Advances in immunosuppression over recent decades have contributed to improved outcomes for kidney transplant recipients (KTR), particularly graft survival. The introduction of cyclosporine and anti-thymocyte antibodies in the 1980s significantly reduced the incidence of early rejection and reduced the need for precise matching of human leukocyte antigens (HLAs). Antibodies directed toward donor HLA antigens (donor-specific antibodies [DSAs]), contribute to the occurrence of allograft rejection (1–13). Preformed DSAs develop after sensitizing exposures such as blood transfusion, pregnancy, or previous transplantation. Donor-specific antibodies are encountered in patients with end stage renal failure awaiting kidney transplantation and require expert care with HLA matching and consideration of desensitization before transplantation (14–17).
Posttransplantation, the development of de novo DSA or reappearance or increase in titers of DSA may be associated with allograft rejection, particularly antibody-mediated rejection (AMR), previously referred to as humoral rejection (1–13). The diagnostic criteria for AMR have evolved over recent years. Renal biopsies in patients with detectable DSA in serum, which showed histologic features of endothelial damage including neutrophil infiltration, necrosis, apoptosis, and thrombosis, have traditionally been termed vascular rejection (18). Several papers before 2003 established the role of DSA in the condition suggesting a diagnosis of AMR. The 2003 update of the 1997 Banff criteria defined AMR on the basis of three criteria: the presence of anti-HLA DSA in serum, allograft histology (polymorphonuclear-rich glomerular and/or peritubular inflammation) and allograft immunohistochemistry (positive staining for C4d+ in peritubular capillaries)(19). The diagnostic criteria continue to be an area of scientific and clinical interest (20).
Antibody-mediated rejection occurs because of direct and complement-mediated effects of the DSA on the allograft (18). Acute AMR is most commonly observed within 3 months posttransplant but can occur beyond this time, typically in response to excessive reduction in immunosuppression or nonadherence (2, 15, 21). The incidence of AMR varies worldwide, depending on the diagnostic criteria used, recipient sensitization and the immunosuppressive regimen, ranging from 3.1% (22) to as high as 30% to 40% (4, 15, 23). Antibody-mediated rejection in KTRs responds poorly to corticosteroids and antithymocyte agents alone, which are the standard treatment of the vastly more common acute cellular rejection (24).
International guidelines do not define an evidence-based treatment for AMR. KDIGO recommends the use of one or more of either corticosteroids, plasmapheresis (plasma exchange, PP), intravenous immunoglobulin (IVIG), anti-CD20 antibodies, or lymphocyte-depleting antibodies (25). Various recent reviews have discussed controversies and options in the treatment of AMR; however, a systematic review that also describes the strength of evidence for current treatments has not been published. Therefore, we conducted a systematic review of the literature to determine the efficacy of treatments for acute AMR in KTRs. The primary studies sought were double-blind randomized controlled trials determining the effect of a treatment on graft survival. We also wished to identify priorities for future research in the treatment of AMR.
The search strategy yielded 10,338 citations in electronic databases, from which five randomized controlled trials (RCTs) and seven other controlled studies in patients with acute AMR or vascular rejection were identified (Fig. 1). Five of these evaluated the effect of PP. A range of treatments (Table 1) and doses were used across these studies (and within individual centers, e.g., (21)). Some treatments were used over an extended period (e.g., IVIG and PP), whereas others were used for shorter periods (e.g., cyclophosphamide, tacrolimus, and biologic agents) reflecting the development of new therapies (Fig. 2).
The 12 controlled studies are summarized in Table 2. Marked heterogeneity was observed among these, including diagnostic criteria, severity of rejection, time since transplantation, and the treatment regimen. Of the RCTs, the median size of each arm was 13 patients (range, 5–23), and four were conducted over 25 years earlier and used outdated diagnostic criteria. Mixed rejection (AMR plus cell-mediated) was either reported, or possible, in each of the RCTs identified. Donor-specific antibodies were only measured in three RCTs (26–28), but these were not used to titrate therapy. Baseline immunosuppression typically included steroids and antiproliferative agents, with variable use of calcineurin inhibitors (Table 2).
The most promising results were reported from an RCT using a protein A immunoadsorption (IA) column (26). Nine of the 10 patients in this study were hemodialysis dependent at the time of enrollment (5 in intervention arm, 4 in control arm) because of AMR by Banff 1997 criteria; IVIG was not administered. At 3 weeks postenrollment, all patients in the active arm were dialysis independent. In contrast, renal function in the four hemodialysis-dependent patients in the control arm did not recover. This study was terminated on interim analysis because of significant benefit in the experimental arm and emerging data from uncontrolled studies reporting benefit from PP and IVIG. Donor-specific antibodies were not detected in all patients in this study, C4d+ deposition was less in the treatment group, and cellular rejection was present in one patient in each treatment arm.
