The impact of donor-recipient size mismatch on lung transplant outcomes

Introduction

Lung transplantation (LT) is an established therapeutic alternative for advanced non-neoplastic chronic lung diseases in which all other available treatment options have been exhausted, provided that post-transplant expectations of success outweigh those of the underlying disease.

One of the many studied risk factors affecting transplant success is donor-recipient size matching. While this variable has shown to influence post-transplant outcomes in other solid organ transplants, such as heart, liver, or kidney (1), its role in LT is less clear and remains controversial. On the one hand, some studies have shown that size mismatch between donor and recipient may affect airway resistance, its tendency to collapse, and lung compliance (2,3). It has also been associated with hemodynamic compromise during the procedure, the development of primary graft dysfunction (PGD), length of stay in the intensive care unit (ICU), persistence of atelectasis, development of pneumothorax, reduced post-transplant exercise capacity, development of chronic lung allograft dysfunction (CLAD), and even overall survival (1,2,4-6). On the other hand, some studies have found no significant impact of this size mismatch on any of these variables (6,7).

There are several strategies to carry out the size matching, including comparisons of lung sizes using plain chest X-ray, volumetric analyses based on computed tomography images, or assessments of lung function (both estimated and measured). There is no consensus on which strategy is better and each one has its limitations (1,4,6-10).

The most studied and commonly used method for size matching is the one based on the predicted total lung capacity (pTLC), a variable which estimates lung size using regression equations based on sex, height, and age. By calculating the ratio between the donor’s and recipient’s pTLC, the degree of concordance between them from this perspective can be determined. However, these equations have the limitation of being developed from healthy populations. On the other hand, they have the theoretical advantage of ignoring biases related to the impact of the recipient’s underlying disease on anatomical configuration or the use of mechanical ventilation in the donor, among other factors (1,4,6-8).

Our study aimed to assess whether a significant size discrepancy between donor and recipient has prognostic implications for CLAD-free survival, mortality, or the combined outcome of CLAD and mortality. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1841/rc).

Methods

A retrospective cohort study was conducted at a single LT reference center (Marqués de Valdecilla University Hospital, Santander, Spain), including all transplant recipients between January 1, 2015, and October 30, 2023.

The primary variable of the study was the ratio of pTLC between the donor and the recipient. The pTLC values were calculated using two different formulas:

• Eq. [1], proposed by Roberts et al. [1991](11):

$$\begin{array}{l}\text{Men:}\text{pTLC}=7.99\times \text{height}\left(\text{meter}\right)-7.08\\ \text{Women:}\text{pTLC}=6.60\times \text{height}\left(\text{meter}\right)-5.79\end{array}$$[1]

• Eq. [2], proposed by Riddell et al. [2021] (1):

$$\begin{array}{l}\text{Men:}\text{pTLC}=0.09\times \text{height}\left(\text{cm}\right)-8.618\\ \text{Women:}\text{pTLC}=0.071\times \text{height}\left(\text{cm}\right)-0.007\times \text{age}\left(\text{years}\right)-5.965\end{array}$$[2]

Two different formulas were employed to determine whether any differences existed between them and to assess if one was superior, given that they rely on different input values. The pTLC for all recipients was available at the time of listing using Eq. [1] at our center, which justified its use. Eq. [2] had previously been evaluated in another study with similar characteristics (1). Since the formulas are not identical, calculations were performed using both. The donor’s pTLC was calculated specifically for the purposes of this study and is not used in the routine practice of our program. During the study period, our program typically performed donor-recipient matching based on height and lung diameters measured via chest X-ray. With the available donor data, each recipient was selected in consensus between a thoracic surgeon and a pulmonologist experienced in LT.

