Challenges to establishing and maintaining kidney transplantation programs in developing countries: What are the coping strategies?

Abstract

Kidney transplantation (KT) is the optimal form of renal replacement therapy for patients with end-stage renal diseases. However, this health service is not available to all patients, especially in developing countries. The deceased donor KT programs are mostly absent, and the living donor KT centers are scarce. Single-center studies presenting experiences from developing countries usually report a variety of challenges. This review addresses these challenges and the opposing strategies by reviewing the single-center experiences of developing countries. The financial challenges hamper the infrastructural and material availability, coverage of transplant costs, and qualification of medical personnel. The sociocultural challenges influence organ donation, equity of beneficence, and regular follow-up work. Low interests and motives for transplantation may result from high medicolegal responsibilities in KT practice, intense potential psychosocial burdens, complex qualification protocols, and low productivity or compensation for KT practice. Low medical literacy about KT advantages is prevalent among clinicians, patients, and the public. The inefficient organizational and regulatory oversight is translated into inefficient healthcare systems, absent national KT programs and registries, uncoordinated job descriptions and qualification protocols, uncoordinated on-site investigations with regulatory constraints, and the prevalence of commercial KT practices. These challenges resulted in noticeable differences between KT services in developed and developing countries. The coping strategies can be summarized in two main mechanisms: The first mechanism is maximizing the available resources by increasing the rates of living kidney donation, promoting the expertise of medical personnel, reducing material consumption, and supporting the establishment and maintenance of KT programs. The latter warrants the expansion of the public sector and the elimination of non-ethical KT practices. The second mechanism is recruiting external resources, including financial, experience, and training agreements.

Key Words: Challenges, Coping strategies, Developing countries, Kidney transplantation, Low resources, Single-center

Core Tip: Kidney transplantation (KT) programs in developing countries are confronted with major financial, sociocultural, regulatory, and political challenges. These challenges result in the delayed establishment or absence of efficient KT programs in most developing countries. They warrant finding different mechanisms to oppose these effects. Maximizing the available resources is mandatory, as represented by investing in living donors and interested medical personnel. In addition, recruiting external resources may be implemented by performing agreements with international academic institutes with expertise in KT and charitable organizations or personnel for practical and financial support.

INTRODUCTION

The World Health Organization (WHO) classified chronic kidney disease (CKD) as the 10^th leading cause of death. CKD is a multi-faceted global health problem. On average, it affects 13.4% of the world's population, and 70% of them are expected to be in developing or low-income countries[1,2].

End-stage renal disease (ESRD) is the terminal stage of CKD. Both the incidence and prevalence of ESRD seem to be increasing worldwide, but the rate of increase is far higher in developing countries than in developed countries. This increase is probably fueled by national underdevelopment, a high incidence of communicable and non-communicable diseases, and poverty[3]. The etiology of CKD has various causes, and it is classically attributed to one of the major contributing pathologies, such as diabetes mellitus, hypertension, glomerulonephritis, interstitial nephritis, and congenital disorders[4]. In developing countries, infections and pollution double the risks of ESRD[2,5]. However, the percentages of ESRD of unknown etiology have been increasingly reported through the last decades, especially in developing countries[6].

Treatment of ESRD constitutes a heavy financial burden, especially in developing countries[3,4,7]. Dialysis and kidney transplantation (KT) are the two modalities of treatment of ESRD. They are inexistent or insufficiently available in developing countries. Even when they are available, the financial affordability of these services remains a major challenge due to the absence of national healthcare insurance coverage in many of these countries. When state support is available, it becomes limited by strict criteria designed for the rationing of dialysis and KT. Hence, in the developing world, renal replacement therapy (RRT) is insufficient, and patients may die prematurely[3,8,9]. Of ESRD patients who need RRT, only 10% receive dialysis or KT[10,11]. In the developed world, almost no one dies because of a lack of RRT, dialysis, and KT units. The majority of cases are in the United States, Brazil, and European countries[12,13].

There has been an upsurge in the number of people accessing RRT globally. However, this is not the case in developing countries like the sub-Saharan countries, where it still accounts for less than 5% of the pool of global RRT[3,14,15]. Moreover, ESRD may lead to a nearly 100% death rate in some countries, such as Guyana, South America, where RRT was not an option until the last two decades[16].

Establishing a KT program in low- and middle-income countries (LMICs) while striving to maintain excellent outcomes and adhere to ethical legal standards is often a formidable and difficult task, requiring expertise and support from developed countries. Maintenance of a KT program is also an extremely complex task in countries with limited resources[5,16-18].

CHALLENGES AGAINST KIDNEY TRANSPLANTATION PROGRAMS

National healthcare systems need to acknowledge and understand the barriers and challenges against RRT to enable KT centers to conduct the necessary interventions towards these disparities and optimize outcomes. There are several different barriers to KT. These barriers can be classified in different ways. Relative to the components of the healthcare process, they may be categorized into patient-related, physician (provider)-related, and system-related. However, individual barriers may lie under more than one category or influence the healthcare system at various levels[19,20]. Hence, they may be better classified based on the nature of the barrier.

Financial and economic challenges

The allocation of small budgets for healthcare systems is a common feature among low-resource countries[4,9]. These financial issues are the main challenge to the availability of proper healthcare facilities. Healthcare systems in developing countries are less funded than in developed countries, where the amounts vary from 0.8% to 4% vs 10% to 15% of gross national income, respectively[3,9,21].

Countries in Latin America provide only 3.7% of their gross domestic product (GDP) to healthcare services. They have one of the lowest numbers of health workforce overall. This region has only 16 nephrologists per million population, compared with the minimum target of 20 nephrologists, as recommended by the Latin American Society of Nephrology and Hypertension[2].

