How Spain Reached 40 Deceased Organ Donors per Million Population.

With 40 donors and more than 100 transplant procedures per million population in 2015, Spain holds a privileged position worldwide in providing transplant services to its patient population. The Spanish success derives from a specific organizational approach to ensure the systematic identification of opportunities for organ donation and their transition to actual donation and to promote public support for the donation of organs after death. The Spanish results are to be highlighted in the context of the dramatic decline in the incidence of brain death and the changes in end-of-life care practices in the country since the beginning of the century. This prompted the system to conceive the 40 donors per million population plan, with three specific objectives: (i) promoting the identification and early referral of possible organ donors from outside of the intensive care unit to consider elective non-therapeutic intensive care and incorporate the option of organ donation into end-of-life care; (ii) facilitating the use of organs from expanded criteria and non-standard risk donors; and (iii) developing the framework for the practice of donation after circulatory death. This article describes the actions undertaken and their impact on donation and transplantation activities.

End-of-life practices in patients with devastating brain injury in Spain: implications for organ donation. / Prácticas clínicas al final de la vida en pacientes con daño cerebral catastrófico en España: implicaciones para la donación de órganos.

OBJECTIVE: To describe end-of-life care practices relevant to organ donation in patients with devastating brain injury in Spain. DESIGN: A multicenter prospective study of a retrospective cohort. PERIOD: 1 November 2014 to 30 April 2015. SETTING: Sixty-eight hospitals authorized for organ procurement. PATIENTS: Patients dying from devastating brain injury (possible donors). Age: 1 month-85 years. PRIMARY ENDPOINTS: Type of care, donation after brain death, donation after circulatory death, intubation/ventilation, referral to the donor coordinator. RESULTS: A total of 1,970 possible donors were identified, of which half received active treatment in an Intensive Care Unit (ICU) until brain death (27%), cardiac arrest (5%) or the withdrawal of life-sustaining therapy (19%). Of the rest, 10% were admitted to the ICU to facilitate organ donation, while 39% were not admitted to the ICU. Of those patients who evolved to a brain death condition (n=695), most transitioned to actual donation (n=446; 64%). Of those who died following the withdrawal of life-sustaining therapy (n=537), 45 (8%) were converted into actual donation after circulatory death donors. The lack of a dedicated donation after circulatory death program was the main reason for non-donation. Thirty-seven percent of the possible donors were not intubated/ventilated at death, mainly because the professional in charge did not consider donation alter discarding therapeutic intubation. Thirty-six percent of the possible donors were never referred to the donor coordinator. CONCLUSIONS: Although deceased donation is optimized in Spain, there are still opportunities for improvement in the identification of possible donors outside the ICU and in the consideration of donation after circulatory death in patients who die following the withdrawal of life-sustaining therapy.

Intensive care practices in brain death diagnosis and organ donation.

We conducted a multicentre study of 1844 patients from 42 Spanish intensive care units, and analysed the clinical characteristics of brain death, the use of ancillary testing, and the clinical decisions taken after the diagnosis of brain death. The main cause of brain death was intracerebral haemorrhage (769/1844, 42%), followed by traumatic brain injury (343/1844, 19%) and subarachnoid haemorrhage (257/1844, 14%). The diagnosis of brain death was made rapidly (50% in the first 24 h). Of those patients who went on to die, the Glasgow Coma Scale on admission was ≤ 8/15 in 1146/1261 (91%) of patients with intracerebral haemorrhage, traumatic brain injury or anoxic encephalopathy; the Hunt and Hess Scale was 4-5 in 207/251 (83%) of patients following subarachnoid haemorrhage; and the National Institutes of Health Stroke Scale was ≥ 15 in 114/129 (89%) of patients with strokes. Brain death was diagnosed exclusively by clinical examination in 92/1844 (5%) of cases. Electroencephalography was the most frequently used ancillary test (1303/1752, 70.7%), followed by transcranial Doppler (652/1752, 37%). Organ donation took place in 70% of patients (1291/1844), with medical unsuitability (267/553, 48%) and family refusal (244/553, 13%) the main reasons for loss of potential donors. All life-sustaining measures were withdrawn in 413/553 of non-donors (75%).

Spanish consensus document for acceptance and rejection of kidneys from expanded criteria donors.

