Version May 2024
INTRODUCTION — Despite considerable effort in promoting living-donor transplantation, many potential recipients with otherwise suitable donors are relegated to the deceased-donor waiting list because of preformed human leukocyte antigen (HLA) antibodies. These are acquired via pregnancy, transfusion, and/or prior transplant. The presence of these anti-HLA antibodies in the potential recipient's blood is called HLA sensitization.
If not adequately suppressed, the presence of such antibodies is likely to result in antibody-mediated rejection (ABMR) and early graft loss. ABMR was recognized early in the history of transplantation as hyperacute rejection caused by the presence of preformed antibodies, most typically in the form of antibodies to donor HLAs. Introduction of pretransplant crossmatch techniques has essentially eliminated hyperacute rejection.
Waitlist times can exceed several years to decades, with disproportionately longer wait for patients with blood group B or O. The time spent on dialysis waiting for the appropriate deceased-donor allograft (DDA) to whom HLA antibodies do not exist has a significant adverse effect on both quality and quantity of life. Preemptive transplantation (performed prior to the need for dialysis) provides improved patient and allograft survival compared with results in patients maintained on dialysis for an extended period of time prior to transplantation.
According to 2022 data from the Organ Procurement and Transplantation Network (OPTN), approximately 12 percent of patients on the DDA waiting list are highly presensitized to HLA (defined as ≥80 percent calculated panel reactive antibody [CPRA]) [1]. As a result, such patients are less likely to be transplanted or will spend an extended period of time on the waiting list, pending availability of a suitable donor kidney. Many of these patients have potential living donors that are excluded without further workup based upon an initial positive crossmatch with the potential recipient, indicating the presence of preformed HLA antibodies.
The increased risk of hyperacute ABMR and subsequent allograft loss when transplanting against preformed HLA antibodies has engendered a general avoidance of this practice. However, reports of successful transplantation across HLA barriers using various desensitization protocols designed to reduce the amount of preexisting antibody to a level that allows for successful engraftment have stimulated increased interest in using immunologically incompatible grafts [2].
Patients with a willing but HLA-incompatible donor may wait for a deceased-donor organ or receive a living-donor organ through desensitization, kidney paired donation (KPD), or a combination of both. The choice between desensitization or KPD for an individual recipient depends upon the likelihood of finding a suitable match through KPD and the chances of successful desensitization.
This topic will review the approaches used in kidney transplantation to overcome the HLA-sensitization barrier. An overview of HLA sensitization and crossmatch testing, KPD, and the diagnosis and treatment of ABMR are discussed separately:
●(See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing".)
●(See "Kidney transplantation in adults: Kidney paired donation".)
●(See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)
ASSESSMENT OF PATIENT SENSITIZATION — HLA sensitization of a potential transplant recipient is first assessed at the time of initial transplant evaluation. The objective is to measure the degree of HLA sensitization, which can be characterized by both the breadth and strength of HLA antibodies. Panel reactive antibodies (PRA) is an estimate of the percentage of the population to which the candidate has antibodies against and is a characterization of the breadth of HLA sensitization. The PRA inversely correlates with the likelihood of a compatible donor match, with higher PRA associated with lower chances of compatible transplantation. On the other hand, HLA antibody strength, represented by mean fluorescence intensity (MFI) or dilutional titers, is one of the main determinants of the ability of successful desensitization for transplant. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing" and "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Laboratory and imaging tests'.)
Transplant centers vary in their approach to measuring HLA sensitization, but all assess for the presence of HLA antibodies by testing patient sera against solubilized HLA antigens attached to solid beads. At our center, we first perform a multiple-antigen flow cytometry bead assay to screen for the presence of HLA antibodies; if positive, a single-antigen bead assay (Luminex) is performed to identify the specific HLA antigens to which the patient has antibodies. At our center, antigens with an MFI ≥5000 are designated as "unacceptable antigens" and entered into UNet, the computer system operated by the United Network for Organ Sharing (UNOS). If an unacceptable antigen for a specific patient is listed in UNet, kidneys from donors with that antigen will not be offered to the patient. A calculated panel reactive antibody (CPRA) is computed based upon the patient's unacceptable antigens. It should be noted that MFI levels can vary by approximately 20 to 25 percent between HLA labs [3] and that MFI threshold levels used to designate an unacceptable antigen are not standardized across transplant centers. In addition, different labs report antibody strength in multiple ways, including MFI and dilutional titers. Dilutional titers more accurately represent the antibody quantity than MFI, especially for high-titer antibodies [4], but either method of reporting is acceptable within the range of antibody strength typically used for classifying an antibody unacceptable for transplant. There is no standard CPRA threshold that defines allosensitization. At our center, patients who have a CPRA ≥30 percent or who are seeking a retransplant are considered to be sensitized and potentially qualify for desensitization.
APPROACH TO THE SENSITIZED TRANSPLANT CANDIDATE — Once the extent of patient sensitization has been established, the need for desensitization prior to transplantation is determined. Our approach varies depending upon whether or not the transplant candidate has a potential living donor and is discussed below (algorithm 1).
Patients with a potential living donor — In sensitized patients (ie, CPRA ≥30 percent or seeking retransplantation) with one or more potential living donors, we first perform a virtual crossmatch to determine if the patient has donor-specific antibodies (DSAs) (algorithm 1). We routinely perform a complement-dependent cytotoxicity (CDC) T and B cell crossmatch and T and B cell flow cytometry crossmatch when the donor is identified. This information is used to help define the potential risk of antibody-mediated rejection (ABMR) and plan for desensitization, if appropriate, or to recommend against transplantation with a particular donor. In addition, all sensitized patients with a potential living donor are also listed for a deceased-donor transplant. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing".)
Our subsequent approach is based upon the results of the CDC and flow crossmatch:
●Positive CDC crossmatch – A positive CDC crossmatch is considered to be a contraindication to transplantation with a potential donor at our center although there are some centers that would consider it. In a large, multicenter study of 22 transplant centers in the United States that perform HLA-incompatible kidney transplants, the incidence of all-cause graft loss at one and five years was 19 and 40 percent, respectively, among recipients of a positive cytotoxic crossmatch [5]. Given the high risk of ABMR and graft loss in patients with a positive CDC crossmatch, we do not desensitize these patients. We evaluate other potential living donors or advise enrolling in a kidney paired donation (KPD) program. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection", section on 'Patients with preexisting DSA before transplant' and "Kidney transplantation in adults: Kidney paired donation".)
