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Solid Organ Transplantation in Singapore

Kee, Terence, MBBS, FRCP, FAMS, FASN, GDipHML1; Shridhar Ganpathi, Iyer, MBBS, MS, FRCS, FAMS2; Sivathasan, Cumaraswamy, MBBS, FRCS, FAMS3; Kong, Sally, BA4; Premaraj, Jeyaraj, MBBS, FRCS, FAMS1; Anantharaman, Vathsala, BS, MD, FRCP, FAMS2

doi: 10.1097/TP.0000000000002235
In View: Around the World

1 SingHealth Transplant Centre, Singapore Health Services, Singapore.

2 National University Centre for Organ Transplantation, National University Health System, Singapore.

3 National Heart Centre, Singapore Health Services, Singapore.

4 National Organ Transplant Unit, Ministry of Health, Singapore.

Received 16 March 2018. Revision received 26 February 2018.

Accepted 5 March 2018.

The author declares no conflicts of interest.

Correspondence: Terence Kee, MBBS, FRCP, FAMS, FASN, GDipHML, Renal Medicine Office, Level 3, The Academia, 20 College Road, Singapore 169856, Singapore. (terence.kee.y.s@singhealth.com.sg).

Singapore is a tropical South-East Asian island city-state located at the southern tip of the Malaysian peninsula (Figure 1). The country has a total land area of 719.1 km2 and is densely populated with a multiethnic population of 5.6 million, of which 3.9 million are Singapore residents.1 The median age of the population is 40 years, with 66.3% aged 20 to 64 years.1 Since achieving status as a sovereign nation in 1965, Singapore ranks fifth on the United Nation Human Development Index and has the third highest gross domestic product (GDP), per capita in the world.2 Singapore spends 2.1% of its GDP on health; life expectancy at birth is 82.9 years; infant mortality is 2.1 per 1000 live births.1

FIGURE 1

FIGURE 1

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FRAMEWORK OF TRANSPLANT HEALTHCARE IN SINGAPORE

Singapore has 18 (8 public sector, 10 private sector) hospitals that provide a total of 12 505 beds; all 18 hospitals provide deceased donors for solid organ transplantation. Kidney and liver transplantations are predominantly performed at 2 academic medical centers (AMC): Singhealth Duke National University of Singapore (SDNUS) and the National University Health System (NUHS) as part of the public sector. Heart and lung transplantations are only performed at the National Heart Centre of the SDNUS while pancreas transplantation is performed at NUHS. National pediatric programs for kidney and liver transplants are active at NUHS.

Kidney transplantation in the public sector used to be a national program but has evolved into 2 separate programs operated by 2 individual AMCs. Liver transplantation in the public sector remains a national program performed at both AMCs under a united leadership framework. Both AMCs have also set up multiorgan transplant centers (SingHealth Transplant at SDNUS and National University Centre for Organ Transplantation at NUHS) to integrate services across different programs while advancing academic transplantation. The private sector also performs transplants, however, limited to live donor kidney and liver transplants, catering to a smaller number of Singaporeans.

Financial support for transplantation is provided through Singapore's 3M model for healthcare financing. The underlying philosophy of the 3M model is that Singaporeans have a personal responsibility toward financing their healthcare while, at the same time, the Singapore Government ensures that enough subsidies and other support is provided so that healthcare is accessible to all. In the 3M model, Singaporeans are required to contribute a portion of their payroll to a national saving scheme, the Central Provident Fund. Within the Central Provident Fund, monthly contributions are allocated to several subaccounts including Medisave that can be used for in-patient and specific out-patient healthcare expenditure and for premiums of the national health insurance plan, Medishield. Based on provisions by Medisave and Medishield, Singaporeans have a significant proportion of their healthcare expenditure covered. For those who are unable to pay for the remaining amount, there is Medifund, a government endowment fund set up to support needy patients.

