Version May 2024
INTRODUCTION — Antibody-mediated rejection (ABMR) is the most common cause of immune-mediated 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 (DSAs) to human leukocyte antigen (HLA) or non-HLA antigens [5]. These criteria were further refined in the Banff 2019 Kidney Meeting Report [6,7].
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 kidney allograft [8,9]. In active ABMR, antibodies bind to graft endothelium and activate complement-dependent and -independent mechanisms that recruit natural killer cells, polymorphonuclear neutrophils, platelets, and macrophages, which contribute to peritubular capillaritis, glomerulitis, cellular necrosis, thrombotic microangiopathy, and a relatively rapid decline in allograft function [8-10].
Chronic ABMR, on the other hand, is a pathophysiological process resulting from a repetitive pattern of thrombotic events and inflammatory changes that lead to endothelial cell injury and allograft matrix remodeling [11,12]. It manifests histologically as transplant glomerulopathy and results in a slow and progressive decline in kidney function [13].
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 [14].
The prevention and treatment of active and chronic ABMR of the kidney 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:
●(See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection".)
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 failure [1,15-18]. Similarly, those with chronic ABMR have a higher risk for graft failure and patient death [1-3,19,20]. 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 [21]. There is also a clear and independent association between microvascular injury and C4d staining (including focal C4d staining in postreperfusion biopsies) with poor outcomes in active or chronic ABMR [22-25]. 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 [19,26-28].
●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) [29]. 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 [30].
•DSA subclass – The immunoglobulin subclass of DSA may also predict outcomes although this information may not be provided by all clinical laboratories. 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 [31]. 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 kidney 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 kidney allograft loss [32]. 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 [33].
•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) [1,28,34-36].
•DSA response to treatment – There is accumulating evidence indicating that a decline in DSA strength after treatment is associated with better graft survival [28,37,38]. However, there is limited information on the definition of a validated positive DSA response.
●Graft function – The degree of kidney allograft dysfunction at the time of kidney biopsy appears to be directly associated with poor outcomes in patients with ABMR [19,25,34,39]. 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) [34]. 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 [19].
One study of 91 patients with active ABMR found that changes in eGFR following the diagnosis of ABMR could predict the risk of subsequent death-censored graft failure using a joint modeling framework [40]. An extrapolated 30 percent improvement in the slope of eGFR in the first 12 months was associated with a 10 percent reduction in death-censored graft failure at five years [40].
●Molecular markers – Several invasive and noninvasive molecular markers are being explored as both diagnostic and prognostic tools in patients with ABMR. The expression of endothelial cell-associated transcripts and DSA-selective transcripts has been shown to be biomarkers of active antibody-mediated injury and may predict worse graft outcomes [26,41]. 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. A multiorgan transplant gene panel, called the Banff Human Organ Transplant panel, is being considered by the Banff committee [7].
Donor-derived cell-free DNA (dd-cfDNA) represents nonencapsulated, fragmented DNA that is continuously shed into the bloodstream from the allograft undergoing injury, with a half-life of approximately 30 minutes. Several assays for measuring dd-cfDNA are available and have been approved by Medicare for use in transplant recipients [42]. In a study of 1092 kidney transplant recipients whose dd-cfDNA levels were monitored over three years, dd-cfDNA levels of ≥0.5 percent were associated with a nearly threefold increased risk of developing a de novo DSA [43]. Persistently elevated dd-cfDNA levels were associated with >25 percent decline in the eGFR.
While the growing number of molecular and multimodality tests offers the advantage of prospective noninvasive monitoring and personalized medicine, further studies are needed to consider the cost and long-term utility of these assays.
●Prediction models – Novel models are being developed to predict long-term kidney allograft failure, including after the treatment of rejection [44]. 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 [44].
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 donor-specific antibody (DSA) prior to transplant have a greater risk for ABMR and graft failure compared with nonsensitized patients [45-47]. 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 (antibodies detected by single antigen bead technology) [45,46,48]. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing", section on 'Assays for crossmatch testing'.)
●Approach to prevention – 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, quality of life, and health care costs. Long-term survival in kidney transplant recipients has improved considerably with desensitization [49,50], 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-incompatible transplantation" 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 [51-53]. Such KPD programs (including the National Kidney Registry, the Alliance for Paired Donation, and single-center programs) enable sensitized patients with immunologically incompatible living donors to be transplanted 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 [54]. Some transplant centers combine desensitization and KPD.
