INTRODUCTION — Antibody-mediated rejection (ABMR) is the most common cause of allograft failure after kidney transplantation [1-4]. The revised Banff 2017 classification of ABMR defines active (previously called acute) and chronic active ABMR as conditions in which histologic evidence of acute and chronic injury is associated with evidence of current/recent antibody interaction with vascular endothelium and serologic evidence of donor-specific antibodies (DSA) to human leukocyte antigen (HLA) or non-HLA antigens [5].
The cellular and molecular pathways that regulate ABMR are still under investigation. However, evidence suggests that B cell and plasma cell activation results in the generation of DSAs, which bind to HLA or non-HLA molecules expressed on endothelial cells within the renal allograft [6,7]. In active ABMR, antibodies bind to graft endothelium and activate complement-dependent and -independent mechanisms that recruit natural killer (NK) cells, polymorphonuclear neutrophils, platelets, and macrophages, which contribute to peritubular capillaritis, glomerulitis, cellular necrosis, thrombotic microangiopathy, and a relatively rapid decline in allograft function [6-8].
Chronic ABMR, on the other hand, is a distinct pathophysiological process resulting from a repetitive pattern of thrombotic events and inflammatory changes that lead to endothelial cell injury and allograft matrix remodeling [9,10]. It manifests histologically as transplant glomerulopathy and results in a slow and progressive decline in kidney function [11].
Increasing evidence suggests that the prevention and treatment of antibody-mediated injury requires a combination of strategies to inhibit B cell development, maturation, and activity. Despite a relatively large number of observational studies, it is not clear which combination therapy is the safest and most effective.
The prevention and treatment of active and chronic ABMR of the renal allograft will be reviewed here. The clinical features and diagnosis of ABMR and the treatment of acute T cell-mediated (cellular) rejection (TCMR) are discussed separately:
PREDICTORS OF OUTCOME — Active and chronic ABMR are both associated with poor outcomes after kidney transplantation. Patients with active ABMR are at increased risk for subsequent rejection, chronic ABMR, and graft loss [1,12-15]. Similarly, those with chronic ABMR have a higher risk for graft loss and patient death [1-3,16,17]. However, not all patients with ABMR have poor outcomes, and many patients maintain stable allograft function for years after treatment of the initial episode of rejection. Risk factors for graft loss in patients with ABMR are discussed below.
Histologic features — Some histopathological features on the kidney biopsy at the time of rejection are associated with worse outcomes. As an example, concurrent, acute T cell-mediated (cellular) rejection (TCMR) is an independent risk factor for graft failure in patients with ABMR [18]. There is also a clear and independent association between microvascular injury and C4d staining (including focal C4d staining in post-reperfusion biopsies) with poor outcomes in active or chronic ABMR [19-22]. Similarly, transplant glomerulopathy and the degree of chronic injury (measured semiquantitatively by adding chronic interstitial, tubular, vascular, and glomerular Banff scores) are associated with worse graft survival [16,23-25].
Donor-specific antibodies — Certain characteristics of donor-specific antibodies (DSAs) have been associated with poor outcomes among patients with ABMR. As examples:
●DSA strength – In a study of 402 consecutive, deceased-donor kidney transplant recipients, the risk for both ABMR and graft loss directly correlated with peak preexisting anti-human leukocyte antigen (HLA) DSA strength, as measured by mean fluorescence intensity (MFI) [26]. Patients with a peak anti-HLA DSA MFI of >6000 had a more than 100-fold higher risk for developing ABMR compared with those with an MFI of <465. Graft survival in patients with a peak anti-HLA DSA MFI of >3000 was lower than that of patients with an MFI of ≤3000. However, in the absence of biopsy-proven rejection and acute inflammation, HLA DSA may not be associated with an increased risk of graft failure [27].
●DSA subclass – The immunoglobulin subclass of DSA may also predict outcomes. In a study of 125 patients with DSAs detected in the first year posttransplant, immunoglobulin G4 (IgG4) immunodominant DSA was associated with later allograft injury, increased allograft glomerulopathy, and interstitial fibrosis/tubular atrophy (IF/TA) [28]. By contrast, IgG3 immunodominant DSA was associated with a shorter time to rejection, increased microvascular injury, C4d capillary deposition, and graft failure. These findings suggest that IgG immunodominant DSA subclasses may identify distinct phenotypes of renal allograft antibody-mediated injury.
●Complement-binding capacity – The ability of anti-HLA DSAs to bind complement, as determined by the C1q assay, may identify patients at high risk for renal allograft loss [29]. However, one study showed that the C1q-binding activity of DSAs largely reflects differences in antibody strength, questioning the biologic significance of the C1q assay [30].
●DSA type – The type of DSA (preexisting or de novo) may also be a predictor of worse outcomes in patients with ABMR. ABMR in patients with a de novo DSA, which is thought to be mostly related to medication nonadherence or inadequate immunosuppression, has been associated with poorer outcomes compared with ABMR in patients with preexisting DSA (ie, presensitized patients) [1,25,31-33].
●DSA response to treatment – There is accumulating evidence indicating that a decline in DSA strength after treatment is associated with better graft survival [25,34,35]. However, there is limited information on the definition of a validated positive DSA response.
Graft function — The degree of renal allograft dysfunction at the time of kidney biopsy appears to be directly associated with poor outcomes in patients with ABMR [16,22,31,36]. As an example, in a retrospective analysis of 205 patients with biopsy-proven ABMR, an estimated glomerular filtration rate (eGFR) of <30 mL/min per 1.73 m2 at diagnosis and a urine protein-to-creatinine ratio of ≥0.30 g/g at the time of biopsy were identified as independent determinants of allograft loss (hazard ratio [HR] 3.27 and 2.44, respectively) [31]. In another study of 123 patients with chronic ABMR, a serum creatinine of >3 mg/dL and urine protein-to-creatinine ratio of >1 g/g at the time of diagnosis were independently associated with graft loss [16]. Other observational studies have reported similar findings among patients with active and chronic ABMR [22,36].
