INTRODUCTION
The organ shortage and the imbalance with the requests of organ waiting lists, means that the use of marginal grafts, defined according to extended criteria donors (ECD), was a valid strategy with which to enlarge the donor pool in recent years 1,2. The use of ECD is linked to an increased risk of post-transplant complications, however, such as primary graft failure or other organ-specific dysfunction, such as late biliary injuries in liver transplantation 3-5. Organ preservation using machine perfusion (MP) minimizes this risk, making it possible to extend the life of a retrieved graft and sometimes improving its functionality.
MP was developed in fields such as donation after death determined according to circulatory (DCD) and neurological (DBD) criteria under Extracorporeal Membrane Oxygenation (ECMO) treatment prior to death, or particular clinical situations such as organizational needs or the procurement of marginal organs 1,6.
In addition to the immediate advantage provided by MP in reducing ischemia-reperfusion damage, organ preservation must be considered as a technology that can impact the health care system, enabling a series of advantages and/or disadvantages. In a recent study, De Simone and Ghinolfi carried out a systematic review of hospital-based health technology assessments of ex-situ MP in adult liver transplantation. The study reported the advantages of MP in reducing the risk of early allograft dysfunction and ischemic biliary complication, potentially improving one-year graft and patient survival, and the graft discard rate 7. Similar studies on lung and kidney transplantation showed the same results 8,9. This approach would positively affect hospital stays and costs if MP was less expensive. Only two studies have specifically addressed this subject, with very different per-patient costs from country to country, depending on the policies of health providers 10,11. It is for these reasons that centers continue to have difficulties using MP.
In 2017, in order to support the use of ECD and organ preservation by transplant centers, the Italian National Transplant Center “(Centro Nazionale Trapianti, CNT)” issued a national reference document for the management of organ donation supporting and guiding transplant centers in using grafts from DCD and extended criteria DBD donors. Recommendations in favor of the extended use of in-situ normothermic regional perfusion in DCD donors, followed by ex-situ MP after organ recovery, were based on the high risk of ischemic damage due to the mandatory 20 minute stand-off for legal death certification. A national organ perfusion protocol ensuring the systematic data collection of all MP procedures in the country intended to assess the effectiveness and efficiency of the method was also approved in the same year 12,13.
This study evaluated the evolution of organ perfusion activity in Italy, the effect on the transplantable organ pool, and the quality of results. It also made a preliminary evaluation of the suitability of organ ex-situ machine perfusion.
MATERIALS AND METHODS
The “Methods of organ perfusion in transplantation” was adopted in 2017, including recommendations for implementing a national program. A database was set up in order to collect the data for ex-situ perfused organs, procured from DCD or DBD donors after regional in-situ perfusion with the following main aims: 1) obtaining systematic information and data as a reference for the national, regional and hospital-based health technology assessment (HTA) of MP procedures; 2) offering the transplant network updated results regarding DCD and DBD discarded or utilized ex-situ perfused organs; 3) collecting early transplant outcomes at 1-3 months; 4) facilitating homogeneous and comparable clinical criteria and timings for the use of MP in Italian transplant centers; and 4) reporting any complication or adverse event related to ex-situ MP. Data was provided by transplant centers and activity results were periodically summarized in a newsletter shared with the entire donation and transplantation national community.
Some simple preliminary indications were proposed: the use of MP was recommended in DCD and extended criteria DBD kidneys, with attention to functional perfusion parameters; the use of MP was strongly suggested in liver transplantation, especially in the case of DCD grafts; and ex-vivo lung perfusion (EVLP) was considered necessary for lung transplants from DCD donors. Specific recommendations were also produced regarding the allocation and consent of potential recipients. In Italy, the use of MP in heart transplantation is still restricted to DBD grafts, and to a small number of centers: no specific recommendations were set in this case, since no heart procurement program from DCD donors is presently active.
