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The Emergence and Development of Solid Organ Transplantation in the Republic of Cyprus

Hadjianastassiou, Vassilis G.1,2,3; Soloukides, Andreas1,4; Prikis, Marios1,5

Author Information
doi: 10.1097/TP.0000000000003386
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INTRODUCTION

The Island of Cyprus is located at the most eastern corner of the Mediterranean sea and Europe (Figure 1). The Republic of Cyprus has a population of about 876 0001 and joined the European Union (EU) in 2004 as a member country.2 Life expectancy is among the highest in the EU with 82 years (women 84, men 80) and the lowest preventable mortality rate.3 The evolution of solid organ transplantation in Cyprus was driven initially by patient groups and a private benefactor. In recent years, the government took the initiative to restructure and advance the field facilitating an improvement of medical expertise and the implementation of a legal framework. With the small population on the island, transplant services have mainly focused on kidney and pancreas transplantation.

FIGURE 1.
FIGURE 1.:
Map of Cyprus in the Eastern corner of Europe. Wikimedia Commons contributors, “Atlas of the world,” Wikimedia Commons, the free media repository. Available at https://commons.wikimedia.org/w/index.php?title=Atlas_of_the_world&oldid=357672317. (Accessed June 12, 2020).

The Emergence Era (1986–2010)

In the mid 1970s, patients with kidney disease, their families, and members of the general population in Cyprus exerted pressure on the government to create the first hemodialysis units in the 2 largest cities on the island.4 In the mid 1980s, efforts of patient advocacy groups were successful in securing public funds to form the Department of Nephrology at the Nicosia General Hospital by Dr Alkis Pierides, a nephrologist recruited from the United States (Mayo Clinic, Rochester, Minnesota). Despite initial resistance and skepticism by the local medical society toward the new specialty, nephrology in Cyprus advanced. This success led to further private initiatives, mainly by patient support groups, and the financial contribution of the late benefactor Georgios Paraskevaides to establish the first Kidney Transplant Center—the Paraskevaidion Surgical and Transplant Center. Subsequently, the center accomplished to recruit a well-known transplant surgeon from the United States (University of Miami, Florida), the late Dr Georgios Kyriakides. The center was receiving financial support for services from both government and private funds.

On October 30, 1986, the first living donor (LD) kidney transplant between a 49-year-old mother as donor to her 22-year-old daughter with systemic lupus erythematosus and lupus nephritis was successfully carried out. With the advancement of clinical transplantation, the First Organ Procurement and Transplant Law was passed in 1987, clearly establishing the definition for brain stem death, thus facilitating the multiorgan procurement and organ transplantation from deceased donors (DDs). Over the next 25 years, nearly 900 kidney transplants were performed. All patients requiring other solid organ transplantation such as heart, lung, or liver were referred abroad to collaborating countries such as the United Kingdom, France, Austria, Greece, and Israel.

Care for end-stage renal disease patients took place in the 5 main government hospitals, whereas the transplant center remained a private not-for-profit institution. Nonetheless, a harmonious relationship existed for many years between the 2 sectors, leading to a successful cooperation for the benefit of patients with chronic kidney disease. However, throughout the years several events led to financial struggles for the institution prohibiting its modernization and development.

Therefore, in 2010, the government developed a strategy aiming to remodel and advance the field of transplantation in Cyprus. The plan involved the creation of a transplant center in the public sector, under state control and supervision in order to follow the strict principles laid down in the new EU Directive, establishing minimum standards for the Safety and Quality of Solid Organ Transplants.5 Subsequently, funding for solid organ transplantation in the private sector was withdrawn, forcing the closure of the center and marking the end of an era.

Clinical Transplantation (2011–2019)

The system of organ procurement and transplantation was reorganized from scratch in 2011. A centralized transplant unit was established at the Nicosia General Hospital (NGH), the largest and most modern hospital in the country, strengthening the connection with the other dialysis and nephrology departments around the country and facilitating a broad referral base. The NGH, managed the vast majority of intensive care patients in the country, had the only emergency neurosurgical unit in the government sector and the biggest unit all over the island. NGH staff offer a broad medical and surgical expertise. Furthermore, its location in the center of the island made it easily accessible by the entire population based on a modern infrastructure with the furthest distance by car from the NGH being only 1.5 hours away. Organ donation and transplantation would take place only at the NGH, benefiting from the expertise of the transplant team and limiting cold ischemia times (CITs) to minimum. Transplantation was organized with emphasis on regulation and licensing, transparency to gain the public’s trust in the system, and a modernized delivery of organ procurement and transplantation.

