Organ transplantation from donors after circulatory death

Summary

The scarcity of organs for transplantation resulted in the increase of organ donation after circulatory death. This review describes the current practice with donors after circulatory death (DCD), recent classification of DCD and organ procurement from DCD. Then the outcome of organ transplantation from is discussed and the new strategies in DCD are presented.

Despite of the fact that DCD are extended criteria donors, strict organ selection and novel technologies as machine perfusion or normothermic perfusion allows better utilization of DCD with a similar outcome as from donors after brain death.

Keywords:
organ transplantation, organ donation, circulatory death, machine perfusion, outcome

INTRODUCTION

Since many years organ transplantation has been a recognized treatment of end-stage organ failure (1). Majority of transplanted organs come from the deceased donors, however in some countries living liver or living kidney donation is well established (2).

Depending on the mechanism of death we recognize two types of deceased donors: donors after brain death (DBD), in whom brain death is diagnosed, and donors after circulatory death (DCD), previously described as nonheart-beating donors or donors after cardiac death. In the early years of organ transplantation all transplanted organs came from DCD, as neurological criteria for human death (so called Harvard criteria of brain death) were described and accepted only in 1967 (3). Since then most of the organs for transplantation have been procured from DBD and many countries introduced a legal acts regulating the criteria of diagnosis of brain death and organ donation from DBD.

The development of surgical and anesthesiological techniques as well as progress in immunosuppressive treatment resulted in the increased number of transplantations. In the same time the main limitation of organ transplantation became the scarcity of available DBD, especially in countries where living donation was limited. This was a main reason for a growing interest in donation after circulatory death in many countries.

The aim of this review is to summarize the current status of donation after circulatory death and the outcome of organ transplantation from DCD.

CLASSIFICATION OF DCD AND DIAGNOSIS OF DEATH IN DCD

DCD categories

Increasing interest in DCD as well as a need for standardization of donation procedure in DCD resulted in the first International Workshop on Nonheart-Beating donors in Maastricht, the Netherlands in 1995, which set up criteria of death declaration in DCD and 4 categories of DCD (4). Several modifications of so-called Maastricht classification of DCD have been proposed and recently the newest modified classification of DCD has been published (table 1) (5–8).

Two first categories (I and II) are called uncontrolled DCD, as in both categories duration of the warm ischemia is usually long as the cessation of circulation occurs as an uncontrolled event. In category I there is no attempt to resuscitation by medical team ("dead on arrival"), so the main limitation for acceptance of a deceased person as a donor is duration of warm ischemia, which should be no longer than 45 minutes (8). Category II encompasses patients with unsuccessful cardio-pulmonary resuscitation. In both categories additional subcategories had been added: IA and IIA when the cessation of circulation was outside the hospital (out-of-hospital), and IB and IIB when it occurred in the hospital (in-hospital). Category III and IV are described as controlled DCD. In category III circulatory death is expected after a planned withdrawal of life-sustaining treatment (WLST) (cardiorespiratory support). A multi-disciplinary team in agreement with a family takes the medical decision of WLST, when further treatment is considered futile. Donors in category IV have a diagnosis of brain death (DBD), however prior to the organ procurement unexpected cessation of circulation occurs. In some European countries, where euthanasia is authorized (Belgium, Luxembourg, the Netherlands), the category V of DCD is recognized, which includes donors with medical-assisted circulatory arrest (9).

Currently, category III DCD predominates in countries like Belgium, the Netherlands, UK and USA, whereas category II DCD in France and in Spain (10).

Diagnosis of death in DCD

In DCD death is diagnosed based on cardio-pulmonary criteria (11). It means that after cessation of circulation either after WLST treatment in category III DCD or after discontinuation of resuscitation in category I and II DCD there is a certain period of time, when no therapeutic action is taken – this is so-called "no-touch" period. Only after this period the patient’s death can be diagnosed and donation procedure can be started. Important to note is that "no-touch" period is not used in type IV DCD, in whom brain death has been already declared.

First recommendations from the first International Workshop on Nonheart-Beating donors suggested that "no-touch" period should be of 10 minutes; however, it was shortened to 5 minutes after publication of recommendations of Institute of Medicine in 1998 (4, 12). Nevertheless, depending on the legal regulations "no-touch" period differs between the countries from 2 to 20 minutes (table 2) (4).

