Treatment Of Primary Graft Dysfunction Research Articles

In vivo lung perfusion for prompt recovery from primary graft dysfunction after lung transplantation

No proven treatment after the development of primary graft dysfunction (PGD) is currently available. Here, we established a novel strategy of in vivo lung perfusion (IVLP) for the treatment of PGD. IVLP involves the application of an in vivo isolated perfusion circuit to an implanted lung. This study aimed to explore the effectiveness of IVLP vs conventional post-lung transplant (LTx) extracorporeal membrane oxygenation (ECMO) treatment using an experimental swine LTx PGD model. After 1.5-hour warm ischemia of the donor lungs, a left LTx was performed. Following the confirmation of PGD development, pigs were divided into 3 groups (n=5 each): control (no intervention), ECMO, and IVLP. After 2hours of treatment, a 4-hour functional assessment was conducted, and samples were obtained. Significantly better oxygenation was achieved in the IVLP group (p≤0.001). Recovery was confirmed immediately and maintained during the following 4-hour observation. The IVLP group also demonstrated better lung compliance than the control group (p=0.045). A histologic evaluation showed that the lung injury score and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed significantly fewer injuries and a better result in the wet-to-dry weight ratio in the IVLP group. A 2-hour IVLP is technically feasible and allows for prompt recovery from PGD after LTx. The posttransplant short-duration IVLP strategy can complement or overcome the limitations of the current practice for donor assessment and PGD management.

Cell death and ischemia-reperfusion injury in lung transplantation.

Lung transplantation is the most effective therapy for patients with end-stage lung disease. However, concern of donor lung damage and ischemia-reperfusion induced lung injury limits the use of "marginal" donor lungs. Recent transcriptomic studies have demonstrated that the enrichment of gene-clusters related to cell death and inflammation are the most profound signals during ischemia-reperfusion in human lung transplants. Herein, we focus on the relationship between inflammation and programmed cell death, especially necroptosis, mitochondrial permeability transition-initiated regulated necrosis, pyroptosis, ferroptosis, and autophagic cell death. Cell death-related molecules have been tested as potential biomarkers for donor lung assessment. Inhibitors for various types of cell death have been explored as therapeutics for ischemia reperfusion injury in lung transplantation. A deeper understanding of these mechanisms may help to improve donor management, organ preservation, prevention and treatment of primary graft dysfunction during and post transplantation. Moreover, evaluation and treatment of cell death and inflammation during ex vivo lung perfusion may be a game changer in donor organ management, assessment, repair, and reconditioning.

Levosimendan for Treatment of Primary Graft Dysfunction After Heart Transplantation: Optimal Timing of Application.

Primary graft dysfunction remains a serious problem after heart transplant. Pharmacological treatment with the calcium sensitizer levosimendan may be an additive treatment for primary graft dysfunction. Patients undergoing heart transplant between 2010 and 2020 were retrospectively reviewed and divided depending on postoperative treatment with (n = 41) or without (n = 109) levosimendan. Recipients who received levosi mendan were further divided with regard to timing of levosimendan application (early group: started ≤48 hours posttransplant [n = 23]; late group: started >48 hours posttransplant [n = 18]). Patients who received levosimendan treatment displayed a remarkable incidence (87.8%) of postoperative primary graft dysfunction with need for venoarterial extracorporeal membrane oxygenation and therefore often presented with perioperative morbidity. Patient with early application of levosimendan showed significantly decreased duration of venoarterial extracorporeal membrane oxygenation support (5.1 ± 3.5 days vs 12.6 ± 9.3 days in those with late application; P < .01) and decreased mortality during venoarterial extracorporeal membrane oxygenation support (0.0% vs 33.3% in early vs late group; P < .01). In addition, compared with patients with late levosimendan application, patients with early application needed fewer blood transfusions (P < .05), had shorter ventilation times (279 ± 235 vs 428 ± 293 h; P = .03), and showed a trend of reduced incidence of postoperative renal failure (69.6% vs 94.4%; P = .06). Moreover, survival analyses indicated an increased survival for patients with early start of levosimendan therapy within the first 48 hours after heart transplant (P = .09). Pharmacotherapy with levosimendan may be a promising additive in the treatment of primary graft dysfunction after heart transplant. With administration of levosimendan within the first 48 hours posttransplant, rates of successful weaning from venoarterial extracorporeal membrane oxygenation and outcomes after heart transplant were shown to increase.

