Principles of organ donation and transplantation

Introduction

Organ transplantation has revolutionised the treatment of end-stage organ failure and is arguably one of the greatest medical advances of the last century. Practice in organ donation and transplantation continues to evolve as a result of remarkable innovations in surgical technique, immunosuppression and organ perfusion and preservation. This has led to excellent post-transplantation survival rates ( Table 10.1 ) that have improved year on year.

Table 10.1

National 1-year and 5-year adult patient survival rates for abdominal organ transplantation in the UK

Source: NHS Blood and Transplant. Annual Report on Kidney Transplantation 2021/22, Pancreas and Islet Transplantation 2021/22 and Liver Transplantation 2021/22.

	1-year patient survival (%) ∗	5-year patient survival (%) ∗∗
Kidney
Living donor	99	94
Deceased donor	97	88
Pancreas	100	88
Simultaneous Pancreas-Kidney	98	91
Liver
Elective	95	84
Super-urgent	90	83

∗ Includes transplants performed between 1 April 2017 - 31 March 2021

∗∗ Includes transplants performed between 1 April 2013 - 31 March 2017

This chapter summarises the principles of organ donation and abdominal organ transplantation.

Principles of organ donation

Organs for transplantation may be donated from deceased donors or living donors. Worldwide, the number of donors falls drastically short of the number of patients in need of a transplant, and this is perhaps the greatest challenge currently faced by the transplant community.

Ethical and legal aspects of organ donation

Consent is the cornerstone of organ donation. The process of consent for organ donation varies according to medical, ethical, societal and legal factors in each country. For deceased organ donation, the legislative framework for consent may be an opt-out system (consent for organ donation is presumed unless the person has specifically registered to opt out) or an opt-in system (explicit consent for organ donation is required). Both systems can be implemented on either a hard basis, where primacy is given to the donor’s wishes, or a soft basis, where family members’ views are considered ( Table 10.2 ). In recent years, there has been a trend towards conversion to opt-out systems in an effort to improve donation rates. For example, in the UK, soft opt-out systems were introduced in Wales in December 2015, in England in May 2020 and in Scotland in March 2021. Under this legislation, all adults who have not opted out, possess the mental capacity to understand the law and have lived in the country for more than 12 months before their death will be deemed to have authorised donation of their organs for transplantation. The legislation is applied softly; thus, if there is objection from family members, organ donation does not proceed. At the time of writing, Northern Ireland still operates under a soft opt-in system but has recently held a consultation on introduction of a soft opt-out system. The benefits of an opt-out approach are hotly debated and evidence is limited. Some studies have shown an association between opt-out systems and higher rates of deceased donation, ^, ^, while others have shown no significant difference in deceased donation rates between opt-in and opt-out systems but have demonstrated that the latter is in fact associated with lower rates of living organ donation. Introduction of an opt-out system is unlikely to provide the sole solution to increasing deceased organ donation rates as other factors such as intensive care capacity, the infrastructure of the transplantation service, healthcare investment as well as public attitudes and awareness play a role.

Table 10.2

Consent systems for deceased organ donation

	Opt-out	Opt-in
Hard	Consent for deceased organ donation is presumed, unless a person has registered to opt out. If a person has not registered to opt out, organ donation can proceed even if family members object	Consent for deceased organ donation is based on whether a person has registered to opt in. If a person has registered to opt in, organ donation can proceed even if family members object
Soft	Consent for deceased organ donation is presumed, unless a person has registered to opt out. If a person has not registered to opt out, organ donation does not proceed if family members object	Consent for deceased organ donation is based on whether a person has registered to opt in. If a person has registered to opt in, organ donation does not proceed if family members object

Living organ donation generates unique ethical concerns. Subjecting healthy individuals to a major surgical procedure with an inherent risk of harm but no physical benefit challenges the ethical principle of nonmaleficence. However, autonomy and beneficence must also be considered; an individual has the right to make an informed decision about becoming a living donor, they may gain significant psychological benefit from the act and could potentially suffer psychological harm if donation does not take place. Valid consent is the fundamental principle underpinning legislation for living donation. It is crucial to ensure that consent for living donation is given voluntarily, without coercion, without any form of reward and from a person who has full capacity to make informed decisions. In the UK, consent for living donation is an extensive process involving an independent regulator, the Human Tissue Authority (HTA), which assesses each individual living donor and recipient to ensure that valid consent has been given.