Other risk factors — The expression of endothelial cell-associated transcripts (ENDATs) and DSA-selective transcripts has been shown to be a biomarker of active antibody-mediated injury and may predict worse graft outcomes [23,37]. These molecular assays, which are not yet in mainstream clinical practice, reflect changes in microcirculatory endothelium not normally detected by routine histopathology and DSA testing and may improve risk stratification and prognostication in patients with ABMR.
Prediction models — Novel prediction models are being developed to predict long-term kidney allograft failure, including after the treatment of rejection [38]. Using an international cohort study including 7557 kidney transplant recipients from 10 academic medical centers from Europe and the United States, 32 candidate prognostic factors for kidney allograft survival were assessed. Of these, eight functional, histologic, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% CI 0.79-0.83). The iBox system showed accuracy when assessed at different times of evaluation posttransplant and was validated in different clinical scenarios including response to rejection therapy, suggesting that the iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials [38].
PREVENTION — Our approach to the prevention of ABMR depends upon the detection of donor-specific antibody (DSA) prior to (preexisting DSA) or after (de novo DSA) transplant.
Patients with preexisting DSA before transplant — Patients with a preexisting DSA prior to transplant have a greater risk for ABMR and graft loss compared with nonsensitized patients [39-41]. This risk is proportional to the strength of DSA as patients with a positive complement-dependent cytotoxicity (CDC) crossmatch have a higher risk of ABMR and graft loss than those with a positive flow crossmatch, who in turn have a higher risk than patients with a positive virtual crossmatch [39,40,42].
Although a common approach to prevent ABMR has been to avoid transplanting highly sensitized patients, this option renders chronic dialysis the only therapeutic option, with significant implications for patient health and quality of life and health care costs. Long-term survival in kidney transplant recipients has improved considerably with desensitization [43,44], which can be used to reduce the level of DSAs pretransplant. In addition, the enrollment of patients in special programs to optimize matching can lead to timely transplants with better outcomes. (See "Kidney transplantation in adults: HLA desensitization" and "Kidney transplantation in adults: Living unrelated donors", section on 'Kidney paired donation'.)
Our general approach to the prevention of ABMR in patients with a preexisting DSA prior to transplant is as follows:
●In patients with a potential living donor, the approach depends upon the results of the most recent crossmatch:
•In patients with a positive CDC crossmatch or a strongly positive flow crossmatch, we, and many other transplant centers, prefer to use kidney paired donation (KPD) programs, rather than desensitization, given the high risk of ABMR and graft loss in such patients [45-47]. Such KPD programs (including the National Kidney Registry, the Alliance for Paired Donation, and the United Network for Organ Sharing [UNOS] Kidney Paired Donations Pilot Program) enable sensitized patients with immunologically incompatible living donors to be transplanted with high-quality grafts from other living donors in similar situations who are willing to exchange organs. Although cost has been a concern for kidney exchange registries in the United States, KPD could help participating centers to avoid complex desensitization protocols while improving long-term outcomes. Mathematical modeling has predicted that an optimized matching algorithm and a national KPD program would improve graft outcomes and reduce health care costs for highly sensitized patients [48]. Some transplant centers combine desensitization and KPD.
•In patients with a positive virtual crossmatch or a mild-to-moderate flow crossmatch (ie, median channel shift of <250), we employ human leukocyte antigen (HLA) desensitization strategies, which include treatment with plasmapheresis, rabbit antithymocyte globulin (rATG)-Thymoglobulin, and rituximab [20,42]. This is discussed in more detail elsewhere. (See "Kidney transplantation in adults: HLA desensitization".)
●In patients without a potential living donor, we employ HLA desensitization strategies. (See "Kidney transplantation in adults: HLA desensitization".)
●In all patients with a preexisting DSA before transplant who undergo kidney transplantation, we use induction and maintenance immunosuppression therapies that are appropriate for patients at high risk for the development of acute rejection [49]. The selection of induction and maintenance immunosuppression in high-risk kidney transplant recipients is discussed elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Initial maintenance immunosuppression in high-risk patients' and "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Patients at high risk of rejection'.)
Monitoring after transplant — The monitoring of renal allograft function in patients with a preexisting DSA before transplant is similar to that performed in nonsensitized patients (see "Kidney transplantation in adults: Overview of care of the adult kidney transplant recipient", section on 'Monitoring kidney allograft function'). In addition, we routinely monitor DSA levels at months 1, 3, 6, and 12 posttransplant and then annually [50]. In patients with a significant rise in DSA or who develop a de novo DSA within the first three months, we perform a renal allograft biopsy. This practice is largely consistent with the recommendations of the Consensus Guidelines on the Testing and Clinical Management Issues Associated with HLA and Non-HLA Antibodies in Transplantation [50]. Patients with a pretransplant DSA undergo protocol kidney biopsies at months 3 and 12 posttransplant.
Some UpToDate contributors to this topic perform a post-reperfusion renal allograft biopsy at the time of transplantation to identify patients at risk for ABMR [20]. In patients who are found to have evidence of positive C4d staining, plasmapheresis (two to three sessions) and a single dose of rituximab 375 mg/m2 (administered after the last session of pheresis) would be added to the induction immunosuppression regimen [20].
