THE CONTEXT AND MILESTONES
Italy is a European country of 60 million inhabitants with a universal public healthcare system (HS) based on a joint central and regional governance. The HS guarantees to all citizens free essential preventive, diagnostic, and therapeutic care, including the management of severe organ dysfunction and eventually organ transplantation in public hospitals under the control of both medical and surgical specialists. After pioneering activities between the 1960s and 1980s (Stefanini in Rome, Confortini in Verona, and Malan in Milano for kidney in the 1960s; Cortesini in Rome for liver in 1982; Gallucci in Padua for heart in 1985; Ricci in Rome 1991 for lung), kidney, liver, heart, and lung transplant programs have been established in >40 hospitals in the country. On the basis of multidisciplinary efforts, expert surgical skills, and international cooperation, 4000 organ transplants have been performed in 2017. During the last 20 years, a dedicated national network for organ and tissue procurement consisting of highly skilled staff has increased the deceased organ donors to 28 per million population (pmp) in 2017. Despite these remarkable results, self-sufficiency and zeroing of waiting lists are still far from being achieved.
ORGANIZATION AND RULES
Organ donation and transplantation in Italy is mainly based on 3 regulations: (1) Law 458/1967 for living donation, (2) Law 578/1993 defining brain death (BD) (as irreversible loss of all cerebral functions) and death certification by neurological (independent council of 3 specialists with a 6 h observation time) or cardiac criteria (20 min of ECG with no cardiac activity), and (3) Law 91/1999 setting up a dedicated national network, that is, the National Transplant Center (CNT), the National Technical Transplant Council, the Regional Transplant Coordinating Centers, the “hospital procurement Coordinator” who is a physician supported by a inhospital team including full- or part-time medical doctors and nurses (mainly intensivists and intensive care unit [ICU] nurses) identifying potential donors in ICUs, emergency departments, or stroke units. In 2015, the European Union (EU) directive on safety and quality of organs for transplantation (2010/53/EU) has been partly implemented. National bodies issue guidelines and carry out a safety and quality surveillance activity, CNT also manages directly national programs (urgencies, pediatric, critical subgroups of waitlisted patients and national reallocation of suboptimal organs); Regional Centers perform donor evaluation, organ allocation, and run quality programs. Hospital-based coordinators detect potential donors and coordinate procurement. Unfortunately, this model has not been applied yet in all the regions due to insufficient resources and personnel; thus, a new National Donation Program has recently been established focusing on (1) improving regional governance, (2) adjusting hospital coordination to the new clinical scenarios that include both donors after brain death (DBD) and donors after circulatory death (DCD), and (3) implementing a quality control based on standardized criteria and indicators acknowledging regional activities of organ donation and transplantation.
Transplant programs can only be run in public hospitals based on a formal authorization that is issued every 2 years by the regional authority on fulfillment of CNT- and Health Ministry–defined criteria in terms of transplant volumes and outcomes.
BD diagnosis and declaration are mandatory by law, irrespective of any possibility of organ donation and must be reported to the regional and national coordination centers. Second-opinion experts are available nationwide, 24/7, to give advice on infectious, neoplastic, and legal problems (around 25% of potential DBD donors per year).1
The family is informed and supported on admission of the potential donor to the ICU; brain death is documented and the situation is explained by the treating doctors; the next of kin are given time to deal with grief after which a procurement coordination team approaches them concerning donation; the family can veto donation only if the potential donor has not had his/her will registered in the national CNT-dedicated information system (SIT). SIT also gathers all relevant donor data, waitlisted patients and transplant outcomes, to assure equity, traceability, transparency, safety, and quality.
Procured organs are first considered for national programs (see above) run by CNT that utilize around 20% of total organs; the remaining organs are allocated in the region where the donation occurred based on agreed-on national, shared criteria. When an organ cannot be used in the donor region, it is then offered by the CNT to all the other Italian centers to minimize organ discarding.
Moreover, all transplant activities and follow-up data of the Italian centers are published on the CNT website (Figure 1).
Organ donation can be performed in any hospital ICU, provided death has been declared by neurological or cardiocirculatory criteria, absolute medical contraindications have been excluded, and personal or family consent have been ascertained. At least one organ donation has been performed in 370 hospitals in 2017.
The 20-minute no-touch period imposed by Italian law has prevented implementation of DCD programs for years.2 In 2015, following a 7-year pilot study, both uncontrolled and controlled DCD have been implemented in a few regions leading to successful kidney, liver,3 and lung4 transplants (Table 1). Innovative strategies based on donor normothermic regional perfusion (nRP) and ex situ organ perfusion have been key factors in preserving organ functionality and limiting ischemic damage despite the prolonged no-touch period5: 2- to 4-hour nRP is routinely performed by intensivists in all potential DCD donors (both controlled and uncontrolled) after the 20-minute no-touch period, monitoring organ function and lactate; recovered organs are then perfused during transport and in the transplant unit by MP under laboratory and bioptic control to assess quality as a basis for a final acceptance of transplantable grafts.3 Lungs have been recovered both with “only lung” uncontrolled DCD protocols in absence of nRP and in combination with splanchnic regional perfusion, using recruitment lung maneuvers and protective ventilation followed by ex vivo lung perfusion reconditioning and final graft assessment.4
The overall current donation potential is still much greater than the volume of realized donations; data from the Italian Registry of Deaths with Acute Cerebral Lesion in ICUs suggest that many BDs are not identified, causing a wide variability in the number of BD declarations and organ donors among regions ranging from 20 to >100 pmp and from 10 to 60 pmp, respectively6 (Figure 2). Expected but missing BD declarations mainly fall within the age range of 60 to 75 years, which is the largest group of patients, mostly suffering from stroke as cause of death. Nevertheless, the median age of utilized organ donors in Italy ranges from 60 to 65 years, and donors up to 99 years have been utilized for liver transplantation. Eventually, the number of donors in the Southern regions is greatly affected by a refusal rate of 40%, compared with 20% in best-performing regions.
