The Living-Related Kidney Transplant Program in Brunei Darussalam: Lessons Learnt from a Nascent National Program in a Small, Muslim, and Asian Country

Brunei Darussalam commenced its living-related renal transplant program in 2013, with subsequent attainment of independent local capacity and proficiency in 2019. The preliminary outcome from the program has already begun to shape the national nephrology landscape with a 36% increment in transplant rate and mitigation of commercialized transplantations. The blueprint for the program was first laid out in 2010 and thereupon executed in four phases. The first phase involved the gathering of evidence to support the establishment of the national program, through researches investigating feasibility, public opinion, quality of life, graft survival, and cost-effectiveness. The second phase focused on laying the foundation of the program through grooming of local expertise, implementation of legal-ethical frameworks, religious legitimization, and propagation of awareness. The third phase worked on facilitating experiential exposure and strengthening local infrastructure through the upgrading of facilities and the introduction of subsidiary services. The fourth phase was implemented in Brunei in 2013 when foreign personnel worked together with the local team to perform the transplants. Between 2013 and 2019, ten kidney transplants were performed, with two being done in 2018 and three in 2019. We hope to inspire other similar countries to develop their own self-sustainable and independent local program.


Introduction
Despite having the smallest population in Asia [1], Brunei has one of the highest rates of end-stage kidney disease (ESKD) in the world [2,3]. ere were 783 patients on renal replacement therapy (RRT) at the end of 2018 [4]. e latest prevalence and incidence of ESKD in the country were 1769 per million population (pmp) and 380 pmp [4], based on a national population of 442,400 [5]. e corresponding prevalence and incidence of transplant in the country were 104 pmp and 9 pmp [4]. Transplant incidence in the country was very low compared to those in developed countries [3] but on par with rates achieved in neighboring Asian countries such as Singapore (18 pmp), Taiwan (13 pmp), Hong Kong (11 pmp), ailand (10 pmp), Philippines (5 pmp), and Malaysia (3 pmp) [2]. Like many of these Asian countries, commercialized transplantations contributed significantly to the overall transplant incidence [6]. Prior to the inception of the local transplant program, patients were sent overseas under full government sponsorship for transplants in the United Kingdom, Singapore, and Malaysia, with the first such case in 1978 [7]. A small number of patients also had kidney transplants by illegal means through commercialization [8].
e national living-related transplant program was established in 2013 with the assistance of foreign expertise. By 2019, the local team was able to perform transplants independently.
Literature on establishing a national transplant program was scarce, especially in the settings of a small, Muslim, and Asian country. Due to the country's small population, there have always been reservations about a program's viability and sustainability due to insufficient demands and expertise retention. Funding and support from experienced international associations were less forthcoming because of the affluent economic status of the country and the presumptive conviction that existing pecuniary resolve could prevail over logistical and expertise restrictions. Small countries also have to grapple with the lack of a recognized training program and the "brain drain" phenomenon with suitable foreign-trained doctors seeking work opportunities overseas [9]. Other small southeast Asian countries like Laos, Cambodia, and Timor Leste [10] have piggybacked on transplant services in neighboring countries due to constraints in setting up their own viable programs. Most Asian countries also have unique barriers that hampered kidney donations, particularly related to uncertain cultural beliefs toward transplant, concerns of posthumous disfigurement, and nonexistent regulation about commercialization [11]. In addition, Muslim countries often had to wrangle with issues like religious permissibility of transplant and the concept of brain death [12]. Over and above that, political will and support in Brunei to initiate this process had been tepid and perfunctory in the past few decades. Moreover, insufficient resources had been invested in research to investigate the cost-effectiveness, efficacy, and merits of a local program. Recent transplant successes were reported in larger Asian countries like Myanmar (1997) [13], Armenia (2002) [14], Nepal (2008) [15], Mongolia (2006) [16], Tajikstan (2009) [17], Uzebekistan (2010) [2018], and Kyrgyzstan (2012) [17]. We drew a lot of optimism and encouragement from these programs, and their outcomes are summarized in Table 1.
Not many clinicians have the privilege and experience to start a transplant program in a country, and the task is not helped by the paucity of data available in the literature. We would, therefore, like to share our experience of setting up a national program in a previously transplant naïve country, especially focusing on overcoming issues like the lack of expertise and facilities and religiocultural and politicallegislative challenges. We will also describe a case series of our patients and present the impact of the program on our services.

