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Evaluation of the Donor After Brain Death and Technique for Organ Procurement
EURSUP-723; No. of Pages 7 EUROPEAN UROLOGY SUPPLEMENTS XXX (2016) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Evaluation of the Donor After Brain Death and Technique for Organ Procurement Tiago Antunes-Lopes a,b,c, Carlos Martins da Silva a,b,c, Francisco Cruz a,b,c,* a
Department of Urology, Hospital de S. Joa˜o, Porto, Portugal; b Faculty of Medicine, University of Porto, Porto, Portugal; c Institute for Molecular and Cell
Biology (IBMC), University of Porto, Porto, Portugal
Article info
Abstract
Keywords: Kidney Transplant Donor Donor after brain death Cold preservation
Context: Renal transplantation is the best treatment modality for replacement of lost renal function in patients with end-stage renal disease. Nevertheless, the gap between the number of kidneys available for donation and the number of patients waiting for an organ is increasing due to an increase in the number of patients with renal failure and, simultaneously, a shortage of kidneys for transplant. Objective: To review the policies available for kidney donation. Evidence acquisition: A review of literature was performed to describe the available policies. Rates of donation were compared according to the different policies for several Western countries. Evidence synthesis: The classical donor type is the deceased heart-beating donor after brain death; however, shortage of organs forced the expansion of the criteria for donation. The concepts of expanded criteria donation and donation after circulatory death have been adopted more recently. Scores based on donor characteristics and histology criteria from kidney biopsies are also used to refine the quality of organs used for transplantation. Live donation is still marginal in many countries. Conclusions: There is an urgent need to increase public awareness of kidney transplantation, to improve strategies to identify new potential donors, and to master the techniques of retrieving and preserving organs. Increasing live donation is also essential to overcome organ shortage. Patient summary: There is an urgent need to increase public awareness of kidney transplantation, to improve strategies to identify new potential donors, and to master the techniques of retrieving and preserving organs. Increasing live donation is also essential to overcome organ shortage. # 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Hospital de S. Joa˜o, Porto, 4200, Portugal. Tel. +351 913231123. E-mail address: [email protected] (F. Cruz).
1.
Introduction
The scarcity of kidney donors remains a barrier to the spread of renal transplantation, which is generally considered the best treatment option for most patients with
end-stage renal disease. The number of patients waiting for kidney transplantation has increased, but the actual supply of organs is far from covering the current demands. Consequently, significant social and legal improvements have been implemented in different countries to increase
http://dx.doi.org/10.1016/j.eursup.2016.08.004 1569-9056/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Antunes-Lopes T, et al. Evaluation of the Donor After Brain Death and Technique for Organ Procurement. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.004
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public awareness of organ donation and to overcome cultural and religious obstacles. Organ donation rates have traditionally been expressed as donors per million of population (pmp). Among the most dynamic countries in transplantation, some have relied almost entirely on living donation (eg, Japan), whereas others have used deceased donation (eg, Spain, Portugal, and Croatia). Nevertheless, in the majority of the countries, both forms of donation are routinely used in balanced practice [1]. Regarding kidney transplantation from deceased donors, the gap between the supply and the demand for kidneys is stabilized only in countries with a donation rate >40 pmp and has increased in countries with lower donation rates [2]. Higher donation rates occur in European countries: In 2013, Croatia reported 47.7 pmp, France reported 46.7 pmp, and Spain reported 46.1 pmp (Fig. 1). High deceased donation rates have been observed in European countries that adopted opt-out consent policies (eg, Spain, France, Portugal, Croatia, Austria, Belgium) [2]. In these countries, consent is presumed unless the person has specifically rejected donation before death. These rates contrast positively with those coming from countries with an opposed policy, the opt-in informed consent law
(eg, United Kingdom, Germany, Netherlands, United States, Canada). Donation policy, however, is not the only factor influencing donation rates. The donation process is influence by other variables such as the incidence of life-threatening trauma and intracerebral hemorrhage, the availability of intensive care facilities, and the rapid identification and correct management of potential donors [1]. Additional measures such as donation after circulatory death (DCD) and the adoption of marginal and expanded criteria for deceased donors (expanded criteria donors [ECDs]) have been implemented to increase the kidney pool obtained from standard criteria donors (SCDs). Currently, DCD already represents >10% of the kidneys from deceased donors in some countries such as the Netherlands, the United Kingdom, the United States, and Canada [3]. Living donation makes an important contribution to kidney transplantation programs worldwide and has some advantages over deceased donation, as demonstrated by generally better functional outcomes. In Europe, living donor transplants compose 15% of all kidney transplantations [4] and represent nearly 40% in the United States [5,6]. Across Europe, however, living donation rates are extremely variable. In 2013, Turkey, the Netherlands, and
Fig. 1 – Worldwide kidney transplant from deceased donors (left) and living donors (right) in 2013 (per million of population). Reproduced with permission from the International Registry in Organ Donation and Transplantation [2].
Please cite this article in press as: Antunes-Lopes T, et al. Evaluation of the Donor After Brain Death and Technique for Organ Procurement. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.004
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Cyprus reported the highest rates of kidney transplants from living donors (31.4 pmp, 31.2 pmp, and 29.7 pmp, respectively), whereas in Spain and Portugal, the living donation rate was very low (8.1 pmp and 4.9 pmp, respectively). In the United Kingdom, the rate was 17.1 pmp (Fig. 1) [2]. 2.
The donor after brain death
2.1.