The global shortage of organ donors has led to the emergence of unethical practices in transplantation. Organ trafficking, transplant commercialism and transplant tourism ( Box 10.1 ) exploit vulnerable and impoverished people through the illicit removal and sale of their organs. These practices are prohibited by the World Health Organisation (WHO) Guiding Principles on Human Cell, Tissue and Organ Transplantation and the Declaration of Istanbul, ^, which provide international ethical standards for organ transplantation.

Organ trafficking, transplant commercialism and transplant tourism are unethical practices that should be prohibited and criminalised, as they exploit vulnerable people, impede equitable access to organ transplantation and prevent countries from achieving self-sufficiency in organ transplantation. ^,

Box 10.1

Definitions of unethical practices in organ transplantation as set out by the declaration of Istanbul

Source: Reprinted from The Lancet, Vol. 372, Steering Committee of the Istanbul Summit, Organ trafficking and transplant tourism and commercialism: the Declaration of Istanbul, (9632):pages 5-6, Copyright (2008) with permission from Elsevier.

Organ trafficking is the recruitment, transport, transfer, harbouring or receipt of living or deceased persons or their organs by means of threat or use of force or other forms of coercion, of abduction, of fraud, of deception, of the abuse of power or of a position of vulnerability, or of the giving to, or the receiving by, a third party of payments or benefits to achieve the transfer of control over the potential donor, for the purpose of exploitation by the removal of organs for transplantation.
Transplant commercialism is a policy or practice in which an organ is treated as a commodity, including by being bought or sold or used for material gain.
Travel for transplantation is the movement of organs, donors, recipients or transplant professionals across jurisdictional borders for transplantation purposes. Travel for transplantation becomes transplant tourism if it involves organ trafficking and/or transplant commercialism or if the resources (organs, professionals and transplant centres) devoted to providing transplants to patients from outside a country undermine the country’s ability to provide transplant services for its own population.

Deceased organ donation

Deceased organ donors may be donors after brain death (DBD) or donors after circulatory death (DCD). Internationally, the majority of organs transplanted from deceased donors are recovered from DBD donors, only a limited number of countries have developed DCD programmes.

Donor identification and referral

The identification and referral of potential deceased organ donors is a fundamental step in the deceased donation process and should be seen as a routine part of end-of-life care. Failure of this step is one of the main reasons for significant differences in deceased donation rates between countries. All clinicians have a responsibility to recognise if a patient under their care becomes a potential organ donor, and to initiate discussions with specialist nurses in organ donation (SNODs) (previously known as transplant coordinators) as early as possible. The General Medical Council (GMC) has published guidance on the duties of doctors with respect to end-of-life care and organ donation ( Box 10.2 ).

Box 10.2

General Medical Council (GMC) guidance regarding end-of-life care and organ donation

Source: General Medical Council, Treatment and care towards the end of life: good practice in decision making © 2010 General Medical Council. Available from: http://www.gmc-uk.org/static/documents/content/Treatment_and_care_towards_the_end_of_life_English_1015.pdf .

81.
If a patient is close to death and their views cannot be determined, you should be prepared to explore with those close to them whether they had expressed any views about organ or tissue donation, if donation is likely to be a possibility.
82.
You should follow any national procedures for identifying potential organ donors and, in appropriate cases, for notifying the local transplant coordinator. You must take account of the requirements in relevant legislation and in any supporting codes of practice, in any discussions that you have with the patient or those close to them. You should make clear that any decision about whether the patient would be a suitable candidate for donation would be made by the transplant coordinator or team, and not by you and the team providing treatment.

Clinical triggers can aid the identification of potential organ donors. UK National Institute for Health and Care Excellence (NICE) guidelines recommend referral to the SNOD if either of the following criteria are met:

1.
A patient with catastrophic brain injury with
- the absence of one or more cranial nerve reflexes and
- a Glasgow Coma Scale (GCS) score of 4 or less that is not explained by sedation and/or
- a decision is made to perform brain stem death tests.
2.
A patient with a life-threatening or life-limiting condition where
- a decision has been made to withdraw life-sustaining treatment and
- this is expected to result in circulatory death.

In order for deceased donation to be successfully realised into a transplant, a sequence of complex steps must be achieved including donor referral, confirmation of brain death (if DBD), assessment of donor suitability, valid consent, tissue typing/screening, coordination of resources for organ retrieval (e.g. operating rooms, anaesthesia, theatre staff etc), allocation of organs and transportation of organs to the accepting centres. It is increasingly recognised that specialised health professionals play an important role in the organ donation and transplantation pathway. In the UK, SNODs facilitate the entire donation process and are trained in communication, family support and end-of-life discussions. When a SNOD is involved in approaching families of eligible donors about deceased donation, the consent rate is significantly higher than when a SNOD is not involved (71% vs 29%, respectively). Similar findings have been reported in other countries.

