The Cadaveric Donor

The cadaveric or brain-dead donor is the source of the majority of organs and tissues for transplantation. The use of the brain-dead person as a donor is supported by the scientific evidence that complete cessation of cortical and brain stem function is followed by the organism death. This scientific concept is acknowledged by the American Medical Association and the American Bar Association. Clinical criteria, outlined in Table 4.2, are usually sufficient to diagnose brain

■I death. The clinical diagnosis can be supported by confirmatory tests like an elec-4 troencephalogram and/or radionuclide cerebral blood-flow studies, especially when * coma coexists with hypothermia or the donors have received neurotropic medication, like opioids or barbiturates. When diagnosing brain death in pediatric donors less than 1 year of age, two neurological examinations in conjunction with electroencephalography, separated by 24 hours, are recommended. Even longer evaluation time, 48 hours, is recommended for infants of less than 2 months of age.4 More details on the definition of brain death and the management of the donor can be found in chapters 1, 3, 5, and 7.

Once the potential organ donor has been identified, his/her suitability needs to be assessed with the critical knowledge that some of the parameters taken into account may be distant from the definition of the "ideal donor" but still be acceptable considering the status of the recipient, the organ to be transplanted and the necessity of using all the organs that offer a "reasonable likelihood" of good post-transplant functioning.

The initial assessment of the potential organ donor follows the same steps no matter what organ is to be donated. The primary goal is to attempt to retrieve as many organs as possible from every donor. After obtaining a very detailed past medical and social history, a thorough physical examination is performed in order to detect any sign of infectious or tumor pathology, and not the least, needle

Table 4.2. Brain death criteria

Clinical

Coma with an established cause: no CNS depressants or hypothermia Absent spontaneous movements except spinal reflexes Positive apnea test Absent cranial reflexes

Confirmatory Tests

Cerebral blood flow scan

CNS = Central nervous system; EEG = electroencephalogram

Reprinted with permission from Busuttil RW, Klintmalm GB, eds. Transplantation of the Liver. Chapter 38, p 387. ©1996 WB Saunders Publishing Co.

track marks, tattoos and body piercing jewelry that may indicate social habits that could result in a contraindication to the donation. Also the presence of skin incision may raise questions about his/her past medical history and help the family members in recollecting previous medical events.

The presence of an extracerebral malignancy or less than a 5-year history of a treated malignancy is an absolute contraindication. Also, when a donor affected by brain tumor has undergone a ventriculo-peritoneal or a ventriculo-atrial shunt, he/she should not be considered for donation due to the increased risk of neo-plastic dissemination. Relative contraindications are represented by low-grade skin I cancers or by low-grade solid organ tumors when a sufficient, more than 2-5 years, Ej tumor-free interval is present and documented.5,6 The acceptance of organs from ® these donors that harbor the risk of transferring a malignancy to the recipients must be weighed against the clinical urgency of the recipients under such circumstances and the recipient's family must be fully informed of the potential risks. It is our policy to reserve these organs only for patients that would otherwise die in hours or days unless transplanted. In the unfortunate event that a cancer is discovered during the autopsy of the donor the transplanted organ should be removed because there is at least a 45% chance that it harbors cancer cells.5 An alternative approach would be to reduce the immunosuppressive regimen and follow the patient closely. This is the only option for a cardiac or a liver transplant recipient short of retransplanting the patient, but this has also been suggested for kidney recipients instead of performing a transplant nephrectomy.

History of AIDS or documented HIV infection is an absolute contraindication to donation. The guidelines for preventing transmission of HIV through organ and tissue transplantation were published in 1994.6,7 Donors who have social history of homosexual practices, intravenous drug abuse, prostitution, incarceration or past medical history of hemophilia are considered high risk for being viral carriers. Specific exclusion criteria are also set for pediatric donors born to mothers belonging to one of the above categories or HIV-positive mothers. They may be accepted if older than 18 months, HIV-negative, with negative physical examination and negative past medical history of infection, and no record of breastfeeding within the last 12 months. Nonetheless, in donors who belong to any of these categories but test negative for HIV, the FDA encourages the donation and transplantation of life-saving organs. Obviously in this situation the circumstances must be fully discussed with the recipient and the family. A bill from the Center for Disease Control dated October 1996 states "In the context of the current organ shortage transplant teams are encouraged to accept and transplant organs from medically appropriate donors who test HIV-antibody negative but have behavioral risk criteria for HIV infection after the transplant team has discussed the risk and benefit with potential recipients and/or their families."

