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

Abstract

Background

Antineutrophil cytoplasmic antibody-associated vasculitis is characterized by small-vessel inflammation and ANCA-positive serology that often lead to end-stage kidney disease. This study investigated the outcomes of renal transplantation in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

Material/Methods

A comprehensive search of PubMed, Scopus, and Embase databases was done to retrieve studies that reported on the outcomes of renal transplantation in these patients. Data on mortality, survival, infection, and relapse rates were analyzed. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale for cohort studies.

Results

Twenty-three retrospective cohort studies were included in this review. Antineutrophil cytoplasmic antibody-associated vasculitis was associated with high post-transplantation mortality rates, with a pooled rate ratio of 11.99 per 100 patient-years, but relatively favorable survival rate (hazard rate of 0.80). After renal transplantation, these patients had elevated infection rates (pooled rate ratio of 52.70 per 100 patient-years), and high risk of relapse (pooled rate ratio of 6.96), emphasizing the importance of vigilant post-transplantation monitoring.

Conclusions

End-stage kidney disease patients with vasculitis, undergoing renal transplantation, are at elevated risk of mortality and postoperative infection compared to patients without antineutrophil cytoplasmic antibody-associated vasculitis. The risk of relapse is also high in these patients. However, renal transplantation offers a survival advantage for vasculitis patients who survive the early post-transplantation period.

PROSPERO Registration Number

CRD42023464690

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:

• Observational studies (cohort studies, case-control studies, cross-sectional studies).

• Adult patients (18 years and older) with a confirmed diagnosis of ANCA-associated vasculitis (AAV) subtypes, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or related subtypes.

• Patients who underwent renal transplantation as a treatment modality for end-stage kidney disease (ESKD) resulting from AAV.

• Studies reporting on renal transplantation as the primary intervention.

• Studies that report relevant primary or secondary outcomes related to renal transplantation in AAV.

• Long-term follow-up data.

• Studies published in English.

Exclusion Criteria:

• Case reports, case series, editorials, letters, commentaries, and conference abstracts.

• Studies not specifically addressing renal transplantation in AAV.

• Studies lacking relevant outcome data or not reporting outcomes related to renal transplantation in AAV.

• Studies published in languages other than English.

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

Twenty-three studies [13–35] that evaluated the outcomes of renal transplantation in patients with ANCA-associated vasculitis were included in this review. A total of 965 records were identified from the electronic search. After removing duplicates, 923 records were subjected to title and abstract screening based on relevancy. Full-text articles of 26 potentially eligible records were thoroughly assessed based on eligibility criteria. Finally, 23 studies [13–35] were included in this review (Figure 1). The details of the included studies are provided in Table 1.

Figure 1.

PRISMA flow chart for study selection.

Table 1.

Characteristics of included studies.

