Inequities in Organ Donation and Transplantation Among Immigrant Populations in Italy: A Narrative Review of Evidence, Gaps in Research and Potential Areas for Intervention

Immigrants from outside Europe have increased over the past two decades, especially in Southern European countries including Italy. This influx coincided with an increased number of immigrants with end-stage organ diseases. In this narrative review, we reviewed evidence of the gaps between native-born and immigrant populations in the Organ Donation and Transplantation (ODT) process in Italy. Consistent with prior studies, despite the availability of a publicly funded health system with universal healthcare coverage, non-European-born individuals living in Italy are less likely to receive living donor kidney transplantation and more likely to have inferior long-term kidney graft function compared with EU-born and Eastern European-born individuals. While these patients are increasingly represented among transplant recipients (especially kidney and liver transplants), refusal rates for organ donation are higher in some ethnic groups compared with native-born and other foreign-born referents, with the potential downstream effects of prolonged waiting times and inferior transplant outcomes. In the process, we identified gaps in relevant research and biases in existing studies. Given the Italian National Transplant Center’s (CNT) commitment to fighting inequities in ODT, we illustrated actions taken by CNT to tackle inequities in ODT among immigrant communities in Italy.

(iv) To assess the features of the transplant education process and follow-up management of immigrant patients, determine the (inter)cultural competence of transplant HCPs, including healthcare practices and organizational features (i.e., diversity responsiveness), the problems most frequently encountered by transplant centers' HCPs, and the usefulness of possible initiatives to improve these processes.
(v) To deliver relevant information about the specific needs of immigrant bereaved donors' families to ICU HCPs, and about the main obstacles to patient education and management in relation to transplantation for transplant centers' HCPs

Stakeholder involvement
The CNT established a permanent working group including representatives of the key stakeholders in the ODT process across the regions participating in the project: regional and local transplant coordinators, ICU specialists, transplant center nurses, psychologists, social workers, cultural mediators, patient and donor associations, gender-specific medicine experts, foreign-born physicians, transplant recipients with an immigration background, communication and medical ethics experts, education specialists, migration medicine and migrants/refugees' assistance experts, and religious communities.All key stakeholders were involved in the study design (see below) since the project start.Multiple meetings were held with stakeholder representatives to enable discussions surrounding the project objectives and its ethical implications (2,3), elicit their perspectives on the potential barriers to communication, education and management, gain insights on how to enable shared decision-making at the different stages of the ODT process, and discuss about earlier national and international experiences of targeted and/or tailored interventions directed towards immigrant populations and individuals, which were reviewed prior to the project start (3).

Study design
This study adopts a cross-sectional approach to pursue the study objectives, and a descriptive, multicenter, nonrandomized, prospective design.The study is based chiefly on self-administered questionnaires and will be performed over a 2-year period (01/05/2023-30/04/2025) including four phases: start-up (3 months), enrollment (8 months), data analyses (6 months), and dissemination of study results (4 months).Three distinct questionnaires were adapted and/or developed for subsequent administration to (a) ethnic and faith communities, (b) ICU, and (c) transplant centers' HCPs, respectively.More specifically, a previously validated questionnaire to explore the factors with the potential to affect decision-making about organ donation (4-6)and empirically test the relations among themfor future administration to immigrant and native-born communities was adapted based on a review of the literature (3), the stakeholder's feedback and various multi-stakeholder group discussions to further customize it to the specific features of the Italian context and the target populations.Similarly, based on earlier models of cultural competence in healthcare (7,8), the questionnaires directed towards ICU/local procurement coordination centers' and transplant centers' HCPs were developed based on the relevant literature (3,(9)(10)(11), stakeholders' feedback and multi-stakeholder group conversations (the qualitative analysis of the stakeholders' feedback regarding the factors with the potential to intervene at the individual, interpersonal, and societal levels at the three stages of the ODT process [these were categorized based on the socio-ecological model ( 12)], and the potential for intervention are reported in Supplementary Table S2 and Supplementary Table S3).

Definitions
'Migrant': "any person who is outside a State of which he or she is a citizen or national, or, in the case of a stateless person, his or her State of birth or habitual residence.The term includes migrants who intend to move permanently or temporarily, and those who move in a regular or documented manner as well as migrants in irregular situations" (13).The immigrant category excludes persons who travel for tourism or business purposes and excludes intra-EU mobility (14).'Ethnicity': "the social group a person belongs to, and either identifies with or is identified with by others, as a result of a mix of cultural and other factors including language, diet, religion, ancestry, and physical features" that are shared by individuals in the same group (15).As recommended by prior reports (16), both the features related to 'ethnicity' (including country of origin or descent) and 'immigrant status' (or family history of immigration) should be considered for the purposes of studies in relation to ODT (16).For instance, the European Public Health Association contends that, although immigration includes also elements of ethnicity, 'visible minorities' are likely to experience more significant inequities relative to their 'White' referents, similar to immigrants (17).