When trained specialist organ donation professionals are involved in deceased organ donation discussions, the consent rate is significantly higher. ^,

Donation after brain death

Donation after brain death requires determination of death by neurological criteria. The concept of brain death was first proposed by Harvard Medical School in 1967. Advances in intensive care techniques meant that comatose patients could be maintained on mechanical ventilation, despite loss of brainstem function and therefore loss of the capacity for spontaneous respiration and consciousness. Consequently, it was proposed that such cases of irreversible coma due to permanent damage to the brain could be defined as death. Subsequently, the concept of brain death was gradually accepted more widely. In the UK, a statement by the Conference of Medical Royal Colleges and their Faculties in 1979 concluded for the first time that brain death equated to the death of the whole person. ^, The current criteria for the diagnosis of brainstem death in the UK are shown in Table 10.3 .

The UK code of practice for the diagnosis of death provides clear criteria for confirming brainstem death and circulatory death.

Table 10.3

Criteria for diagnosis of brainstem death in the UK

Source: Academy of Medical Royal Colleges. A code of practice for the diagnosis and confirmation of death. 2008. http://aomrc.org.uk/wp-content/uploads/2016/04/Code_Practice_Confirmation_Diagnosis_Death_1008-4.pdf . Reproduced with permission.

Preconditions

Patient is deeply comatose, unresponsive and apnoeic with his/her lungs being artificially ventilated
Patient’s condition is due to irreversible brain damage of known aetiology

Exclusions

There should be no evidence that this state is due to:
Depressant drugs
Neuromuscular blocking drugs
Hypothermia ∗
Circulatory, metabolic or endocrine disturbance

Clinical examination

Absence of brainstem reflexes:
Pupils are fixed and do not respond to sharp changes in the intensity of incident light
No corneal reflex
No oculo-vestibular reflex ^∗∗
No motor responses within the cranial nerve distribution by adequate stimulation of any somatic area
No cough reflex response to bronchial stimulation by a suction catheter placed down the trachea to the carina
No gag reflex to stimulation of the posterior pharynx with a spatula
Apnoea despite an induced moderate hypercarbia and mild acidaemia ^∗∗∗

∗ Core temperature should be > 34°C at the time of testing.

∗∗ Caloric test: no eye movements are seen during or following the slow injection of at least 50 mL of ice-cold water over 1 minute into each external auditory meatus in turn. Clear access to the tympanic membrane must be established by direct inspection and the head should be at 30° to the horizontal plane, unless this positioning is contraindicated by the presence of an unstable spinal injury.

∗∗∗ The apnoea test should be the last brainstem reflex to be tested and should not be performed if any of the preceding tests confirm the presence of brainstem reflexes. A controlled rise in arterial PaCO ₂ (> 6.0 KPa or > 6.5 KPa in the context of chronic CO ₂ retention or intravenous bicarbonate) with corresponding acidaemia (pH < 7.40) should be induced whilst maintaining a normal PaO ₂ and blood pressure. The patient should be disconnected from the ventilator for 5 minutes to confirm no spontaneous respiratory response. A further confirmatory arterial blood gas sample should be obtained to ensure that the PaCO ₂ has increased from the starting level by more than 0.5 KPa.

Brainstem death testing must be carried out by two doctors (at least one of which should be a consultant) who have been registered for more than 5 years and are competent in the procedure. Neither doctor should be a member of the transplant team. Testing should be undertaken by the doctors together and on two separate occasions. Death will be confirmed after the second set of tests, but the legal time of death is after completion of the first set of tests. The diagnosis of brainstem death can generally be confirmed by clinical criteria alone, but on rare occasions where there is uncertainty over the completion or interpretation of clinical examination (e.g. extensive facio-maxillary injuries, high cervical cord injury), ancillary tests may be required (e.g. cerebral angiography, electroencephalogram, evoked potentials). There are considerable international differences in the definition of brain death. For instance, in the USA, irreversible loss of all brain function (including the brainstem) must be confirmed, while in the UK confirmation of irreversible cessation of brainstem function is adequate (based upon the fact that the capacity for consciousness and cardiorespiratory function reside in the brainstem). There is also wide variation in the diagnostic criteria for brain death, including whether apnoea testing is required and the way in which it is conducted, the number and seniority of clinicians required for brain death testing and whether ancillary tests are mandatory. ^, Furthermore, in some countries brain death is not legally or culturally accepted as the death of an individual under any circumstances.