Four RCTs evaluated the effect of plasma exchange: it was reported to be beneficial in one study (27), potentially harmful in another study (29) and no effect in two studies (28, 30). The regimen used varied in dose, frequency, and treatment intervals among the studies, and IVIG was not administered.
Controlled but nonrandomized studies supported the effect of rituximab (31–34), PP (32–35), and bortezomib (33, 36) (Table 2). Some studies used a combination of these therapies, so the relative importance of an individual treatment could not be determined. For example, a difference in effect was not observed between bortezomib and a combination of rituximab, PP, and IVIG (37); therefore, it is not clear from this study if any of these treatments were useful.
Because the controlled trials were all small in size and differed with respect to inclusion criteria and treatment regimens, statistical analyses were not conducted.
A large number of case series and case reports were identified, and similar marked heterogeneity was observed in diagnostic criteria, treatment, and dosing regimens. Reflecting the trends in treatment, and potentially the increasing incidence of AMR, the relative frequency with which the more popular treatments were administered during the last 40 years is shown in Figure 2.
Newer, costlier treatments, such as rituximab, bortezomib, and eculizumab, were increasingly used to treat refractory AMR, rather than as initial therapy. A systematic review presented in abstract form suggested that rituximab was potentially effective in the treatment of refractory AMR (odds ratio, 9; 95% confidence interval, 4.5–18). Given the likelihood that these studies were small and of low methodologic quality, the significance of the odds ratio is unclear; similarly, the authors concluded that an RCT was required to confirm this observation (38).
An evidence-based practice guideline recommended that IVIG be administered after PP for the treatment of AMR. It was also stated that this suggestion was based on low-quality studies and that the optimal dose of IVIG was unclear (published doses varied between 0.1 and 2 g/kg) (39).
A randomized controlled trial demonstrated that IVIG was effective for the treatment of steroid-resistant rejection, and although this study has been mentioned by some to support the use of IVIG, it was ineligible for inclusion in our systematic review because 83% of the patients had Banff 1 (pure cellular) rejection on biopsy (40).
Grading of the Evidence
The evidence supporting the efficacy of each proposed treatment is shown in Table 1. Because of the small size of the RCTs, generally outdated diagnostic criteria, and inadequate documentation of allocation, the evidence supporting these treatments was downgraded to “low.” The evidence supporting all other interventions was classified “very low.” We considered upgrading rituximab to low, given the results of the systematic review (38), but it has only been published in abstract form, and the inclusion criteria was limited to treatment refractory cases.
There is insufficient evidence to adequately guide the treatment of AMR. Overall, relevant RCTs were of low quality. No RCTs for IVIG in the treatment of AMR were identified, and yet it is a popular treatment (Fig. 2), presumably on the merit of case series and experimental data. As a result of the long period covered by this systematic review, varied and often outdated diagnostic criteria were used, and it is probable that cases differing to our current understanding of AMR were included. Baseline immunosuppression commonly differed to the modern practice of calcineurin inhibitors and mycophenolate, further limiting the relevance of a number of these studies to current practice. A large number of case reports and case series were identified for which treatment regimens varied markedly. Dose-response studies were not found, further limiting our ability to recommend an optimal dose regimen. The majority of studies report positive responses to existing therapy (allograft survival of 70%–100%, patient survival of 94%–100% (41)), although it is well established that uncontrolled or poorly blinded studies favor positive outcomes. Although knowledge of the diagnosis and pathophysiology of AMR is advancing, evidence supporting existing treatments is poor. Future research should focus on adequately controlled trials, requiring multicenter recruitment because of the rarity of AMR, consistent diagnostic criteria, and rationalization of existing treatment regimens for the purpose of decreasing complications, inconvenience, and expense.
Evidence Supporting the Current Treatments for AMR
Use of the treatments described in Table 1 is largely ad hoc, extrapolating from other clinical conditions and supported by experimental data. The current rationale for treatment of AMR is to interfere with multiple pathophysiologic pathways using combination therapy. Although some combinations are popular, on the basis of the current data, we could not determine the optimal treatment regimen nor the relative importance of one therapy over another. The low incidence of AMR has also limited the opportunity to define the optimal dosing regimen for many treatments. This is reflected in current regimens; for example, IVIG doses in the literature vary between 0.1 and 2 g/kg (39, 41).
Of the more commonly used treatments listed in Table 1, IA has the strongest evidence (based on one small RCT that was terminated after an early interim analysis suggested a strong treatment effect). Despite its apparent efficacy, few reports of IA for the treatment of AMR exist (Fig. 2).