Patients with de novo DSA after transplant — Kidney transplant recipients who develop a de novo DSA after transplantation can present with late-onset ABMR. As mentioned above, ABMR in patients with a de novo DSA has been associated with poorer outcomes compared with ABMR in patients with preexisting DSA (see 'Donor-specific antibodies' above). The two most common causes of ABMR due to a de novo DSA are medication nonadherence and inadequate immunosuppression, the latter of which is frequently attributed to the use of minimization strategies. In addition, acute T cell-mediated (cellular) rejection (TCMR), malignancy, and opportunistic infections (such as BK polyomavirus and cytomegalovirus [CMV] infection) that require a reduction in immunosuppression may also influence the development of late-onset ABMR [1,2,51,52].
Prevention of ABMR should focus on addressing nonadherence and under-immunosuppression while balancing the safety and efficacy of long-term immunosuppression. We maintain the majority of our patients on a triple therapy immunosuppression regimen (tacrolimus, mycophenolate, and prednisone) and monitor whole blood tacrolimus levels monthly in the first three years posttransplant and every three months thereafter. In patients who do not tolerate tacrolimus, we switch to belatacept, rather than sirolimus or everolimus. We monitor DSA annually and perform renal allograft biopsies in all patients who develop a de novo DSA.
●(See "Psychiatric aspects of organ transplantation", section on 'Nonadherence'.)
An analysis of two randomized trials showed that the conversion of cyclosporine to everolimus at 3 to 4.5 months after transplant was associated with significantly higher rates of de novo DSA (10.8 versus 23 percent) and ABMR (3 versus 13 percent) [53]. By contrast, treatment with belatacept, a selective costimulation blocker that targets the CD80/CD86-CD28 interaction to prevent T cell activation, was associated with a low rate of de novo DSA over seven years of treatment in phase III trials, although this was not an initial endpoint of those studies [54]. Although there has been no head-to-head comparison between tacrolimus and belatacept, these data suggest that costimulation blockade may be safe and effective in preventing de novo DSA and late ABMR. Similarly, glucocorticoid withdrawal or avoidance may not increase the risk of de novo DSA if adequate immunosuppression is otherwise maintained, although this is difficult to standardize. In a five-year, longitudinal study, 37 kidney transplant recipients were randomly assigned to chronic glucocorticoid therapy or early glucocorticoid withdrawal at day 7 posttransplant; all patients received rATG-Thymoglobulin for induction and tacrolimus and mycophenolate as maintenance immunosuppression [55]. Only one patient in the chronic glucocorticoid treatment arm and none in the glucocorticoid withdrawal arm developed a de novo DSA.
TREATMENT OF ACTIVE ANTIBODY-MEDIATED REJECTION — The primary goal of treating ABMR is to remove existing donor-specific antibodies (DSAs) and to eradicate the clonal population of B cells or plasma cells that is responsible for their production. In general, we treat all patients who have evidence of active ABMR on biopsy. Although we do not routinely perform surveillance or protocol allograft biopsies at our institution, we would treat patients who are discovered to have subclinical ABMR by surveillance biopsy. In addition, we treat patients with C4d-negative ABMR with the same approach that we use in patients with C4d-positive ABMR.
●(See 'Patients with subclinical rejection' below.)
●(See 'Patients with C4d-negative ABMR' below.)
The optimal treatment of active ABMR is unclear, and there have been no randomized, controlled trials with adequate statistical power to compare the safety and efficacy of different therapeutic strategies [56]. Our recommendations for the treatment of ABMR are primarily based upon available, low-quality evidence and are largely consistent with the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines and the 2019 Transplantation Society Working Group Expert Consensus [57,58].
Approach to initial therapy — Although patients with active ABMR could possibly be treated on an outpatient basis, we typically advocate inpatient admission for patients because of the complexity of the treatment regimen. Our approach to the initial treatment of active ABMR depends upon the timing of the diagnosis of ABMR (algorithm 1):
●In patients who are diagnosed with active ABMR within the first year posttransplant, we treat with a combination of glucocorticoids, plasmapheresis and intravenous (IV) immune globulin (IVIG), and, in some patients, rituximab as follows:
•We give IV methylprednisolone at a dose of 300 to 500 mg daily for three to five days, followed by a rapid oral prednisone taper to the patient's previous maintenance dose of prednisone. If there are no concerns for nonadherence, we augment the maintenance prednisone dose. As an example, if the rejection occurred while the patient was taking 5 mg/day, we would increase the maintenance prednisone to 7.5 to 10 mg/day.
•Plasmapheresis is performed daily or every other day for a maximum of six sessions or until the serum creatinine is within 20 to 30 percent of the baseline. The initial treatment is typically a one-and-one-half-volume exchange with albumin, and subsequent treatments are a one-volume exchange with albumin. We prefer an every-other-day plasmapheresis schedule as albumin alone can often be administered for replacement with interval recovery of the prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen to acceptable levels without the need to administer fresh frozen plasma. This avoids the risk of antigen sensitization; however, one to two units of fresh frozen plasma may be used for replacement at the end of a plasmapheresis treatment if indicated by preprocedure laboratory values or in the appropriate clinical setting, such as a same-day renal allograft biopsy. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
•We administer IVIG at a dose of 100 mg/kg after each session of plasmapheresis. We typically give 500 mg/kg per day for one to two days after the final session of plasmapheresis, with a total cumulative target dose of at least 1000 mg/kg of IVIG. In obese patients, some centers determine the IVIG dose based upon the patient's ideal body weight (calculator 1). Sucrose-free IVIG solutions that are no more than 5 percent concentrated are preferred to decrease the risk of acute kidney injury. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects", section on 'Acute kidney injury'.)
•In patients with evidence of microvascular inflammation on biopsy (ie, Banff glomerulitis score [g] + peritubular capillary score [ptc] >0), we administer rituximab as a single dose of 200 to 375 mg/m2 after completion of plasmapheresis and IVIG [59].
•In addition, we augment other components of maintenance immunosuppression as needed. This is discussed elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Patients with acute rejection'.)
