Primary Graft Dysfunction Cases Research Articles

Early serum biomarkers to characterise different phenotypes of primary graft dysfunction after lung transplantation: a systematic scoping review.

Lung transplantation (LUTX) is often complicated by primary graft dysfunction (PGD). Plasma biomarkers hold potential for PGD phenotyping and targeted therapy. This scoping review aims to collect the available literature in search of serum biomarkers for PGD phenotyping. Following JBI and PRISMA guidelines, we conducted a systematic review searching MEDLINE, Web of Science, EMBASE and The Cochrane Library for papers reporting the association between serum biomarkers measured within 72 h of reperfusion and PGD, following International Society for Heart and Lung Transplantation (ISHLT) guidelines. We extracted study details, patient demographics, PGD definition and timing, biomarker concentration, and their performance in identifying PGD cases. Among the 1050 papers screened, 25 prospective observational studies were included, with only nine conducted in the last decade. These papers included 1793 unique adult patients (1195 double LUTX, median study size 100 (IQR 44-119)). Most (n=21) compared PGD grade 3 to less severe PGD, but only four adhered to 2016 PGD definitions. Enzyme-linked immunosorbent assays and the multiplex bead array technique were utilised in 23 and two papers, respectively. In total, 26 candidate biomarkers were identified, comprising 13 inflammatory, three endothelial activation, three epithelial injury, three cellular damage and two coagulation dysregulation markers. Only five biomarkers (sRAGE, ICAM-1, PAI-1, SP-D, FSTL-1) underwent area under the receiver operating characteristic curve analysis, yielding a median value of 0.58 (0.51-0.78) in 406 patients (276 double LUTX). Several biomarkers exhibit promise for future studies aimed at PGD phenotyping after LUTX. To uncover the significant existing knowledge gaps, further international prospective studies incorporating updated diagnostic criteria, modern platforms and advanced statistical approaches are essential.

Interstitial Glucose Metabolism Monitoring as an Additional Method for Objective Assessment of Donor Liver, Prediction and Immediate Diagnosis of Early Graft Dysfunction.

A retrospective observational single-center study included 32 cases of liver transplantation. Along with standard methods for assessing the initial function of grafts during the first week after surgery, interstitial (in the transplanted liver) concentrations of glucose and its metabolites were monitored. In 18 cases, the interstitial glucose metabolism was also studied during static cold storage (SCS). With the development of early allograft dysfunction (EAD), compared with the uneventful post-transplant period, statistically significantly higher interstitial lactate concentrations were observed as early as 3 h after reperfusion: 12.3 [10.1; 15.6] mmol/L versus 7.2 [3.9; 9.9] mmol/L (p=0.003). A value above 8.8 mmol/L may be considered as a criterion for the immediate diagnosis of EAD (sensitivity - 89%, specificity - 65%).Interstitial lactate concentration at the end of SCS and the area under the "lactate concentration-SCS duration" curve were associated with the initial graft function. Values of these parameters greater than 15.4 mmol/L and 76.1 mmol/L·h, respectively, with a sensitivity of 100% in both cases and a specificity of 77 and 85%, may be used to assess the risk of primary EAD. Monitoring of interstitial concentrations of glucose and its metabolites, primarily, lactate, is an objective additional method for the assessment of the donor liver viability both during SCS and in the early postoperative period.

Primary Graft Dysfunction in Heart Transplant Recipients-Risk Factors and Longitudinal Outcomes.

Before the 33rd Annual International Society for Heart and Lung Transplantation conference, there was significant intercenter variability in definitions of primary graft dysfunction (PGD). The incidence, risk factors, and outcomes of consensus-defined PGD warrant further investigation. We retrospectively examined 448 adult cardiac transplant recipients at our institution from 2005 to 2017. Patient and procedural characteristics were compared between PGD cases and controls. Multivariable logistic regression was used to model PGD and immediate postoperative high-inotrope requirement for hypothesized risk factors. Patients were followed for a mean 5.3 years to determine longitudinal mortality. The incidence of PGD was 16.5%. No significant differences were found with respect to age, sex, race, body mass index, predicted heart mass mismatch, pretransplant amiodarone therapy, or pretransplant mechanical circulatory support (MCS) between recipients with PGD versus no PGD. Each 10 minute increase in ischemic time was associated with 5% greater odds of PGD (OR = 1.05 [95% CI, 1.00-1.10]; p = 0.049). Pretransplant MCS, predicted heart mass mismatch ≥30%, and pretransplant amiodarone therapy were associated with high-immediate postoperative inotropic requirement. The 30 day, 1 year, and 5 year mortality for patients with PGD were 28.4%, 38.0%, and 45.8%, respectively, compared with 1.9%, 7.1%, and 21.5% for those without PGD (log-rank, p < 0.0001). PGD heralded high 30 day, 1 year, and 5 year mortality. Pretransplant MCS, predicted heart mass mismatch, and amiodarone exposure were associated with high-inotrope requirement, while prolonged ischemic time and multiple perioperative transfusions were associated with consensus-defined PGD, which may have important clinical implications under the revised United Network for Organ Sharing allocation system.