Randomized controlled trials have not confirmed a benefit from plasmapheresis (Table 2), and a review in 1983 reported marked variability in its apparent effect with response rates between 0% and 93% in 13 noncontrolled case series (42). However, the treatment regimen used in these earlier studies did not routinely include IVIG, in contrast to current practice, so the risk-benefit reported by these older studies may differ to current practice. Despite the serious limitations of older studies, PP is a common treatment for AMR (Fig. 2).
In the absence of high level evidence supporting existing regimens for treatment of AMR, treatment decisions may be supported by data from desensitizing protocols. For example, both IA and PP decrease DSAs and PRA (14–16, 43–50); IVIG also lowers the PRA in highly sensitized patients, and the effect may persist for months (17, 51–54). A single cycle of bortezomib did not decrease the DSA titer posttransplantation (55), and there is marked interindividual variability in the magnitude of response to rituximab pretransplantation (56). Eculizumab seems to reduce the incidence of AMR in highly sensitized individuals when administered immediately posttransplant (23). These observed effects may differ in patients posttransplantation with AMR because of ongoing antigenic stimulation; however, it may be possible to extrapolate from these studies to determine that a certain dose of a treatment may have an effect.
Thus, the optimal treatment of AMR is unknown. A topical question is the risk-benefit of biologic agents. Although current regimens may be effective in the treatment of acute AMR, they may also be associated with unnecessary adverse effects, inconvenience, or cost. Therefore, further studies are required to determine the optimal treatment of AMR.
More clinical studies, ideally RCTs, are required to optimize the treatment of AMR and given the low incidence of AMR this is likely to require multicenter involvement. Such studies should vary a single therapy, or dose, and continue other treatments. Uncontrolled studies suggest possible benefit of existing combinations of treatment, so there may be some hesitation with comparing the therapy with placebo. Alternative approaches are to compare existing treatments, to clarify the dose-response relationship, and to validate biomarkers that may be used to tailor treatment. Some of these issues were discussed in a recent FDA open workshop (57).
Plasmapheresis is a common treatment despite immunoadsorption having superior evidence and a similar mechanism of action, and therefore, direct comparison of these treatments would be appropriate. Given the increasing use of rituximab and bortezomib (Fig. 2) with conflicting data on efficacy (58), it would be useful to establish the optimal dose and to compare these treatments directly.
Future clinical trials should also explore the role of a biomarker-based approach to monitoring the response to therapy. The most commonly used biomarkers are plasma creatinine concentration and urine output, but these are nonspecific because they reflect multiple physiologic and pathologic processes. Few studies identified in this systematic review reported biomarkers considered more specific to AMR, including changes in plasma DSA titers or PRA, and histology or histochemical (i.e., C4d deposition) on renal biopsy.
A biomarker approach to treatment is appealing because it may allow the dose and duration of treatment to be adjusted to the individual. For example, it may be useful for identifying patients in which treatment is required, those requiring an augmentation in treatment, or for indicating when a treatment may be reduced or ceased. However, there are limitations with existing biomarkers, and validation of alternatives is a field of ongoing research.
In conclusion, data supporting current treatments for AMR in KTRs are of low quality. Therefore, more research is required to confirm the effect of existing regimens. This should include large, multicenter randomized controlled studies. The effect of dose on the response, and use of biomarkers to guide therapy, should be explored further. This is a step toward rationalizing the current treatment of AMR and to optimize benefits and minimize hazards, including prevention of adverse reactions and minimizing cost and futility.
This systematic review was conducted according to the PRISMA guidelines (http://www.prisma-statement.org/). Our study was not registered with the prospective registration database PROSPERO (http://www.crd.york.ac.uk/prospero/) because it was commenced before the database being established.
We searched MEDLINE (1950 to March, Week 1 2011), EMBASE (1980 to March, Week1 2011), the Cochrane Register of Controlled Trials (CENTRAL 2009-latest issue), and conference proceedings from 2010 and 2011 (American Transplantation Congress, World Congress of Nephrology, American Society of Nephrology, European Dialysis and Transplantation Association, World Transplant Congress and Transplantation Society of Australia and New Zealand) for controlled trials, case series, and reports of the treatment of AMR. Experts in the field were contacted to ascertain unpublished or additional papers. No restrictions were imposed on the basis of publication status.
The databases were searched using a highly sensitive search strategy (see Appendix) identifying IVIG, monoclonal antibodies (rituximab or eculizumab), proteasome inhibitors (bortezomib), and PP as either text word or medical subject headings (MeSH). Plasmapheresis and plasma exchange were considered interchangeable treatments. Antibody-mediated rejection was defined by current Banff classification (19). In the pre-Banff classification period, we included articles examining vascular rejection because this was believed to be antibody mediated at the time. Graft rejection, antibody-mediated rejection, humoral rejection, and vascular rejection were searched as text words and MeSH terms. These terms were searched by kidney or renal transplantation. Pediatric patients and dual kidney-pancreas transplants were excluded. Two authors (S.J. and D.R.) independently reviewed titles and abstracts, selecting papers that potentially met the inclusion criteria. The reference lists were also reviewed for other relevant publications.
