONAL STUDIES.


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  		TABLE 2. MULTIVARIABLE COX PROPORTIONAL HAZARDS MODEL OF RISK FACTORS FOR BRONCHIOLITIS OBLITERANS SYNDROME STAGE 1

 
CLINICAL RISK FACTORS

Numerous studies have been designed to identify the clinical risk factors associated with increased risk for developing PGD after transplant with the goal of early support and intervention to improve outcomes. Many of these studies, however, are hampered by small numbers, being conducted at single centers, and often over numerous treatment eras. These risk factors can be categorized as donor, recipient, and operative variables (Table 3).


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  		TABLE 3. POSSIBLE PRIMARY GRAFT DYSFUNCTION RISK FACTORS

 
Donor Variables
These risk factors relate to inherent or acquired characteristics of the lung donor. Consistent with findings in other solid organ transplant procedures with regards to poorer outcomes with older donors, increased donor age has been associated with PGD, with increased risk occurring in donors greater than 32 to 45 years of age (3, 12, 27). Younger donor age, donor African-American race, and donor female gender have also been identified as potential risk factors for PGD, though these findings have not been validated and mechanisms for such associations remain speculative (3). A positive donor smoking history has also been identified as a possible risk factor for PGD, though not consistently (28, 29).

The donor-acquired risk factors that potentially can contribute to the development of PGD have recently been reviewed (28), including prolonged mechanical ventilation, aspiration pneumonitis/pneumonia, trauma, and hemodynamic instability after brain death. Such risk factors have theoretical bases for an association with PGD, but definitive studies have not been shown linking such donor factors to the development PGD, limited by small patient numbers and a lack of uniformity in donor management. In a multicenter prospective cohort study examining the risk factors for PGD at 24 and 72 hours, there were no donor-related risk factors that were independently associated with Grade 3 PGD after multivariable analysis (30). However, this study was conducted before the institution of the Lung Allocation Score (LAS), and it has not yet been shown whether the LAS has impacted on donor selection practices. Nevertheless, efforts to standardize the management of organ donors are clearly warranted and will help determine the true impact of inherent and acquired donor risk factors on PGD.

Recipient-related Variables
Reviewed extensively by Barr and colleagues, numerous studies have examined recipient-related risk factors for poor clinical outcomes after lung transplantation (11). However, not all of them examined PGD directly, and similar to other risk factor analyses, many studies employ small numbers and variable definitions of PGD. There is no conclusive evidence that recipient age, sex, race, body weight, underlying hepatic or renal impairment, left heart disease, diabetes, or medication use before surgery (steroids, inotropes) are directly associated with an increased risk of PGD development (11). Similarly, a history of prior thoracic surgery or pretransplant mechanical ventilation has not been shown to directly be associated with PGD.

There is strong evidence that elevated recipient pulmonary artery pressures are associated with increased PGD risk. Elevated pulmonary artery pressure was noted by Whitson and coworkers to increase the risk of Grade 3 PGD within the first 48 hours after transplant (12), and several studies have noted an association between a recipient diagnosis of pulmonary arterial hypertension (PAH) and PGD (2, 3, 18). The association between a diagnosis of secondary PAH and PGD is not as strong, though recent work by Lee and colleagues has shown an independent association between elevated mean pulmonary arterial pressures at the time of surgery with Grade 3 PGD at 72 hours, independent of underlying diagnosis (30). Other disease associations with PGD are less clear: patients with COPD may have the lowest risk of PGD (3, 16, 31). The relationship between PGD and suppurative and restrictive lung diseases is not proven, although diffuse parenchymal lung disease has been suggested to increase risk of PGD (11, 30).