●Negative CDC crossmatch and positive flow cytometry crossmatch – In patients with a negative CDC crossmatch but a positive flow cytometry crossmatch, our approach depends upon the strength of the flow crossmatch, as determined by the median channel shift (MCS):
•If the MCS is ≤250, we offer HLA desensitization depending upon the overall specificity and strength of DSAs. To assess this, we calculate a relative intensity score (RIS) for the patient, assigning 10 points for each DSA in the strong-binding range (MFI ≥10,000), 5 points for each moderate-intensity DSA (MFI 5000 to 9999), and 2 points for each weak DSA (MFI <5000) [6]. If the RIS is less than 17 points, we proceed with our standard desensitization protocol and transplantation. In rare cases in which a patient has an MCS ≤250 but an RIS greater than 17 points (most patients with an RIS >17 have an MCS >250), we would not attempt desensitization and would pursue other potential donors or KPD. (See 'Living-donor transplantation' below.)
•If the MCS is >250, we typically do not perform desensitization and prefer to pursue other potential donors or KPD. (See 'Living-donor transplantation' below.)
●Negative CDC crossmatch and negative flow cytometry crossmatch – Such patients can either be DSA negative, crossmatch negative or DSA positive, crossmatch negative. Included are patients who have historical DSA, not present at the time of transplant, a scenario often encountered because DSA can fluctuate above and below the level of detection. Furthermore, patients may have memory B cells that can re-emerge upon antigen stimulation. As an example, mothers may have previous exposure to HLA antigens from childbirth and are capable of a memory response when receiving a transplant from a child even if DSA are not detectable on screening. Thus, sensitized patients with a negative crossmatch are at risk for developing acute and/or chronic ABMR [7], and we proceed with desensitization in conjunction with transplantation, even with a negative crossmatch [8]. However, it should be noted that some centers do not administer desensitization in this scenario.
Patients without a potential living donor — In sensitized patients (CPRA ≥30 percent) who do not have a potential living donor, we list for deceased-donor transplant and offer pretransplant desensitization once the patient is considered to be within reasonable range for a deceased-donor kidney transplant offer. This is determined based upon the number of years of waiting time accrued and number of points allotted by the kidney allocation system for their degree of allosensitization. (See 'Deceased-donor transplantation' below and "Kidney transplantation in adults: Organ sharing", section on 'National deceased-donor kidney allocation policy'.)
APPROACH TO HLA-INCOMPATIBLE TRANSPLANTATION — Approaches to HLA-incompatible transplantation vary among transplant centers and are usually institution specific. The ability to safely and successfully perform desensitization involves ready access to a multidisciplinary team including an HLA laboratory, plasmapheresis team, transplant pathology, and transplant pharmacy, among others. The approach used at our center is described below.
Pretransplant HLA desensitization
Overview of desensitization — The overall goal of HLA desensitization is twofold:
●To increase the chance of successful kidney transplantation in patients with broad HLA antibody sensitization
●To prevent antibody-mediated rejection (ABMR) in such patients after transplantation
Desensitization may be performed in patients awaiting either living- or deceased-donor transplantation. The goals of desensitization are similar in both contexts, but the approach may be slightly different because of the unpredictable timing of deceased-donor transplantation in relation to administration of desensitization therapy. Although there is no uniformly accepted HLA-desensitization protocol, most commonly used protocols employ a combination of the following strategies:
●Immunomodulation of the recipient immune system, typically with intravenous immune globulins (IVIG)
●Depletion of the B cell population responsible for anti-HLA antibody production, most commonly with the anti-CD20 agent rituximab
●Removal of circulating anti-HLA antibodies, typically with extracorporeal methods such as plasmapheresis
Our approach to desensitization — HLA-desensitization strategies vary at different transplant centers depending upon clinical experience and preference. There are no high-quality data in the form of randomized controlled trials comparing existing desensitization approaches, and the optimal therapy is undefined. For most transplant candidates who qualify for HLA desensitization, we suggest pretransplant desensitization with high-dose IVIG and rituximab rather than high-dose IVIG alone or other desensitization regimens. In our experience, desensitization with this protocol has been shown to reduce both the breadth (CPRA) and strength (MCS or titer) of antibody and shorten the time to transplantation [9,10], permitting transplantation in approximately 75 to 80 percent of patients [11]. Our specific protocols for living-donor and deceased-donor transplantation are detailed below. (See 'Living-donor transplantation' below and 'Deceased-donor transplantation' below.)
The combination of high-dose (2 g/kg per dose) IVIG and rituximab has been found to be safe and effective in reducing anti-HLA antibody levels and increasing rates of transplantation among highly sensitized patients awaiting transplant from either a living or deceased donor.
●In an open-label, phase I/II study, 20 highly sensitized kidney transplant candidates received IVIG (2 g/kg on days 0 and 30) plus rituximab (1 g on days 7 and 22) [9]. After receiving this regimen, patients were eligible for kidney transplantation from either a living or deceased donor. With this approach, 16 of 20 patients received a kidney transplant. Treatment with IVIG and rituximab decreased mean PRA levels from 77 percent before treatment to 44 percent after treatment and lowered the mean time to transplantation from 144 to 5 months. The acute rejection rate was 50 percent; however, most episodes were reversible, and at one year, the mean serum creatinine concentration was 1.5 mg/dL (133 micromol/L), with patient and allograft survival rates of 100 and 94 percent, respectively.
●In a follow-up study of 76 highly sensitized patients (75 percent with PRA ≥80 percent), desensitization with a similar protocol reduced classes I and II flow cytometry PRA levels and flow cytometry crossmatch MCS, permitting transplantation in all patients [10].
The addition of rituximab to IVIG appears to be superior to high-dose IVIG alone for the desensitization of highly sensitized transplant candidates. The following studies illustrate the range of findings:
●One randomized trial compared the use of IVIG plus rituximab with IVIG plus placebo for desensitization among highly sensitized kidney transplant candidates awaiting deceased-donor kidney transplantation [12]. Patients were randomly assigned to receive IVIG 2 g/kg (maximum dose 140 g) on days 1 and 20 with either rituximab (1 g) or placebo on day 15. The study intended to enroll 90 patients but was stopped early after only 15 patients were enrolled due to the occurrence of three serious adverse events, all of which were episodes of ABMR. Of the 15 enrolled patients, 13 received transplants (six in the IVIG plus rituximab arm and seven in the IVIG plus placebo arm). After unblinding, it was discovered that all episodes of ABMR occurred among patients who received IVIG plus placebo; no donor-specific antibody (DSA) rebound was seen in those receiving IVIG plus rituximab. In addition, there were two cases of graft loss in the IVIG plus placebo arm compared with none in the IVIG plus rituximab arm.