In the recent years, more than 60% of available deceased donors are either older than 50 yr or have significant vascular comorbidities. This makes the acceptance and rejection criteria of renal allografts very rigorous, especially in cases of younger recipients, and at the same time encourages live donations. In our country, there is a lack of homogeneity in the percentages of use of expanded criteria donor (ECD) allografts between the different autonomous communities. Furthermore, the criteria vary greatly, and in some cases, great importance is given to the biopsy while in others very little. In this study, we present a unified and homogenous criteria agreed upon by consensus of a 10-member Panel representing major scientific societies related to renal transplantation in Spain. The criteria are to be used in accepting and/or rejecting kidneys from the so-called ECDs. The goal was to standardize the use of these organs, to optimize the results, and most importantly to provide for the maximum well being of our patients. Finally, we believe that after taking into account the Panel's thorough review of specific scientific literature, this document will be adaptable to other national renal transplant programmes.

Benchmarking in the process of donation after brain death: a methodology to identify best performer hospitals.

A benchmarking approach was developed in Spain to identify and spread critical success factors in the process of donation after brain death. This paper describes the methodology to identify the best performer hospitals in the period 2003-2007 with 106 hospitals throughout the country participating in the project. The process of donation after brain death was structured into three phases: referral of possible donors after brain death (DBD) to critical care units (CCUs) from outside units, management of possible DBDs within the CCUs and obtaining consent for organ donation. Indicators to assess performance in each phase were constructed and the factors influencing these indicators were studied to ensure that comparable groups of hospitals could be established. Availability of neurosurgery and CCU resources had a positive impact on the referral of possible DBDs to CCUs and those hospitals with fewer annual potential DBDs more frequently achieved 100% consent rates. Hospitals were grouped into each subprocess according to influencing factors. Hospitals with the best results were identified for each phase and hospital group. The subsequent study of their practices will lead to the identification of critical factors for success, which implemented in an adapted way should fortunately lead to increasing organ availability.

Continuously evaluating performance in deceased donation: the Spanish quality assurance program.

The Spanish Quality Assurance Program applied to the process of donation after brain death entails an internal stage consisting of a continuous clinical chart review of deaths in critical care units (CCUs) performed by transplant coordinators and periodical external audits to selected centers. This paper describes the methodology and provides the most relevant results of this program, with information analyzed from 206,345 CCU deaths. According to the internal audit, 2.3% of hospital deaths and 12.4% of CCU deaths in Spain yield potential donors (clinical criteria consistent with brain death). Out of the potential donors, 54.6% become actual donors, 26% are lost due to medical unsuitability, 13.3% due to refusals to donation, 3.1% due to maintenance problems and 3% due to other reasons. Although the national pool of potential donors after brain death has progressively decreased from 65.2 per million population (pmp) in 2001 to 49 pmp in 2010, the number of actual donors after brain death has remained at about 30 pmp. External audits reveal that the number of actual donors could be 21.6% higher if all potential donors were identified and preventable losses avoided. We encourage other countries to develop similar comprehensive approaches to deceased donation performance.

International practices of organ donation.

Organ donation and transplant rates vary widely across the globe, but there remains an almost universal shortage of deceased donors. The unmet need for transplants has resulted in many systematic approaches to increase donor rates, but there have also been practices that have crossed the boundaries of legal and ethical acceptability. Recent years have seen intense interest from international political organizations, led by the World Health Organization, and professional bodies, led by The Transplantation Society. Their efforts have focused on the development of a series of legal and ethical frameworks, designed to encourage all countries to eradicate unacceptable practices while introducing programmes that strive to achieve national or regional self-sufficiency in meeting the need for organ transplants. These programmes should seek to reduce both the need for transplantation and also develop deceased donation to its maximum potential. Living donation remains the mainstay of transplantation in many parts of the world, and many of the controversial--and unacceptable--areas of practice are found in the exploitation of living donors. However, until lessons are learnt, and applied, from countries with highly developed deceased donor programmes, these abuses of human rights will be difficult to eradicate. A clear international framework is now in place to achieve this.

[The etiology of congenital diaphragmatic hernia and esophageal atresia: the Hox genes]. / Los genes Hox en la etiología de la hernia diafragmática congénita y la atresia de esófago.