Generally, this low expenditure reflects on the availability of RRT modalities. KT seems to be more sensitive to the effects of financial burdens because the latter affects each step of KT. KT costs are pronounced during each step, from preparation to late follow-up[19,22,23]. The financial challenges hamper the establishment and maintenance of KT programs and result in low rates and outcomes of KT due to a lack of the following requirements:

Infrastructure and material requirements for KT units: Infrastructural configurations and logistics are essential requirements for establishing an organ transplantation facility. They are directly based on the economic challenges[17,20,24,25]. In developing countries, it is difficult to construct specific-criteria operative theaters, intensive care units, specific laboratories for immunological workups and pathological studying, services for living and deceased kidney donation, and up-to-the-edge radiological and interventional equipment[20,26-28]. These challenges led to the delayed establishment of KT programs[29-32] or the configuration of inefficient KT programs[17,33-35] in developing countries from different regions[17,34,36] (Table 1).

Table 1 Examples of challenges and shortages in the establishment or maintenance of kidney transplantation programs in studies from developing countries.

Ref.	Country	Shortage
Budiani-Saberi and Mostafa[33], 2011	Egypt	Commercial living donors care
Haddiya et al[24], 2012	Morocco	Lacking human and material resources
Okafor[17], 2016	Nigeria	Absent DDKT
		Lacking human and material resources
Mekdim et al[32], 2017	Ethiopia	Delayed program establishment
		In September 2015, the first Ethiopian KT program was launched in Addis Ababa, in collaboration with the University of Michigan
Davidson et al[5], 2015	South Africa	Materials for immunological tests: HLA and cross-matches
Ahmed et al[31], 2018	Sudan	Materials for immunological tests
		Delayed program establishment: In 2000, it was established with the assistance of visiting teams from England
Naqvi and Rizvi[34], 2018	Pakistan	Organ selling
Guy-Frank et al[16], 2019	Guyana	Unavailability of RRT: HD and KT. Only HD before 2007 with limited sessions (high costs)
		Delayed program establishment; started in 2008 with the assistance of volunteer teams from the United States
Bakr et al[35], 2020	Egypt	Absent DDKT program
Babloyan et al[36], 2021	Armenia	Financial issues for immunosuppressive and antiviral agents
		Irregular deceased KT program; Delayed establishment of LDKT program; launched in 2002, assisted by Belgium, Switzerland, and International Society of Nephrology and Guy’s Hospital (London)
Gadelkareem et al[30], 2023	Egypt	Delayed program establishment
		Incomplete national KT program

DDKT: Deceased donor kidney transplantation; HD: Hemodialysis; HLA: Human leucocytic antigen; KT: Kidney transplantation; LDKT: Living donor kidney transplantation; RRT: Renal replacement therapy.

In South Africa, Davidson et al[5] reported that human leucocytic antigen (HLA) typing was initially limited to class 1 (HLA-A, and -B). However, class 2 HLA typing has only been available since 2013 for HLA-DR and HLA-DQ loci. In addition, Single Luminex antigen testing was not available before 2013 and was only introduced to patients awaiting deceased donor KT (DDKT) on the waiting list after 2013. Moreover, B-cell cross-matches were not available at the time of the study[5]. Also, Ahmed et al[31] reported on the challenges of KT in Sudan and showed that economic constraints were significant factors that influenced the establishment and maintenance of living donor KT (LDKT) practice. They reported that a few KT centers are available with remarkable insufficiencies in medical supplies and materials that sometimes lead to the discontinuation of LDKT practice. They attracted attention to the lack of medical materials as a common challenge for KT in developing countries. Thus, the financial constraints significantly influenced the supply and price of reagents for immunological tests and other blood tests. Hence, they were obliged to send these samples abroad for analysis as out-of-pocket payments by the patients[31].

Coverage of costs of the KT process: Coverage of all KT costs is available only in 31% of countries worldwide. These costs are needed for preparation, surgery, follow-up, medications (immunosuppressive drugs), and treatment of complications[37].

Lower socioeconomic conditions are a significant factor in the lack of access to KT due to delays in seeking care and the costs of medical evaluations, resulting in late referrals and late waitlisting. Receiving a KT represents a huge financial burden on patients and families[38-40]. In addition, KT recipients have a high potential for out-of-pocket extra expenses for other requirements, such as copayments and travel costs. They may be obliged to resolve their personal or family savings. These factors are more prominent burdens for families with lower socioeconomic conditions. In addition, patients may miss medication visits after KT due to these burdens[19].

In many low-resource countries, health insurance policies do not cover all ESRD patients. Sometimes, this deficiency is compensated by a state-funded policy. However, it is still a form of incomplete financial coverage of the costs. In turn, it fuels concerns about out-of-pocket health expenditure, which is a pressing issue and far exceeds half of total health spending in developing countries[41-43].

In Egypt, the out-of-pocket health expenditure policy represents an economic threat to the viability and sustainability of Egyptian households to the degree of catastrophic health expenditure[44,45]. In a study by Fasseeh et al[46], the percent of GDP, which represents the total health expenditure, was almost constant through the last decade, around 5.5%. Out-of-pocket healthcare expenditure contributed to more than 60% of the total healthcare expenditure, followed by government spending through the Ministry of Finance (37%)[46]. This issue has drawn the attention of anthropologists to study it in association with the sociocultural and political views of patients with ESRD[47-51]. Generally, many patients in African countries have to pay for the costs of RRT out-of-pocket, on a continent where widespread poverty is prevalent[3].

In developing countries, many centers may adopt a regimen of no induction immunosuppression, despite the recently introduced induction immunosuppressive agents. This is due to the unavailability and economic issues[36,52,53]. Regarding the maintenance of immunosuppression, patients may not be able to afford the high prices of these drugs. This may result in nonadherence to medication with a high potential for graft loss[54,55].

From the hospital's perspective, an Iranian study of the cost-effectiveness analysis of dialysis and KT showed that the average cost-effectiveness ratio of dialysis was 8.4 times greater than LDKT and 14.07 times higher than DDKT. Hence, the authors recommended increasing kidney donation from both deceased and living resources[56]. In a Brazilian study, savings per patient in DDKT were Brazil Real (BRL) 37000 and BRL 74000 compared to hemodialysis and peritoneal dialysis, respectively. In LDKT, however, savings were even greater: BRL 46000 and BRL 82000 compared to hemodialysis and peritoneal dialysis, respectively. In addition to the advantages in survival and quality-of-life analyses, this benefit characterizes KT as the best clinical and financial alternative in Brazil[57].

