Does donor–recipient age mismatch have an influence on outcome after lung transplantation? A single-centre experience

Abstract

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OBJECTIVES

Lack of organ donors demands transplantation of older lung allografts for recipients between 0 and 50 years. So far, it has not yet been investigated whether donor–recipient age mismatch affects long-term outcome.

METHODS

Records of patients aged between 0 and 50 years were retrospectively reviewed. Donor–recipient age mismatch was calculated subtracting recipient age from donor age. Multivariable Cox regression analyses was performed to assess donor–recipient age mismatch regarding the end points’ overall patient mortality, mortality conditioned to hospital discharge, biopsy-confirmed rejection and chronic lung allograft dysfunction. Furthermore, we performed competing risk analysis to analyse if age mismatch affects biopsy-confirmed rejection and CLAD while death being a competing risk.

RESULTS

Between January 2010 and September 2021, out of 1363 patients who underwent lung transplantation at our institution, 409 patients fulfilled the eligibility criteria and were included. Age mismatch ranged between 0 and 56 years. Multivariable analysis revealed that donor–recipient age mismatch does not affect overall patient mortality (P = 0.19), biopsy-confirmed rejection (P = 0.68) and chronic lung allograft dysfunction (P = 0.42). There was no difference seen in CLAD (P = 0.166) and biopsy-confirmed rejection (P = 0.944) with the competing risk death (P = 0.765 and P = 0.851; respectively).

CONCLUSIONS

Age mismatch between recipients and donors of lung allografts does not affect long-term outcomes after lung transplantation.

ΙΝTRODUCTION

Lung transplantation is the only curative treatment for end-stage pulmonary diseases. Particularly in Europe, donor-age steadily increased over the past years. Shortage of available organs for transplantation requires extension of the lung transplant donor pool. Donor–recipient matchings plays an important role in lung allocation [1]. Among many factors like blood group and body height, age is highly considered in finding a suitable organ for the respective lung transplant candidate [2]. Providing that general organ selection criteria are fulfilled; it remains questionable whether high age mismatch in lung allocation impacts postoperative outcomes and survival. Here, we investigate outcomes of lung recipients aged between 0 and 50 years whose donors had an age mismatched ranged between 0 and 56 years.

PATIENTS AND METHODS

Patients and variable definition

Records of patients transplanted between January 2010 and September 2021 at our institution were retrospectively analysed and only patients aged between 0 and 50 years were included.

Donor–recipient age mismatch was calculated by subtracting recipient age from donor age.

The follow-up ended on 1 October 2021, it was 100% complete and amounted to a median of 58 (31–89) months. Overall patient mortality, mortality conditioned to hospital discharge, incidence of biopsy-confirmed rejection and incidence of chronic lung allograft dysfunction (CLAD) were considered end points. CLAD was defined as a decline in the forced expiratory volume in 1 s (FEV₁) <81% compared to the baseline FEV₁, after exclusion of other causes [3, 4]. Only patients with ≥2 spirometric measurements, who survived >90 days, were analysed for CLAD. Biopsy-confirmed acute cellular rejection was defined according to the grading of the International Society of Heart and Lung Transplantation [5, 6]. The variable terminology human leukocyte antigen (HLA) I, HLAII and HLAI + II means mismatch in human leucocyte antigens I, II or both, respectively.

Ethical statement

This retrospective study was approved by the ethics committee of Hannover Medical School, Hannover, Germany (registration number: 10394_BO_K_2022). Because the study was retrospective, the informed consent was waived.

Statistics

SPSS 26.0 (IBM, Armonk, NY, USA) was used for statistical analysis. The primary outcome was overall patient mortality. Secondary outcomes were mortality conditioned to hospital discharge, biopsy-confirmed acute rejection and CLAD.

Cox multivariable regression analysis was performed to assess donor–recipient age mismatch for the primary and secondary outcomes. Variables were included according to clinical considerations and are depicted in Table 1. To assess the heterogeneity of our study population, we additionally subdivided the patient population according to recipient-age groups: >0 to ≤10, >10 to ≤20, >20 to ≤30, >30 to ≤40 and >40 to <50 years. Also with the subdivided patient population, we performed competing risk analysis to investigate the competing outcomes of biopsy-confirmed rejection as well as CLAD versus death. Two-tailed P-values ≤0.05 were considered significant.

