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Transplantation in the Sensitized Recipient and Across ABO Blood Groups
Naturally occurring antibodies against blood group antigens and acquired alloantibodies against donor human leukocyte antigens (HLAs; secondary to a prior kidney transplant, blood transfusions, or pregnancy) may pose major barriers to a successful renal transplantation. Because approximately 20% of renal allograft candidates may be blood group incompatible with their living donor and more than one-third will demonstrate some level of anti-HLA antibody pretransplant, understanding the unique issues pertaining to donor-specific antibody (DSA) is important for the proper management of these patients.
Over the past decade innovative strategies have been utilized to avoid incompatible transplantation, including the expansion of multicenter kidney paired donation programs and the increased priority for deceased donor allocation to highly sensitized candidates in the US. Yet evidence is mounting that a role for incompatible transplantation (ABO and/or HLA) still exists in select circumstances.
This chapter discusses the current options for transplantation in sensitized renal transplant candidates or those with ABO-incompatible living donors. Specific emphasis is placed on what is known regarding the mechanisms and treatment of both early and late antibody-mediated injury, including the results of some recent therapeutic trials. Finally, current knowledge regarding the mechanism of antibody production in the setting of renal transplantation is outlined, highlighting important gaps in current knowledge in this emerging field.
Sensitized Patients
Historically, some of the first evidence for alloantibody was the retrospective study of Patel and Terasaki in 1969. This study showed that ability of the recipient’s serum to lyse donor cells in vitro was associated with allograft loss within hours of transplantation in a high percentage of cases. Thus for many years the presence of a “positive crossmatch” because of DSA was generally considered to be an absolute contraindication to kidney transplantation. However, in the late 1990s, several groups began to employ protocols aimed at overcoming the antibody barrier. In the early 2000s, an increased understanding of the histology associated with antibody and new techniques that enhanced the ability to understand the specificity and strength of DSA helped clarify the risks and outcomes of transplantation for patients with DSA. In the past decade, the development of paired living donation and increased national sharing for highly sensitized patients has provided more options for these patients, yet many still are not transplanted. Recently an increasing number of clinical trials have been instituted to test new agents that raise hopes that new therapy might further improve the transplantation rates and the long-term outcomes of highly sensitized renal transplant candidates.
Alloantibody Detection
To understand the therapeutic options for sensitized patients, one first must understand the various assays used to determine the presence of alloantibody ( Table 22.1 ). A more detailed description of these assays is presented elsewhere in this book (see Chapter 10 ), but some key concepts will be covered here. The sensitivity of the assay is important in determining the presence and amount of antibody. For example, complement-dependent cytotoxicity (CDC) assays in which the recipient serum is tested for its ability to lyse target lymphocytes is relatively insensitive. Antihuman globulin (T cell AHG) can be added to enhance the ability to detect class I anti-HLA antibodies, but this assay is still considered the least sensitive of antibody detection techniques. Flow cytometric crossmatch methods are semiquantitative and are more sensitive for detecting anti–class I and II antibodies.
Table 22.1
Alloantibody Detection Assays
| Screening Assays | |
| Panel-reactive antibody (T cell only) | |
| Solid-phase bead or ELISA assay | |
| Donor-Specific Alloantibody Detection Tests | |
| Anti–Class I | Sensitivity |
|---|---|
| T-cell cytotoxicity (NIH-CDC) assay | Lowest Highest |
| T-cell AHG-CDC assay | |
| T-cell flow cytometric crossmatch | |
| Solid-phase bead or ELISA assay |
| Anti–Class I, II, or Both | Sensitivity |
|---|---|
| B-cell cytotoxicity (NIH-CDC) assay | Lowest Highest |
| B-cell flow cytometric crossmatch | |
| Solid-phase bead or ELISA assay |
AHG-CDC, antihuman globulin complement-dependent cytotoxicity; ELISA, enzyme-linked immunosorbent assay; NIH-CDC, National Institutions of Health complement-dependent cytotoxicity.
Solid-phase assays have revolutionized this field because they are the most sensitive, but also provide information regarding the specificity of the HLA antibody. For this test, single HLAs are bound to microspheres or enzyme-linked immunosorbent assay (ELISA) plates. For solid-phase assays such as the commonly used LABscreen, the level of alloantibody is usually expressed as the mean fluorescence intensity (MFI). MFI levels considered to be positive vary between laboratories and transplant programs, but an MFI level of >1000 generally is accepted as positive.
Commercially available modified solid-phase assay tests have also been developed to detect complement binding (C1q or C3d). DSA with C1q and/or C3d binding positivity is associated with the development of antibody-mediated rejection (AMR) and allograft loss, and some groups routinely use these tests to distinguish the most deleterious DSA. However, it remains unclear whether C1q positivity is superior to using MFI or antibody titer to predict AMR or allograft loss, and thus testing for C1q or C3d binding is not universally performed.
In practice, a solid-phase assay is commonly used as an initial screening tool to determine the presence of alloantibody at the time the transplant candidate is being evaluated. This test is used to determine which HLA antigens to avoid at the time of transplantation and can be used to determine the breadth of sensitization against HLA by calculating the panel-reactive antibody (cPRA). The cPRA provides information regarding the probability of finding a donor against whom the recipient has no DSA, but does not give information about the level of alloantibody. Currently, the cPRA can be used as a factor in deceased donor allocation, as will be discussed later. The PRA was historically determined when the transplant candidate’s serum was added to a panel of cells that represented the donor pool (hence the name “panel-reactive antibody”), but that method is now infrequently used.
When a potential donor is identified, both solid-phase and crossmatch assays are performed and interpreted together in context (i.e., sensitization history). However, as the breadth of antibodies detectable by the solid-phase assay has expanded, some experts support the use of solid-phase assays alone for a virtual crossmatch.