BACKGROUND: Prenatal administration of adriamycin or nitrofen to pregnant mice produce in the embryos, respectively, esophageal atresia/VACTERL association (EA) or congenital diaphragmatic hernia (CDH). Various genes and signalling pathways like sonic hedgehog, Gli family, retinoic acid and homeotic genes have been pointed out in the origin of these malformations. Hox genes are master regulatory genes involved in embryo segmentation and other main development processes. Hoxa3, Hoxb3, Hoxc3, Hoxc4 and Hoxa5 knock-out mice show cardiac, tracheal, lung and diaphragmatic malformations, EA and phenotypes that resemble that of VACTERL syndrome. We present herein some of our findings in the expression of these genes in both experimental models. MATERIAL AND METHODS: Pregnant mice were exposed either to 4 mg/kg of adriamycin or vehicle on embryonic days 7,5 and 8,5; embryos were recovered at four endpoints (E13 to 16). On the other hand, nitrofen was given to pregnant mice on embryonic day 8th and embryos were recovered at E14, E16 and E19. The embryos or, separately, their lungs and hearts, were randomly processed for immunohistochemical or molecular biology studies (RT-PCR). We used antibodies for Hoxa3, Hoxb3 and Hoxd3 proteins and specific primers for Hoxa3, Hoxa5, Hoxb3, Hoxb5, Hoxc4 and Hoxd3 genes. RESULTS: EA: Upon immunohistochemistry, adriamycin-exposed embryos showed a severe decrease in expression of Hoxa3, Hoxb3 and Hoxb3 proteins in heart, skin, foregut but not in the heart. RT-PCR studies showed a statistically significant decrease of the four genes studied in the lungs of OA mice when compared to controls. CDH: Upon RT-PCR assessment the expression of Hoxa5 and Hoxb3 were higher in nitrofen-exposed mice than in controls on E14 and E19 and weaker on E16. As regards immunohistochemical localization, expression of the three genes was similar in nitrofen and control animals. CONCLUSIONS: Both experimental models exhibit an alteration in the expression of several proximal Hox genes, specially in lung and car- diac tissues. The malformations in these organs associated with CDH and EA could be in part caused by these alterations. Due to their specific participation in lung and foregut morphogenesis, their study could let us to better understand the mechanisms of CDH and EA.

Implementation of a National Priority Allocation System for Hypersensitized Patients in Spain, Based on Virtual Crossmatch: Initial Results.

Access to kidney transplantation for patients with high levels of antibodies against HLA is a major challenge. This issue makes it difficult to detect compatible donors for those patients in a certain geographical area. Consequently, hypersensitized patients remain on the waiting list for long periods and their quality of life deteriorates. Our purpose was to increase access to transplantation for highly sensitized patients by developing a national priority allocation system based on virtual crossmatch. Between June 15, 2015, and May 15, 2016, 675 patients on the kidney transplant waiting list with calculated panel-reactive antibodies ≥98% and undergoing dialysis for at least 12 months were included in the study; 86.1% of the patients had previously received at least one transplant. Solid-phase immunoassays were used to identify class I and II HLA antibodies in all patients. Participating hospitals assigned to the program one of the kidneys of every identified brain-dead real donor between 18 and 70 years old. Survival data were collected for the recipients transplanted between June 15, 2015, and December 31, 2015. In all, 475 (290 male and 185 female) brain-dead donors were assigned to the program. Virtual crossmatch was negative for 191 (41%) donors, 149 offers were accepted, and 102 (21.8%) kidneys were transplanted. At the end of the study, patient and graft survival were both 93.4%. The implementation of a national prioritization system based on virtual crossmatch increased access to transplantation for highly sensitized patients, with excellent results in terms of patient and graft survival.

Emergency organ transplantation in Spain: liver emergency and outcomes.

The 2 main indications for emergency liver transplantation are severe acute hepatic insufficiency and emergency retransplantation. In Spain, since the creation of the National Transplant Organisation (NTO), known as "the Spanish model," there have been high rates of donation, with a mean of 33.9 donors per million inhabitants in 2003 and 34.6 donors per million inhabitants in 2004. According to data provided by the NTO, there were 169 liver emergencies in the 2-year period 2003-2004. The time on the waiting list in an emergency situation was limited; 82.8% of cases were resolved in less than 48 hours. During this 2-year period, there were 2077 liver transplantations, including 128 emergence patients, which accounted for 6.1% of transplantations.

[Liver and intestinal transplant in paediatric population]. / El trasplante hepático e intestinal en la población pediátrica.

Our organizational model allows an annual 1,000 liver transplants. Pediatric liver transplantation constitutes 5% of such activity and provides, in children with severe, progressive and irreversible liver disease, a 1 year-survival of 90% and more than 80% after 15 years of follow-up. The main indication is biliary atresia followed by metabolic liver disease and acute liver failure. Around half of the procedures are performed in children under two years and 25-30% in the first year of life. The waiting list remains at around 35 patients, with an average of 100 patients enrolled annually and 60 of them finally transplanted after an average of 136.3 days on the waiting list. The prioritization of the candidates uses the PELD as an objective tool for decision-making. However, the progressive aging of donors, with a profile increasingly different from the requirements of the pediatric patients included in the waiting list, requires strategies such as living donor liver transplantation and the split liver transplantation, to increase the probability of transplant while reducing both time and mortality on the waiting list at the same time. Pediatric intestinal transplantation registers a low indication but involves strict requirements that outline a very uncommon donor in our country which, together with the absence of alternatives that outweigh the impact of these difficulties, penalizes the chances of transplant for these patients.