Surgical protocols were reviewed, and the need for graft volume reduction was recorded, along with the type of reduction (wedge resection or lobectomy) and its location. The decision to perform graft reduction was made by the lead surgeon intraoperatively upon identifying size mismatch. None of them were planned resections. Diaphragmatic traction was only recorded if it was necessary in the cases that required atypical resections. The surgical approach of choice in our program is bilateral anterior thoracotomy. A clamshell thoracotomy is only performed in cases where extracorporeal membrane oxygenation (ECMO) is required during surgery or when severe complications arise.

Patients were divided into four groups based on whether there was a size discrepancy of more than 10% or more than 20% according to the results obtained with each formula. In addition to size mismatch, potential impacts on post-transplant outcomes were assessed based on donor-recipient sex matching, establishing three groups: same-sex; male donor-female recipient; female donor-male recipient.

Along with demographic variables of donors and recipients, variables related to the surgery (operation time, need for transfusions, ischemia time) and immediate post-transplant postoperative variables (mechanical ventilation time, need for tracheostomy, ICU and total length of stay were registered. PGD was defined and graded according to ISHLT criteria (12): PGD was recorded at 0, 24, 48, and 72 hours after surgery. Acute cellular rejection post-transplant was defined and graded according to the ISHLT Working Formulation (13). CLAD diagnosis was established using ISHLT criteria (14). Additionally, long-term survival and a combined variable of CLAD and/or mortality were evaluated.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Cantabria Ethics and Research Committee (CEIm) under study code 2024.364. Informed consent was not required for this study, as it was a retrospective analysis and not all participants were able to provide it. This exemption was approved by the ethics committee.

Statistical analysis

IBM SPSS Statistics 20 software was used for statistical analysis. Continuous variables were presented as mean ± standard deviation for normally distributed data and as medians with interquartile ranges (P25–P75) for non-normally distributed data. Categorical variables were presented as frequencies and percentages.

The Smirnov-Kolmogorov test was used to assess whether continuous quantitative variables followed a normal distribution. To study the association between a normally distributed quantitative variable and a qualitative variable, the Student’s t-test was used. For the association between a non-normally distributed quantitative variable and a qualitative variable, the Mann-Whitney U test was employed, and for categorical variables with more than two categories, the Kruskal-Wallis test was used. For the association between two qualitative variables, the Chi-squared test was applied. Kaplan-Meier analysis was used to estimate the free of CLAD time or mortality function, and the log-rank test was used to compare survival or CLAD curves between two or more groups. Cox regression analysis was performed for the combined CLAD-mortality outcome: in the multivariate analysis, variables with a P value ≤0.05 from univariate analysis were included, using the “backward stepwise” method; results were expressed as hazard ratios with 95% confidence intervals. In addition, a binary logistic regression analysis was performed to identify variables associated with a significant size difference (>20%) using the more sensitive formula of the two; in the multivariate analysis, variables with a P value <0.05 from the univariate analysis were included, using the “backward stepwise” method, and the results were presented as Odds Ratio with a 95% confidence interval. Correlation studies between non-normally distributed quantitative variables were conducted using Spearman’s Rho.

A P value ≤0.05 was considered statistically significant.

Results

A total of 380 patients were included, with baseline pre-transplant characteristics, size discrepancies between donor and recipient, and variables related to the surgery presented in Table 1. Donor characteristics are detailed in Table S1.

For men, using Eq. [1], the pTLC was 6.16±0.70, and using Eq. [2], it was 6.30±0.79. For women, using Eq. [1], the pTLC was 5.15±0.58, and using Eq. [2], it was 5.41±0.62. Table 2 shows the donor-recipient matching in terms of both absolute values of the pTLC ratio and the percentage of patients with more than a 10% and more than a 20% size discrepancy. A 10% and 8.2% of patients had a size discrepancy of more than 20% using Eq. [1] and Eq. [2], respectively. Using Eq. [1], there were 38 instances of size mismatch greater than 20%, with 10 involving undersized donors and 28 involving oversized donors relative to the recipient. When applying Eq. [2] with the same 20% threshold, 10 donors were smaller and 21 were larger than the corresponding recipients.