ORGAN PROCUREMENT IN DCD

Organ procurement in DCD differs from that in DBD, mostly due the fact that circulatory arrest occurs before starting perfusion with cold preservation solution. There are also differences in the approach to organ donation in the uncontrolled DCD (type I and II) and controlled DCD (type III–V) due to logistics of the procurement (figure 1) (13–15).

The main goal in the first phase of organ procurement is to limit to the minimum the period of first warm ischemia or no flow status in the DCD, which does not occur in DBD. To achieve this two procurement techniques can be used: (i) cold perfusion via femoral artery after cannulation with triple-lumen double-balloon catheter with cannulation of femoral vein for venting, or (ii) super-rapid technique (thoraco-laparotomy) with direct aortic cannulation for cold perfusion and venous exsanguination and aorta cross clamping above the diaphragm (16–18). Cold perfusion has been replaced in some centers with normothermic regional perfusion (NRP) in uncontrolled and recently also for controlled DCD (19, 20).

ORGAN-SPECIFIC SELECTION IN DCD

Organs from DCD sustain an inevitable period of warm ischemia between the circulatory arrest and cold perfusion of the organs. This may cause a warm ischemic damage resulting in the higher incidence of primary non-function (PNF) and delayed graft function (DGF) as well as organ specific complications i.e. non-anastomotic biliary strictures in liver transplantation. This is the reason, why DCD are considered as extended criteria donors and organ specific limitations are applied above those for DBD (21).

Therefore, irrespective for type of an organ efforts shall be made to minimize both warm and cold ischemia times during DCD organ procurement and transplantation (22–25).

Kidneys

Donor age in DCD is independent risk factor for PNF, DGF and 1-year graft survival and the kidneys from donors >60 years has almost doubled hazard ratio for graft failure compared to DCD kidneys <40 years. DCD kidney from old donors should be used with caution, especially if additional risk factors are present as BMI>45, diabetes, hypertension or cerebrovascular accident as a cause of death (23). These kidneys should also not be transplanted into young recipients (23, 26). Warm ischemia time (WIT) in DCD kidney should be minimized to 20–30 minutes and kidneys with WIT>40 minutes has significantly high incidence of PNF (23, 27).

Pancreas

A recent recommendation suggests that transplantation of vascularized pancreas from DCD aged >50 year should be approached with caution and only if other risk factors are favorable (24, 28). Donor BMI >30 kg/m² is contraindication for pancreas transplantation, however islets can be used from obese donors. A first WIT should be limited to 30 minutes for vascularized pancreas transplantation and to 60 minutes for islet Langerhans transplantation (24, 28).

Liver

At the 6^th International DCD Meeting in Paris several recommendations regarding DCD liver transplantation were proposed (8). Standard controlled DCD liver is defined if donor age is <50 year, BMI <30, intensive care stay <5 days, transaminases levels below 4 times normal values or with downtrend, withdrawal time <30 minutes, first WIT < minutes, liver steatosis less than 10% and aimed CIT less than 8 hours (29, 30). If DCD graft does not meet aforementioned criteria it is considered as extended DCD graft and it may be used cautiously taking into account the benefit of the recipient. For uncontrolled DCD liver the following criteria are contraindication for transplantation: no flow period >15 minutes, time from circulatory arrest to perfusion >150 minutes, unsuccessful implementation of NRP, rising transaminases during NRP (above 4 times normal value), poor macroscopic appearance of the liver and poor bile duct vascularization (31).

Lungs

For DCD lung transplantation the same criteria are valid as for extended criteria donors: donor age <65 years, smoking <20 pack years, clear chest X-ray, mechanical ventilation <5 days, blood transfusion <5 units RBC and oxygenation pO₂ > 40 kPa (22). Additionally, a time between WSLT and circulatory arrest should be < 90 min and a first warm ischemic period of < 60 min. For lung transplantation from uncontrolled DCD specific donation criteria applies (22, 32).