Study settings
The Italian National Health System is a regionally based system presenting variations across regions which may impact on various levels of healthcare delivery depending on resource availability and organizational standards.The study will therefore be performed across eight regions representative of the Northern (Lombardy, Piedmont, Veneto, Friuli Venezia-Giulia), Central (Emilia-Romagna, Tuscany, Lazio) and Southern (Sicily) Italian areas (the overall presence of foreign citizens in the regions participating in the project is reported in Supplementary Figure S1 and the distribution of the most represented populations at the national and regional levels in Supplementary Table S1).

Study population
The study population will comprise three distinct groups, namely (a) ethnic and faith communities (including nativeborn populations, i.e., individuals who are native-born of at least one native-born parent), (b) ICU, and (c) transplant centers' HCPs (physicians, nurses, health and social care workers, psychologists, social workers, cultural mediators, volunteers and experts in bioethics/clinical ethics).

Inclusion and exclusion criteria Inclusion criteria
For ethnic and faith communities: individuals aged ≥18 years, residing in the regions involved in the project, having the ability to understand the informative sheet and providing formal consent to processing personal data.
For healthcare professionals: all individuals working in the ICUs and/or local hospital coordination centers and transplant centers in the regions involved in the project (physicians, nurses, health and social care workers, psychologists, social workers, cultural mediators, volunteers and experts in bioethics/clinical ethics) and providing formal consent to processing personal data will be recruited.

Exclusion criteria
All subjects who meet the inclusion criteria but are unable to understand the informative sheet, do not agree to participate in the study, or do not consent to processing personal data.

Ethnic and faith communities
Given the composition of the ethnic and faith communities in the regions involved in the study (the size of the populations based on citizenship are reported in Supplementary Table S1), the sample size is 1,500 questionnaires for a 95% confidence interval and a 5% error limit, with reference to the variability of responses, since unknown, maximum possible and equal to 50%.Thus, assuming a collection of 200-300 questionnaires from native-born populations, the remaining 1,200-1,300 questionnaires will be collected from communities with an immigration background; the expected sample size contains a correction with reference to the proportion (expected <10%) of questionnaires with some incomplete responses (<15%).
(Our total population is the unknown n (for the regions considered) -Assumed frequency (%) of the outcome factor in the population (p): 50% (thus it is assumed the greatest response variability, that is used precisely when the response in the population is unknown) -Confidence limits as % of 100 (absolute +/-%): 5% -Level of error: Ɛ=5% Equation [as derived from Schaeffer et al. (18)]: where: n=sample size N=population size p=the estimated proportion Ɛ=desired absolute precision or absolute level of precision Z 2 α/2 = the critical value of the Normal distribution at α/2 (e.g. for a confidence level of 95%, α is 0.05 and the critical value is 1.96) -Correction for Finite Population : n_cfp=n/(1+(n-1)/N)

ICU healthcare professionals
The total number of ICUs in the participating regions is 272.For a 95% confidence interval and an error limit of 5%, with reference to the variability of responses, since unknown, maximum possible and equal to 50% .Based on earlier studies performed with these facilities, and the direct knowledge of the network, an adherence of at least 80% of ICUs is expected.With a minimum of 3 HCPs completing the questionnaire per facility, the expected sample is approximately 800 questionnaires.However, considering the objective of HCPs' training, no constraints will be placed on the maximum number of adherences, which therefore could exceed the number indicated.

Transplant centers' healthcare professionals
The total number of transplant centers is 70.Estimating an involvement of all facilities, and assuming the completion of at least 5 questionnaires at each center, the expected sample size is 280-320 questionnaires.

Variables and measurements Socio-demographic characteristics
For ethnic and faith communities, socio-demographic data including age group, place of birth, parents' place of birth (if born abroad), respondent's and/or parents' (if born abroad) time elapsed since immigration, gender, years of schooling, occupational category, marital status, presence of children, religious/spiritual faith, and frequency of participation in the life of one's religious community will be collected.As for HCPs, the socio-demographic characteristics collected will include gender, age group, place of birth, nationality, religious/spiritual faith, participation in religious activities, profession, time spent working in the ICU/in transplantation, participation in educational courses for the development of (inter)cultural competences, and prior professional experience in developing countries.For transplant centers' HCPs, the indicative number of immigrant transplant candidates evaluated over the past 5 years, the problems most frequently affecting the time for wait-listing and follow-up management (ranking), will also be assessed.