Hepatitis B antigen positivity represents active infection and infectivity and is an absolute contraindication to organ donation while hepatitis B surface antibody positivity reflects immunity or lack of infectivity, and therefore, allows transplantation of the organs. The case of a donor who has anti-HBc antibody and is hepatitis B surface antigen negative is a situation that could represent a resolved acute infection or a chronic carrier status and the organs may be used in recipients who already are infected by the hepatitis B virus using hepatitis B immunoglobulin following transplantation as prophylaxis for the recurrence. The use of such donors in recipients who are not hepatitis B core positive is debated due to the relatively high recurrence rate but can still be considered for kidney recipients where the risk of infection seems to be minimal.8

The use of hepatitis C antibody positive donors has become more frequent in the past 5 years and the guidelines for the utilization of the hepatitis C positive organs are drawn in the paragraph about infections.

The second step is the evaluation of all those criteria that do not follow absolute and strict parameters but which overall analysis must give, as a result, a graft with the highest chance of good functioning after the transplant. Some of these criteria are different according to the organ to be transplanted and will be analyzed separately.

Many lessons have been learned regarding the age factor. Transplant surgeons recognize an "ideal donor age" and know that at the two extremes from this "ideal age," infants and very old grafts, do not function as well and that both graft and patient survival decrease. However, it is also clear that without the use of the older or the very young donors the donor pool would shrink even more and more patients would die on the waiting list. Therefore, the use of these grafts is justified by the greater number of patients who will survive once transplanted. Ideally, the best results are achieved when donors younger than 45 years are used. In the past decade three important factors have influenced an increase in the donor pool age limit far beyond 45-years-old used in the 60s and 70s. First, the decrease in traumatic deaths that usually occurs with younger people (from 34.3% in 1988 to 21.9% in 1993),1 second, the increased awareness about HIV and, third the exclusion of donors potentially at risk, (again, more typical of younger people) and the ever increasing demand for organs. These factors and the good results obtained with the older donors reflect the change in the donor pool in the period from 1988 to 1995, with the donor pool 50-64 years old increasing from 2.5% to 17.9%, the donor pool above 65 years of age increasing from 0.1% to 5% and the donor pool 18-34 years old decreasing by 13% in the same period.1

In general the "ideal donor age" can be set between 10-12 years old and 45-50 years old. For kidney transplant the best results have been obtained with donors between 18 and 38 years of age. The 2- and 5-year-graft survival from these donors is 79.3% and 63.9%, respectively, compared to 69.2% and 49.4% for grafts from donors 50-64 years old and 61.3% and 40.3% for grafts from donors 65 years and older.1 A decrease in the graft survival rate at 2 and 5 years can be appreciated also for grafts from donors of age 6 to 10 years and 1 to 5, 69.9% and 56%, and 66.9% and 55.1%, respectively. It is interesting to note that the causes of graft loss from donors of 5 years or younger are more often caused by technical complications and vascular thrombosis that may be related to the size of the graft vessels and the difficulties in performing the anastomosis or to an increased responsiveness to vasospastic stimuli.9

The age of the donor plays as an independent factor in the survival of the liver graft, and consequently, in the patient survival. UNOS data show that graft survival decreases from 62.5% to 45% at 5 years when the donor age increases from 11-17 years to 50-64 years. Patient survival at 5 years decreases from 71.1% when the donor age is 11-34 years to 59.9% when donor age is 50-64 years. The more dramatic decrease in graft and patient survival is appreciated when the donors of 11-34 years of age are compared with the ones above 65 years with a drop of 20% in graft survival at 3 years.

In pancreas transplantation donor age also plays a critical role in the outcome of the graft. There are very few studies on pediatric pancreas donors but very good results have been obtained with donors as young as 5 years.10 It is instead generally accepted that when donors older than 45 are utilized the graft survival decreases with a drop as high as 20% at 1 year when donors younger than 50 years of age are compared with donors older than 50 years.11,12

Gender

At the present time grafts are not allocated according to gender, and donor/ recipient sex mismatch does not play a role in the scheme. Nevertheless, there have been several reports of poorer results when a graft from a female donor is given to a male. The reason for this decreased graft survival is unknown, but it is speculated that the estrogen/androgen receptor may be a factor.13,14 Gender mismatch seems to have even a stronger impact if the donor is elderly, but becomes less important if there is a complete HLA match or if a retransplant is performed.15 Due to the present shortage of suitable donors and the lack of scientific knowledge to support the above described clinical findings, gender does not influence organ allocation and gender mismatched organ transplants are an accepted practice in any center.