Donor Preconditioning with Inhaled Sevoflurane Mitigates the Effects of Ischemia-Reperfusion Injury in a Swine Model of Lung Transplantation.

Primary graft dysfunction (PGD) and ischemia-reperfusion injury (IRI) occur in up to 30% of patients undergoing lung transplantation and may impact on the clinical outcome. Several strategies for the prevention and treatment of PGD have been proposed, but with limited use in clinical practice. In this study, we investigate the potential application of sevoflurane (SEV) preconditioning to mitigate IRI after lung transplantation. The study included two groups of swines (preconditioned and not preconditioned with SEV) undergoing left lung transplantation after 24-hour of cold ischemia. Recipients' data was collected for 6 hours after reperfusion. Outcome analysis included assessment of ventilatory, hemodynamic, and hemogasanalytic parameters, evaluation of cellularity and cytokines in BAL samples, and histological analysis of tissue samples. Hemogasanalytic, hemodynamic, and respiratory parameters were significantly favorable, and the histological score showed less inflammatory and fibrotic injury in animals receiving SEV treatment. BAL cellular and cytokine profiling showed an anti-inflammatory pattern in animals receiving SEV compared to controls. In a swine model of lung transplantation after prolonged cold ischemia, SEV showed to mitigate the adverse effects of ischemia/reperfusion and to improve animal survival. Given the low cost and easy applicability, the administration of SEV in lung donors may be more extensively explored in clinical practice.

Long non-coding RNA X-inactive specific transcript silencing ameliorates primary graft dysfunction following lung transplantation through microRNA-21-dependent mechanism.

BackgroundPrimary graft dysfunction (PGD) is a known acute lung injury (ALI) and a major cause of fatality post-lung transplantation. Though some long non-coding RNAs (lncRNAs) have been studied in ALI through regulation of microRNAs (miRNAs), their effects on PGD remain undefined. The present study aims to explore the underlying mechanism of lncRNA X-inactive specific transcript (XIST) in PGD after lung transplantation.MethodsInitially, the expression of miR-21, IL-12A and XIST was determined by RT-qPCR and western blot analysis. The dual luciferase reporter assay, RNA pull-down and RIP assay were performed to identify the targeting relationship between miR-21 and IL-12A and the binding relationship between miR-21 and XIST. Loss- and gain-of-function investigations were conducted in rats treated with prolonged cold ischemia and polymorphonuclear neutrophils (PMNs).FindingsmiR-21 was decreased, whilst XIST and IL-12A were increased in the bronchoalveolar lavage fluid of PGD patients after lung transplantation. Enhanced miR-21 expression in rats and PMNs resulted in downregulated expression of pro-inflammatory factors and chemokines, and enhanced the apoptosis of PMNs. XIST was found to upregulate IL-12A expression in a miR-21-dependent manner. Additionally, XIST silencing enhanced the apoptosis of PMNs and inhibited the neutrophil extracellular trap (NET) formation through upregulation of miR-21 but downregulation of IL-12A in vivo.InterpretationIn summary, lncRNA XIST upregulates IL-12A by binding to miR-21, thereby inducing NET formation and accelerating PGD after lung transplantation. This suggests that inhibition of XIST and NET may be beneficial for the treatment of PGD.

Extracorporeal Membrane Oxygenation for Treatment of Primary Graft Dysfunction in Heart Transplant: Comparison of Central and Peripheral Cannulation

Primary graft dysfunction (PGD) is one common cause of early death after heart transplantation (htx). The use of extracorporeal life support (ECLS, veno-arterial ECMO) after htx has enormously increased during the last years. Representing a very helpful, short-term device in patients with PGD, it is still discussed controversially whether peripheral cannulation with closed chest really achieves favourable results compared to an ECLS-setting with central cannulation. We aimed to compare both cannulation techniques in our patients following htx.

