A study of knowledge and acceptance of kidney xenotransplantation among Chinese kidney transplant recipients and candidates

In recent years, the implementation of the first case of pig‐to‐human heart xenotransplantation and the report of three cases of pig‐to‐brain‐dead human recipient kidney transplantation indicate that xenotransplantation is getting closer to clinical application. In the near future, China may also launch clinical trials of kidney xenotransplantation. Therefore, it is necessary to investigate the level of knowledge and acceptance of xenotransplantation among kidney transplant recipients and candidates in China. This study aims to investigate the level of comprehension and acceptance of kidney xenotransplantation in kidney transplant recipients and explore related factors, providing a reference for promoting the application and clinical trials of xenotransplantation in the near future.

A recent meta-analysis identified factors associated with views on xenotransplantation; among them, personal experience of organ donation was most closely associated with a favorable view, while religious belief was most strongly associated with an unfavorable view. 18However, the studies cited in the review used a variety of different methods and xenotransplantation may be viewed differently today than when the study was conducted.Therefore, results from these studies have limitations as a basis for determining current attitudes towards xenotransplantation in patients with kidney disease and kidney transplant recipients.This study aims to investigate the level of comprehension and acceptance of kidney xenotransplantation in kidney transplant recipients and explore related factors, providing a reference for promoting the application and clinical trials of xenotransplantation in the near future.

Study population
Kidney transplant recipients and candidates have a better understanding of the benefits brought by transplantation, desires to a transplant or retransplant after graft failure and may have more transplant back-ground knowledge than the general public.Studying their views on xenotransplantation can provide a more relevant reference for the promotion of this technology in the future.Therefore, kidney transplant recipients and candidates were selected as the main study population in this study (This study was conducted in accordance with Chinese law and approved by the IRB of Tongji Hospital of Huazhong University of Science and Technology).
Between October 2022 and February 2023, respondents completed questionnaires posted on the center's Organ Donation and Transplantation website or during outpatient visits.

2.2
The questionnaire

Composition of the questionnaire
The design of the questionnaire was based on previous studies and was

Validity and reliability of the scale
We obtained a Cronbach alpha coefficient of 0.838.The Kaiser-Meyer-Olkin sampling adequacy measure is 0.777, and Bartlett's test of sphericity is significant with a p-value of <.001.

Statistical analysis
Data analysis was performed using IBM SPSS Statistics 26.0.The count data were described by frequency and percentage; measurement data were described by median and quartile; the validity and reliability of the questionnaire were measured by Cronbach alpha coefficient, Kaiser-Meyer-Olkin (KMO) test, and Bartlett's spherical test.Scores were compared using nonparametric tests.The Chi-square test or Fisher's exact test was used to compare the differences in the answers.
p < .05 was considered as statistically significant.

The answers to the questions in each dimension
The chi-square test or Fisher's exact test was used to compare the differences in the answers of different groups with different characteristics in each dimension.Chi-square test was used when the theoretical cell frequency was ≤20% and T < 5. Fisher exact test was used when > 20% cells had at least 1 T < 1. Variables that were statistically significant in the chi-square test were included in the multivariate logistic regression.p < .05 was considered statistically significant (Table 1 1).

"Risks and concerns"
When respondents were asked about the risks associated with xenotransplantation, 5.2% said there was no risk, while 118 (50.9%) respondents agreed that there were risks.Results from chi-square test showed that the degree of concern about the risks of xenotransplantation was related to the level of education and the level of knowledge about xenotransplantation clinical trial cases.Respondents with a college degree or higher were more concerned than those with a high-school degree or less, respectively (59.2% vs. 42.1%,p = .015).
Consecutively, respondents with knowledge of the U.S. clinical trial cases were more concerned than those who did not know (54.3% vs. 44.4%, p = .022).
32.8% of respondents were worried about the risk of immune rejection.Results from chi-square test showed that there was no statistical difference between the variables.
81.9% were worried about the risk of disease transmission from animals.Chi-square test results showed that concern about the risk of disease transmission from animals was related to religious beliefs.
Religious respondents were less concerned about the risk of disease transmission from animals than nonreligious respondents (60.5% vs. 80.5%, p = .005).
81.5% are concerned about the risk of swine virus infection.Chisquare test results showed that concerns about the risk of swine virus infection were related to religious belief and level of education.
Religious respondents were less concerned about the risk of swine virus infection than those of no religion (68.5% vs. 85.4%, p = .009).Respondents with a college degree or higher were more concerned about the risk of swine virus than Respondents with a high-school degree or less (86.4% vs. 75.7%,p = .043).