●In a study of 54 deceased-donor kidney transplant recipients with preformed DSA at the time of transplant, 36 received IVIG 2 g/kg on the day of transplant and on days 21, 42, and 63 posttransplant, and 18 received the same IVIG dosing schedule in conjunction with one dose of rituximab on day 4 posttransplant and plasmapheresis three times per week for the first three weeks posttransplant [13]. Although there was no difference in the incidence of active ABMR between the two groups, patients treated with IVIG/rituximab/plasmapheresis had a higher measured glomerular filtration rate (GFR; 54 versus 43 mL/min/1.73 m2) and less proteinuria (0.1 versus 0.5 g/L) at one year posttransplant compared with those treated with IVIG alone. Protocol biopsies performed at one year revealed fewer cases of subclinical ABMR and transplant glomerulopathy and a lower degree of peritubular capillaritis among patients receiving IVIG/rituximab/plasmapheresis. In addition, fewer patients treated with IVIG/rituximab/plasmapheresis remained positive for DSA at one year (29 versus 75 percent).
Living-donor transplantation — For patients with a potential living donor who qualify for HLA desensitization, we administer pretransplant desensitization with high-dose IVIG and rituximab (see 'Our approach to desensitization' above). Our desensitization protocol for living-donor transplantation is as follows:
●We administer rituximab 375 mg/m2 on days 0 and 14. We premedicate for each dose of rituximab with intravenous (IV) methylprednisolone 40 mg, acetaminophen 650 mg given orally, and diphenhydramine 50 mg given orally.
●We administer IVIG 2 g/kg (maximum dose of 140 g per treatment) on days 28 and 42. We premedicate for each dose of IVIG with IV methylprednisolone 40 mg, acetaminophen 650 mg given orally, and diphenhydramine 50 mg given orally.
●Upon completion of this desensitization protocol, we repeat a donor-specific complement-dependent cytotoxicity (CDC) T and B cell crossmatch and a flow cytometry T and B cell crossmatch. The flow cytometry crossmatch is performed after pronase digestion, which removes CD20 from B cells and non-HLA antigens from T and B cells, enabling more precise determinations of HLA-specific antibodies and eliminating rituximab effect. Desensitization is considered successful if the patient has an acceptable crossmatch, which is defined at our center as a negative CDC crossmatch in a ≥1:2 dilution of patient sera, a negative flow cytometry crossmatch, or a positive flow cytometry crossmatch with MCS ≤250.
If the results of the crossmatch are acceptable, transplant surgery is performed within one week. If the results of the crossmatch are not considered to be acceptable, we either pursue alternative desensitization therapies or enroll the patient in kidney paired donation (KPD). (See 'Other desensitization regimens' below and "Kidney transplantation in adults: Kidney paired donation".)
Transplant centers vary in practice and may prefer to enroll a patient in KPD first for a predetermined time interval after which if a compatible match is not found, desensitization is pursued. Factors that affect the likelihood of donor matching through KPD, such as blood type and CPRA, should guide the recommendation in order to minimize the time waiting for transplantation. Data from the National Kidney Registry indicate that 35 to 40 percent of all candidates in a KPD program do not match to a donor within one year, and the percentages are even higher if the candidate is blood type O (43 percent), highly sensitized (CPRA ≥97 percent; 58 percent), or both (90 percent) [14].
Deceased-donor transplantation — In patients waitlisted for a deceased-donor transplant who qualify for desensitization (see 'Patients without a potential living donor' above), the goals of desensitization are the same as those for patients with a living donor. However, the approach is slightly different because of the unpredictable timing of deceased-donor transplantation in relation to the administration of desensitization therapy. Because the precise date of transplant is not known, we offer desensitization therapy when a deceased-donor organ offer is considered likely within one year. This estimation is based upon the patient's kidney allocation points, determined by the amount of accrued waiting time and allocation priority afforded by the patient's calculated panel reactive antibody (CPRA). If a deceased-donor organ is not considered likely within one year, we have the patient remain on the deceased-donor list without specific desensitization treatment. All patients must have prior authorization from their insurance company for all therapies associated with desensitization as well as for the actual transplant surgery before desensitization can proceed. (See "Kidney transplantation in adults: Organ sharing", section on 'National deceased-donor kidney allocation policy'.)
●High-dose IVIG and rituximab as initial desensitization – In patients awaiting deceased-donor transplantation, we perform pretransplant desensitization with high-dose IVIG and rituximab using the same regimen as that used in patients awaiting living-donor transplantation (see 'Living-donor transplantation' above and 'Our approach to desensitization' above). Upon completion of this desensitization protocol, we perform Luminex single-antigen testing monthly to maintain current sera for crossmatch testing. It is rare that the CPRA needs to be adjusted since desensitization often does not completely eliminate HLA antibodies (ie, the breadth of antibody sensitization) but commonly reduces their strength (ie, MFI or dilutional titer).
●Addition of plasmapheresis for subsequent courses of desensitization – If the patient has not received a deceased-donor kidney transplant within six months of completing the initial course of desensitization, we administer a second course of desensitization that consists of plasmapheresis followed by high-dose IVIG and rituximab [13]. Plasmapheresis is performed to reduce the levels of circulating anti-HLA antibodies.
•We perform alternate-day plasmapheresis for five sessions, using 1.5 volume exchanges with 5 percent albumin replacement with each plasmapheresis session. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
•We administer one dose of IVIG 2 g/kg (maximum dose of 140 g) immediately following the last session of plasmapheresis. We premedicate for IVIG with IV methylprednisolone 40 mg, acetaminophen 650 mg given orally, and diphenhydramine 50 mg given orally.
•We administer rituximab 375 mg/m2 one week after the last session of plasmapheresis. We premedicate for rituximab with IV methylprednisolone 40 mg, acetaminophen 650 mg given orally, and diphenhydramine 50 mg given orally.
Rituximab is administered one week after plasmapheresis and IVIG infusion to minimize the influence of neonatal Fc receptor (FcRn) saturation by IVIG. FcRn, which is highly expressed on vascular endothelial cells and myeloid cells, binds under acidic conditions to serum immunoglobulin G (IgG) and inhibits its degradation, thereby prolonging the half-life of antibodies [15]. Saturation of FcRn by high-dose IVIG can overwhelm the ability of FcRn to prevent degradation of IgG and is one proposed mechanism by which IVIG enhances clearance of pathogenic autoantibodies in autoimmune diseases [16] (see "Overview of intravenous immune globulin (IVIG) therapy", section on 'Suppression of inflammatory/autoimmune processes'). However, IVIG may potentially reduce the half-life and efficacy of other therapeutic IgG antibodies administered in close proximity to IVIG. As an example, in one study of patients with multifocal motor neuropathy, patients who received the monoclonal antibody eculizumab together with IVIG had lower serum concentrations of eculizumab compared with those who received eculizumab alone [17]. Similar findings have been reported in patients concomitantly receiving the anti-C5 monoclonal antibody tesidolumab with IVIG [18]. Thus, at our center, we wait at least 7 to 10 days after high-dose IVIG infusion before administering any other chimeric or humanized monoclonal antibody.
We perform desensitization with plasmapheresis, high-dose IVIG, and rituximab every six months until the patient receives a deceased-donor transplant. We perform Luminex single-antigen testing monthly to maintain current sera for crossmatch testing.