Operative-related Variables
The type of transplant procedure (single versus bilateral) has not been shown to be an independent risk factor for the development of PGD. Confounding by the use of cardiopulmonary bypass (CPB) in bilateral transplant procedures and a higher prevalence of patients with PAH requiring bilateral transplants does not allow for firm conclusions about bilateral lung transplantation and PGD. The association between PGD and CPB, independent of indication for use, is controversial: preoperative PAH is more common in patient groups requiring CPB who then develop PGD, confounding the association between CPB and PGD (32). Other groups have demonstrated that in lung transplant recipients without a diagnosis of pulmonary arterial hypertension, the need for CPB predicted worse early outcomes and early death (31). In contrast, others have shown that the use of CPB was not an independent risk factor for PGD and that patients had similar early outcomes when CPB was not dictated by pulmonary hypertension or other factors (3, 33).

Another operative risk factor of interest is the transfusion of blood products. It has been demonstrated previously that bilateral lung transplant procedures, use of CPB, and recipients with a diagnosis of Eisenmenger syndrome or cystic fibrosis had a significant demand for more blood products in the first 24 hours after transplant surgery (34). However, this study did not specifically address the development of PGD. It has been well documented that transfusion-related lung injury (TRALI) can result in an ARDS-like picture similar to that seen with PGD (35). Recent multicenter studies have shown an independent association between blood product administration and increased risk for PGD, but the exact relationship between the two processes is not yet clear (30, 36). The ischemia/reperfusion injury (IRI) of PGD may be a "priming" event that activates the pulmonary endothelium to allow for subsequent inflammatory neutrophils to perpetuate the lung injury seen with TRALI (37). Conversely, the lung injury of TRALI might accentuate any underlying mild IRI, resulting in the onset of clinically significant PGD. TRALI could therefore be the result of, concurrent to, or a causal factor for the development of PGD.

Further refinement of the ISHLT PGD definition and grading scheme as well as uniform donor management protocols will better allow for the rapid, reliable identification of patients most at risk for developing PGD. Prospective, multicentered studies are clearly indicated.

PATHOGENESIS AND TRANSLATIONAL STUDIES

PGD is the end result of multiple pathologic mechanisms. While progress has been made to better understand the consequences of the lung transplant procedure and how they relate to the clinical manifestation of PGD (donor brain death, pulmonary ischemia, cold organ preservation, reperfusion), much work still needs to be done. It is clear that stress from reactive oxygen species (ROS) generation during the ischemia/reperfusion process is an important driving force for PGD (38). In addition to direct injury from ROS on pulmonary endothelium and epithelium, inflammatory cascades are initiated, adhesion molecules are up-regulated, and procoagulant factors are increased that contribute to lung injury (36, 39–41).

van der Kaaij and colleagues developed a long-term animal model of lung IRI to better ask whether IRI exclusively results in PGD (42). Studies employing such models will improve understanding of the acute and chronic consequences of PGD. Furthermore, how these patterns of acute lung injury result in the long term allograft rejection of BOS is an area of great interest. Animal models and translational studies are the starting ground for clarifying these mechanisms. A few recent studies highlighting these efforts are detailed herein.

The Wilkes group has published exciting studies exploring both the short- and long-term impact of immunity against a newly identified and otherwise sequestered lung antigen, collagen type V. Using a rat model, the authors showed that IRI unmasks antigenic collagen V and that lymphocytes expressing IL-17 and IL-23 induce rejection pathology (43). More recently, this group explored whether pretransplant collagen V–specific cellular immunity impacts on PGD. In 55 patients awaiting lung transplant, delayed-type hypersensitivity to collagen V was assayed, and P/F ratios were impaired significantly up to 72 hours after transplant in collagen V-reactive versus nonreactive patients (44). This study suggests that activation of innate immunity by collagen V–specific Th-17 memory cells is an additional pathway to PGD. Matrix metalloprotease inhibition in the donor and recipient may therefore be a potential therapeutic avenue to reduce exposure of collagen V and hence IRI-induced inflammation (45). Long-term collagen V–specific immune responses have also been shown to be linked to the incidence and severity BOS in a 7-year prospective study of peripheral blood mononuclear cells in transplant recipients (46).