However, the costs may be different in other countries, such as Sudan. Elsharif et al[58] found that the annual cost of hemodialysis was United States $ 6847. The total costs of the first and second years of KT were United States $ 14825 and United States $ 10651, respectively. However, the total admission days and absences from work were fewer in the KT group, rendering hemodialysis less expensive than KT[58].

Training and promotion of the expertise of medical personnel: Promoting training in KT is a great challenge for the practice of KT. It is usually accomplished through separate training courses, workshops, and specified corners or quotes for the training of healthcare personnel in scientific meetings or congresses. In addition, training grants or stays in centers mastering KT may be offered. However, its financial coverage is creating a problem in developing countries. Despite the complex coordination efforts and recruiting rules, support is mandatory from scientific societies, healthcare administration, and pharmaceutical companies[59].

Specifically, the vascular anastomoses of a KT are time-sensitive, and the inexperience of young surgeons or urologists can negatively impact outcomes. Hence, training in KT surgery and medicine is fundamental. Simulating models are used to teach surgical anatomy and operative skills in KT surgery. Training programs using these models are mostly available from centers with a long history and expertise in KT[60-62]. These centers are mostly from developed countries with high costs. However, novel models have been introduced to reduce the cost issues[59,61]. On the other hand, many experiments in developing countries reported the presence of deficient numbers of nephrologists with expertise in KT. The African countries, especially those in the sub-Saharan region, do not have trained personnel for KT[26].

Sociocultural challenges

Socioeconomic and sociocultural challenges are overlapping problems and influence all aspects of the KT process. This spectrum is a mixture of religious, traditional, and ideological challenges[19,51]. These challenges influence the establishment of a KT program through the following axes:

Effects on organ donation: Kidney donation is a principal item in any KT program. This resource is highly sensitive to religious instructions and traditional beliefs. Hence, the challenges are viewed through:

(1) Religion and science: The justification of organ donation is based on a balanced interpretation of scientific facts and religious instructions. Religious reasons may be the motivating factor for organ donation among the population, but at the same time, they may be the reason for refusing to donate organs among others. However, knowing the agreements between religion and law towards encouraging organ donation, 76% of the participants in the relevant studies would donate their organs[51,63].

In Egypt, although patients with ESRD have the information that any individual can lead a normal life with one kidney, they may be reluctant to allow a family member to be a kidney donor. They may feel guilty that they will receive an unrepayable favor from a relative. Also, they are worried about the potentially harmful effects of donating an organ to a sibling, spouse, or brother. Generally, those patients express their concerns about the safety of the donor based on religious instructions, such as asserting that the body, as a trust from God, was created in God’s perfect wisdom[48,51].

And (2) Traditions: Beliefs such as humiliation of the body or effects on fecundity may discourage organ donation. In a study from Syria, the refusal to disfigure a dead body by removing an organ represented the most common reason to refuse organ donation[63]. Anthropological studies have investigated these traditional beliefs about human body dignity and the political effects on biomedical decisions[48,51].

The delayed establishment of DDKT programs in most developing countries is a clear example of the effect of sociocultural factors on KT[4]. Anthropological analysis has been carried out to investigate the causes of the delayed establishment of the DDKT program in developing countries like Egypt. Many sociocultural factors were discussed, including religion, ethical violations, distrusted healthcare system, and the effect of the media and movies that circulate bad stories about organ transplantation[47,49,50].

Effects on equity of benefits and risks: Gender and age rates show discrepancies in the corresponding rates of donors and recipients. Females are major contributors to kidney donation but are minor beneficiaries as KT recipients[30]. Although these discrepancies are known worldwide, they are rich subjects for the anthropological studies that have tried to analyze their root causes in developing countries. These studies addressed the social roots of the female gender role in the protection of the family. They analyzed the social and physiological concepts that put the mother or the wife in the position of the person who should do everything for the family without waiting for rewards from the other members of the family[47,64].

The balance between the rates of related and unrelated LDKTs in developing countries is another sociocultural challenge. Unrelated LDKT seems to occur more commonly in the private sector than in the governmental sector[35,65]. There is no doubt that social factors are not the only contributors to the increasing unrelated LDKT in the private sector, where many organizational and legislative issues underlie this imbalance[66,67].

Effects on the regular follow-up: Low sociocultural standards are associated with improper post-KT management and outcomes. The latter may be due to noncompliance, unhealthy hygiene, misunderstanding of instructions, etc. Noncompliance with medication is common among KT recipients[68,69]. It may result in more than 35% of documented graft losses and failures. Specifically, compliance with immunosuppressive medications and lifestyle modifications is essential for the maintenance of a successful KT[68,70].

Patients with non-adherence to follow-up visits have 1.5 times the risk of acute rejection. In addition, combined medication and appointment non-adherence result in a higher risk of graft loss compared to those who have individual non-adherence[69-71]. The reasons for noncompliance include low financial resources, a lack of perception of the severity of consequences, health and religious beliefs, a lack of social support, and medication complexity or adverse effects[69,72].

Low interests and fading motives for kidney transplantation

Owing to the complex challenges of maintaining an integrated healthcare system in developing countries[5,20], there are common attitudes to prioritize the management of patients with other common comorbidities over the introduction of advanced surgeries such as KT. These attitudes might promote the shift of focus of the healthcare system and doctors away from KT. Hence, there are limited numbers of KT physicians and surgeons in those countries, especially in the public or governmental sector. Significant numbers of physicians and surgeons shift to the private sector, immigrate to high-income countries, or drop the profession, seeking high financial rewards. It has been reported that more than 60% of healthcare services are provided via the private healthcare sector[73]. This might be attributed to:

The high medicolegal responsibilities: KT centers, including the personnel, are under regular monitoring and review by different agencies to maintain high performance and provide proper care for patients accessing KT. Then, the complications are highly scrutinized, and strict actions may be taken against transplant centers with below-expected outcomes[5,20,74].

Intense psychosocial burdens under the current healthcare systems: Generally, healthcare systems in developing countries are commonly shared between the governmental and private sectors. This construction represents a license for clinicians to work in both sectors, with competitive attitudes towards the financial rewards that are more prominent in the private sector[73].