●IVIG plus tocilizumab as alternative second-line therapy – As an alternative, if the patient does not receive a kidney transplant within six months after the second round of desensitization, we offer the patient treatment with the combination of high-dose IVIG (2 g/kg given on days 0 and 30) and tocilizumab (8 mg/kg on day 15, then repeated monthly), a monoclonal antibody directed against the interleukin (IL) 6 receptor that has been used for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab'.)
The use of IVIG and tocilizumab was evaluated in a pilot trial of 10 highly sensitized transplant candidates who did not respond to desensitization with high-dose IVIG and rituximab (with or without plasmapheresis) [19]. Of the eight patients who completed the trial (two were removed from the study because of nonadherence), five were transplanted with a mean time to transplant of 8.1 months from initiation of tocilizumab (25 months from initial desensitization therapy). The mean relative intensity score (RIS), a measure of DSA strength and number, decreased from 7.8 before treatment to 3.2 at the time of transplant. Larger, controlled trials are required to confirm the efficacy of this desensitization regimen.
Other desensitization regimens — Alternative approaches to HLA desensitization that may be used at other transplant centers that perform HLA-incompatible transplantation are discussed below.
●Low-dose IVIG plus plasmapheresis – For desensitization prior to living-donor transplantation, some transplant centers use a protocol that consists of low-dose IVIG in combination with alternate-day plasmapheresis [20-23].
In this protocol, alternate-day plasmapheresis is performed prior to transplantation, and IVIG (or cytomegalovirus [CMV] antibody immune globulin, depending upon the institutional protocol) is administered at a dose of 100 mg/kg after each session. The number of pretransplant treatments is estimated based upon the baseline DSA titer. Tacrolimus and mycophenolate mofetil are typically started with the initiation of plasmapheresis although this practice may vary from center to center. Once the DSA levels and pretransplant crossmatch are considered acceptable, transplantation proceeds. Some centers routinely continue plasmapheresis after transplantation for a prespecified number of treatments, while others only perform posttransplant plasmapheresis for the treatment of acute ABMR.
Long-term follow-up of patients desensitized with alternate-day plasmapheresis and low-dose IVIG suggests a significant survival benefit with this approach. In one study, patient survival in 211 HLA-sensitized patients transplanted after desensitization with plasmapheresis and low-dose IVIG was compared with that of two matched control groups of patients on a waiting list for kidney transplant who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group) [23]. Survival in desensitized patients was greater at three, five, and eight years (86, 81, and 81 percent, respectively), compared with that in patients in the dialysis-only group (67, 52, and 31 percent, respectively) and patients in the dialysis-or-transplantation group (77, 66, and 49 percent, respectively).
Disadvantages of this protocol include its high financial cost and resource requirements. Numerous pretransplant treatment sessions may be required to obtain an adequately low DSA titer that will permit successful transplantation, and several posttransplant treatment sessions are often required to limit the rise of DSA titers and prevent ABMR. As the timing of the actual transplant surgery must be adjusted to allow for an acceptable antibody titer, this protocol is only suitable for potential recipients of a living-donor transplant. (See 'Costs of HLA-incompatible transplant' below.)
There are no randomized trials comparing the use of low-dose IVIG and plasmapheresis with high-dose IVIG for desensitization. One retrospective study compared three different desensitization regimens in living-donor transplant recipients with a positive T cell CDC crossmatch: high-dose IVIG (2 g/kg) given one to three days prior to transplant; plasmapheresis, low-dose IVIG (100 mg/kg), and rituximab 375 mg/m2; and plasmapheresis, low-dose IVIG (100 mg/kg), and rituximab 375 mg/m2 with pretransplant rabbit antithymocyte globulin (rATG)-Thymoglobulin and intensive posttransplant DSA monitoring [24]. All patients with a baseline crossmatch titer <1:4 achieved a negative crossmatch regardless of desensitization regimen, compared with only 1 of 10 patients with a baseline crossmatch titer >1:32. Among patients with a baseline titer of 1:8 and 1:16, only 33 percent who received high-dose IVIG achieved a negative CDC crossmatch, compared with 87 percent in the two groups who received plasmapheresis/low-dose IVIG/rituximab. Among patients who were transplanted, rates of ABMR were 80, 37, and 29 percent for patients receiving high-dose IVIG, plasmapheresis/IVIG/rituximab, and plasmapheresis/IVIG/rituximab/rATG-Thymoglobulin, respectively. These findings suggest the following:
•High-dose IVIG and plasmapheresis/low-dose IVIG/rituximab are similarly effective for desensitization when the T cell CDC crossmatch is positive at a low titer (<1:4).
•None of the desensitization protocols are effective when the T cell CDC crossmatch is positive at a high titer (>1:32).
•Plasmapheresis/low-dose IVIG/rituximab may be more effective than high-dose IVIG when the T cell CDC crossmatch is positive at an intermediate titer (1:8 to 1:16). However, it should be noted that patients desensitized with high-dose IVIG did not receive rituximab, which may have contributed to their higher rate of ABMR.
Given the high rates of ABMR with all three desensitization protocols, we recommend caution when pursuing a transplant with a positive CDC crossmatch. As previously mentioned, we do not proceed with desensitization or transplant in patients with a baseline positive CDC crossmatch at our center. (See 'Patients with a potential living donor' above.)
●Proteosome inhibitors – Bortezomib and carfilzomib are proteosome inhibitors that target differentiated plasma cells, which are responsible for antibody secretion. At our center, we do not routinely use these agents as part of an HLA-desensitization strategy due to their unclear efficacy and adverse side effect profile.
•Bortezomib – Bortezomib is a reversible proteasome inhibitor that has been successfully used in the treatment of ABMR. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection", section on 'Proteasome inhibitors'.)
The largest study of bortezomib-based desensitization was a prospective trial of 44 sensitized patients (current or peak cytotoxic PRA or CPRA >20 percent), conducted in five phases over three years [25]. All patients had a living donor and a positive CDC or flow cytometry crossmatch with DSAs. The treatment protocol in each study phase consisted of bortezomib (1.3 mg/m2 per dose for six to eight doses), a single dose of rituximab 375 mg/m2, and plasmapheresis; phases differed in the bortezomib dosing density and number of plasmapheresis sessions. A total of 19 out of 44 (43 percent) patients were transplanted during the study. Six of 15 (40 percent) patients with DSAs and a positive T cell flow cytometry crossmatch against a living donor achieved a negative crossmatch; four were transplanted, while two were not transplanted due to a persistent DSA with an MFI >3500. Six out of 44 (13.5 percent) experienced a 50 percent reduction in the cytotoxic PRA of at least 50 percent; those with high titer DSAs were less likely to exhibit a response. Among responders, the reduction in DSAs was durable with minimal short-term rebound although later-term rebound at 90 days and beyond was observed depending upon the treatment protocol used. At six months after transplant, the rates of acute rejection and ABMR were 18.8 and 12.5 percent, respectively. Overall, bortezomib was generally well tolerated at the doses used in this study.