●In patients who are diagnosed with active ABMR after the first year posttransplant, we treat with glucocorticoids using the same approach as described above in patients diagnosed with ABMR within the first year posttransplant. However, we do not perform plasmapheresis in such patients because of the lack of evidence supporting the safety and efficacy of plasmapheresis in late-onset ABMR. We administer IVIG at a dose of 200 mg/kg every two weeks for three doses. In obese patients, some centers determine the IVIG dose based upon the patient's ideal body weight (calculator 1). Sucrose-free IVIG solutions that are no more than 5 percent concentrated are preferred to decrease the risk of acute kidney injury. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects", section on 'Acute kidney injury'.)
In patients with evidence of microvascular inflammation on biopsy, we administer rituximab as a single dose of 375 mg/m2 after completion of IVIG. We also augment maintenance immunosuppression. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Patients with acute rejection'.)
In all patients who are treated for active ABMR, we recommence antimicrobial and antiviral prophylaxis with a regimen that is identical to that administered in the immediate posttransplant period. This includes prophylaxis against Pneumocystis pneumonia (PCP), cytomegalovirus (CMV) infection and disease, and herpes simplex infection (in patients who are at low CMV risk) for three months. In addition, we also administer antifungal prophylaxis and a prophylactic histamine-2 (H2) blocker for prevention of peptic ulcer disease, 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'.)
We do not routinely use immunoadsorption, bortezomib, tocilizumab, eculizumab, or splenectomy in the initial treatment of patients with ABMR. However, some of these therapies can be considered in patients who do not respond to initial treatment. (See 'Second-line agents in patients who have failed initial therapy' below and 'Less frequently used therapies' below.)
As mentioned above, there is a lack of high-quality evidence in the form of large, randomized, controlled trials to guide the optimal therapy of patients with active ABMR. The best data come from the following studies:
●A systematic review that included five randomized and seven nonrandomized, controlled trials evaluated the effects of different treatments on graft survival among kidney transplant recipients with active ABMR [60]. All of the randomized trials were small (median of 13 patients per treatment arm), and most were conducted using outdated diagnostic criteria for ABMR. Four randomized, controlled trials assessed the benefit of plasmapheresis; one study reported a benefit, one suggested potential harm, and two showed no effect. However, the plasmapheresis regimen differed in dose, frequency, and treatment interval among the studies, and IVIG was not administered. One randomized, controlled trial found a benefit with the use of protein immunoadsorption (see 'Immunoadsorption' below). The nonrandomized, controlled studies suggested a potential benefit from treatment with rituximab, plasmapheresis, and bortezomib; however, because some studies used a combination of these therapies, the effect of individual therapies could not be distinguished.
●A phase III, multicenter, randomized, placebo-controlled trial (Impact of Treatment With Rituximab on the Progression of Humoral Acute Rejection After Renal Transplantation [RITUX ERAH]) examined the effect of rituximab among 38 kidney transplant recipients with biopsy-proven, active ABMR [61]. Patients were randomly assigned to rituximab (375 mg/m2) or placebo at day 5 of treatment; all patients were treated with plasmapheresis, IVIG, and glucocorticoids. There was no difference between the two groups in the frequency of the primary endpoint, defined as a composite measure of graft loss or absence of improvement in kidney function at day 12 (52.6 and 57.9 percent of patients in the rituximab and placebo groups, respectively). Both groups showed an improvement in histologic features of ABMR and Banff scores at one and six months, with a trend in favor of the rituximab group. Although both groups showed a decrease in DSA intensity as early as day 12, there was no difference between the groups at 12 months. However, it should be noted that this study was underpowered, and significant differences between the groups may have been missed.
●The benefit of a combination therapy including plasmapheresis, IVIG, and rituximab was suggested by an observational study from France that compared the efficacy of plasmapheresis/IVIG/rituximab versus high-dose IVIG alone in the treatment of ABMR [62]. Graft survival at 36 months was 92 percent among patients treated with plasmapheresis/IVIG/rituximab versus 50 percent of those treated with IVIG alone. At three months posttreatment, DSAs were significantly lower in the plasmapheresis/IVIG/rituximab group. Another study confirmed that patients with active clinical or subclinical ABMR in the first year posttransplant have better outcomes if treated with a combination strategy including plasmapheresis [63].
Monitoring the response to therapy — Our approach to monitoring patients during therapy for active ABMR depends upon whether the patient is hospitalized for treatment or treated as an outpatient. As mentioned above, patients with active ABMR can be treated on an outpatient basis, but we typically advocate inpatient admission for patients given the complexity of the treatment regimen.
In patients who are treated in the outpatient setting, we monitor serum creatinine, electrolytes, and a complete blood count prior to each plasmapheresis session or on a weekly basis for four weeks if plasmapheresis is not performed. Patients who receive plasmapheresis are seen and evaluated during plasmapheresis sessions and then in the clinic at four weeks from the start of therapy; those who do not receive plasmapheresis undergo weekly labs for one month and monthly thereafter. All patients are seen for follow-up in the clinic at three months from the start of treatment, at which time we measure a DSA level and repeat a renal allograft biopsy if a biopsy has not been performed earlier in the course of treatment [59].