Despite the technologic advances in HLA detection, there remains a considerable lack of standardization of practice among transplant centers regarding the method, interpretation, and reporting of the various tests. This lack of standardization, combined with the small number of patients who undergo incompatible transplantation at individual centers, limits the ability to understand immunologic risk in various settings. Major efforts are underway internationally to standardize practices, and our understanding of the immunologic risk of incompatible transplantation has advanced.
Clinical Approaches to Sensitized Patients
Ideally alloantibody would be avoided at the time of transplantation, but that is not always possible. The next section describes the options for patients with preformed anti-HLA antibodies before transplantation.
Deceased Donor Transplantation
If sensitized patients do not have any prospective living donors, their only transplant option is to be placed on the deceased donor waiting list. Approximately 30,000 patients on the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) cadaver donor kidney waiting list are “sensitized” and currently about 7000 patients have a cPRA of 99% or 100% in the in US.
In 2014 the deceased donor kidney allocation system (KAS) changed, and it now offers renewed hope for sensitized transplant candidates. This system increases the allocation priority for sensitized candidates on a sliding scale starting with a cPRA of 20%. Although all patients with a cPRA of greater than 80% received allocation points in the old US system, now patients with a cPRA of 80% to 84% receive 2.5 points and those with a cPRA of 100% receive 202 points. Patients with 99% and 100% cPRA have even greater access to the available donor pool because they also now have regional and national priority. Indeed, these changes have increased the number of sensitized patients who have been transplanted. Within the first year of implementation, nearly 1000 patients with cPRA of 99% or 100% received a transplant.
The Acceptable Mismatch Program of Eurotransplant is another approach to transplanting sensitized candidates with a deceased donor. In this program, anti-HLA antibodies are identified using a CDC assay. Highly sensitized patients (PRA >85%) are placed at the top of the kidney match run and organs are allocated based on the absence of DSA against the donor HLA (i.e., “acceptable mismatch” for HLA). In this program, approximately 60% of the highly sensitized patients are transplanted within 2 years after inclusion in this acceptable mismatch program and the short-term graft survival appears similar to that of unsensitized patients. Low levels of DSA that are present at the time of transplant are not considered at the time of allocation, and it is unclear what the long-term outcomes will be in this program.
Kidney Paired Donation
If a sensitized candidate has potential living donors, these donors should be HLA-typed to find a crossmatch-negative donor. If no such donor can be found, sensitized candidates may opt to enter into one of the growing number of paired living donor programs. These “exchange” schemes have been shown to increase the transplantation rate of ABO-incompatible and sensitized patients ( Fig. 22.1 ). Although these programs increase the number of potential donors for sensitized individuals, patients with antibodies against a wide variety of HLA types still may not be able to find a crossmatch-negative donor, even if the donor pool is very large. One of the central questions in paired donation is: How long should a sensitized patient wait for a crossmatch-negative donor versus proceeding to a transplant using a donor against whom the recipient has DSA? Because many sensitized patients may not find a DSA-negative donor, most paired donor programs employ “optimization” protocols that seek to identify donors for sensitized patients with lower levels of DSA than their original donor. Thus transplantation of a sensitized patient in this setting might employ both paired donation and living donor incompatible transplant protocols.
Kidney Transplantation in the Presence of DSA
A viable option for sensitized candidates is to perform a kidney transplant despite the presence of DSA. Overall, data suggests that patient survival may be improved after incompatible transplant compared with remaining on dialysis ( Fig. 22.2 ). This is despite reduced allograft survival as will be discussed in the next section. In a multicenter trial involving 22 centers in the US, the survival of 1025 patients who received an incompatible living donor kidney transplant were matched with controls who remained on the waitlist or received a deceased donor transplant. At 1, 3, and 5 years patients who received an incompatible kidney transplant had improved survival (see Fig. 22.2 ). This patient survival benefit was significant at 8 years across all levels of incompatibility (DSA positive only and positive flow cytometric crossmatch). Specifically, at 5 years the patient survival was 86.0% in those patients who received an incompatible living donor transplant, 74.4% in those who received a deceased donor transplant and/or remained on the waitlist, and 59.2% in those patients who remained on the waitlist and did not receive a transplant.
The survival advantage of an incompatible transplant compared with being on the waiting list in the US was not found in a recent study. A matched cohort analysis was performed in the United Kingdom comparing 213 patients who underwent positive crossmatch transplantation and 852 matched controls. The patient survival was similar among patients who received a positive crossmatch transplant or remained on dialysis at 3 and 7 years. In this cohort, the 5-year patient survival after incompatible transplant was 68% after HLA-incompatible transplantation, 89% after compatible living donor transplant, and 77% for compatible deceased donor transplant. The differences in the results between the US and United Kingdom cohort are likely related to the increased mortality on dialysis in the US and high-risk transplant group from the United Kingdom (all patients received positive crossmatch transplants in the United Kingdom whereas 185 patients in the US cohort had positive DSA by solid-phase single-antigen bead assay, but had a negative crossmatch).
Regardless of the patient survival advantage after incompatible transplantation, allograft survival is reduced. These transplants are also associated with higher rates of hospital readmission in the first year posttransplant and are more expensive. The potential disadvantages of incompatible transplantation should not be used to discourage this practice, but should be used for clinical decision making.
Whereas avoiding DSA is ideal, many highly sensitized patients remain on the waiting list despite paired donor programs and increased priority for deceased donors. When considering a transplant in the setting of DSA, the major risk to consider is that of graft loss. Some incompatible transplants are relatively low risk whereas others are prohibitively high risk for early graft loss. Thus before we discuss the various options for incompatible transplantation, we need to examine the concept of immunologic risk associated with DSA.
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