-In patients with a positive virtual crossmatch (antibodies detected by single antigen bead technology) 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 [23,48]. This is discussed in more detail elsewhere. (See "Kidney transplantation in adults: HLA-incompatible transplantation".)
•In patients without a potential living donor, we employ HLA desensitization strategies. (See "Kidney transplantation in adults: HLA-incompatible transplantation".)
•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 [55]. The selection of induction and maintenance immunosuppression in high-risk kidney transplant recipients is discussed elsewhere. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Patients at high risk of rejection' and "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
●Monitoring after transplant – The monitoring of kidney allograft function in patients with a preexisting DSA before transplant is similar to that performed in nonsensitized patients (see "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 [56]. In patients with a significant rise in DSA or who develop a de novo DSA within the first three months, we perform a kidney 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 [56]. Patients with a pretransplant DSA undergo protocol kidney biopsies at months 3 and 12 posttransplant.
Some UpToDate contributors to this topic perform a postreperfusion kidney allograft biopsy at the time of transplantation to identify patients at risk for ABMR [23]. In patients who are found to have evidence of positive C4d staining, plasmapheresis (two to three sessions), intravenous immune globulin (IVIG), and a single dose of rituximab 375 mg/m2 (administered after the last session of plasmapheresis) would be added to the induction immunosuppression regimen [23].
Patients with de novo DSA after transplant — Kidney transplant recipients who develop a de novo donor-specific antibody (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 'Predictors of outcome' 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 [1,2,57,58].
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 kidney allograft biopsies in all patients who develop a de novo DSA. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
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 (11 versus 23 percent) and ABMR (3 versus 13 percent) [59]. 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 [60]. 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 [61]. 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
Goals of therapy — The primary goal of treating ABMR is to reduce the titer of existing pathogenic donor-specific antibodies (DSAs), to eradicate the clonal population of B cells or plasma cells that is responsible for their production, to prevent complement activation and reduce endothelial injury, and to preserve graft function [14]. For most patients, this involves treatment with the combination of glucocorticoids and intravenous immune globulin (IVIG), with the addition of plasmapheresis and/or rituximab in selected patients. However, complete elimination of DSA commonly does not occur, and to attempt it may lead to dangerous over-immunosuppression. 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 and 'Patients with C4d-negative ABMR' below.)
The optimal treatment of active ABMR is unclear, and there have been no large randomized, controlled trials comparing the safety and efficacy of different therapeutic strategies [62]. 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 clinical practice guidelines and the 2019 Transplantation Society Working Group Expert Consensus [14,63].
Approach to initial therapy — Although patients could be treated on an outpatient basis, we advocate inpatient admission for patients with comorbidities such as diabetes 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). At our centers, we consider ABMR that presents within the first posttransplant year to be early-onset ABMR and ABMR that presents after the first posttransplant year to be late-onset ABMR. However, there is no uniform consensus as to what time threshold determines early versus late ABMR, and other centers may use different thresholds.
Patients who are ≤1 year posttransplant — For most patients who are diagnosed with active ABMR within the first year posttransplant (early onset), we suggest initial therapy with the combination of glucocorticoids, plasmapheresis, and IVIG rather than other therapies. In addition, some experts administer rituximab if the patient is younger (eg, age <70 years), has better allograft function (eg, estimated glomerular filtration rate [eGFR] ≥20 mL/min/1.73 m2 and lower chronicity scores on biopsy [ie, interstitial fibrosis + tubular atrophy + fibrous intimal thickening + allograft glomerulopathy <8]), and has evidence of severe disease (eg, higher DSA, diffuse C4d staining, or more extensive microvascular inflammation [ie, glomerulitis score + peritubular capillary score ≥4] on biopsy) [64]. For all patients, we augment other components of maintenance immunosuppression as needed, as discussed elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
●Dosing of glucocorticoids – We give intravenous (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 regimen – Plasmapheresis is performed daily or every other day for a maximum of six sessions [65] 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, partial thromboplastin time, 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 to reduce bleeding risk in the appropriate clinical setting, such as a same-day kidney allograft biopsy. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
●Dosing of IVIG – 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 patients with obesity, 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'.)
●Dosing of rituximab – If rituximab is given, we administer a single dose of either 200 mg or 375 mg/m2 after completion of plasmapheresis and IVIG [64].