First Author	Year	Study period	Study design	Study setting	Study location	Inclusion criteria
Silva et al [13]	2023	2011–2020	Retrospective cohort	Single-centre	Portugal	AAV with ESKD as her CHCC
Kauffmann et al [14]	2021	2008–2021	Retrospective cohort	Population-database	France	Renal failure due to GPA or MPA on dialysis
Rathmann et al [15]	2021	1997–2017	Retrospective cohort	Population-database	Sweden	Histology, ANCA or surrogate markers positive
Kuhnel et al [16]	2021	1990–2018	Retrospective cohort	Population-database	Australia & New Zealand	Primary Kidney Disease with ANCA associated Vasculitis
Hasegawa et al [17]	2021	2005–2016	Retrospective cohort	Multi-centre	Japan	ANCA positive, signs of renal involvement
Miyabe et al [18]	2019	2000–2016	Retrospective cohort	Single-centre	Japan	AAV
Wang et al [19]	2019	2005–2015	Retrospective cohort	Single-centre	China	AAV as per CHCC
Park et al [20]	2018	2000–2017	Retrospective cohort	Single-centre	Korea	AAV as per CHCC
Buttigieg et al [21]	2017	1987–2013	Retrospective cohort	Single-centre	Scotland	ANCA positive, signs of renal invlvement
Hasegawa et al [22]	2015	1991–2012	Retrospective cohort	Single-centre	Japan	AAV as per EMAA MPO-ANCA only
Weiner et al [23]	2015	1997–2009	Retrospective cohort	Multi-centre	Sweden, UK and Czech Republic	≥75y, MPA or GPA as per EMAA
Chen et al [24]	2014	1997–2011	Retrospective cohort	Single-centre	China	AAV as per CHCC1 and ACR1, HD/PD >3mo
Merino et al [25]	2010	1989–2008	Retrospective cohort	Multi-centre	Spain	Pauci-immune GN GPA, EGPA, Anti-GBM
Borao-Cengotita-Bengoa et al [26]	2010	1990–2006	Retrospective cohort	Single-centre	Spain	AAV as per CHCC and ACR (for GPA only)
Lionaki et al [27]	2009	1986–2017	Inception cohort	Multi-centre	US	ANCA +ve and ESRD; compared with ANCA +ve and preserved renal function
Weidanz et al [28]	2007	1971–2004	Retrospective cohort	Single-centre	UK	AAV as per CHCC and ACR, Dialysis > 4 weeks
Weidner et al [29]	2004	NR	Retrospective cohort	Single-centre	Germany	AAV as per CHCC with biopsy
Booth et al [30]	2003	1995–2000	Retrospective cohort	Multi-centre	UK	AAV as per CHCC with renal involvement
Haubitz et al [31]	1998	1976–1993	Retrospective cohort	Single-centre	Germany	GPA as per CHCC and ACR, undergoing chronic dialysis
Allen et al [32]	1998	1974–1997	Retrospective cohort	Single-centre	UK	AAV as per CHCC who developed ESRD
Schleiffer et al [33]	1998	1984–1993	Retrospective cohort	Single-centre	Germany	AAV as per CHCC and ACR
Garrett et al [34]	1992	1987–1988	Retrospective cohort	Single-centre	UK	ANCA +ve with clinical or histology suggestive of vasculitis
Coward et al [35]	1986	NR	Retrospective cohort	Single-centre	UK	Renal biopsy of GPA or PAN
First Author	Exclusion criteria	N (N with ESKD)	Mean follow-up, years (SD)	Mean age, years (SD)	Types of AAV	Outcomes reported
Silva et al [13]	NR	27	2.2 (0.8)	39 (16)	NR	Survival
Kauffmann et al [14]	Patients not paired with national health data	229	3.2 (2.3)	66 (13)	142 GPA, 87 MPA	Survival, relapse, infection
Rathmann et al [15]	NR	325 (51)	2.2	NR	NR	Infection
Kuhnel et al [16]	Uncertain or unreported cause of kidney failure	254	NR	56 (5)	NR	Survival, infection
Hasegawa et al [17]	AVR, AS at onset of AAV	97 (39)	9.2 (5.8)	65 (11)	2 GPA, 37 MPA	Survival
Miyabe et al [18]	IHD < 6 months	11	5 (4.1)	58 (!5)	1 GPA, 10 MPA	Survival, relapse
Wang et al [19]	Renal Recovery	20	1.9 (2)	52 (14)	6 GPA, 14 MPA	Survival
Park et al [20]	NR	144 (4)	NR	37 (16)	1 GPA, 3 MPA	Survival
Buttigieg et al [21]	NR	24	5	45 (13)	17 GPA, 7 MPA	Survival
Hasegawa et al [22]	<20 years old	−89	4.5 (4.3)	68 (11)	1 GPA, 88 MPA	Survival, relapse, infection
Weiner et al [23]	EGPA, PAN, Anti-GBM, secondary vasculitis	151 (37)	1.4***	NR	NR	Survival
Chen et al [24]	Secondary vasculitis, Anti-GBM	49	NR	58 (12)	5 GPA, 38 MPA, 6 RLV	Survival
Merino et al [25]	GPA, EGPA, Anti-GBM	−19	6.1 (5.8)	66 (12)	19 MPA or RLV	Survival, relapse
Borao-Cengotita-Bengoa et al [26]	Inconclusive or missing biopsy	31 (14)	8.5 (7.1)	52 (20)	3 GPA, 11 MPA	Survival, relapse
Lionaki et al [27]	Patients censored at transplantation	452 (93)	2 (1.5)	56 (22)	14 GPA, 48 MPA, 1 EGPA, 49 RLV	Survival, relapse, infection
Weidanz et al [28]	Recovered renal function, Anti-GBM, IgAV	−46	2.6 (2.1)	58 (17)	21 GPA, 24 MPA, 1 EGPA	Survival, relapse, infection
Weidner et al [29]	No renal involvement	80 (18)	5.9 (3.4)	NR	12 GPA, 6 MPA	Survival
Booth et al [30]	NR	246 (68)	3.6***	NR	NR	Survival
Haubitz et al [31]	Patients censored at transplantation	−35	3.4 (2.5)	45 (18)	35 GPA	Survival, relapse
Allen et al [32]	Recovered renal function, Death within 2 mo of dialysis onset	−59	5.2 (3.3)	52 (13–77)**	23 GPA, 23 MPA, 3 EGPA	Survival, relapse
Schleiffer et al [33]	NR	23 (9)	2.9 (2.8)	56 (15)	5 GPA, 4 MPA	Survival
Garrett et al [34]	NR	30 (5)	1.2***	NR	NR	Survival, infection
Coward et al [35]	SLE, HSP	36 (9)*	5.0 (3.6)	42 (10)	6 GPA, 3 MPA	Survival

AAV – ANCA associated vasculitis; ANCA – anti-neutrophil cytoplasmic antibody; GPA – granulomatosis with polyangiitis; MPA – microscopic polyangiitis; EGPA – eosinophilic granulomatosis with polyangiitis; ESKD – end stage kidney disease; GBM – glomerular basement membrane; CHCC – Chapel hill consensus conference; ACR – albumin to Creatinine ratio; PAN – Polyarteritis nodosa; SLE – systemic lupus erythromatosis; HSP – Henoch-Schonlein purpura.