Are Those with Primary Graft Dysfunction More Likely to Have Acute Cellular Rejection or Donor-Specific Antibodies after Heart Transplantation?

<h3>Purpose</h3> Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HT). We sought to determine the association between PGD and incidence of acute cellular rejection (ACR) and development of <i>de novo</i> donor specific antibodies (DSA) within two years post-HTx. <h3>Methods</h3> Consecutive adult HT recipients (n=351) from 1/2010 to 7/2018 at a single center were included. Multi-organ and re-transplants were excluded. Definition of moderate and severe PGD was based on the 2014 ISHLT consensus, which includes dependence on extracorporeal membrane oxygenation or intra-aortic balloon pump. The primary outcome was the incidence of ACR (ISHLT grade 2R or 3R) and the development of <i>de novo</i> DSA (mean fluorescence intensity >500) within 2 years post-HTx. <h3>Results</h3> The cohort was predominantly male (70.6%), with a mean age of 54.1±12.5 years; 34.6% had a durable left ventricular assist device as a bridge to HTx. There were 33 (9.1%) cases of moderate or severe PGD. HLA was assessed in a mean of 15 and 24 samples per patient in those with and without PGD respectively. At two years, patients with PGD had lower incidence of development of <i>de novo</i> DSA against HLA-C (1.6 vs. 3.2%, p=0.047), DP (1.3 vs. 4.3%, p=0.002), DQ (3.3% vs. 11.8%, p<0.001), DR (4.9 vs. 12.4%, p<0.001) compared to patients without PGD (Table 1). In patients with and without PGD, there were 7 and 8 endomyocardial biopsies performed per patient, respectively within two years post-HTx. Patients with PGD had similar incidence of ISHLT 2R or 3R ACR compared to those without PGD (5.3% vs. 3.1%, p=0.07). Finally, there was no difference in PGD among patients who received empiric treatment for ACR without positive endomyocardial biopsy results (3.1% in PGD vs. 3.7% in no PGD, p=0.47). <h3>Conclusion</h3> Development of <i>de novo</i> DSA was lower in the PGD group and there was no difference in overall incidence of ACR in patients with and without PGD at 2 years post-HTx.

A CLUE for Better Assessment of Donor Lungs: Novel Technique in Clinical Ex-Vivo Lung Perfusion

Direct lung ultrasound evaluation (CLUE) technique was proven to be an accurate method for monitoring extravascular lung water in donor lungs during ex-vivo lung perfusion (EVLP) in porcine and human lung models. The aim of this study was to examine the application of CLUE in the clinical setting. Lungs were evaluated in acellular EVLP with standard protocol. Ultrasound images were obtained at each point of 4 lines passing through the anterior, lateral, posterior, and diaphragmatic surfaces of each lung. Images were graded according to the percentage of B-lines and presence of consolidation. CLUE scores were calculated at the beginning (initial) and the end (final) of EVLP for the whole lung, each side and lobe using this equation: CLUE Score = (No. of Grade 1 images x 1 + No. of Grade 2 images x 2 + No. of Grade 3 images x 3 + No. of Grade 4 images x 4 + No. of Consolidation images x 5) / Total No. of images taken. In our clinical EVLP program, 36 lungs from 18 donors were evaluated by CLUE. Eighteen lungs were deemed suitable and were transplanted (8 double & 2 single) with no hospital mortality. There were no cases of primary graft dysfunction (PGD) grade 2 observed and one recipient had PGD 3 at 72 hours. Final CLUE score was significantly lower in suitable lungs compared to non-suitable (0.86 ± 0.4 vs 1.80 ± 0.3, p < 0.001). CLUE score had the highest area under the receiver-operating characteristic curve (0.98, with threshold of 1.4, specificity 94% & sensitivity 92%) when compared to other evaluation parameters like Δ PO2 (0.68) and dynamic compliance (0.89). Initial CLUE score of standard donor lungs which were perfused for logistic reasons was significantly lower than marginal lungs (0.58 ± 0.3 vs 1.38 ± 0.4, p = 0.001) with threshold of 0.93. Initial CLUE score was significantly higher in lungs put in prone position compared to the supine group (1.56 ± 0.5 vs 1.12 ± 0.5, p = 0.004). The change in initial to final CLUE score in prone group showed significant improvement (1.00 ± 0.4 vs 1.69 ± 0.4, p = 0.004) especially in the upper lobes (1.34 ± 0.8 vs 2.67 ± 0.7, p = 0.009). CLUE technique shows the highest accuracy in evaluating donor lungs for transplant compared to other parameters used in EVLP. CLUE can help in improving the outcomes of lung transplant by guiding decision making through the whole process of EVLP and providing a comprehensive precise assessment of individual lungs and lobes.

