Introduction
(Article introduction authored by Conquest Editorial Team)
Advancements in immunosuppression have significantly improved outcomes for kidney transplant recipients (KTR), particularly in graft survival. The introduction of cyclosporine and anti-thymocyte antibodies in the 1980s reduced early rejection rates and diminished the necessity for precise HLA matching. Donor-specific antibodies (DSAs) play a crucial role in allograft rejection, with preformed DSAs necessitating careful HLA matching and potential desensitization pre-transplantation. Post-transplantation, de novo DSAs or increases in titers may lead to allograft rejection, particularly antibody-mediated rejection (AMR).
The diagnostic criteria for AMR have evolved, with emphasis on DSA presence, allograft histology, and immunohistochemistry. AMR is challenging to treat, with guidelines recommending various modalities including corticosteroids, plasmapheresis, intravenous immunoglobulin, and antibody therapies. However, evidence-based treatments for AMR remain undefined, prompting the need for systematic reviews to determine efficacy and identify research priorities.
Methods
The search strategy encompassed multiple databases and conference proceedings, including MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and various transplant-related conferences.
The search terms targeted specific treatments for antibody-mediated rejection (AMR) such as IVIG, rituximab, eculizumab, bortezomib, and plasmapheresis (PP). Inclusion criteria required histopathologic confirmation of rejection, and conference abstracts were included if they explicitly mentioned AMR.
Two authors independently screened titles and abstracts, with a third arbitrator resolving any discrepancies. Data extraction from controlled trials included key details like diagnostic criteria, intervention specifics, outcomes, and adverse events. The quality of evidence was assessed using the Cochrane Collaboration’s tool, with treatment efficacy graded as high, low, or very low based on the GRADE system, considering factors like study design, magnitude of effect, and potential biases.
Results
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.
Five of these evaluated the effect of PP. A range of treatments and doses were used across these studies. 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.
Controlled Trials
The median arm size in randomized controlled trials (RCTs) was 13 patients, with some studies employing outdated diagnostic criteria. Mixed rejection was observed in all RCTs, with donor-specific antibodies measured in only three studies but not utilized for therapy titration. Baseline immunosuppression typically included steroids and antiproliferative agents, with variable use of calcineurin inhibitors. Promising results were reported from an RCT using protein A immunoadsorption, with significant dialysis independence observed in the experimental arm. Four RCTs assessed plasma exchange, showing mixed results, while nonrandomized studies supported rituximab, plasma exchange, and bortezomib. Due to the small size and heterogeneity of controlled trials, statistical analyses were not feasible.
Other Publications
A plethora of case series and reports displayed significant heterogeneity in diagnostic criteria, treatment modalities, and dosing regimens for antibody-mediated rejection (AMR).
There are evolving trends in treatment preferences over the past four decades, with newer, more expensive therapies like rituximab, bortezomib, and eculizumab increasingly utilized for refractory AMR rather than as first-line options.
A preliminary systematic review suggested potential efficacy of rituximab for refractory AMR, but its significance remains uncertain due to small and possibly low-quality studies, prompting the need for a randomized controlled trial for validation.
Although an evidence-based guideline recommended intravenous immunoglobulin (IVIG) post-plasma exchange for AMR treatment, the supporting evidence was of low quality, and optimal dosing remains unclear, varying widely between published studies.
Notably, a randomized controlled trial demonstrated IVIG efficacy for steroid-resistant rejection, yet its inclusion was ineligible for the systematic review due to predominant cellular rejection cases.
Grading of evidence across interventions was generally low or very low due to small RCT sizes, outdated diagnostic criteria, and insufficient allocation documentation, with potential consideration for upgrading rituximab evidence pending further validation beyond abstract form.
Discussion
Insufficient evidence exists to guide the treatment of antibody-mediated rejection (AMR), with relevant randomized controlled trials (RCTs) generally of low quality.
Despite the popularity of intravenous immunoglobulin (IVIG) as a treatment for AMR, no RCTs specifically for IVIG in AMR were identified, likely relying on case series and experimental data for its use.
Varied and often outdated diagnostic criteria were utilized across studies, potentially including cases not aligned with current understanding of AMR. Moreover, baseline immunosuppression differed from modern practice, further limiting study relevance. Treatment regimens varied widely among identified case reports and series, with a lack of dose-response studies hindering optimal regimen recommendations.
While many studies reported positive outcomes with existing therapy, the evidence base remains weak, highlighting the need for well-controlled multicenter trials with consistent diagnostic criteria and rationalized treatment regimens to improve patient outcomes and reduce complications and costs associated with AMR management.
Evidence Supporting the Current Treatments for AMR
The use of treatments for antibody-mediated rejection (AMR) is largely based on ad hoc approaches, often extrapolating from other clinical conditions and supported by experimental data.
The current rationale involves interfering with multiple pathophysiologic pathways using combination therapy, although the optimal regimen or relative importance of specific therapies remains undetermined.
Limited incidence of AMR has hindered defining optimal dosing regimens for many treatments, reflected in variable IVIG doses reported in the literature.
While immunoadsorption (IA) shows promise based on limited evidence, few reports exist on its use for AMR.
Plasmapheresis, despite common use, lacks confirmed benefit from randomized controlled trials, with historical data showing variable response rates possibly influenced by absence of IVIG.
Decision-making in treatment may draw insights from desensitizing protocols, with various treatments affecting donor-specific antibodies (DSAs) and panel reactive antibodies (PRA) differently.
However, the optimal treatment for AMR remains elusive, warranting further research to balance efficacy against potential adverse effects, inconvenience, and cost.
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. The effect of dose on the response, and use of biomarkers to guide therapy, should be explored further.
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