We do not routinely use immunoadsorption, proteasome inhibitors, interleukin (IL)-6 blockade, complement inhibitors, or splenectomy in the initial treatment of patients with ABMR. However, some these therapies can be considered in patients who do not respond to initial treatment. (See 'Second-line therapies for refractory ABMR' below and 'Less frequently used therapies' below.)
There is no high-quality evidence to guide the optimal therapy of patients with active ABMR. The best data come from the following studies, which included patients with ABMR diagnosed within or after the first year posttransplant:
●A 2018 systematic review that included 10 randomized and 11 nonrandomized, controlled trials evaluated the effects of different treatments on graft survival among kidney transplant recipients with active ABMR [66]. All of the randomized trials were small, and the criteria used for the diagnosis of ABMR varied among studies. Five randomized trials assessed the benefit of antibody removal by plasmapheresis (four trials) or immunoadsorption (one trial) on graft survival. The estimated pooled effect did not suggest improved graft survival with antibody removal (hazard ratio [HR] 0.76, 95% CI 0.35-1.63). However, the control group was different for each trial, and among the trials evaluating plasmapheresis, the plasmapheresis regimen differed in dose, frequency, and treatment interval. A sensitivity analysis of the three trials with longer follow-up (two to five years) suggested a benefit with antibody removal (HR 0.46, 95% CI 0.26-0.82).
●Two retrospective studies evaluated the effects of plasmapheresis and IVIG on long-term graft survival among patients with acute ABMR, chronic ABMR, or features of both. In one study of 35 patients with ABMR (diagnosed at a mean of 59 months after transplant), treatment with plasmapheresis and IVIG was associated with better 10-year graft survival compared with treatment without plasmapheresis and IVIG (74 versus 35 percent) [67]. A second study detected no difference in graft failure between patients treated with plasmapheresis and IVIG with or without rituximab and those receiving no specific treatment [68].
●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; all patients received pulse glucocorticoids [69]. The median onset of ABMR in both treatment groups was 15 days after transplantation. 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 [70].
●A phase III, multicenter, randomized, placebo-controlled trial examined the effect of rituximab among 38 kidney transplant recipients with biopsy-proven, active ABMR [71]. 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. ABMR occurred within the first three months of transplant in 58 and 53 percent of patients in the rituximab and placebo groups, respectively. 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 (53 and 58 percent of patients in the rituximab and placebo groups, respectively). Long-term follow-up of the patients found no difference in death-censored graft survival or kidney function at seven years [72].
●In an observational study of 78 patients with ABMR diagnosed >3 months after transplant (mean of 7.3 years, range 3 months to 27 years) who were treated with glucocorticoids and IVIG with or without rituximab, there was no significant difference in kidney function at 6 and 12 months after ABMR between patients receiving and those not receiving rituximab treatment [64]. However, beyond 12 months of follow-up, treatment with rituximab was associated with improved graft survival (85 versus 68 percent, respectively), suggesting a delayed benefit with rituximab.
Patients who are >1 year posttransplant — For most patients who are diagnosed with active ABMR after the first year posttransplant (late onset), we suggest initial therapy with glucocorticoids and IVIG rather than glucocorticoids, IVIG, and plasmapheresis. We do not perform plasmapheresis in such patients because of the lack of evidence supporting the safety and efficacy of plasmapheresis in later-onset ABMR. However, some transplant centers continue to administer plasmapheresis for ABMR diagnosed after one year posttransplant. In addition, some experts administer rituximab if the patient is younger (eg, age <70 years), has better allograft function (eg, eGFR ≥20 mL/min/1.73 m2 and lower chronicity scores on biopsy [ie, interstitial fibrosis + tubular atrophy + fibrous intimal thickening + allograft glomerulopathy <8]), and has evidence of severe disease (eg, higher DSA, diffuse C4d staining, or more extensive microvascular inflammation [ie, glomerulitis score + peritubular capillary score ≥4] on biopsy) [64]. For all patients, we also augment maintenance immunosuppression, as discussed elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
●We administer glucocorticoids using the same approach as described above for patients diagnosed with ABMR within the first year posttransplant. (See 'Patients who are ≤1 year posttransplant' above.)
●We administer IVIG at a dose of 200 mg/kg every two weeks for three doses. In patients with obesity, 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'.)
●If rituximab is given, we administer a single dose of 375 mg/m2 after completion of IVIG.
