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Retransplantation

Aigner, Clemens

Current Opinion in Organ Transplantation: October 2015 - Volume 20 - Issue 5 - p 521–526
doi: 10.1097/MOT.0000000000000237
LUNG TRANSPLANTATION: Edited by Stephanie G. Norfolk
Free

Purpose of review With a continuously rising number of lung-transplant procedures performed worldwide, there is an increasing demand for pulmonary retransplantation once recipients develop lung allograft dysfunction. Due to the scarcity of donor organs, it is crucial to identify those recipients who benefit most from a retransplant procedure.

Recent findings Similar to primary lung transplantation, patients in an elective, ambulatory status with chronic lung allograft dysfunction can expect the best outcome. Recently, refinements in the sub-selection of this patient group have been established, and during the past years, survival after elective retransplantation has clearly improved. Additionally, technical advances in bridging devices have led to the possibility to offer the most appropriate bridging method based on the individual gas exchange and hemodynamic situation of the patient. This includes the recently introduced concept of awake bridging. These advances paved the way to improved bridging success and better post-transplant outcome, which led to increasing interest in bridging patients to retransplant procedures as well.

Summary Patient selection in pulmonary retransplantation is crucial. Patients with obstructive chronic lung allograft dysfunction in an ambulatory setting are the ideal candidates. Awake bridging strategies for acutely deteriorating patients can provide equal outcomes to elective patients. Nevertheless, avoiding the development of chronic lung allograft dysfunction is the primary goal.

Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria

Correspondence to Clemens Aigner, MD, MBA, FETCS, Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Tel: +43 1 40400 56200; fax: +43 1 40400 56400; e-mail: clemens.aigner@meduniwien.ac.at

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INTRODUCTION

Lung transplantation has made major progress during the past years. The spectrum of indications for transplantation has significantly expanded and the number of contraindications has substantially diminished. A major shift in indications was observed with the introduction of the lung allocation score (LAS) in several countries. Retransplantation of the lung has been applied as last therapeutic option for patients with primary graft dysfunction (PGD), chronic lung allograft dysfunction (CLAD) and anastomotic or distal airway problems after lung or heart-lung transplantation, who are refractory to other treatments. While retransplantation still accounts for a small percentage of all lung-transplant procedures performed worldwide, it is becoming an increasingly accepted and more frequently used therapy. With a continuous rise in the number of lung-transplant (LuTX) procedures performed annually worldwide, there is also an ongoing increase in the demand for retransplant procedures. Survival rates have significantly improved over time; however, the procedure is still not fully comparable with primary transplantation. This review gives an overview on recent developments and strategies in the field of pulmonary retransplantation.

Box 1

Box 1

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CURRENT STATUS

Retransplantations account for 4% of the total number of lung transplants reported to the registry of the International Society for Heart and Lung Transplantation. This registry covers data submitted by 241 lung-transplant centers worldwide (Fig. 1). There is a geographic difference with European centers having a higher percentage of retransplant procedures compared to the North American Centers (5.0 vs. 3.6%). The most common indication for retransplantation is bronchiolitis obliterans syndrome (BOS). The percentage of women undergoing retransplantation is slightly higher compared to men (4.4 vs. 3.8%) [1▪▪].

FIGURE 1

FIGURE 1

Already in the very early phase of lung transplantation, patients with PDG were identified as poor candidates for retransplantation [2]. Several reports unanimously described the best outcome in ambulatory, nonventilated patients with BOS operated in experienced centers [3–5]. In 1995, the first multicenter series of 80 patients undergoing pulmonary retransplantation in 34 centers worldwide reported a 45% 1-year and 36% 3-year survival. Continuous refinements in patient selection, advances in operative technique and perioperative management, as well as new developments in immunosuppression and treatment of CLAD led to improved outcome. Survival rates of elective retransplantation approach those of primary transplantation in adult, as well as in pediatric patients, without fully reaching them. Recent publications report about 1-year survival rates in the range of 60–78% [6–9]. This gap indicates a risk, which is still higher compared to the primary procedure. Patient selection criteria for retransplantation are basically similar to those for the initial lung transplant; however, the operation itself is frequently more challenging compared to the primary procedure. In the perioperative period, the management of coagulation and postoperative bleeding in the presence of pronounced adhesions, together with the need for extracorporeal support, can be a limiting factor, as well as medical comorbidities caused by side effects of long-term immunosuppression.