The Singapore Government also provides additional subsidies for transplant surgery and immunosuppressive drugs making transplantation financially accessible. Voluntary welfare organizations have also contributed to transplant funding such as the National Kidney Foundation, which has set up a Kidney Live Donor Support Fund that provides financial support for (i) one-time reimbursement for loss of income and expenditure related to hospitalization for live donor surgery, (ii) annual medical follow-up following donation, and (iii) insurance coverage. This donor support fund is restricted to financially constrained Singaporeans who want to donate a kidney at one of the AMCs in the country. The Kidney Dialysis Foundation also provides funds to donors supporting costs for donor surgery and to recipients supporting hemodialysis while waiting for live donor kidney transplants (The Bridge to Transplant Program).

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LEGISLATION FOR TRANSPLANTATION IN SINGAPORE

The first legislation for transplantation, the Medical Education Therapy Research Act (MTERA) was passed by the Singapore Parliament in 1972. This was an opt-in legislation allowing individuals 18 years or older to register their wish to donate organs or any other body parts for transplantation, education, or research upon death. However, none of the subsequent deceased donor kidney transplants performed after the introduction of MTERA have originated from registered donors and only 82 deceased donor kidney transplants have been performed between 1972 and 1987.3 Furthermore, the sign-up rates to donate organs under MTERA have been and continue to be very poor. Indeed, only 45 202 individuals (of 3.5 million Singapore citizens and permanent residents in the year 2007) pledged to donate, representing a mere 1.3% of the resident population.4

Due to the shortage of donor organs, kidneys were imported into Singapore from foreign organ procurement agencies between 1983 and 1987 with poor outcomes, mainly linked to prolonged ischemia times and poor human leukocyte antigen matches.5 Thus, an alternative legislation called the Human Organ Transplant Act (HOTA) was passed to increase kidney donations in 1988. Human Organ Transplant Act applies only to Singapore citizens and permanent residents and has passed through several amendments over the years to meet transplant needs in Singapore.3

In its current form, HOTA is an opting-out legislation for suitable corneas, kidneys, hearts, and livers to be removed for transplantation upon death. Organs cannot be removed under HOTA if the individual is not a Singaporean citizen or permanent resident, younger than 21 years, had suffered from a mental disorder, or had opted out during life. The choice to opt out starts at age 21 years or after receiving citizenship or permanent resident status, when an information booklet about HOTA and a form to opt out will be provided. Alternatively, an opting out form can be registered at any time. The donation status is always confirmed at the time of death of a Singaporean citizen or permanent resident to ensure that a documented opting out desire is absent. Notably, HOTA is the only opting out legislation in the world that includes Muslims supported by local Islamic authorities. For lung and pancreas donations, permission needs to be sought from the next of kin under the MTERA.

Organs and tissues from deceased donors are allocated as a priority to Singapore citizens and permanent residents. If a foreigner in Singapore requires transplantation, it is usually a live donor kidney or liver transplant under the statuatory regulation of HOTA; legislation explicitly prohibits organ trading in all forms while requiring the appointment of a national transplant ethics committee (TEC) to review and provide approval of living donors. The TEC panel consists of 3 individuals including a layperson and 2 physicians (of whom 1 is from an external hospital); the TEC determines, (i) whether informed consent has been obtained from the donor and, (ii) evaluates any suspicion of organ trading or the presence of any “fraud, duress or undue influence “affecting the consent to donate. Singapore has adapted a strong position against commercial transplantation and is aligned with the guidelines laid out by the Declaration of Istanbul. Indeed, the laws against organ trading in Singapore were enforced in 2008 when 2 potential donors, the intended recipient and a broker were charged and jailed for being involved in the trading of a kidney for transplantation.