Materials and Methods
is case series described in detail the ten transplant cases that were performed in the country. e objectives of the study were to share our experience with phases of the establishment of a kidney transplant program and share our results of the first cases done. e duration of the study was from 2013 to the end of 2019 during which 10 kidney transplants were done. Personal patients' data were obtained through personal accounts from clinicians and recorded data in hospital computerized information system. Data collected included patient demographics and data pertaining to the operations, hospital stays, and outpatient follow-ups. Patient demographics included gender, age, the relationship between patients, year of operation, etiology, medication, blood group, crossmatch results, blood results, and radiographic findings. e operation, inpatient, and follow-up data were also collected. ese results are presented in Tables 1-3. Data for the country were obtained from the Brunei Dialysis and Transplant Registry [4] and unpublished registry data from the Department of Renal Services, Ministry of Health (MOH). e collected data included incidence, prevalence, the total number of patients in each of the modalities, and percentage increments per year. In addition, data were also obtained from previous publications from the department [9] and historical records from the MOH. e data that were collected included the year of the transplant, the country where transplants were performed, and sponsorship details of the transplant. Statistical analysis was done with Excel and Shapiro-Wilk test (p > 0.05), and a visual inspection of the histogram was done for age, operation time, and warm ischemia time. ese data are presented in Tables 4 and 5. Table 2 showed the demographic, operative, and hospital stay details of all our ten transplant recipients. e age of the patient was normally distributed. e mean age of recipients was 30.5 ± 9.3 years. e majority of recipients have an unknown cause of ESKD, and only three showed biopsy evidence of chronic glomerulonephritis. ree out of ten recipients had donor-specific antibodies of which two received desensitization prior to the transplant. Operation time was normally distributed, and the mean operation time was 267.7 ± 43.3 minutes. e mean and median warm ischemic time was 112.9 ± 30.4. One surgical reexploration for infected wound hematoma was required. Hospital stay was not normally distributed, and the median hospital stay was 15 days. Table 3 showed the follow-up details of the recipients. e mean and median discharge creatinine was 106.5 ± 27.5 and 92 mmol/l. All patients had excellent graft function at one year, with all five patients who had two years of followup maintaining stable results. Table 4 showed the demographic, operative, and hospital stay details of all our ten transplant donors. e mean age and median age of donors were 38.6 ± 11.9 and 43 years. e mean hospital stay and median hospital stay were 5.8 ± 3.1 and 6 days. e mean discharge creatinine and median discharge creatinine were 106 ± 28.5 and 104 mmol/l. Table 5 showed the absolute number of patients on renal replacement therapy in Brunei since the inception of the transplant program in 2013. e percentage increments for transplant (+36%) and peritoneal dialysis (PD) (+98%) have outpaced those for HD (+14%) significantly in the last seven years. Table 6 demonstrated the type of kidney transplants that Brunei Nationals had in the past 35 years with a significant downward trend for foreign kidney transplant commercialization, particularly since the inception of the program in 2013. e patient would typically stay abroad for 3-6 months. e absence of a local program meant that many eligible patients have forfeited transplant opportunities because they had not been able to take time away from family and work. Additionally, permanent and temporary residents of the country (which comprised 30% of the population⁵) were not entitled to have government-funded treatment. e vision of an independent program was only able to come to fruition when a local team took the initiative to instigate a pioneering project to start a local transplant program ten years ago.

Discussion
From the outset, the project was divided into four phases. Each phase was meticulously planned, and specific objectives and targets were established and evaluated at regular intervals. e phases are described in Table 6 and subsequent sections.

