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Update in Renal Transplantation
Colm C. Magee, MD;
Manuel Pascual, MD
Arch Intern Med. 2004;164:1373-1388.
ABSTRACT
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Renal transplantation is the treatment of choice for most patients with end-stage renal disease. The shortage of donor organs, however, remains a major obstacle to successful, early transplantation. This shortage has actually worsened despite an increase in living family-related and unrelated donors. On the other hand, over the last 10 years, allograft and recipient survival have significantly improved. This encouraging outcome reflects many factors, particularly a favorable shift in the balance between the efficacy and toxicity of immunosuppressive regimens. As acute rejection and early graft loss have become less common, the focus is increasingly directed toward the prevention and treatment of the long-term complications of renal transplantation. These include suboptimal allograft function, premature death, cardiovascular disease, and bone disease. Thus, a multidisciplinary approach—rather than management of immunological issues alone—is now required to optimize long-term outcomes of renal transplant recipients.
INTRODUCTION
Successful renal transplantation allows freedom from the lifestyle restrictions and complications associated with dialysis and is therefore associated with better quality of life.1 One study of United States Renal Data System (USRDS) data compared outcomes in patients on the transplant waiting list (ie, who were continuing to receive dialysis) with those of controls who had received a kidney transplant. It found that, after 3 to 4 years of follow-up, transplantation reduced the risk of death overall by 68%.2 Transplantation conferred a survival benefit in almost all subgroups, including in elderly or obese patients or those with hepatitis C. In addition, over the long term, it is more cost-efficient than dialysis.3 Thus, transplantation remains the optimal therapy for patients with end-stage renal disease (ESRD).
TRANSPLANTATION OUTCOMES
Short-term outcomes such as allograft survival, patient survival, and rates of acute rejection in the first 12 months after transplantation are excellent and continue to improve. For recipients of a first cadaveric kidney in the United States, current 1-year patient and graft survival probabilities are about 95% and 88%, respectively. For recipients of a first living donor kidney, current 1-year patient and graft survival probabilities are 98% and 94%, respectively4 (Figure 1). Registry data indicate that rates of acute rejection in the first 6 months have decreased to less than 20%5 (Figure 2). Similar improvements have been reported from other countries. These impressive results reflect incremental improvements in crossmatching tests (pretransplantation in vitro assays to detect donor antibodies to recipient HLA antigens), immunosuppressive regimens, antimicrobial prophylaxis, and overall surgical and medical care. For example, more effective anti-cytomegalovirus (CMV) prophylaxis with ganciclovir or valganciclovir has reduced—but not eliminated—the morbidity and mortality related to CMV disease.6 This reduction, in turn, has allowed the relatively safe use of more intensive immunosuppressive protocols, and thus lower rates of acute rejection.
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Figure 1. One-year survival probabilities for first cadaveric and living donor allografts and their recipients, adjusted for age, sex, race, and primary diagnosis. Despite impressive increases in cadaveric allograft survival, living donor allograft survival is consistently superior. Source: US Renal Data System 2002 Annual Data Report.
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Figure 2. Annual incidences of early acute rejection, late acute rejection, and delayed graft function. Note that although rejection rates have fallen dramatically, rates of delayed graft function remain unchanged. The latter reflects nonimmunological variables such as ischemia times and use of suboptimal cadaveric donors. Adapted with permission from Gjertson.5
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Although static in the 1980s, long-term renal allograft survival has slowly but steadily increased in the last decade. For example, estimated cadaveric graft half-lives were 7.9 years for the 1988-1989 (2-year) cohort, 9.2 years for the 1994-1995 cohort, and 11.6 years for the 1998-1999 cohort.7 Of note, this improvement was concurrent with greater use of organs from older and less optimal deceased donors. The half-lives of living donor grafts have also improved, even though donor age has increased and the degree of matching for HLA antigens decreased.7 The latter change reflects the major increase in living unrelated donors such as spouses. Estimated living donor graft half-lives were 12.5 years for the 1988-1989 cohort, 15.8 years for the 1994-1995 cohort, and 19.3 years for the 1998-1999 cohort.7
CURRENT IMMUNOSUPPRESSIVE REGIMENS
Because the risk of acute rejection is greatest in the early posttransplantation period, more intensive immunosuppression is given at that time and progressively decreased in the following weeks and months. As long as the allograft is viable, some immunosuppresion is required. The degree of maintenance immunosuppression required is now a matter of debate; standard immunosuppression is associated with many adverse effects including nephrotoxicity, increased risk of infection, and cancer. Furthermore, it does not allow the development of allograft tolerance.8 Single-center results with very-low-dose maintenance immunosuppression are encouraging9 but larger, randomized studies are required before such strategies can be widely recommended.