TA B L E 1
44.8% were worried about other unknown risks and 38.4% were concerned that the unknown risks of xenotransplantation could be dangerous to their families.Results from chi-square test showed that concerns about other unknown risks were related to religious belief.
Religious respondents were less concerned about unknown risks than those of no religion (33.3% vs. 48.3%,p = .027)(Table 1).32 (13.8%) respondents agreed that porcine kidneys will function better than human kidneys, the rate being higher among rural respondents and respondents who were willing to donate their organs compared to urban respondents (24.5% vs. 10.6%, p = .001)and respondents who were unwilling to donate their organs (12.5% vs. 5.6%, p = .003).
191(82.3%) respondents believed that a pig kidney transplant organ can function for 5 years or more (Figure 1).Results from chi-square test showed that there was no statistical difference between variables (Table 1).

Other questions out of dimensions
In order to improve the reliability and validity of the scale, we deleted some of the questionnaire questions and their responses, but these questions also have high reference value, so we listed them separately and did not include them in the data analysis. In

Single factor analysis
The results of single factor analysis showed that the scores were statistically significant in terms of gender, age, location, degree of education, medical-related careers, knowledge of clinical trial cases and willingness to donate organs.
In "Knowledge and attitude," male respondents scored significantly higher than female respondents (18 vs. 17, p = .014),respondents with medical-related careers scored significantly higher than those none (18 vs. 17, p = .004),and respondents who knew about the U.S. clinical trial cases scored significantly higher than those who did not (18 vs. 16, p = .000).
In "Risks and concerns," respondents with a college degree or higher had significantly lower scores than respondents with a high-school degree or less (6 vs. 7, p = .008).
In "Social psychology," respondents aged ≤60 years scored significantly higher than those aged >60 years (10 vs. 8, p = .011).Respondents who knew about the U.S clinical trial cases had significantly higher scores than those who did not (10 vs. 8, p = .000).
In "Efficacy and cost," male respondents scored significantly higher than female respondents (11.5 vs. 11, p = .015),and respondents from rural backgrounds scored significantly higher than respondents from urban areas (12 vs. 11, p = .020).Respondents who knew about U.S. clinical trial cases scored significantly higher than those who did not (12 vs. 11, p = .003).Furthermore, respondents who were willing to donate their organs had significantly higher scores than those who were unwilling or unsure (11 or 11 vs. 9.5, p = .019).

Multiple factor analysis
The factors with statistical significance in univariate analysis, multinomial variables (such as "times of kidney transplantation" and "willingness to donate organs") requiring pairwise comparison were included in multivariate analysis.After adjusting with other factors, the factor "medical-related careers" lost statistical significance in "Knowledge and attitude" and the factor "Location" lost statistical significance in "Efficacy and cost" (p = .050).In pairwise comparison of the factor "willingness to donate organs," it showed statistical significance that"willing" and "not sure" respondents had higher scores than those "unwilling" (Table 5).The final results are presented as box plots (Figure 2).

DISCUSSION
To the best of our knowledge, this is the first study in China to assesses respondents' knowledge and acceptance of xenotransplantation.We also compared how different characteristics of the respondents lead to different levels of knowledge and acceptance, exploring possible factors that may affect kidney transplant recipients' perceptions of xenotransplantation.