Brainstem death may result from intracranial causes such as trauma or haemorrhage, or from extracranial causes such as cardiorespiratory arrest leading to impaired cerebral perfusion. Brainstem death triggers complex physiological changes that jeopardise organ function and ultimately lead to cardiac arrest. Effective management of DBD donors involves active care from the time of brainstem death to the point of organ retrieval in order to prevent organ damage and maximise the number of transplantable organs. Around the time of brainstem death there is a rise in intracranial pressure, which limits cerebral perfusion and oxygen delivery. Cushing’s reflex describes the compensatory hypertension that ensues as an attempt to restore cerebral perfusion, which stimulates arterial baroreceptors and causes reflex bradycardia. Subsequently, there is a period of intense sympathetic activity (the catecholamine storm), followed by an agonal phase of hypotension with reduced vasomotor tone, impaired cardiac output, neurogenic pulmonary oedema and a systemic inflammatory response. Loss of central regulation results in haemodynamic instability, hypothermia and diabetes insipidus. Without adequate therapy, rapid deterioration and cardiac arrest follow. Optimal donor management is aimed at detecting and correcting the cardiovascular, respiratory and metabolic derangement of brainstem death. Therapy should be based on specific physiological targets ( Box 10.3 ), and typically involves correction of hypovolaemia, vasoconstriction, lung protective ventilation and the administration of hormonal therapy including methylprednisolone, vasopressin and insulin. Active donor management is continued whilst the donor is transferred to the operating theatre for the multiorgan retrieval procedure and up until the point that the aorta is cannulated and organs are perfused in situ with cold preservation fluid.

Box 10.3

Physiological targets in the management of brainstem death donors

Source: NHS Blood and Transplant. UK National Organ Donation Commitee. DBD donor optimisation extended care bundle. 2012. https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/4522/donor-optimisation-extended-care-bundle.pdf .

Pa o ₂ ≥ 10.0 kPa ( F i o ₂ < 0.4 as able)
Pa co ₂ 5–6.5 kPa (or higher as long as pH > 7.25)
MAP 60–80 mmHg
CVP 4–10 mmHg (secondary goal)
Cardiac index > 2.1 L/min/m ²
S cv o ₂ > 60 %
SVRI (secondary goal) 1800–2400 dyn∗s/cm ⁵ /m ²
Temperature 36–37.5°C
Blood glucose 4.0–10.0 mmol/L
Urine output 0.5–2.0 mL/kg/h

Donation after circulatory death

Donation after circulatory death occurs after the irreversible cessation of cardiorespiratory function. The clinical scenario in which cardiorespiratory arrest occurs can be classified into four different categories known as the Maastricht Classification, which were first described in 1995 and subsequently updated in 2013 ( Table 10.4 ). These categories can be described as either ‘controlled’ or ‘uncontrolled’, referring to whether cardiac arrest was planned and expected or sudden and unexpected, respectively. In most countries, the majority of DCD donations are ‘controlled’ Maastricht category III. This is usually in the context of a critically ill patient who does not fulfil the criteria for brainstem death, but where life-sustaining cardiorespiratory support is no longer considered to be in the patient’s best interests, and is withdrawn under controlled circumstances. ‘Uncontrolled’ donation is the predominant type of DCD donation in a limited number of countries (e.g. Spain, France).

The Maastricht classification is the universally accepted method for describing the four categories of donors after circulatory death.

Table 10.4

Modified Maastricht classification of donation after circulatory death

Reproduced from Thuong M, Ruiz A, Evrard P, et al. New classification of donation after circulatory death donors definitions and terminology. Transpl Int 2016;29(7):749-59 with permission from John Wiley & Sons, Inc.

Type	Category	Circumstances	Scenario
Uncontrolled	I	Found dead Ia. Out of hospital Ib. In hospital	Sudden unexpected cardiac arrest, with no attempt at resuscitation by a medical team
Uncontrolled	II	Witnessed cardiac arrest IIa. Out of hospital IIb. In hospital	Sudden unexpected cardiac arrest, with unsuccessful attempt at resuscitation by a medical team
Controlled	III	Withdrawal of life-sustaining therapy	Planned expected cardiac arrest, following the withdrawal of life-sustaining therapy
Uncontrolled or Controlled	IV	Cardiac arrest while brain dead	Sudden unexpected or planned expected cardiac arrest after brain death diagnosis, but before organ recovery

After confirmation of circulatory death, there is a mandatory ‘no touch’ observation period before organ retrieval can commence. In most countries (including the UK), this period is 5 minutes, but it varies from 2 minutes in Australia to 30 minutes in Russia. ^,

Despite a substantial increase in DCD donation in recent years, its practice is not universally accepted. In some countries such as the Netherlands and the UK, DCD donation now accounts for around 40–60% of all deceased donors. However, in most countries DCD donation remains uncommon, and in several countries it is prohibited by the law (e.g. Germany, Greece, Estonia).