Renal metabolism of gut glucagon-like immunoreactivity.

To examine the role of the kidney in the catabolism of gut glucagon-like immunoreactivity (GLI), we compared the plasma GLI responses of normal and nephrectomized dogs given intraduodenal glucose loads and studied the clearance of gut GLI by the isolated perfused rat kidney. Both basal and postload plasma samples were analyzed with a glucagon C-terminal specific antibody and a GLI-reacting N-terminal antibody. The GLI response was taken to be the difference between the increments seen with these two antibodies after glucose loading. Although glucose-induced GLI increments could not be detected in untreated plasma from nephrectomized dogs, chromatographed plasma revealed a significant rise in GLI-fraction II (7000--12000 daltons) in both nephrectomized and normal dogs (732 +/- 200 and 586 +/- 111 pg/ml, respectively). We also found that crystalline glucagon was cleared by the isolated closed-circuit perfused rat kidney, but gut-GLI either as crude extract or as peak I (7000--12000 daltons) was not. Our data suggest that the kidney may not play an important role in gut-GLI catabolism.

International issues in transplantation. Setting the scene and flagging the most urgent and controversial issues.

Organ transplantation is the primary technique for treatment of end-stage organ failure and has benefited more than one million persons world wide. A number of patients have survived for well over 25 years and survival rates at 5 years can be 70% or higher for many organ transplant programs. However, currently more than 40,000 patients are waiting for a kidney, and in western Europe mortality rates for patients waiting for a heart, liver, or lung range from 15 to 30%. The potential need for transplants is even greater and this imbalance between supply and demand creates technical and ethical problems including the risk of organ trafficking. Consequently the number of available organs must be increased. In some cases the organ shortage reflects a true lack of donors, but more often it results from the failure to turn potential into actual donors. The transplant commission of the Council of Europe has just approved a document recommending that member states ensure that all potential donors are identified and as many as possible converted to actual donors. Even with the highest organ donation rate, the indications for organ and tissue transplantation will continue to increase, perpetuating the gap between supply and demand. Organ transplantation, whether living or cadaveric, might be supplemented or replaced by the use of artificial organs, although problems such as power supply, thrombosis, infection, and biocompatibility pose obstacles to long-term function. The use of animals as an alternative source is considered, but so many problems still remain unresolved that xenotransplantation cannot be put forth as a solution at this time. This paper reviews these issues and, citing the Spanish experience, offers strategies to improve the organ donation rate.

Factors that influence the development of an organ donation program.

The shortage of cadaveric donors is a universal problem that imposes a severe limit on the number of patients who can benefit from transplantation. At the same time, there is an ever-increasing demand for cadaveric solid organs all over the world. The organ shortage is not due to a lack of potential donors, but rather to a failure to turn many potential into actual donors. Spain is the only example in the world of continuous improvement in cadaveric organ donation registered in a large country during more than 10 years. This success is due to a proactive donor detection program performed by well-trained transplant coordinators, introduction of systematic death audits in hospitals, and the combination of a positive social atmosphere, an adequate management of mass media relations, and on adequate economic reimbursement for the hospitals. This model can be partial or totally adapted to other countries or regions, if basic conditions are guaranteed. A careful study of local characteristics, which influence organ donation in a direct or indirect way, should be performed before planning specific actions to improve organ donor rates. The principle factors that influence the development of this type of program are described in this article.

The potential organ donor pool: international figures.

By understanding the size and characteristics of the potential donor pool, the concentration and location of the potential donors and factors influencing low rates of donation, it is possible to identify opportunities to improve the organ donation system. The exact donor gap needs to be established for each hospital/area, as published figures do not necessary reflect local potential. Nevertheless, marked differences with respect to the minimum standards in the number, location, and characteristics of organ donors should be considered as suggestive of low performance. The first stage where potential donors are lost is the detection of people who can be diagnosed as brain dead and, hence, could be considered a potential organ donor. Improving the donor identification implies the development of donor detection programmes. That and other initiatives to improve the donation rate need to be started in hospitals after the assessment of the local potential and local factors specifically implicated in the local performance.