Rationale and Objective
Antibody-mediated rejection (AMR) is a significant contributor to graft loss in kidney transplant recipients and accounts for up to 76% of death-censored graft failures beyond the first year of transplantation.1 The optimal treatment of AMR remains uncertain, in part caused by continuously evolving diagnostic criteria for AMR,2 as well as our incomplete understanding of the mechanisms behind donor-specific antibody (DSA) development and subsequent DSA-mediated endothelial injury.3 AMR represents a pathological spectrum that often co-exists with T-cell-mediated rejection.2 At one end of the spectrum, acute AMR is characterized by microvascular inflammation, endothelial injury, and serological evidence of DSA,4 and may respond to current therapeutic strategies. At the other end of the spectrum, chronic AMR is characterized by transplant glomerulopathy, a form of advanced glomerular injury and remodeling,4 and is unlikely to be reversed by current therapies.
Clinical practice guidelines for the treatment of AMR have remained largely unrevised since the 2009 KDIGO guideline, which recommends a combination of one or more of corticosteroids, plasmapheresis, intravenous immunoglobulin (IVIG), anti-CD20 antibody, and lymphocyte-depleting antibody.5 Previous controlled trials of treatments for AMR have been heterogeneous, underpowered, and of low quality.6 In recent years, there has also been a focus on novel therapies that target B-cell and plasma cell depletion, as well as inhibition of complement-dependent endothelial damage. These therapies include rituximab, a monoclonal antibody to CD-20; bortezomib, a proteasome inhibitor; complement factor 1 (C1) inhibitors; and eculizumab, a monoclonal antibody against complement factor 5.3 Whether these newer agents have improved clinical outcomes in patients with AMR has not been systematically examined.
We previously published a systematic review of the treatment of AMR that demonstrated a paucity of high-quality evidence for the use of plasmapheresis and IVIG, and weak evidence of benefit for rituximab and bortezomib in adult kidney transplant recipients.6 In this updated review, we expand the inclusion criteria to include all adult and pediatric kidney transplant recipients, and incorporate contemporary therapeutic strategies for the treatment of acute and chronic AMR to determine their effect on graft survival, function, and adverse events.
MATERIALS AND METHODS
Protocol and Registration
We prospectively developed a protocol for this systematic review and registered it with PROSPERO, an international prospective register of systematic reviews (PROSPERO 2016: CRD42016049834).
We included all published controlled trials in any language that evaluated histopathologically diagnosed acute and/or chronic AMR in both adult and pediatric kidney transplant recipients. For earlier trials, where no standardized international classification of rejection existed, we considered clinical status (eg, “steroid-resistant”) and accepted biopsy results that were suggestive of AMR. For conference abstracts, if the diagnosis of AMR was stated, then this was sufficient for inclusion.
We searched MEDLINE (1950 to February 2017), EMBASE (1980 to February 2017), and the Cochrane Register of Controlled Trials (2009 to February 2017) for conference abstracts and published studies of controlled trials in the treatment of AMR. In addition, for all full-text records that were screened, we hand-searched references lists and contacted experts in the field to ascertain additional studies.
Search Strategy and Study Selection
We developed a sensitive search strategy that used a combination of text words and Medical Subject Headings (MeSH) to describe treatments of AMR, including plasmapheresis, IVIG, immunoadsorption columns, rituximab, bortezomib, and eculizumab (Appendix I, SDC, http://links.lww.com/TP/B514). We narrowed the studies to “clinical trials” under the search filter. Two authors (S.S.W. and T.D.Y.) independently screened all titles under this search strategy and performed the final selection of studies based on full-text evaluation. We further reviewed the reference lists of the selected studies for additional publications. Disagreements were resolved by discussions between all authors.
Data Collection and Data Items
We constructed standardized data extraction forms using REDCap (Research Electronic Data Capture), a secure web-based application designed to support data capture for research studies.7 Two authors (S.S.W. and T.D.Y.) independently extracted study characteristics and outcomes, including study design, participant characteristics, AMR definition, donor source, time since transplantation, treatment details for intervention and comparator arms, graft survival, and adverse events.