More than 8800 patients are waitlisted in Italy (Table 1). The number of waitlisted patients has been stable over time; in 2017, a decline by 200 patients has been observed thanks to a record of 2000 performed transplants. The mean transplant waiting time for kidney and liver transplants is 2.1 and 0.4 years, respectively, with 2200 and 1450 newly listed patients and a mortality rate on the waitlist of 1.9% and 3.5%. A worrisome annual mortality rate of 8.6% is observed for patients waiting for lung transplants with average waiting times of 1.1 years. The increasing number of long-term ventricular assist device utilization (from 67 in 2010 to 131 in 2015) has possibly offset the decrease in utilized heart donors, keeping waiting list and mortality rates (5%) stable.
Organ transplantation is performed in >40 Italian hospitals, mainly located in the northern regions: 41 kidney, 22 liver, 11 lung, and 16 heart programs are active with sizable differences in the number of transplants per center (Table 1). Pilot programs for bowel, pancreatic isles, and vascularized composite allotransplantation transplants are performed in selected centers; hand (Monza, 2000) and face transplants (Rome, 2018); uterus transplantation has been approved in Catania (Sicily).
Transplant outcomes in Italy are of high quality with similar or better results compared with other European countries. The utilization of older deceased donors has increased through the implementation of specific protocols (including biopsies7); routine utilization shows encouraging results.8 Milano criteria9 for patients with hepatocellular carcinoma have been established and are currently used around the world for patients with hepatocellular carcinomas.10
The utilization of most recovered organs has been improved through nationwide organ reallocation; moreover, an intense exchange of organs based on international cooperation in Europe is routinely performed. Thanks to devoted regional funds for humanitarian health assistance or through the commitment of hospitals funded by the Church, pediatric transplants for patients referred by international charities/humanitarian organizations are also performed.
Transplants from living donors remain low and are only performed in few centers.
Paired kidney exchange programs have been implemented and include international cooperations (Spain and Portugal) with chains activated by living-related, altruistic and deceased donors.
A few Italian patients have traveled abroad to be transplanted, although there has not been any evidence of transplant tourism. Any financial remuneration for deceased or living organ donation is strictly forbidden, and World Health Organization principles are strictly observed.
Hematopoietic Stem Cell Transplant
The hematopoietic stem cell transplants started by the end of the 1970s. Numbers have steadily increased over the last 10 years; >50 000 transplants have been performed, with approximately two-thirds autologous and one-third allogenic donors (approximately 50% from unrelated donors). Currently, there are 87 transplant centers, 61 of which perform autologous and allogenic transplant procedures and 26 performing autologous hematopoietic stem cell transplants only. Moreover, 9 pediatric centers and 14 centers performing both adult and pediatric transplants are active. The search for adult voluntary donors and for units of cord blood is coordinated by the Italian Bone Marrow Donor Registry founded in 2001 as stated by Law 52/2001. With its 400 000 adult donors and >35 000 cord blood units, the Italian registry is one of largest registries, internationally.
The Italian National Transplant Centre coordinates and fosters international relationships with foreign in-the-field organizations. Since 2001, CNT and the Italian Transplant Network have engaged in bi- and multilateral agreements for international organ exchanges. Moreover, CNT has participated in several EU-funded projects (in 11 as principal investigator and 15 as coinvestigator) and in international collaborations at European or international levels, including the South Alliance for Transplant or the World Health Organization collaborating center NOTIFY.
With many achievements, several changes remain:
- Increase of deceased DBD organ donation; reduction of discrepancies between northern and southern regions
- Nationwide implementation of DCD programs and organ preservation by ex situ perfusion techniques
- Improvement of organ utilization
- Improvement of living organ donation, including paired kidney exchange programs
Addressing those challenges is expected to make an already well functioning Italian Transplantation structure even better.
The authors specially thank the Italian National Transplant Network, especially transplant centers, regional transplant coordination centers, hospital procurement coordinators, ICU staff and second-opinion experts, and all CNT staff.
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9. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–699.
10. Cillo U, Burra P, Mazzaferro V, et al; I-BELT (Italian Board of Experts in the Field of Liver Transplantation). A multistep, consensus-based approach to organ allocation in liver transplantation: toward a “blended principle model”. Am J Transplant. 2015;15(10):2552–2561.