Knowledge and attitude regarding xenotransplantation
The awareness rate of the term xenotransplantation was relatively high among respondents and most of the respondents indicated that they knew the clinical trial cases of xenotransplantation, which may be related to our center's latest updates and reports on the progress of TA B L E 4 Scores for knowledge and acceptance of xenotransplantation among 232 respondents with different characteristics in each dimension and results of nonparametric test.We discovered that most respondents (73.7%) had a favorable attitude towards accepting a xenograft if it was proven to be scientifically feasible.The statistics are higher than study populations in other reports, such as among Chinese medical students (63.9%), 9 Irish citizens (62%), 19 and Latin-American residents in Spain (40%). 12Kidney transplant recipients and candidates had more positive attitudes towards xenotransplantation than other groups, this may be explained by the fact that people waiting for a kidney or who presented the possibility of a retransplantation, considering their own needs and the personal experience of suffering from organ failure, were more looking forward to this new therapy.

Efficacy and cost
As for animal ethics, 48 (20.7%) respondents agreed porcine kidney xenotransplantation was not ethical for animals which was similar to the results of studies in other populations. 20,21Although there were some concerns about animal ethics, this did not significantly diminish the favorable attitude of the respondents towards xenotransplantation.Results from chi-square test showed that religious respondents were less concerned about risk of disease transmission from animals such as swine virus infection and other unknown risks than those of no religion, perhaps religious respondents may get spiritual protection from religions.

Risks and concerns regarding xenotransplantation
The recently published case report of a genetically engineered pigto-human cardiac xenotransplantation reported widespread endothelial injury, indicating antibody-mediated rejection. 22Nonetheless, respondents in our study were more concerned about the risks of infection than they were about the risk of rejection or unknown risks.This may be related to the information lag and lack of news coverage of the latest progress in xenotransplantation.

Social psychology regarding xenotransplantation
Respondents were generally less worried that kidney xenotransplantation might change human nature, while young and middle-aged respondents and those who were informed about the U.S. clinical trial cases were significantly less worried about the psychological changes brought by xenotransplantation. Surprisingly, only 21.1% of respondents were worried about being discriminated against by others after kidney xenotransplantation, which was statistically lower than worries expressed by medical students or other populations in previous studies.Concerns about discrimination are comparatively much lower among respondents who knew about the U.S. clinical trial cases.This indicates that respondents are generally more concerned with the effectiveness of xenotransplantation than with the potential psychosocial burden it may have.

Efficacy and cost regarding xenotransplantation
It is surprising that most respondents believe that xenotransplantation can solve the organ shortage problem (83.3%), and the majority of respondents (82.3%) believed that xenografts could function for 5 years or more (Figure 2).On the other hand, the majority of respondents were not sure whether pig kidneys worked better than human kidneys and just a few respondents (11.4%) believed that xenografts would function better than allografts, of which more respondents from rural backgrounds believe so.Decades of development of human kidney transplantation and kidney transplant recipients' good experience of human kidney transplantation may result in few kidney transplant recipients considering porcine kidney function better than human kidney.Summing up the above points, kidney transplant recipients and candidates probably agreed that porcine kidney had similar function to human kidney and they could complement each other to solve the problem of organ shortage.42.7% of them had a stronger acceptance and agreed that kidney xenotransplantation can replace human transplantation.
In addition, a good percentage of respondents (40.1%) agreed that xenotransplantation would be less costly than allograft transplantation.It is concluded that respondents may hold expectations that are too high about the efficacy and cost of xenotransplantation, as recent preclinical animal studies have shown that the longest survival time of macaques has not exceeded for more than 5 years. 23,24

Groups best fitted for xenotransplantation
According to the final score analysis, male respondents, those wellinformed on the U.S. case, and those willing to donate their organs scored higher than other groups.Respondents with higher education Patients with O blood type, advanced age, or HLA-sensitivity were regarded as the most suitable groups for xenotransplantation, 25 but in our study, respondents with O blood type, advanced age or HLA-sensitivity did not show higher scores than other groups.