Data on the reversal of ABMR are limited [4,59,63]. In general, one-year graft survival after treatment of clinical and subclinical ABMR is approximately 80 and 95 percent, respectively [63]. Patients are considered to have a successful reversal of ABMR if they meet all of the following parameters within three months of treatment:
●Decrease in serum creatinine to within 20 to 30 percent of the baseline level
●Decrease in proteinuria to the baseline level
●Decrease in immunodominant DSA by >50 percent
●Resolution of changes associated with ABMR on repeat kidney biopsy (see "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'Histologic findings')
Most patients with ABMR with a successful response to anti-rejection therapy will demonstrate an improvement in serum creatinine within seven days of treatment. Our subsequent approach to treatment is based upon the response to initial therapy:
●In patients with a decrease in serum creatinine in response to therapy, we increase the maintenance tacrolimus dose to achieve a trough level 20 to 25 percent above the level at the time of rejection and resume routine monitoring of allograft function. For patients who are taking the immediate-release formulation of tacrolimus and cannot tolerate higher doses, extended-release tacrolimus, which has fewer side effects and may allow for a higher and therapeutic trough to be obtained, is an alternative option [64]. Typically, maintenance immunosuppression is also augmented by increasing the daily dose of oral prednisone. (See "Kidney transplantation in adults: Overview of care of the adult kidney transplant recipient", section on 'Monitoring kidney allograft function' and "Pharmacology of cyclosporine and tacrolimus", section on 'Switching formulations'.)
●Patients without any decrease in serum creatinine after seven days of rejection treatment are considered to have failed initial treatment. In such patients, ongoing rejection and/or another cause of renal allograft dysfunction should be suspected, and a repeat renal allograft biopsy should be performed. Our subsequent approach depends upon the histopathological and clinical findings of the patient. If the biopsy reveals no evidence of an acute, reversible process or reveals extensive fibrosis (indicating nonviable kidney tissue), we typically discontinue treatment of acute rejection. If the biopsy demonstrates evidence of persistent active ABMR, second-line agents for the treatment of ABMR can be used as rescue therapy (see 'Second-line agents in patients who have failed initial therapy' below and 'Less frequently used therapies' below). However, the intensity of additional therapy with plasmapheresis and other agents such as bortezomib and anti-complement therapy should be weighed against preexisting comorbidities and the risk of infectious and malignant complications.
Second-line agents in patients who have failed initial therapy — Most patients with active ABMR will respond to a combination of glucocorticoids, plasmapheresis, IVIG, and rituximab. However, in patients who do not respond to initial treatment with this combination, the following agents can be considered as rescue therapy.
Bortezomib — Bortezomib is a potent, reversible proteasome inhibitor that has been approved by the US Food and Drug Administration (FDA) as first-line therapy for multiple myeloma since 2008. Bortezomib reduces intracellular protein degradation by inhibiting proteasomal activity and results in apoptosis, mainly via inhibition of nuclear factor kappa-B (NFkB)-induced survival signals. The drug is particularly effective against differentiated plasma cells because of the high rate of protein synthesis in these cells [65,66]. (See "Multiple myeloma: Selection of initial chemotherapy for symptomatic disease".)
Several case reports/series have demonstrated the effectiveness of bortezomib in treating ABMR, successfully reversing acute rejection, and/or reducing DSAs [67-72]. In one study, two patients treated with bortezomib for active ABMR showed a transient decrease in bone marrow plasma cells in vivo and persistent alterations in alloantibody specificities. Total immunoglobulin G (IgG) levels were unchanged, suggesting that proteasome activity is important for plasma cell longevity and its inhibition may control antibody production in vivo [67]. In another study, two patients underwent bortezomib-based therapy for active ABMR occurring within the first two weeks posttransplant [71]. Both patients experienced prompt reversal of ABMR and elimination of detectable DSA within 14 days of treatment. However, a follow-up study of 28 patients with active ABMR found that bortezomib therapy was associated with better DSA and histologic response in patients with early (within six months of transplant) rejection but not late ABMR [72].
The use of bortezomib in patients with late ABMR was examined in a randomized, placebo-controlled trial of 44 kidney transplant recipients who were ≥6 months posttransplant, had a positive DSA, and had histologic evidence of active or chronic ABMR [73]. Patients were randomly assigned to treatment with two cycles of bortezomib (1.3 mg/m2 intravenously on days 1, 4, 8, and 11) or placebo; baseline immunosuppression was adjusted as needed according to a predefined protocol. At 24 months posttreatment, there was no significant difference between the groups in the slope of estimated glomerular filtration rate (eGFR) per year (-4.7 versus -5.2 mL/min/1.73m2 per year in the bortezomib- and placebo-treated groups, respectively). Patient and graft survival were comparable between the groups, and there were no differences in median measured GFR, proteinuria, DSA levels, or morphologic or molecular rejection phenotypes in 24-month allograft biopsy samples. However, bortezomib-treated patients experienced higher rates of gastrointestinal and hematologic toxicity.
Eculizumab — Eculizumab is a fully humanized, monoclonal antibody directed against the C5 fragment of the complement cascade and inhibits the generation of the membrane attack complex (MAC). It has received US FDA approval for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement blockade (eculizumab)' and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria", section on 'Eculizumab'.)
In kidney transplantation, eculizumab has been used to prevent ABMR in highly sensitized recipients who undergo desensitization [9]. There are also reports of its successful use as a salvage agent in treating refractory active ABMR [74-80]. The doses used have been similar to those used for the treatment of aHUS, and the duration of dosing has been variable. The lack of randomized, controlled trials proving its efficacy and safety has limited its use in kidney transplant recipients. In addition, ABMR has occurred in kidney transplant recipients who were receiving eculizumab for other indications such as receipt of a positive crossmatch kidney or HUS [81,82]. Eculizumab has not been shown to be effective for the treatment of C4d-negative active and chronic ABMR, suggesting that its efficacy may be limited to acute, complement-mediated processes [9,81,83].