The present study analyzed data for ex-situ organ perfusion and related transplants. The percentage of discarded organs after MP was calculated. One year recipient and graft survival was registered in the CNT Informative Transplant System (SIT) database and linked to each MP. The outcomes of all the DBD and DCD transplants performed in a specific time interval in Italy were considered to compare survival rates.
MP procedures performed in Italy were updated based on a survey carried out by transplant centers in 2022. A questionnaire was sent to all transplant centers (38 kidney, 22 liver, 10 lungs, and 16 heart). All 86 centers answered.
The effect of using MP on the pool of organs available for transplantation was evaluated by comparing the number of perfusions performed by centers with MP to the total number of organ transplants that they performed.
Statistical analysis
Descriptive statistics included the total number and percentage for categorical variables. As several continuous covariates showed a skewed distribution, median and interquartile range (IQR) were used as summary statistics. Associations between categorical variables were evaluated by chi-square test; Fisher’s exact test was preferred for sparse tables. The outcomes in the survival analysis were the graft survival, defined as the time from transplant to either graft failure or patient death, whichever occurred first. The Kaplan-Meier estimator was used to estimate the post-transplant graft survival probability. 95% confidence intervals are reported, along with the point estimations. The log-rank test was used to compare groups. Factors with p-values of < 0.05 were considered as independently predictive of the outcome. All analyses were performed using Stata version 17.0 StatCorp LLC Texas USA.
RESULTS
Questionnaire results
Sixty-two percent of the transplant centers performed at least one MP procedure (53/86) up to 2020. Eight percent more centers started using MP in 2021.
Detailed data for MP availability, number of procedures performed, including methods and final decisions about organ suitability, were collected from a total of 53 transplant centers; 15 liver (since 2015), out of the total 22; 26 kidney (since 2017) out of the total 38; 9 lung (since 2011), out of the total 10; and 3 heart (since 2017) out of the total 16. 1615 MP procedures were undertaken in nine years (2011-2020).
There were 12,027 organ transplants performed in total by the centers using MP (50.4% liver, 36% kidney, 10.7% lung and 2.9% heart) compared to 16,739 transplants performed by all centers (43.4% liver, 42.9% kidney, 7.8% lung and 5.9% heart) (Tabs. I-IV).
Liver transplantation
From 2015 to 2020, 336 liver grafts (LGs) from DBD were perfused and 322 (95.8%) were also transplanted, which is equal to 5% of 5,905 liver transplants (LTx) performed in the period by the centers using MPs. We observed an important increase in the number of LTx performed with perfused grafts over time, from 0.3% in 2015 to 12% of the total LTx performed in 2020. We observed the same trend in liver perfused grafts from DCD (Fig. 1). Of the overall DBD and DCD transplant activity, 487 out of 6,070 LTx performed were perfused grafts, equal to 8% of total LTx performed by the centers using MP, and with an increasing trend from 1% in 2015 to 16% in 2020 (Tab. I). Finally, only three liver transplant centers (LTCs) carried out this activity in 2015; in 2020, 17 out of the total 22 LTCs performed ex-situ organ perfusion.
No significant differences were observed in one-year graft survival between DBD and DCD perfused grafts (one-year graft survival being 90.6% [95% CI (86.0-93.7)] and 89.8% [95% CI (83.4-93.8)] respectively, p = 0.87), or between perfused grafts (DBD+DCD) and non-perfused grafts (one-year graft survival being 90.3% [95% CI (86,8-93.0)] vs 88.1% [95% CI (87.3-88.9)] respectively, p = 0.49), and between perfused and not perfused DBD grafts (one-year graft survival being 90.6% [95% CI (85.9-93.7)] vs 88.1% [95% CI (87.3-88.1) respectively, p = 0.67, Fig. 2A].
Kidney transplantation
Between 2017 and 2020, 528 DBD kidney grafts (KGs) were perfused and 488 (92%) were also transplanted, equal to 11.3% of 4,325 kidney transplants (KTx) performed in the period by the centers using MP (26/38). In the same period, 328 DCD kidneys were perfused and 242 (73%) were transplanted (Fig. 3). Out of 856 (DBD+DCD) perfused kidney grafts, 730 were transplanted in these centers, which is equal to 17% of overall KTx performed by the same centers (Tab. II).
