Organ Donation
Author: Scott R. Johnson, MD, Surgical Director, Renal Transplant Program, Beth Israel Deaconess Medical Center, Instructor of Surgery, Harvard Medical School, Boston, Mass.
Editor’s Note—The field of transplantation can trace its roots back to the turn of the century, when experimentation in animal models yielded important information on both the technical aspects of transplant surgery and the significance of graft rejection. Basic science research performed in the 1930-40s provided insight into the immune response that characterized both cellular and humoral rejection. Although human transplantation has been attempted on many occasions, it was not until the 1950s when human transplantation met with success.1 In the last 2 decades, many of the most important discoveries to benefit transplant recipients have been made. The introduction of new immunosuppressive agents and improved immunosuppressive protocols has greatly improved allograft survival in all organs. The newer agents have given clinicians an expanding armamentarium in preventing rejection. The introduction of new surgical techniques such as laparoscopic donor nephrectomy and living-related liver transplant has increased the donor pool for those organs and provided life-saving options for many individuals. The demonstration of prolonged islet cell survival in a clinical setting has finally heralded a much-awaited treatment for diabetes mellitus.2
Despite these advances, organ shortage remains the most critical obstacle that transplant physicians and recipients must overcome. There are currently more than 80,000 individuals awaiting organ transplantation in this country. Based upon Organ Procurement and Transplantation Network (OPTN) data as of December 13, 2002, only 12,000 organ transplants had been performed, and 3100 of these were from living donors for the current year. Each year the number of listed individuals awaiting transplants grows, but the number of available organ donors has not kept pace with this increasing demand (see Figure 1 below).
| Figure 1. Transplant Activity by Year |
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This is has led to a marked and steady increase in the average waiting time for organ transplantation (see Figure 2 below).
| Figure 2. Waiting Times by Organ and Blood Type |
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Wait times for organs in this country vary by region (see Figure 3 below) but in general average 18-24 months for a liver, 3-4 years for a kidney, and 1-2 years for a pancreas.3
| Figure 3. Renal Allograft Wait Times by State |
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Increasing public awareness about the options of organ donation has been and presently is the focus of increasing the supply of cadaveric organs. Despite this, the number of cadaveric organs procured in this country remains stable. Methods to increase the supply of cadaveric organs are being explored and include presumed consent and offering an honorarium to donor families to cover funeral expenses. Presumed consent implies that all individuals, at the time of their death, have consented for organ donation unless a public authority has been notified of an individual’s refusal to donate. This policy would remove a potential donor’s family from the consent process. Variations on this theme have been proposed in Maryland and Pennsylvania that would require the permission of the family of the donor if they can be located.4 This policy would be expected to increase the number of donor organs available, as has been shown in countries where it has been implemented.5 Individuals not interested in donating their organs after death would have multiple venues to make this declaration known.
The objective of this monograph is to provide an overview of the process of organ donation form consent until transplantation of the recovered organs into the selected recipients. A discussion of the role of newer immunosuppressive agents, their mechanisms of action, and their effects on patient and graft survival as well as quality of life after transplantation will also be incorporated. The discussion will also seek to familiarize clinicians with a variety of new pharmacologic agents that have recently come into clinical use as antirejection agents and, finally, to describe several new techniques that have already made a significant effect on organ transplantation.
Organ Donation
All of transplantation begins with organ donation; if not for the exhaustive work of the donor coordinators in conjunction with the organ procurement organizations (OPOs), transplantation would not be feasible. Currently, UNOS or the United Network of Organ Sharing retains the government contract to oversee and distribute all cadaveric organs that are procured in this country. This organization came about from a series of observations that occurred in the late 1960s. At that time, several centers noted that kidney allograft survival was improved in the setting of better HLA matching. These centers developed a computerized database that sought to identify the best HLA-matched recipient for each organ procured, which was called the "Kidney center" and was the precursor of UNOS. As time went on, many centers joined this computerized system, and the need to expand this program to a national level was apparent. UNOS was incorporated in 1984 as a separate nonprofit organization and in 1986 received the federal contract to oversee the OPTN.6
All individuals who reach brain death criteria or are terminally weaned from a ventilator are potential candidates for organ donation. There are few absolute contraindications for organ donation. The most likely reasons for refusal of an OPO to pursue organ donation include a recent history of malignancy, infectious disease (HIV, hepatitis B or C), sexual promiscuity, or intravenous drug use. Finally, poor donor quality is occasionally cited as a reason for OPO decline. In this setting the donor may have sustained prolonged "down time" with hypoxia, hypotension, and/or complete cardiovascular collapse prior to establishment of hemodynamic stability. The laboratory studies may demonstrate severe end organ injury with marked elevation in transaminases, azotemia, abnormal ECG or echocardiography, and an inability to correct these abnormalities with resuscitative efforts. These organs generally function poorly if at all after transplant. The donor coordinators in conjunction with the OPO will rarely turn down a potential donor without contacting a transplant center to inquire as to the suitability of the organs to be procured. The ultimate decision on the use of an organ for transplant rests with the recipient transplant center.