Brain death diagnosis
The concept of brain death has evolved over the years, and guidelines for determining brain death have been substantially refined [7]. The declaration of brain death is based on the absence of a set of responses to neurologic stimuli [8]. Brain death should be considered in any comatose patient who is a potential organ donor, without age limits. Brain death occurs when a person has an irreversible catastrophic brain injury that causes total cessation of brain functions. Some causes of brain death include trauma (eg, severe head injury caused by a motor vehicle crash, gunshot wound, fall, or blow to the head), cerebrovascular injury (eg, stroke or aneurysm), anoxia (eg, drowning or heart attack when the patient is resuscitated but not before a lack of blood flow or oxygen to the brain has caused brain death), and brain tumor. The flowchart in Figure 2 presents the general approach to the diagnosis of brain death. Several prerequisites must be met before brain death examination. First, clinical or imaging evidence of a catastrophic brain injury compatible with a possible diagnosis of brain death should be available. Coma Exclusion of confounding condions • Hypothermia • Drug intoxicaons • Endocrine crisis • Severe electrolyte/acid-base disturbances
Prerequisites • Cause of coma • Supporve neuroimaging
Clinical Examinaon • Absence of motor response • Absence of brainstem reflexes • Apnea with documented PaCO2 ≥60 mmHg
Complete clinical examinaon YES
NO
Confirmatory Studies
Diagnosis of Brain Death YES
Absence of cerebral blood flow NO Brain death diagnosis not supported Fig. 2 – Brain death diagnosis. Adapted with permission from Saunders Elsevier [10].
3
Table 1 – Brainstem reflexes in brain death diagnosis Pupillary reflex (cranial nerves II and III): Pupils show no response to light Ocular movement (cranial nerves III, VI, and VIII) Oculocephalic reflex: The pupils will not show any movement as the head is turned rapidly to one side or the other (‘‘doll’s eye’’ sign) Vestibulo-ocular reflex: Each external auditory canal is irrigated with 50 ml of ice water, ‘‘caloric reflex test’’; in brain death, no eye movement will be seen for 1-min observation Facial sensation and facial motor response (cranial nerves V and VII) Absence of corneal reflex (cranial nerves V1 and VII) Absence of jaw reflex (cranial nerve V3) Absence of facial movement to noxious stimuli (cranial nerves V3 and VII) Pharyngeal and tracheal reflexes (cranial nerves IX and X) Pharyngeal reflex (‘‘gag reflex,’’ cranial nerves IX and X) Tracheal reflex (‘‘cough reflex,’’ cranial nerve X)
Second, the exclusion or resolution of several confounding conditions that may interfere with clinical assessment should be confirmed. Drug intoxication or poisoning must be ruled out, which implies a drug screen and a pause for clearance whenever a test is positive. In addition, the donor candidate must have a core body temperature >32 8C, as hypothermia influences papillary light response. Once these prerequisites have been met, three major findings must be established: coma, absence of brainstem reflexes, and apnea [7]. Coma is the absence of motor response or eye movement to noxious stimuli (nail bed pressure or supraorbital pressure). Clinical expertise is necessary to differentiate between spontaneous or reflex movements and central and cerebral motor responses to pain. Afterward, the clinician has to verify the absence of brainstem reflexes, described in Table 1. Finally, the absence of a drive to breathe when PaCO2 is >60 mm Hg or with a 20-mm Hg increment from baseline (PaCO2 35–45 mm Hg) completes the clinical evaluation of brain death. Normally, hypercarbia stimulates the respiratory center in the medulla, triggering respiratory movements. The following prerequisites must also be accomplished: normotension (systolic blood pressure >90 mm Hg), normothermia (with a current temperature >36 8C), normovolemia, normocapnea (PaCO2 35–45 mm Hg), absence of hypoxia, and no history of CO2 retention. For assessment, the patient is preoxygenated with 100% O2 (target is PaO2 >200 mm Hg), and then ventilation frequency is reduced to 10–12 breaths per minute and arterial PO2, PCO2, and pH are measured. The patient is disconnected from the ventilator and closely observed for respiratory movements. If these are not observed and PaCO2 is >60 mm Hg or 20 mm Hg above baseline normal PaCO2, the test is positive and compatible with clinical diagnosis of brain death. This test may not be applied to all candidates, as nearly 10% of patients will be too unstable. In patients for whom a complete examination is not possible, ancillary testing can be useful, in accordance with institutional or state guidelines (cerebral angiography, cerebral scintigraphy, isotope angiography, transcranial Doppler ultrasound, electroencephalogram) [9]. Philosophical, medicolegal, and ethical and religious debates about divergence between brain death determination and criteria for death according to personal or religious
Please cite this article in press as: Antunes-Lopes T, et al. Evaluation of the Donor After Brain Death and Technique for Organ Procurement. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.004
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beliefs make communication with families an essential step [7]. 2.2.
Criteria for donation after brain death
The potential donor has to be evaluated for any transmissible pathologic condition and for the quality of organs considered for transplantation. The classical donor type is the deceased heart-beating donor after brain death (DBD). These are usually young people with irreversible brain damage incurred during motor vehicle accidents, referred to as SCDs [9]. The criteria for an ideal SCD is age 6–50 yr; normal renal function; no hypertension; no diabetes mellitus; no malignancy other than a primary brain tumor or treated superficial skin cancer; no generalized viral or bacterial infection; acceptable urinalysis; and negative assays for syphilis, hepatitis, human immunodeficiency virus, and human T- lymphoproliferative virus [10]. The concepts of expanded criteria donation and DCD have been adopted more recently to expand the donor pool and to overcome the shortage of kidneys obtained from SCDs. ECDs include donors aged >60 yr or donors aged 50–59 yr with at least two of the following conditions: cerebrovascular cause of death, hypertension, and serum creatinine level >1.5 mg/dl [11,12]. Despite the lack of an absolute age limit for donation, short ischemia time—which is relevant for every organ, whatever the type of donor—is fundamental for organs retrieved from ECDs. In addition, a careful donor examination is required for ECDs, as older donors are more prone to harbor comorbidities that might contraindicate donation. The potential donor also must be checked for infectious diseases, malignant tumors, and cardiovascular diseases. Kidney transplant survival rates are significantly inferior when organs are obtained from ECDs compared with the ideal deceased donor. Nevertheless, transplantation of an ECD kidney still provides a substantial survival advantage over dialysis, estimated at 18 mo [9]. 2.2.1.
Infectious diseases
In general, donor-to-recipient infection transmission may occur and may cause serious and potentially fatal consequences. Infections that preclude transplantation are listed in Table 2 [9]. However, most donor infections are not contraindications to transplantation [13], and effective treatment of preexisting donor infections may permit donation without risks. Likewise, transplantation of a donor organ with a chronic viral infection to a recipient with a similar infection is acceptable if informed consent is obtained [14]. 2.2.2.