Size

Body size is not one of the criteria in allocating kidney grafts. Technically, it is always possible to place the kidney in the retroperitoneal space and perform the vascular anastomosis in the adult recipient regardless of the size of the graft. As mentioned earlier, the use of kidneys from pediatric donors less than 5 years of age is associated with a higher incidence of surgical complications related to the vascular anastomosis. Of greater importance is the issue regarding the function of a kidney donated by a small size donor, pediatric or not, when transplanted in a patient with a bigger body habitus. There are reports of decreased graft functioning and survival when there is a greater than 20% body weight discrepancy between donor and recipient, probably because of a smaller nephron reserve that would enhance susceptibility to immunologic or nephrotoxic injuries. This factor has been suggested as one of the variables in the poorer results when a kidney from a female donor is given to a male recipient or when a pediatric donor is used for an adult.15 In the latter case en bloc renal transplantation, using both kidneys from a pediatric donor on a single aortic and vena cava conduit has been used in order to overcome size mismatch.

In liver transplantation chest circumference, height and weight are recorded in the recipient information together with blood group, sex, age and diagnosis. A recipient of about 170 pounds can accommodate a liver from a donor with a weight range of 100 to 300 pounds, especially when ascites is present. The transplant of a liver too big for the recipient can have devastating consequences on its function

■I such as caval compression and venous congestion, parenchymal necrosis, portal 4 vein thrombosis, delayed closure of the abdomen and need for a splenectomy. A ® small liver in a large recipient can be a problem becasue of rotation of the allograft around the cava-axis creating a kink in the suprahepatic vena cava and venous congestion of the liver. The size factor has always been a problem in pediatric transplantation due to the small number of pediatric donors available. In pediat-ric liver transplantation, a donor-recipient weight ratio can be used as a guide to determine if the whole organ can be transplanted or a reduced size using the left lobe with the donor vena cava or a split using segments 2 and 3 of the donor without vena cava will be needed. Different values of donor-recipient weight ratio, from 2 to 12, have been reported when the technique of reduced size liver transplantation is used, to be critical nevertheless, a donor recipient weight ratio greater than 6 indicates the need for size reduction of the graft, especially in the absence of splenomegaly or ascites in the recipient.16

The other very important implication of size is the presence of fatty liver in the overweight donors. Obese donors are at high risk for having severe macrovesicular steatosis which is associated with high incidence of primary nonfunction.17 When presented with an obese donor, > 130% ideal body weight, a biopsy of the graft should be performed and a percentage of macrovesicular fat greater than 40% should preclude transplantation. The importance of microvesicular fatty infiltration is not clear but a recent report states that no difference in patient and graft survival is seen if grafts with severe microvesicular steatosis are used.18 When borderline fatty grafts are used, keeping the cold ischemia time short, i.e., less than 6 hours, appears to minimize the problem of poor graft function connected with fatty infiltration. It is essential to visually evaluate the graft both at the time of the first exploration and after the portal flush. A liver with a yellowish appearance, rounded margins and firm consistency after flushing should be discarded or should at least require a biopsy. The increasing use of donor percutaneous liver biopsy has allowed a useful preoperative screening and saved unnecessary surgical explorations. Nevertheless, if the surgeon in charge of the donor operation judges that the liver is not obviously unusable it is our policy to bring the graft back home with a biopsy. It is important to stress that these biopsies have to be obtained with a tru-cut needle, processed as frozen sections, prepared with regular hematoxylin-eosin stain without using any fat stains, since they stain even a normal liver, and read by a pathologist with expertise in the field and by the transplant surgeon. A tru-cut needle biopsy is favored over a wedge biopsy because the latter is always affected by subcapsular changes.