Treatment of primary graft dysfunction after lung transplantation with orally inhaled AP301: A prospective, randomized pilot study

Primary graft dysfunction (PGD) after lung transplantation (LTx) carries significant morbidity and mortality in the early post-operative period and is associated with the development of chronic lung allograft dysfunction. AP301, an activator of epithelial sodium channel-mediated Na+ uptake represents a new concept for prevention and treatment of pulmonary edema and has shown promising results in the pre-clinical setting. This pilot study investigated the clinical effect of inhaled AP301 on patients with development of PGD > 1 according to International Society of Heart and Lung Transplantation criteria after primary LTx in a high-volume center and was conducted as a randomized, placebo-controlled, single-center pilot-study including 20 patients. All consecutive patients fulfilling inclusion criteria were screened for PGD at arrival on the intensive care unit (ICU) after LTx. After randomization, inhaled AP301 or placebo was administered by nebulizer twice daily for 7 days or until extubation. Otherwise, patients were treated according to routine clinical protocol. Partial pressure of arterial oxygen (Pao2)/fraction of inspired oxygen (Fio2) values were obtained until extubation and assessed as a primary outcome parameter. Patients were monitored for 30 days within the study protocol. From July 2013 to August 2014, 20 patients were randomized 1:1 to AP301 (Group 1) or placebo (Group 2). Both groups were comparable with regard to sex (40% women/60% men vs 50% women/50% men), mean age (55 ± 13 vs 54 ± 6 years), comorbidities, and diagnosis leading to LTx. The Pao2/Fio2 ratio at the time of inclusion was comparable in both groups, with a mean 235.65 ± 90.78 vs 214.2 ± 95.84 (p = 0.405), and there was no significant difference in the extravascular lung water index (13.88 ± 5.28 vs 16 ± 6.29 ml/kg, p = 0.476). The primary end point was mean Pao2/Fio2 ratio values between baseline and Day 3. In the AP301 group, only 1 patient was ventilated at Day 4 and no patients were ventilated after Day 4. In the placebo group, 5 patients were ventilated on Day 4 and 2 patients on Days 5, 6, and 7. The mean increase in the Pao2/Fio2 ratio was significantly higher in Group 1 patients, and the mean between baseline and at 72 hours was 365.6 ± 90.4 in Group 1 vs 335.2 ± 42.3 in Group 2 (p = 0.049). The duration of intubation was shorter in Group 1 than in Group 2 patients (2 ± 0.82 vs 3.7 ± 1.95 days; p = 0.02). ICU stay was 7.5 ± 3.13 days in Group 1 vs 10.8 ± 8.65 days in group 2 (p = 0.57). Survival at 30 days was 100%. No severe adverse events were recorded. This study was designed as a proof-of-concept pilot study. Although it was not powered to achieve statistical significances, the study demonstrated relevant clinical effects of inhaled AP301 on patients with PGD after primary LTx. The improved gas exchange led to a significantly shorter duration of mechanical ventilation and a trend towards a shorter ICU stay. Further investigation of AP301 for treatment of PGD in larger studies is warranted. The trial is registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000716-21/AT.

(373) - Treatment of Primary Graft Dysfunction with Plasmapheresis Improves Outcome

(373) - Treatment of Primary Graft Dysfunction with Plasmapheresis Improves Outcome

Bridge to lung transplantation and rescue post-transplant: the expanding role of extracorporeal membrane oxygenation.

Over the last several decades, the growth of lung transplantation has been hindered by a much higher demand for donor lungs than can be supplied, leading to considerable waiting time and mortality among patients waiting for transplant. This has led to the search for an alternative bridging strategy in patients with end-stage lung disease. The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation as well as a rescue strategy post-transplant for primary graft dysfunction (PGD) has been studied previously, however due to initially poor outcomes, its use was not heavily instituted. In recent years, with significant improvement in technologies, several single and multi-center studies have shown promising outcomes related to the use of ECMO as a bridging strategy as well as a therapy for patients suffering from PGD post-transplant. These results have challenged our current notion on ECMO use and hence forced us to reexamine the utility, efficacy and safety of ECMO in conjunction with lung transplantation. Through this review, we will address the various aspects related to ECMO use as a bridge to lung transplantation as well as a rescue post-transplant in the treatment of PGD. We will emphasize newer technologies related to ECMO use, examine recent observational studies and randomized trials of ECMO use before and after lung transplantation, and reflect upon our own institutional experience with the use of ECMO in these difficult clinical situations.