In 2017, a Live Donor Kidney Paired Exchange program for sensitized patients was signed between Israel and Cyprus, 2 countries in very close geographical proximity. The first 2 pairs in this International Exchange are eagerly awaited.

Legislation

The Law on Procurement and Transplantation of Human Organs was passed in 2012 to abide by the equivalent EU Directive 2010/53/EU for harmonization of standards of quality and safety in organ transplantation within the EU.5 The law established the Cyprus Transplant Council (CTC), which had a regulatory and licensing role over the Organ Retrieval & Transplant organization. The CTC was formed by 10 members, 2 of which were representatives of patient associations facilitating a strong voice within the regulatory body for those in need. Other stakeholders included representatives of the National Bioethics Committee, the Law Society, the Medical Society, and others. Furthermore, the CTC was designed to play the crucial role of an “independent assessor,” determining the existence of a strong relation between LDs and their recipients, especially when donor and recipient were biologically unrelated (defined by a genetic distance beyond the third degree). This approach secured that the principles of the Declaration of Istanbul were preserved and implemented in practice.6 Donation after brain stem death was clearly defined; donation after circulatory death is currently not established. The role of the transplant coordinator was legally defined and a formal reporting system of any relevant wrongdoing in the chain of donation and transplantation was set up. The law also established the official development and maintenance of registers for organ donors (with obligatory annual follow-up of LDs by the transplant center) and kidney transplant recipients. The Histocompatibility and Immunogenetics laboratory, which is administratively independent of the transplant unit kept records of waitlisted patients. The separate documentation of waitlisted patients avoided conflicts of interest and upheld the principles of clinical governance. Data collection since 2011 remains to be near-complete with median follow-up time of 4.5 years.

Transparency

Key in establishing equity of access to kidney transplantation is based on the introduction of an organ allocation software program, held and run by the Histocompatibility and Immunogenetics laboratory documenting HLA details, and serum antibody details of potential kidney transplant recipients. Data on DDs are entered into the system and an organ allocation matching run hierarchy is being created. Match run results and the ultimate organ allocation are recorded in the system, with the CTC being able to verify that due process is followed. The software variables include the following: ABO Blood Group, HLA mismatching, HLA-DR, and HLA-B homozygosity. For organ allocation, pediatric patients and recipients of dual pancreas-kidney grafts, waiting time, and donor-recipient age difference are also considered.

The use of standardized criteria and the ability to record and review the allocation ensured unbiased, fair, and equitable organ allocation and transparency in the system, thereby reinforcing confidence in the organ donation-transplantation chain.

Outcomes at the NGH

The transplant center at the NGH consisted of a single transplant surgeon, 2 part-time general surgeons; initially the center had the support of 1 nephrologist (2011–2014) and by 2019 additional 3 nephrologists have been added. A total of 215 and a mean of 25 kidney transplants a year have been performed since 2011. Sixty-two DD kidney transplants (1 of which was the first and only simultaneous pancreas-kidney) and 153 LD transplants were carried out with comparable graft survival (Log-rank chi = 0.066; P = 0.797). Clinical management protocols have been written, standardized, regularly reviewed, and updated following clinical audits to ensure optimized care.

The vast majority of patients received induction treatment with Basiliximab and maintenance immunosuppression with tacrolimus, mycophenolate, and prednisone. CIT were short (DD = 8 h, LD = 4 h; mean CIT).

Graft and patient survival rates are shown in Figure 2 (combined LD and DD program 1- and 5-y graft survival were 99% and 94% and, patient survival, 98% and 93%, respectively). Twenty-two percent of recipients had either diabetes mellitus or ischemic heart disease (or both) as comorbidities, 12% had a previous transplant, 20% received a preemptive transplant. Mean age at transplantation was 49 years (age range 3–72 y) and mean dialysis time before transplant was 24 months. Seven of 215 patients were pediatric recipients (age range 3–15 y) and 6 of 215 underwent ABO-incompatible kidney transplantation after desensitization. Delayed graft function was diagnosed only in 10 of 215 patients (5%) with a median duration of 8 days. Laparoscopic hand–assisted nephrectomies were performed in all 153 LD with none converted to an open procedure. Mean serum creatinine of recipients by 1 year was 1.2 mg/dL.

FIGURE 2.
FIGURE 2.:
Patient and graft survival. DD, deceased donor; LD, living donor.