Bharat and coworkers also aimed to explore the link between PGD-induced inflammation and chronic allograft rejection through analysis of alloantibodies (anti–human leukocyte antigen [HLA] antibodies) and a LUMINEX assay evaluating a battery of cytokines and chemokines in 127 lung transplant subjects (47). Patients with PGD had elevated proinflammatory mediators during the early post-transplant period compared with patients with no PGD. At 5 years after transplant, patients with a history of PGD had increased development of de novo anti-HLA type II alloantibodies. The authors concluded that PGD induces proinflammatory cytokines to up-regulate HLA-II antigens in the allograft. By inducing a proinflammatory state after transplant and increasing donor HLA-II expression, PGD promotes the development of donor specific alloimmunity, therefore mechanistically linking PGD and BOS (47).

Complement activation after IRI likely enhances damage via several mechanisms, including smooth muscle contraction and up-regulation of vascular permeability (48). Westall and coworkers examined early post-transplant graft deposition of complement factors C3d and C4d for correlation with clinical outcome (49). The authors found that complement staining was increased in lung transplant recipients with a history of severe PGD or infection, but not in those with acute cellular or chronic rejection. In a subgroup analysis of nine patients with early BOS in the absence of acute rejection or CMV infection, there was significant lung allograft C3d/C4d deposition and histologic evidence of antibody-mediated rejection.

These and other studies are beginning to establish a clear indication that the lung injury pattern of PGD has an important impact on long-term alloimmunity of the lung allograft. Only by better understanding the pathogenesis of this process can potential intervening actions be taken.

PREVENTION AND MANAGEMENT

Prevention
Previous research has focused on improving lung preservation techniques to prevent IRI and PGD (Table 4). Such techniques include factors such as the volume, temperature, pressure, and components of preservation solutions, and inflation and ventilation parameters of the organs during transport. Such protocols are not universally standard and vary between institutions, making comparisons difficult. There have been only a few randomized, controlled trials examining the prevention of PGD during lung transplantation, with modest early impact on clinical parameters. These and other recent studies will be highlighted below.


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  		TABLE 4. SUMMARY OF NOTABLE STUDIES AIMED AT PRIMARY GRAFT DYSFUNCTION PREVENTION

 
Inhaled nitric oxide (iNO) has been investigated as a potential agent for the prevention of PGD, given the effects of iNO on pulmonary vasodilation, capillary integrity, and prevention of leukocyte adhesion and platelet aggregation (50). In a prospective, randomized, blinded clinical trial, Meade and colleagues evaluated whether the prophylactic administration of iNO in 84 patients who had undergone transplant could affect the incidence of PGD (51). There was no difference in PGD incidence when iNO was started 10 minutes after reperfusion. A similar trial was conducted more recently by Botha and coworkers showing no benefit of iNO administered at the onset of reperfusion on PGD Grade 3 incidence, gas exchange, neutrophil sequestration, or bronchoalveolar lavage concentration of proinflammatory cytokines (52). As will be discussed below, although iNO may have a role in established PGD to improve gas exchange, it has not been shown to be an effective prophylactic agent.

Other agents investigated in randomized, placebo-controlled trials for PGD prevention include the soluble complement receptor-1 inhibitor (sCR1), and the platelet-activating factor antagonist BN 52021. Keshavjee and colleagues, and Zamora and coworkers, showed that in 28 patients who had undergone lung transplant receiving sCR1 before reperfusion, 50% were extubated within 24 hours, compared with only 19% of patients not receiving the treatment agent. Duration of mechanical ventilation and length of ICU stay also tended to be lower in the treatment group (53, 54). However, there was no significant effect on P/F, operative deaths, incidence of infection or rejection, nor hospital length of stay in this study. The platelet-activating factor antagonist BN52021 was evaluated by Wittwer and colleagues in 24 patients who had undergone lung transplant (55), administered during flushing of the preserved organ and after reperfusion. Oxygenation scores and X-ray findings were improved in the treatment groups during the first 12 hours; however, these differences were not sustained at later time points. While encouraging, these small trials point toward the multifactorial nature of PGD pathogenesis as well as the difficulty of finding specific targets that have a significant impact on PGD incidence or mortality.