One area where transplant physicians have made significant progress in expanding the donor pool is with the use of so-called "marginal" or "extended criteria" donors. A recent consensus conference has defined "extended criteria donor," for renal transplant, as having a 70% increased risk of graft failure at 1 year. The donor factors that give rise to this outcome include age older than 60, or age older than 50 with any 2 of the following risk factors: hypertension, creatinine greater than 1.5 mg/dL, or death via a cerebrovascular accident (CVA). The use of these organs will be expected to have a reduction in long-term graft survival from 90.6% to 84.5% at 1 year and 79.4% to 68.0% at 3 years in the "normal" vs extended donor, respectively.49 Several groups have embarked upon an aggressive policy of using organs recovered from these individuals with excellent results.7
When an individual who sustains a life-threatening injury from trauma, stroke, cerebrovascular accident (CVA), and/or anoxia has been declared brain dead or approaching brain death, the hospital is required by the HCFA Final Rule on Conditions of Participation for hospitals in Medicare /Medicaid to report in-hospital deaths to local OPOs. This law became effective on August 22, 1998, in order to help identify all potential organ donors and increase organ donation.8 A donor coordinator will conduct a brief interview with the referring health care professional to determine the candidacy of the referred patient. If the patient is deemed an acceptable candidate, the coordinator will proceed to the referring institution for a more definitive evaluation. Before an approach to the family is made for consent for organ donation, the coordinator will conduct an exhaustive review of the medical and social history. The coordinator will specifically seek to identify the cause of death (ie, trauma, CVA, anoxic injury) and the events surrounding the injury. This is important to identify factors that may preclude specific organ donation such as injury to the spleen, pancreas, liver, kidneys, heart, and lungs. Additionally, the coordinator will seek to determine if there was any "down time" that will adversely affect organ function.
Certain chronic disease states will adversely affect post-transplant organ function as well as graft survival, and their presence in the donor may cause a transplant center to decline a specific organ offer. Prolonged or uncontrolled hypertension and diabetes mellitus may adversely affect kidney, pancreas, and cardiac allograft function but will probably not affect liver function. Infectious diseases such as HIV, hepatitis B or C may preclude all transplants due to the high risk of transmission, with several notable exceptions. The presence of hepatitis B core antibody (Hep BcAb) implies that an individual has been previously exposed to the hepatitis B virus and has successfully cleared it. The risk of transmission of hepatitis B from Hep BcAb-positive, hepatitis B surface antigen (Hep B sAg)-negative donors, to surface antibody-positive (Hep B sAb) recipients is low. In a study of renal transplant recipients who received renal transplants from Hep BcAb-positive and Hep BsAg-negative donors, the authors noted no increased risk of graft loss or patient death compared to controls. An increased risk of seroconversion to Hep BcAb-positive status was seen but not in seroconversion to Hep B sAg-positive status.9 In addition the use of organs from donors with hepatitis C and their implantation into recipients with hepatitis C has met with success without significant adverse consequences.10 These 2 strategies provide additional means to increase the donor pool.
In most instances, coordinators will not speak to family members or inquire about organ donation until brain death has been declared or a decision has been made to proceed with a terminal, ventilator wean. Rarely, families will discuss the option of organ donation upon learning the prognosis of their loved one. In this instance, they may request a consultation to discuss the option of organ donation prior to a declaration of brain death. If consent is granted, the coordinators will assume management of the patient, and all financial obligations from this time forward will be the responsibility of the OPO. The management of the patient will focus on 3 aspects:
1) Optimization of hemodynamic status and oxygen perfusion of tissues
2) Laboratory studies
- Routine chemistries, hematology, and coagulation studies
- Infectious disease (HIV, hepatitis A, B, C, EBV, CMV, and HTLV I and II)
- Tissue typing (HLA class I A and B locus, class II DR locus)
- Blood Type
3) Additional diagnostic exams
- CXR, EKG
- Bronchoscopy—Lung transplant
- Cardiac Echo/catheterization—Heart transplant.
Most organ donors are in the ICU and are critically ill. Many donors have sustained head injuries and in the process of management have undergone forced diuresis to control elevated intracranial hypertension. Additionally, many head-injured patients experience diabetes insipidus resulting in voluminous urine output, and further complicating matters is the addition of pressors to maintain cerebral perfusion pressures above 70 mm hg. This constellation of factors results in profoundly hypovolemic, vasoconstricted patients with poor end organ perfusion. In the process of brain stem herniation, a large source of endogenous catecholamines is released that can precipitate severe hypertension, vasoconstriction, arrhythmias, bradycardia, as well as hypotension. The coordinators must spend a great deal of time resuscitating these individuals to euvolemia—preferably in the absence of vasopressors. During this resuscitative effort, chemistry, hematologic studies, serologies, (ie, HIV, EBV, CMV, HTLV I, II, RPR, hepatitis B and C) blood, and HLA typing are obtained. Additional studies such as bronchoscopy, echocardiography, and cardiac catheterization may also be requested if cardiac and or lung procurement are considered.