The main target of immunosuppressive drugs remains the CD4+ T cell because of its critical role in orchestrating the rejection response.10 Most immunosuppressive regimens incorporate glucocorticoids, a calcineurin inhibitor (CNI), and an antiproliferative agent (Table 1). The rationale for such "triple therapy" is that adequate immunosuppression can be achieved without a need for toxic doses of any one agent.
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Table 1. Drugs Used in Maintenance Immunosuppression of Kidney Transplant Recipients
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In the immediate posttransplantation period, induction therapy with lymphocyte-depleting antibodies or anti-interleukin 2 (anti–IL-2) receptor monoclonal antibodies is sometimes also used to provide additional immunosuppression. Induction therapy also allows delayed introduction of CNIs, the early use of which might exacerbate delayed graft function (usually defined as initial failure of the allograft to function, with a need for dialysis within the first week after transplantation). The long-term benefits of induction therapy are controversial, as registry data suggest little effect on overall graft survival.11 Since immediately after transplantation most activated T cells should be reactive only against donor antigens, and only activated T cells should express the full IL-2 receptor, IL-2 receptor blockers potentially provide specific and safe immunosuppression.
Glucocorticoids
Glucocorticoids remain a cornerstone of immunosuppression in most patients. Dosage is progressively decreased in the first 3 to 6 months after transplantation, eg, to 5 to 10 mg/d of prednisone. The adverse effects of steroids are well known; of particular importance in transplant recipients are hyperlipidemia, hypertension, glucose intolerance, and osteoporosis. Unfortunately, complete withdrawal of steroids has traditionally been associated with rejection, and with both short- and long-term graft dysfunction in a subset of recipients.12 However, there is optimism that newer immunosuppressants such as mycophenolate mofetil (MMF) and tacrolimus will allow the safe use of much lower doses of steroids or their avoidance altogether. Certainly, nonsteroid or low-dose protocols should now be considered in patients at risk for significant toxicity (eg, those with pretransplantation osteoporosis), and steroid withdrawal should be considered in patients who have developed significant posttransplantation toxicity (eg, new onset of diabetes mellitus). Recipients treated without steroids must be followed up closely for possible rejection.
Calcineurin Inhibitors: Cyclosporine and Tacrolimus
These drugs inhibit calcineurin, a pivotal enzyme in T-cell–receptor signaling, and thereby reduce the synthesis of several critical T-cell growth factors, including IL-2.10 Trough blood concentrations are used to guide dosing but recent studies have shown that lower C2 concentrations (ie, blood concentrations 2 hours after ingestion) of cyclosporine correlate better with the risk of acute rejection.13-14 There are no published studies to date showing better long-term outcomes with C2 monitoring of cyclosporine metabolism.