Ethnic and faith communities
Factors influencing living will manifestation to be an organ donor Knowledge (8 items) will be assessed using a yes and no scale.Attitude (4 items), beliefs (2 items), descriptive norms (1 item), perceived control (2 items), distrust towards caregivers (1 item), body integrity (2 items), trait transfer (2 items), perceived benefits (2 items), ick factors (2 items), jinx factors (1 item), religious beliefs (2 items), and subjective norms (2 items) will be measured on a 5-point Likert scale (1 = strongly disagree, 2 = disagree, 3 = neither disagree nor agree, 4 = agree, 5 = strongly agree).Participants will also be asked about the interpersonal and mass media source(s) from which, if so, they have obtained information about organ donation.The reason underlying the act of not having yet expressed one's opinion about organ donation (if applicable), will be assessed through a multiple-choice question.Two open-ended qualitative questions will finally serve to acquire additional comments surrounding ODT and suggestions to improve the cultural appropriateness of future informative initiatives.

ICU healthcare professionals
The data collected about the specific hospital/healthcare organization and ICU (10 items) will include the location (i.e., region), number of beds, patients' type (adult/pediatric), presence/absence of a neurosurgery unit and transplant center, indicative share of immigrant patients admitted to the ICU and of immigrant donors over the past 5 years, most frequent reason for organ donation refusal, residency of family members during donation interview (Italy/foreign country).The following dimensions will be measured on 5-point Likert scales: (Inter)cultural awareness, sensitivity, knowledge and attitudes ( 11

Transplant centers' healthcare professionals
The data collected about the specific hospital/healthcare organization and transplant center (6 items) will include the location (i.e., region), university/non university hospital, type of organ(s) (kidney, liver, heart, lung, other) and patients (adult/pediatric) transplanted, number of transplants performed over the past year, indicative share of immigrant patients transplanted over the past 5 years.The following dimensions will be assessed using the same 5-point Likert scales as for ICU HCPs: (Inter)cultural awareness, sensitivity, knowledge and attitudes (7 items), Practices and behaviors (12 items), Patient-centered communication (14 items), and Usefulness of specific interventions (10 items).Two open-ended qualitative questions will finally serve to acquire additional comments and suggestions to improve the process of transplant education and follow-up management of foreign patients and improve the overall transplant process among this patient population.

Data collection
After providing formal consent to participation in the study and to the processing of personal data, individuals from ethnic and faith communities and ICU and transplant centers' HCPs will be eligible for participation in the study.All data will be collected through a self-administered questionnaire on an online platform entirely managed and safely stored by the CNT.

Ethnic and faith communities
The presentation of the FAITH project and the dissemination of the questionnaire directed towards ethnic and faith communities will be sent by the CNT to regional transplant coordinators, patient and donor associations, and ethnic and faith representatives in the stakeholders working group.Regional transplant coordinators (or their delegates) will partner with local institutional authorities and with local ethnic and faith representatives.A co-design approach will be adopted.Therefore, ethnic and faith representatives will instruct on the most appropriate methods and contexts/types of community-based informative events for project presentation and questionnaire dissemination.Dissemination will be performed also by local patient and donor associations, and other institutional actors operating in the different regions involved in the project, so as to further adapt these initiatives to the specific features of the different local areas.
During the informative community-based events, links to the questionnaire -in the different available languages -will be shared with participants via QR codes that will be displayed at the venues where the events will be held.By doing so, participants will have the opportunity, should they wish, to fill out the questionnaire on site, taking the opportunity to ask for more information and/or clarification from the people involved in the project (the project coordinator and/or the General Manager of the CNT -or their delegates -will guarantee their presence during the events).However, participation in the study is voluntary and, therefore, there will be no obligation to complete the questionnaire.The flowchart of the presentation of the FAITH project and questionnaire dissemination is reported in Supplementary Figure S2, Panel A).

ICUs' and Transplant centers' healthcare professionals
As illustrated in Supplementary Figure S2, Panel B and Panel C, the CNT will send the project presentation, together with the informative sheets directed towards ICUs' and transplant centers' HCPs to the Welfare General Directorates of the Regions involved in the project and/or to regional transplant coordination centers, which, in turn, will contact the General Directorates of the Hospitals located in their respective Regions.The General Directorates, through local organ procurement and transplant coordinators will disseminate the following documentation to a completely anonymous mailing list (recipients will all be listed in Blind Carbon Copy, BCC) of the HCPs working in the ICUs and transplant centers, of the respective healthcare organizations, respectively: project brochure, informative sheet and link to the questionnaire.