We identified all publications (controlled trials, case series, or case reports) pertaining to the treatment of antibody-mediated, humoral, or vascular rejection in KTRs. A histopathologic diagnosis on kidney biopsy was required for full text publications. In the case of conference abstracts, if the diagnosis was stated to be AMR, then this was considered sufficient as histopathologic changes are required by current Banff criteria. No language restrictions were imposed, and relevant non-English language publications were translated.
Each potentially relevant publication was reviewed by two authors (S.J. and D.R.), and in the case of disagreement regarding whether it fulfilled inclusion criteria, this was resolved by an arbitrator (S.C.).
Case series and reports were also reviewed to determine the types of treatments given to patients with AMR for the purpose of ascertaining trends in the therapy of AMR over time.
Data Extraction and Trial Quality
Independent reviewers (S.J. and D.R.) extracted data from controlled trials using a preformed spreadsheet. The risk of bias and trial quality was assessed using the Cochrane Collaboration’s tool for assessing bias (59). As per this tool, allocation concealment was considered adequate if the method of randomization was obscured to participants and investigators, at least before randomization. Intention-to-treat analysis was considered adequate if the patients were analyzed by the group to which they were allocated at the time of randomization. Loss to follow-up was defined by the proportion of population who discontinued the treatment and in whom data could not be identified in trial analysis.
Where available, the following were obtained from the controlled trials: the diagnostic criteria for rejection, time since transplantation, source of kidney (deceased or live donor), recipient sensitization (as per (60)), type and dose of each intervention after the diagnosis, background immunosuppression, primary and secondary outcomes, creatinine at the time of diagnosis and after treatment, response to treatment including graft loss, mortality and graft function, adverse events (infection, malignancy, and death), and the incorporation of biomarkers in treatment decisions. The intervention was considered to be beneficial overall if a statistically significant improvement in allograft survival was reported.
Grading of the Evidence
Using the GRADE system (61), the strength of evidence supporting the efficacy of each of the proposed treatments was determined. Here, the evidence supporting a treatment was graded as “high” if randomized controlled trials were available, “low” if data were limited to that obtained from nonrandomized controlled studies, and “very low” if limited to uncontrolled studies, including case series and case reports. A treatment could be reclassified to a higher grade if (i) a large magnitude of effect exists, (ii) a dose-response gradient was present, or (iii) if all plausible confounders or other biases increase confidence in the estimated effect. Furthermore, a treatment could be reclassified to a lower grade in the presence of the following: (i) a serious limitation to study quality, (ii) important inconsistency, (iii) some uncertainty about directness, (iv) imprecise or sparse data, or (v) high probability of reporting bias.
Grading was performed independently by D.R. and S.J., and where there was disagreement about a final grade, this was resolved by an arbitrator (S.C.).
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Appendix. Search criteria used for this systematic review
- 1 exp Kidney Transplantation/ (69824)
- 2 (transplant* adj40 (kidney* or renal*)).tw. (62122)
- 3 1 or 2 (84222)
- 4 exp Antibodies, Monoclonal/ (153289)
- 5 (monoclonal* adj40 antibod*).tw. (154724)
- 6 (monoclonal* adj40 anti-bod*).tw. (52)
- 7 exp Immunoglobulins, Intravenous/ (7994)
- 8 (intravenous* adj40 immunoglobulin*).tw. (7577)
- 9 IvIg.tw. (3382)
- 10 octagam.tw. (12)
- 11 intragam*.tw. (16)
- 12 exp Plasmapheresis/ (7011)
- 13 plasmapher*.tw. (6216)
- 14 exp Plasma Exchange/ (4270)
- 15 (plasma* adj40 exchange*).tw. (11807)
- 16 rituximab*.tw. (5827)
- 17 (anti-cd20* adj40 antibod*).tw. (1632)
- 18 (CD20* adj30 antibod*).tw. (2948)
- 19 bortezomib*.tw. (2081)
- 20 (proteasome* adj40 inhibit*).tw. (7697)
- 21 eculizumab*.tw. (108)
- 22 (C5* adj40 antibod*).tw. (4796)
- 23 or/4-22 (259861)
- 24 exp Graft Rejection/ (45141)
- 25 (acute* adj30 (reject* and humoral*)).tw. (563)
- 26 (antibod* adj40 reject*).tw. (6372)
- 27 (anti-bod* adj40 reject*).tw. (7)
- 28 (humor* adj40 reject*).tw. (1413)
- 29 (allograft* adj40 reject*).tw. (16159)
- 30 or/24-29 (52160)
- 31 3 and 23 and 30 (2636)