Phase 1: Gathering Evidence for Feasibility, Sustainability, and Cost-Effectiveness (2009-2012).
e team wanted to answer several key questions that were specific to the needs of the country. A study in 2010 involving 300 participants (approximately 0.1% of the country's eligible population) demonstrated that 78.7% were willing to donate their kidneys if the need arose. 59.7% wanted to have a local program in the country [18]. Another project on the quality of life involving 129 patients confirmed that transplant patients had a better quality of life than HD and PD patients using the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire [19]. A 2012 study, done to assess the graft and patient survival rates of all transplant patients over twenty years (1993 to 2012) [8], showed that the 5-and 10year patient survival of 93.3% and 90.1% were equivalent to rates achieved in most developed countries.
is study demonstrated that the local team has the capacity to look after long-term patients. Lastly, a cost-effectiveness study in 2012 showed that having taken into account the costs of maintenance immunosuppressive treatment, hospital stays, and operation fees, the transplant was more cost-effective than dialysis in the first year. e discrepancy in costings between the two modalities widened considerably after the first year of transplant (which included costs of sending patients overseas). (2012)(2013). Phase 2 was concerned with assembling and empowering a core local team to spearhead the project on various fronts, especially to address the multitude of nonclinical issues including ethics, law, religion, and policy.

Phase 2: Assembling Core Local Team, Compiling Transplant Dossier, and Forging Foreign Affiliations
To assemble a local team, we enlisted three experienced local surgeons-a general surgeon, urologist, and vascular surgeon and deliberately fragmented the transplant surgery into different parts to cater to their existing expertise. e intentions were to have the urologist retrieving the donor's kidney and performing the ureteric anastomosis, the vascular surgeon operating the vascular anastomosis, and the general surgeon anchoring the entire procedure and preparing the transplant vascular bed. As the three surgeons were very experienced, it was felt that they could acquire the required skills with less exposure and training than a freshly trained surgeon performing an entire unfragmented procedure. Numerous studies have shown that experienced general surgeons and urologists can have safe transplant outcomes with limited training exposure [20][21][22]. Additional team members, including a nephrologist and transplant coordinator, were exposed to structured training in the United Kingdom specifically for training on the work-up process, inpatient management, postoperative follow-up, preparing policy papers, and running public workshops to improve public awareness. e team worked with the lawyers from the Attorney General Office in drafting the National Transplant Act, which primarily focused on the prohibition and penalization       [24]. rough continuous dialogue, engagement, and consultation, we were able to convince the local religious authorities to issue a religious decree (fatwa) to legalize transplantation in the country. We also had to assist the MOH in the setting up of the National Transplant Ethics Committee (NTEC) and the National Transplant Committee (NATCOM). NTEC is concerned with evaluating and providing approval for transplants in accordance with the ethical principles laid out by the DOI and NATCOM supports and oversees the operational aspects and provides a recommendation to the MOH for any transplant-related activities.  . ese centers received funding from ISN and TTS to develop and support training links. Transplant Links Community (TLC), a UK charitable organization, has also made commendable efforts in establishing transplant activities in Barbados, Zambia, Jamaica, Bangladesh, Nigeria, Kenya, Ghana, and Trinidad [26]. Mongolia started its program after sending a core team of clinicians to ailand, China, United Kingdom, and Finland to receive intensive training in leading transplant centers [16]. Similarly, Myanmar started its transplant program with the assistance of a joint international team, having sent doctors and nursing staff for proper training abroad [13]. Tapping in on the experience and success of these models, we explored transplant establishments in many countries but eventually decided to forge a working partnership with a Malaysian private hospital that utilized the service of a visiting Australian transplant surgeon.