Application of Predicted Heart Mass Difference in a Canadian Cohort of Heart Transplant Recipients

Purpose Recipient-donor sex-mismatch is a predictor of 1-year mortality after heart transplant (HT). A more granular construct for size mismatch is the difference in heart mass. A retrospective analysis of the UNOS Database showed that only the lowest undersized septile (>19%) was associated with 1 year mortality. These findings have not been validated. We aimed to assess the prognostic value of donor and recipient predicted heart mass (pHM) difference at 2 large Canadian HT centers. Methods A retrospective study of consecutive adult HT recipients (2004 - 2014) was performed at Toronto General Hospital and the Ottawa Heart Institute. The pHM difference, defined as a percent difference between donor and recipient pHM was calculated as previously described: [(pHMrecipient -pHMdonor)/pHMrecipient]]*100. Multivariable Cox and logistic regression models were used to evaluate the association between pHM difference and 1-year mortality and moderate or severe primary graft dysfunction (PGD), adjusted for ischemic time and donor age. Due to the non-linear nature of pHM difference, we applied restricted cubic splines. Results 412 patients (mean age 50±13 years, 71% male) were analyzed. Average ischemic time was 3.7±1.1 hours. Median pHM difference was 3.3% (IQR-15.5-7.0%). 25 (6%) donors were undersized by >19%. There were 46 deaths (6%) and 55 (13%) cases of moderate or severe PGD at 1 year post-transplant. pHM difference was not associated with 1-year mortality (HR 0.99 per 1% increase in pHM difference, 95% CI 0.96-1.02; figure ) or PGD (OR 0.99 per 1% increase in pHM difference, 95% CI 0.96-1.01; figure ). Ischemic time was the only significant predictor of mortality and PGD: HR 1.34 per hour increase, 95% CI 1.08 to 1.68 for mortality and OR 1.64, 95% CI 1.28-2.11 for PGD). Conclusion In this cohort, there was no association between pHM difference and 1-year mortality or moderate/severe PGD. Longer ischemic times may account for the lack of association between pHM and 1-year outcomes Recipient-donor sex-mismatch is a predictor of 1-year mortality after heart transplant (HT). A more granular construct for size mismatch is the difference in heart mass. A retrospective analysis of the UNOS Database showed that only the lowest undersized septile (>19%) was associated with 1 year mortality. These findings have not been validated. We aimed to assess the prognostic value of donor and recipient predicted heart mass (pHM) difference at 2 large Canadian HT centers. A retrospective study of consecutive adult HT recipients (2004 - 2014) was performed at Toronto General Hospital and the Ottawa Heart Institute. The pHM difference, defined as a percent difference between donor and recipient pHM was calculated as previously described: [(pHMrecipient -pHMdonor)/pHMrecipient]]*100. Multivariable Cox and logistic regression models were used to evaluate the association between pHM difference and 1-year mortality and moderate or severe primary graft dysfunction (PGD), adjusted for ischemic time and donor age. Due to the non-linear nature of pHM difference, we applied restricted cubic splines. 412 patients (mean age 50±13 years, 71% male) were analyzed. Average ischemic time was 3.7±1.1 hours. Median pHM difference was 3.3% (IQR-15.5-7.0%). 25 (6%) donors were undersized by >19%. There were 46 deaths (6%) and 55 (13%) cases of moderate or severe PGD at 1 year post-transplant. pHM difference was not associated with 1-year mortality (HR 0.99 per 1% increase in pHM difference, 95% CI 0.96-1.02; figure ) or PGD (OR 0.99 per 1% increase in pHM difference, 95% CI 0.96-1.01; figure ). Ischemic time was the only significant predictor of mortality and PGD: HR 1.34 per hour increase, 95% CI 1.08 to 1.68 for mortality and OR 1.64, 95% CI 1.28-2.11 for PGD). In this cohort, there was no association between pHM difference and 1-year mortality or moderate/severe PGD. Longer ischemic times may account for the lack of association between pHM and 1-year outcomes