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INDICATIONS FOR RETRANSPLANTATION

Pulmonary retransplantation is an option for lung-transplant recipients with severe allograft dysfunction not amenable to other therapeutic options. Selection criteria ultimately are similar to those for primary lung transplantation. Constantly, survival rates of retransplantation for PGD or early after the primary procedure are very poor [3–10,11▪,12▪,13,14]. Thus, retransplantation for PGD should be avoided and restricted to chronic lung allograft problems. Retransplantation for airway problems is mentioned only by a few studies. Retransplantation for bronchial anastomotic stenosis yields reasonable outcome [7], whereas retransplantation for dehiscence is primarily of historical interest and has a dismal outcome [5].

The development of CLAD is one of the main factors limiting long-term outcome after lung transplantation. However, recently, different phenotypes of CLAD have been described [15,16]. The restrictive phenotype might be associated with a worse survival after retransplantation and earlier redevelopment of CLAD. A retrospective multicenter study by four European and North American centers investigated this topic and found that median survival in patients retransplanted for BOS was 5.3 years and comparable to ISHLT registry data for primary transplantation (6.1 years), whereas median survival after retransplantation in patients with restrictive CLAD was only 1.7 years. The overall incidence of CLAD redevelopment was 30 and 41%, and patients with restrictive phenotype redeveloped CLAD at earlier time-points after re-transplantation [17▪].

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OPERATIVE APPROACH

The question whether double or single lung transplantation is the ideal procedure for retransplantation has never been definitely answered. In the situation of single lung transplantation as primary procedures and single lung retransplantation, the question whether to replace to old graft or the native lung is equally challenging and lacking solid data [10]. The decision ultimately depends on a variety of factors. Comparable to primary transplantation, the presence of suppurative infection or pronounced pulmonary arterial hypertension warrants a bilateral procedure. Technical issues leading to single lung transplantation as the first procedure (e.g. previous pneumonectomy, pleural adhesions, chest wall deformities) might leave no other option than an ipsilateral replacement. Given the clearly superior outcome of bilateral transplantation in all indications in primary lung transplantation, it seems logical to transfer this principle to retransplantation as well. Even though no clear data are available [1▪▪], a bilateral procedure is preferable in most cases.

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BRIDGE TO RETRANSPLANTATION

Bridging to transplantation with extracorporeal support has been a controversial issue for a long time and was initially considered to be a relative contraindication for lung transplantation by ISHLT recommendations. However, while a few centers have been using this technique successfully since more than a decade [18], recently, a broader interest in this topic was gained since the LAS allowed adequately prioritizing patients on extracorporeal devices. A large number of single-center experiences in bridging patients to primary transplantation with good outcomes in carefully selected patients have been reported. Technical advances in bridging devices allowed an ‘individualized bridging’ and led to the possibility to offer the most appropriate method based on the individual gas exchange and hemodynamic situation of the patient. These advances paved the way to higher successful bridging rates and better post-transplant outcome, which led to an increased interest in bridging patients to retransplant procedures as well.

Mainly young patients already on the waiting list with rapid deterioration of a chronic pulmonary disease and adequate functional status prior to deterioration in the absence of other chronic organ dysfunction are considered to be good candidates [19]. The need for mechanical ventilation or extracorporeal support predisposes the patient to coagulation disorders, renal dysfunction and infectious problems. Efforts to minimize the negative side effects of extracorporeal support have led to the development of innovative, less invasive technical solutions such as double lumen cannulas for veno-venous ECMO and pumpless devices. The most recent advancement in this field is the concept of awake bridging to transplantation. It offers the potential to minimize the detrimental side effects of long-term sedation like deterioration of the patient's muscular status and to perform mobilization and some physiotherapy. Several centers reported recent experience with this technique [11▪,20]. The same concept is also applicable in the setting of retransplantation for CLAD. Successful bridging rates of up to 100% and outcomes approaching the results of elective retransplantation have been described specifically in this setting [11▪]. In our own recent experience with 39 retransplantations from 2008 to 2012, awake bridging to retransplantation resulted in 0% waiting list mortality and 0% perioperative mortality, compared to 13 and 20% in elective patients and 39 and 29% in patients with sedated bridging. Survival rates at 90 days, 1 year and 2 years were 80, 70 and 53% in elective patients, compared to 72, 43 and 29% in sedated bridging and 100, 60 and 60% in awake bridging (Fig. 2).