OUTCOME

Kidney transplantation

DCD kidney transplantation is associated with significantly higher incidence of PNF and DGF as compared with DBD (1–22% and 28–88% vs 1–10% and 13–35%, respectively) (33–36). Although majority of the reports demonstrated that the higher incidence of DGF after DCD kidney transplantation does not affect graft survival opposite to DBD kidney transplantation, a recent study on the outcome of paired DCD kidney showed overall graft loss at 3 years was significantly higher in kidneys with DGF compared to kidney with immediate function (14% vs 4% with a hazard ratio of 4,31) (33–37). On the other hand, in a recent review from the UK database, 5- and 10-year graft survival in the recipients of DCD kidneys was 86% and 75% respectively, compared to 85% and 74% in DBD kidney recipients with a median follow-up of 7,5 years (38). Adjusted patient survival at 5 years was not different between DCD and DBD kidneys.

There were also no differences in the outcome of kidney transplantation from DCD category II and category III (35).

Pancreas transplantation

Two recent systematic reviews with meta-analysis showed comparable patient and pancreas graft survival between DBD and DCD (39, 40). 1-year graft survival both in simultaneous pancreas-kidney transplantation and pancreas alone transplantation was not different between DCD and DBD (87,2 vs 86,5% and 76,6% vs 74,9%, respectively). Similarly, there were no differences in 3- and 10-years pancreas graft survival between DBD and DCD. However, the occurrence of graft thrombosis was significantly higher in DCD (9,2%) compared to DBD (5,2%) grafts. HbA_1c lever 1-year after pancreas transplantation did not differ between DCD (5,43%) and DBD (5,63%).

Liver transplantation

In the countries with a high DCD donation rate DCD liver transplantation currently represents 1–21% of all deceased liver transplantation (25). DCD itself is a risk factor for graft survival after liver transplantation and it was included in donor risk index both in the United States as in Europe (41, 42). A recent study from Eurotransplant region reported hazard ratio of 1,7 for DCD livers for graft failure compared with DBD livers (43). The higher risk of graft failure in the DCD grafts is mostly due to the fact that these grafts are at high risk for developing biliary complications, namely non-anastomotic strictures (NAS, also called ischemic cholangiopathy or ischemic type biliary lesions) (44). In the meta-analysis the incidence of non-anastomotic strictures varies from 3% to 39% and is remains the main cause of retransplantation in DCD (45–47). However, in the recent years the incidence of NAS is decreasing due to introduction of strict donor selection in respect to first WIT, the length of agonal phase as well introduction of perfusion techniques as NRP or machine perfusion (48)

Although in the majority reports patient survival is lower (but not significant) or equal in DCD compared with DBD and it ranges from 74% to 92% in DCD category III, the analysis of the Scientific Registry of Transplant Recipients demonstrated one and 3-year survival was 82% and 71% for DCD compared with 86% and 77% for DBD recipients (44, 46, 47, 49, 50).

Graft survival in DCD is usually lower compared to the DBD and it ranges from 69% to 86% at one year and from 63% to 78% at 3 years, which has been also confirmed in by a recent meta-analysis where 1-year and 3-year graft survival were lower in DCD compared to DBD (45). On the other hand, nowadays careful donor selection improved short- and long-term outcome of DCD liver transplantation (51, 52)

The outcome of liver transplantation from uncontrolled DCD can be comparable to the outcome from controlled DCD when strict donor selection criteria are used (31).

Lung transplantation

Similarly to transplantation of other organs first attempt of using DCD lungs for transplantation was due to the shortage of DBD lungs (53, 54). The first short-term results were encouraging, so nowadays DCD lung donors of category 3 are widely accepted in the countries with DCD donation (55, 56). A recent systematic review and meta-analysis showed no significant differences in 1-year survival after lung transplantation between DCD and DBD donors (1-year survival in DCD ranged from 68% to 94%) (57). There were also no differences in primary graft dysfunction (4–6% in DCD vs 6–11% in DBD), the incidence of acute cellular rejection (6–33% in DCD vs 3–46% in DBD), reported airway complications and the rate of bronchiolitis obliterans syndrome between DCD and DBD. Interestingly, 4 out of 6 studies included in the meta-analysis reporting 3- and 5-year mortality favored DCD over DBD. 3- and 5-year survival among DCD varied from 74% to 90% and 71% to 90% compared with DBD (from 73% to 85% and 61% to 84%). The data from International Society for Heart and Lung Transplantation DCD Registry showed similar post-transplant outcomes with no significant differences in 1- and 5-year survival between DCD and DBD (89% and 61% vs 885 and 61% respectively) (58).

