Outcomes of Renal Transplantation in ANCA-Associated Vasculitis: A Systematic Review and Meta-Analysis

Introduction

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare, complex autoimmune conditions [1–4]. This heterogeneous spectrum of diseases includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis, and renal-limited ANCA vasculitis [5,6]. Renal damage is a hallmark feature of the disease, with 50–80% of patients rapidly progressing to glomerulonephritis [7]. Notably, end-stage kidney disease (ESKD) develops in 20–40% of AAV patients [8,9].

While kidney transplantation remains the optimal renal replacement therapy for eligible patients with AAV and ESKD, it is associated with unique complications in this population. Factors such as histological features, patient age, glomerular filtration rate, and PR3-ANCA status at the time of kidney transplantation have all been identified as poor prognostic indicators [10–12]. Despite a relatively low rate of AAV relapse after kidney transplantation (about 0.02 events per patient-year), the absence of clear guidelines regarding the timing and indications for kidney transplantation, as well as the risk factors for post-transplantation AAV relapse, have raised concerns about the potential adverse effects of disease recurrence on both graft and patient survival.

While individual studies [13–16] have explored the outcomes of ANCA-associated renal transplantation, no comprehensive meta-analysis of these outcomes is available to date.

This systematic review summarizes the existing data and provides insight into the factors influencing transplantation outcomes in AAV patients with ESKD, including primary outcomes like graft and patient survival, and secondary outcomes like disease recurrence, and post-transplantation complications.

Material and Methods

RESEARCH QUESTION:

What are the outcomes of renal transplantation in patients with ANCA-associated vasculitis?

Population/Participants (P): Patients with ESKD undergoing kidney transplantation.

Exposure (E): Patients with AAV.

Comparison (C): Patients with no AAV.

Outcomes (O): Primary outcomes like graft and patient survival and secondary outcomes like disease recurrence, and post-transplantation complications.

SEARCH STRATEGY:

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were strictly followed, and the protocol was registered at PROSPERO with registration number CRD42023464690. Comprehensive searches of relevant electronic databases, including PubMed, Embase, and Scopus, were performed to identify studies published up to 30 September 2023. Combinations of the following keywords and Medical Subject Headings (MeSH) terms were used: “ANCA-associated vasculitis”; “AAV”; “renal transplantation”; “kidney transplant”; “outcomes”; “graft survival”; “disease recurrence”. Search string was as follows: (ANCA-Associated Vasculitis/therapy [MeSH Terms] OR “ANCA-associated vasculitis” OR “AAV” OR “Granulomatosis with Polyangiitis” OR “GPA” OR “Microscopic Polyangiitis” OR “MPA”) AND (Kidney Transplantation [MeSH Terms] OR “Renal transplantation” OR “Kidney transplant” OR “Kidney transplantation” OR “Kidney graft”) AND (Treatment Outcome [MeSH Terms] OR “Outcomes” OR “Graft survival” OR “Patient survival” OR “Disease recurrence” OR “Complications” OR “Risk factors”).

Bibliographies of included articles and applicable reviews were also screened to identify missed studies. A manual screening of issues of relevant nephrology journals was done for any potentially eligible studies that were missed.

Inclusion criteria:

Exclusion Criteria:

DATA EXTRACTION:

Initial screening of titles and abstracts for eligibility was independently done by 2 reviewers. Full-text articles were then read, and any discrepancies or disagreements were resolved by discussion. A standardized form for data extraction included study characteristics (author, publication year, study design), patient demographics (age, sex), AAV subtype, and relevant outcome data like survival, relapse rate, infection, and mortality.

QUALITY ASSESSMENT:

The quality and risk of bias were assessed by the Newcastle-Ottawa Scale for observational studies. Two reviewers independently assessed each study, and resolved differences by discussion.

STATISTICAL ANALYSIS:

A meta-analysis was conducted using statistics software (RevMan 5.4v, Cochrane Collaboration, UK). For studies with comparable outcome measures, pooled estimates, including hazard ratios (HRs), odds ratios (ORs), or mean differences (MDs) with 95% confidence interval (CI) were calculated and plotted as forest plots. The “Inverse Variance (IV), Random” method was used to calculate the effect estimates for each outcome. Heterogeneity among studies was assessed using the I² statistic, and a random-effects model was used if substantial heterogeneity was detected. I2 >70% indicated high heterogeneity and I2 <50% indicated low heterogeneity. The publication bias was assessed using the visualization of funnel plots.