Table 2 – Infections that preclude transplantation Active fungal, parasitic, viral, or bacterial meningitis or encephalitis Bacterial Tuberculosis Perforated bowel or intra-abdominal sepsis Viral Active hepatitis B and C Rabies Retroviral infections, including HIV, HTLV-1, and HTLV-2 Active herpes simplex, EBV, varicella, CMV viremia, or pneumonia West Nile virus Fungal Active infection with Cryptococcus, Aspergillus, Histoplasma, or Coccidioides; active candidemia; or invasive yeast Parasites Active infection with Trypanosoma cruzi (Chagas), Leishmania, Strongyloides, or Plasmodium sp. (malaria) Prion Creutzfeldt-Jakob disease EBV = Epstein-Barr virus; HIV = human CMV = cytomegalovirus; immunodeficiency virus; HTLV = human T-lymphotropic virus.
cancer [16]. A past history of malignancy is no longer a contraindication for organ donation. Moreover, some cancers, namely, basal cell carcinoma, nonmetastatic spinocellular skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the vocal cords, and low-grade brain tumors without prior surgical manipulation, do not preclude kidney donation [17]. However, there are oncologic conditions that are absolute contraindications for donation. These include the presence of an active cancer, metastatic cancer (with few exceptions, like testicular cancer), and cancers with high recurrence rates (eg, advanced breast carcinoma, melanoma, leukemia, lymphoma) [18]. Moreover, in the presence of brain hemorrhage of unknown etiology, brain metastasis must be ruled out as a potential cause [19]. Taking into account the low risk of recurrence, kidneys with small low-grade renal carcinomas can be considered for local excision and then transplanted if the recipient has given appropriate informed consent. Due to donor shortage, several transplantation programs accept donors with only 5 yr of follow-up without recurrence of the malignancy [16]. In these cases, a careful risk–benefit evaluation must be done, weighing the risk of tumor transmission versus mortality from renal disease if the patient remains on the waiting list for transplant. As the average age of donors increases, so does their risk of cancer. Recently, a donor-screening protocol (Table 3) was proposed based on cancer incidence in the general population, donor age, risk factors, and donor examination. The cost-efficacy of such a screening program needs to be examined over time before large-scale implementation [15].
Malignancies
Donor-transmitted malignancies have been reported and have become a relevant matter of concern when dealing with older DBDs [15]. Concerning the risk of cancer transmission, donors can be included in one of three groups: donors without cancer, donors with a history of cancer, and donors with a preoperative diagnosis of
2.2.3.
Age, comorbidities, and renal function
The allocation of deceased donor kidneys has become more complex because of the increasing difficulty of matching age and comorbidities between donors and recipients [20]. The first parameter that was found to negatively affect graft survival was high donor age [21,22]. The decline
Please cite this article in press as: Antunes-Lopes T, et al. Evaluation of the Donor After Brain Death and Technique for Organ Procurement. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.004
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Table 3 – Recommended screening protocols for specific malignancies in donors after brain death Malignancy
Recommended screening protocol
Lung cancer
Heavy smokers* aged 55–75 yr screened with helical CT; donors with spouses who smoke heavily should also undergo helical CT US for women aged >50 yr who have not had a mammogram within the past 2 yr; biopsy of identified lesions CTC or CS in patients aged >60 yr; donors aged >50 yr with a first-degree relative with colon cancer and who have a polyp >1 cm should be regarded as highly suspicious PSA screening and DRE in patients aged >50 yr; if PSA is not available, then DRE only
Breast cancer
Colon cancer
Prostate cancer
CT = computed tomography; CTC = computed CS = colonoscopy; tomography colonography; DRE = digital rectal examination; PSA = prostate-specific antigen; US = ultrasound. Adapted from Hassanain et al [15]. * >10 cigarettes per day.
of renal function with age is very variable [23]. Nevertheless, the aging kidney loses nephrons and shows a stepwise reduction in glomerular filtration rate. In the older donor, normal creatinine often underestimates kidney function because of reduced muscle mass. In addition, donor comorbidities such as hypertension and death from cerebrovascular accident are considered surrogate markers of impaired kidney function and are predictors of reduced graft survival. The concept of expanded criteria donation was introduced in 2002 to incorporate these parameters in a guide for organ allocation [24]. ECDs were defined as those whose relative risk of allograft failure is >1.7 in comparison with SCDs. They include all donors aged 60 yr or those aged 50–59 yr with at least two of the following criteria: serum creatinine >1.5 mg/dl, a cerebrovascular accident as the cause of death, or a history of hypertension. These three criteria, together with age, are considered surrogate markers of reduced nephron mass [24,25]. The dichotomous SCD/ECD classification system is not perfect because it misclassifies kidneys in opposing directions: Some kidneys labeled as SCD have reduced allograft survival, whereas some ECD kidneys perform well. To further refine prediction of allograft failure, several prognostic scoring systems were added to the simplistic SCD/ECD classification that include more clinical and histologic donor variables and recipient parameters [25]. The United Network of Organ Sharing kidney transplantation committee approved and implemented (by the end of 2014) a new allocation policy [26] based on the Kidney Donor Risk Index (KDRI) that represents the relative risk of post-transplant graft failure from a particular deceased donor compared with the average donor [27]. The Kidney Donor Profile Index (KDPI) is a numeric score that results from ranking the KDRI in percentiles with reference to a given Organ Procurement and Transplantation Network donor cohort [28]. This scoring system is based on 10 donor factors intended to refine the evaluation of the kidney quality without the need of a biopsy. Included
5
in the KDRI/KDPI formula are donor age, height, weight, ethnicity, serum creatinine level, history of diabetes, history of hypertension, hepatitis C status, cause of death, and whether the donation occur after cardiac arrest [27]. As it becomes evident, all information used to calculate KDRI and KDPI is based on the donor. The characteristics of the recipient candidate (HLA matching) and the transplant procedure (single vs en bloc) are not weighted; therefore, one must realize that KDRI and KDPI reflect how the kidney is likely to function in terms of expected graft survival if transplanted into the ‘‘average recipient’’ [29]. KDRI and KDPI are nevertheless an improvement over the ECD/SCD dichotomy. They provide a more precise measure of donor quality because 10 donor factors are incorporated instead of 4 in the ECD definition. A continuous score is given instead of a binary (yes/no) indicator, and the indexes take into consideration that ECDs may be substantially distinct. The KDRI/KDPI calculator is freely accessible online (https://optn.transplant.hrsa.gov/ resources/allocation-calculators/kdpi-calculator/). Already implemented in United States, this score will probably play a role in deceased donor kidney allocation policies across Europe in the near future. The KDRI/KDPI should help transplant programs better allocate the scarce resource of deceased donor kidneys [29]. Kidney biopsy has been intensely debated as an independent predictor of donor quality above and beyond clinical indices. In a retrospective analysis of 65 baseline biopsies, a percentage of >20% glomerulosclerosis was associated with an increased incidence of delayed graft function and poor outcome of transplanted kidneys [30]. However, other authors did not find a correlation between the percentage of glomerulosclerosis in the donor kidney biopsies and 1-yr graft survival and function [31]. Therefore, although donor biopsy findings have a predictive ability, it remains unclear to what extent histologic data improve a score if donor age and function have already been integrated as variables. Moreover, the use of histologic data has increased the number of rejected kidneys. In the United States, the implementation of the ECD program >10 yr ago increased the number of retrieved kidneys, but the percentage of kidneys retrieved and then rejected rose to >40% [28]. Currently, the percentage of glomerulosclerosis may not be used as the sole criterion for discarding deceased donor kidneys [31,32]. 3.