When serology results are available and acceptable and tissue typing is complete, these data are entered into the UNOS database and the computer-generated recipient list is obtained. Each organ has its own hierarchy of factors that determine the priority of the recipient, and this hierarchy is independent of the other organs. Upon receiving the list, the coordinators begin to offer the organs to transplant centers throughout the country. Each center receives the donor information and reviews their potential recipient to insure they are in satisfactory medical condition to receive the graft. The center generally will try to decline or accept an organ within 1 hour of the offer. The coordinators will routinely offer up to 7 organs per donor (heart, pancreas, liver, 2 kidneys, and 2 lungs), and this may require multiple phone calls per organ to complete placement. When all organs are accepted by recipient centers, an operating time is established that must be coordinated with the recipient centers. In many instances, multiple teams will arrive in the operating room to remove their respective organ(s). As such, the procurement time must take the arrival of multiple teams, the donor operation, and the recipient operation in the setting of cardiac transplantation into account. The entire process may take several hours to coordinate.
A question that is routinely asked of transplant physicians is what the role of the attending physician should be in the events surrounding the declaration of brain death. The principle role of any physician will be in the education of his or her patients on the benefits of transplantation, to encourage individuals to become organ donors, and most importantly, to stress that the decision should be discussed with family members. Hopefully, this will have occurred long before an unforeseen event occurs. Multiple studies have been performed that clearly demonstrate that to optimize the rate of familial consent for donation the declaration of death must be separated from the request for organ donation.11 This concept is often referred to as "decoupling." Families typically perceive a declaration of brain death and a subsequent request for donation, by the same individual, as a conflict of interest. Many are concerned that their loved ones will not receive the best medical care available in this situation. The best solution is to allow the donor coordinators to pursue donor consent after a declaration of brain death has been made. They are capable of spending the necessary time with the families to discuss the options of organ and tissue donation, answer questions pertaining to incurred expenses, funeral arrangements, directed donation, and myriad other concerns that may arise. If family members wish to pursue a discussion with the declaring physician about organ transplantation then it is certainly beneficial to discuss this topic.
Pharmacopoeia
Immunosuppressive agents can be classified into several categories depending upon the predominant usage. Induction agents are typically given immediately prior to and during the first several days after transplantation. The purpose behind their use is to boost the antirejection therapy in the early post-transplant period, for high-immunologic-risk patients, or to provide a non-nephrotoxic-based therapy until renal function improves. The drugs used for induction are primarily antibodies, such as OKT3 (monoclonal antibody to the T-cell receptor), thymoglobulin (polyclonal antibody against lymphocytes), Simulect (basiliximab), or Zenapex (dacluzimab) (both are anti-interleukin-2 receptor antibodies), but almost any agent can be used in this fashion. Maintenance drugs provide a long-term basal level of immunosuppression that is typically administered early after transplant and is generally given for the life of the allograft. These agents are given orally and may require periodic drug level monitoring to ensure therapeutic levels and minimize potential toxicities. Rejection-reversing agents are given during an episode of acute rejection, which is diagnosed by allograft biopsy in the setting of graft dysfunction.
Graft dysfunction is usually heralded by an elevation of the serum creatinine for renal transplants and elevation in alkaline phosphatase or transaminases in liver transplant. The diagnosis of pancreas allograft rejection is usually exhibited by an elevated creatinine when the transplant was performed as a simultaneous kidney-pancreas (SPK) transplant (both organs from same donor) but can be more troublesome if the pancreas transplant was performed as an isolated procedure (pancreas transplant alone/PTA) or the graft came from a different donor than the kidney (pancreas after kidney/PAK). Many of the previously described agents can reverse rejection, but generally steroid pulses, given intravenously, are the first-line agents for the treatment of acute rejection. If this fails, then conversion to anti-lymphocyte antibodies is the next progression. These agents include thymoglobulin (polyclonal antibody from rabbit), ATGAM (polyclonal antibody from horse), or OKT3 (monoclonal antibody from mouse). These agents are given over a 7- to 10-day course and have myriad side effects including neutropenia, fevers, rigors, diarrhea, and pulmonary edema.30 The effects are worse with initial doses and subside as treatment continues.