Recipients of KT express their perception of KT outcomes in different ways based on their health status. Disproportionally, they may rank graft loss worse than death[75,76]. The perception of the outcomes is markedly related to the emotional status of those patients[77]. Also, they may be exaggerated by financial issues, such as in paid or private sector practice and improper healthcare systems[50,73]. With the initial practice of KT in developing countries, there are usually remarkable psychosocial and emotional challenges. Low sociocultural levels may be associated with high positive expectations that formulate KT as a cure. This narrow-capacity expectation makes the patients and their families find it difficult to accept any major complications that may threaten the graft or the patient's survival. The most particular event is the graft failure and return of the patient to dialysis. This highlights the importance of pre-KT counseling and post-KT comprehensive follow-up. The intensity of these emotional damages usually does not match the realities of KT as a process of therapy with a large scale of complications[18,77].

From personal experiences, lacking standards of the job description, medical literacy among urologists and other physicians about KT outcomes, and selfish individual expectations of KT physicians and surgeons create non-scientific competition among the personnel. All these issues are discouraging factors for the work in peaceful teamwork, which is a mere requirement for any KT program. These challenges influence the outcome of the program and patient safety. Hence, they warrant the presence of a competent program medical director. The latter should have a well-defined role and high skills to manage all the administrative, regulatory, financial, and educational aspects of a KT program[78].

Limited number of centers for KT: Lack of personnel is a major limiting factor in providing RRT in developing countries. In Africa, only Mauritius has 5 or more nephrologists per million population. About 80% of the total number of nephrologists in Africa reside in six countries: Algeria, Egypt, Mauritius, Morocco, Tunisia, and Libya[3,79]. KT activity is still very low in sub-Saharan countries, and graft and patient survival figures are also lower than reported figures from developed economies. Active KT programs are available in only six countries in the sub-Saharan region[5].

Low productivity and compensation: In comparison to general clinicians, transplant clinicians spend significant time on secondary activities such as medical chart reviews, administrative committee meetings, community coordination, and travel to remote outreach clinics. Although these activities are essential to multidisciplinary care and regulatory requirements, financial compensation may not be sufficient, even in developing countries. This pattern leads to low job satisfaction and threatens to sustain a sufficient KT workforce[80].

In developing countries, these issues are more prominent and are a major cause of the emigration of KT clinicians and a significant reduction in their numbers. This is part of a general phenomenon in developing countries[73].

Complex qualifications and work protocols: KT is classified as an advanced surgical procedure, which warrants the availability of high surgical skills and expertise. The time of the vascular anastomoses of KT and the warm ischemia time are significant indicators. They have been shown to have a direct relationship with the development of important negative outcomes such as delayed graft function, graft loss, and mortality. The regular training rounds or rotations of surgery are mostly insufficient to provide the required levels of experience for young transplant surgeons or urologists[61,81,82]. This complexity of KT procedures may indicate further training programs for practicing with self-confidence and expertise sufficient to guarantee surgical safety for the donors and recipients. Highly skilled surgeons are recommended for these surgeries[61,83].

Low medical literacy about the advantages of KT for ESRD patients

General physicians and nephrologists: There are low levels of sound medical information about the advantages of KT over dialysis, early referral to KT centers, and patient counseling. Differences in the attitudes and perceptions of nephrologists influence their decision to refer patients for KT. Hence, a lack of or late referrals by nephrologists to KT centers represents a barrier to KT[19].

ESRD patients: Those patients may be scheduled for regular dialysis without having a chance to know whether KT is possible to be performed in their locality.

A lower education level is a barrier to KT. College graduates experience three times higher rates of being waitlisted and receiving KT when compared with patients without a high school degree. Lower education levels may be associated with a higher rate of allograft loss. However, they might not be modifiable during the assessment of patients for KT. Physicians should recognize this challenge as a potential barrier to KT[19].

Generally, a lack of patients' knowledge regarding KT is a barrier to access to KT, even in countries that have free universal coverage of healthcare[84]. Many studies have reported that patients with ESRD on dialysis have an overall negative attitude towards KT. The reasons for the negative attitude seem to be related to the lack of knowledge and the underlying depression of the disease itself. The absence of trust in the healthcare system has been reported as an important factor promoting unwillingness to have KT[19,85-87].

Public: They represent the pool of potential kidney donors. The majority of the public has no sufficient knowledge about KT. Many studies from different countries and regions showed low knowledge about KT and organ donation among the public[86,88,89]. In a study by Mohamed et al[89] about the knowledge and attitudes toward organ donation and transplantation in Minia governorate, Egypt, only 28% of the students had good knowledge, and 32% of them had poor knowledge of all the tested items. Additionally, 34% of the students had a negative attitude towards organ donation and transplantation[89]. Similarly, a study from Oman included 2125 students and showed that only 34.1% had good knowledge about organ donation and more than 70% had a low attitude[88].

In a questionnaire-based study from Egypt by Afifi et al[90], 56% of the participants were aware of the presence of organ donation programs in Egypt. This awareness percentage was not paralleled by a significant improvement in the scores of knowledge about organ donation. However, this score was significantly associated with the educational level. Also, attitudes towards organ donation were significantly improved by the education level[90].

In addition, a study from Syria about the knowledge and attitudes towards deceased organ donation showed that more positive attitudes were found in those with better knowledge about brain death. However, these attitudes may not translate into more willingness to donate organs[63].

Organizational and regulatory challenges

Inefficient healthcare systems: The health system includes organizations and people who carry out actions to promote, restore, or maintain the health of populations. A health system includes leadership and governance, health information systems, health financing, health workforce, medicinal products, vaccines, and technologies, and the delivery of health services[2]. Proper management delivers satisfactory outcomes regarding the healthcare of the target population. However, improper distribution of resources, low rewards, absence of safety, and financial deficiencies discourage proper outcomes. KT is a sensitive topic that warrants a proper and integrated healthcare system. The absence of the latter results in the inability to establish and maintain national KT programs[73].

Lack of national programs and registries: Globally, only 57% of world countries had a KT registry[37]. In the Arab countries, despite the early start of KT practice in some of these countries, there are still many of them struggling with various barriers to establishing national KT programs[91].