Risk of Bias and Quality of Evidence
For randomized controlled trials (RCTs), we used the Cochrane Risk of Bias Assessment Tool to assess risk of bias in individual studies over the following domains: random sequence generation, allocation concealment, blinding of participants and study personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other risk of bias.8 For nonrandomized studies, we assessed bias using the Cochrane Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool under the following bias domains: confounding, selection, intervention classification, missing data, outcome measurement, and selective reporting.9 Two authors (S.S.W. and T.D.Y.) independently assessed the risk of bias for each study, and disagreements were resolved by discussion. The quality of evidence for each treatment for the outcome of graft survival was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Evidence was assigned a quality level of high, moderate, low, or very low based on the following domains: study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias.10 Quality assessment was based on randomized evidence where available and on nonrandomized evidence when no RCTs had been performed.
Where reported, extracted continuous data are presented as mean and standard deviation or median and interquartile range. Extracted data on graft survival are presented as hazard ratios (HRs) and 95% confidence intervals (CIs) where time-to-event data was reported, or as relative risk and 95% CI where actuarial graft failure was reported.
We aimed a priori to perform a meta-analysis of all RCTs. However, because of the small number of studies for each treatment strategy and the marked between-study heterogeneity, it was only possible to estimate a pooled statistic for the comparison between antibody removal and control for the outcome of graft survival. Where time-to-event data were not presented, we extracted the necessary descriptive and statistical information published by the authors to calculate the HR as described by published methodology.11 A pooled HR with 95% CI was then calculated using a random effects model, and heterogeneity was quantified using I2 and χ2 statistics. Sources of heterogeneity were explored with sensitivity analysis. All statistical analyses were performed using Stata V.14.2 (StataCorp, College Station, TX).
A total of 14,380 records were identified through the updated search conducted on February 15, 2017, of which 53 records were retrieved for full-text evaluation. Forty-four records were excluded as they were not controlled studies (37 records), they did not evaluate treatments of AMR (6 records), or they did not report outcome data (1 record), yielding 9 studies identified by the updated search. In addition to the 12 studies from the previous review,6 a total of 21 studies12-34 involving 751 participants were included in the updated review (Figure 1).
Characteristics of the included studies are presented in Table 1. Of the 21 studies, 10 were RCTs and 11 were nonrandomized studies. Nine of the nonrandomized studies were retrospective. Treatments for AMR included antibody removal with plasmapheresis alone,13,14,16-19 plasmapheresis and IVIG,20,21 and column immunoadsorption.12 In addition, there were four studies of rituximab compared to standard of care,22-25 four studies of bortezomib compared to rituximab,27-30 one study of combination bortezomib and rituximab,31 two studies of C1 inhibitors,32,33 and one study of eculizumab.34 Follow-up ranged from 1 month to 7 years, with the majority of studies reporting at least 6 months of follow-up.
Definition of AMR
The year of publication ranged from 1981 to 2017, during which the definition of AMR evolved substantially. Accordingly, the criteria used for the diagnosis of AMR varied markedly between studies. Earlier studies of plasmapheresis were conducted in patients diagnosed with steroid-resistant vascular rejection, whereas the majority of studies from 2007 onwards used Banff criteria for the diagnosis of AMR. There were two studies of mixed acute cellular rejection and AMR,23,27 including one pediatric study of rituximab that used criteria of mixed acute cellular and humoral rejection with B-cell infiltrates on histology23 (Table 1).
Acute Versus Chronic AMR
In addition to variability in the diagnostic criteria for AMR, studies varied in whether they included acute or chronic AMR. There were eight studies of acute AMR, three of which investigated antibody removal with column immunoadsorption12 or plasmapheresis.13,16 There was only one controlled study of chronic AMR that investigated treatment with eculizumab.34 Six studies included patients with both acute and chronic AMR, and six studies did not report on chronicity (Table 1).
Risk of Bias and Quality of Evidence
Ten RCTs were included in the systematic review, and the overall risk of bias assessed using the Cochrane Risk of Bias Tool was unclear (Figure 2A). Only 2 out of the 10 RCTs reported on random sequence generation12,22 and allocation concealment.16,22 A further randomized study did not perform an intention-to-treat analysis, although it was the only double-blind, placebo-controlled study.22 Blinding of outcome assessment was not a source of bias in most studies because of the objective nature of the outcomes of graft failure and serum creatinine measurement.
