Key words : Children, End-stage renal disease, Deceased donor, Developing countries, Pediatric nephrology, Renal transplantation

Introduction

The incidence of chronic kidney disease (CKD) in children remains largely unknown in the developing world. Generally, children are referred late, with 24% to 63% presenting at end-stage renal disease (ESRD). Reasons for late referrals are neglect, long distances from the tertiary centers, and economic constraints.¹ The prevalence of pediatric renal replacement therapy (RRT) and transplantation is low in developing countries, at 6% to 12% and <1 to 5 per million child population (pmcp), respectively.² This is due to low gross domestic product (GDP) per capita of <$10 000, government expenditure on health of <2.6% to 9% of GDP, and paucity of facilities. The reported incidences of pediatric CKD and ESRD are <1.0 to 8 and 3.4 to 35 pmcp, respectively.²

Pediatric kidney transplantation (PKT) is the best option for treatment of children with ESRD. Success in areas like the Middle East (ME) remains challenging. Living kidney donation is the most widely practiced type of donation in the ME. However, some countries like Iran, Turkey, Kuwait, the Kingdom of Saudi Arabia (KSA), and most recently the United Arab Emirates (UAE) already have well-established deceased donation programs.

In developed countries, PKT has become a routinely successful procedure, where 1-year graft survival is more than 99% from living donors and more than 97% from deceased donors and 5-year graft survival is more than 90% from both living and deceased donors.³ These outcomes are a cumulative effect of 2 decades of improvements in dialysis procedures, surgical techniques, immunosuppression, diagnosis, treatment of rejection, and effective control of infections.⁴ In contrast, overall rates of kidney transplant remain low in developing countries, mainly because of economic reasons and the paucity of facilities.⁵ In children, rates are largely unknown and, where reported, are low. The main reasons are poor economic indications, low government expenditure on health, and underdeveloped RRT programs for children.^6-9

In the ME, the most important challenges to providing optimal treatment to children with ESRD are poor economics and the paucity of RRT and transplant facilities. Although the ME population is around 800 million, one-third is under 15 years of age (ie, 280 million children). Epidemiological information from the ME on PKT is scant and primarily based on patients referred to tertiary medical centers. Most reports are single-center experiences.

The present study aimed to collect data on the volume of PKT from ME countries in an attempt to have an idea about the overall PKT rate in the ME and to create later a regional registry in close collaboration with the Middle East Society for Organ Transplantation community. Thus, this registry could hold all organ transplant data from this region, including pediatric data, and be updated on a regular basis. For the purpose of this study, all known ME kidney transplant (KT) centers and national KT societies from across the ME were contacted to answer specific questions related to both adult KT and PKT from living and deceased donors that were performed in each country during a recent year. We preferred 2021 as the recent year; however, if data were not available, data from 2020 or 2019 could be used. We did receive the requested data from all ME countries except Bahrain and Oman because no recent data were available from these 2 countries. Thus, these 2 countries were not included in the study results.

In this report, an overview of PKT in ME countries is presented, as well as challenges encountered and their solutions for establishing successful and viable PKT programs.

Results

All obtained information related to the following data from each country are displayed in Table 1: population, data year (2021, 2020, or 2019), total number (adult + pediatric) of KTs performed in the mentioned year, KT rate per million population (pmp) per year, number of total deceased KTs per year if available, total number of PKTs, PKT rate pmp per year, PKT share of total transplants, and number of total deceased donor PKTs per year if available.

Over a single year, 8772 total KTs were performed for adults and pediatric patients in ME countries. The total KT rate pmp per year was 10.9. ranging from 1.2 in Yemen and Pakistan to 39.7 in Turkey, which achieved the highest KT rate in the ME. The total KTs versus PKTs per the recent year (2019-2021) from both living and deceased donors in the ME are shown in Figure 1.

There were 746 PKTs (ie, pediatric recipients below 18 years of age) in ME countries during a single recent year. Thus, the average PKT rate pmp per year was 0.93, ranging from 0.04 in Pakistan to 3.2 in Syria, which had the highest PKT rate pmp per year in the ME (Figure 2).

The total number of KTs for adult and pediatric recipients from deceased donors was 1399 in ME countries during a single recent year. Thus, the percent of deceased donor KTs was 15.9%, ranging from 0% in 10 the countries where deceased transplant program is lacking to 64.2% in Iran, which had the highest deceased donor KT percent of total KTs in the country. Moreover, Iran alone has performed 63.5% (888/1399) of all deceased donor KTs in the whole ME in the single recent year.