Organ preservation solution composition has been adjusted over the years to optimize lung function after transplant and to allow for longer ischemic times. Extracellular-type preservation solutions have generally been regarded as the most efficacious in reducing PGD incidence (56). More recently, Oto and coworkers directly compared three most commonly used preservation solutions (Perfadex, Euro-Collins, and Papworth) in 157 consecutive lung transplants. Early clinical outcomes such as oxygenation, PGD grade, ICU stay, and 30-day mortality were not significantly different between the three solutions, though Perfadex trended toward superiority when compared with the other two (57). After multivariable analyses, however, Perfadex use was significantly associated with a lower incidence of PGD Grades 2 and 3 at 48 hours after transplant.

The relationship between reperfusion technique and PGD has been extensively studied, as reviewed by Barr and colleagues (11). Reperfusion after ischemia from organ preservation leads to neutrophil migration, capillary plugging, and the initiation and propagation of a robust inflammatory cascade that all may have downstream effects on PGD development. Schnickel and coworkers at UCLA published their examination of 100 consecutive transplant procedures employing a modified reperfusion technique (58). This technique involved cannulation of the main or individual pulmonary artery and reperfusing with recipient blood depleted of leukocytes, supplemented with nitroglycerin, adjusted for pH and calcium level, and enriched with glutamate and dextrose. Low perfusion pressure was maintained for 10 minutes before weaning from CPB or pulmonary artery clamp removal. The authors found that the incidence of severe PGD (P/F < 150 with chest X-ray infiltrate) was 2%, and the 30-day survival rate was 97% (58).

Several studies exploring PGD prevention are being conducted with some promise, employing animal models and novel agents, but it remains to be seen what the broader applicability of these preliminary studies will be. In addition, such studies are hampered by small numbers and differences in center-specific protocols; multicenter trials will need to be conducted to provide firm conclusions on potential agents. In addition, agents such as matrix metalloprotease inhibitors (45) can potentially be studied in the future in larger scale, but as with other experimental agents, safety and cost are important limiting factors in human trials. An alternative may be dietary modification of antioxidant and antiinflammatory machinery as a potential nontoxic and readily available means of affecting PGD, an approach shown successful in some animal models of IRI (59, 60).

Treatment
Treatment of established PGD largely remains supportive. As recently reviewed, treatment strategies are similar to those for patients with ARDS, employing low-stretch ventilation for the prevention of barotrauma and avoidance of excessive fluid administration in the setting of capillary leak from IRI (50). Importantly, there are no clinical studies that have systematically evaluated the strategies that have been applied from the ARDS literature to PGD. Postoperative care is therefore still largely individualized by center. Several experimental therapeutic modalities are highlighted here.

While inhaled NO does not seem to have a role in prophylaxis against PGD development, it may be beneficial in clinical settings of established PGD. There have been several reports and case series that show improved outcomes with iNO administration (61–63). However, there have also been studies that do not show efficacy in the setting of PGD (64). Lack of randomized clinical trials showing survival benefit precludes widespread recommendation of the use of iNO for the treatment of PGD, though its use may be justified in selected cases of severe hypoxemia and/or elevated pulmonary artery pressures. Again, extrapolating from use in studies with ARDS, the beneficial effects of iNO may be real, but also appear to be transient (50). Similarly, the use of inhaled prostacyclin as a pulmonary vasodilator has not been studied for efficacy in PGD treatment, but it is used in settings of refractory hypoxia after lung transplant, often with concomitant delayed right heart recovery from severe pulmonary hypertension.

Extracorporeal membrane oxygenation (ECMO) use has been studied in the setting of refractory hypoxia in lung transplant settings, particularly when PGD is combined with hemodynamic instability (16, 65, 66). Reports from several centers detailing their experience with ECMO in the setting of severe PGD have led to ECMO being generally regarded to be a potentially life-saving salvage treatment option if instituted early in the course of severe PGD and no later than 7 days after transplant (50). Studies are ongoing examining the optimal use of ECMO (cannulation site, duration, timing of initiation) to improve outcomes and to minimize complications such as bleeding, cardiac tamponade, and renal failure.