Prior to 1984, the principle immunosuppressant agents consisted of prednisone (pred) and azathioprine (aza). These agents do not directly target the immunologic cells responsible for allograft rejection but suppress all immunologic activity. As such, large doses of these agents were required to achieve satisfactory efficacy at controlling rejection. Despite the large doses of steroids, allograft rejection rates of greater than 70% were observed in most organs (see Figure 4 below). The consequence of this regimen was a significant incidence of rejection, graft loss related to rejection, and complications related to large dose steroids and azathioprine—namely malignancy, osteoporosis, diabetes, and infection.12
| Figure 4. Renal Rejection Rates by Protocol |
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The introduction of cylclosporine in 1984 heralded a new class of drugs known as calcineurin inhibitors (CNI).13 These agents have traditionally been used in conjunction with steroids and azathioprine or Cellcept®. CNIs bind to receptors in immune cells, termed immunophilins, which then bind to calcineurin and inhibit the production of or signal transduction of activating cytokines. Interleukin-2 is the most important cytokine inhibited and is required for both activation and clonal expansion of immune cells. In 1990, FK506/tacrolimus or Prograf®, which is 20-40 times more potent than cyclosporine, was introduced.14 When compared with cyclosporine and azathioprine in the European multicenter trial, the Prograf®/aza/steroid combination reduced acute rejection from 45% at 1 year to 25% at 1 year.15 This increased potency has permitted it to be used not only as part of a standard 3-drug regimen, but in a variety of settings such as refractory rejection, dual therapy regimens, (Prograf® and steroids) and occasionally as monotherapy. Although cyclosporine and Prograf® have a similar mechanism of action, they bind to different receptors in the cytoplasm. This ultimately leads to subtle differences in efficacy and side effects. The introduction of CNIs has been one of the most important discoveries that have advanced transplantation to its present state of accepted surgical therapy for end-stage organ disease.
Although these agents are responsible for the marked improvement in allograft survival, they have many side effects associated with their use including diabetes, hypertension, tremors, headaches, and excessive hair growth. No side effect has been more troublesome than the nephrotoxicity of these agents. This effect is dose dependent and can be seen acutely or more commonly in a chronic setting. In conjunction with hypertension and diabetes, it can lead to renal failure in both kidney transplant recipients as well as other organ recipients. It is not unusual for a successful heart, lung, or liver transplant recipient to present 5-10 years later with end-stage renal failure from CNI toxicity.16 Despite these side effects, the introduction of cyclosporine significantly reduced allograft rejection in renal transplant recipients and dramatically prolonged 3-year graft survival from 48% to 76%.17 Prograf® has further reduced the incidence of allograft rejection at 1 year, and in a standard 3-drug regimen rejection rates approached 10-20% at 1 year.18 These agents are given orally in 2 divided doses. Cyclosporine is initially given at 5-8 mg/kg/d (divided), and therapeutic levels are monitored with target 12-hour trough levels of 350 ng/mL in the first month after transplant, declining to basal a target of 100-150 ng/mL at the end of the first year. Prograf® is given at a dose of 0.1 mg/kg/d (divided), and early target levels are 10-15 ng/mL, declining to 5-8 ng/mL at the end of the first post-transplant year.
In 1975, rapamycin or sirolimus was discovered and has been introduced into transplant practice over the past 10 years. It represents the most recent agent to reach the clinical setting. Rapamycin binds to the mammalian target of rapamycin (mTOR) and prevents the cell from progressing from G1 to GS. This effect occurs in a different part of the cell cycle than the actions of Prograf® and cyclosporine. This agent has a prolonged half-life of 16 hours and thus is given as a once-daily dose of 2 mg to 5 mg. Drug monitoring can be performed and is currently done in most instances, but levels are generally performed at few institutions, thus delaying the results. Typical target levels are 10-15 ng/mL in the early post-transplant period and declining thereafter.19 The fact that rapamycin targets a different aspect of the cell-cycle than the CNIs and does not display any nephrotoxic effects poses several very intriguing uses for this agent.20 The different targets of rapamycin and the other CNIs result in a synergistic combination when used together. This latter effect has permitted transplant clinicians to use this agent as part of steroid withdrawal or avoidance protocols in renal transplant recipients. In these protocols, rapamycin is used with low-dose cyclosporine or Prograf® and steroids are gradually withdrawn or completely avoided.21 It may be used as part of a 3-drug regimen with prednisone and Cellcept®, or in combination with a reduced Prograf® or cyclosporine dose and prednisone. Both of these regimens have demonstrated excellent efficacy at preventing rejection.22,23
One of the more important uses of rapamycin has been to maintain adequate levels of immunosuppression in the setting of renal dysfunction after transplant. In about 20-30% of kidney transplants, the allograft suffers from acute tubular necrosis in the early transplant period. In order to reduce nephrotoxin exposure during this period of delayed graft function (DGF) many centers will avoid the use of CNIs. The use of a rapamycin-based induction protocol has been effective in this setting.24 Chronic CNI toxicity can lead to progressive interstitial fibrosis and functional renal deterioration. In this setting, the discontinuation of the CNI and introduction of rapamycin can maintain renal function for extended periods of time.25 This agent has found many uses in current post-transplant regimens. Side effects of rapamycin include delayed wound healing, mouth ulcers, and dyslipidemia as well as leukopenia and thrombocytopenia—these latter effects are dose dependent. The hyperlipidemic effect is most troubling in the patient population that frequently suffers from hypertension and diabetes mellitus. Concerns that it may accelerate heart and peripheral vascular disease seem justified.