Of the 746 PKTs, 166 PKT were from deceased donors. Thus, the percent of deceased donor PKTs was 22.2% of total PKTs, ranging from 0% in 11 countries, to 59.2% in Iran, and 100% in Tunisia. Iran alone has performed 63.9% (106/166) of all deceased donor PKTs in the whole ME in the single recent year.

The average PKT share was about 8.5% of total KTs, ranging from 3.2 in Iraq to 20% in Algeria, which had the highest PKT share of the total KTs.

Discussion

The PKT rate pmp per year, which was shown to be 0.93 in our study, could also be calculated based on the pediatric population (pmcp) instead of total population (pmp). In the ME, about 35% of the population is under 18 years of age; thus, the PKT rate pmcp per year is 2.7 (ranging from 0.01 in Pakistan to 9.1 in Syria). In Europe, the rate of PKT has been shown to range from 0 to 13.5 pmcp.¹⁰ Similar data for PKT are very limited from low- and low-middle income countries, with some reporting rates of PKT as low as <4 pmcp.^2,11,12 Moreover, the COVID-19 pandemic has added to the existing disparities in KT rates across regions.¹³

On the other hand, some unpublished data on annual PKT rates in the ME from nearly 10 years ago (between 2008 and 2012) have enabled us to look at the progression of PKT rates over the past decade in this region. The total population and pediatric population of the ME at that time were estimated to be 650 and 230 million, respectively. The total (adult and pediatric) KTs was 7672, with 568 being pediatric recipients. Thus, the pediatric share was about 7.4% of total transplants at that time, meaning that the current pediatric transplant share is higher by 1.1% than a decade ago. Moreover, the current average PKT pmp and pmcp results per year in our present study (0.93 and 2.7, respectively) are also higher than 10 years ago (0.87 and 2.5, respectively). However, the total KT rate pmp per year in our present study (10.9) was less than shown a decade ago (11.8).

One of the most important highlights on PKT in the present study was the observation that 22.2% (166/746) of all PKTs performed in a recent year in the ME were from deceased donors, which is more than double that shown 10 years ago, where it was about 9% of total PKTs. This increase in the deceased PKT rate has happened despite the recent COVID-19 pandemic, which affected overall KT activities to different extents worldwide.¹³

Challenges of Pediatric Kidney Transplant in the Middle East

Transplant outcomes rely on a sound kidney failure care program. Underresourced countries have unique challenges regarding care of adults¹⁴ and children¹⁵ with kidney failure. To a large extent, the status of kidney failure care in children depends on the standards of adult kidney care existing in the region. The real challenge that underresourced countries face is prompt detection of CKD in children, early referral, and the availability of optimal CKD and dialysis care services. The reality is that, despite considerable progress in health care in recent years, the proportion of children presenting for the first time with ESRD is 24% to 63%.¹ Inequalities have impacted several steps in the overall process, from diagnosis of kidney failure to receiving a transplant at the country, institution, and family levels.¹⁶

There are specific issues relevant to PKT in under-resourced regions like the ME. These issues are highlighted by limitations in the capacity of the health workforce, regulatory norms, medical issues, economic burden, factors beyond financial hardship, and ethical considerations relevant to these regions.¹⁷ In general, challenges could be classified into pretransplant and posttransplant challenges.

Pretransplant Challenges

The etiology of pediatric ESRD is unknown, but the rate of ESRD is shown to be very high, reaching up to 50% of patients in Pakistan compared with only 6.2% in North America (as shown in North American Pediatric Renal Trials and Collaborative Studies [NAPRTCS]) and 7.4% in Europe (per European Renal Association-European Dialysis and Transplant Association).⁶

Delayed referral of children with CKD to specialized centers is 24% to 63% present in ESRD.¹ Obstructive nephropathy accounted for 56% of the etiology of pediatric CKD in one study from Syria.¹⁸

Another challenge is the wide range of comorbidities, including poor nutritional status, poor left ventricular function, anemia and multiple blood transfusions, hypertension, diabetes, infections, and severe bone disease.