FIGURE 2

FIGURE 2

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LUNG ALLOCATION SCORE AND RECENT REGISTRY ANALYSES

With the introduction of the LAS, the number of retransplantations has significantly risen. A recent UNOS registry analysis compared outcomes of early and late retransplantation specifically focusing on the LAS era. Confirming the results of other studies, early retransplantation, within 90 days after the primary procedure, was associated with a significant survival disadvantage, whereas retransplantation more than 90 days after the primary procedure had a survival comparable to primary LTX after propensity score matching. Factors conferring worse outcome in the retransplant population include ICU admission, unilateral transplantation, poor functional status and obviously PGD as indication for retransplantation. Thus, the authors question the utility of early retransplantation [12▪].

Recently, another evaluation of a nationwide US registry over 25 years, covering 791 retransplant procedures out of a total of 23 180 primary transplant procedures, was published with the aim of identifying risk factors associated with retransplantation [13]. This study obviously suffers the limitations all large registry analyses, however, was able to identify some risk factors for retransplantation within 1 year after the primary procedure (admission to the ICU at the time of the primary transplantation and advancing donor age). Double lung transplantation and increasing recipient age – the latter probably due to a selection bias – were negative predictors of retransplantation within 1 year. Retransplantation within 5 years was associated with admission to the ICU, advancing donor age and BMI above 25 kg/m2. Advancing recipient age, COPD and bilateral lung transplantation were negatively associated with the likelihood of retransplantation within 5 years. However, these data might ultimately reflect or demonstrate a clear selection bias in favor of retransplanting young recipients with primarily cystic fibrosis.

Another recent study [14] summarizes the regional experience with pulmonary retransplantation in the Scandinavian countries. From 1992 to 2013, 75 patients underwent retransplantation [53 single, 21 double, 1 re-HLTX; median age 50 (range 22–64) years]. One-and 5-year survival significantly improved in the more recent period (1992–1999, 37.5 and 25% vs. 2000–2013, 81 and 57.2%).

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PEDIATRIC RETRANSPLANTATION

Lung transplantation in pediatric recipients is a relatively rare procedure with only around 100 cases reported to the ISHLT registry annually [21▪▪]. More than 70% of transplanted children are in the age group between 11 and 18 years. Retransplantations in this setting are obviously even less frequent, with only 5–8 procedures reported annually since 2000. Outcome after pediatric retransplantation is worse compared to primary transplantation, with a 1-year survival of 56.88% and a 5-year survival of 33.9%; however, these results have significantly improved in the past years, and 5-year survival rates of more than 40% have been reported by single centers [9] and in patients undergoing retransplantation more than 12 months after primary transplantation. Mirroring the situation in adult recipients’ survival rates for retransplantation later than 12 months after the primary procedure are significantly better compared to early retransplantation less than a year after primary lung transplantation [8]. Due to continuous improvements in outcome, more patients are presenting for retransplantation and a growing number of experienced centers started to perform pediatric retransplantation. Lobar and size-reduced lung transplantations are important options in pediatric recipients. However, numbers are low, and recently, no single center has reported more than 10 pediatric cases per year.

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CONCLUSION

Early retransplantation for PGD poses a high risk of death and should be avoided. Outcomes of retransplantation for CLAD in ambulatory patients approach results of primary transplantation. The obstructive form of CLAD seems to have a more favorable outcome compared to restrictive allograft dysfunction. There are no clear data about single vs. bilateral retransplantation; however, in view of the ISHLT registry data, a bilateral procedure seems to be preferable. Bridging patients with extracorporeal devices to retransplantation is possible with good results in selected patients. Awake bridging is a promising approach with excellent successful bridging rates and post-transplant survival comparable to elective retransplantation.

Nevertheless, even in view of all advances achieved in retransplantation, improving outcomes after primary lung transplantation and avoiding the development of CLAD should be the primary focus.

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Acknowledgements

I would like to thank Professor Walter Klepetko and the entire lung transplant group at Medical University of Vienna for their continuous support.

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Financial support and sponsorship

None.

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Conflicts of interest

None.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1▪▪. Yusen RD, Edwards LB, Kucheryavaya AY, et al. International Society for Heart and Lung Transplantation. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report: 2014; focus theme: retransplantation. J Heart Lung Transplant 2014; 33:1009–1024.