A major concern over the use of DCD organs is the exposure to longer periods of warm ischaemia, leading to potentially inferior graft outcomes. Warm ischaemia is of particular concern because at normothermic temperatures full metabolic processes continue, thus inducing more rapid ischaemic damage than under hypothermic conditions when metabolism is slowed. Following withdrawal of life-sustaining treatment in a DCD donor, cardiovascular instability causes organ hypoperfusion. Functional warm ischaemia starts when there is a sustained (at least 2 minutes) fall of systolic blood pressure below 50 mmHg and continues throughout the subsequent period of circulatory arrest until in situ cold perfusion is instituted. The definition of functional warm ischemia is not universally agreed and therefore other indicators such as withdrawal time (e.g. time from withdrawal of therapy to circulatory arrest) or true warm ischaemia time (e.g. time from circulatory arrest to in situ perfusion) are used in the literature. Once death is verified and the mandatory ‘no touch’ period is completed, the donor is transferred to the operating theatre and undergoes rapid laparotomy for organ retrieval. It is only when cold perfusion is achieved and the organs are cooled that warm ischaemia is halted and the period of cold ischaemia begins. The same metabolic processes that lead to cell death continue during cold ischaemia but at a much slower rate, and so cells and organs are able to survive for longer periods. Guidelines for maximum functional warm ischaemia times for specific organs are shown in Table 10.5 .

Table 10.5

Recommended maximum functional warm ischaemia times for donation after circulatory death

Source: NHS Blood and Transplant. National standards for organ retrieval form deceased donors. MPD1043/8, 2018. Available from: https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/12548/mpd1043-nors-standard.pdf .

Organ	Stand-down time from the onset of functional warm ischaemia
Liver	30 minutes
Pancreas	30 minutes
Lungs	60 minutes
Kidney	180 minutes

DCD organs are associated with a higher risk of post-transplantation complications such as delayed graft function in kidney grafts, ^, graft thrombosis in pancreas grafts and biliary complications including ischaemic cholangiopathy in liver grafts. Despite this, patient and graft survival rates are comparable between DCD and DBD grafts for kidney, lung and pancreas transplantation. ^, For liver transplantation, the evidence is less clear, with early reports demonstrating inferior graft and patient survival from DCD compared with DBD livers, ^, but more contemporary meta-analysis suggesting this may no longer be the case.

DCD liver transplantation is associated with a higher risk of biliary complications including ischaemic cholangiopathy.

Short- and long-term survival outcomes are similar between DBD and DCD kidney transplantation; however, DCD grafts are associated with a higher risk of delayed graft function.

There is no difference in short- and long-term survival outcomes between DBD and DCD pancreas transplantation. DCD grafts are associated with a higher risk of graft thrombosis unless antemortem heparin is administered (antemortem heparin administration is prohibited in some countries including the UK).

There is growing interest in the use of machine perfusion technology to minimise the consequences of ischaemia. These technologies can be applied either in situ or ex situ and at hypothermic or normothermic temperatures. Normothermic regional perfusion (NRP) is a recent advance in DCD donation. It involves perfusing the abdominal (A-NRP) or thoraco-abdominal organs (TA-NRP) in situ with oxygenated blood at body temperature using a modified extracorporeal membrane oxygenator (ECMO) circuit following circulatory arrest and prior to cold perfusion and organ retrieval. Initial results from observational studies suggest that NRP reduces the risk of ischaemic cholangiopathy and improves early graft survival in DCD livers. ^, Further evidence from randomised controlled trials and for other organs is awaited. Ex situ machine perfusion is also being explored for liver transplantation with encouraging early results. These techniques allow for more objective assessment of organ viability and enable organ ‘resuscitation’ prior to transplantation. Ex situ hypothermic machine perfusion is increasingly used in kidneys as an alternative to cold static storage during transport, with good evidence for decreased rates of delayed graft function and better short-term graft survival.

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