Cause of Death

Although not very often contemplated in the screening of the donor, the cause of death may alert the transplant surgeon to some of the factors that may play a role in the retrieval operation itself and also in the long-term outcome of the graft. For example, in a donor who died in a motor-vehicle accident attention should be directed to the possibility of abdominal and/or thoracic injuries. Donor death by cerebral vascular accident should warn the accepting surgeon of the possibility of vascular disease of the aorta involving the orifices of the celiac axis and the renal arteries, thus making the transplant not feasible or increasing the chances of arterial complications after the transplant. In a liver donor whose death was associated with a prolonged hypoxic event, i.e., suffocation, drowning in warm water, esophageal intubation, it is important to consider the possibility of hypoxic hepatic cellular damage and impending cellular death manifested by nuclear pyk-nosis. Liver grafts from donors who died of cranial injury have proved to have better survival than in the case of cerebral hemorrhage.19 There have been reports that donor death by head injury plays a role as an independent factor on graft outcome.20 A report from Gruessner points out how the association between donor age and cardio-cerebral cause of death could become a significant detrimental factor in posttransplant pancreas function.21

Past Medical History

There is little data available regarding criteria of acceptance for donors with previous history of hypertension and/or diabetes. A short history of hypertension, well controlled with only one medication, should not be of major concern to the accepting surgeon. Donors requiring more than one medication to control their hypertension and/or whose medical history is positive for insulin-dependent diabetes mellitus, peripheral vascular disease or myocardial infarction should undergo a biopsy of both kidneys prior to the acceptance of the organs. The biopsy allows the assessment of the degree of glomerulosclerosis, interstitial fibrosis and arterial changes and thus determines the suitability of the kidneys for transplantation.

Diabetes per se is not a contraindication to organ donation, with even some evidence that diabetic nephropathy can be reversed after transplant of the kidney in a nondiabetic patient. However, the presence of other comorbidities and a long history of insulin-dependent diabetes mellitus would warrant a biopsy of the graft prior to the transplant. In liver transplantation, diabetes and hypertension do not play a role in ruling out a potential donor but when long lasting, severe and/or associated with other risk factors like old age or obesity, they mandate a biopsy of the graft to assess fatty infiltration. Any history of metabolic disease like alpha1-antitrypsin deficiency, hemophilia, glycogen storage disease or sarcoidosis is an absolute contraindication to the use of the liver graft. Oxalosis is also a contraindication for kidney donation, since the patients are usually discovered by renal dysfunction. Regarding pancreas transplantation two absolute contraindications to the use of the allograft are past medical history in the donor and the donor who is positive for pancreatitis or diabetes mellitus.

Infections

Most surgeons would refuse donors with active systemic bacterial infection because of the risk of transmitting it to the immunosuppressed patient. An infectious process localized to any organ system outside the abdominal cavity does not represent an absolute contraindication to liver, kidney or pancreas transplantation. A donor with history of treated sepsis with recent negative blood culture is suitable for donation. Also, in the case of meningococcal and pneumococcal sepsis, donors who have received 24-48 hours of penicillin should be considered. An

■I interesting issue is raised by the hepatitis C serology positive donor. Most of the 4 reports confirm the risk of transferring the virus from the donor to the recipient and the high probability of the recipient developing active disease. At the same time there seems to be increasing consensus in transplanting kidneys from hepatitis C positive donors in hepatitis C positive recipients.22 The almost universal seroconversion in a recipient of a hepatitis C serology positive donor and the high incidence of histology-proven recurrence make the hepatitis C positive donors suitable only for patients with end-stage liver disease caused by hepatitis virus C. In hepatitis C positive recipients, the use of hepatitis C positive donors have not demonstrated any impact on disease recurrence and graft or patient survival. A biopsy of the donor positive liver is mandatory in order to exclude those organs with histopathological signs of viral damage. However, for hepatitis C positive recipients in an urgent need for a transplant, using informed consent, we have used hepatitis C positive donors with chronic active hepatitis and even bridging fibrosis with good results.23

Positive cytomegalovirus (CMV) serology in the donor does not seem to have any adverse effect on patient and graft survival even when the recipient is seronegative for CMV.24 This is in contrast with earlier experiences that showed a decreased graft and patient survival when a graft from a CMV positive donor was given to a CMV negative recipient and reflected the excellent results obtained from prophylaxis with the anti-viral medication ganciclovir. Nevertheless, documented severe CMV infection may affect the allocation of the organ since it can have a negative impact on patient and graft survival when the recipient is CMV negative.19,25

Organ Function

The stability or deterioration of the function of each organ since the event leading to brain death must be evaluated, taking into consideration the cause of death, any cardiac arrest, cardiovascular stability and the donor age. Organs from young donors, less than 25 years old, withstand even a significant injury and seem to heal quickly with minimal consequences on posttransplant organ function. Often the stabilization of the donor hemodynamics and the normalization of the fluid status are crucial and sufficient actions in stopping a downward trend in the patient condition and the function of the potentially transplantable organs, but no further delay should occur in the organ's procurement.