This is the annual report of the ISHLT registry with a special focus on retransplantation.

2. Miller JD, Patterson GA. Retransplantation following isolated lung transplantation. Semin Thorac Cardiovasc Surg 1992; 4:122–125.
3. Novick RJ, Stitt L, Schäfers HJ, et al. Pulmonary retransplantation: does the indication for operation influence postoperative lung function? J Thorac Cardiovasc Surg 1996; 112:1504–1514.
4. Novick RJ, Stitt LW, Al-Kattan K, et al. Pulmonary retransplantation: predictors of graft function and survival in 230 patients. Pulmonary Retransplant Registry. Ann Thorac Surg 1998; 65:227–234.
5. Strueber M, Fischer S, Gottlieb J, et al. Long-term outcome after pulmonary retransplantation. J Thorac Cardiovasc Surg 2006; 132:407–412.
6. Kawut SM1, Lederer DJ, Keshavjee S, et al. Outcomes after lung retransplantation in the modern era. Am J Respir Crit Care Med 2008; 177:114–120.
7. Aigner C, Jaksch P, Taghavi S, et al. Pulmonary retransplantation: is it worth the effort? A long-term analysis of 46 cases. J Heart Lung Transplant 2008; 27:60–65.
8. Scully BB, Zafar F, Schecter MG, et al. Lung retransplantation in children: appropriate when selectively applied. Ann Thorac Surg 2011; 91:574–579.
9. Müller C, Görler H, Ballmann M, et al. Pulmonary retransplantation in paediatric patients: a justified therapeutic option? A single-centre experience. Eur J Cardiothorac Surg 2011; 39:201–205.
10. Brugière O1, Thabut G, Castier Y, et al. Lung retransplantation for bronchiolitis obliterans syndrome: long-term follow-up in a series of 15 recipients. Chest 2003; 123:1832–1837.
11▪. Lang G, Kim D, Aigner C, et al. Awake extracorporeal membrane oxygenation bridging for pulmonary retransplantation provides comparable results to elective retransplantation. J Heart Lung Transplant 2014; 33:1264–1272.

This study puts a special focus on awake ECMO as bridge to retransplantation

12▪. Osho AA, Castleberry AW, Snyder LD, et al. Differential outcomes with early and late repeat transplantation in the era of the lung allocation score. Ann Thorac Surg 2014; 98:1914–1920.

This study highlights the outcomes of retransplantation in the LAS era.

13. Hayanga JA, Yang J, Aboagye J, et al. Risk factors associated with lung retransplantation: evaluation of a nationwide registry over a quarter century. Ann Thorac Surg 2014; 98:1742–1746.Large retrospective registry analysis..
14. Lindstedt S, Dellgren G, Iversen M, et al. Nordic Thoracic Transplantation Study Group (NTTSG). Pulmonary retransplantation in the Nordic countries. Ann Thorac Surg 2015; 99:1781–1787.
15. Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant 2011; 30:735–742.
16. Verleden GM, Raghu G, Meyer KC, et al. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant 2014; 33:127–133.
17▪. Verleden SE1, Todd JL, Sato M, et al. Impact of CLAD phenotype on survival after lung retransplantation: a multicenter study. Am J Transplant 2015; doi: 10.1111/ajt.13281. [Epub ahead of print].

This retrospective multicenter study addresses different outcomes for obstructive and restrictive phenotype of chronic lung allograft dysfunction.

18. Aigner C, Wisser W, Taghavi S, et al. Institutional experience with extracorporeal membrane oxygenation in lung transplantation. Eur J Cardiothorac Surg 2007; 31:468–473.
19. Bermudez CA, Rocha RV, Zaldonis D, et al. Extracorporeal membrane oxygenation as a bridge to lung transplant: midterm outcomes. Ann Thorac Surg 2011; 92:1226–1231.
20. Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation. Am J Respir Crit Care Med 2012; 185:763–768.
21▪▪. Benden C, Goldfarb SB, Edwards LB, et al. International Society for Heart and Lung Transplantation The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart-lung transplantation report: 2014; focus theme: retransplantation. JHLT 2014; 33:1025–1033.
Keywords:

bridge to transplantation; chronic lung allograft dysfunction; lung transplantation; retransplantation

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