In 2017, only 16 out of 42 kidney transplant centers (KTCs) carried out this activity, rising to 26 in 2020. No clinically significant differences were observed in one-year graft survival between DBD and DCD perfused grafts (one-year graft survival being 99.2% [95% CI (97.6-99.7)] and 96.3% [95% CI (92.7-99.1)] respectively, p = 0.28), and between perfused grafts (DBD+DCD) and non-perfused grafts (one-year graft survival being 97.4% [95% CI (97.2-97.6)] vs 98.1% [95% CI (96.7-99.0)] respectively, p = n.d., and between perfused and non-perfused DBD grafts (one-year graft survival being 97.4% [95% CI (97.2-97.6)] vs 99.2% [95% CI (97.6-99.7) respectively, p = n.d., Figure 2B].
Lung transplantation
Italian lung transplant centers started performing EVLP in 2011 in DBD and in 2014 in DCD, with 218 procedures overall (173 from DBD and 45 from DCD), and 137 (62.8%) transplants performed, 113 (65.3%) from DBD and 24 (53.3%) from DCD, respectively. Compared to the liver, the number of performed perfusions did not increase steadily, but there were irregular peaks over the years. (Fig. 4). Initially, there were only four lung transplant centers that adopted EVLP (out of 10 overall centers), and to date all centers can use EVLP.
With respect to the overall DBD transplant activity, the percentage of lungs transplanted after EVLP was 8.9% (113/1263), and if we consider total transplants (DBD + DCD) performed by the centers using MP, the percentage of lungs transplanted after EVLP increases to 10.6% (137/1287; Table III), despite of the important setback observed during the COVID-19 pandemic.
No statistically significant difference in transplant outcome was observed when comparing perfused grafts (DBD+DCD) and non-perfused grafts, with one-year graft survival at 90.4% [95% CI (84-94.3)] vs 93% [95% CI (91.7-94), p = 0.15] respectively.
The one-year graft survival of DBD perfused grafts was 89% [95% CI (82-94)], which is lower than that of non-perfused DBD grafts (93% [95% CI (92-94), p = 0.6), but the difference was not statistically significant (Fig. 2C).
Heart transplantation
Between 2017 and 2020, 56 heart grafts (HGs) from DBD were perfused in only 3 out of 16 heart transplant centers (HTCs), and 47 of them (84%) were transplanted, corresponding to 4.8% of 982 heart transplants performed in the period by the centers using MP. The annual trend of perfused and transplanted hearts shows an important decrease in MP activity (-52%) from 2018 to 2020 (Fig. 5). The activity of the three centers compared to their transplant activity demonstrates a corresponding decrease from 2018 (22%) to 2020 (9%), as shown in Table I.
One-year overall graft survival was lower for non-perfused grafts compared with perfused grafts, although the difference was not statistically significant (one-year graft survival being 93.0% [95% CI (92.0-93.0)] vs 97.0% [95% CI (81.0-100)] respectively, p = 0.12).
Although the current use of ex-vivo heart perfusion (EVHP) is limited to three HTCs, participation will probably increase in the near future because a further three Italian centers already have MP available, and four more will acquire it shortly.
DISCUSSION
The use of ECD, including DCD and marginal DBD, is a feasible solution to organ shortage and long waiting lists. The ex-situ perfusion of ECD organs is one of the most promising procedures offered to the transplantation community in recent years.
The use of normothermic ex-situ MP has potential advantages, such as the ability to observe and measure organ biochemical performance and quality during the preservation period, while hypothermic perfusion decreases cellular metabolism requirements and reduces potential reperfusion-ischemic damage; in both cases, MP can also help to extend the time to complete pending organ suitability investigations at the time of organ procurement, improving transplant safety 7-9,14-19. The ability to preserve an organ for longer also helps in solving eventual logistical-organizational problems, such as the unavailability of a theatre, surgical/anesthesiology team, or a bed in intensive care, which would prevent the transplant center being able to accept the organ and perform the transplant 11,15. This allows the donation resource to be used in the best possible way, reducing the percentage of discarded organs and improving the performance of the system.