Data analyses
After all data are collected, analysis will be performed using Stata (Stata 17.0, StataCorp LLC Texas TX 77845), R (R 3.6.1).Statistical analyses will be performed separately for the three distinct databases corresponding to the target populations.Descriptive statistics will be given as total number and percentage for categorical or qualitative variables; median and interquartile range (IQR) otherwise.Associations between categorical variables will be evaluated by chisquare test; Fisher's exact test will be preferred in case of sparse tables.Exploratory data analysis will be performed to examine the relationships between the different variables through clustering and graphical methods (multivariate visualizations) to map the interactions between dimensions.The multivariate models provided for the Structural Equation Modeling scales of the administered questionnaires will also be applied for the evaluation of the objectives, and correlations with the main demographic and identifying group (i.e., ethnic and faith communities, and ICU and transplant center's HCPs) will be assessed with reference to the dimensions in the questionnaires.Factor Analysis models will be adopted (exploratory, and, when this will apply, confirmatory) with the construction of correlation matrices, after the evaluation of some indices (Kaiser-Meyer-Olkin index for adequacy of sampling and Bartlett's Sphericity index) to verify the application of models with Varimax rotation.The models' goodness of fit will be assessed based on Cronbach's alpha.

Expected outcomes
Studies will report on the findings of the project and provide additional insights of the interactions between factors at the individual, interpersonal and societal levels in relation to living will manifestation about organ donation.The collected data will serve to inform the future development of informative initiatives directed toward different ethnic and faith communities in Italy.Further, the data will allow the identification of potential areas for intervention both at the educational level (i.e., development of communicative/relational skills of ICUs' and transplant centers' HCPs) and at the structural/organizational level (diversity responsiveness of health care organizations).At the same time, the study results will enable the development of a list of recommendationswhich will be shared and further developed and refined with all stakeholderson how to enable shared decision-making at the different stages of the ODT process for the prevention of inequities for individuals with an immigration background in Italy.The FAITH project will serve also to stimulate the debate surrounding ODT within and among different ethnic and faith communities, to promote and enhance dialogue among all stakeholders, and, ultimately, to increase awareness about the core issues of this study among all of the actors involved.
Research to assess and report on the actual impact of the FAITH project on existing inequities in ODT among immigrant communities in Italy in the longer term are warranted.Future, qualitative studies including in-depth interviews and/or focus group discussions with bereaved family members, patients pursuing transplant, and (potential) living donors from migrant minority communities will further explore barriers to care.

Ethics and dissemination
The study protocol was approved by the National ethics committee for clinical trials of public research bodies and other national public institutions of the Italian National Institutes of Health, Rome, Italy (Protocol number: 0024027 -19/05/2023).Three information sheets presenting the overall study objective, and, respectively, the distinct specific objectives for the three target groups will be provided for all participants.Acceptance of the informative sheet and of the data protection form will be obtained from all participants.Further, to improve understanding, the informative sheets and the questionnaire directed towards immigrant communities will be translated in the languages of the more numerous populations in Italy (Supplementary Table S1).The collected data will be retained for as long as necessary during the study period, but no longer than 12 months after its completion.After that time, the data will be completely anonymized and retained indefinitely.All collected data and information will be stored on the servers of the CNT according to the security measures related to its management.The data will be analyzed and subsequently published in aggregate form and, in no case, will the information be traced back to individual subjects and, with reference to HCPs, neither to individual subjects nor to individual healthcare organizations.The study will be conducted in accordance with the ethical principles set forth in the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report, as per recommendations of the European Commission Guide to Ethics in Social Science and Humanities.
The study results will be disseminated through scientific publications, conference communications, publication on the CNT website, and shared during events organized by the CNT and other partners of the FAITH project.The table illustrates the feedback received by the stakeholders in the working group of the FAITH project of the CNT answering the following key questions: (1) What are the potential barriers to living will expression?(2) What are the potential obstacles/difficulties most frequently encountered within the relationship between ICU healthcare professionals and bereaved families in the context of organ donation as part of end of life care?(3) What are the potential needs of patients and potential living donors (i.e.gaps in knowledge/understanding of aspects relevant to transplant accessibility and outcome, health beliefs, preferred educational formats, other needs and/or problems encountered)?P1 refers to living will manifestations, P2 to the relationship between ICU healthcare professionals and potential deceased donor families, and P3 to the relationship between transplant professionals and transplant candidates, recipients and (when this is applicable) their potential living donors.The results have been categorized based on the socio-ecological model (47).We acknowledge that the factors intervening at the different levels have the potential to reciprocally influence one another.However, investigation of these aspects was beyond the scope of this study at this stage of the project.-establish trusting relationship with family members by showing care (ideal to identify a reference person all throughout the process) -make sure that family members are aware of the entire diagnostic and therapeutic process which preceded the determination of death of their beloved one -inform about the procedures for the management of the deceased person's body after the determination of death -agree and be open to speak with all of the family members that the family asks to be present during organ donation conversations -identify the decision-maker within the family unit (both the legal and, if this applies, also the cultural one) -when this may be needed, perform conversations with both female and male HCPs -reassure family members that the body of their beloved one will be treated with care and respect in the event of donation