(1) Absence of registries for living donors (LDs): They are the main source of graft in developing countries, representing 80% to 100%. However, these rates are far lower than those in developed countries[4,37]. For example, about 600–650 LDKTs are performed in North African countries per year; most are in Egypt[4]. In the Middle East region, LDKT is the main form of KT also[92].

And (2) Absence of DDKT programs: Despite the established legislation for DDKT in many countries, such type of KT is mostly absent on the practical level in African countries[4,93]. Sociocultural and economic challenges back this defect. Egypt is one of the African countries that have tried to establish a DDKT program, but it is still a hard task confronted with sociocultural and economic burdens. These burdens represented a significant challenge for KT in Egypt[4,35]. South Africa remains the only country in Africa that has a DDKT program, representing the major source of grafts. However, this program has many challenges, such as the human immunodeficiency virus and tuberculosis[5,15]. The latter led to a decrease in the number of DDKTs in the last few years[5,93,94].

In India, organ donation centers are at a very primordial stage. They are almost absent in the North-Eastern region. It seems that policymakers and other stakeholders in a big country like India underestimate the magnitude of the benefits of KT programs to ESRD patients. They implement insufficient national policies to emphasize urgent attention to organ transplantation[95].

Lacking management of living kidney donors: Living kidney donation is more prevalent than deceased donation in developing countries. This practice warrants a proper healthcare system with strict legislation to prevent non-ethical threats. This sparks many medical and ethical issues regarding all the steps, such as allocation, registry, and healthcare after donation. If follow-up care for LDs is still improper in countries with advanced KT systems based on altruistic donation, it is largely absent in countries where financial issues control organ donation. Post-donation healthcare is mandatory not only for altruistic LDs but also for victims of organ trafficking. Those donors are often not candidates for a donation and are subject to poor surgical practices. Such follow-up is essential not only as a basic right but also as an important administrative step to regain public trust in transplants against propagating commercialism[33,92].

(1) Absence of allocation systems: Most developing countries have inefficient KT programs. This means the absence of well-integrated patient referral and organ allocation systems. The most important part of the KT program is the presence of DDKT practice because it warrants establishing an allocation system. Hence, the absence of DDKT in most developing countries may be the main factor of lacking allocation policies. One of the clear examples is the KT program of Egypt, which has been dependent on LDKT practice for about 50 years. Despite the presence of a large-volume KT center like Mansoura Urology and Nephrology Center, there is a clear absence of DDKT[35]. In the absence of a national KT program and an inefficient healthcare system, the LDKT practice may be expanded, resulting in uncontrolled KT practice in the private sector. The latter is dependent on individual referrals of the patients.

Other countries tried to find ways to establish a national comprehensive KT program, such as the Iranian Model[96], the private-public partnership model in Pakistan[7], and the KT program of South Africa[5]. However, all these models are not ideal alternatives to a complete program with both DDKT and LDKT divisions. Specifically, the absence of integrated waitlisting and donor allocation policies is a hallmark of lacking systems, even in countries with early beginning KT practice[5,33-35,37].

And (2) Absence of medical registration systems in most RRT centers: In several African countries, nephrologists have attempted to establish registries, but these attempts have not successfully resulted in regular registries. Registries can be traced only in a few African countries, such as South Africa, Egypt, Tunisia, and Ghana, that have regularly published national data on the provision of RRT[4,97,98]. Unfortunately, this shortage led to the absence of or a lack of accurate statistical references for tracing the outcomes and complications[3,4,21]. There is no doubt that these delays in establishing nationwide registries are underlined by the low economic status of most African countries. However, the hope may still be preserved with the novel directions of performing regional or collaborative registries by scientific associations in parallel to the old registries in other regions, such as the European Renal Association-European Dialysis and Transplant Association Registry[3,98].

Uncoordinated job descriptions and qualification protocols for clinicians in different disciplines of the KT team: A multidisciplinary team in KT is a basic requirement for building an efficient program. This warrants an integrated healthcare system and a well-qualified workforce[20]. On configuring a KT team, however, there may be significant difficulties in choosing suitable personnel, such as clinicians, nurses, coordinators, etc. This promotes improperly configured teams and the inclusion of inefficient or unqualified personnel. Despite the clear legislative materials, the absence of precise qualification strategies for the inclusion of personnel (surgeons, nephrologists, or others) in KT teams leads to uncoordinated work and distracts the team from the proper work. In turn, unfavorable outcomes and disputes arise among the personnel within the same team. These disputes may be exaggerated by the individual interests of the team members and generate an unsafe environment for all components of the team and even the whole program. Unless there is proper legislation, a coordinated healthcare system, and oversight regulations, as mentioned above, physicians and surgeons may quit KT programs. The reasons may be bad outcomes, unsuitable work standards, and the absence of safety for the donors, patients, and personnel[20,51].

Uncoordinated on-site guidance and regulatory protocols: In developing countries, if we investigate the personnel in institutes seeking the establishment of KT units about whether they want to participate in such a complex task, there will be positive answers based on their initial enthusiasm. However, this enthusiasm is not sufficient to build or establish a good program. The start is always with LDKT programs because they are easier than DDKT programs[20].

In Egypt, well-designed legislative and scoring schedules are mostly available from the Egyptian Supreme Committee of Organ Transplantation[30,83]. In addition, public institutes and university hospitals are now available in each governorate, and basic resources are mostly available to establish LDKT units or centers. This may refer to the availability of physicians and surgeons at these hospitals being higher than at other hospitals in the governmental sector. However, there are still insufficient numbers of KT centers and an absent DDKT program[30,35].

Then, the question is: What is the problem? Away from the economic and sociocultural factors, the coordination between the supervising healthcare system and the institutional workforce may be missing. In other words, the guidance to implement well-designed legislative rules and schedules on-site is absent. Hence, the description, justification, interpretation, and validation of protocols and mechanisms should be implemented on-site for the establishment of a new KT unit. Detailed events from our experience in establishing a LDKT program were the need to facilitate communications between the supervising authorized personnel and the on-practice personnel. In addition, the adaptation of the old infrastructure and administrative procedures of the health facilities to the new standards of KT requirements, which were mostly not suitable, was another detail to be recognized. Of course, the economic and financial issues have prevented the creation of completely novel infrastructure and procedures. Strict protocols and pure electronic systems were mostly different from the old ones, and their changes were clear examples of the demanding efforts that backboned establishing a LDKT program in Upper Egypt, continuing for the eighth year with promising outcomes[29,30].