Up to 79.7% of the matches were of the same sex. A significant size discrepancy between donor and recipient was found when the pairing was of different sexes, both in absolute terms and as a percentage of patients. Using Eq. [1], among the 38 patients with a size discrepancy greater than 20%, only 6 cases (15.8%) involved donor-recipient pairs of the same sex. Another 6 cases (15.8%) had a male donor for a female recipient, while the remaining 26 cases (68.4%) involved a female donor for a male recipient. Of these 38 recipients, 28 (73.7%) had interstitial lung disease (ILD), 8 (21.1%) had chronic obstructive pulmonary disease (COPD), and 2 (5.3%) had pulmonary arterial hypertension (PAH). Consequently, a female donor was matched with a male recipient in 23 cases.

No differences were observed in size discrepancy using the ratio or the 20% cutoff based on transplant type, but significant differences were noted in size discrepancy of more than 10% between single and bilateral lung transplants.

Intraoperatively, size reduction was required in 11 recipients due to donor-recipient size mismatch. Of these, 10 underwent atypical resections, while one required a lobectomy of both the right and left upper lobes. In 6 of the 11 cases, diaphragmatic traction was also necessary during the procedure. Only 6 patients required a clamshell thoracotomy. In 2 cases, chest closure was not feasible at the end of surgery due to significant edema, necessitating temporary open chest management. Both chests were successfully closed 48 hours later after resolution of the edema.

Table 3 presents the results for mechanical ventilation time, ICU stay, total hospital stay, and PGD grade 3 for size discrepancies of more than 10% and 20% using both formulas, both overall and subdivided into single and bilateral lung transplants. A significant difference was only noted in orotracheal intubation time for patients with more than a 10% size discrepancy using Eq. [2] {1 [1–1] vs. 1 [1–4] days; P=0.04}. Using the donor/recipient pTLC ratio, no differences were found in PGD grade 3 with Eq. [1] (OR =2.333; 95% CI: 0.197–27.602; P=0.50) or with Eq. [2] (OR =2.430; 95% CI: 0.186–31.701; P=0.47). No correlation was observed between the donor/recipient pTLC ratio and mechanical ventilation time (P=0.67), ICU stay time (P=0.83), or hospital stay time (P=0.89) using Eq. [1]. The same results were obtained with Eq. [2] (P=0.64; P=0.79; P=0.83, respectively).

Regarding the need for tracheostomy, using Eq. [1], no statistically significant differences were found for size discrepancies of more than 20% (5.2% vs. 0%; P=0.52) or more than 10% (2.4% vs. 8.9%; P=0.11). No differences were found with Eq. [2] for discrepancies of more than 20% (5% vs. 0%; P=0.64) or more than 10% (3.8% vs. 6.2%; P=0.40). Similarly, when analyzing single and bilateral lung transplants separately, no significant differences were observed.

It was found that in COPD patients, the donor-recipient pTLC ratio was significantly higher than in ILD patients (Table S2). Age and height characteristics were similar between COPD and ILD patients, although a higher predominance of males and greater weight were observed among ILD patients.

During the study period, a total of 77 patients (20.3%) developed CLAD, and 105 patients (27.6%) died. The composite endpoint of CLAD or death was reached in 152 patients (40%). Table 4 provides the log-rank values from Kaplan-Meier survival analysis for survival, CLAD, or the combined outcome of death or CLAD for the two formulas with size discrepancies of more than 10% or 20%, stratified by transplant type. A statistically significant difference in time free from death or CLAD was found only for patients with more than a 20% size discrepancy using Eq. [1] (Figure 1).

Figure 1 Long-term results for 20% donor-recipient size differences using Eq. [1]. (A) Survival; (B) CLAD; (C) CLAD or death. CLAD, chronic lung allograft dysfunction.