•
Trust building: -improve prevention and/or early care of chronic conditions to increase confidence towards the healthcare system and HCPs

•
Transplant education: -share multilingual informative material about treatment options for ESKD: hemodialysis, peritoneal dialysis, deceased donor and living donor kidney Tx early in the process (i.e. at nephrology and dialysis outpatient clinics) -use simplified informative material (i.e.bullet-point lists, comics) -deliver information gradually and verify understanding (i.e.ask the patient and family members to repeat back the contents of information using their own words) at each encounter -ask the patient about his/her favorite educational format (i.e.in-person conversations, paper-or video-based educational material for use outside of clinical encounters) -elicit the patient's and patient's family's representation of organ donation (living and deceased) and Tx -when this may be needed, perform conversations with both female and male HCPs -create personalized objectives according to the patient's individual circumstances -develop pathways to transplant information in group settings, also involving other couples who have already gone through the LD process -develop and expose patients and families to video-based testimonials (i.e. from patients who have already received Tx about improvements in quality of life after Tx and the need for adherence to complex post-Tx regimens) -develop counseling and educational strategies adapted to the specific needs of migrant and ethnic minority populations and further tailor them to the individual needs (i.e. according to level of health literacy, education, language proficiency, individual life circumstances, etc.) -create a network of shared experiences to improve education and provide ongoing social and psychological support • Psychosocial assessments: -identify logistical, structural and socioeconomic problems early in the process so as to enable planning of appropriate management of pre-and post-Tx requirements -explore the individual migration projects so as to implement strategies to enable optimal follow-up in the event of willingness to emigrate to another country -practice active listening with bereaved family members to elicit their individual views and needs about end-of-life care -offer the opportunity to involve a representative of the reference religious/spiritual community or of the healthcare organization -respect and strive to meet religious/spiritual care requests -choose an appropriate communicative setting for the donation conversation (choose a neutral and appropriate place) -explore the patient's and family's knowledge of available treatment options and their beliefs about them elicit the patient's and family's representation and beliefs about medications, lifestyle factors and dietary habits with the potential to compromise adherence to pre-and post-Tx regimens -establish support groups at Tx centers -improve information about Tx and ensure good follow-up management -identify trusted support person to accompany the Tx process -inform, educate and involve the patient's family in the process • Bureaucratic procedures: -create dedicated desks to facilitate the bureaucratic process and deliver multilingual informative materials The table illustrates the feedback received by the stakeholders in the working group of the FAITH project of the CNT answering the key question of how to potentially intervene to enhance communication, education and management of migrant and ethnic minority populations/individuals at the three different stages of the ODT process.These initiatives require the participation and inclusion of migrant and ethnic minority communities and individuals (i.e.patients and, when this applies, potential living donors) at all stages of the process (from the development through to the evaluation stage).

Table S2 .
Stakeholders' feedback on barriers to communication, education and management of immigrant and ethnic minority populations and individuals in the ODT process

Table S3 .
The stakeholders' working group includes the following representatives: regional and local transplant coordinators, intensive care transplant center nurses, psychologists, social workers, patient and donor associations, gender-specific medicine experts, foreign-born physicians, transplant recipients with an immigration background, communication and medical ethics experts, education specialists, migration medicine and migrants/refugees' assistance experts, and religious communities The multistakeholder groups were composed respectively by the following stakeholder representatives: (a) cultural mediators, ICU specialists and transplant coordinators, religious communities, patients' and donors' associations, communication specialists, and bioethics/clinical ethics experts; (b) cultural mediators, ICU specialists, regional and European transplant coordinators, and religious communities; (c) psychologists, social workers, nephrologists, migration medicine experts, and transplant center clinicians and nurses.These data were preliminarily presented as an oral presentation at the 45 th conference of the Italian Society of Organ Transplantation (SITO) in Trieste, Italy (October 23-25, 2022).Stakeholders' feedback on potential interventions to improve communication, education and management of migrant and ethnic minority populations/individuals in the ODT process