However, in a study of 10 highly sensitized kidney transplant candidates with DSAs against their intended living donor, the use of 32 doses of bortezomib (1.3 mg/m2) as monotherapy resulted in only a modest reduction in DSAs with no change in CPRA [26]. In addition, the treatment was not well tolerated due to adverse effects. Thus, although a bortezomib-based desensitization protocol allowed some transplant candidates to achieve a negative crossmatch, the benefit was limited to only a minority; most patients did not achieve a satisfactory reduction in DSAs nor were transplanted, and many experienced side effects.
•Carfilzomib – Carfilzomib is a second-generation, irreversible proteasome inhibitor that may have more durable effects on plasma cells than the first-generation, reversible proteasome inhibitor bortezomib. Additionally, it has a more favorable toxicity profile than bortezomib with notably less association with peripheral neuropathy. Its use for desensitization was reported in a small study of 13 highly sensitized candidates designed to assess safety and preliminary efficacy in conjunction with plasmapheresis [27]. All patients received escalating doses of carfilzomib from 20 to 36 mg/m2 over 12 doses followed by three sessions of plasmapheresis on days 47, 49, and 51. An additional subgroup received plasmapheresis throughout the desensitization schedule before carfilzomib dosing. The treatment was generally well tolerated, and no cases of peripheral neuropathy or heart failure were reported. MFI reduction with carfilzomib alone was modest in most patients and was more pronounced after plasmapheresis. Antibody rebound to baseline levels developed in all patients within five months after completion of desensitization. Further studies are needed to better define the safety and efficacy of carfilzomib as a desensitization agent for kidney transplantation.
●Eculizumab – Eculizumab is a humanized monoclonal antibody directed against the terminal complement component C5 that has been used as a salvage agent in treating refractory active ABMR. We do not routinely use eculizumab as part of an HLA-desensitization strategy due to its cost and unclear benefit. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection", section on 'Complement inhibitors'.)
There are limited data for the use of eculizumab for HLA desensitization. One study examined the use of eculizumab among 30 living-donor transplant recipients with an initial positive B cell flow cytometry crossmatch MCS between 200 and 450 [28,29]. Patients with a pretransplant MCS ≥300 received plasmapheresis prior to transplantation to achieve an MCS <300 by the day of transplant. Eculizumab was administered as follows: 1200 mg immediately prior to transplant, 600 mg on postoperative day 1, and 600 mg weekly thereafter for four weeks. At week 4 posttransplant, patients with a B cell flow cytometry crossmatch MCS >200 received additional eculizumab (1200 mg on week 5, then every two weeks thereafter until the MCS improved to <200). Outcomes were compared with those of a historical control group of 48 living-donor recipients of a positive crossmatch transplant who were desensitized with a similar protocol without eculizumab.
Patients who received eculizumab had a lower incidence of active ABMR over a mean of 38 months compared with historical controls over a mean of 73 months (7 versus 44 percent, respectively). However, among eculizumab-treated patients, there was a high incidence of transplant glomerulopathy due to persistence of DSAs (45 versus 64 percent in the control group), suggesting other mechanisms for graft injury besides complement activation. The percentage of patients who had a B cell flow cytometry crossmatch MCS >200 at six months was similar between eculizumab-treated patients and controls (46 versus 41 percent), suggesting no additional benefit of eculizumab on the reduction of DSA compared with standard therapy. Among these patients, there was no difference in transplant glomerulopathy at one year (50 versus 36 percent). By contrast, among patients who exhibited an improvement in MCS to <200 at six months, none of the eculizumab-treated patients had transplant glomerulopathy at one year, compared with 42 percent of historical controls. Although inconclusive, this observation suggests that patients who are treated with eculizumab and have a reduction in DSA by six months may be less likely to develop chronic ABMR than those not treated with eculizumab.
Investigational approaches — Several investigational therapies are being evaluated as desensitization regimens. These are discussed below:
●Imlifidase – The IgG-degrading enzyme derived from Streptococcus pyogenes (imlifidase [IdeS]) is a recombinant cysteine protease that cleaves all four subclasses of human IgG into F(ab')2 and Fc fragments, inhibiting CDC and antibody-dependent cellular cytotoxicity. Imlifidase has received conditional approval by the European Medicines Agency (EMA) for desensitization in kidney transplantation in the European Union. Imlifidase is not yet US Food and Drug Administration (FDA) approved for use in the United States.
The efficacy of imlifidase as a desensitization strategy was initially evaluated in two independent phase I/II trials from the United States and Sweden that included 25 highly HLA-sensitized patients (median CPRA of 96 and 81 percent in the United States and Swedish studies, respectively) [30]. Among these patients, 92 percent received a deceased-donor transplant, 92 percent had anti-HLA DSAs at the time of transplant, and 80 percent had a positive flow cytometry crossmatch at the time of transplant. All patients received imlifidase (0.24 mg/kg in the United States study and 0.25 mg/kg or 0.50 mg/kg in the Swedish study) administered intravenously four to six hours before transplantation. Patients in the United States study received induction with alemtuzumab as well as high-dose IVIG and rituximab, while those in the Swedish study received induction with horse antithymocyte globulin; all patients received maintenance immunosuppression consisting of tacrolimus, mycophenolate mofetil, and prednisone. The following results were noted:
•Treatment with imlifidase produced complete cleavage of IgG into F(ab')2 and Fc fragments within six hours of infusion. Intact IgG remained absent in all patients for at least seven days, and there was a persistent reduction in IgG levels at 28 days after infusion.
•Patients in the Swedish study, who did not receive IVIG and rituximab following imlifidase, experienced DSA rebound beginning at 7 to 14 days after transplant. By contrast, patients in the United States study, who all received IVIG and rituximab following imlifidase, experienced less DSA rebound.
•Three of 11 patients (27 percent) in the Swedish study developed ABMR at a mean of two weeks after transplantation. Two of 14 patients (14 percent) in the United States study met Banff 2013 criteria for ABMR at two and five months after transplantation; an additional five patients had evidence of microvascular inflammation but no DSA.
•One patient in the United States study had hyperacute rejection immediately after revascularization. This was thought to be mediated by an IgM antibody as the patient did not have detectable DSA after imlifidase treatment.
•Mean estimated GFR (eGFR) at one to six months posttransplant was 49 mL/min/1.73 m2 in the Swedish study and 70 mL/min/1.73 m2 in the United States study.