Eleven nonrandomized studies were included in the systematic review and were assessed using the Cochrane ROBINS-I tool. The overall risk of bias was serious in all nonrandomized studies (Figure 2B). Nine out of 11 studies had a serious risk of confounding, and 4 had a serious risk of selection bias.
The overall quality of evidence for the outcome of graft survival is described using the GRADE system in Table 2. No treatments were supported by high-quality evidence. The quality of evidence was moderate for rituximab, very low for eculizumab, and low for the remaining treatment modalities.
Outcome 1: Graft Survival
Overall, the reporting of outcome data for graft survival was inadequate with most studies providing only the number of graft failures without measures of effect or precision. Graft survival was only reported as time-to-event data in three studies, all of which were nonrandomized studies with historical controls20,24,25 (Table 3).
Antibody Removal and Graft Survival
There were five RCTs comparing antibody removal by plasmapheresis or immunoadsorption to control that reported on graft survival.12-14,16,17 As none of these reported time-to-event data, HRs for graft failure were estimated from the extracted data (Table 3). The estimated pooled effect using a random-effects model did not suggest a benefit for antibody removal for the outcome of graft survival (HR 0.76; 95% CI 0.35-1.63; P = 0.475, Figure 3). However, important heterogeneity was observed (I2 = 59%, χ2 for heterogeneity = 9.78; df = 4; P = 0.044) and was likely related to heterogeneity in both intervention and control therapies. Four out of the five studies examined antibody removal with plasmapheresis,13,14,16,17 whereas the remaining RCT12 studied antibody removal using column immunoadsorption. The control group was different for each study, including one or more of intravenous methylprednisolone, ATG, conversion to tacrolimus, cyclophosphamide, and total body irradiation (Table 1). In addition, follow-up time varied significantly and individual studies with longer follow-up (2-5 years) showed a trend toward a benefit for antibody removal,12-14 whereas studies with a shorter follow-up (1-7 months) showed a trend toward no benefit.16,17 This was supported by a sensitivity analysis restricted to the three studies with longer follow-up, which demonstrated a significant effect for antibody removal (n = 92; HR 0.46; 95% CI 0.26-0.82; P = 0.009, figure not shown). A separate sensitivity analysis including all five RCTs performed with a fixed-effects model did not substantially alter the direction or magnitude of the pooled estimate (HR 0.74; 95% CI 0.47-1.16; P = 0.204).
Effect of Plasmapheresis and IVIG on Graft Survival
There were two retrospective cohort studies investigating plasmapheresis and IVIG that included patients with acute AMR, chronic AMR, and in some patients, elements of both. Approximately 50% of patients in the first study had chronic lesions on histology at the time of diagnosis, and the study authors noted improved graft survival in the intervention compared to the control group with a mean follow-up of 7 years (HR 0.26; 95% CI not reported; P < 0.001).20 In the second study, 63% of patients had chronic lesions at diagnosis and no difference in actuarial graft failure was found between groups21 (Table 3).
Rituximab and Graft Survival
There has been one double-blind RCT of 40 patients comparing rituximab and standard of care to placebo and standard of care for the treatment of acute AMR.22 Standard of care consisted of six sessions of plasmapheresis with IVIG at a dose of 100 mg/kg after each plasmapheresis session, followed by 2 g/kg over 2 days at the end of the plasmapheresis cycle. Patients were followed for 1 year, at which time there was no difference in actuarial graft survival between the two groups. Notably, the rate of graft failure was only 5% at 1 year in both placebo and intervention arms. Two patients randomized to rituximab did not receive the intervention and were not accounted for in the final analysis, and there was treatment crossover in one patient in each group, introducing potential for bias in the analysis. Nevertheless, this RCT demonstrated both the efficacy of plasmapheresis and IVIG as standard of care, as well as the absence of additional benefit from rituximab at 1 year in the treatment of acute AMR.