All studies were retrospective cohort studies examining renal transplantation outcomes in patients with ANCA-associated vasculitis (AAV) over several years. The studies were conducted from 1986 to 2023, and included 2503 patients, many of whom had ESKD necessitating renal transplantation. The mean follow-up (post-transplantation monitoring) across the studies ranged from 1.2 to 9.2 years. The average age of patients at start of the studies varied from 39 to 68 years. Various types of AAV were represented, with GPA and MPA being the most common. The reported primary outcomes were related to survival, relapse, and infection rates. Quality of the included studies was moderate to high, with scores ranging between 7 and 9, as shown in Table 2.

Table 2.

Quality of included studies assessed by Newcastle-Ottawa Scale.

Study	Year	Selection
		Representativeness of the exposed cohort	Selection of the nonexposed cohort		Ascertainment of exposure	Demonstration that outcome of interest
Silva et al [13]	2023	0	1		1	1
Kauffmann et al [14]	2021	0	1		1	1
Rathmann et al [15]	2021	0	1		1	1
Kuhnel et al [16]	2021	1	1		0	1
Hasegawa et al [17]	2021	1	1		1	1
Miyabe et al [18]	2019	1	1		0	1
Wang et al [19]	2019	1	1		1	1
Park et al. (20]	2018	1	1		1	1
Buttigieg et al. (21]	2017	1	1		1	1
Hasegawa et al [22]	2015	0	1		1	1
Weiner et al [23]	2015	1	1		0	1
Chen et al [24]	2014	1	1		0	1
Merino et al [25]	2010	1	1		0	1
Borao-Cengotita-Bengoa et al [26]	2010	0	1		1	1
Lionaki et al [27]	2009	1	1		1	1
Weidanz et al [28]	2007	1	1		0	1
Weidner et al [29]	2004	1	1		1	1
Booth et al [30]	2003	1	1		1	1
Haubitz et al [31]	1998	1	1		1	1
Allen et al [32]	1998	1	1		1	1
Schleiffer et al [33]	1998	1	1		0	1
Garrett et al [34]	1992	1	1		1	1
Coward et al [35]	1986	1	1		1	1
Study	Year	Comparability		Outcome		Total
		Basis of the design or analysis	Assessment of outcome	follow-up long enough for outcomes	Adequate follow up
Silva et al [13]	2023	1	1	1	1	7
Kauffmann et al [14]	2021	1	1	1	1	7
Rathmann et al [15]	2021	1	1	1	1	7
Kuhnel et al [16]	2021	1	1	1	1	7
Hasegawa et al [17]	2021	2	1	1	1	9
Miyabe et al [18]	2019	1	1	1	1	7
Wang et al [19]	2019	1	1	1	1	8
Park et al. (20]	2018	1	1	1	1	8
Buttigieg et al. (21]	2017	1	1	1	1	8
Hasegawa et al [22]	2015	1	1	1	1	7
Weiner et al [23]	2015	1	1	1	1	7
Chen et al [24]	2014	1	1	1	1	7
Merino et al [25]	2010	1	1	1	1	7
Borao-Cengotita-Bengoa et al [26]	2010	1	1	1	1	7
Lionaki et al [27]	2009	1	1	1	1	8
Weidanz et al [28]	2007	1	1	1	1	7
Weidner et al [29]	2004	1	1	1	1	8
Booth et al [30]	2003	1	1	1	1	8
Haubitz et al [31]	1998	1	1	1	1	8
Allen et al [32]	1998	1	1	1	1	8
Schleiffer et al [33]	1998	1	1	1	1	7
Garrett et al [34]	1992	1	1	1	1	8
Coward et al [35]	1986	1	1	1	1	8

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).

Figure 2.

Forest plot showing the rate of mortality per 100 patient-years in ANCA-associated vasculitis patients undergoing renal transplantation.

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).

Figure 3.

Forest plot showing the cumulative survival rate after 5 years of follow-up in ANCA-associated vasculitis patients undergoing renal transplantation.

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).

Figure 4.

Forest plot showing rate of infection per 100 patient-years in ANCA-associated vasculitis patients undergoing renal transplantation.

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).

Figure 5.

Forest plot showing relapse rate per 100 patient-years in ANCA-associated vasculitis patients undergoing renal transplantation.

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.