Study limitations
This study has several limitations.First, the sample size of this study was small, with only 232 renal transplant recipients included as study subjects.Second, this study was conducted at a transplant center in central China, therefore the results of this study may not be generalizable to respondents in other parts of China or to populations from other countries.[28] Although religious affiliation was a factor influencing respondents' answers to specific questions, it did not seem to have a prevalent impact on the scores of each dimension in our survey.This may be explained by the fact that more than 75% of respondents in this study claimed to have no religious affiliation.

Recommendations for the future
As shown in this study, respondents had a relatively good awareness and acceptance of xenotransplantation.However, the potential risk

CONCLUSION
The level of awareness on the term xenotransplantation was overall high for respondents and most had expressed a generally favorable ical trials and the initiation of clinical trials for xenotransplantation, due to progress made in CRISPR-Cas9 technology for gene editing and the utilization of new immunosuppressants combined with immune tolerance induction strategies.In December 2021 and January 2022, successful porcine kidney transplants were performed on three braindead patients by teams at New York University and the University of Alabama at Birmingham.Additionally, in 2021, University of Maryland achieved a groundbreaking milestone by successfully conducting a pig-to-human cardiac xenotransplant. 1-3These exciting achievements bode well for the possibility for kidney xenotransplantation to enter clinical trial stages and to be applied in the near future.Kidney transplant recipients and candidates, especially those with blood type O, advanced age, or are HLA-sensitized, face transplant or retransplant after graft failure and may benefit the most from xenotransplantation, their attitudes towards xenotransplantation serve as important references for xenotransplantation to be used as a clinical practice.
edited according to the characteristics of kidney transplant recipients and candidates.It consists of two parts: The first part (questions 1-12) enquires about the basic characteristics of the population and contains 12 items of general information.The second part (questions 13-34) contains 22 scale questions on knowledge and acceptance towards xenotransplantation.The 22 scale questions of this section were divided into four categories; "Knowledge and Attitude" (awareness of kidney xenotransplantation and attitude towards kidney xenotransplantation), "Risks and Concerns" (concerns of risks, including risk of immune rejection, risk of infectious disease from animals, and unknown risks), "Social Psychology" (worries about changes in human characteristics, mind, personality, and discrimination by others after kidney xenotransplantation), and "Efficacy and Cost" (expectations about the effectiveness and financial cost of xenotransplantation compared with allograft).Scores from answering scale questions are assigned according to the number of answer options and Likert score: dichotomous options are assigned a score of 0-1; The three-level options are assigned a score of 1-3 (Appendix 1).

F I G U R E 1
Expected functional time (years) of the xenografts [n (%)].

F I G U R E 2
Variables that were statistically significant and comparison of scores of dimensions.Box graphs indicate median (Q1, Q3).*p < .05;**p < .01,and ***p < .001.xenotransplantation.However, when assessed with results from questions in other categories, most respondents did not have a comprehensive understanding of the specific knowledge of xenotransplantation or the main risks of xenotransplantation and may have unrealistically high expectations of its effectiveness.
Overall, respondents were very concerned about the risks associated with xenotransplantation.As the level of education and knowledge about xenotransplantation increased, concerns about the risk of xenotransplantation among respondents increased significantly.
were more sensitive to the risks posed by xenotransplantation and might not be a group suitable as first-time xenotransplantation recipients.Compared with the elderly, Young and middle-aged patients are more suitable for xenotransplantation in terms of social and psychological acceptance.Patients from rural backgrounds are more optimistic about the effectiveness of xenotransplantation and are therefore more suitable for xenotransplantation.
of xenograft rejection was largely overlooked by respondents.Furthermore, respondents tended to overestimate the effectiveness of xenografts because they may believe that immunosuppressive agents can significantly prevent immune rejection of renal transplantation.The information lag and lack of press coverage on xenotransplantation may also contribute to this phenomenon.In summary, we make the following suggestions for subsequent clinical trials of xenotransplantation.It is recommended to increase the frequency of updates and publicity on the latest developments in xenotransplantation, and to strengthen public knowledge related to xenotransplantation; Respondents tend to overlook the risk of immune rejection and overestimate the effectiveness of xenografts, so publicized reports should place more emphasize on explaining the potential risks of immune rejection and inform the public about the results of preclinical animal research.