Although HOTA has effectively increased the pool of potential donors to more than 3 million individuals that have not-opted out in 2007, deceased organ donation rates remain very low: in 2016, deceased donor kidney, liver, and heart transplant rates were only 10.2, 7.6 and 1.0 per million population, respectively. One reason for the small volume in deceased organ donation is the low referral rate of potential donors by intensive care units. Moreover, conversion rates have been low; a survey in 2007 revealed that 69.8% of 86 referred donors did not donate because of cardiac arrest prior to the declaration of brain death, early withdrawal of life support, inability to meet brain death certification, and a lack of consent for organ donation and a lack of consent for organ donation in cases where the MTERA is applicable.4 In view of these findings, efforts have been made to (i) improve standards and processes in declaring brain death, (ii) implement ministry of health funded case managers to coordinate the process for brain death certification and counseling for organ donation, (iii) establish organ donation oversight committees in hospitals to oversee and coordinate policies and processes related to organ donation, (iv) initiate audits of converted donor referrals, and (v) include intensive care unit social workers and religious support caring for the deceased donor's next of kin during the decision process. It remains to be seen whether these initiatives will lead to increasing donation rates.

With the increasing complexity of organ procurement and growth of transplant programs, the National Organ Transplant Unit (NOTU) has been established in 1998 by the Ministry of Health to oversee national activities on organ donation and transplantation in Singapore. NOTU supports all operational aspects of organ/tissue procurement, waitlist management, allocation of organs and initiatives to improve organ donation and transplantation. NOTU also collects data on donor referrals, outcomes of organ/tissues procured, adverse events pertaining to organ transplant services while maintaining several national registries. NOTU also facilitates meetings of the National Transplant Ethics Committee, the Advisory Committee on Transplantation in addition to various organ transplant subcommittees that provide recommendations to the Advisory Committee on Transplantation which then advices the Ministry of Health.

Data pertaining to donor referrals and transplants are reported annually by NOTU; outcome data are collected by the National Disease Registry Office and presented in the Annual Singapore Renal Registry Report available online.

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KIDNEY AND PANCREAS TRANSPLANTATION

The first deceased donor kidney transplant and the first living kidney donor transplant have been performed at the Singapore General Hospital (SGH) in 1970 and 1976, respectively. At that time, the demand for a transplantation program was driven by the shortage of hemodialysis facilities with a growing population of patients with end-stage renal failure.

With the implementation of HOTA, 662 deceased donor kidney transplants were performed over a 16-year period (1988-2004; average annual rate, 41.3). With an increasing waitlist (208 patients in 1988 and 673 in 2003) HOTA has included donors who died from any causes in 2004 (previously, it was restricted only to accidental causes of death) and Muslim donors (since 2008).

Those changes, however, have only resulted into 218 deceased donor kidney transplants from 2010 to 2016 (average annual rate of 31.1). Based on the 2016 United States Renal Data System Annual Report, Singapore ranked fifth for the incidence of end-stage renal failure patients but among the bottom 20 countries for kidney transplantation.6

Thus, deceased donor kidney transplants across positive B-cell crossmatches in addition to an increased utilization of expanded criteria donors (representing 40% of the deceased donor pool) have been introduced to expand access to deceased donor transplantation.7 Most recently, a donation after circulatory death program has been implemented in 2 hospitals.

The lack of deceased donor kidney transplants has been compensated, at least in part by live donor kidney transplants. Indeed, 175 living kidney donor transplants have been performed from 2012 to 2016 (Figure 2), with the introduction of laparoscopic donor nephrectomies (in 2000), HLA incompatible kidney transplantation (in 2004), ABO-incompatible kidney transplantation (in 2009) and the first paired kidney donor exchange (in 2015). Despite these advances, only 48.4% of the public was willing to be a living kidney donor with fears of surgical risks and poorer health consequent to donation being psychosocial barriers.8

FIGURE 2

FIGURE 2

A first simultaneous kidney-pancreas transplant has been performed in 2012 at the National University Hospital (NUH). Although, the volume has remained small, indications have been expanded to type 2 diabetics. Moreover, there are plans to embark on a clinical islet cell transplantation program.

Outcomes for kidney transplants have been excellent with 1- and 5-year graft survival for deceased donor kidney transplants (95.4% and 83.7%, respectively) and living donor kidney transplants (99.1% and 94.5%, respectively).9 Patient survival at 1 and 5 years for deceased donor kidney transplant have been 97.3% and 90.9%, respectively, and 99.1% and 96.4% for living donor kidney transplant.9

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LIVER TRANSPLANTATION

The first deceased donor liver transplant was performed in 1990 at NUH; the 25-year old recipient did very well and gave birth to a healthy baby boy in 1996.