Tacrolimus is more effective than cyclosporine in preventing acute rejection at doses currently used, and there is now some evidence that medium-term outcomes are better with tacrolimus.15 For these reasons and because its adverse effects profile is perceived to be better, tacrolimus is becoming the CNI of choice in kidney transplant recipients in many centers in the United States.16 Both drugs are metabolized by the intestinal and hepatic cytochrome P450 system. Inducers or inhibitors of this system should be prescribed with caution and more frequent monitoring of cyclosporine and tacrolimus concentrations should be performed. Although both drugs can cause acute nephrotoxicity, their role in causing significant chronic allograft dysfunction is unclear.17
Antiproliferative Drugs
Antiproliferative drugs include azathioprine, MMF, and sirolimus. These drugs function principally by inhibiting mitosis and thus proliferation of lymphocytes. The antiproliferative effects are not lymphocyte specific, however, and bone marrow suppression is the most common adverse effect. Azathioprine has been used in clinical transplantation for over 40 years but MMF is a more powerful immunosuppressant associated with better short-term—and probably better long-term—outcomes.18-19 Thus, in the last 5 years, MMF has replaced azathioprine for patients with new transplants in many centers. The combination of MMF and tacrolimus is very effective in preventing acute rejection but is associated with a high incidence of adverse gastrointestinal effects such as nausea, abdominal discomfort, and diarrhea. This probably reflects both intrinsic effects of tacrolimus and the higher MMF plasma concentrations obtained when the drug is prescribed with tacrolimus rather than cyclosporine.20
Sirolimus (rapamycin) is the most recently licensed immunosuppressive agent in renal transplantation. It functions by inhibiting "signal 3" in T-cell activation—by blocking the downstream effects of IL-2 and other growth factors on initiation of the cell cycle and, ultimately, inhibiting T-cell proliferation.21 Sirolimus is also metabolized via the cytochrome P450 system. In a randomized controlled trial, sirolimus was associated with a lower incidence of acute rejection but, when combined with cyclosporine and steroids, with more adverse effects than azathioprine.22 Two properties of sirolimus may benefit transplant recipients. First, its antiproliferative effects could prevent graft atherosclerosis (a beneficial effect analogous to that of sirolimus-coated stents in coronary artery disease); second, its antineoplastic effects could reduce the high incidence of posttransplantation tumors. Data on long-term outcomes with sirolimus are not yet available, however. Therefore, its role in the prevention of these important posttransplantation complications and in routine maintenance therapy remains to be defined.
FUTURE IMMUNOSUPPRESSIVE DRUGS AND REGIMENS
Most drugs under investigation continue to target T cells because of their central role in allograft rejection, but there is growing interest in anti–B-cell and antiplasma therapies. Experimental agents include those modulating cell surface molecule interactions, T-cell receptor signaling (such as inhibitors of Janus kinase [Jak]), or lymphocyte trafficking.23 The search for safe and effective tolerance-inducing regimens in human transplantation continues. Tolerance is best defined as the absence of destructive antigraft immune responses in the presence of an otherwise competent immune system.24 Tolerance to self-antigens is the norm in humans and manipulation of its physiological mechanisms is a focus of ongoing research.24
The availability in clinical practice of at least 6 distinct maintenance drugs and several lymphocyte-depleting and IL-2–receptor antibody preparations now allows physicians much more flexibility in prescribing for the individual patient: a one-size-fits-all approach is no longer necessary or desirable. In this era of low acute rejection rates, more attention can be paid to minimizing adverse effects of immunosuppressants.25 For example, recipients with hyperlipidemia and hypertension can be prescribed tacrolimus, MMF, and minimal doses of steroids; conversely, cyclosporine might be preferable to tacrolimus in recipients at high risk for posttransplantation diabetes (see below). There is also a revival of interest in regimens that avoid or minimize exposure to steroids or the CNIs.25-26
Has the improvement in short-term outcomes been won at a heavy price? Are we seeing more complications related to excessive immunosuppression? On the one hand, recipient survival is clearly improving. Lower rates of acute rejection mean that fewer recipients are receiving extra courses of high-dose steroids and lymphocyte-depleting antibodies to treat acute rejection. Rates of CMV disease have fallen in the 1990s, reflecting better antiviral prophylaxis.6 On the other hand, the rise in incidence of reported cases of polyoma virus–induced interstitial nephritis very likely reflects the consequences of more intense immunosuppression.27 There is also evidence that rates of posttransplantation lymphoproliferative disease (PTLD) have increased slightly in the 1990s.28 Only in the next 10 to 20 years will we learn whether the more intensive regimens of the 1990s lead to even greater rates of neoplasia late after transplantation.
CONTROLLING THE HUMORAL ALLOIMMUNE RESPONSE
Antibody responses against donor organs have traditionally proved very difficult to control. Recently, important advances have been made in reversing humoral immune responses after transplantation (ie, treating humoral rejection) and before transplantation (ie, eliminating donor-recipient HLA incompatibilities, thus allowing more transplantation procedures).
Acute Humoral Rejection
Acute humoral rejection is less common than cellular rejection but is traditionally associated with a poorer prognosis. Staining of the renal peritubular capillaries for the complement-split product, C4d, has been shown to be an accurate histologic marker of this form of rejection, facilitating its early identification.29 We and others have also demonstrated that a regimen of plasmapheresis (to remove antidonor antibodies) and of enhanced immunosuppression with tacrolimus, MMF, and intravenous IgG (to further suppress production of antidonor antibodies) can completely reverse humoral rejection, allowing restoration of excellent graft function.30-31 The role of sirolimus in controlling humoral rejection is being evaluated.