11 . 14 . 15 . 16 . 17 . 18 . 19 . 20 .□ 21 . 22 . 23 . 24 . 25 . 26 . 27 . 28 .□□
attitude towards the procedure.The promising results of xenotransplantation clinical trials, in addition to receiving support from groups having characteristics such as being male, young and middle-aged, and willing to donate organs, had contributed to rising expectations for future development of xenotransplantation.However, most respondents did not have a comprehensive understanding of the specific knowledge of xenotransplantation, most respondents tend to overlook the major risks of xenotransplantation and had high expectations of xenotransplantation's effectiveness.It is necessary to increase the speed at which the latest progress of xenotransplantation is updated, and strengthen the public's knowledge related to xenotransplantation. Do you know the clinical trial cases in 2022?Know that pigs used for xenotransplantation are genetically modified?Would genetic modification or modification affect your support for xenotransplantation? Would you be willing to accept porcine kidney xenotransplantation if it is scientifically proven to be feasible?If you were seriously ill and needed a kidney transplant, but no suitable human organ was available, would you accept a porcine kidney temporarily or would you wait for a human organ?If the porcine kidney worked well in your body, would you keep the porcine kidney rather than remove the porcine kidney for a human kidney transplant?If you accept porcine xenogeneic kidney, are you willing to accept long-term follow-up of you and your family by medical institutions?Do you think porcine kidney xenotransplantation is ethical for animals?□ □ Do you know xenotransplantation may need to take new immunosuppressants for life?(deleted) Do you think there are risks associated with xenotransplantation? Do you think there is a greater risk of immune rejection for xenotransplantation? Are you concerned about the infection of animal diseases after kidney transplantation?Are you concerned about swine virus infection after xenotransplantation? Are you concerned that the unknown risks of xenotransplantation could be dangerous to your family?Do you think there are other unmentioned risks associated with porcine kidney xenotransplantation? Do you think the human characteristics will change after receiving a porcine kidney transplant?Are you worried that your mind will change after receiving xenotransplantation? you worried about personality changes after kidney transplantation?you worried that others will look at you differently if you accept a pig kidney?□ □ Efficacy and cost 31.Do you think that xenotransplantation can solve the problem of organ shortage?you think porcine kidney xenotransplantation can replace human kidney transplantation?you think the function of porcine kidney will be better than human kidney?□ □ If you received a porcine kidney xenograft, would you disclose to others that you received a pig kidney?long do you think the pig kidney transplant organ can function?
Questions of the scale and answers [n (%)].
Risks and concerns 21.Do you think there are risks associated with xenotransplantation? 118 (50.9) 102 (44.0) 12 (5.2) 22. Do you think there is a greater risk of immune rejection for xenotransplantation? 76 (32.8) 141 (60.8) 15 (6.5) 23.Are you concerned about the infection risks of animal diseases after kidney transplantation?190 (81.9) 42 (18.1)24.Are you concerned about the risk of swine virus infection Questions out of the scale and answers [n (%)].Dimensions of the scale and scores.
Kidney transplant recipients and candidates scored relatively high on knowledge and acceptance of xenotransplantation with a total score of 45 (40, 49) (75 out of 100)."Knowledge and attitude" has the highest score of 17(15, 19)(85.0out of 100); the "Risks and concerns" has the lowest average total score of 7 (5, 8) (50 out of 100); the score of "Social psychology" was 10 (8, 12) (83.3 out of 100), while the score of "Efficacy and cost" was 11 (9, 12) (78.6 out of 100) (Table3).TA B L E 2 Results of multiple factor analysis.
aA statistically significant result.TA B L E 5Note: Variables that were statistically significant in the nonparametric test were included in the multiple linear regression.p-value < .05. a A statistically significant result.