The FDA approved mycophenolate mofetil, which is marketed under the name of Cellcept®, for human use in 1995. This antiproliferative agent interferes with purine synthesis by non-competitively binding to inosinic acid monophosphate dehydrogenase. This disrupts clonal expansion of immune cells in response to exposure to foreign antigen. It is typically used in regimens with steroids, and a CNI and has been shown in numerous studies to significantly reduce the incidence of acute rejection after transplantation. When compared to azathioprine, all studies have demonstrated the superiority of this agent in preventing allograft rejection, and currently it has a prominent role in immunosuppression regimens in all solid organ transplant recipients.26 It is generally used in twice-daily dosing regimens of 1 g to 1.5 g per dose. The main toxicities associated with its use are leukopenia, diarrhea, and nausea. These side effects can be quite troubling, and up to 20% of individuals will require discontinuation of the drug and conversion to azathioprine. Additional side effects include increased susceptibility to infections such as CMV. Several drugs may interact with Cellcept® and produce profound neutropenia including allopurinol, rapamycin, and ganciclovir.27
Dacluzimab and basiliximab are 2 antibody preparations against the interleukin-2 (IL-2) receptor. The IL-2 receptor is expressed only on activated immune cells, thus these agents target only activated immune cells and demonstrate increasing specificity of newer agents to target only those cells responsible for rejection. As was discussed earlier, interleukin-2 is required for the clonal expansion and activation of immune cells. These antibodies are chimeric, in that the hypervariable region of the antibody is of murine origin and the constant region of the antibody is of human origin. This results in prolonged half-life of the agent and dramatic reduction in side effects. Currently, these antibodies are typically used as induction agents, given around the time of allograft implantation, and have been shown to reduce the incidence of early allograft rejection.28 Dacluzimab is given immediately prior to transplant and weekly thereafter for 4 weeks. Basiliximab is given immediately prior to transplant and then on postoperative day 4. Using these regimens, suppression of the IL-2 receptor is seen for 30 days. Unlike other antibody preparations, these agents have few, if any, side effects.29
Most transplant centers use very strict immunosuppressive strategies after organ implantation. This includes steroid weaning to baseline levels and guidelines for CNI levels. Traditionally, immunosuppression regimens are most potent, with higher steroid doses and CNI levels, in the first months after transplant. This is the period when rejection is most likely to occur and the time when infectious complications of antirejection therapy are seen, such as CMV disease. Programs have protocols for managing the side effects of these agents, which include leukopenia, nausea, diarrhea, hypertension, diabetes, and many others. In individuals developing post-transplant diabetes, strategies including q12h prednisone dosing rather than once daily and discontinuation of Prograf® and conversion to cyclosporine may prove beneficial. Nausea and diarrhea are frequent occurrences with Cellcept® and can be ameliorated with decrease in dosage from 1 g b.i.d. to 250 or 500 mg b.i.d. or conversion to q6h regimens. In rare circumstances, Cellcept® must be discontinued entirely and azathioprine substituted. The CNIs are metabolized by the cytochrome P450 system, and many commonly prescribed drugs can dramatically alter the kinetics of CNI metabolism and hence drug levels. Several notorious agents include ketoconazole and fluconazole, which compete with the system and can dramatically raise CNI levels to toxic states and precipitate renal failure, tremors, headaches, and seizures. Antiseizure (dilantin, tegretol, phenobarbitol) agents can induce the P450 system and increase the metabolic rate thus diminishing CNI levels and precipitating allograft rejection. Many other commonly prescribed antibiotics (erythromycin, tetracycline) and antihypertensives (cardizem) will also alter CNI levels and must be taken into consideration when prescribing these drugs.30
Prior to the introduction of ganciclovir, CMV disease was a significant and potentially life-threatening infectious complication occurring after transplant. CMV disease can present as an isolated finding of fevers, thrombocytopenia, and leukopenia, with a self-limited course to a more invasive and malignant form that includes CMV pneumonia, gastritis, esophagitis, colitis, enteritis-causing diarrhea, GI bleeding, and frank perforation. Hepatitis mimicking rejection and retinitis leading to blindness have also been reported. With the introduction of intravenous ganciclovir, most of the invasive CMV infections have became less prevalent in the transplant population, and those that have occurred usually can be effectively treated. The development of oral formulations of ganciclovir has been troubled by poor bioavailability but permitted adequate prophylaxis for CMV disease in the early post-transplant period. Recently, Valcyte® (valganciclovir) has been introduced and is a metabolite of ganciclovir with much improved bioavailability. The result of this effort has been a dramatic decline in both the incidence and severity of CMV disease post-transplant.31
Kidney Transplant
The first successful renal transplant was performed at Brigham and Women’s Hospital in Boston, Mass, in 1954 when a kidney from an identical sibling was removed and transplanted into his brother.1 Over the last 50 years, many advances have taken place that have made organ transplantation an accepted medical therapy for end-organ disease. As we have seen, the introduction of new immunosuppressive agents has improved allograft survival at 1 year from 70% in 1985 to nearly 90% today (see Figure 4). The graft half-life, the time at which 50% of allografts have failed, of an unmatched cadaveric donor is 10.1 years increasing to 14.5 years for an HLA-identical cadaveric donor and increasing further to 17.3 years for an unmatched living donor and 31.8 years for an HLA-identical living donor32 (see Figure 5 below).