Retrieval techniques
The management of the deceased donor is carried out by the critical care physician in the intensive care unit and by the anesthesiologist in the operation room, ensuring adequate ventilation and circulatory support under standardized donor management guidelines to achieve the best outcomes [9]. However, urologists should have a role at each step of organ donation, first in close collaboration with the intensive care unit and then with the other surgical teams that are potentially involved. The urologist must be familiar with the techniques of deceased organ donor explantation: multiorgan retrieval
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(total midline approach with median sternotomy) and kidneys-only retrieval (classic abdominal midline or cruciate incisions). Multiple organ recovery implies good coordination and cooperation among surgical teams under the leadership of the local transplant coordinator. In general, each organ should be procured as quickly as possible to minimize ischemic injury to the others [16]. In the setting of combined thoracic and multiple abdominal organ retrieval, dissection is started by the thoracic and liver teams. After cross-clamping and perfusion, the organs are removed in the following order: heart, lungs, liver, pancreas, and kidneys. Detailed description of surgical techniques of multiorgan and kidneys-only retrieval is not within the scope of this review. Excellent descriptions can be found elsewhere [10,33]. The principles of abdominal organ procurement are the same regardless of the organs removed. These include wide exposure, control of the vessels above and below the organs to be removed, initiation of preservation in situ (infusion of cold preservation solution and surface cooling with ice slush), isolation of organs to be removed in continuity with their central vascular structures, and orderly retrieval of the organs. In addition, as part of the retrieval procedure, generous specimens for histocompatibility tests should be obtained, iliac vessels should be collected for vascular reconstruction of pancreas and liver grafts, and organ packaging should be properly done [10,33].
preservation, is not visibly better than simple cold static storage for all kidneys [34]. Modern preservation solutions can now offer results with static storage equivalent to HMP at much lower costs; therefore, static storage is currently the preferred method of renal graft preservation for SCDs at most centers; however, HMP may show beneficial effects in deceased cardiac donors [39] and ECDs [40]. A recent large multicenter European randomized controlled trial compared HMP and static cold storage across all donor types [41]. HMP was associated with a significantly reduced risk of delayed graft function and improved graft survival. Likewise, a recent systematic review and meta-analysis concluded that HMP was associated with faster recovery of graft function, with a relative risk benefit between 0.70 and 0.92 [42]. Further studies in the field of renal preservation may establish which preservation strategy is better for a particular donor type. In Europe, various clinical trials to evaluate several targeted therapies proposed by the Consortium for Organ Preservation in Europe have already started. They will investigate the role of oxygenated HMP preservation and reconditioning, particularly in ECD kidneys. In summary, HMP may have the potential to reduce delayed graft function, to decrease primary nonfunction rates, and to improve graft survival in the ECD and DCD settings.
4.
Despite medical and technological advances and global awareness of organ donation and transplantation, the gap between supply and demand continues to widen. Organized and systematic organ procurement and transplantation networks have been replicated and important measures implemented to expand the donor pool and to optimize the organs available for transplantation. This is an exciting time to be involved in the field of organ donation and transplantation, as novel technologies bring new possibilities for donor selection, retrieval techniques, and organ preservation.
Kidney preservation
Successful transplantation is highly dependent on minimizing ischemic damage. Suppression of metabolism is essential to maintain organ viability during the preservation period; therefore, reduction of the core temperature of the kidney <4 8C is necessary [34]. Simple cooling of kidneys in ice water cannot preserve renal function beyond 12 h [35], so additional preservation techniques are used. Contemporary cold storage of the kidneys is done by surface cooling, hypothermic pulsatile perfusion, or flushing with an ice cold solution, followed by cold storage [36]. The duration of cold ischemia should nevertheless be as short as possible, not exceeding 24 h, as a progressive decrease of renal function can be expected with prolonged storage, even under ideal conditions. Despite the beneficial concept of hypothermia, undesirable changes still occur in the preserved organ, even if stored under ideal conditions. Kidney changes include cell swelling, acidosis, altered enzymatic activity, calcium accumulation, and production of reactive oxygen species [34,36]. Storage solutions are used to minimize cell swelling during hypothermic ischemia, to maintain intra- and extracellular electrolyte gradient, to buffer acidosis, to provide energy sources, and to reduce oxidative reperfusion injury [34]. Today, Celsior solution, University of Wisconsin solution, and HTK (histidine–tryptophan–ketoglutarate) solution are equally effective and commonly used in both multiorgan and kidneys-only retrieval procedures [34,37,38]. Cold storage with hypothermic machine perfusion (HMP), once considered the gold standard method for renal
5.
Conclusions
Conflicts of interest The authors have nothing to disclose. Funding support None.