A follow-up, phase II, multinational study further investigated the ability of imlifidase to convert a positive crossmatch test to negative among 19 highly sensitized kidney transplant recipients (median CPRA 99.83 percent) [31]. Of these, 13 received a deceased-donor kidney transplant, five received a living-donor transplant, and one patient was not transplanted after developing an infusion-related reaction to imlifidase. Imlifidase resulted in negative crossmatches in 17 of 19 patients (89 percent) within 24 hours after treatment. DSA rebound occurred in most patients between 3 and 14 days post imlifidase although MFI was generally lower than pretreatment levels. At six months posttransplant, patient and graft survival were 100 and 89 percent, respectively, and the median eGFR among the 16 patients with a functioning graft was 47 mL/min/1.73 m2. Rejection developed in 9 of 18 recipients (50 percent); of these, seven had ABMR.
Three-year outcomes were reported in an analysis that pooled patients from four open-label, phase II studies [32]. Among 39 patients who underwent a positive crossmatch kidney transplant, 15 (38 percent) experienced ABMR. Overall three-year graft survival was 84 percent; among patients who experienced ABMR, three-year graft survival was 93 percent compared with 77 percent among patients who did not experience ABMR. Among 13 patients with CPRA ≥99.9 percent who were considered unlikely to have been transplanted under conventional protocols and received a positive crossmatch deceased-donor allograft, three-year graft survival was comparable with that of the overall study population (92 percent). Seven of these 13 patients (54 percent) experienced ABMR within six months of transplant although none of the graft losses were attributed to ABMR.
Overall, the early experience with imlifidase is promising and indicates that its use can permit incompatible transplantation although a larger body of data is still needed.
●Clazakizumab – Clazakizumab is a humanized anti-IL-6 monoclonal antibody that was initially being developed as a treatment for rheumatoid arthritis but is presently being investigated as a treatment for chronic active ABMR in kidney transplantation. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection", section on 'Treatment of chronic antibody-mediated rejection'.)
The use of clazakizumab in HLA desensitization was evaluated in a pilot study of 20 highly sensitized patients (mean CPRA 96 percent) awaiting kidney transplantation who received plasmapheresis, high-dose IVIG, and clazakizumab 25 mg by subcutaneous injection monthly for six doses [33]. Transplanted patients continued to receive monthly clazakizumab until 12 months after transplant. Nearly all patients had a reduction in the sum MFI for both class I and class II HLA antibodies, enabling 18 patients to receive a deceased-donor kidney transplant (16 within 270 days of enrollment). Among transplanted patients, only one had a persistent DSA at months 6 and 12, and none of the patients who were DSA negative at transplant developed a de novo DSA. There were four cases of rejection (22 percent) and one graft loss due to surgical complications at transplant; no patients died. While these findings are promising, additional studies are needed to validate this single-center experience.
●Obinutuzumab – Obinutuzumab is a third-generation anti-CD20 monoclonal antibody. In contrast to rituximab, B cell death with obinutuzumab is less reliant on complement-dependent cytotoxicity and is mediated primarily through antibody-dependent cellular cytotoxicity. Both rituximab and obinutuzumab effectively deplete B cells in the peripheral blood; however, obinutuzumab more effectively depletes B cells in the secondary lymphoid organs and may have more lasting effects on memory B cells and plasma cells due to its mechanism of action.
The use of obinutuzumab for desensitization was evaluated in a trial of 25 highly sensitized kidney transplant candidates who received either a single infusion of obinutuzumab 1000 mg followed by IVIG 2 g/kg (maximum dose 140 g) at weeks 3 and 6 (n = 5) or obinutuzumab 1000 mg on days 1 and 15 and an optional 1000 mg dose at week 24 in addition to IVIG 2 g/kg at weeks 3 and 6 (n = 20) [34]. Of the 25 patients enrolled, eight received kidney transplants (seven of whom were desensitized with the multiple-dose regimen) and received additional obinutuzumab infusions at transplant and 24 weeks posttransplantation. Only 4 of 25 patients (16 percent) had statistically significant reductions in overall mean MFI from baseline, and MFI reductions in individual patients were inconsistent across alleles. Nevertheless, 14 of 24 patients (one patient was not included in efficacy analyses because of receipt of a transplant six days after obinutuzumab treatment) had a decrease in the number of unacceptable antigens, and 12 of 24 had lowering of their CPRA enabled by modest reductions in MFI. These findings suggest that obinutuzumab may be considered as a desensitization agent although its effect on HLA antibody reduction is mild.
Transplant immunosuppression
●Induction and early posttransplant immunosuppression – Recipients of an HLA-incompatible kidney transplant are considered to be at high risk for rejection and should receive lymphocyte-depleting antibodies (rATG-Thymoglobulin or alemtuzumab) for induction immunosuppression therapy. At our center, we prefer to administer alemtuzumab. However, alemtuzumab is not readily available to all medical centers that perform kidney transplantation. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Patients at high risk of rejection'.)
In addition to alemtuzumab, we administer immunomodulatory therapy with intravenous immune globulins (IVIG) and rituximab near the time of transplant.
•In living-donor transplant recipients, we complete pretransplant IVIG and rituximab desensitization therapy within one week of transplant (see 'Living-donor transplantation' above). We administer alemtuzumab 30 mg subcutaneously on the day of transplantation. We then give an additional course of IVIG 2 g/kg (maximum dose 140 g) within 7 to 14 days after transplant.
•In deceased-donor transplant recipients, we administer alemtuzumab 30 mg subcutaneously and IVIG 2 g/kg (maximum dose of 140 g) at the time of transplantation. We subsequently give an additional dose of IVIG 2 g/kg within 7 to 14 days after transplant. Rituximab 375 mg/m2 is also given within 7 to 14 days after transplant if it has not been received within six months of the transplant.
There are no high-quality data comparing different induction therapies among HLA-incompatible kidney transplant recipients. Our preference for alemtuzumab is based primarily upon our clinical experience with this agent in this patient population.
IVIG and rituximab are administered in addition to alemtuzumab to reduce or eliminate anti-HLA antibody rebound in the early posttransplant period. The effect of this treatment was shown in a report of two separate open-label trials evaluating the use of a streptococcal IgG endopeptidase (imlifidase) in HLA-incompatible kidney transplantation [30]. All patients received imlifidase just prior to transplant; in one trial, patients were given horse antithymocyte globulin as induction therapy, whereas in the second trial, patients were given alemtuzumab for induction but also received IVIG and rituximab before and after transplant. At one-month posttransplant, fewer patients who received IVIG and rituximab developed DSA rebound compared with those who did not. (See 'Investigational approaches' above.)
A discussion of the evidence for the use of alemtuzumab and rituximab as induction therapy is presented elsewhere. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Rituximab' and "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Alemtuzumab'.)
●Maintenance immunosuppression – In recipients of an HLA-incompatible kidney transplant, we administer a triple-therapy maintenance immunosuppression regimen starting on the day of transplant that includes a calcineurin inhibitor (tacrolimus), an antimetabolite (mycophenolate), and prednisone. This combination is similar to the initial maintenance immunosuppression used in most HLA-compatible kidney transplant recipients in the United States. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Approach to maintenance therapy'.)