| Figure 5. Renal Allograft Survival by Type and Donor |
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Currently, with the broad use of newer immunosuppressive agents, acute rejection is experienced by 10% of individuals as compared to 30-50% of recipients just 15 years ago. Acute rejection can be reversed in nearly all, and graft loss related to acute rejection is an infrequent occurrence. The factors that contribute most to allograft loss are chronic rejection, now termed chronic allograft nephropathy, and death with a functioning kidney.33
Chronic allograft nephropathy (CAN) has replaced the term for chronic rejection as we have improved our understanding of this process. Although initially thought to be a function of prolonged immunologic injury to the kidney, chronic allograft nephropathy represents a constellation of insults to the organ that ultimately leads to interstitial fibrosis, hyalinization of the glomeruli, and thickening of the walls of the arterial vessels. These insults are both immune- and nonimmune-mediated and eventually lead to loss of kidney function and return to dialysis. Several factors contribute to the development of chronic allograft nephropathy and include acute and severe rejection, hypertension, CNI toxicity, delayed graft function, and many other factors have also been reported. CAN usually manifests as a slow steady rise in the serum creatinine. It can be seen within a few months after successful transplantation but typically occurs several years after transplant. Diagnosis is made with a percutaneous biopsy of the transplant kidney. Biopsy is important in this setting to rule out other causes of renal dysfunction such as acute rejection, recurrent renal disease, infection, or other potentially treatable conditions. Treatment of CAN is currently a much-debated subject. Discontinuation of CNIs and substitution of rapamycin is a standard practice in many centers. Whether this strategy will demonstrate improved allograft survival remains to be seen. In most instances, renal function will deteriorate and return to dialysis will be required. The best strategies for management are likely to be prevention of the inciting events, such as rejection and delayed graft function, coupled with aggressive control of hypertension, hyperlipidemia, and other risk factors.34
The kidney transplant recipient population has a high incidence of hypertension, which may have given rise to renal failure, occurred with renal failure, or as sequelae of post-transplant medications. Currently, the most frequent indication for renal transplant is diabetes mellitus, which usually requires 10-20 years of disease before progression to renal failure. The combination of diabetes, hypertension, dyslipidemia, hyperhomocystinemia, and other cardiovascular risk factors such as obesity, smoking, and family history inevitably identifies a high-risk population for the occurrence of significant cardiovascular disease. This constellation of cardiovascular risk factors leads to a significant mortality rate in transplant recipients. In fact, several studies have reported death with a functioning graft as the most common form of renal allograft loss after transplant.35 Currently, one of the objectives of the transplant community is to modify these secondary risk factors to extend both patient and graft survival. Strategies to modify these secondary risk factors include the introduction of strict regimens of hypertension and diabetes control. Also, the introduction of statins to the post-transplant medicine regimen has been shown, at least in 1 retrospective study, to reduce mortality.36
Techniques
The first laparoscopic donor nephrectomy was performed by Lloyd Ratner in 1995 at Johns Hopkins University.37 From that time, the technique has exploded on the scene and has in some centers been responsible for a dramatic increase in the number of live donor kidney transplants that are performed in this country. In some centers, live donor kidney transplants comprise in excess of 50% of the annual number of renal transplants performed.38
The procedure entails placing the patient in a lateral decubitus position, donor side up, and 2-3 5 mm trocars and 1 12 mm trocar are introduced into the donor’s abdominal cavity. Using these trocars, the donor kidney is isolated from the surrounding structures until it is attached to the donor by the renal artery and vein. These structures are then divided using an endoscopic vascular stapler, and the kidney is removed. The kidney can be extracted from the peritoneal cavity via a rapidly placed abdominal incision, once the vessels are divided, or from a previously placed incision that allows the surgeon to introduce a hand (handport) into the peritoneal cavity to facilitate the dissection. The procedure requires approximately 2-4 hours to complete and is timed such that the explanted kidney can be rapidly implanted into the donor within minutes of its removal.
Several studies have been performed comparing the results of a standard open nephrectomy with the results after a laparoscopic donor nephrectomy. The studies have consistently demonstrated a shorter operating room time with the open technique by 30-45 minutes. Blood loss, postoperative complications, and discharge serum creatinine have been comparable. The laparoscopic donors routinely demonstrate an earlier return to strenuous activities, work, and discontinuation of narcotics. Additionally, when surveyed, laparoscopic donors on average felt that they had returned to "100% normal condition" at day 33 (median) compared to greater than 6 weeks after open technique (median not yet achieved).39 As we have seen from other laparoscopic procedures, postoperative discomfort is improved, hospital stay is reduced and averages 48-72 hours, and most patients can return to routine activities in 1-2 weeks. This is accomplished without jeopardizing renal function and allograft survival in the recipient.