Prevalent commercial and paid KT practices in developing countries: There is a universal consensus that ethical principles are mandatory to establish and maintain organ transplantation. In addition, the poor resources and social minorities of some populations should not be in favor of others who could pay[20,34].

North Africa hosts six countries: The Western Desert Republic, Morocco, Algeria, Tunisia, Libya, and Egypt, from west to east. Some definitions also include Mauritania and/or Sudan. KT is mostly performed using LDs, and a significant proportion of KT is performed by unrelated LDs, particularly in Egypt, which creates an ethical debate[4]. Hence, Egypt has become one of these countries stigmatized by KT commercial activities[50,51,66]. The official authorities have carried out many interventions to overcome this stigma and overcome these activities[99,100]. The cause may be attributed to low-quality and slow-flowing KT workups in public or governmental centers, low salaries of KT clinicians and other personnel, loss of trust in the public healthcare system, and socioeconomic factors such as poverty and illiteracy[50,73].

In developed countries, cardiovascular disorders represent the major cause of death among KT recipients. Infections represent a significant factor influencing the outcomes of KT. They are a major problem in developing countries, including viral (such as cytomegalovirus, hepatitis C virus, and HIV), bacterial, and fungal infections[5].

All the previous challenges are contributors to the reduced total outcomes of KT. Unfortunately, these challenges have negative feedback on the whole process: The healthcare system, KT teams, and patients[21,37].

COPING STRATEGIES

Maximization of the available local resources

Increasing the rate of living kidney donation: In developing countries, LDs represent the major resource for grafts. Hence, they represent an expandable source to increase the number of LDKT in these countries[13,20]. There are many mechanisms for maximizing the rate of living kidney donation:

(1) Relaxing the age limits of the related kidney donors: The youngest age for living kidney donation is mostly controversial and ranges between 18 and 21 years. Accordingly, the legal age of consent in most countries is 21 years[101,102]. The debate is usually to avoid the longer cumulative lifetime risk of developing conditions that predispose them to CKD, such as diabetes, hypertension, and obesity. A normal initial LD evaluation is not a guarantee against the potential lifetime risk of ESRD[103]. In Egypt, kidney donation in the age range of 18–21 years is often considered a relative contraindication, where it may be allowed only when the donation is to one of the parents. Also, the opposite is correct: Relaxing the upper limit from 50 to 60 years, allowing parents with an age between 50 and 60 years to donate to their sons or daughters. These relaxations of the age limits expand the age range for donation between the donors and recipients within the family from 21–50 years to 18–60 years. This suggestion may need official approval by the Egyptian legislative authorities.

(2) Donor exchange programs: These strategies are very effective and less costly for the resolution of the immunological barriers. Despite the low costs and LDKT as the main policy, their implementation in developing countries is still significantly low. In Egypt, for example, LDKT has been practiced for about 50 years, but the programs of paired kidney donation have not been implemented. However, the KT community has become more vigilant about the need for these strategies. The rate of decline of willing related potential LDs is more than 80%, leaving major proportions of potential recipients on long-term dialysis or for death[30]. Hence, there are strong recommendations for the introduction of paired kidney donation to the Egyptian LDKT program to reduce the decline of potential LDs[30,100,104].

And (3) Healthcare education programs for the public: Improving education about living kidney donation for both potential recipients and LDs is a promising strategy for increasing rates of LDKT. It helps overcome the improper knowledge and socioeconomic barriers to LDKT[105]. There are many interventions to improve the rate of kidney donation, such as sending a donation letter[106]. Education programs should be tailored to the needs and sociocultural characteristics of the potential donor and recipient populations[107,108].

Investing in medical personnel: Although the number of experienced personnel is small, the potential number of personnel may be high in developing countries. To motivate recruiting personnel from the national healthcare workforce to participate in KT programs, the following strategies may be beneficial:

(1) Increasing the financial compensation of organ transplant teams: The low salaries or rewards should be increased for medical personnel, specifically those involved in organ transplantation. There are considerable numbers of studies that have searched for the effects and mechanisms of overcoming the financial causes of the shortage of practitioners in developing countries[73].

(2) Well-configured plans for regular training, education, and qualification: Many studies have studied the effect of healthcare education on patients' knowledge about KT. They showed that increasing patient knowledge leads to an increased willingness to be evaluated for KT and eventually receive it[109-111]. Patients with sufficient knowledge about the improved quality of life after KT have five times more willingness to receive KT compared with those with insufficient knowledge[112]. Healthcare education is recommended to reduce the high rates of non-compliance with medications and lifestyle modifications[68].

On the other hand, education of medical personnel in primary healthcare facilities is essential to encourage timely referral to nephrology care and KT centers[19]. Generally, the power of youth represents the versatility of developing countries, such as those in the Middle East. This principle can be applied to the field of organ transplantation, including KT. Hence, the perspectives of young transplant professionals are very important for improving the performance of KT programs in developing countries. On the other hand, the challenges of KT would be transferred to young professionals who are pursuing a career in transplantation. These challenges are related to KT education, training, and the healthcare systems. Scientific societies related to KT represent the school for training and the transfer of the wisdom of the leaders to the young professionals. For example, the Middle East Society for Organ Transplantation Region proposed a platform to mitigate these challenges and increase the recruitment and engagement of young physicians and surgeons in the KT practice[113,114]. Webinars represent an electronic education and teaching approach in many KT societies.

Several studies reported the unavailability of nephrologists and surgeons for building a KT program. To establish their KT programs, in-charge personnel in these countries allowed the training of local surgeons in external institutes or hospitals[16,31,32]. For example, Guyanese surgeons completed fellowship training in abdominal organ transplantation outside the country before establishing the KT program in Guyana. Volunteer KT teams helped in the transition from external to local surgeons. After that, several KTs were performed in collaboration[16].