The Toronto group published an analysis of ECMO use for lung transplant within a larger registry of 31,340 ECMO cases of varying indications. Their aims were to better determine optimum ECMO treatment strategies, given that it is difficult for a single center to accumulate a large enough experience with ECMO for the indication of lung transplantation (67). They detected an overall 42% survival rate, and 93 of 151 patients had ECMO discontinued due to lung recovery, suggesting an appreciable salvage rate with ECMO use. In 2007, the University of Wisconsin published a retrospective review of 22 patients who received ECMO after lung transplantation. Thirty-day, 1-year, and 3-year survival rates were 75%, 54%, and 36%. Most patients who had been treated with ECMO died of multi-organ failure (68). Late institution of ECMO resulted in 100% mortality, similar to that seen in previously published studies (69).

Several groups have asked the question of whether ECMO should replace CPB intraoperatively and whether this may impact outcomes. The Vienna group published their retrospective review of 130 patients who had undergone lung transplant and who received ECMO support intraoperatively for hemodynamic or respiratory instability. Fifty-one of these patients had prolonged ECMO support into the perioperative period, and five of these patients had ECMO reinstituted for severe PGD. The authors' conclusions were that ECMO could replace CPB with equivalent results and with favorable survival rates (70). Ko and coworkers expand on their experience with using ECMO instead of CPB, and they found no increase in blood product use compared with CPB (71). ECMO was performed through the femoral venoarterial route, thereby not disturbing the operative field with bypass cannula required for CPB. However, a group in Germany had conflicting results, showing a trend toward improved 90-day survival, less blood product requirements, and lower operative time in the CPB group compared with the ECMO group (72). There may be a role for ECMO specifically for patients with pulmonary hypertension, and several groups have routinely used ECMO at the time of transplantation in these patients instead of CPB (71, 73, 74).

Pulmonary surfactant dysfunction is noted to occur as a result of ischemia and reperfusion, leading to alveolar collapse, Formula mismatching, and decreased oxygenation (50), all likely contributing to PGD. Exogenous administration of surfactant has been shown to attenuate IRI in animal models (75, 76). Drawing upon translational studies in which exogenous surfactant administration improved oxygenation and pulmonary compliance in animal models (77–79), Kermeen and colleagues directly instilled surfactant via bronchoscopy into each segmental bronchus of six patients who developed severe IRI out of a series of 106 consecutive lung or heart-lung transplants. Severe IRI was defined by infiltrates and worsening hypoxia with decreased lung compliance within 72 hours of transplant (80). Radiographic infiltrates resolved in all cases within 24 hours, and at 19 months survival was 100% (80). However, this study was not a controlled trial; therefore, more widespread use will require further investigation.

Other therapeutic strategies continue to be evaluated that may hold promise. For instance, N-acetylcysteine administration has been shown to attenuate IRI in rat models (81) and may act via a surfactant-protective mechanism (82). Another strategy being investigated is selective inhibition of the transcriptional activation response to oxidative stress, such as the p38 and c-jun kinase pathways. Wolf and coworkers administered p38 and c-jun kinase inhibitors to rats undergoing IRI and showed significant reductions in transcription factor activation and markers of lung injury. Their data also point to the pulmonary macrophage as a key coordinator of lung injury response to oxidative stress (83).

MOLECULAR MARKERS

At present, there are no molecular or genetic markers to predict PGD. However, there is great potential to achieve this objective given recent advances that allow for determination of the molecular and genetic signature of PGD. If reliable biomarkers can be identified, they may provide insight into pathogenesis as well as prognostic value to predict the natural history of patients with PGD.

Molecular fingerprinting techniques with microarray technology and functional genomics have been applied to various forms of acute lung injury (84). Such techniques are being used specifically in IRI, though the clinical application of such data is not yet clear (85). Ray and colleagues observed changes in gene expression across donor lungs that developed PGD versus those that did not, noting differences in genes involved in signaling, apoptosis, and stress-activated pathways (86). While certainly preliminary, this study highlights potential prognostic information that can be obtained from the genetic profile of lung donors in addition to at-risk recipients; such information will better allow matching of organs and more precise risk stratification.