RESULTS

Patient characteristics

A total of 1363 lung transplantations have been carried out at our institution between January 2010 and September 2021. Among them, 621 (46%) transplantations were performed for patients aged between 0 and 50 years. Only lung recipients whose donors were older or at least the same age (n = 409, 30%) were included in the Cox regression analysis. The median donor–recipient age mismatch was 14 years with an interquartile range between 6 and 23 years. The minimum age mismatch was 0 years, and the maximum age mismatch was 56 years. The mean or frequency of the single variables used for Cox multivariable analysis is depicted in Table 2. Overall data of subgroups are described in Table 3. Overall survival (freedom from mortality), freedom from biopsy confirmed rejection and freedom from CLAD are depicted with Kaplan-Meier curves in the supplementary material (figure 2,3 and 4).

Cox regression analysis and competing risk analysis

Multivariable Cox regression analysis showed that age mismatch does not affect survival [hazard ratio (HR) 1.014; confidence interval (CI) 0.993–1.034, P = 0.192], biopsy-confirmed rejection (HR 0.997, CI 0.981–1.013, P = 0.678) and CLAD (HR 1.007, CI 0.99.1.025, P = 0.42).

After subdividing our patient population in the different subgroups mentioned above our data cannot show that age mismatch increases the risk for the outcomes survival, biopsy-confirmed rejection and CLAD except in the age subpopulation >10 to ≤20 years, where there is a slight increase in the risk for CLAD (HR 1.041, CI 1.010–1.073, P = 0.01) (Table 4).

Competing risk analysis showed no difference in CLAD (P = 0.166; Fig. 1) and biopsy-confirmed rejection (P = 0.944; Fig. 2) with the competing risk death (P = 0.765 and P = 0.851; respectively).

In the overall patient cohort, re-transplant (HR 2.173, CI 1.153–4.096, P = 0–016), HLAI mismatch (HR 1.795, CI 1.104–2.920, P = 0.018), donor smoking history (HR 1.589, CI 1.054–2.396, P = 0.027), clamshell incision (HR 2.503, CI 1.356–4.619, P = 0.003) and idiopathic pulmonary fibrosis (HR 1.748, CI 1.027–2.974, P = 0.04) significantly increase mortality. In the age group >10 to ≤20 years, re-transplant (HR 49.7, CI 2.99–824.54, P = 0.006), aspiration of the donor lung and lobar lung resection (HR 2.847, CI 1.106–7.327, P = 0.03) increase the risk for CLAD. In the group of >20 to ≤30-year-old patients, HLAII mismatch (HR 2.059, CI 1.025, P = 0.028) and donor smoking history (HR 2.143, CI 1.025–4.478, P = 0.043) increase the risk for biopsy-confirmed rejection. Chronic renal failure (HR 6.016, CI 1.333–27.15, P = 0.001) and HLAI + II mismatch (HR 9.961, CI 2.505–39.6, P = 0.001) increase the risk for CLAD in this age group.

In the age group of >30 to ≤40 years, HLAI mismatch (HR 3.631, CI 1.384–9.524, P = 0.009), donor smoking history (HR 2.4, CI 0.979–5.888, P = 0.056) and use of intraoperative extracorporeal membrane oxygenation (ECMO) (HR 3.399, CI 1.344–8.598, P = 0.01) increase mortality while idiopathic pulmonary fibrosis (HR 3.153, CI 1.082–9.187, P = 0.035) and postoperatively extended ECMO (HR 2.707, CI 1.115–6.569, P = 0.028) increase the risk for CLAD.

In >40- to <50-year-old patients, Clamshell incision (HR 4.167, CI 1.429–12.15, P = 0.009) and lobar resection (HR4.922, CI 1.709–14.8, P = 0.003) increase the risk for mortality. The use of postoperative ECMO increases the risk for biopsy-confirmed rejection in this age group (HR 7.561, CI 1.748–32.71, P = 0.007).

DISCUSSION

Shortage of donor lungs for lung transplant candidates aged between 0 and 50 years demands extension of the donor pool. Transplantation of older and age-mismatched lung allografts provides 1 option. The usage of older donor lungs for transplantation has been a controversial topic in the last 2 decades.

In this retrospective study, we analysed whether donor–recipient age mismatch affects long-term outcomes as mortality, mortality conditioned to hospital discharge, freedom from biopsy-confirmed rejection and freedom from CLAD. For none of the mentioned end points, donor–recipient age mismatch appeared to be a risk factor, according to multivariable Cox regression analysis including several pre- and intraoperative factors. The subgroup analysis showed that age mismatch increases the hazard for CLAD in patients being >10 to ≤20 years. However, the hazard ratio of 1.041 is very low. Furthermore, competing risk analysis does not indicate a difference caused by age mismatch regarding CLAD and biopsy-confirmed rejection with the competing risk being death.