Phase 3: Experiential Exposure and Strengthening Local Foundation (2012).
is phase was concerned with getting  Journal of Transplantation the team experienced and the local infrastructure and manpower ready for the incipient program. We started sending patients with our medical team to our allied foreign center in 2002 to obtain experiential exposure in surgical, medical, and nursing training. e team stayed with the patient for the duration of the hospital stay abroad until the patient was deemed fit for discharge to Brunei.
With a focus on strengthening local facilities, particular attention was given to environmental infection aversion strategies and ventilation engineering controls to prevent transmission of infections.
rough guidance from our infection control team, we were able to introduce purposebuilt ward facilities and procure consumables to enable the proper use of disinfectants and cleaners and maintenance of medical equipment. We also established new services to the laboratory in preparation for the program like calcineurin inhibitor assays, nuclear medicine scan, bone density scan, and new medications into our formulary. For services that we cannot implement, we sent tests to overseas laboratories in Singapore and Malaysia for crossmatching (CDC, Luminex, and flow cytometry), viral assay, and everolimus assay.
We took into account the varied contributions of members of the interdisciplinary team and their potential impact on transplant outcomes and enhancing living kidney donations. Special efforts were made to conciliate their roles and instill an ethos of shared program ownership. Allied healthcare professionals were given special emphasis in their training through MOH-endorsed workshops, designed to help them integrate and identify with the vision of the team and to facilitate their involvement during the workup and follow-up phases.

Phase 4: Implementation and Consolidation of Transplant Program (2013 to Current).
e first transplant in Brunei was performed on 21/11/2013. A transplant team comprising a physician, a surgeon, and two nurses were flown in from Malaysia and Australia to guide and assist with the procedures. By the third transplant, we had acquired self-sufficiency in many areas and, only the Australian surgeon continued to come to the country at that point. e initial few years of the program were hampered by inadequate staffing and lukewarm interest from the public. As we progressed with a few successful stories (that we had deliberately played out in the press), the public began to register more interest. By the tenth transplant, the team was deemed to have acquired full proficiency in independently performing the transplants and running the program. roughout the course of several transplants, we were able to gradually improve and introduce new services to the program (Table 3), through numerous audits and quality improvement projects. To maintain self-sufficiency and governance, we have an active research unit that had churned out several review articles on transplantation between 2017 and 2019. is was to enable the team to acquaint themselves with transplant literature and keep abreast with the latest transplant developments. Review articles have been published on aspirin usage in kidney transplants [27], hematological cytopenia in kidney transplants [28], use of fluoroquinolone in BK virus nephropathy [29], cigarette smoking in kidney transplants [30], and dual kidney transplantations [31]. Another recent local-driven study in 2017 showed that lack of donors (71%), lack of awareness of the program (21.2%), and unwillingness to take risks (26.5%) were the main barriers to the progress of the program [32].
Our recipient stayed in the hospital with a mean stay of 15 days which is higher than 6-12 reported in the literature [33].
is may reflect extra vigilance in a newly set-up transplant program. One-year patient survival and graft survival were 100%. ree of our patients reached 5 years, and graft and patient survival was 100%. Our results are comparable to those reported in other studies [34]. We did not observe major complications in our donors. Only three have a minor complication. We noticed 20% rejections (2/ 10) which are comparable to those reported of 15-20% from various centers [35]. ese findings reflect the cautious establishment of the new kidney transplant program under the supervision of an experienced and trained transplant surgeon along with the local team and maintaining safety at the same time. We expect that our number will go up in the near future. To garner public interest, we have initiated quarterly seminars with potential future recipients and donors to discuss the risks and benefits of transplantations with a focus on autonomy, benevolence, and nonmaleficence. We put an emphasis on previous transplant recipients and donors conducting the lectures and seminars, specifically addressing local issues like religion, family apprehensions, and the danger of commercialization. We acknowledge few limitations of our study. Our numbers are low. Due to retrospective data collection, we missed important data like cold ischemia time and donor operation time.

Conclusion
e challenges that we faced were unique and covered many nonclinical areas that were not normally encountered by established centers. We had to overcome technical, religious, cultural, political, and legislative barriers to inaugurate our national program. As stated from the outset, the core principles of the program were hinged around the ideals of equity, quality, sustainability, and morality; henceforth, the pace of the fledging program can only be determined by the slow disentanglement of existing limitations to enable the successful fulfillment of these virtues. It has been a truly enriching and gratifying journey, and we hope that our experience can inspire and benefit other new centers, especially in small and developing countries.

Data Availability
e retrospective data used to support the findings of this study are included within the article.