A second randomized study examined the role of rituximab and thymoglobulin compared to thymoglobulin alone in pediatric transplant recipients with mixed T-cell and B-cell infiltrates on biopsy, of which a subgroup of eight patients also had evidence of AMR as defined by positive C4d staining. There was no difference in graft survival between the two groups and no evidence for benefit of rituximab in the setting of mixed acute AMR and CMR.23
In addition, there have been two retrospective cohort studies in acute AMR that compared rituximab, plasmapheresis, and IVIG to plasmapheresis and IVIG or IVIG alone, both of which demonstrated improved graft survival in the rituximab group.24,25 However, because of the historical nature of the control groups, patients in the rituximab group received a higher dose of plasmapheresis and IVIG, limiting the ability to make a direct comparison between groups.
Bortezomib and Graft Survival
Bortezomib is a proteasome inhibitor that has been trialed in the setting of AMR in one small RCT27 and four nonrandomized retrospective studies.28-31 All of these studies were underpowered and most have been published in abstract form only. The single randomized trial allocated 29 patients with mixed acute cellular and AMR to one of three arms: bortezomib, anti-thymocyte globulin (ATG), and plasmapheresis; rituximab, ATG, and plasmapheresis; or ATG and plasmapheresis alone. There was no difference in graft survival between the three groups after 3 years of follow-up, although there was potential for crossover into the bortezomib group in the trial design.27
Complement Inhibitors and Graft Survival
There was one randomized study of C1 inhibition in acute AMR in which 18 patients were assigned to C1 inhibitor, plasmapheresis, and IVIG or placebo, plasmapheresis, and IVIG. Graft survival was assessed at day 20 and at this early timepoint there were no graft failures in either group, although the C1-inhibitor group had less transplant glomerulopathy at 6 months.32 There has been one randomized study of eculizumab compared to observation alone in 15 patients with chronic AMR, and no difference was found in actuarial graft survival after 1 year of follow-up.34
Outcome 2: Graft Function
Thirteen out of 21 studies reported graft function either as a change in serum creatinine, estimated glomerular filtration rate (eGFR), or creatinine clearance from baseline to an arbitrary time point (Table 4). The timeframe chosen by authors ranged from 6 days to 2 years. Because of the heterogeneity of the outcome measures and the different time points at which they were reported, we were unable to calculate a pooled estimate of effect. Of the four studies involving plasmapheresis or plasmapheresis and IVIG, three studies13,19,20 demonstrated a statistically significant improvement in short-term graft function at 2 weeks, 6 months, or 1 year compared with the control group. Studies involving rituximab22,24 and eculizumab34 did not show a difference in graft function between groups at 1 year, 2 years, and 6 months, respectively. Studies of bortezomib and C1 inhibition were mixed with two out of four bortezomib studies29,30 and one out of two C1-inhibitor studies32 reporting improved short-term graft function.
Adverse events were reported in only seven studies,20,22-24,29,32,34 typically the more recent studies of rituximab, bortezomib, and eculizumab (Table 5).
This study represents an updated summary of the controlled evidence for therapeutic strategies in the treatment of AMR. Since the original systematic review on this topic was published,6 plasmapheresis and IVIG has emerged as the most common standard of care for the treatment of acute AMR in recent trials of newer therapeutic agents. However, the basis for this remains a small number of low-quality controlled studies in the setting of a mixture of acute and chronic AMR. Ideally, a high-quality RCT with sufficient power to assess the efficacy of plasmapheresis and IVIG as treatments for acute AMR would provide reassurance that this strategy should indeed be the standard of care it has become. However, it is highly unlikely that such a trial will be performed because of the ethical dilemma of assigning patients to no treatment, which is historically associated with high risks of graft loss,25,35 when plasmapheresis and IVIG have been associated with 95% graft survival at 1 year in the control arm of the RITUX-ERAH trial.22
In this same trial, rituximab was not shown to have added benefit over plasmapheresis and IVIG, in contrast to findings from previous observational studies,24,26 although it should be noted that the 12-month follow-up period may not have been long enough to detect a difference in graft survival. Trials of bortezomib have been underpowered and inconclusive to date; however, a further RCT of bortezomib for the treatment of chronic AMR has been registered and is in the data analysis stage.36 Although there has been much interest in targeting the complement system in the treatment of AMR, trials of C1 and C5 inhibitory agents have thus far been negative. Although the majority of these trials have been pilot studies, the multiple roles and redundancies built in to the complement system may be a factor that limits the clinical impact of targeting a single complement component, particularly in chronic AMR.