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Please cite this article in press as: Antunes-Lopes T, et al. Evaluation of the Donor After Brain Death and Technique for Organ Procurement. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.004
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Evaluation of the Donor After Brain Death and Technique for Organ Procurement Tiago Antunes-Lopes a,b,c, Carlos Martins da Silva a,b,c, Francisco Cruz a,b,c,* a
Department of Urology, Hospital de S. Joa˜o, Porto, Portugal; b Faculty of Medicine, University of Porto, Porto, Portugal; c Institute for Molecular and Cell
Biology (IBMC), University of Porto, Porto, Portugal
Article info
Abstract
Keywords: Kidney Transplant Donor Donor after brain death Cold preservation
Context: Renal transplantation is the best treatment modality for replacement of lost renal function in patients with end-stage renal disease. Nevertheless, the gap between the number of kidneys available for donation and the number of patients waiting for an organ is increasing due to an increase in the number of patients with renal failure and, simultaneously, a shortage of kidneys for transplant. Objective: To review the policies available for kidney donation. Evidence acquisition: A review of literature was performed to describe the available policies. Rates of donation were compared according to the different policies for several Western countries. Evidence synthesis: The classical donor type is the deceased heart-beating donor after brain death; however, shortage of organs forced the expansion of the criteria for donation. The concepts of expanded criteria donation and donation after circulatory death have been adopted more recently. Scores based on donor characteristics and histology criteria from kidney biopsies are also used to refine the quality of organs used for transplantation. Live donation is still marginal in many countries. Conclusions: There is an urgent need to increase public awareness of kidney transplantation, to improve strategies to identify new potential donors, and to master the techniques of retrieving and preserving organs. Increasing live donation is also essential to overcome organ shortage. Patient summary: There is an urgent need to increase public awareness of kidney transplantation, to improve strategies to identify new potential donors, and to master the techniques of retrieving and preserving organs. Increasing live donation is also essential to overcome organ shortage. # 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Hospital de S. Joa˜o, Porto, 4200, Portugal. Tel. +351 913231123. E-mail address: [email protected] (F. Cruz).
1.
Introduction
The scarcity of kidney donors remains a barrier to the spread of renal transplantation, which is generally considered the best treatment option for most patients with
end-stage renal disease. The number of patients waiting for kidney transplantation has increased, but the actual supply of organs is far from covering the current demands. Consequently, significant social and legal improvements have been implemented in different countries to increase
http://dx.doi.org/10.1016/j.eursup.2016.08.004 1569-9056/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Antunes-Lopes T, et al. Evaluation of the Donor After Brain Death and Technique for Organ Procurement. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.004
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public awareness of organ donation and to overcome cultural and religious obstacles. Organ donation rates have traditionally been expressed as donors per million of population (pmp). Among the most dynamic countries in transplantation, some have relied almost entirely on living donation (eg, Japan), whereas others have used deceased donation (eg, Spain, Portugal, and Croatia). Nevertheless, in the majority of the countries, both forms of donation are routinely used in balanced practice [1]. Regarding kidney transplantation from deceased donors, the gap between the supply and the demand for kidneys is stabilized only in countries with a donation rate >40 pmp and has increased in countries with lower donation rates [2]. Higher donation rates occur in European countries: In 2013, Croatia reported 47.7 pmp, France reported 46.7 pmp, and Spain reported 46.1 pmp (Fig. 1). High deceased donation rates have been observed in European countries that adopted opt-out consent policies (eg, Spain, France, Portugal, Croatia, Austria, Belgium) [2]. In these countries, consent is presumed unless the person has specifically rejected donation before death. These rates contrast positively with those coming from countries with an opposed policy, the opt-in informed consent law
(eg, United Kingdom, Germany, Netherlands, United States, Canada). Donation policy, however, is not the only factor influencing donation rates. The donation process is influence by other variables such as the incidence of life-threatening trauma and intracerebral hemorrhage, the availability of intensive care facilities, and the rapid identification and correct management of potential donors [1]. Additional measures such as donation after circulatory death (DCD) and the adoption of marginal and expanded criteria for deceased donors (expanded criteria donors [ECDs]) have been implemented to increase the kidney pool obtained from standard criteria donors (SCDs). Currently, DCD already represents >10% of the kidneys from deceased donors in some countries such as the Netherlands, the United Kingdom, the United States, and Canada [3]. Living donation makes an important contribution to kidney transplantation programs worldwide and has some advantages over deceased donation, as demonstrated by generally better functional outcomes. In Europe, living donor transplants compose 15% of all kidney transplantations [4] and represent nearly 40% in the United States [5,6]. Across Europe, however, living donation rates are extremely variable. In 2013, Turkey, the Netherlands, and
Fig. 1 – Worldwide kidney transplant from deceased donors (left) and living donors (right) in 2013 (per million of population). Reproduced with permission from the International Registry in Organ Donation and Transplantation [2].
Please cite this article in press as: Antunes-Lopes T, et al. Evaluation of the Donor After Brain Death and Technique for Organ Procurement. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.004
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Cyprus reported the highest rates of kidney transplants from living donors (31.4 pmp, 31.2 pmp, and 29.7 pmp, respectively), whereas in Spain and Portugal, the living donation rate was very low (8.1 pmp and 4.9 pmp, respectively). In the United Kingdom, the rate was 17.1 pmp (Fig. 1) [2]. 2.
The donor after brain death
2.1.
Brain death diagnosis
The concept of brain death has evolved over the years, and guidelines for determining brain death have been substantially refined [7]. The declaration of brain death is based on the absence of a set of responses to neurologic stimuli [8]. Brain death should be considered in any comatose patient who is a potential organ donor, without age limits. Brain death occurs when a person has an irreversible catastrophic brain injury that causes total cessation of brain functions. Some causes of brain death include trauma (eg, severe head injury caused by a motor vehicle crash, gunshot wound, fall, or blow to the head), cerebrovascular injury (eg, stroke or aneurysm), anoxia (eg, drowning or heart attack when the patient is resuscitated but not before a lack of blood flow or oxygen to the brain has caused brain death), and brain tumor. The flowchart in Figure 2 presents the general approach to the diagnosis of brain death. Several prerequisites must be met before brain death examination. First, clinical or imaging evidence of a catastrophic brain injury compatible with a possible diagnosis of brain death should be available. Coma Exclusion of confounding condions • Hypothermia • Drug intoxicaons • Endocrine crisis • Severe electrolyte/acid-base disturbances
Prerequisites • Cause of coma • Supporve neuroimaging
Clinical Examinaon • Absence of motor response • Absence of brainstem reflexes • Apnea with documented PaCO2 ≥60 mmHg
Complete clinical examinaon YES
NO
Confirmatory Studies
Diagnosis of Brain Death YES
Absence of cerebral blood flow NO Brain death diagnosis not supported Fig. 2 – Brain death diagnosis. Adapted with permission from Saunders Elsevier [10].