Liver Transplantation
The most notable changes in the field of liver transplantation have been the continued improvement in both patient and allograft survival. This benefit is multifactorial but in large part is a direct result of improved operative techniques and better management of the immunosuppressive regimen. Prior to 1995, 1- and 3-year patient and graft survival rates routinely were 70-75% and 70-80% and 70% and 65-70%, respectively.47 In 2001, UNOS has reported patient and graft survivals at 1 and 3 years of 85% and 77% and 80 and 71%, respectively. Additional improvements include management of hepatitis B, which prior to the availability of hepatitis immune globulin was a relative if not absolute contraindication for orthotopic liver transplant. Historically, individuals transplanted with hepatitis B had reinfection of the transplanted liver and a rapidly progressive course leading to hepatic failure and death. In an important multicenter European study, 372 patients received hepatitis B immune globulin or HBIG for 6 months after liver transplant. This therapy significantly prevented or delayed the re-infection rate of the transplanted liver and dramatically improved both patient and allograft survival. Currently, patient and allograft survival in individuals receiving liver transplants for hepatitis B are comparable to individuals receiving transplants for other indications.40
The continued disparity between individuals requiring hepatic transplantation and the number of cadaveric organs available has continued to grow over the last 15 years. This has led to prolonged wait times as well as an increase in recipient mortality while awaiting transplantation. The number of individuals currently listed for orthotopic hepatic transplantation, at the time of this writing according to the UNOS web site, was 17,306 and the number of liver transplants performed in 2002 was 3531. In response to this discrepancy, live donor liver transplantation was introduced in 1991.41 This technique has evolved from a rare occurrence to one that is frequently performed at most major transplant centers—in 2002, 271 live donor liver transplants had been performed nationwide.48 The original procedure involved resecting the left lateral segment of a parent and transplanting it into a child but due to the worsening allograft shortages, centers began to experiment with the technique of removing either the right or left lobe of the liver and transplanting it into a related recipient. Much of this work was completed in Japan, where brain death laws have only recently been established, but cultural differences severely curtail the availability of cadaveric organs. One of the many contributions to the field of surgery that have been made by transplant surgeons involves better understanding of hepatic anatomy and techniques of hepatic resection. Currently, major hepatic resection can be performed with mortality rates that approach 0%, thus making live donor liver transplant a realistic and safe alternative to cadaveric transplantation.42
Potential donors undergo extensive preoperative work-up, which includes psychosocial evaluation prior to performance of invasive testing. An exhaustive history is taken to identify medical conditions or history of liver disease that would preclude donation. Tests are then performed to rule out infectious diseases that could be passed on to the recipient, such as HIV, HTLV I/II, syphilis, and hepatitis A, B, and C. Hepatic imaging is then performed to identify any aberrant anatomy and to calculate a donor liver volume. The donor operation must be conducted such that the donor and the recipient are left with a satisfactory liver volume to prevent hepatic insufficiency and death. This can be performed with CT angiography and volumetric reconstruction or with magnetic resonance imaging/angiography (MRI/A). There are several formulas for calculating satisfactory hepatic volume after the donor operation, but generally both donor and recipient require remnant volumes equivalent to 40% of their preoperative liver volume. After completion of the procedure, both donor and recipient livers will hypertrophy and double in size in the first postoperative week and approach a normal liver volume by 1 month after surgery.
Several advantages are notable with living donor liver transplantation that like living donor kidney transplant may improve recipient outcomes and include a short cold ischemia time and absence of hepatic steatosis, which is frequently found in cadaveric organs and may jeopardize early hepatic function after transplant. Despite the use of optimal donor livers, graft survival in this setting is comparable to that seen with cadaveric organs. Live donor liver transplant is a scheduled operation that can be performed at a predetermined date, thus allowing the recipient’s medical condition to be optimized. Although the procedure is life saving for individuals with end-tage hepatic disease, it is probably best suited for individuals presenting with rapidly advancing hepatic disease, hepatic malignancies, and small individuals, all of whom would otherwise have poor outcomes related to prolonged wait times on a cadaveric list, which nationally averages 18-22 months from listing to transplantation based upon recent OPTN data obtained from the web site. Initially, only a few centers performed this operation but currently, almost all transplant centers are offering this option to their recipients. In fact, in 1996 only 56 live donor liver transplants were performed in this country rising to 509 live donor transplants in 2001.