C1-Esterase-Inhibitor for Primary Graft Dysfunction in Lung Transplantation

Primary graft dysfunction (PGD) is the most important cause of early morbidity and mortality in lung transplantation (LTX) with an incidence of 8% to 20%. We hypothesized that application of C1-esterase-inhibitor (C1-INH) in LTX-recipients showing early signs of severe PGD would attenuate the condition. Starting as of May 2010, all recipients showing a PaO2/FiO2 ratio of less than 100 as early sign of PGD at first measurement in the OR were immediately treated with C1-INH. Postoperative courses of C1-INH-treated recipients were compared with a subgroup of recipients that developed severe PGD (PGD3-group) within 72 hours after LTX but did not receive C1-INH. Additionally, a third group consisting of all remaining recipients was assembled. A total of 275 LTX were performed between May 2010 and September 2012 at our center. Among these, 24 patients (8.7%) revealed a first PaO2/FiO2 ratio less than 100 and were treated with C1-INH (C1-INH-group). The PGD3-group consisted of 14 patients; the control cohort consisted of 237 patients. PGD scores were significantly higher in the C1-INH-group and PGD3-group as compared with the control group at all times postoperatively. ICU stay was longest in the PGD3 cohort and prolonged in C1-INH patients compared with the control group (29 [2-70] vs. 9 [2-83] vs. 3 [1-166] days, P=0.002). One-year survival in the PGD3-cohort was 71.4%, the C1-INH-treated-group had a one-year-survival of 82.5%, the control group had the best outcome (95%) (P=0.001). Treatment of PGD with C1-INH led to acceptable outcome. Although survival in the C1-INH treated patients was lower than in the remaining collective, it was as good or better, compared with the PGD3 group and as what is internationally regarded as reasonable after LTX.

Receptor for Advanced Glycation End Products in Donor Lungs Is Associated with Primary Graft Dysfunction After Lung Transplantation

Development of primary graft dysfunction (PGD) is associated with poor outcomes after transplantation. We hypothesized that Receptor for Advanced Glycation End-products (RAGE) levels in donor lungs is associated with the development of PGD. Furthermore, we hypothesized that RAGE levels would be increased with PGD in recipients after transplantation. We measured RAGE in bronchoalveolar lavage fluid (BALf) from 25 donors and 34 recipients. RAGE was also detected in biopsies (transbronchial biopsy) from recipients with and without PGD. RAGE levels were significantly higher in donor lungs that subsequently developed sustained PGD versus transplanted lungs that did not display PGD. Donor RAGE level was a predictor of recipient PGD (odds ratio = 1.768 per 0.25 ng/mL increase in donor RAGE level). In addition, RAGE levels remained high for 14 days in those recipients that developed severe graft dysfunction. Recipients may be at higher risk for developing PGD if they receive transplanted organs that have higher levels of soluble RAGE prior to explantation. Moreover, the clinical and pathologic abnormalities associated with PGD posttransplantation are associated with increased RAGE expression. These findings also raise the possibility that targeting the RAGE signaling pathway could be a novel strategy for treatment and/or prevention of PGD.