3
Table 1 – Brainstem reflexes in brain death diagnosis Pupillary reflex (cranial nerves II and III): Pupils show no response to light Ocular movement (cranial nerves III, VI, and VIII) Oculocephalic reflex: The pupils will not show any movement as the head is turned rapidly to one side or the other (‘‘doll’s eye’’ sign) Vestibulo-ocular reflex: Each external auditory canal is irrigated with 50 ml of ice water, ‘‘caloric reflex test’’; in brain death, no eye movement will be seen for 1-min observation Facial sensation and facial motor response (cranial nerves V and VII) Absence of corneal reflex (cranial nerves V1 and VII) Absence of jaw reflex (cranial nerve V3) Absence of facial movement to noxious stimuli (cranial nerves V3 and VII) Pharyngeal and tracheal reflexes (cranial nerves IX and X) Pharyngeal reflex (‘‘gag reflex,’’ cranial nerves IX and X) Tracheal reflex (‘‘cough reflex,’’ cranial nerve X)
Second, the exclusion or resolution of several confounding conditions that may interfere with clinical assessment should be confirmed. Drug intoxication or poisoning must be ruled out, which implies a drug screen and a pause for clearance whenever a test is positive. In addition, the donor candidate must have a core body temperature >32 8C, as hypothermia influences papillary light response. Once these prerequisites have been met, three major findings must be established: coma, absence of brainstem reflexes, and apnea [7]. Coma is the absence of motor response or eye movement to noxious stimuli (nail bed pressure or supraorbital pressure). Clinical expertise is necessary to differentiate between spontaneous or reflex movements and central and cerebral motor responses to pain. Afterward, the clinician has to verify the absence of brainstem reflexes, described in Table 1. Finally, the absence of a drive to breathe when PaCO2 is >60 mm Hg or with a 20-mm Hg increment from baseline (PaCO2 35–45 mm Hg) completes the clinical evaluation of brain death. Normally, hypercarbia stimulates the respiratory center in the medulla, triggering respiratory movements. The following prerequisites must also be accomplished: normotension (systolic blood pressure >90 mm Hg), normothermia (with a current temperature >36 8C), normovolemia, normocapnea (PaCO2 35–45 mm Hg), absence of hypoxia, and no history of CO2 retention. For assessment, the patient is preoxygenated with 100% O2 (target is PaO2 >200 mm Hg), and then ventilation frequency is reduced to 10–12 breaths per minute and arterial PO2, PCO2, and pH are measured. The patient is disconnected from the ventilator and closely observed for respiratory movements. If these are not observed and PaCO2 is >60 mm Hg or 20 mm Hg above baseline normal PaCO2, the test is positive and compatible with clinical diagnosis of brain death. This test may not be applied to all candidates, as nearly 10% of patients will be too unstable. In patients for whom a complete examination is not possible, ancillary testing can be useful, in accordance with institutional or state guidelines (cerebral angiography, cerebral scintigraphy, isotope angiography, transcranial Doppler ultrasound, electroencephalogram) [9]. Philosophical, medicolegal, and ethical and religious debates about divergence between brain death determination and criteria for death according to personal or religious
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beliefs make communication with families an essential step [7]. 2.2.
Criteria for donation after brain death
The potential donor has to be evaluated for any transmissible pathologic condition and for the quality of organs considered for transplantation. The classical donor type is the deceased heart-beating donor after brain death (DBD). These are usually young people with irreversible brain damage incurred during motor vehicle accidents, referred to as SCDs [9]. The criteria for an ideal SCD is age 6–50 yr; normal renal function; no hypertension; no diabetes mellitus; no malignancy other than a primary brain tumor or treated superficial skin cancer; no generalized viral or bacterial infection; acceptable urinalysis; and negative assays for syphilis, hepatitis, human immunodeficiency virus, and human T- lymphoproliferative virus [10]. The concepts of expanded criteria donation and DCD have been adopted more recently to expand the donor pool and to overcome the shortage of kidneys obtained from SCDs. ECDs include donors aged >60 yr or donors aged 50–59 yr with at least two of the following conditions: cerebrovascular cause of death, hypertension, and serum creatinine level >1.5 mg/dl [11,12]. Despite the lack of an absolute age limit for donation, short ischemia time—which is relevant for every organ, whatever the type of donor—is fundamental for organs retrieved from ECDs. In addition, a careful donor examination is required for ECDs, as older donors are more prone to harbor comorbidities that might contraindicate donation. The potential donor also must be checked for infectious diseases, malignant tumors, and cardiovascular diseases. Kidney transplant survival rates are significantly inferior when organs are obtained from ECDs compared with the ideal deceased donor. Nevertheless, transplantation of an ECD kidney still provides a substantial survival advantage over dialysis, estimated at 18 mo [9]. 2.2.1.
Infectious diseases
In general, donor-to-recipient infection transmission may occur and may cause serious and potentially fatal consequences. Infections that preclude transplantation are listed in Table 2 [9]. However, most donor infections are not contraindications to transplantation [13], and effective treatment of preexisting donor infections may permit donation without risks. Likewise, transplantation of a donor organ with a chronic viral infection to a recipient with a similar infection is acceptable if informed consent is obtained [14]. 2.2.2.