Donor-Recipient Size Matching via Chest X-ray Measurements and Primary Graft Dysfunction Risk in Lung Transplantation

Purpose Donor to recipient (D-R) lung size matching using predicted total lung capacity (pTLC) has been shown to be associated with the risk of primary graft dysfunction (PGD) following lung transplant (LTx) but the effect varies with underlying recipient diagnosis, potentially owing to differences in actual TLC. Chest x-ray (CXR) measurements to estimate true D-R TLC could account for disease-related effects, but their role in D-R size matching is unknown. We hypothesized that CXR measurements would estimate actual TLC values and that mismatches would increase PGD risk. Methods We retrospectively reviewed adult double lung transplant recipients between 2007 and 2016. We measured lung size on pre-transplant donor and recipient CXRs using apex to costophrenic angle (ACPA) distance (Figure 1A), taking the mean of the left and right (donors the largest of the 3 most recent CXRs; recipients the most recent CXR prior to LTx). We defined “oversized” as D-R ratio > 1 and “undersized” ≤ 1. The primary outcome was grade 3 PGD (presence of edema on CXR + PaO2/FiO2 Results 206 patients met inclusion criteria, 32 (16%) of whom developed grade 3 PGD at 48 or 72 hours. Median D-R ACPA ratio was 0.92 (IQR 0.83-1.09) and recipient ACPA was strongly related to recipient actual TLC (Figure 1B, R2 0.7297 [quadratic]). D-R ACPA ratio was larger in those patients who developed PGD vs. non-PGD cases (1.01 [IQR 0.91-1.18] vs. 0.91 [IQR 0.83-1.07] p = 0.01). Oversizing (ACPA ratio > 1) increased grade 3 PGD risk (adjusted OR 2.3 [95% CI 1.0-5.2], p = 0.04). Conclusion Oversizing via CXR was associated with increased PGD risk. CXR measurement appears to serve as an estimate of true TLC. D-R ACPA ratio shows promise as a size matching tool in donor allocation and requires further investigation.

The Perioperative Lung Transplant Virome: Torque Teno Viruses Are Elevated in Donor Lungs and Show Divergent Dynamics in Primary Graft Dysfunction.

Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. To date, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 mo after transplant and found that levels of Anellovirus, mainly torque teno viruses (TTVs), were significantly higher than in nontransplanted healthy controls. We used quantitative polymerase chain reaction to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and postreperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were elevated 100-fold in donor lungs compared with healthy adults (p = 0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from before to after transplant than did control recipients (p = 0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung.

The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia

Donor smoking history and higher fraction of inspired oxygen (FIO2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion. We performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD). There were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with FIO2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects. Plasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion.

Primary Graft Dysfunction Following Heart Transplantation; Validity of a Pragmatic Self-Reporting Definition

Purpose There are no international consensus definitions of primary graft dysfunction(PGD) and failure(PGF) following heart transplantation(HTx), this limits audit and research. We report the characteristics of centre self-reported PGD(s-rPGD) cases using post-operative inotrope support and outcome data. Methods and Materials In a UK-wide prospective study we asked centres to s-rPGD as “a severe impairment of systolic graft function affecting the right, left, or both ventricles accompanied by hypotension, low cardiac output, and high filling pressures in the absence of hyperacute rejection or technical factors”. We collected donor and recipient data including pre- and post-operative support, morbidity, mortality data and recipient cause of death to establish if s-rPGD would be a valid outcome measure. Results Of 294 HTx, s-rPGD incidence was 94/294 (32%). S-rPGD cases had older donors 41(32-48) vs 36(28-43); p=0.003 and slightly older recipients 47(35-55) vs 39(20-53); p=0.034. Recipients with s-rPGD were more likely to have previous cardiac surgery and be in hospital on inotropes.[table1]The 90-day allograft mortality following VAD use were 17/48(35%). Conclusions Self-reported PGD is a reliable outcome measure characterised by high inotrope and VAD use and capturing all graft failure-related deaths. We believe our definition can be used in prospective studies to reduce the high 30-day mortality rate of this condition. Results s-rPGD(N=94) Non-PG(N=199) p Inotrope score post transplant(median(IQR)) 6-hour 0.57(0.30,1.15) 0.55(0.24,0.98) =0.07 24-hour 0.66(0.38,1.38) 0.35(0.18,0.89) =0.001 48-hour 0.46(0.14,1.13) 0.143(0.002,0.44) 72-hour 0.35(0.05,0.94) 0.002(0,0.22) Prolonged(72h-inotropes) 63/84(75%) 39/184(21%) IABP 46/85(54%) 31/184(17%) =0.001 VAD/ECMO 27/88(31%) 0/198(0%) 30-day Mortality 29/83(35%) 9/183(5%) ITU-LOS median(25th,75thcentile) 8(5,20) 5(4,9) =0.003

Obesity and Primary Graft Dysfunction after Lung Transplantation

Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation. To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation. We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios. Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7-2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30–50%) for each 5 kg/m(2) increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass. Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.