Special populations
Patients with mixed acute rejection — Patients with mixed acute rejection (ie, concurrent histologic evidence of both ABMR and acute T cell-mediated (cellular) rejection [TCMR; Banff grade 2A or greater]) should be treated for both ABMR and TCMR. We treat with the combination of glucocorticoids, plasmapheresis, and IVIG, as detailed above (see 'Approach to initial therapy' above), and add rabbit antithymocyte globulin (rATG)-Thymoglobulin to the treatment regimen. In this setting, we generally perform plasmapheresis and administer IVIG on an alternate-day schedule (eg, Monday, Wednesday, Friday, and Sunday) for a minimum of four treatments. We administer rATG-Thymoglobulin (1.5 to 3 mg/kg) on an alternate-day schedule on the intervening days (eg, Tuesday, Thursday, and Saturday), for a total of three doses.
A discussion of the evidence for the use of rATG-Thymoglobulin in patients with acute TCMR is presented elsewhere. (See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the renal allograft", section on 'Banff grade II or III rejection'.)
Patients with subclinical rejection — Subclinical rejection is defined as the presence of histologic evidence of acute rejection on biopsy without an elevation in the serum creatinine concentration. This diagnosis is typically established by a protocol, or surveillance, biopsy, which is obtained at a protocol-driven, prespecified time after transplant rather than for a clinical indication. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'Subclinical rejection'.)
In all patients who are found to have evidence of subclinical ABMR, we use the same therapeutic approach as that used to treat patients with clinical ABMR (see 'Approach to initial therapy' above), based upon evidence from retrospective studies that suggest that treatment of subclinical ABMR may be associated with improved graft outcomes. One study compared graft outcomes of 219 kidney transplant recipients with ABMR (77 subclinical, 142 clinical) with matched controls without ABMR [63]. One- and five-year graft survival among patients with subclinical ABMR were 95.9 and 75.7 percent, respectively, compared with 96.8 and 88.4 percent in controls. Overall, the risk of graft loss in patients with subclinical ABMR was 2.15-fold greater than that in matched controls. However, there was no significant difference in graft loss between those with treated subclinical ABMR and the controls.
Patients with C4d-negative ABMR — Some patients have histologic evidence of ABMR and a positive DSA but have little or no C4d staining in the peritubular capillaries, an entity recognized as C4d-negative ABMR. Such patients should be treated using the same approach as that for patients with C4d-positive ABMR [84]. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'C4d-negative antibody-mediated rejection' and 'Approach to initial therapy' above.)
Patients with a non-HLA DSA — ABMR can also occur in patients with non-human leukocyte antigen (HLA) donor-specific antibodies (DSAs), such as anti-angiotensin II type 1 (AT1) receptor antibodies [85] and antiendothelial antibodies [86]. The immunosuppressive treatment of ABMR in such patients is generally the same as that in patients with ABMR and an anti-HLA DSA. Patients who are found to have an anti-AT1 receptor antibody should receive, in addition to immunosuppressive therapy, an angiotensin II receptor blocker, which may inhibit AT1-receptor antibody-mediated effects [85,87]. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'Detection of donor-specific antibodies'.)
Less frequently used therapies
Immunoadsorption — Immunoadsorption with protein A (IA) has been used to reverse ABMR [88,89]. In the only controlled, open-label trial, 10 patients with severe ABMR were randomly assigned to IA or no IA (with the option of rescue IA after three weeks) [89]. All IA-treated patients responded to therapy (although one death occurred independent of IA), while four control patients remained dialysis dependent. Rescue IA was not successful.
While not available in the United States, selective IA treatment is an attractive alternative to the nonselective combination of plasmapheresis and IVIG. Given the improved outcomes in treating ABMR with plasmapheresis and IVIG, as compared with historical controls, and with IA, as compared with a control group in this small study, further analysis would ideally compare the two treatment methods in a larger number of patients. Although both forms of treatment are expensive, the selective modality of IA without a requirement for IVIG administration would appear preferable if similar outcomes are evident. As previously described, the relative contribution of IVIG or plasmapheresis in treating ABMR is unclear, and further analysis of IA may assist in clarifying this issue.
Splenectomy — We do not routinely perform splenectomy in patients with ABMR, given the lack of evidence that this intervention is safer or more efficacious than available medical therapy. However, some centers consider splenectomy in treating ABMR refractory to plasmapheresis and/or IVIG [90,91].
●Four kidney transplant recipients (two ABO incompatible, one crossmatch positive, one with known risk factors) who were diagnosed with an ABMR and failed standard therapy (average 11 days) with steroid, plasmapheresis, IVIG, rATG-Thymoglobulin, and rituximab (three patients) or alemtuzumab (one patient) were treated with laparoscopic splenectomy [90]. Urine output improved immediately, and serum creatinine decreased within 48 hours.
●Five patients who underwent a living-donor kidney transplant after desensitization for a positive crossmatch had an ABMR [91]. After rescue attempts with plasmapheresis and IVIG failed, they underwent splenectomy followed by plasmapheresis and IVIG. Allograft function returned within 48 hours of the procedure.
Experimental therapies
C1 inhibitors — Activation of the complement pathway is an important step in the pathogenesis of ABMR. Binding of anti-human leukocyte antigen (HLA) DSAs to complement fraction C1q, the first component in the activation of the complement cascade, has been associated with poor graft outcomes and severe phenotypes of ABMR [29]. These findings have provided the rationale for the use of proximal complement inhibition using C1 inhibitors (C1 INHs) in the treatment of ABMR. C1 INHs have been approved by the US FDA for use in patients with hereditary angioedema. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'First-line agents: Dosing, efficacy, and adverse reactions'.)
The use of a plasma-derived C1 INH in the treatment of active ABMR was evaluated in a phase IIb, multicenter, randomized, controlled trial of 18 kidney transplant recipients with biopsy-proven, active ABMR [92]. Patients were randomly assigned to receive C1 INH 20,000 units or placebo every other day for two weeks (total of seven doses) as adjunct therapy to standard-of-care treatment with plasmapheresis, IVIG, and rituximab. Resolution of ABMR occurred in 78 and 67 percent of patients treated with C1 INH and placebo, respectively. There was no significant difference between the groups in posttreatment renal histopathology or graft survival on day 20; however, a trend toward sustained improvement in graft function at day 90 was observed in the C1 INH group.