Desensitization to HLA Alloantigens
A significant minority of patients are "highly sensitized" in that they exhibit immunological reactivity to a broad panel of non–self-human antigens, particularly those of the HLA system. This reactivity reflects prior exposure to the antigens via previous transplantation, blood products, or pregnancy. All physicians involved in the care of patients with renal disease should be aware that transfusion of red cells to these patients should be minimized; if required, leukocyte-depleted products should be used, as it is the leukocyte fraction that is richest in HLA antigens. Fortunately, erythropoietin can reduce transfusion requirements and related sensitization.32
Highly sensitized patients often cannot find a compatible living donor and wait many years for a cadaveric allograft. A recent exciting advance has been the successful desensitization of some of these patients, thus allowing living donor or cadaveric transplantation. Several centers have reported encouraging short-term results—albeit with small patient numbers—using regimens that include plasmapheresis, intravenous IgG, MMF, and tacrolimus.30, 33 Intravenous IgG alone may suffice, and has the advantage of minimal toxicity.34 Longer-term results of these approaches are awaited but desensitization will likely be increasingly offered to highly sensitized patients otherwise precluded from transplantation. Excellent short-term outcomes are also being reported with transplantation of kidneys across the ABO blood group "barrier."
OVERCOMING THE ORGAN SHORTAGE
The incidence and prevalence of dialysis-dependent patients continue to increase in the United States and in most other countries.4 Unfortunately, even with a slight increase in numbers of available cadaveric donors and a large increase in living donors, transplantation has not kept pace with the "epidemic" of ESRD. Thus, the rate of transplantation per 100 dialysis patient-years is actually decreasing in the United States (Figure 3). The inevitable outcome is longer waiting times. Indeed, the management of patients on the waiting list (ensuring that they remain fit for transplantation) is becoming a significant workload for larger transplantation centers.7 Several strategies to increase organ donation rates are discussed here.
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Figure 3. The solid line shows steady increase in the incident number of patients with end-stage renal disease (ESRD) in the United States in the late 1990s. Although the absolute number of transplantations per year has increased somewhat, this has meant that the rate of transplantations per 100 patients receiving dialysis days has fallen (dashed line). The gray line shows the rate of transplantations in black Americans alone per 100 dialysis patient-days. Source: US Renal Data System 2002 Annual Data Report.
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Increasing Living Related and Unrelated Donation
The many advantages of living donation are summarized in Table 2. One major advantage is that preemptive transplantation (before the need for dialysis) is more feasible. Not only does preemptive transplantation avoid complications associated with dialysis itself but recent studies show it to be associated with less acute rejection and better allograft survival rates.35 This intriguing finding may reflect the avoidance of proinflammatory effects of advanced uremia or dialysis itself. For preemptive transplantation to succeed, early referral of patients with chronic kidney disease to nephrologists and transplantation centers is essential.
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Table 2. Potential Advantages of Living Donor Kidney Transplantation
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The advantages of living donation—and greater public and provider awareness of this method—have spurred increases of 68% and 1000%, respectively, in the numbers of living related and unrelated donors in the United States over the last decade.4 In fact, the number of living donors surpassed that of cadaveric donors in 2001 and 2002.36 Despite the poor matching for HLA antigens associated with unrelated donation, outcomes are excellent.37 This emphasizes the benefits of transplanting a healthy kidney, ie, minimum perioperative ischemia and reperfusion injury.