There are several potential disadvantages of live donor liver transplantation. Most notably, the risk of death is unknown in this setting but is estimated at 0.0-5% for hepatic lobectomies for benign or malignant disease.42 This is probably not a fair comparison due to the medical comorbidities of those individuals undergoing hepatic surgery for disease. Individuals with medical comorbidities would not be candidates for live donor liver transplant. There have been several deaths reported nationwide in donors, the most recent occurring last December in New York City, but current estimates calculate the donor death rate at 0.28%. Other complications include bile leaks in both donor and recipient, the latter having a higher incidence of biliary complications than cadaveric recipients.43
Although UNOS governs all factors related to cadaveric organ procurement and distribution at a national level, regional differences occurred related to wait times and listing criteria. Patients in some areas of the country waited 4-6 years prior to receiving a cadaveric hepatic transplantation, while individuals in other areas waited 14-18 months or less. Individuals in regions with longer wait times endured much higher morbidity and mortality while awaiting transplantation. In areas where wait times were dramatically prolonged, the allocation system favored transplantation of individuals that had medically decompensated related to their liver disease, and these individuals experienced higher morbidity and mortality when transplanted. As a result, patient and graft survival were reduced in this cohort, and costs of medical care were markedly increased. Prior to the introduction of the new allocation system, the previous system placed patients into 1 of 4 categories based on both objective and subjective findings. In response to this, a model to determine need for liver transplantation was devised that was based upon objective criteria that were accurately able to predict mortality.
The model originally formulated by physicians at the Mayo Clinic in Rochester, Minn, has come to be known as the model for end-stage liver disease (MELD). This model uses 3 objective laboratory tests, INR, serum creatinine, and bilirubin values, which are entered into a formula and a MELD score of 6 (least ill) to 40 (most ill) is calculated. When a cadaveric liver becomes available, UNOS distributes the organ to the recipient with the highest MELD score. The objectives of this system are to ensure equitable regional sharing of cadaveric liver allografts and to distribute organs to individuals prior to the onset of multisystem organ complications of end-stage liver disease that dramatically worsen the results of orthotopic hepatic transplantation.44
Islet Cell Transplant
The transplantation of human islets had its roots back in the early 1970s. Initial work was performed with rodents, and as techniques improved researchers used higher animal models. At each successive step, the isolation and the acceptance of the islets became increasingly difficult. Prior to 1999, very few human islet transplantations had been performed and only by a few institutions. These met with equivocal success. Many of the individuals receiving islets had poor glucose control as measured by hemoglobin A1c levels, and few had detectable insulin levels (c-peptide). The explanation for these suboptimal results centered on islet isolation, nonimmune destruction of cells, and ongoing islet cell rejection. In these early series, about 35% of recipients had measurable c-peptide levels, and only 8-10% of individuals remained insulin free at 1-year.46 In 1999, using what is commonly referred to as the Edmonton protocol, researchers from the University of Alberta published their results using newer isolation techniques and a novel immunosuppressive strategy to finally demonstrate "long-term" islet survival. The immunosuppressive protocol used induction with dacluzimab followed by maintenance immunosuppression with Prograf® and rapamycin. The authors found that steroids and the uremic state were toxic to islets and were best avoided in islet transplantation. Hence, the traditional dogma of transplanting pancreatic equivalents into diabetics with end-stage renal disease was questioned and avoided. Candidates for islet transplant were individuals with metabolic instability or hypoglycemic unawareness. Their initial report demonstrated euglycemia in all 12 recipients of islet cell transplants at 1 year, and longer follow-up has demonstrated 80% of recipients remain euglycemic. The pitfall of the technique was that many of the individuals required more than 1 cadaveric pancreas to be procured to provide sufficient islet cell mass to maintain euglycemia.2 The initial hope that islet cell transplantation would allow a more liberal use of available cadaveric pancreata was not demonstrated. In fact, it has become clear that rather than increasing the donor pool, this procedure may, in fact, decrease the donor pool. Although this is disappointing, the demonstration of long-term islet survival and euglycemia marks a significant advance for this experimental treatment. As a direct result of the Edmonton experience, the National Institutes of Health (NIH) has launched a multicenter trial to examine the Edmonton protocol as well as to examine the role of tolerance inducing therapies in this setting.45
Conclusion
The field of transplantation has experienced remarkable growth in the last 20 years in terms of numbers of organs transplanted, expansion of the indications, and candidates for transplant. This is clearly a response to the exceptional results that have been reported for all transplant recipients receiving any of the available organs. Currently all transplanted organs are being performed with 1-year expected patient and graft survival approaching 90% and excellent long-term results. The future of transplant must weigh heavily on tolerance, the ability of a recipient to accept a transplanted organ without the need for life-long immunosuppression, and increasing the availability of organs for transplant. Many centers are actively investigating protocols with new agents that are attempting to induce tolerance in recipients of solid organ transplants. Xenotransplantation, transplantation across animal species, is also being actively investigated, not only in academic medical centers but also by major pharmaceutical companies. Xenotransplantation has many significant hurdles to overcome prior to achieving clinical use, but transplantation has a history of overcoming hurdles.
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