Gabriel C. Oniscu

Introduction

The remarkable progress of kidney transplantation over the past five decades has been brought about by surgical refinements, developments in immunosuppression and a better understanding of post-transplant care, with consequent reduction in acute rejection and graft failure rates and a continuous improvement in long-term outcome. Kidney transplantation is now available despite the social and legal realities of various societies worldwide. More recent years have brought new and tougher challenges. A non-exhaustive list includes extended criteria donors, donation after cardiac death (DCD), challenging comorbidity of transplant candidates, more transplant candidates than ever before and complex ethical dilemmas.So have we reached the limit of what is achievable? The answer is far from that. Renal transplantation is on the brink of an evolution/revolution that will translate into better organs, more transplants and better long-term outcome for the recipients.

This chapter will discuss the recent developments in renal transplantation, highlighting current practice and future trends at various stages of the patient’s journey.

Demand inflation or supply recession?

Renal transplantation is firmly established as the optimal form of renal replacement therapy. Despite significant improvements in dialysis, transplantation remains superior, both in terms of survival and quality of life.¹ In fact, very few patients will not benefit from transplantation.² And herein lies our problem, as nearly every patient who starts dialysis aspires to receive a renal transplant. An escalating demand for transplantation has been evident over the years, patients joining the transplant lists in higher numbers than ever before. The demographic trend to an ageing population in many countries has also led to an increase in the age of patients requiring transplantation. Currently in the UK, one-third of the waiting list patients are aged 60 or over and 25% of the transplants are performed in this age group (Fig. 7.1). A similar trend has been seen in the USA, where older patients represent the fastest growing group on the list.

Unfortunately, the rise in demand means that not everybody will become a transplant candidate. Rationing policies (overt or covert) lead to a significant number of patients, particularly of older age, never joining the list. Despite the fact that some of the reasons are clear (comorbidity burden), there remains a wide practice variation in the evaluation of transplant candidacy,³ which inevitably leads to a well-documented inequity in access. Similarly, those patients who do join the waiting list require a more careful assessment to ensure their suitability for a transplant, in the current context of longer waiting times. Sadly, the increase in waiting time has been associated with an increase in waiting list mortality, which ranges from around 3% per 100 waiting-list years for young patients to around 9% for patients aged 65 or over (US data). These two intertwined factors have led to the inevitable question that perhaps the current demand may be artificially too high. Several studies have shown that some groups of patients (e.g. the elderly) will spend a disproportionate amount of time on the list and the chance of transplantation reduces dramatically with increasing waiting times. Furthermore, all patients over 60 years of age currently joining the waiting list have a 50% risk of dying on the list, without a kidney transplant.⁴ In an ideal world, these patients may well benefit from transplantation but, in reality, their hopes may be inappropriately raised by a listing decision.⁵

In many countries, the number of available deceased donor organs has reached a peak and despite repeated initiatives to increase donation, and a relaxation of donor acceptance criteria (e.g. extended criteria donors), the gap is ever increasing. Many of the reasons for this trend have been well documented (reduction in trauma death, better neurological care, ageing population). Although an increase in living donation has offered some hope, in many countries even this form of donation has been static over the last few years.

Innovations in living donation

Since the early days of transplantation, living donation has seen a phenomenal expansion. In the UK, this expansion has been more obvious since 2008, with the number of living donor transplants exceeding that of deceased donor kidney transplants for the last four consecutive years. However, in other countries, such as the USA, living donation has been relatively static since 2004, with around 6000 transplants performed each year.

Changes in surgical techniques (discussed later in the chapter) are considered to be the driving force behind the exponential expansion seen in the late 1990s. However, in order to allow further expansion, new strategies were required.

Altruistic donation (non-directed donation) has seen a surge following the reported success of spousal and unrelated living donor transplantation with ‘read across’ to stranger donation.⁶ This has introduced a whole new level of complexity and ethical dilemmas in the evaluation of the living donor. However, beyond the ethical challenges (motivation, nature of altruism, emotional benefit derived from donation), it is widely accepted that there are benefits in the practice of altruistic donation, as donors gain self-esteem and the society sees an increase in the donor pool. Altruistic donor kidneys are allocated to a matched recipient on the waiting list and this can be carried out by use of one of a number of models of allocation: donor-centric, recipient-centric and socio-centric allocation.^7,8 In the donor-centric setting, the kidney is allocated to the recipient likely to have the best outcome, whilst in the recipient-centric scenario, the kidney is allocated to the patient with the greatest need. The socio-centric model treats the kidney as a national resource and is allocated as per national algorithm as for any deceased donor kidney.