There is no high-quality evidence to guide the optimal therapy of patients with ABMR who present after the first year posttransplant. Our approach of treating later-onset ABMR without plasmapheresis is supported by observational data suggesting that plasmapheresis (in combination with IVIG and glucocorticoids) is less effective at improving graft function in patients with ABMR after the first posttransplant year than in those with ABMR within the first posttransplant year [65]. Evidence in support of IVIG and glucocorticoids is presented elsewhere in this topic. (See 'Patients who are ≤1 year posttransplant' above.)
Prophylactic measures for all patients — 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, 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'.)
Monitoring and modifying 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 advocate inpatient admission for patients with comorbidities (eg, diabetes), 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. There is no consensus on the role of DSA monitoring after plasmapheresis, and clinical practice varies. We consider an allograft biopsy if a biopsy has not been performed earlier in the course of treatment and if there is no improvement in kidney function [64].
Data on the reversal of ABMR are limited [4,64,70]. In general, one-year graft survival after treatment of clinical and subclinical ABMR is approximately 80 and 95 percent, respectively [70]. 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 kidney allograft rejection", section on 'Active antibody-mediated rejection')
Most patients with ABMR with a successful response to antirejection therapy will demonstrate an improvement in serum creatinine within seven days of treatment. Modification of therapy 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 [73]. Typically, maintenance immunosuppression is also augmented by increasing the daily dose of oral prednisone and maximizing the dose of the antiproliferative agent (eg, mycophenolate). (See "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 be unresponsive to initial treatment. In such patients, ongoing rejection and/or another cause of kidney allograft dysfunction should be suspected, and a repeat kidney 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. However, the intensity of additional therapy with plasmapheresis and other agents such as bortezomib and anticomplement therapy should be weighed against preexisting comorbidities and the risk of infectious and malignant complications. (See 'Second-line therapies for refractory ABMR' below.)
Second-line therapies for refractory ABMR — 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 therapies can be considered as rescue therapy.
Proteasome inhibitors — Bortezomib is a proteasome inhibitor that is commonly used for the treatment of multiple myeloma. The drug is particularly effective against differentiated plasma cells because of the high rate of protein synthesis in these cells [74,75]. (See "Multiple myeloma: Initial treatment".)
At our centers, we do not routinely use bortezomib in patients with refractory ABMR. However, several case reports/series have demonstrated the effectiveness of bortezomib in treating ABMR, successfully reversing acute rejection, and/or reducing DSAs [76-81]. 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 IgG levels were unchanged, suggesting that proteasome activity is important for plasma cell longevity and its inhibition may control antibody production in vivo [76]. In another study, two patients underwent bortezomib-based therapy for active ABMR occurring within the first two weeks posttransplant [80]. 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 [81].
The use of bortezomib in patients with late ABMR was examined in a trial that randomly assigned 44 kidney transplant recipients who were ≥6 months posttransplant, had a positive DSA, and had histologic evidence of active or chronic ABMR to two cycles of bortezomib or placebo [82]. At 24 months posttreatment, there were no significant differences between the groups in patient and graft survival, median measured glomerular filtration rate (GFR), proteinuria, DSA levels, or morphologic or molecular rejection phenotypes in allograft biopsy samples. However, bortezomib-treated patients experienced higher rates of gastrointestinal and hematologic toxicity.
Complement inhibitors — Activation of the complement pathway is an important step in the pathogenesis of ABMR, providing the rationale for the use of complement inhibition in the treatment of ABMR.
●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. It has received US Food and Drug Administration (FDA) approval for treatment of paroxysmal nocturnal hemoglobinuria 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'.)
If eculizumab is used, we typically administer 1200 mg IV as the initial dose, followed by 900 mg IV weekly for three to four weeks. Treatment with eculizumab may be associated with life-threatening and fatal meningococcal infections. Patients should receive meningococcal vaccination at least two weeks prior to initiation of eculizumab whenever possible. We also administer daily antimicrobial prophylaxis for prevention of meningococcal infection in patients treated with eculizumab, despite vaccination, due to increased infection risk with immunosuppression. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)
In kidney transplantation, eculizumab has been used to prevent ABMR in highly sensitized recipients who undergo desensitization [11]. There are also reports of its successful use as a salvage agent in treating refractory active ABMR [83-89]. 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 [90,91]. 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 [11,90,92].