Similar findings were reported in a prospective pilot study of six kidney transplant recipients with active ABMR and acute allograft dysfunction that were unresponsive to treatment with plasmapheresis, IVIG, and rituximab [93]. All patients received the C1 INH Berinert (20 units/kg on days 1, 2, and 3 and then twice weekly) and high-dose IVIG (2 g/kg once per month) for six months; maintenance immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisone. At six months, all patients showed an improvement in estimated glomerular filtration rate (eGFR) compared with baseline at the time of inclusion in the study. Renal allograft biopsies at six months revealed no significant change in histologic features; however, C4d deposition was observed in only one of six patients compared with five of six patients at baseline. In addition, of the six patients who were positive for a C1q-binding circulating DSA at the start of the study, only one had a positive DSA at six months.
Further studies are needed to determine the efficacy and safety of proximal complement inhibition in the treatment of active ABMR.
TREATMENT OF CHRONIC ANTIBODY-MEDIATED REJECTION — Chronic ABMR, the most common cause of graft failure, is more difficult to treat than active ABMR since irreversible tissue damage has already occurred to the renal allograft. Although evidence suggests that the treatment of antibody-mediated injury requires a combination of strategies to inhibit B cell development, maturation, and activity, it is not clear which combination therapy is safe and effective in patients with chronic ABMR [4,16,83,94-96].
We treat all patients with evidence of chronic ABMR using a combination of glucocorticoids and intravenous (IV) immune globulin (IVIG). We add rituximab to the treatment regimen if there is evidence of active microvascular inflammation on kidney biopsy. We do not use eculizumab or bortezomib in the treatment of chronic ABMR. Our approach in patients with chronic ABMR is similar to that used in patients with active ABMR that occurs after the first year posttransplant. (See 'Approach to initial therapy' above.)
Similar to active ABMR, there is no high-quality evidence to guide the optimal treatment of chronic ABMR, and our approach is based primarily upon the following observational studies:
●In a large observational study of 123 consecutive kidney transplant recipients with biopsy-proven, chronic ABMR, 76 percent of patients lost their grafts with a median survival of 1.9 years after the diagnosis of chronic ABMR [16]. Treatment with glucocorticoids and IVIG was associated with a lower risk of graft loss (hazard ratio [HR] 0.44, 95% CI 0.20-0.96). Patients with surviving grafts had a more significant reduction in donor-specific antibodies (DSAs), suggesting the need for more mechanistic interventional clinical trials targeting DSA in patients with chronic ABMR.
●In one study of four kidney transplant recipients with chronic ABMR diagnosed between 1 and 27 years posttransplant, treatment with a combination of rituximab and IVIG improved graft function in all patients; DSAs were reduced in two of the four patients [94].
●In a retrospective review of 31 patients with chronic ABMR, the median graft survival time was greater among patients treated with rituximab compared with those treated without rituximab (685 versus 439 days) [96].
One randomized, placebo-controlled trial of 25 patients with chronic ABMR found no difference in the decline in estimated glomerular filtration rate (eGFR) at one year between patients treated with the combination of IVIG (four doses of 500 mg/kg) with rituximab (375 mg/m2) and those treated with placebo [97]. However, the study only achieved one-half of its targeted patient enrollment and was therefore underpowered to identify a significant difference in the primary endpoint.
The use of eculizumab in the treatment of chronic ABMR was evaluated in a pilot, randomized, controlled trial of 15 transplant recipients with positive DSA, deteriorating kidney function, and histologic evidence of ABMR [83]. Patients were randomly assigned in a 2:1 ratio to treatment with eculizumab (10 patients) or no eculizumab (5 patients) for six months, followed by six months of observation. At 12 months, there were no differences in graft function or expression of endothelial cell-associated transcripts (ENDATs), a molecular signature predictive of ABMR, between the two groups.
Bortezomib has not been shown to be effective in the treatment of patients with chronic ABMR. (See 'Bortezomib' above.)
Tocilizumab is 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' and "Systemic juvenile idiopathic arthritis: Treatment", section on 'Interleukin 6 inhibitors'). One study has assessed the use of tocilizumab as rescue therapy in 36 kidney transplant patients with chronic ABMR who failed standard-of-care treatment with IVIG and rituximab, with or without plasma exchange [98]. Tocilizumab was administered as 8 mg/kg monthly, with a maximal dose of 800 mg for 6 to 25 months. Graft- and patient-survival rates in tocilizumab-treated patients were 80 and 91 percent at six years posttreatment, respectively. Significant reductions in DSAs and stabilization of renal allograft function were observed at two years. No significant adverse events or severe adverse events were reported. Tocilizumab is not routinely used in the treatment of chronic ABMR but may represent a potential alternative approach to stabilize graft function.
The diagnosis of chronic ABMR in kidney transplant recipients is discussed elsewhere. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'Chronic active antibody-mediated rejection'.)
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
●Antibody-mediated rejection (ABMR) is the most common cause of allograft failure after kidney transplantation. Increasing evidence suggests that the prevention and treatment of antibody-mediated injury requires a combination of strategies to inhibit B cell development, maturation, and activity. Despite a relatively large number of observational studies, it is not clear which combination therapy is the safest and most effective. (See 'Introduction' above.)
●Active and chronic ABMR are both associated with poor outcomes after kidney transplantation. Patients with active ABMR are at increased risk for subsequent rejection, chronic ABMR, and graft loss. Similarly, those with chronic ABMR have a higher risk for graft loss and patient death. However, not all patients with ABMR have poor outcomes, and many patients maintain stable allograft function for years after treatment of the initial episode of rejection. (See 'Predictors of outcome' above.)