Monitoring after transplantation — Following HLA desensitization and transplantation, patients are monitored using an approach that is similar to that used in recipients of HLA-compatible transplants. (See "Overview of care of the adult kidney transplant recipient", section on 'Routine follow-up and laboratory monitoring'.)
We monitor serum creatinine concentration and a urinalysis twice weekly for the first month posttransplant, then weekly for one month, then every two weeks for one month, and then every one to two months for the first year after transplantation. Given the increased risk for ABMR in HLA-incompatible transplant recipients, we perform a kidney allograft biopsy in all patients who develop graft dysfunction suspicious for rejection. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction", section on 'Allograft dysfunction >1 week posttransplantation'.)
In addition, we routinely monitor DSA levels monthly for the first three months posttransplant; then at months 6, 9, and 12; and annually thereafter. Patients with persistent or de novo DSAs should be evaluated with a kidney allograft biopsy to exclude the possibility of ABMR. DSA testing in the early posttransplant period may not be entirely reliable, however, since the recent administration of IVIG can result in false-positive results due to nonspecific binding of antibody to single-antigen (Luminex) beads. This effect of IVIG becomes negligible by approximately two months after transplant. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection", section on 'Prevention'.)
OUTCOMES OF HLA-INCOMPATIBLE TRANSPLANTATION
Patient and graft survival — It is often a difficult decision to proceed with an HLA-incompatible kidney transplant rather than to wait longer for a more suitable donor, especially given the excess in mortality observed among patients on dialysis compared with those receiving a transplant [35]. In virtually all patient populations, the long-term risk of death is lower with kidney transplant compared with dialysis [36-40]. In a large multicenter study of 1025 recipients of an HLA-incompatible living-donor kidney transplant, there was higher short- and long-term (up to eight years) patient survival among recipients of an HLA-incompatible transplant compared with waitlisted matched controls [41]. These findings were consistent among recipients who had a positive Luminex assay/negative flow cytometric crossmatch, positive flow cytometric crossmatch, or positive cytotoxic crossmatch.
In our experience, patient and graft survival are comparable between highly sensitized recipients administered desensitization before transplant and less sensitized recipients not receiving pretransplant desensitization. In an analysis of 910 deceased-donor and living-donor transplant recipients (372 of whom received pretransplant desensitization because of HLA sensitization or ABO-incompatible transplantation), there was no difference in graft or patient survival up to 60 months between HLA-sensitized recipients of pretransplant desensitization and lower immunologic risk recipients [42].
Overall, however, an increasing degree of incompatibility is associated with a higher risk of graft loss and death. Patients with donor-specific antibody (DSA) but a negative crossmatch were observed to have a similar risk of death or graft loss compared with compatible recipients; by contrast, a positive flow or cytotoxic crossmatch was associated with a 1.65- and 1.80-fold higher risk of graft loss and a 1.32- and 1.51-fold higher risk of death compared with compatible recipients [5]. In this study, five-year unadjusted graft loss was 17, 20, 29, and 40 percent for compatible recipients, recipients with DSA but a negative flow crossmatch, recipients with a positive flow crossmatch but negative cytotoxic crossmatch, and recipients of a positive cytotoxic crossmatch kidney transplant, respectively. Five-year unadjusted mortality was 9, 10, 13, and 19 percent for compatible recipients, recipients with DSA but a negative flow crossmatch, recipients with a positive flow crossmatch but negative cytotoxic crossmatch, and recipients of a positive cytotoxic crossmatch kidney transplant, respectively.
Costs of HLA-incompatible transplant — The costs of HLA-incompatible kidney transplantation are higher than those of HLA-compatible kidney transplantation, not only due to the use of injectable medications with or without plasmapheresis for the desensitization procedure, but also due to longer hospitalizations, more frequent biopsy procedures, and higher rejection rates. The mean organ acquisition cost of an HLA-incompatible living-donor kidney transplant was reported to be USD $151,024 compared with USD $106,306 for matched controls; higher degrees of incompatibility (DSA with negative flow crossmatch, positive flow but negative cytotoxic crossmatch, and positive cytotoxic crossmatch) were associated with incrementally higher unadjusted costs [43]. After adjustment for differences in baseline recipient and donor characteristics between the incompatible and matched control groups, however, there was no significant difference in cost associated with transplantation with DSA and negative flow crossmatch and transplantation with positive flow but negative cytotoxic crossmatch. Transplantation across a positive cytotoxic crossmatch was associated with a higher cost compared with transplantation with DSA and negative flow crossmatch and transplantation with positive flow but negative cytotoxic crossmatch.
COMPLICATIONS OF HLA-INCOMPATIBLE TRANSPLANTATION
Rejection — Recipients of HLA-incompatible transplantation are inherently at higher immunologic risk compared with patients who receive a compatible transplant. In a study of 1406 HLA-incompatible and 17,542 HLA-compatible living-donor recipients from 25 transplant centers across the United States, the rate of acute rejection was higher among HLA-incompatible recipients (21 versus 8 percent) [44]. The risk of rejection increased in parallel with the degree of incompatibility, with acute rejection observed in 18 percent of patients with a donor-specific antibody (DSA) but a negative flow cytometry crossmatch, 21 percent of those with a positive flow but negative cytotoxic crossmatch, and 22 percent of those with a positive cytotoxic crossmatch. The increased rate of rejection is mostly attributed to an elevated risk for antibody-mediated rejection (ABMR) [42].
Infection — Although there are key differences between ABO-incompatible and HLA-incompatible transplants, both have similarities in their use of pretransplant desensitization. Given the limited data on infection-related complications in HLA-incompatible recipients, data from the ABO-incompatible population are often extrapolated to the HLA-incompatible population. The reported rates of infection vary by patient population. In some studies, the rate of infections overall is not higher than those in average transplant recipients. As an example, a retrospective analysis of 361 kidney transplant recipients compared infectious outcomes between patients who received rituximab and high-dose intravenous immune globulins (IVIG) for desensitization prior to HLA- or ABO-incompatible transplant and a group of nonsensitized, ABO-compatible transplant recipients [45-47]. All patients received similar antimicrobial prophylaxis and viral surveillance. After an average of 18 months, there were no significant differences in the rates of bacterial, viral, fungal, and serious infections between the two groups. (See "Kidney transplantation in adults: ABO-incompatible transplantation", section on 'Pretransplant ABO desensitization'.)
However, infection remains an important cause of death in the desensitized population:
●A cohort study from the Korean Organ Transplantation Registry study group reported clinical outcomes among 1964 living-donor recipients, including 248 ABO-incompatible recipients, 144 HLA-incompatible recipients, and 31 ABO- and HLA-incompatible recipients [48]. Among recipients of an incompatible transplant, infection was the most common cause of death (8 of 9 deaths [89 percent]). By comparison, only 3 of 11 (27 percent) deaths in the compatible group were attributed to infection.