Table 2 – Infections that preclude transplantation Active fungal, parasitic, viral, or bacterial meningitis or encephalitis Bacterial Tuberculosis Perforated bowel or intra-abdominal sepsis Viral Active hepatitis B and C Rabies Retroviral infections, including HIV, HTLV-1, and HTLV-2 Active herpes simplex, EBV, varicella, CMV viremia, or pneumonia West Nile virus Fungal Active infection with Cryptococcus, Aspergillus, Histoplasma, or Coccidioides; active candidemia; or invasive yeast Parasites Active infection with Trypanosoma cruzi (Chagas), Leishmania, Strongyloides, or Plasmodium sp. (malaria) Prion Creutzfeldt-Jakob disease EBV = Epstein-Barr virus; HIV = human CMV = cytomegalovirus; immunodeficiency virus; HTLV = human T-lymphotropic virus.
cancer [16]. A past history of malignancy is no longer a contraindication for organ donation. Moreover, some cancers, namely, basal cell carcinoma, nonmetastatic spinocellular skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the vocal cords, and low-grade brain tumors without prior surgical manipulation, do not preclude kidney donation [17]. However, there are oncologic conditions that are absolute contraindications for donation. These include the presence of an active cancer, metastatic cancer (with few exceptions, like testicular cancer), and cancers with high recurrence rates (eg, advanced breast carcinoma, melanoma, leukemia, lymphoma) [18]. Moreover, in the presence of brain hemorrhage of unknown etiology, brain metastasis must be ruled out as a potential cause [19]. Taking into account the low risk of recurrence, kidneys with small low-grade renal carcinomas can be considered for local excision and then transplanted if the recipient has given appropriate informed consent. Due to donor shortage, several transplantation programs accept donors with only 5 yr of follow-up without recurrence of the malignancy [16]. In these cases, a careful risk–benefit evaluation must be done, weighing the risk of tumor transmission versus mortality from renal disease if the patient remains on the waiting list for transplant. As the average age of donors increases, so does their risk of cancer. Recently, a donor-screening protocol (Table 3) was proposed based on cancer incidence in the general population, donor age, risk factors, and donor examination. The cost-efficacy of such a screening program needs to be examined over time before large-scale implementation [15].
Malignancies
Donor-transmitted malignancies have been reported and have become a relevant matter of concern when dealing with older DBDs [15]. Concerning the risk of cancer transmission, donors can be included in one of three groups: donors without cancer, donors with a history of cancer, and donors with a preoperative diagnosis of
2.2.3.
Age, comorbidities, and renal function
The allocation of deceased donor kidneys has become more complex because of the increasing difficulty of matching age and comorbidities between donors and recipients [20]. The first parameter that was found to negatively affect graft survival was high donor age [21,22]. The decline
Please cite this article in press as: Antunes-Lopes T, et al. Evaluation of the Donor After Brain Death and Technique for Organ Procurement. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.004
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Table 3 – Recommended screening protocols for specific malignancies in donors after brain death Malignancy
Recommended screening protocol
Lung cancer
Heavy smokers* aged 55–75 yr screened with helical CT; donors with spouses who smoke heavily should also undergo helical CT US for women aged >50 yr who have not had a mammogram within the past 2 yr; biopsy of identified lesions CTC or CS in patients aged >60 yr; donors aged >50 yr with a first-degree relative with colon cancer and who have a polyp >1 cm should be regarded as highly suspicious PSA screening and DRE in patients aged >50 yr; if PSA is not available, then DRE only
Breast cancer
Colon cancer
Prostate cancer
CT = computed tomography; CTC = computed CS = colonoscopy; tomography colonography; DRE = digital rectal examination; PSA = prostate-specific antigen; US = ultrasound. Adapted from Hassanain et al [15]. * >10 cigarettes per day.
of renal function with age is very variable [23]. Nevertheless, the aging kidney loses nephrons and shows a stepwise reduction in glomerular filtration rate. In the older donor, normal creatinine often underestimates kidney function because of reduced muscle mass. In addition, donor comorbidities such as hypertension and death from cerebrovascular accident are considered surrogate markers of impaired kidney function and are predictors of reduced graft survival. The concept of expanded criteria donation was introduced in 2002 to incorporate these parameters in a guide for organ allocation [24]. ECDs were defined as those whose relative risk of allograft failure is >1.7 in comparison with SCDs. They include all donors aged 60 yr or those aged 50–59 yr with at least two of the following criteria: serum creatinine >1.5 mg/dl, a cerebrovascular accident as the cause of death, or a history of hypertension. These three criteria, together with age, are considered surrogate markers of reduced nephron mass [24,25]. The dichotomous SCD/ECD classification system is not perfect because it misclassifies kidneys in opposing directions: Some kidneys labeled as SCD have reduced allograft survival, whereas some ECD kidneys perform well. To further refine prediction of allograft failure, several prognostic scoring systems were added to the simplistic SCD/ECD classification that include more clinical and histologic donor variables and recipient parameters [25]. The United Network of Organ Sharing kidney transplantation committee approved and implemented (by the end of 2014) a new allocation policy [26] based on the Kidney Donor Risk Index (KDRI) that represents the relative risk of post-transplant graft failure from a particular deceased donor compared with the average donor [27]. The Kidney Donor Profile Index (KDPI) is a numeric score that results from ranking the KDRI in percentiles with reference to a given Organ Procurement and Transplantation Network donor cohort [28]. This scoring system is based on 10 donor factors intended to refine the evaluation of the kidney quality without the need of a biopsy. Included
5
in the KDRI/KDPI formula are donor age, height, weight, ethnicity, serum creatinine level, history of diabetes, history of hypertension, hepatitis C status, cause of death, and whether the donation occur after cardiac arrest [27]. As it becomes evident, all information used to calculate KDRI and KDPI is based on the donor. The characteristics of the recipient candidate (HLA matching) and the transplant procedure (single vs en bloc) are not weighted; therefore, one must realize that KDRI and KDPI reflect how the kidney is likely to function in terms of expected graft survival if transplanted into the ‘‘average recipient’’ [29]. KDRI and KDPI are nevertheless an improvement over the ECD/SCD dichotomy. They provide a more precise measure of donor quality because 10 donor factors are incorporated instead of 4 in the ECD definition. A continuous score is given instead of a binary (yes/no) indicator, and the indexes take into consideration that ECDs may be substantially distinct. The KDRI/KDPI calculator is freely accessible online (https://optn.transplant.hrsa.gov/ resources/allocation-calculators/kdpi-calculator/). Already implemented in United States, this score will probably play a role in deceased donor kidney allocation policies across Europe in the near future. The KDRI/KDPI should help transplant programs better allocate the scarce resource of deceased donor kidneys [29]. Kidney biopsy has been intensely debated as an independent predictor of donor quality above and beyond clinical indices. In a retrospective analysis of 65 baseline biopsies, a percentage of >20% glomerulosclerosis was associated with an increased incidence of delayed graft function and poor outcome of transplanted kidneys [30]. However, other authors did not find a correlation between the percentage of glomerulosclerosis in the donor kidney biopsies and 1-yr graft survival and function [31]. Therefore, although donor biopsy findings have a predictive ability, it remains unclear to what extent histologic data improve a score if donor age and function have already been integrated as variables. Moreover, the use of histologic data has increased the number of rejected kidneys. In the United States, the implementation of the ECD program >10 yr ago increased the number of retrieved kidneys, but the percentage of kidneys retrieved and then rejected rose to >40% [28]. Currently, the percentage of glomerulosclerosis may not be used as the sole criterion for discarding deceased donor kidneys [31,32]. 3.