●Our approach to the prevention of ABMR depends upon the detection of donor-specific antibody (DSA) prior to (preexisting DSA) or after (de novo DSA) transplant:
•Our general approach to the prevention of ABMR in patients with a preexisting DSA prior to transplant is as follows:
-In patients with a potential living donor, the approach depends upon the results of the most recent crossmatch. In patients with a positive complement-dependent cytotoxicity (CDC) crossmatch or a strongly positive flow crossmatch, we, and many other transplant centers, prefer to use kidney paired donation (KPD) programs, rather than desensitization, given the high risk of ABMR and graft loss in such patients. Some transplant centers combine desensitization and KPD. In patients with a positive virtual crossmatch or a mild-to-moderate flow crossmatch (ie, median channel shift of <200), we employ human leukocyte antigen (HLA) desensitization strategies, which include treatment with plasmapheresis, rabbit antithymocyte globulin (rATG)-Thymoglobulin, and rituximab.
-In patients without a potential living donor, we employ HLA desensitization strategies.
-In all patients with a preexisting DSA before transplant who undergo kidney transplantation, we use induction and maintenance immunosuppression therapies that are appropriate for patients at high risk for the development of acute rejection. (See 'Patients with preexisting DSA before transplant' above.)
•In patients with a de novo DSA after transplant, prevention of ABMR should focus on addressing nonadherence and under-immunosuppression while balancing the safety and efficacy of long-term immunosuppression. (See 'Patients with de novo DSA after transplant' above.)
●The primary goal of treating ABMR is to remove existing DSAs and to eradicate the clonal population of B cells or plasma cells that is responsible for their production. In general, we treat all patients who have evidence of active ABMR on biopsy. Although we do not routinely perform surveillance or protocol allograft biopsies at our institution, we would treat patients who are discovered to have subclinical ABMR by surveillance biopsy. In addition, we treat patients with C4d-negative ABMR with the same approach that we use in patients with C4d-positive ABMR.
•(See 'Treatment of active antibody-mediated rejection' above.)
•(See 'Patients with subclinical rejection' above.)
•(See 'Patients with C4d-negative ABMR' above.)
●Although patients with active ABMR can be treated on an outpatient basis, we typically advocate inpatient admission for patients because of the complexity of the treatment regimen. Our approach to the initial treatment of active ABMR depends upon the timing of the diagnosis of ABMR (algorithm 1):
•In patients who are diagnosed with active ABMR within the first year posttransplant, we treat with a combination of glucocorticoids, plasmapheresis and intravenous immune globulin (IVIG), and, in some patients, rituximab. (See 'Approach to initial therapy' above.)
•In patients who are diagnosed with active ABMR after the first year posttransplant, we treat with glucocorticoids using the same approach as in patients diagnosed with ABMR within the first year posttransplant. However, we do not perform plasmapheresis in such patients because of the lack of evidence supporting the safety and efficacy of plasmapheresis in late-onset ABMR.
In all patients who are treated for active ABMR, we recommence antimicrobial and antiviral prophylaxis with a regimen that is identical to that administered in the immediate posttransplant period. We do not routinely use immunoadsorption, bortezomib, eculizumab, or splenectomy in the initial treatment of patients with ABMR. However, some of these therapies can be considered in patients who do not respond to initial treatment. (See 'Second-line agents in patients who have failed initial therapy' above and 'Less frequently used therapies' above.)
●Patients with mixed acute rejection (ie, concurrent histologic evidence of both ABMR and acute T cell-mediated (cellular) rejection [TCMR; Banff grade 2A or greater]) should be treated for both ABMR and TCMR. We treat with the combination of glucocorticoids, plasmapheresis, and IVIG and add rATG-Thymoglobulin to the treatment regimen. (See 'Patients with mixed acute rejection' above.)
●Patients are considered to have a successful reversal of ABMR if they meet all of the following parameters within three months of treatment: decrease in serum creatinine to within 20 to 30 percent of the baseline level, decrease in proteinuria to the baseline level, decrease in immunodominant DSA by >50 percent, and resolution of changes associated with ABMR on repeat kidney biopsy.
●Most patients with ABMR with a successful response to anti-rejection therapy will demonstrate an improvement in serum creatinine within seven days of treatment. Our subsequent approach to treatment is based upon the response to initial therapy:
•In patients with a decrease in serum creatinine in response to therapy, we increase the maintenance tacrolimus dose to achieve a trough level 20 to 25 percent above the level at the time of rejection and resume routine monitoring of allograft function. For patients who are taking the immediate-release formulation of tacrolimus and cannot tolerate higher doses, extended-release tacrolimus, which has fewer side effects and may allow for a higher and therapeutic trough to be obtained, is an alternative option. Typically, maintenance immunosuppression is also augmented by increasing the daily dose of oral prednisone.
•Patients without any decrease in serum creatinine after seven days of rejection treatment are considered to have failed initial treatment. In such patients, ongoing rejection and/or another cause of renal allograft dysfunction should be suspected, and a repeat renal allograft biopsy should be performed. Our subsequent approach depends upon the histopathological and clinical findings of the patient. (See 'Monitoring the response to therapy' above.)
●Chronic ABMR, the most common cause of graft failure, is more difficult to treat than active ABMR since irreversible tissue damage has already occurred to the renal allograft. It is not clear which combination therapy is safe and effective in patients with chronic ABMR. We treat all patients with evidence of chronic ABMR using a combination of glucocorticoids and IVIG. We add rituximab to the treatment regimen if there is evidence of active microvascular inflammation on kidney biopsy. We do not use eculizumab or bortezomib in the treatment of chronic ABMR. (See 'Treatment of chronic antibody-mediated rejection' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Christina Klein, MD, who contributed to an earlier version of this topic review.
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