Kidney paired donation was initially proposed in 1986⁹ in order to allow two incompatible donor–recipient pairs to exchange kidneys to allow two compatible transplants to take place. Donor–recipient incompatibility accounts for approximately 35–50% of pairs being declined transplantation,^10,11 and represents a significant obstacle for further expansion of living donation.

In order to increase the donor pool and the number of potential matches, several variations of paired donation have been developed. Paired donation may now include a three-way (or higher number) of exchanges, which although logistically more challenging make the finding of a matched pair easier. Another protocol involves the deceased donor waiting list (list paired donation), whereby the incompatible living donor donates to a recipient on the list and in return, their incompatible recipient acquires priority on the waiting list for a deceased donor.¹² An alternative paired exchange protocol (altruistic unbalanced paired kidney exchange) includes compatible pairs in the match run.^13,14 These pairs may participate in exchange schemes for medical reasons (finding a younger donor or a better match) or altruistic reasons (helping another incompatible pair). Although ethically complex, this approach could lead to a 10% increase in the number of transplants in a paired programme.

Altruistic donation has been combined with the paired exchange programmes in order to increase the flexibility of the paired schemes and increase the potential donor pool for match runs. In a domino paired donation, the altruistic kidney donor initiates a chain of matches, by donating the kidney to the first recipient. The recipient’s incompatible donor then donates to the next compatible recipient, whose donor donates to the national waiting list, creating a domino effect.⁷ This scheme could be extended to include multiple centres and several incompatible pairs before finally transplanting a recipient on the deceased donor list.¹⁵ An alternative arrangement is the non-simultaneous extended altruistic donor (NEAD) chain.¹⁶ This consists of domino paired donation segments, except that the last donor in the first segment (‘bridge donor’) is asked to donate later and trigger another segment of the chain. The NEAD chain is a significant departure from the requirement of simultaneous donation in the paired exchange, but so far no chains have been broken due to a donor’s unwillingness to donate, once their incompatible recipient has been transplanted. This new approach raises the prospect of multiple transplants with shorter waiting times, but does require an entirely new level of logistics and cooperation, all within a delicate ethical environment.

Paired exchange and altruistic donation options are summarised in Fig. 7.2.

Incompatible transplantation

The above developments are relatively new and the impact on reducing the number of incompatible pairs that can be transplanted in the paired exchange schemes is yet to be fully understood. It is estimated that around 30% of the incompatible pairs cannot be transplanted in the paired exchange scheme and for these patients, transplantation across blood group or sensitisation barriers is the only option. Despite initial poor results, novel protocols have facilitated transplantation for ABO- and human leucocyte antigen (HLA)-incompatible transplant recipients with better levels of success.

Trends in deceased kidney donation

Traditionally, kidneys are the most commonly donated organs. Allowing for wide international variations, and some potential for development in emerging transplant nations, it is true to say that in many countries the number of donors after brain death (DBDs) has peaked. Changes in population demographics, a reduction in death from trauma and changes in neurosurgical practice have contributed to these trends. Furthermore, changes in population demographics have also meant that donors are more likely to be older and have more comorbid conditions, leading to more marginal organs being accepted for transplantation.

The decrease in DBD organs has been replaced by a resurgence of donation after cardiac death (DCD) and currently, in the UK, one-third of all kidney transplants are from DCD donors. This increase is an under-representation of the upsurge in real activity, as even in the most dynamic DCD programmes, only approximately 20–25% of referrals proceed to actual donation.²⁵ The utilisation rate of DCD is highest in the UK (93%) compared with all other European countries.²⁶

DCD donation is established in the USA and 10 European countries (Austria, Belgium, Czech Republic, France, Italy, Latvia, the Netherlands, Spain, Switzerland and UK). In six other European countries (Finland, Germany, Greece, Poland, Portugal and Luxembourg), DCD donation is yet to be legalised.

The recent revival of category II DCD donation is largely due to the success of the Spanish programmes.²⁷ The fundamental difference between the current Spanish programmes and the earlier category II DCD programmes (such as the ones in Newcastle and Leicester in the UK) is the use of normothermic regional perfusion (NRP) to optimise the function of abdominal organs.

The organisation of a category II DCD programme requires significant logistics and excellent cooperation between donation teams and extra-hospital services (ambulance, legal authorities and police). Close working between the transplant unit and the emergency department is key.

The complex ethical questions facing category II DCD donation have been debated widely,²⁸ but it is important to reiterate that an open and sensitive discussion, within the legal framework and moral environment of each individual country, is likely to resolve many of these issues and facilitate such programmes. The benefit is likely to be substantial.