Kidney

The assessment of renal function is based on creatinine and BUN at the time of the admission of the donor to the hospital and on hourly urine output. Increasing creatinine values or decreasing urine output may reflect acute tubular necrosis (ATN) due to prerenal factors and does recover after the transplant. A study by Busson analyzing donor serum creatinine levels and hourly urine output did not show any significant difference in graft survival even in the presence of creatinine higher than 3mg/mL and urine output less than 30 mL/h.19 However, a biopsy should be performed in those donors who, together with increasing creatinine I values and decreasing urine output, have other comorbidities that affect renal func- Ej tion. This is particularly important in donors with history of diabetes in order to ® diagnose Kimmelsteil-Wilson nephropathy.

Liver

Presently, the only method of assessing liver function is the evaluation of liver function tests, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamine transferase (GGT), alkaline phosphatase and of the coagulation parameters. Although they are not perfect predictors of posttrans-plant graft function they do give a fair indication of the liver status. It is ideal to have liver function tests within normal limits; although, this is rarely seen in most of the donors, but a slight or moderate increase in values usually does not constitute a serious problem.26 It is normal to accept a graft from a donor who first presented with moderately elevated liver biochemistries that decline to normal or near-normal after the resuscitation phase. Donor age and cause of death are crucial factors to take into account when assessing such organs. Initial transaminases as high as 800 U/liter in a young donor following traumatic death, that subsequently improved declining toward normal values, reflect the function of a graft that is usually perfectly usable. On the other hand, rising levels should warn the surgeon of a suffering liver and suggest a biopsy of the graft. In these cases it is also very important to diagnose the cause of poor functioning of the liver and act promptly on the donor in order to save the organs. In summary, the transplant surgeon must always evaluate the organ function and its development in relation to the cause of death, the donor age and past medical history. Despite the reports of good assessment of liver function with the MEGX test and its use as a predictive tool of posttransplant organ functioning, this test has not achieved widespread use in the United States.27 The measurement of amylase level and glycemia are the only indirect methods of determining good pancreatic function. It is clear that the isolated amylase level per se is not an indicator of poor function, and most of the transplant surgeons do not consider an elevated amylasemia as a criterion to reject the donor. The presence of hyperglycemia in a donor without history of diabetes is no longer a contraindication to the use of the pancreas. Earlier reports of decreased graft survival in pancreata obtained from hyperglycemic donors28,29 have not been confirmed by more recent studies.11,30

Hospital Course

A short hospital stay is always preferable and in some reports is associated with better outcome,20 but as long as the donor has had a stable course and no signs of sepsis, there is not a set length of stay that should preclude the use of the organs. The main problems caused by a long hospital stay are the deterioration of organ function secondary to complications and use of potentially toxic drugs, and the increased risk for nosocomial infections (staphylococcus, klebsiella, fungi).

The use of vasopressors and cardiopressors in the form of dopamine and/or

■I epinephrine to maintain normal/acceptable cardiovascular hemodynamics is com4 mon. These medications are often required to maintain a mean blood pressure * above 60 mm Hg that allows good perfusion of the transplantable organs.14,26 We strive to maintain the systolic blood pressure above 100 mm Hg and start vasopressors only if absolutely necessary. The use of vasopressors instead of fluid resuscitation is routine in patients with head injury. Once brain death has been established, appropriate fluid therapy should be favored over vasopressors to maintain hemodynamic stability and the vasopressors should be stopped or at least decreased. To rule out a potential donor only on the basis of high doses of vaso-and cardiopressors is not always appropriate. Past medical history, length of time that the pressor medication has been infused and change in the dosage of pressor medications over time in order to maintain adequate perfusion pressure are all factors that must be considered prior to accepting or refusing the potential donor. A single center study, looking at pancreatic graft function, outlined duration of brain death prior to the procurement, 15 hours or longer, and length of hospital stay from admission to brain death, 48 hours or longer, as predictors of graft failure.31

The factors above must be critically analyzed by the transplant surgeon and taken into consideration at the time of the surgery when the organs are visually evaluated, the anatomy defined and the vasculature examined. The final decision in transplanting the organ comes from the summation of all the information acquired during the work-up and actual status of the organ at the time of the retrieval.

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