●In an analysis of 1420 ABO-incompatible living-donor kidney transplant recipients from 101 European transplant centers reported to the Collaborative Transplant Study between 2005 to 2012, there was a significantly higher rate of death from infection in the first year posttransplant among recipients of an ABO-incompatible versus ABO-compatible transplant [49]. However, the absolute risk difference was small, approximating 1 percent. In addition, an adjusted analysis to account for differences in baseline characteristics between the groups was not performed, and, therefore, it cannot be concluded whether the difference in infection-related death between ABO-incompatible and ABO-compatible recipients was attributable to desensitization versus other factors.
Before beginning desensitization, we vaccinate against encapsulated organisms such as meningococcus and pneumococcus in preparation for the possibility that a patient might require complement inhibition (ie, eculizumab) as rescue therapy for ABMR after transplant. In addition, we follow American Society of Transplantation pre- and posttransplant vaccine guidelines for all patients, including but not limited to vaccines against coronavirus 2019 (COVID-19), hepatitis B, and varicella [50]. Importantly, we have observed that patients treated with anti-CD20 monoclonal antibodies did not develop antibody responses to COVID-19 vaccination; however, they did develop robust T cell responses, which, we feel, afforded protection against severe infection in these patients [51].
There is minimal effect of vaccines on HLA sensitization [52-56], and we do not alter the desensitization or HLA antibody monitoring schedule because of vaccination.
In all recipients of an HLA-incompatible transplant, we administer antimicrobial and antiviral prophylaxis with a regimen that is identical to that administered to recipients of an HLA-compatible transplant. This includes prophylaxis against Pneumocystis pneumonia (PJP), cytomegalovirus (CMV) infection and disease, and herpes simplex infection (in patients who are at low CMV risk). In addition, we also administer antifungal prophylaxis although this practice may vary by transplant center. A detailed discussion of the different prophylactic regimens is presented separately:
●(See "Prophylaxis of infections in solid organ transplantation", section on 'Pneumocystis pneumonia'.)
●(See "Prophylaxis of infections in solid organ transplantation", section on 'Antifungal prophylaxis'.)
Malignancy — Studies evaluating malignancy risk in HLA-incompatible kidney transplantation are limited, and data from the ABO-incompatible transplant population are generally extrapolated to the HLA-incompatible transplant population. Most studies have found that ABO-incompatible recipients do not have an increased risk of malignancy compared with ABO-compatible transplant patients. In one single-center study of 69 ABO-incompatible, 27 HLA-incompatible, and 10 ABO- and HLA-incompatible living-donor kidney transplant recipients, malignancies were uncommon overall, and their incidence was not significantly different between the three groups [57]. (See "Kidney transplantation in adults: ABO-incompatible transplantation", section on 'Malignancy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●Overview – A significant number of kidney transplant candidates with otherwise suitable living donors are relegated to the deceased-donor waiting list because of preformed human leukocyte antigen (HLA) antibodies. These are acquired via pregnancy, transfusion, or prior transplant. The presence of these anti-HLA antibodies in the potential recipient's blood is called HLA sensitization. Although transplanting against preformed HLA antibodies is associated with an increased risk of antibody-mediated rejection (ABMR) and allograft loss, desensitization protocols designed to reduce the amount of preexisting antibody to a level that allows for successful engraftment may permit transplantation in select recipients. (See 'Introduction' above.)
●Assessment of patient sensitization – The degree of HLA sensitization of a potential transplant recipient is first determined at the time of initial transplant evaluation by testing patient sera against solubilized HLA antigens attached to solid beads. HLA sensitization is reported as the calculated panel reactive antibody (CPRA), which is computed based upon the patient's unacceptable antigens. There is no standard CPRA threshold that defines allosensitization. At our center, patients who have a CPRA ≥30 percent or who are seeking a retransplant are considered to be sensitized and potentially qualify for desensitization. (See 'Assessment of patient sensitization' above.)
●Approach to the sensitized transplant candidate – Once the extent of patient sensitization has been established, the need for desensitization prior to transplantation is determined. Our approach varies depending upon whether or not the transplant candidate has a potential living donor (algorithm 1). (See 'Approach to the sensitized transplant candidate' above.)
●Approach to HLA-incompatible transplantation – Approaches to HLA-incompatible transplantation vary among transplant centers and are usually institution specific. There are no high-quality data in the form of randomized controlled trials comparing existing desensitization approaches, and the optimal therapy is undefined. The approach used at our center is as follows (see 'Approach to HLA-incompatible transplantation' above):
•Pretransplant desensitization – For most transplant candidates who qualify for HLA desensitization, we suggest pretransplant desensitization with high-dose intravenous immune globulins (IVIG) and rituximab rather than high-dose IVIG alone or other desensitization regimens (Grade 2C). Our center-specific protocols for living-donor and deceased-donor transplantation are detailed above. (See 'Living-donor transplantation' above and 'Deceased-donor transplantation' above.)
•Transplant immunosuppression – Recipients of an HLA-incompatible kidney transplant are considered to be at high risk for rejection and should receive lymphocyte-depleting antibodies (rabbit antithymocyte globulin [rATG]-Thymoglobulin or alemtuzumab) for induction immunosuppression therapy. At our center, we prefer to administer alemtuzumab. However, alemtuzumab is not readily available to all medical centers that perform kidney transplantation. In addition to alemtuzumab, IVIG and rituximab are also administered near the time of transplant to reduce or eliminate anti-HLA antibody rebound in the early posttransplant period. Maintenance immunosuppression is similar to that used in most HLA-compatible kidney transplant recipients. (See 'Transplant immunosuppression' above.)
•Posttransplant monitoring – Following HLA desensitization and transplantation, patients are monitored using an approach that is similar to that used in recipients of HLA-compatible transplants. In addition, we routinely monitor donor-specific antibody (DSA) levels monthly for the first three months posttransplant; then at months 6, 9, and 12; and annually thereafter. Patients with persistent or de novo DSAs should be evaluated with a kidney allograft biopsy to exclude the possibility of ABMR. (See 'Monitoring after transplantation' above.)
●Outcomes – In our experience, patient and graft survival are comparable between highly sensitized recipients administered desensitization before transplant and less sensitized recipients not receiving pretransplant desensitization. Overall, however, an increasing degree of incompatibility is associated with a higher risk of graft loss and death. (See 'Outcomes of HLA-incompatible transplantation' above.)
●Complications – Complications of HLA-incompatible transplantation include a higher risk of acute rejection, mostly due to ABMR. Data on infection-related complications in this population are limited, with some studies showing similar rates of overall infections compared with average transplant recipients. (See 'Complications of HLA-incompatible transplantation' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Christina L Klein, MD, who contributed to an earlier version of this topic review.
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