The clinical impact of studies included in this systematic review was also limited by inadequate outcome reporting, which highlights some of the issues surrounding the use of graft function as a surrogate for graft survival outcomes in kidney transplantation. Included studies reported different metrics of graft function at different time periods, rendering the estimation of an overall effect challenging. Ideally, RCTs should assess definitive endpoints such as time-dependent patient and graft survival; however, such outcomes require long periods of follow-up and increase the cost of trials substantially.37 Various surrogate markers have been proposed to address this, including serum creatinine at 1 year38 as well as proteinuria measures.39 More recently, a ≥30% decline in eGFR between 1 year and 3 years posttransplantation has been strongly associated with longer-term hard outcomes.40 Our systematic review also highlights the need for improved adverse event reporting in kidney transplantation trials, although this is a significant issue pertaining to many RCTs.41 Although short-term adverse events such as drug side effects and infections may be easily captured, important long-term adverse events such as cardiovascular morbidity and malignancy may require the use of data linkage to national databases.42 Thus future trial designs for the treatment of AMR should ideally have a minimum follow-up period of 1 to 3 years and include better adverse event reporting. Other desirable outcome measures include urinary protein excretion, donor-specific antibodies, and histology. Ultimately, until a standardized surrogate marker is validated in kidney transplantation, graft and patient survival should remain the gold-standard endpoint.
This systematic review presents the entirety of the controlled evidence for treatments of AMR, detected using a comprehensive search strategy of all major databases. Although the evidence presented is complete, we were only able to perform pooled analysis for the effect of antibody removal compared to control for the outcome of graft survival because of the insufficient number of RCTs available for more recent therapeutic agents. The pooled analysis should be interpreted with caution, however, given that the estimates of effect from individual studies were calculated from the published data, rather than from individual patient observations in each trial. In addition, there were important sources of clinical and methodological heterogeneity in the trials, including marked heterogeneity in intervention and control protocols, diagnostic criteria, chronicity of AMR, and duration of follow-up. The finding of a significant reduction in graft loss in trials of antibody removal that have at least 2 years of follow-up in our sensitivity analysis, compared to no benefit in the overall pooled analysis, highlights the impact of such heterogeneity. This systematic review therefore provides clinicians with a detailed summary of the published controlled trials and an awareness of the limitations of the evidence that our current clinical practice is based on.
This review also highlights clinical questions that remain unanswered by the evidence so far. For example, there have been no controlled trials assessing the frequency and volume of plasma exchanged, the composition of the exchange fluid, nor the dose, frequency, and duration of IVIG. Similarly, the role of specifically targeting T cells in the treatment of AMR remains unknown and may be an avenue for further study. Rationale for T-cell-based treatments include (1) the requirement for T-cell help to promote anti-HLA antibody production,43,44 (2) recent evidence that T-cell-mediated rejection is a precursor to the development of de novo DSA and subsequent AMR,35,45 and (3) observational data suggesting improved graft survival in cases of AMR where treatment included T-cell depletion.25 More fundamentally, our understanding of the pathogenesis of AMR remains incomplete, and further inquiry into the mechanisms and signaling pathways leading to B-cell activation, differentiation, and ultimately the development of donor-specific antibodies may reveal new targets for the treatment of AMR.
Plasmapheresis and IVIG have become standard of care for the treatment of acute AMR despite limited low-quality evidence. The addition of rituximab may make little or no difference to the outcome of AMR at 1 year, and the efficacy of newer agents such as bortezomib and complement inhibitors are being evaluated in ongoing studies. Along with a more standardized approach to reporting important clinical outcomes, including adverse events, future research should focus on elucidating the pathogenesis of AMR with the aim of identifying novel targets for therapeutic strategies.
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