Results

META-ANALYSIS:

Of 23 selected studies, 18 were eligible for the meta-analysis, and were found to report similar outcomes, to systematically analyze and quantify the outcomes of renal transplantation in AAV patients, with a focus on mortality, survival, infection rates, and relapse rates. The rest of the studies were analyzed qualitatively.

AAV patients who underwent renal transplantation had an approximately 12-fold higher mortality rate (RR of 11.99). The 95% CI of 9.09–15.82 was indicative of the level of uncertainty associated with the estimate (Figure 2).

The cumulative survival estimate of HR 0.80 [0.43, 1.50] indicated that the mortality risk in AAV patients was comparable to that of patients without AAV (Figure 3).

AAV was linked to a significant, 53-fold increase in the rate of infections (RR of 52.70). The 95% CI ranged from 21.74 to 127.74, indicating a wide range of uncertainty (Figure 4).

The relapse rate (RR of 6.96) indicated a significantly higher relapse rate in AAV patients undergoing renal transplantation. The 95% CI ranged from 5.62 to 8.62, showing a relatively narrow range of uncertainty (Figure 5).

Discussion

This study analyzed the outcomes of renal transplantation in patients with AAV, and showed that AAV was associated with a high post-transplantation mortality rate, increased infection risk, and a high relapse rate. However, AAV patients who survived renal transplantation had overall favorable long-term outcomes.

The meta-analysis revealed a high mortality rate in AAV patients, with a pooled rate ratio of 11.99 per 100 patient-years. This rate underscores the considerable risk faced by AAV patients following the surgery. Several factors may contribute to this increased mortality risk. First, the extensive immunosuppression required to prevent graft rejection can render AAV patients more susceptible to infections, malignancies, and other transplantation-related complications [36,37]. Second, AAV is characterized by small-vessel inflammation, thus potentially presenting ongoing post-transplantation challenges [38]. Nevertheless, our results showed that AAV patients have a favorable survival rate, with a hazard ratio (HR) of 0.80. This suggests that while AAV patients face a higher mortality risk, those who do survive may experience relatively satisfactory long-term outcomes. Our findings underscore the delicate balance between managing AAV and preventing graft rejection, requiring close post-transplant monitoring and management.

The high post-transplantation infection rates in AAV patients are a matter of concern. Immunosuppressive regimens in renal transplantation patients make them highly susceptible to infections [36,39]. The high rate of infections observed in our study further emphasizes the importance of stringent infection control measures in the post-transplantation care of AAV patients.

Our study has some limitations. The diversity in patient populations across the studies was a source of heterogeneity. Variability was observed in terms of patient demographics, clinical characteristics, and comorbidities. Differences in the inclusion criteria, such as the specific types of AAV considered (GPA, MPA, or others), and the definitions of end-stage kidney disease (ESKD) may have influenced patient selection. The geographic locations of the studies also introduced potential regional disparities in patient characteristics and clinical practices. Clinical practices were not standardized across the studies, including the choice of immunosuppressive regimens, post-transplantation monitoring protocols, and management of infections and relapses. Different institutions and regions may have distinct protocols and preferences, introducing variability in patient care, which can directly impact outcomes like infection rates, relapse rates, and patient survival. While a random-effects model may address some of the heterogeneity by providing more conservative estimates [40–42], the presence of heterogeneity should not be overlooked. Further studies, incorporating standardized protocols and larger sample sizes, are needed to provide more precise insights into the outcomes of renal transplantation in AAV patients.

The findings of this systematic review have several clinical implications. They emphasize the necessity for continuous research and the development of standardized protocols for patient selection, immunosuppressive regimens, and post-transplantation monitoring. A multidisciplinary approach involving nephrologists, rheumatologists, and transplant specialists is crucial in achieving better outcomes for AAV patients after transplantation.

Conclusions

In conclusion, renal transplantation remains a vital therapeutic option for AAV patients with ESKD. The high post-transplantation mortality rate, increased infection risk, and an increased relapse rate, reported by our study may guide clinicians in optimizing care of AAV patients undergoing renal transplantation. A comprehensive understanding of the complexities of managing AAV-associated renal transplantation is crucial for providing informed care, mitigating risks, and improving patient outcomes in this population of ESKD patients.