There are also challenges in pediatric dialysis as dialysis facilities are nonexistent in rural areas (where 70% of the population resides) and poverty prevents travel to tertiary hospitals. In addition, there are issues with regard to vascular access and a lack of technical expertise, which are especially important if we consider the better graft survival shown with preemptive kidney transplant and transplants following less than 6 months of dialysis. Extended dialysis time can result in poorer graft outcomes.19

Deceased donor programs for children are either not available or inactive in most of the ME countries except for Iran, Turkey, KSA, Kuwait, and UAE. However, in North America, children get priority on waiting list and hence get early transplant.

Finally, other pretransplant issues are technical issues related to transplant operation, such as size disparity given the fact that infants may receive adult kidneys, vascular and ureteric anastomosis, intraoperative and postoperative care in the intensive care unit, transplant for patients with lower urinary tract anomalies, and retransplant.

Posttransplant Challenges

Immunosuppression
Issues in immunosuppression are especially the external ones such as drug availability, cost considerations, and monitoring. Internal issues are also challenges, including the heightened immune response, variable drug handling, immunosuppressive toxicity, susceptibility to infection, and susceptibility to posttransplant lymphoproliferative disease. Across 32 countries in Europe, a strong association has been observed between country income based on the GDP per capita and rates of PKT. For every US $1000 increase in GDP per capita, the KT rate increased by 0.2.10 However, analysis of geographic measures of socioeconomic status from the United Nations Organ Sharing registry data has revealed that socioeconomic status did not predict 1-year PKT outcomes.²⁰ Figure 3 shows the GDP per capita in 2020 compared with maintenance immunosuppression cost (in US dollars) per year in certain ME countries where this cost exceeds alone the GDP sometimes by several folds.

Graft rejection

Acute rejection rates have steadily declined over time with the introduction of increasingly effective immunosuppression. In Pakistan, for instance, the use of induction agents and tailoring of immunosuppression at the Sindh Institute of Urology and Transplantation (SIUT) in Karachi was not only cost-effective but also reduced rejection rates from 48% in the period of 1986 to 1995 to 17% in the period of 2006 to 2011.² In the KSA, the same observation was recently reported, showing acute rejection rate decline from 31% in 1997 to 9% in 2021.²¹ In Egypt, the cumulative acute rejection rate (2009-2018) at a single center was 32%.²² In Oman, the cumulative acute rejection rate (1994-2015) was 18%.²³ However, the cumulative acute rejection rate (1987-2010) shown by NAPRTCS was 15%.²⁴ Interestingly, the 2018 report from NAPRTCS reported a probability of first rejection at 1 year posttransplant of 12.7% from living donors and 13.2% from deceased donors.³ The rate of graft loss due to acute rejection has been reported to range from 2% to 41%, depending on immunosuppression protocols and donor type, with high numbers in countries with deceased donor programs.²

Minimization

Trials have shown that steroids are not necessary for low-risk children, and calcineurin inhibitors may be withdrawn in some children. Thus, monotherapy may be practical in some children. However, in the ME, concerns remain about the safety of such a strategy, and minimization protocols are still far from being widely applied and accepted.

Infections

In PKT, infections are the “major killer.” Urinary tract infections are the most common in pediatric patients, with rate of incidence ranging between 15% and 33%.²⁵ Urinary tract infections may result in an increased risk of graft loss, especially if associated with urinary tract abnormalities. However, Epstein-Barr and BK virus infections are the most serious; fungal and parasitic infections are uncommon.

Graft survival

Most of the available data on graft survival after PKT in the ME region are from single-center experiences. The 1- and 5- year graft survival rates can range from 90% to 98% and 78% to 92%, respectively. Table 2 shows the 1- and 5-year graft survival rates of PKT in several ME countries; if available, data from living donor and deceased donor PKTs were compared with the 2018 NAPRTCS report.  Graft survival rate in these single centers was similar to that shown in the NAPRTCS report.^{3,21-23,26-28}