Between 1990 and 2005, liver transplantation was performed only at NUH; in 2005, an additional liver transplant program was established at SGH, which then performed its first liver transplant in 2006.

Between 1990 and 2004, a total of 100 liver transplants were performed in 56 adults and 44 pediatric patients.10 Biliary atresia was the most common indication for pediatric liver transplantation, whereas hepatocellular carcinoma and decompensated hepatitis B cirrhosis were the most common indication for adult liver transplantation.

To increase the volume of liver transplants, marginal donor grafts have been accepted since 2008. With those changes, conversion rates have increased from 31.6% (2001-2007) to 73.8% (2008 to 2011). Nevertheless, annual liver transplant rates have increased only modestly (from 4 in 2007 to 19 in 2016) (Figure 2).

Living donor liver transplantation now accounts for 40% of all liver transplants. Liver transplant programs in Singapore have been on a continuous journey of improving volume liver transplantation rates and have also implemented split liver donations,11 transplantation in situations of extensive portomesenteric thrombosis12 and Budd Chiari Syndrome as well as combined heart-liver transplants.13 The first ABO incompatible living donor liver transplant was performed in 2017 at SGH.

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HEART AND LUNG TRANSPLANTATION

The first adult heart transplant was performed in 1990 at the National Heart Centre Singapore. Ischemic cardiomyopathy and dilated cardiomyopathy are the major indications for heart transplantation.14 72 heart transplants have been performed between July 1990 and December 2016, including 3 retransplants (average of 3 transplants/year); to meet the increasing demand, a rate of 12 to 15 heart transplants/year would need to be realized. Hearts are allocated based on wait time and a scoring system assessing disease severity including ambulatory patients on mechanical cardiac support (MCS) or hospitalization with MCS or inotropic support.

With low cardiac transplant rates, MCS has made great strides treating patients with advanced heart failure by serving as a bridge to heart transplantation or destination therapy in Singapore. Current 5-year survival rates of patients on MCS are 84.8%, allowing patients to endure long waiting times of more than 7 years. Currently, there are over 20 patients on the waiting list for a heart transplant and all of them are supported by MCS.

Despite low numbers, 1-, 5-, and 10-year graft survival rates are 91.5%, 75.2%, and 63.5%, comparing favorably with data of the International Heart and Lung Transplant Registry.

The first lung transplant in Singapore was also performed at the National Heart Centre Singapore in 2000. Twelve lung transplants have been performed until 2016.

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PEDIATRIC TRANSPLANTATION IN SINGAPORE

The first living donor pediatric kidney and liver transplant were performed in 1989 and 1991, respectively, both at NUH.15,16 A total of 86 pediatric renal transplants have been performed since then, with the majority (58%) from living kidney donors. As for pediatric liver transplants, a total of 148 pediatric liver transplants have been accomplished between 1991 and 2017 (86% from living liver donors).

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CONCLUSIONS

Within 5 years of gaining independence as a sovereign nation, Singapore, then recognized as a developing country performed its first transplant procedure. Solid organ transplantation subsequently expanded over 3 decades to meet the demand of a growing population of Singaporeans with end-organ failures. Currently, transplant centers in Singapore can perform the most complex transplants with excellent outcomes but continue to face fundamental challenges in improving organ donation rates despite having a well-established opting-out legislation.

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REFERENCES

1. Statistics Singapore. Population Trends2016. www.singstat.gov.sg. Accessed October 1, 2017.
2. United Nationals Development Programme Human Development Reports. www.hdr.undp.org. Accessed October 1, 2017.
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5. Lim SM, Soh P, Pwee HS, et al. Trans-Pacific sharing of kidneys requiring preservation for more than 50 hours: an analysis of 33 cases. Transplant Proc. 1990;22:336–337.
6. United States Renal Data System Annual Data Report 2016. Chapter 13: International Comparisons. http://www.usrds.org. Accessed 1st October 2017.
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