Fischer et al. [7] analysed donor lungs ≥50 years, compared it to donor lungs < 50 years and asserted that short- and long-term survival of older donor lungs was like younger donor lungs if lung grafts were carefully selected. De Perrot et al. [8] set the cut-off age to group younger and older donors at 60 years. They found out that lungs from older donors result in a decreased long-term survival, primarily attributable to an increased incidence of bronchiolitis obliterans syndrome.

Hayes et al. conducted a retrospective cohort study using propensity score matching including 23 704 lung transplant recipients from the United Network for Organ Sharing thoracic database. The recipients aged either ≥60 and <60 or ≥65 and <65 and their respective donors were either ≥50 years or <50 years old. The results showed that older donor age did not affect overall survival in older recipients, but the long-term survival of younger recipients who received organs from older donors was limited [9]. In contrast, the Eurotransplant International Foundation did not find an increased 3-year mortality when lung grafts from donors ≥55 years were transplanted, regardless the recipients age [10].

Sommer et al. analysed lung transplantation from donors ≥70 years and found it to be safe. FEV₁ 12 months after transplantation was decreased in patients who received lungs older than 70 years, but only in patients who primarily suffered from idiopathic pulmonary fibrosis and not in patients whose underlying disease was lung emphysema [11].

Hecker et al. also investigated donors ≥60 and ≥ 70 years and observed no difference in short- and long-term outcome. When donor age is high, Hecker et al. [12] recommended a strict fulfilment of other selection criteria, e.g. smoking status or ventilation time.

Renard et al. advocate the usage of lungs older than 65 years for transplantation. They also characterized their donors older than 65 years and showed that donors were of shorter stature, smoked less, had fewer bronchoscopic abnormalities, and less chest opacity [13].

In an analysis of 11 835 lung transplantation from the United Network for Organ Sharing database, Mulvihill et al. [14] concluded that recipients of organs from donors older than 50 years had a decreased survival.

The publications cited above reject but also support transplantation of ‘older’ lungs. However, in 2 aspects they differed from our work. First, patient selection in our work was different from the data analysed by the authors cited above. We investigated only recipients aged between 0 and 50 years. Second, we focused our analysis on age differences and not on an older donor populations per se. The median donor age in our high-mismatch group was 50 (41–56) years, i.e. most of these donors were not old. Only 10 out of 409 donors were older than 70 years.

Limitations

Our study should be interpreted bearing in mind its limitations, which include the single-centre setting, the retrospective design and the limited number of patients.

CONCLUSION

Donor–recipient age mismatch does not affect overall patient mortality, mortality conditioned to hospital discharge, incidence of biopsy-confirmed rejection and CLAD. Therefore, age mismatch alone is not a limiting factor regarding the acceptance of donor lungs if general organ selection criteria are fulfilled.

SUPPLEMENTARY MATERIAL

Supplementary material is available at EJCTS online.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest: Gregor Warnecke has received congress fees and travel grants from Biotest AG and Transmedics, outside the submitted work. Fabio Ius has received congress fees from Biotest AG, outside the submitted work. The other authors report conflict of interest.

DATA AVAILABILITY

The data underlying this article will be shared on reasonable request to the corresponding author.

Author contributions

Maximilian Franz: Conceptualization; Formal analysis; Investigation; Methodology; Writing—original draft. Khalil Aburahma: Conceptualization; Formal analysis; Methodology; Visualization; Writing—original draft. Murat Avsar: Data curation; Formal analysis; Methodology. Dietmar Boethig: Data curation; Formal analysis; Supervision. Mark Greer: Conceptualization; Data curation; Investigation; Writing—review & editing. Hani Alhadidi: Supervision; Validation; Writing—review & editing. Wiebke Sommer: Data curation; Formal analysis; Validation; Writing—review & editing. Igor Tudorache: Validation; Visualization; Writing—review & editing. Gregor Warnecke: Supervision; Validation; Writing—review & editing. Axel Haverich: Conceptualization; Supervision; Writing—review & editing. Fabio Ius: Conceptualization; Data curation; Investigation; Supervision; Validation; Writing—review & editing. Jawad Salman: Conceptualization; Data curation; Formal analysis; Investigation; Supervision; Writing—original draft.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Francoise Le Pimpec-Barthes, Suresh Keshavamurthy, Bartosz Kubisa and the other, anonymous reviewer(s) for their contribution to the peer review process of this article.

REFERENCES

ABBREVIATIONS

ABBREVIATIONS
 
• CI

  Confidence interval

 
• CLAD

  Chronic lung allograft dysfunction

 
• ECMO

  Extracorporeal membrane oxygenation

 
• FEV₁

  Forced expiratory volume in 1 s

 
• HLA

  Human leukocyte antigen

 
• HR

  Hazard ratio

Author notes