●C1 inhibitors – 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 [32]. These findings have provided the rationale for the use of proximal complement inhibition using C1 inhibitors (C1 INHs) in the treatment of ABMR. However, C1 INHs are not routinely used in clinical practice for ABMR pending further studies of their efficacy and safety in this setting. C1 INHs have been approved by the 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'.)
Evidence supporting the use of C1 INHs for active ABMR is limited [93,94]. In a phase IIb, multicenter trial that randomly assigned 18 kidney transplant recipients with biopsy-proven, active ABMR to receive C1 INH 20,000 units or placebo every other day for two weeks as adjunct therapy to plasmapheresis, IVIG, and rituximab, resolution of ABMR occurred in 78 and 67 percent of patients treated with C1 INH and placebo, respectively [93]. There was no significant difference between the groups in posttreatment kidney 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.
Less frequently used therapies — Less frequently used therapies for refractory ABMR include the following:
●Immunoadsorption – Immunoadsorption with protein A (IA) has been used to reverse ABMR [95,96]. 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) [96]. 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 [97,98].
•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 glucocorticoids, plasmapheresis, IVIG, rabbit antithymocyte globulin (rATG)-Thymoglobulin, and rituximab (three patients) or alemtuzumab (one patient) were treated with laparoscopic splenectomy [97]. 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 ABMR [98]. 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.
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, IVIG, and plasmapheresis (in patients ≤1 year posttransplant), as detailed above (see 'Approach to initial therapy' above), and add 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", 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 kidney 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 [70]. One- and five-year graft survival among patients with subclinical ABMR were 96 and 76 percent, respectively, compared with 97 and 88 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.
●In another study that compared graft outcomes among 220 kidney transplant recipients (118 with clinical ABMR, 25 with subclinical ABMR, and 77 controls without ABMR), those with clinical and subclinical ABMR received similar treatment that included pulse glucocorticoids, IVIG, and plasmapheresis (for those with rejection within three months of transplant), with or without rituximab [99]. Rates of death-censored graft failure were not significantly different between the subclinical ABMR and control groups.
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 [100]. (See 'Approach to initial therapy' above and "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection", section on 'Active antibody-mediated rejection'.)
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 [101] and antiendothelial antibodies [102]. 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 [101,103]. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection", section on 'Laboratory findings'.)
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 kidney allograft [2,19]. 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 [4,19,92,104-106].
For patients with chronic ABMR, we suggest initial therapy with glucocorticoids and intravenous immune globulin (IVIG) rather than other therapies. In addition, some experts administer rituximab if the patient is younger (eg, age <70 years), has better allograft function (eg, estimate glomerular filtration rate [eGFR] ≥20 mL/min/1.73 m2 and lower chronicity scores on biopsy [ie, interstitial fibrosis + tubular atrophy + fibrous intimal thickening + allograft glomerulopathy <8]), and has evidence of severe disease (eg, higher donor-specific antibodies (DSA), diffuse C4d staining, or more extensive microvascular inflammation [ie, glomerulitis score + peritubular capillary score ≥4] on biopsy) [64]. This treatment approach is the same as that used for patients with active ABMR that occurs after the first year posttransplant. If the patient does not respond to initial therapy, we treat with tocilizumab. (See 'Patients who are >1 year posttransplant' above.)
There is no high-quality evidence to guide the optimal therapy of chronic ABMR, and evidence supporting our treatment approach comes primarily from observational studies [19]:
●In an observational study of 123 kidney transplant recipients with biopsy-proven chronic ABMR, 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) [19]. Patients with surviving grafts had a more significant reduction in DSAs, suggesting the need for more mechanistic interventional clinical trials targeting DSA in patients with chronic ABMR.
●In another study of 78 kidney transplant recipients diagnosed with late (defined as >3 months after transplant) ABMR (40 with chronic active ABMR), treatment with glucocorticoids and IVIG with or without rituximab was associated with a decline in DSA, microvascular inflammation, and C4d Banff scores [64]. In multivariate analyses, use of rituximab was associated with a lower risk of graft loss (HR 0.23, 95% CI 0.06-0.84).
Limited data suggest that treatment with interleukin (IL) 6 blockade may benefit patients with chronic ABMR. As examples:
●One study has assessed the use of tocilizumab, a monoclonal antibody against the IL-6 receptor, as rescue therapy in 36 kidney transplant patients with chronic ABMR who were unresponsive to standard-of-care treatment with IVIG and rituximab, with or without plasma exchange [107]. 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 kidney allograft function were observed at two years. No significant adverse events or severe adverse events were reported.