Institutional experience with extracorporeal membrane oxygenation in lung transplantation☆

Extracorporeal membrane oxygenation (ECMO) is currently accepted in lung transplantation either to bridge patients to transplantation or to treat postoperatively arising severe primary graft failure. Based on promising initial experiences we have since 2001 implemented ECMO as the standard of intraoperative extracorporeal support in lung transplantation (LuTX) patients with haemodynamic or respiratory instability with the potential to prolong ECMO support into the perioperative period. The aim of this paper is to summarise our total experience with the use of ECMO in LuTX. We retrospectively reviewed all 306 patients undergoing primary lung transplantation from 1/2001 to 1/2006 with regard to the different forms of ECMO use. Results of all patients requiring ECMO were compared to those without ECMO during the observation period. ECMO was used in 147 patients in total. Two patients were bridged to transplantation. A total of 130 patients received intraoperative ECMO support. In 51 of these patients ECMO was prolonged into the perioperative period. Five of these patients required ECMO support again in the postoperative period due to graft dysfunction. Contrary cardiopulmonary bypass was used in 27 patients mainly with concomitant cardiac defects. Eleven of these patients needed therapeutic ECMO in the further course. A total of 149 patients without relevant risk factors were transplanted without any intraoperative extracorporeal support. Six of these patients required ECMO support in the postoperative period for treatment of primary graft dysfunction. Overall 3-month, 1-year and 3-year survival rates were 88.6%, 82.1% and 74.63%. The mentioned survival rates were 85.4%, 74.2% and 67.6% in the intraoperative+/-prolonged ECMO group; 93.5%, 91.9% and 86.5% in the no support group and 74.0%, 65.9% and 57.7% in the CPB group. ECMO is a valuable tool in lung transplantation providing the potential to bridge patients to transplantation, to replace CPB with at least equal results and to overcome severe postoperative complications. Favourable survival rates can be achieved despite the fact that ECMO is used in the more complex patient population undergoing lung transplantation as well as to overcome already established severe complications.

Bilateral Sequential Lung Transplantation

Bilateral Sequential Lung Transplantation

Primary Graft Dysfunction in Lung Transplantation

Following the initial successful lung transplants reported by the Toronto Lung Transplant Group in 1986, lung transplantation has evolved into an effective treatment of isolated pulmonary failure and has been performed in more than 20,000 recipients. Increased experience, adjustments, and additions to the surgical technique and improved perioperative care have combined to decrease morbidity and improve survival in lung transplant recipients. An area in which improvements have been made but that continues to cause major morbidity, mortality, and impact on long-term allograft function is primary allograft dysfunction, which occurs in 11 to 60% transplant patients, depending on the diagnostic criteria applied. The basis of this potentially devastating complication is likely ischemia reperfusion injury of the donor allograft with activation of recipient innate immunity. This article discusses mechanisms of primary graft dysfunction in light of recent International Society for Heart and Lung Transplantation consensus definitions, and considers successful strategies for prevention and treatment of primary graft dysfunction.

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part I: Introduction and Methods

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part I: Introduction and Methods

Treatment of primary graft dysfunction after kidney transplantation by renal artery stent

Treatment of primary graft dysfunction after kidney transplantation by renal artery stent

Treatment of primary graft dysfunction after kidney transplantation by renal artery stent

Renal artery stenosis is a rare cause of primary graft failure after kidney transplantation [1]. Percutaneous transluminal angioplasty (PTA) is the treatment of choice, however, this technique has its limitations in elastic stenoses that are resistant to dilatation [2,3]. The procedure is of high risk, especially in the early phase after transplantation. If renal artery stenosis is refractory to PTA, the placement of an endovascular prosthesis (Palmaz stent) may be necessary. To our knowledge there are no reports in the literature regarding transplant renal artery stenting in the early period after transplantation. artery (Figure la). Renal biopsy ruled out rejection and other parenchymal disorders. Arterial angiography confirmed the CDS diagnosis and angioplasty was performed using a 5-mm dilation balloon (Figure 2a). However, due to elastic recoil, there was not much improvement angiographically and kidney function and blood pressure did not substantially improve. To overcome the remaining high-grade stenosis, an intravascular endoprosthesis (Palmaz stent, 10 mm in length, dilated up to 5 mm) was successfully implanted into the stenotic region (Figure 2b). Immediately thereafter, diuresis increased (3000 ml/day), serum creatinine level dropped to 141.4 umol/1, and blood pressure improved. Control CDS confirmed that the endoprosthesis was correctly placed with just a slight narrowing at the suture, but no turbulences were detected (Figure lb). Three months postoperatively, the patient had stable renal function with a serum creatinine of 123.7 umol/1.