Elevated Plasma Long Pentraxin-3 Levels and Primary Graft Dysfunction After Lung Transplantation for Idiopathic Pulmonary Fibrosis

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

Single lung transplantation and fatal fat embolism acquired from the donor: management and literature review

Fat embolism (FE) is a consequence of skeletal trauma that occurs in more than 90% of cases of severe trauma. However, most of these emboli are clinically insignificant. We report the case of a 59-yr-old man with massive progressive fibrosis who died from widespread FE after a single-lung transplantation (SLT). The lung donor was a 22-yr-old woman who died from traumatic cerebral injury. She had sustained a closed fracture of the tibia, fibula and pelvis. The PaO(2)/FiO(2) before procurement was 452 mmHg. A left SLT using cardiopulmonary bypass was performed. In the immediate postoperative period, profound pulmonary edema in the transplanted lung developed, with overinflation of the native lung and systemic hypotension. Severe Primary Graft Dysfunction (PGD) was suspected and nitric oxide (NO) and independent lung ventilation (ILV) initiated. Over the next 24 h the patient's condition deteriorated and extracorporeal membrane oxygenation (ECMO) was initiated. The patient died 45 h after transplantation as cardiovascular and respiratory function continued to decline and massive thoracic bleeding secondary to coagulopathy appeared. Post-mortem examination revealed both massive FE in the non-transplanted donor lung and in the allograft lung. Only two previous cases of donor-acquired FE and PGD after lung transplantation (LT) have been reported. Occult pulmonary FE in a traumatized donor should be considered a cause of PGD.

Plasma Cytokines and Chemokines in Primary Graft Dysfunction Post-Lung Transplantation

Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case-control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein-1 (MCP-1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)-inducible protein (IP-10)/chemokine CXC motif ligand 10 (CXCL10) (both p < 0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL-13) (p = 0.05) and higher levels of IL-2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, and IFN-gamma decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.

Donor Liver Dysfunction: Application of a New Scoring System to Identify the Marginal Donor

Livers from marginal donors are increasingly used for transplantation due to the shortage of donor organs. The definition of a marginal donor remains unclear; prediction of organ function is a challenge. In the literature the use of steatotic livers has been associated with poor liver function or even primary dysfunction of the allograft. Tekin et al created a scoring system that classifies a donor as marginal or nonmarginal, using a mathematical model based on donor age and steatosis degree. The aims of this study were to apply the Tekin method to identify marginal and nonmarginal donors and evaluate the influence of the cold ischemia time (CIT) on allograft evolution. We retrospectively reviewed deceased donor liver transplantations performed from October 1995 to March 2006, namely, 177 adult liver transplantations in 163 patients. Fifty-five were excluded due to retransplantation (14) or insufficient data (41). Donor age and macrovesicular steatosis were evaluated according to the mathematical formula proposed by Tekin et al, classifying the donors as marginal versus nonmarginal. The authors also analyzed the CIT, 3-month mortality, and development of primary nonfunction or primary dysfunction. The median donor age was 38.9 years (range, 6–71). The postreperfusion biopsy specimen showed moderate to intense steatosis (>30%) in 14.75% of specimens, with no steatosis or mild steatosis in 85.25%. Sixty-one grafts (50%) developed primary graft dysfunction (PGD): 10 grafts, with primary nonfunction (PNF); and 51 with initial poor function (IPF). Using the criteria provided by Tekin et al, we obtained 41 marginal and 81 nonmarginal allografts. The marginal group showed 61.9% PGD, compared with 59.2% of PGD by the nonmarginal group. The CIT was greater than 12 hours in 5 marginal group transplants and 4 PGD cases (80%). Of the nonmarginal allografts, the CIT was greater than 12 hours in 29.6%, with 75% PGD. The 3-month graft survival rate was 80% in the marginal group with ischemia time more than 12 hours: 86.1% of the same group when CIT was less than 12 hours, and 82.7% in the nonmarginal group. In contrast, when we analyzed the occurrance of allograft dysfunction, the 3-month mortality rate was 34% among, grafts with dysfunction, whereas, in those without initial dysfunction, it was 4.1%. In conclusion, the score suggested by Tekin et al that classifies the donors as ideal (nonmarginal) or marginal was not able to predict initial primary dysfunction.