In the Cox regression analysis (Table 5), a size discrepancy of more than 20% between donor and recipient using Eq. [1] was identified as an independent risk factor for the combined outcome of death or CLAD [HR =1.606 (1.007–2.561); P=0.046]. The donor’s pTLC was not associated with time free from CLAD for either Eq. [1] [HR =1.185 (95% CI: 0.947–1.482); P=0.14] or Eq. [2] [HR =1.178 (95% CI: 0.945–1.469); P=0.15].

A binary logistic regression analysis was conducted to identify variables associated with a donor-recipient size discrepancy greater than 20% based on Eq. [1] (Table S3). While variables such as ILD, Lung Allocation Score (LAS) at the time of waitlist inclusion, and donor height were significant in the univariate analysis, only donor-recipient sex mismatch remained an independent predictor in the multivariate analysis.

Discussion

In light of these results, significant size discrepancies between donor and recipient, as estimated by two different pTLC formulas, do not appear to impact early postoperative outcomes in LT; however, they may still carry long-term implications, potentially increasing the risk of CLAD and mortality. Some studies have indicated that size mismatch between donor and recipient may have prognostic implications (1,2,4-6), although there is currently no consensus on the preferred method for size matching. The most studied one is the pTLC ratio between donor and recipient, which is a straightforward approach requiring only the sex, weight, and height of both individuals. However, it does not take in count the severity or type of underlying pathology and has not been validated across all population groups (1,3,5-7). A more novel strategy involves volumetric data from CT imaging, which is a more precise approach that considers anatomical characteristics resulting from underlying pathology or previous surgeries and can evaluate each lung separately. However, this technique is much more costly and less reliable in patients with ILD due to difficulty of identifying healthy parenchyma based on Hounsfield Unit values; furthermore, predictive models derived from this technique have not yet been developed or validated (1,7,8). Simpler methods include matching based on chest X-ray of donor and recipient [which, while less demanding, are not free from technical limitations or those arising from the underlying pathology (8,10)], or matching based on the height of both individuals [which ignores the impact of underlying pathology, sex, or age (1,8,9)]. Regardless, our results demonstrate that using simple methods based on anthropometric data and chest diameters measured by X-ray, donor, and recipient can be matched with considerable accuracy. Regardless of the used formula, the ratio was 1.02 for the entire cohort, and less than 10% of matches had a size difference of more than 20%. Furthermore, no substantial differences were observed in the pTLC calculated using one formula versus the other one, indicating that both can be useful for routine clinical practice. Nevertheless, Eq. [1] appears to be more sensitive, as it identifies a greater number of mismatched cases and being the only method through which a potential long-term impact—specifically on CLAD and mortality—was observed.

It is noteworthy that sex mismatch impacts size matching. Although nearly 80% of pairings were of the same sex, there were 15% of female donors paired with male recipients. Interestingly, when matching from male to female, the grafts were significantly larger than the expected based on the recipient’s pTLC, whereas the reverse matching from female to male resulted in smaller grafts. The general trend is to select donors and recipients of the same sex to avoid these TLC discrepancies and also due to anatomical differences such as bronchial diameter or pulmonary artery size. Anatomical differences between men and women may more frequently lead to the need for bronchial telescoping (which has been associated with a higher risk of airway stenosis) (15,16) and narrowing at the pulmonary artery anastomosis (17). Despite these observed size differences in our results, donor-recipient matching with different sexes did not have implications for any immediate or long-term postoperative variables.

Size matching between donor and recipient is particularly important when there are significant alterations in TLC, both in obstructive and restrictive diseases, which together currently account for more than 80% of transplant indications. For COPD patients, who have marked hyperinflation, there is a risk of using significantly larger grafts than would be appropriate. Some studies have associated the use of larger grafts with worse outcomes, although others have demonstrated lower PGD rates associated with decreases in mean pulmonary arterial pressure and pulmonary vascular resistance, or even a delay in the development of obliterative bronchiolitis related to supranormal expiratory flows (2,4). Conversely, in patients with restrictive diseases, there may be a tendency to use smaller grafts, which has already been shown to be a risk factor for PGD (partly due to increased pulmonary vascular resistance and partly due to differences in tidal volume of mechanical ventilation, which is typically adjusted based on recipient characteristics rather than donor) and to impact overall survival, CLAD development, or hemodynamic compromise of the recipient (1,2,4,5,8). As expected, our results demonstrate that COPD patients had a significantly higher pTLC compared to ILD patients. However, there was greater precision in donor-recipient matching among ILD patients compared to COPD patients, with a tendency towards using larger grafts in the latter.