And (3) Reduction of non-medical and regulatory duties for the medical workforce: Reducing the collateral issues that may distract the teams or exhaust their power is another factor that may help preserve the workforce's duties. In developing countries, medical personnel may be hired to manage non-medical activities, such as investigating regulations and providing logistic duties. These activities should be reserved for specified paramedical personnel[5,20,26].

Reduction of the consumption of medical supplies and medications: KT indicates a long list of medications, which are mainly headed by immunological workups, surgical procedures, and immunosuppressive agents. The latter is a main contributor to the high costs of KT. Decreasing the costs of KT warrants decreasing the consumption of medical supplies and medications whenever possible, but without adding risks to the recipients or donors[20].

Reducing the medication amount mostly reduces the total cost of medications. In turn, the reduction in maintenance therapy helps reduce these costs. Reduction of the doses of tacrolimus may be accomplished by using drug enhancers such as calcium channel blockers and ketoconazole[115]. In addition, reducing the amount of medication may improve or prevent non-compliance[116].

Decreasing the consumption of materials in comprehensive national programs was presented in Pakistan. For example, a reusable dialyzer and the use of generic drugs provided an annual saving of United States $ 5.8 million[25].

Promotion of KT programs and system: (1) Completion and maintenance of national KT programs: Integrated kidney care is a recent strategy to optimize the care provided to patients with CKD. It is to develop synergistic links between the different options of RRT, including conservative treatment and preventive care for people with or at risk for milder forms of CKD[28]. This strategy warrants well-configured registries and consistent guidelines[20].

Tonelli et al[28] suggested an infographic framework to support decision-makers in establishing and implementing integrated kidney care programs in LMICs. They represented the components of the program proportional to the associated health gains, clarifying the priority for investment. Generally, interventions that control or prevent the progression of early stages of CKD to ESRD should be the highest priority. These interventions aim at treating primary kidney disease. Within the modalities of RRT, KT should be the highest priority but HD should be the lowest priority[28]. Prioritization of KT over dialysis modalities is attributed to the best clinical outcomes at the lowest cost[116,117]. Regarding the countries that choose to offer RRT, a mix of all three modalities of RRT will often be most appropriate[28].

(2) Expansion of KT programs in the public healthcare sector: Related LDKT is more commonly performed in governmental KT centers[35]. However, unrelated LDKT is more commonly performed in the private sector[65]. Hence, control of the private sector will significantly decrease legislative and ethical violations. The private KT sector should be controlled by standardizing the prices of healthcare services, applying legislative standards, and limiting the profit margin from organ transplantation[20].

Major kidney and liver transplantation centers of the public sector in developing countries could be strengthened to become the flagships in promoting the clean image of transplantation. This should be a model that people can see as an example of service being fair, transparent, and equitable for all who need it. This may be achieved by increasing the financial value of the state-funded cases. In turn, it mandates an extra national financial burden[34]. In Pakistan, a model named Free of Cost was implemented to increase access to RRT and KT for all ESRD patients with a life-long follow-up and medications. This model represents a form of a national donation to fund RRT services by both the public and governmental partners based on the concept of community-government partnership[25].

(3) Ethical control of living kidney donation: Control of the ethical violation issues of KT is a must to improve the performance and outcomes of any KT program, including the prevention of commercial kidney donation[50,20]. In the absence of public or private commitments to the healthcare of commercial LDs, some organizations may supervise and control such practices. For example, the Coalition for Organ-Failure Solutions (COFS) conducts outreach programs to identify victims of organ trafficking, assess their consequences, and arrange support services. In Egypt, COFS had provisions about the follow-up care of commercial LDs, appropriateness as an ingredient for advancing regulation proposals, and movements to end organ trafficking[33].

And (4) Approaches to overcome paid kidney donation: New approaches to mitigate the effects of commercial KT have been proposed, such as the private-public partnership. The latter, underpinned by transparency, public audit, and accountability, is warranted for effective KT services in developing countries[7].

Governmental reimbursement programs for living kidney donations are more prevalent approaches for legitimizing the payment for organ donation. However, the type of reimbursement programs and the ethical dimension of each type currently represent concerns that warrant studying[118,119].

In a unique but debatable model, Iran introduced a government-controlled market for paid kidney donation. This model, known as the Iranian Model, is the only one of its type in the world, which resulted in the elimination of the waiting lists for the LDKT Iranian program. Iranian researchers have continuously advocated the benefits of this model[96]. However, this model is still not spreading outside Iran, with continuous counter-criticism from the other researchers. It has largely been known that Iranian researchers are often prevented from presenting their model at international transplant conferences and publishing it in transplant journals. However, the late publication of data about this program seems to be positively perceived, with some caution as a disclosure of the vagueness and ambiguity of the Iranian Model[120].

Recruiting external resources

Organizational support from developed countries: These intercontinental forms of assistance and supervision by KT professionals usually take different forms from individuals, international societies, or groups such as the Transplant Links Community (TLC). They come with a sense of responsibility towards the patients with ESRD in low-resource countries. Then, they should have the enthusiasm to lobby and act to change the prevailing unfavorable shortage of services to better levels of establishing sustainable programs of RRT[26]. These forms of external resources can be reviewed under the following headings:

(1) International agreements and cooperation protocols with expert centers: In this form of utilization of external resources, agreements can be held between certain centers in developing countries and developed countries. Also, the agreement may be with volunteer persons, such as transplant surgeons. Examples of this form include an agreement between volunteer KT surgeons from the United States and the Guyanese Ministry of Health to establish a national KT program in Guyana. Funding for this project was based on the US-based Guyanese Americans and the Subraj Foundation[16].

Another example is our experience, represented by an agreement between the Assiut KT Unit, representing Assiut University, Egypt, and the Urology and KT Department, Martin Luther University, Germany[30].

And (2) International charitable organizations supporting KT: Charitable donations fund activities represent an ideal form of external resources that are directly participating in establishing and maintaining KT practice in developing countries. The TLC is a clear example of organizational promotion for the national programs of KT. TLC was founded in 2006 and registered as a United Kingdom charity in 2007[26,121]. The aim is to mentor units of KT in developing countries and to drive skill transfer through the performance of LDKT. The ultimate goal is the program's sustainability.