Retrieval techniques
The management of the deceased donor is carried out by the critical care physician in the intensive care unit and by the anesthesiologist in the operation room, ensuring adequate ventilation and circulatory support under standardized donor management guidelines to achieve the best outcomes [9]. However, urologists should have a role at each step of organ donation, first in close collaboration with the intensive care unit and then with the other surgical teams that are potentially involved. The urologist must be familiar with the techniques of deceased organ donor explantation: multiorgan retrieval
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(total midline approach with median sternotomy) and kidneys-only retrieval (classic abdominal midline or cruciate incisions). Multiple organ recovery implies good coordination and cooperation among surgical teams under the leadership of the local transplant coordinator. In general, each organ should be procured as quickly as possible to minimize ischemic injury to the others [16]. In the setting of combined thoracic and multiple abdominal organ retrieval, dissection is started by the thoracic and liver teams. After cross-clamping and perfusion, the organs are removed in the following order: heart, lungs, liver, pancreas, and kidneys. Detailed description of surgical techniques of multiorgan and kidneys-only retrieval is not within the scope of this review. Excellent descriptions can be found elsewhere [10,33]. The principles of abdominal organ procurement are the same regardless of the organs removed. These include wide exposure, control of the vessels above and below the organs to be removed, initiation of preservation in situ (infusion of cold preservation solution and surface cooling with ice slush), isolation of organs to be removed in continuity with their central vascular structures, and orderly retrieval of the organs. In addition, as part of the retrieval procedure, generous specimens for histocompatibility tests should be obtained, iliac vessels should be collected for vascular reconstruction of pancreas and liver grafts, and organ packaging should be properly done [10,33].
preservation, is not visibly better than simple cold static storage for all kidneys [34]. Modern preservation solutions can now offer results with static storage equivalent to HMP at much lower costs; therefore, static storage is currently the preferred method of renal graft preservation for SCDs at most centers; however, HMP may show beneficial effects in deceased cardiac donors [39] and ECDs [40]. A recent large multicenter European randomized controlled trial compared HMP and static cold storage across all donor types [41]. HMP was associated with a significantly reduced risk of delayed graft function and improved graft survival. Likewise, a recent systematic review and meta-analysis concluded that HMP was associated with faster recovery of graft function, with a relative risk benefit between 0.70 and 0.92 [42]. Further studies in the field of renal preservation may establish which preservation strategy is better for a particular donor type. In Europe, various clinical trials to evaluate several targeted therapies proposed by the Consortium for Organ Preservation in Europe have already started. They will investigate the role of oxygenated HMP preservation and reconditioning, particularly in ECD kidneys. In summary, HMP may have the potential to reduce delayed graft function, to decrease primary nonfunction rates, and to improve graft survival in the ECD and DCD settings.
4.
Despite medical and technological advances and global awareness of organ donation and transplantation, the gap between supply and demand continues to widen. Organized and systematic organ procurement and transplantation networks have been replicated and important measures implemented to expand the donor pool and to optimize the organs available for transplantation. This is an exciting time to be involved in the field of organ donation and transplantation, as novel technologies bring new possibilities for donor selection, retrieval techniques, and organ preservation.
Kidney preservation
Successful transplantation is highly dependent on minimizing ischemic damage. Suppression of metabolism is essential to maintain organ viability during the preservation period; therefore, reduction of the core temperature of the kidney <4 8C is necessary [34]. Simple cooling of kidneys in ice water cannot preserve renal function beyond 12 h [35], so additional preservation techniques are used. Contemporary cold storage of the kidneys is done by surface cooling, hypothermic pulsatile perfusion, or flushing with an ice cold solution, followed by cold storage [36]. The duration of cold ischemia should nevertheless be as short as possible, not exceeding 24 h, as a progressive decrease of renal function can be expected with prolonged storage, even under ideal conditions. Despite the beneficial concept of hypothermia, undesirable changes still occur in the preserved organ, even if stored under ideal conditions. Kidney changes include cell swelling, acidosis, altered enzymatic activity, calcium accumulation, and production of reactive oxygen species [34,36]. Storage solutions are used to minimize cell swelling during hypothermic ischemia, to maintain intra- and extracellular electrolyte gradient, to buffer acidosis, to provide energy sources, and to reduce oxidative reperfusion injury [34]. Today, Celsior solution, University of Wisconsin solution, and HTK (histidine–tryptophan–ketoglutarate) solution are equally effective and commonly used in both multiorgan and kidneys-only retrieval procedures [34,37,38]. Cold storage with hypothermic machine perfusion (HMP), once considered the gold standard method for renal
5.
Conclusions
Conflicts of interest The authors have nothing to disclose. Funding support None.
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Please cite this article in press as: Antunes-Lopes T, et al. Evaluation of the Donor After Brain Death and Technique for Organ Procurement. Eur Urol Suppl (2016), http://dx.doi.org/10.1016/j.eursup.2016.08.004