Various studies have highlighted how significant size discrepancies between donor and recipient can have important prognostic implications in the immediate postoperative period, affecting variables such as PGD, mechanical ventilation time, the need for lung volume reduction, ICU stay, or mortality within the first 30 days (1,2,4,8). However, with the two formulas used in our study, significant size discrepancies did not impact relevant variables such as PGD, mechanical ventilation time, ICU stay, or total hospital stay. Only using Eq. [2], patients with less than a 10% size discrepancy had a longer mechanical ventilation time, which lacks physiological rationale and seems more related to azar given the rest of the results.

The impact of size discrepancies between donor and recipient on long-term variables remains unclear, with studies either finding no relationship between size mismatch and various post-transplant outcomes, as seen in Mason et al. (7), or demonstrating some impact on overall survival, CLAD development, or obliterative bronchiolitis (2,4). In our study, while no significant differences were observed in CLAD development or overall survival when analyzed independently, size discrepancies greater than 20% as calculated by Eq. [1] were associated with a significantly increased risk of the combined endpoint of CLAD or death. This suggests that Eq. [1], which identified a greater number of mismatched cases, may be more sensitive in detecting clinically meaningful size disparities with potential long-term prognostic implications. In contrast, these associations were not observed with Eq. [2], possibly due to its lower sensitivity and more limited classification of mismatch.

Although these findings are considered relevant, they are not without limitations. The study is unicentric and retrospective, with the inherent methodological constraints of such a design. Moreover, no formal statistical comparison was conducted between the two formulas used to estimate pTLC, although Eq. [1] appeared to be more sensitive—identifying a higher number of size mismatches and being the only one associated with the combined endpoint of CLAD or death. Additionally, the proportion of significant size mismatches in our cohort was relatively low, with fewer than 10% of patients presenting a >20% discrepancy, which limits the statistical power of subgroup analyses. The number of single-lung transplants included was also small, precluding meaningful conclusions regarding whether the impact of size mismatch differs between single and bilateral procedures. Racial disparities, which may significantly influence predicted lung volumes, were another limitation: over 95% of recipients in our cohort were Caucasian, and the low number of non-Caucasian recipients did not allow for subgroup analysis. This limitation is further compounded by the absence of donor race data, preventing any assessment of potential donor-recipient racial mismatch effects. Furthermore, only two formulas for pTLC calculation were evaluated, and no volumetric methods based on computed tomography were used. Finally, long-term complications such as airway stenosis were not assessed. Despite these limitations, the study has important strengths, including its foundation on a transplant program with over two decades of experience. Donor-recipient matching based on anthropometric data is consistently performed by the same thoracic surgeon and a small group of experienced transplant pulmonologists, reducing variability in clinical decision-making. Similarly, interpretation of subjective variables such as PGD, acute rejection, and CLAD is performed by the same professionals, ensuring greater consistency and reliability.