●A phase II, randomized pilot trial evaluated the safety and efficacy of the anti-IL-6 antibody clazakizumab in 20 kidney transplant recipients with late (≥1 year posttransplant) ABMR (18 with chronic active ABMR) [108]. Patients were randomly assigned to receive subcutaneous clazakizumab or placebo monthly for 12 weeks, followed by a 40-week open-label extension, during which all patients received clazakizumab. Five patients (25 percent) receiving active treatment developed serious infections, and two (10 percent) developed diverticulitis, leading to withdrawal from the study. Patients receiving clazakizumab experienced a decrease in DSA. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (39 percent), disappearance of capillary C4d deposits in five (28 percent), and resolution of morphologic ABMR activity in four (22 percent). While proteinuria remained stable, mean decline in eGFR over the first 12 weeks was slower with clazakizumab compared with placebo (-0.96 versus -2.43 mL/min/1.73 m2 per month). During the open-label extension phase, the slope of eGFR decline among patients who were switched from placebo to clazakizumab improved and no longer differed significantly from that of patients initially assigned to clazakizumab.
A larger randomized, placebo-controlled trial evaluating clazakizumab for the treatment of chronic ABMR is in progress (NCT03744910).
Eculizumab and bortezomib have not been shown to be effective in patients with chronic ABMR [92].
The diagnosis of chronic ABMR in kidney transplant recipients is discussed elsewhere. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection", section on 'Chronic 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
●Overview – Antibody-mediated rejection (ABMR) is the most common cause of immune-mediated allograft failure after kidney transplantation. Prevention and treatment of ABMR requires a combination of strategies to inhibit B cell development, maturation, and activity. Active and chronic ABMR are both associated with poor outcomes. (See 'Predictors of outcome' above.)
●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:
•Preexisting DSA – Our approach is as follows (see 'Patients with preexisting DSA before transplant' above):
-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 prefer to use kidney paired donation (KPD) programs rather than desensitization, given the high risk of ABMR and graft loss in such patients. 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.
-In patients without a potential living donor, we employ HLA desensitization strategies.
•De novo DSA – In patients with a de novo DSA after transplant, prevention 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.)
●Treatment of active ABMR – 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.
•Initial therapy – Our approach to initial therapy depends upon the timing of the diagnosis of ABMR (algorithm 1):
-Within one year posttransplant – For most patients who are diagnosed with active ABMR within the first year posttransplant, we suggest initial therapy with the combination of glucocorticoids, plasmapheresis, and intravenous immune globulin (IVIG) rather than other therapies (Grade 2C). In addition, some experts administer rituximab if the patient is <70 years old, has better allograft function, and has severe disease. For all patients, we augment other components of maintenance immunosuppression as needed. (See 'Patients who are ≤1 year posttransplant' above.)
-After one year posttransplant – For most patients who are diagnosed with active ABMR after the first year posttransplant, we suggest initial therapy with glucocorticoids and IVIG rather than glucocorticoids, plasmapheresis, and IVIG (Grade 2C). 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 addition, some experts administer rituximab if the patient is <70 years old, has better allograft function, and has severe disease. For all patients, we also augment maintenance immunosuppression, as discussed elsewhere. (See 'Patients who are >1 year posttransplant' above.)
•Prophylaxis – 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. 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. (See 'Prophylactic measures for all patients' above.)
•Refractory ABMR – Most patients with active ABMR will respond to a combination of glucocorticoids, plasmapheresis, IVIG, and rituximab. In patients who do not respond to initial treatment with this combination, rescue therapies include proteasome inhibitors, complement inhibitors, immunoadsorption, or splenectomy. (See 'Second-line therapies for refractory ABMR' above.)
●Treatment of chronic ABMR – Chronic ABMR, the most common cause of graft failure, is more difficult to treat than active ABMR since irreversible tissue damage has already occurred in the allograft. It is not clear which combination therapy is safe and effective in patients with chronic ABMR. For patients with chronic ABMR, we suggest initial therapy with glucocorticoids and IVIG rather than other therapies (Grade 2C). In addition, some experts administer rituximab if the patient is <70 years old, has better allograft function, and has severe disease. If the patient does not respond to initial therapy, we treat with tocilizumab. (See 'Treatment of chronic antibody-mediated rejection' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Christina Klein, MD, and Arjang Djamali, MD, MS, FASN, who contributed to earlier versions of this topic review.
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