HEART TRANSPLANTATION

In 1967 the first human heart transplantation was performed from DCD, however heart transplantation after circulatory arrest was almost abandoned after introduction of DBD (59). Due to high mortality rate in infants on the waiting list for heart transplantation the concept of DCD heart transplantation was successfully introduced in Denver in 2008 (60). This was also one of the reasons of changing terminology from "nonheart-beating donation" and later "donation after cardiac death" to the present term of "donation after circulatory death", as the heart itself is not dead. Recently two approaches of DCD heart donation are used: direct procurement with subsequent ex-situ perfusion or rapid normothermic perfusion followed by ex-situ perfusion (61, 62). The first results of heart transplantation from DCD are promising with 1-year survival from 75% to 100% (62).

NEW STRATEGIES IN DCD

Ex-situ machine perfusion

Two randomized controlled trials comparing static storage versus hypothermic machine perfusion (HMP) of DCD kidneys did not show difference in 1-year patient and graft survival, however a majority of the studies or meta-analyses showed lower incidence of DGF in perfused DCD kidneys as compared with DCD kidneys placed in cold storage (63–65). In many centers HMP of DCD kidneys became a part of routine clinical practice due to improved short-term results, although the medium to long-term effects of MP are less clear as a recent meta-analysis showed (66).

Ex-vivo normothermic machine perfusion (NMP) use oxygenated blood at 37C to mimic in-vivo environment allowing resuscitation of donor organs and the clinical assessment and biochemical evaluation of the function of the organ.

Hosgood and Nicholson reported their first kidney transplantation using NMP in 2011 and 2 years later the results of their first clinical study comparing NMP with CS in kidneys from extended criteria donors demonstrated significantly lower DGF rate in NMP kidneys (67–68).

Guarrera et al. reported encouraging results of the use of hypothermic MP in extended liver grafts (69). Another group from Zurich used hypothermic oxygenated perfusion (HOPE) in DCD livers with excellent results (70). The results of international-match case analysis of DCD livers treated with HOPE compared with DCD livers preserved with cold storage showed lower incidence of biliary complications including NAS, higher 1-year graft survival and decreased hepatic injury (71). The preliminary results of the use of NMP in extend criteria liver grafts including DCD are very promising proving that this technique is feasible and well tolerated (72). First human clinical trial of NMP in liver transplantation including also 4 DCD graft showed 100% 6-months survival with 15% early allograft dysfunction (73). Another report demonstrated excellent results of LT using NMP from DCD, who were declined by other centers (74)

Similarly to DCD kidneys and livers ex-situ lung perfusion plays an important role in the DCD lung transplantation, especially in the assessment of uncertain grafts (75).

Normothermic regional perfusion (NRP)

In 1997 Johnson et al. described the use of extracorporeal membrane oxygenation (ECMO) in the organ donation setting (76). NRP allows restoration of circulation with oxygenated blood in the donor in-situ and it was further developed in Spain for uncontrolled DCD (19). The results of kidney, liver and lung transplantation using NRP in category II DCD are comparable to the results from controlled DCD (77). NRP was also introduced to the category III DCD as it allows dynamic assessment of organ function prior to transplantation and therefore it may help in better selection of organs suitable for transplantation (20, 78, 79). Recently successful use of NRP in combination with HMP in DCD liver transplantation has been reported (80).

In DCD heart transplantation machine perfusion or NRP are the only viable options for a proper functional assessment of the donor heart (61, 81).

CONCLUSIONS

Donors after circulatory death are valuable source of organs for transplantation. Although DCD are extended criteria donors, strict organ selection procured from DCD according to the current guidelines helps to achieve similar outcome as in DBD. Novel technologies as MP or NRP allow better organ selection and better preservation resulting in further increase of DCD organ procurement rate.

Address for correspondence:

Wojciech Polak, MD, PhD, FEBS

P. O. Box 2040

3000 CA Rotterdam

The Netherlands

e-mail: w.polak@erasmusmc.nl