Conclusions

In conclusion, significant donor-recipient size discrepancies do not appear to influence early postoperative outcomes in lung transplant recipients; however, our findings suggest that they may have important implications for long-term prognosis, particularly regarding the development of CLAD and mortality. These results underscore the importance of optimizing donor-recipient size matching whenever possible, particularly when the matching involves donors and recipients of different sexes and for recipients with ILD. Based on the data presented, we propose incorporating Eq. [1] into our routine clinical decision-making, as it demonstrated greater sensitivity in identifying mismatched cases and was the only method associated with adverse long-term outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1841/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1841/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1841/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1841/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Cantabria Ethics and Research Committee (CEIm) under study code 2024.364. Informed consent was not required for this study, as it was a retrospective analysis and not all participants were able to provide it. This exemption was approved by the ethics committee.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Riddell P, Ma J, Dunne B, et al. A simplified strategy for donor-recipient size-matching in lung transplant for interstitial lung disease. J Heart Lung Transplant 2021;40:1422-30. [Crossref] [PubMed]
2. Eberlein M, Permutt S, Chahla MF, et al. Lung size mismatch in bilateral lung transplantation is associated with allograft function and bronchiolitis obliterans syndrome. Chest 2012;141:451-60. [Crossref] [PubMed]
3. Hussain M, Thornton M, Hussain T, et al. Evaluating the Use of CT-Derived Lung Volumes in Donor-Recipient Lung Size Matching for Lung Transplantation in Patients With Interstitial Lung Disease and/or Idiopathic Pulmonary Fibrosis. Transplant Proc 2023;55:623-8. [Crossref] [PubMed]
4. Eberlein M, Reed RM, Maidaa M, et al. Donor-recipient size matching and survival after lung transplantation. A cohort study. Ann Am Thorac Soc 2013;10:418-25. [Crossref] [PubMed]
5. Chambers DC, Cherikh WS, Harhay MO, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: Donor and recipient size match. J Heart Lung Transplant 2019;38:1042-55. [Crossref] [PubMed]
6. Barnard JB, Davies O, Curry P, et al. Size matching in lung transplantation: an evidence-based review. J Heart Lung Transplant 2013;32:849-60. [Crossref] [PubMed]
7. Mason DP, Batizy LH, Wu J, et al. Matching donor to recipient in lung transplantation: How much does size matter? J Thorac Cardiovasc Surg 2009;137:1234-40.e1. [Crossref] [PubMed]
8. Prabhu NK, Wong MK, Klapper JA, et al. Computed Tomography Volumetrics for Size Matching in Lung Transplantation for Restrictive Disease. Ann Thorac Surg 2024;117:413-21. [Crossref] [PubMed]
9. Konheim JA, Kon ZN, Pasrija C, et al. Predictive equations for lung volumes from computed tomography for size matching in pulmonary transplantation. J Thorac Cardiovasc Surg 2016;151:1163-9.e1. [Crossref] [PubMed]
10. Vazquez Guillamet R, Vazquez Guillamet MC, Rjob A, et al. Uncertainty analysis of chest X-ray lung height measurements and size matching for lung transplantation. J Thorac Dis 2022;14:1042-51. [Crossref] [PubMed]
11. Roberts CM, MacRae KD, Winning AJ, et al. Reference values and prediction equations for normal lung function in a non-smoking white urban population. Thorax 1991;46:643-50. [Crossref] [PubMed]
12. Snell GI, Yusen RD, Weill D, et al. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2017;36:1097-103. [Crossref] [PubMed]
13. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005;24:1710-20. [Crossref] [PubMed]
14. Verleden GM, Glanville AR, Lease ED, et al. Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant 2019;38:493-503. [Crossref] [PubMed]
15. Dark JH. Pathophysiology and Predictors of Bronchial Complications After Lung Transplantation. Thorac Surg Clin 2018;28:357-63. [Crossref] [PubMed]
16. Garfein ES, Ginsberg ME, Gorenstein L, et al. Superiority of end-to-end versus telescoped bronchial anastomosis in single lung transplantation for pulmonary emphysema. J Thorac Cardiovasc Surg 2001;121:149-54. [Crossref] [PubMed]
17. Kumar N, Hussain N, Kumar J, et al. Evaluating the Impact of Pulmonary Artery Obstruction After Lung Transplant Surgery: A Systematic Review and Meta-analysis. Transplantation 2021;105:711-22. [Crossref] [PubMed]