Achievements and Challenges

Significant progress has been achieved in offering all available modern day transplantation services for patients with chronic kidney disease in Cyprus. These include laparoscopic donor nephrectomy as well as pediatric, ABO-incompatible, and even simultaneous pancreas-kidney transplantation.

Work remains to be done for patients requiring other solid organ transplants (heart, lungs, liver). The system of referrals needs to be centralized and transplant recipients need to be followed up by specialists affiliated with the transplant center. Referral criteria will need to be standardized and outcomes of patients referred abroad for transplant will need to be audited regularly.

Fundamental work is still required in addressing public awareness for the need of organ donation and transplantation for patients with irreversible organ failure. Systematic educational campaigns should target schools, universities, civil service, and other government funded organizations.

At present, only 3000 citizens have registered as potential organ donors (a mere 0.4% of the catchment population), with the biggest rise in registrations being in the last year, following the introduction of legislation linking the potential donor registration with driving license applications. The rate of actual DDs per million population varied between 2 and 6/y from 2013 to 2019.

Transplant coordinators will need to be appointed in all the main hospitals with intensive care capacity. Intensive care health professionals will need to be trained in all the relevant issues of organ donation and transplantation. More awareness is required for the benefits of preemptive kidney transplantation and thus of earlier patient referral for transplant evaluation by regional nephrology departments and renal units.

Brain death audits will need to be implemented to identify reasons for failure to progress to donation and further education programs will need to support this effort. A recent population study commissioned by the CTC evaluating a random sample of 1000 participants, revealed that 30% believed that brain death is reversible and 60% believed that it was impossible for post–brain death organ donation to proceed. Encouragingly, 82% of the participants in the 18- to 24-year-old group and 70% of the 25- to 44-year-old group were interested to learn more about organ donation.7

CONCLUSIONS

Despite social, ethical, and financial hurdles, superimposed on the population’s small size, solid organ transplantation in Cyprus emerged, and subsequently developed into a modern system, with results comparable to many transplant networks in larger and more developed countries. Future efforts will need to concentrate on public and healthcare worker awareness campaigns.

ACKNOWLEDGMENTS

Solid organ transplantation may very well be the strongest multidisciplinary clinical effort. The authors acknowledge the efforts and contributions of the following individuals and organizations, which among others, have supported establishing a modern, high-standard program in Cyprus. Dr G. Kyriakides (founding transplant surgeon); Dr A. Pierides (founding director of Nephrology); G. Paraskevaides (benefactor); Dr A. Varnavidou-Nicolaidou (director, Histocompatibility and Immunogenetics Laboratory); Drs N. Michael and P. Loizou (general surgeons, NGH); Dr E. Xinis (anesthesiologist, NGH); C. Despoti, M. Poullou, I. Kyriakou, and E. Nikolaou (transplant coordinators); Dr I. Savva (nephrologist); Dr E. Toumasi (nephrologist); Dr K. Constantinou (nephrologist); Dr M. Zavros & Dr. K. Demetriou (director & assistant director of Nephrology, NGH); nephrology team at NGH, Dr O. Kalakouta-Poyiatzi (chief medical officer, Ministry of Health, representative of Cyprus) Prof. C. Phellas (chair, National Bioethics Committee); Dr M. Voniatis (former chair, National Bioethics Committee); Dr A. Elia (pediatric nephrologist, Archbishop Makarios III Hospital); C. Stylianou, D. Papaioannou-Voniati, D. Georgiou, R. Mean, and G. Stylianou (Histocompatibility and Immunogenetics Laboratory); and the members of the Cyprus Transplant Association and the Cyprus Kidney Association. Not forgetting the many medical, nursing, support, operating theater, and laboratory staff of Nicosia General Hospital and referring dialysis units from Paphos, Limassol, Larnaca, and Famagusta. Above all, we are indebted to the families of deceased donors who altruistically gave the gift of life.

REFERENCES

1. Eurostat: Population of the Countries of the European Union-Cyprus. January 1 2019. European Commission website. Available at https://ec.europa.eu/eurostat/tgm/table.do?tab=table&plugin=1&language=en&pcode=tps00001. Accessed May 18, 2020
2. The European Union—Cyprus. European Commission website. 2020. Available at https://europa.eu/european-union/about-eu/countried/member-countried/cyprus_en. Accessed May 18, 2020
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5. Directive 2010/45/EU of the European Parliament and of the Council of 7 July 2010 on standards of quality and safety of human organs intended for transplantation. EUR-Lex-Access to European Union Law website. 2010. Available at http://data.europa.eu/eli/dir/2010/53/oj. Accessed May 18, 2020
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