However, to achieve these goals, the mentoring of these units or centers must consider all relevant aspects of development. In addition, it may take a prolonged period to wean these units from direct external assistance. On the other hand, political support and financial underpinnings are fundamental factors in the sustainability of these programs. These intercontinental forms of assistance and supervision by KT professionals from the developed world, as individuals, international societies, or groups such as TLC, come as an indicator of the responsibility of the developed world to help the developing world improve KT services[26].

International individual financial donations: These forms are not common, and personal relations usually play a vital role in recruiting them.

Efficacy of coping strategies

As reviewed above, the challenges to establishing and maintaining efficient KT programs in developing countries are various, multifaceted, and overlapping with each other. However, the financial challenges are the most prevalent ones and underlie most other challenges. Although the challenges of KT programs may differ by the WHO regions, the financial challenges are common characteristics in most developing countries and regions[121-124]. In parallel, recruiting financial resources and reducing consumption are the most adopted coping strategies. These strategies helped resolve significant burdens in countries such as Egypt, where out-of-pocket expenditures of healthcare are the major approach. KT may not be far different from other healthcare services, because many KT centers recruit financial donations[44,46].

Another characteristic is the prevalence of sociocultural challenges in the Eastern Mediterranean and South-East Asian Regions[121,125]. This represented a complex challenge in many countries, due to the strong association between religious instructions and ethical considerations of organ transplantations. An extensive study of sociocultural issues has been conducted, addressing many factors, such as the levels of poverty, religious interpretations, and political strategies[47-51]. For example, the stakeholders of healthcare policies in Egypt have achieved significant progress towards a national KT program. In the last decades, they established a legislative base, constructed national guidelines, planned the Universal Health Insurance Program, and implemented strict steps against commercial KT activities[33,46,83,100,102]. Despite its slow pattern, we witness the progress of the KT program in Egypt through the increased number of KT centers and serious steps of a national KT program[30,122].

Different regions of the WHO may show some variabilities in the prioritization of the challenges and the corresponding coping strategies[125,126]. In most regions, the financial and sociocultural challenges are the most demanding and persistent ones (Table 2). However, recruiting external assistance and qualification of KT physicians and surgeons by supervising intuitions or volunteer individuals is a common effective coping strategy among the different WHO regions[121-125] (Table 2). In all regions[121-125], many successful examples have been reported[16,18,26,30].

Table 2 Distribution of the challenges to the establishment and maintenance of kidney transplantation programs in different regions of the World Health Organization.

Regions	Challenges ordered relative to significance in each region	Proposed coping strategies
Regions	Challenges ordered relative to significance in each region	Proposed coping strategies
AFR	Financial challenges: Lacking human and material resources[5,17,32], delayed program establishment, and absent DDKT[5,17]	To recruit external resources: Training and qualification of KT physicians and surgeons[18,32], out-of-pocket payment[17,31]
	Sociocultural challenges: Religious and traditional beliefs[17,123]	Insignificant workups[17,123]
AMR	Lacking health workforce: Low number of nephrologists[16]	To recruit external resources: Collaboration with expert centers for training[2]
	Financial challenges: Delayed program establishment[16]	To recruit external resources: Financial support by charitable foundations and public-private partnerships[16], the model of the Integrated Healthcare program[20], and reduction of consumption[20,114]
SEAR & WPR	Lacking legislations: Commercial KT and transplant tourism[125]	Activation of local legislation and Istanbul Declaration[125,126]
	Lacking medical personnel[125]	Overseas KT under governmental supervision[125,126]
	Financial challenges[125]	National insurance coverage programs[125]
	Sociocultural challenges: Lacking DDKT[125]	Increasing governmental services and education programs[125,126]
EUR	Financial issues: Delayed establishment of LDKT program[36]	To recruit external resources: Training and qualification of KT physicians and surgeons[36]
	Political policies and consequences[36]	Establishing a national program[36]
EMR	Commercial and organ selling practices [33,34,66,67]	Establishing effective legislation[20,98], governmental reimbursement[117,118], and creation of novel models: Private-public partnership[7] and Iranian Model[119]
	Sociocultural challenges: Religious and traditional beliefs[122]	Anthropologic studies[47-51], education programs
	Organizational and administrative insufficiencies: Delayed or incomplete establishment of the national KT program[30,35]	National and intercontinental registries[96,97]. Establishing effective legislation[20]
	Financial challenges: Lacking human and material resources[24,31]	To recruit external resources: Training and qualification of KT physicians and surgeons[31]. Reduction of consumption[20,14]

AFR: African region; AMR: Region of the Americas; DDKT: Deceased donor kidney transplantation; KT: Kidney transplantation; LDKT: Living donor kidney transplantation; SEAR: South-East Asian Region; EUR: European region; EMR: Eastern Mediterranean Region; WPR: Western pacific region.

CONCLUSION

The major categories of challenges to KT programs in developing countries include financial, sociocultural, regulatory, and organizational challenges. Delayed establishment or absence of efficient KT programs is the main feature in most developing countries, especially in the African Region of the WHO. Their sub-categories are overlapping and multifaceted. As these challenges may differ among the WHO regions, they warrant finding different coping mechanisms. Maximizing the available resources is mandatory, as represented by investing in LDs, qualification of local medical personnel, and activation of the local and international legislative bases. The latter is mandatory to overcome commercialism and tourism in KT practices. In addition, recruiting external resources is another major coping policy. It may be implemented by performing agreements with international academic institutes with expertise in KT and charitable organizations with funding and training capacities. In addition, individual agreements with volunteer physicians and surgeons from developed countries may be an alternative approach. Implemented coping strategies showed variable success rates. However, increasing living kidney donation is a good local resource, and agreements with centers in developed countries are a common successful strategy for the qualification of the medical personnel for establishing and maintaining successful KT programs. Many efforts are still needed to overcome these persistent challenges. Focused financial and economic corrections and educational programs in developing countries should be attempted. Consequently, most of these challenges can be reduced. Establishing national and regional registries with well-integrated DDKT programs will not be amenable unless all these challenges have been ameliorated or reduced.