For reasons that include patient preference, surgeon preference, and marketing strategy, laparoscopic nephrectomy is becoming the donor nephrectomy method of choice in the larger transplantation centers in the United States.38 To the donor it has the benefits of less postoperative pain, quicker convalescence, and a better cosmetic result than with the traditional open nephrectomy. These benefits have probably contributed to the increase in donation rates.39 Disadvantages of the laparoscopic method include higher rates of early graft dysfunction, probably for the following reasons: higher intra-abdominal pressures during the procedure; longer warm ischemia duration; less experience with the technique, which entails a learning curve; and more manipulation of the renal vessels.40 One randomized trial found better donor and similar recipient outcomes with hand-assisted than with open live-donor nephrectomy.41
Balancing the professional goal of alleviating the recipient's illness with the precept, "first, do no harm," is crucial in the evaluation of potential living kidney donors. Four conditions must be satisfied before living donation can proceed: the risk to the donor must be low, the donor must be fully informed, the decision to donate must be independent and voluntary, and there must be a good chance of a successful recipient outcome.42 To avoid conflict of interest, the proposed donor should be meticulously evaluated by a physician not involved in the care of the proposed recipient.43 Potential kidney donors must be informed that donation can have adverse medical, psychological, and financial consequences. Most donors, however, obtain psychological benefits from the donation.43 With the careful selection of donors and an experienced surgical team, the incidence of serious perioperative complications is very low.43 Most follow-up studies of individuals who have undergone nephrectomy—for donation or other reasons—are reassuring.43-44 Minor asymptomatic increases in urinary protein excretion may occur and blood pressure may become slightly elevated. Nevertheless, concern has been expressed about the long-term medical consequences to the donor.45-46 Ideally, a national registry of donors would be established to allow more rigorous long-term follow-up.
More Use of Expanded-Criteria Donors
As the name suggests, expanded-criteria donors are those who traditionally would not have been considered for donation. The term applies mainly, but not exclusively, to cadaveric donation and encompasses non–heart-beating (NHB) donors, elderly donors, and donors with diseases such as hypertension; examples are shown in Table 3. The main concern regarding many forms of expanded-criteria donation is the transplantation of an inadequately functioning nephron mass.47 Not surprisingly, short- and long-term outcomes with such grafts have been somewhat inferior to those obtained from "normal-criteria" donors. However, it should be emphasized that receiving an allograft from an expanded-criteria donor confers a significant survival advantage over remaining a dialysis patient on the transplant waiting list.48
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Table 3. Examples of the Conditions Encountered With Expanded-Criteria Donors
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Most deceased donors have sustained brainstem death but maintain renal perfusion because of cardiorespiratory support. It is estimated that the use of allografts from NHB donors—those who have sustained cardiorespiratory arrest—could increase the supply of cadaveric kidneys by up to 40%.49 The use of allografts from NHB donors has lagged behind this estimate, particularly in the United States, for several reasons.49 First, early posttransplantation complications, such as primary nonfunction of the allograft and delayed graft function, are more common with such allografts. This is to be expected, as prolonged hypotension is well known to cause temporary ischemic kidney damage. Case-control studies and registry data, however, indicate that it does not necessarily translate into poorer long-term graft or recipient survival.50-51 Second, in many centers, there are unresolved—but not unresolvable—legal and logistic issues related to the diagnosis of cardiac death in the context of organ retrieval; to obtaining family consent; and to starting organ preservation measures (such as in situ cooling) before consent is available.52 Very clear criteria for cardiac death must be developed by cardiologists and anesthesiologists (as neurologists have for brain death) and there must never be a perception that an anticipated NHB donation is influencing the care of critically ill patients. It is important to note that, albeit with much effort, NHB donation can significantly increase organ supply and yield excellent results.
Other Strategies
Spain has achieved near-maximal rates of cadaveric organ donation through the placement of specialized transplant-coordinating staff in all major hospitals,53 and the Spanish model is currently being implemented in other countries. In the United States, using a standardized donor management protocol has been shown to increase organ procurement rates.54 Other proposals to increase rates of cadaveric donation include adoption of presumed consent to donate (in practice, not feasible in the United States or many Western countries), and use of financial incentives.55 The latter is highly controversial, and opponents argue that it represents the commodification of body parts and encourages exploitation of the poor.
Xenotransplantation
If transplantation of vital organs from other mammals to humans were safe and effective, the organ crisis could be solved. Most research has concentrated on pig-into-primate combinations. Several major obstacles must be overcome before transplantation of whole porcine organs into humans becomes feasible. First, although hyperacute rejection involving complement has been mostly overcome by the development of transgenic pigs expressing human regulators of complement activity, very aggressive forms of humoral and cellular rejection still occur.56 Preventing these immunological complications may require very aggressive immunosuppression. Second, the transmission of zoonotic diseases—particularly retroviruses—from animals to humans remains a concern.57-58 Third, even if immunological incompatibility is overcome, physiological incompatibility may be problematic. Would a porcine kidney respond correctly to human antidiuretic hormone? Would its vitamin D derivatives and erythropoietin be physiologically active? Finally, research in this area is extremely expensive and industry support has waned somewhat.59 Thus, whole-organ xenotransplantation is unlikely to become a clinical reality soon. Alternatives under study include transplantation of xenogeneic cells or pancreatic islets, or immunoisolation of xenogeneic tissue in capsules or membranes.