Italian national data is currently relatively heterogeneous, but MP may be efficient in expanding the pool of available organs and increasing the number of transplants. The crude numbers certainly suggest that organ preservation in Italy began slowly, with the recommendations set up by CNT, and gradually developed based on the good results obtained.
Certainly, the costs of the MP procedure has been one of the most limiting factors in the development of the program: transplant hospitals struggle to find suitable financial resources to support the activity, especially now that it has changed from an initial experimental period to a more stable phase. Most of the high-volume transplant centers now have a MP program. Furthermore, both the consolidated results, as well as the growth of evidence-based scientific knowledge in this field, should allow the structured use of MP over time. Although a shared agreement has not yet been reached regarding indications for the use of MP, most Italian transplant centers are working in this direction, under the CNT supervision.
The role of the CNT as the competent authority for the donation and transplantation field, is to support and guide innovative procedures that can have a positive effect on transplant activity in terms of increasing the number of transplants and improving the entire donation and transplantation process.
CNT established the systematic collection of national perfusion data in order to support MP activity, promote its development over time and collect measurable indicators of effectiveness, such as the expansion of the organs pool available for transplantation. This is essential so as to measure the effectiveness of the program and to demonstrate the strategic relevance of the results, in order to encourage health authorities to support the program.
The present study has demonstrated a remarkable increase in ex-situ perfusion procedures, with a gradual implementation of MP in Italian kidney, liver, and lung transplant centers, up to around 10% for those centers participating in the program. Although comparisons between the outcomes of ex-vivo perfused and not-perfused organs are limited by the lack of detailed clinical data, and by potential differences in MP criteria among the centers, and across the years, the one-year graft survival rates of perfused grafts are very satisfactory, from both DBD and DCD donors, and they are similar to those of non-perfused DBD organs. The results demonstrate that the outcomes of perfused grafts are more than acceptable for liver, lung and kidney transplants, encouraging the transplant community to implement MP facilities and increase the use of MP.
Our analysis has some limitations: an important limitation is related to the small number of DCD donors considered, and, most of all, to the inclusion of both controlled and uncontrolled DCD together in the data analysis. Only one-year graft survival rates were studied, in the absence of complete information on complications, duration of hospital stay and long-lasting follow-up.
Lastly, it is not clear whether the increase in the organ pool is the only effect of MP utilization or if other variables may have played a role over the period. Although some of the evidence in our analysis is very promising, there is a clear need for more information from high quality and appropriately powered trials.
More generally, the standardization of data collection and reporting will allow comparisons of trials 20. The standardization of nomenclature for MP in order to maximize consistency and to enable reliable comparisons and meta-analyses of studies is a fundamental and urgent prerequisite for national and international comparisons of results 21.
Conflicts of interest and the relationships between researchers and commercial medical industry is a critical issue. The role of external (particularly commercial) parties in trial design and analysis should be clearly stated, including that of the holders of data and the parties responsible for analysis, as these relationships have the potential to affect study validity and interpretation 20.
Most published studies have been funded by private companies, and are thus potentially biased due to commercial reasons/interests. Multicenter studies in the MP field are urgently needed, and the national transplant authorities could thus be the ideal reference point for reliable data, free from any professional or economic conflicts of interest.
Information about the cost of MP is not easily available, and cost-benefit analysis needs reliable clinical and organizational data, as well as prolonged follow-up for transplant recipients and their quality of life.