A recent study by Calfee and coworkers identified a novel marker of alveolar type I cell injury; alveolar type I cells are integral in alveolar fluid transport and for the resolution of pulmonary edema. Higher levels of RAGE, or receptor for advanced glycation end-products, were significantly associated with a longer duration of mechanical ventilation and longer ICU stay when measured 4 hours after reperfusion (87). In addition, PGD was not as predictive of these outcomes in their cohort of 20 patients, raising the prospect that such biomarkers may prove more sensitive and provide better prognostic value than other clinically derived measures. Similarly, Krenn and colleagues examined pretransplant levels of serum vascular endothelial growth factor (VEGF), a regulator of vascular permeability, and showed that VEGF concentrations were significantly higher in patients with PGD Grade 3 versus those with Grades 0–2 and control subjects (88). Drawing on the multifactorial nature of PGD pathogenesis, other recent studies describing potential markers to predict PGD include: cytokine levels such as IL-8 (89) and IL-6/IL-10 (90), serum indicators of hypercoaguability and impaired fibrinolysis (91), and cell adhesion (36), and reduced donor pulmonary vein gas PO2 (92). Such candidate markers need to be assessed with larger numbers in prospective impact studies before widespread use (93).

NON–HEART-BEATING DONORS, ISCHEMIC TIMES, AND PGD

With increasing numbers of patients with end-stage lung diseases requiring life-saving lung transplants, the critical organ shortage has spurred growing interest in the use of non–heart-beating donors (donors of cardiac determinant of death [DCDD]) in addition to traditional brain-dead, heart-beating donors, also called donors of neurological determinant of death (DNDD). The maximum tolerated warm ischemia period when lungs remain in the donor's body after cardiac arrest is thought to be approximately 1 hour. In terms of impact on PGD incidence and severity, it is currently unknown how this period of warm ischemia compares to often prolonged periods of cold ischemia after lung harvesting from DNDD. Total cold ischemic time has been investigated as a risk factor for the development of PGD in DNDD with variable results; in DCDD, there are potentially different effects of warm ischemia on PGD, thought largely due to the lack of autonomic instability following brain death. This is an important area for future research, and early evidence may point to the increased feasibility of using DCDD. Neyrinck and colleagues showed that in an animal model of isolated reperfusion, 1-hour-warm ischemic lungs from DCDD were less susceptible to IRI than lungs retrieved after 5 hours of in situ mechanical ventilation after brain death (94). Efforts are also being made to increase the tolerable warm ischemia time of lungs in the cadaver with the administration of agents such as nebulized N-acetyl cysteine (an antioxidant), IV nitroglycerin (a nitric oxide donor), and fibrinolytics to reduce microthrombi formation (95–97). Positive results of such studies would have profound impact on expanding the potential donor pool as well as how we approach organ donor management.

CONCLUSIONS

The clinical impact of PGD on lung transplantation is clear, and if improvements in short- and long-term outcomes are to be made, further research into the diverse mechanisms of PGD is needed. Potential therapeutic agents need to be identified as these mechanisms are elucidated. More powerful tools will be used to identify both donors and recipients most at risk for developing PGD based on molecular and genetic profiles. As this work progresses, the definition of PGD may need to be further refined to provide the most accurate outcomes measures in clinical research and ensure standardization and applicability of these findings. Finally, as technical issues are resolved surrounding efforts to expand the donor pool via non–heart-beating donors and living related donors, this impact on the incidence and pathogenesis of PGD will have to be assessed.

FOOTNOTES

Conflict of Interest Statement: J.C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.D.C. received consultant fees of less than $2,000 from Enzon Pharmaceuticals for serving on an Advisory Board for a clinical trial of induction therapy.

(Received in original form August 14, 2008; accepted in final form September 22, 2008)

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