TRANSPLANTATION IN SPECIFIC GROUPS
The Elderly
The elderly are forming an increasing percentage of the ESRD population.4 Many elderly patients with ESRD have significant comorbidity, particularly cardiovascular disease and type 2 diabetes. Nevertheless, age per se is not a contraindication to transplantation: among elderly patients carefully screened and deemed fit for the procedure, long-term outcomes are clearly better with transplantation than dialysis.2, 60-61 The percentage of recipients with a functioning transplant who are older than 65 years increased from 5.2% in 1992 to 10.6% in 2000,4 and elderly patients experience the same benefits from living donor transplantation as younger patients. Interestingly, although matching older cadaveric kidneys to older recipients is a common practice—presumably in an attempt to allocate the best kidneys to younger recipients—it may not improve overall graft survival.62 Elderly recipients should receive less intensive immunosuppression to minimize their relatively high risk of infection, as acute rejection is less common in this subgroup.
Black Americans
In the United States, incident rates of ESRD in blacks continue to be almost 4 times greater than in whites.4 Even after adjusting for clinical variables, blacks are less likely than whites to be referred for renal transplantation evaluation and to be placed on a transplant waiting list.63-64 When they are, rates of living and cadaveric donor transplantation are also lower for blacks, who thus must wait longer for a transplant. The latter discrepancy is illustrated in Figure 3. Potential living donors who are black are more likely to have contraindications to donation such as hypertension or type 2 diabetes mellitus.65 Although 12% of cadaveric donors are black, a percentage similar to that of blacks in the United States, overall, most cadaveric donors are white.66 Because distributions of HLA antigens and ABO blood groups differ between blacks and whites, algorithms of organ distribution based on these important characteristics tend to disadvantage blacks. Furthermore, blacks on the waiting list tend to be more highly sensitized to HLA antigens than their white counterparts. Adjusting for these variables reduces but does not eliminate discrepancies in wait-listing and in waiting times, however.67 These differences probably also reflect economic, psychosocial, and unmeasured clinical factors.67-68 Similar patterns regarding access to effective therapies such as cardiovascular surgery or treatment of lung cancer have been well documented.68-69 Even after renal transplantation, outcomes are poorer in blacks: compared with other ethnic groups, they have higher rates of acute rejection and lower rates of allograft survival.4, 65
What can be done to remedy the discrepancies in access to renal transplantation? First, formal educational programs oriented toward minorities can significantly increase their living donation rates.70 Second, a reduction in emphasis on HLA matching in the organ allocation algorithm would direct more cadaveric kidneys to blacks (this change is now being implemented).71 Of course, such a change is only worthwhile if the slightly poorer HLA matching has minimal impact on allograft survival for all recipients.
What can be done to improve posttransplant outcomes in blacks? Standard measures, such as a greater use of living donors, will help. Post hoc analysis of several trials suggest that rejection rates in black recipients can be lowered with the use of tacrolimus or higher doses of MMF.72-73 Prolongation of Medicare or other benefits for immunosuppressive drugs will particularly benefit blacks, as they are at greater risk for late rejection and graft loss when immunosuppressive drugs are stopped because of the inability to pay.65 Single-center and registry data from the 1990s are showing a reduction in the racial disparities in renal allograft survival, probably due in large part to the use of the newer immunosuppressive drugs.70, 74 More work needs to be done in this area, however.
Patients With End-Stage Renal Disease and HIV Infection
Until recently, human immunodeficiency virus (HIV) infection was considered an absolute contraindication to renal transplantation. This reflected fears that immunosuppression would facilitate progression of infection, and that valuable allografts would be wasted because of the relatively short survival time of HIV-positive patients who undergo transplantation. With dramatic improvements in the survival time of HIV-positive patients, these premises are being reexamined.75-76 Those HIV-positive patients interested in transplantation should be referred to specialized centers as their management is extremely complex. One difficulty is the potential for significant interactions between the multiple antiviral and immunosuppressive medicines, some of which inhibit and some of which induce the cytochrome P450 system.75
HIGH MORBIDITY AND MORTALITY LATE AFTER TRANSPLANT: AN ONGOING PROBLEM
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