Strategies to counterbalance the increased costs of organ transplantation are needed from the perspective of the Italian national health system-based hospital practice and disease-related group reimbursement policy 7. These strategies should be developed and tested at regional and national level. Ad hoc education and adequate medical and technical personnel resources should be programmed; the standardization of procedures and transparency of clinical results should be guaranteed, particularly when marginal organs are used and offered for consent to patients on the waiting list. The national transplant network and patients could both take advantage of the clear periodical CNT website publication of MP results and recipient follow-up.
The effectiveness and suitability of transplanted patient treatments are critical issues in the clinical governance of the national network. In Italy, the CNT is responsible for the suitability and safety of novel technical procedures included in the clinical management in the centers. Specifically, innovative procedures based on artificial treatments of organs after retrieval for function evaluation and final decision of usability should be evaluated and eventually approved by CNT.
A national consensus committee is thus desirable, to address the clinical and organizational criteria for ex-situ organ perfusion, functional evaluation and organ usability in the different donation pathways (DBD, uncontrolled and controlled DCD) and context (e-CPR prior-to-death, transportation, and delayed allocation). Clinical criteria should be revised annually: nationally collected data on transplant outcome and complications, possible adverse events related to MP, cost benefit analysis, new procedures and published multicenter study.
A clear methodology and shared responsibility should be ensured in data collections from transplant centers and regional transplant centers towards the CNT Informative Transplant System (SIT). All perfused organs should be included in the ad hoc national MP dataset and related outcomes in the quality database. Each center could take advantage of the complete reliable data and compare local results with national results, or develop proper single center or multicenter research projects.
Adequate datasets should be defined for national and local registries to enable reliable health technology assessment, including clinical indications, cost-effectiveness, economical sustainability, and criteria for the diffuse implementation of innovative procedures as the ex-situ graft MP.
Each region should include MP in its annual program and planning document, and consider the number of cases for each organ transplant program, personnel support and quality clinical data collection aim at proper technology assessment, funding for machine availability, external technical support, and disposable materials. A dedicated personnel educational pathway should be designed on the basis of nationally validated standards.
Public-private cooperation could be considered if clear rules are respected, and activities are independently monitored. Facilitating models for public-private collaborative research in this field are desirable.
Different operative modalities for machine availability may be considered and tested, including service, leasing, and purchase with shared regional or national public procurement systems. Any adverse event or complication related to ex-situ MP should be immediately reported to the CNT and regional transplant coordinator, and audited.
The national expert committee chaired by CNT, should analyze clinical results annually, and approve procedures or suggest corrective actions.
CONCLUSIONS
Ex-situ organ perfusion may now be a way to expand the pool of organs available for transplantation. MP effectiveness is supported by well-established clinical evidence, but this still lacks clear shared indications. It is necessary to implement this activity as far as possible in order to consolidate the scientific evidence and increase the number of centers that use MP. Machine perfusion technology and innovative clinical procedures are thus a strategic target for the Italian transplant network and the national transplant authority (CNT).
The CNT can help centers to reduce the cost of MP, which is the main obstacle to their implementation in all transplant centers.
A solid and well-structured national data collection is the only way to obtain the clinical evidence of results and efficacy that could allow dedicated funds or ad hoc reimbursement to be received for this activity, such as DRGs. Over the time, this activity could become cost-effective and affordable, because increasing perfusions means we could obtain a reduction in the price of MP facilities and more transplants at lower cost. The use of MO could also have a positive effect on complications after transplants, reducing patient hospital stays, and thus a highly positive effect on overall health care system.
Acknowledgements
We wish to thank all the transplant centers of the Italian National Transplant Network who collaborated with us to collect these data.
Conflict of interest statement
The Authors declare no conflict of interest.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contributions
ST: designed the work, analyzed and interpreted data, drafted the work, approved the final version and reviewed the accuracy and integrity of the work; FV: designed the work, methodology, data management, approved the final version; FP: designed the work, analyzed and interpreted data, revisited critically the manuscript for intellectual content, approved the final version and reviewed the accuracy and integrity of the work; MC: designed the work, analyzed and interpreted data, revisited critically the manuscript for intellectual content, approved the final version and reviewed the accuracy and integrity of the work; FP: methodology, data management, supervision, approved the final version; LM: methodology, data management and statistical analysis, approved the final version; ST: methodology, data management and statistical analysis, approved the final version; PF: acquisition and interpretation of data, writing, approved the final version; DP: acquisition and interpretation of data, writing, approved the final version; AO: acquisition and interpretation of data, writing, approved the final version.