Growth after transplant

One of the goals of renal transplant in children is to restore an optimal quality of life, including the optimization of final height. However, catch-up growth posttransplant is generally not sufficient to compensate for the deficit that may occur during the pretransplant period. Growth retardation posttransplant is multifactorial and associated with impaired medical and psychosocial outcomes. Despite numerous recent developments in PKT, achieving an adequate final height remains a challenging issue for such recipients. Data from the NAPRTCS 2006 annual report reported that the mean height standard deviation score (SDS) was -1.4 in a cohort of over 1500 patients aged 19 years or more.²⁹ On the other hand, reports from the ME are in fact few and from single centers. In a report from Gazi University Faculty of Medicine (Ankara, Turkey), the mean height SDS values were -2.3 ± 1.3 at the time of transplant and -1.4 ± 1.1 after a mean posttransplant duration of 4.2 ± 2.0 years in a cohort of 37 kidney transplant patients with a mean age of 17.0 ± 2.9 years. Although the posttransplant growth was much better versus the pretransplant period, the posttransplant growth was still less than anticipated.³⁰

Compliance and quality of

The immunosuppression side effects have a significant impact on quality of life, and adolescents are especially susceptible to medical nonadherence, which is the sixth most common cause of graft failure according to the 2004 report of NAPRTCS. In fact, graft loss due to nonadherence is underreported because it can be miscoded as chronic rejection.³¹ Interestingly, one of the lowest noncompliance rates in pediatric transplants worldwide has been reported from the SIUT Center in Karachi (Pakistan), which was 7% in 2002.³²

Hurdles Toward Initiating Deceased Organ Donation in the Middle East

Deceased donor KT programs are currently only available in 8 of the 18 ME countries included in this study. However, deceased programs are active in some ME countries, including Iran, Turkey, KSA, Kuwait, and UAE.
Initiating a deceased organ donation program is widely considered as an essential component of a comprehensive approach to respond to the ever-increasing worldwide organ shortages. The lack of a legal framework is a major obstacle in certain ME countries. Even when it does exist (such as in Egypt and Syria), a deceased donor program may still not be in place for complex reasons. Limited resources and small numbers of organized teams of transplant surgeons and nephrologists and a lack of public awareness, education, and motivation continue to be hurdles for organ donation. Ironically, the existence of “renal commerce” had delayed the start of deceased donor programs, as paid renal donation masked the need and urge to start a national deceased donor program at the expense of tarnishing the reputation of transplant among ordinary people.³³

Combatting Organ Commercialism

One of the important challenges of organ transplant in the ME that has played a role in delaying deceased donation programs is the practice of “kidney selling” in many places across the ME. Kidney selling has quickly become a common and readily available source of organs, and vendors have found ways to sell their kidneys through disreputable brokers. This practice has raised ethical concerns regarding organ commercialism, exploitation of the poor, and undermining public trust of the transplant system.34 We are in a global struggle to combat organ commercialism, and the principles expressed in the Istanbul Declaration,35 as well as in the World Health Assembly (WHA) 57.18 resolution on human organ and tissue transplantation of May 2004,36 have called upon member states to “take measures to protect the poorest and vulnerable groups from transplant tourism and the sale of tissues and organs.” The key figures in transplant communities from the ME need to meet regularly, discuss thoroughly, and exchange thoughts and opinions on how to approach and offset this dilemma so that necessary actions can occur to fulfill the direction of the aforementioned resolutions and make donated organs as community resources and not be marketed for financial gain.

Overcoming Challenges in Developing Countries

A model for funding RRT and transplant has economic constraints. A paucity of RRT facilities in the government and the high costs in the private sector in Pakistan have necessitated a system where RRT and transplant could be funded and offered “free of charge” to patients with lifelong follow-up and medications.² This model of community-government partnership has sustained itself for more than 30 years with funding from 2 partners. To maintain a large number of patients, a number of economizing strategies were introduced to reduce costs without compromising quality. Basic hemodialysis machines were used, which cost 30% less than more sophisticated units. In addition, dialysis fluid is prepared in house by self-importing bulk reagents and dialysis is reused on automated systems, except for patients who are hepatitis B positive. The use of generic immunosuppressants can also cut costs.³⁷

Societal Acceptance of Renal Replacement Therapy and Transplantation

Free treatment and access to RRT and transplant for children are not the only hurdles in the developing world. Apprehensions on long-term transplant outcomes and the well-being of donors are also important issues. Good outcomes and rehabilitation of children posttransplant on one hand was a driver for others to have their children transplanted,³² and donor well-being on the other. Donor well-being through donor follow-up clinics³⁷ can provide proof to prospective donors that one can live a normal life after organ donation. Indeed, many of the apprehensions are removed when kidney donors propagate donation.

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