Ethical consideration
Not applicable.
Figures and tables
Figure 1. Liver grafts perfused and transplanted.
Figure 2. A) liver graft survival; B) kidney graft survival; C) lung grafts survival.
Figure 3. Kidney grafts perfused and transplanted.
Figure 4. EVLP procedures transplanted vs not transplanted in the period.
Figure 5. Heart grafts perfused and transplanted from DBD.
| Total LTx performed in the year | LTx performed in LTCs with MP facilities | Total of LTx from DCD + DBD perfused grafts | % LTx from perfused grafts/LTx performed in LTCs with MP facilities | |
|---|---|---|---|---|
| 2015 | 1071 | 925 | 7 | 1% |
| 2016 | 1214 | 1007 | 40 | 4% |
| 2017 | 1295 | 1075 | 46 | 4% |
| 2018 | 1220 | 1016 | 86 | 8% |
| 2019 | 1277 | 1062 | 150 | 14% |
| 2020 | 1182 | 985 | 158 | 16% |
| 7259 | 6070 | 487 | 8% |
| Total KTx performed in the year | KTx performed in KTCs with MP facilities | Total of KTx from DBD perfused grafts | Total of KTx from DCD perfused grafts | Total of KTx from DCD + DBD perfused grafts | % KTx from perfused grafts/KTx performed in KTCs with MP facilities | |
|---|---|---|---|---|---|---|
| 2017 | 1935 | 1031 | 72 | 38 | 110 | 11% |
| 2018 | 1828 | 1145 | 150 | 56 | 206 | 18% |
| 2019 | 1799 | 1127 | 138 | 84 | 222 | 20% |
| 2020 | 1623 | 1022 | 128 | 64 | 192 | 19% |
| 7185 | 4325 | 488 | 242 | 730 | 17% |
| Total LungTx performed in the year | LungTx performed in LungTCs with MP facilities | DBD graft LungTx | DCD graft LungTx | Total of LungTx from DBD perfused grafts | Total of LungTx from DCD + DBD perfused grafts | % LungTx from perfused grafts/LungTx performed in LungTCs with MP facilities | |
|---|---|---|---|---|---|---|---|
| 2011 | 120 | 117 | 117 | 6 | 6 | 5% | |
| 2012 | 113 | 109 | 109 | 12 | 12 | 11% | |
| 2013 | 141 | 135 | 135 | 11 | 11 | 8% | |
| 2014 | 126 | 123 | 122 | 1 | 17 | 18 | 15% |
| 2015 | 112 | 111 | 110 | 1 | 11 | 12 | 11% |
| 2016 | 147 | 143 | 143 | 0 | 11 | 11 | 8% |
| 2017 | 144 | 143 | 140 | 3 | 14 | 17 | 12% |
| 2018 | 143 | 140 | 137 | 3 | 11 | 14 | 10% |
| 2019 | 153 | 152 | 139 | 13 | 13 | 26 | 17% |
| 2020 | 115 | 113 | 110 | 3 | 3 | 6 | 5% |
| 1314 | 1286 | 1262 | 24 | 109 | 133 | 10% |
| Total HTx performed in the year | HTx performed in HTCs with MP facilities | Total of HTx from perfused grafts | % HTx from perfused grafts HTx performed in HTCs with MP facilities | |
|---|---|---|---|---|
| 2017 | 265 | 96 | 14 | 15% |
| 2018 | 232 | 85 | 19 | 22% |
| 2019 | 246 | 84 | 7 | 8% |
| 2020 | 238 | 81 | 7 | 9% |
| 981 | 346 | 47 | 14% |
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