ANCA-Associated Glomerulonephritis: Diagnosis and Therapy Proceedings of the Henry Shavelle Lectureship.

Introduction

Kidney involvement occurs frequently in patients with granulomatosis with polyangiitis and microscopic polyangiitis. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and related glomerulonephritis (GN) is present in 57.6–58.8% of cases with granulomatosis with polyangiitis and in 82.2–82.8% of cases with microscopic polyangiitis [ 1 , 2 ]; thus, kidney disease is the most important manifestation associated with an organ-/life-threatening disease. Patients with ANCA-GN, especially those presenting with severe impairment of kidney function at baseline, have a worse survival probability, and those presenting with a median serum creatinine ≥5.8 mg/dL (“severe kidney” cluster), a high frequency of end-stage kidney disease (ESKD), which traditionally occurs early after diagnosis. The severity of kidney disease also dictates intensity of immunosuppression, and kidney function recovery as an endpoint has moved into the center of attention, as eGFR after achievement of remission is also relevant for target levels of low-density lipoprotein (LDL) cholesterol and blood pressure [ 3 ]. Control of traditional risk factors has been neglected in the management of ANCA-GN for decades, but given the high burden of cardiovascular morbidity and excess mortality rate [ 4 ], it is of relevance when considering long-term prognosis. Disease-related risk factors are attributable to damage accrual, i.e., presence of chronic kidney disease with residual proteinuria, and a persistent inflammatory state. Relevant clinical trials have refined the regimens used in the maintenance of remission, and repeated administrations of rituximab as used in MAINRITSAN3 [ 5 ] or MAINTANCAVAS [ 6 ], in the latter trial in a tailored fashion, lead to sustained remission rates of ≥95% over long-term follow-up, thus limiting the risk of repeated renal relapses leading to further decline in kidney function. In this review, our focus is on the progress of our understanding of ANCA-GN, including the path to diagnosis of the disease, the role of established and experimental biomarkers, kidney biopsies in both diagnosis and prognosis, estimated glomerular filtration rate (eGFR) recovery as relevant outcome, definition of renal remission, therapies which are used to induce and maintain remission, and finally aspects to be considered after kidney transplantation following ESKD due to ANCA-GN.

Established Diagnostic and Prognostic Biomarkers of ANCA-GN

ANCA as Diagnostic and Prognostic Biomarkers in ANCA-GN

Diagnosis of AAV and GN relies on the careful synthesis and interpretation of clinical findings, laboratory tests, and imaging studies, using a strict gating strategy based on clinical manifestations, which results in the highest diagnostic yield [ 3 , 7 ]. ANCA testing should be performed by commercially available immunoassays to detect presence of MPO- and PR3-ANCA as these tests are more specific and have higher predictive value compared to indirect immunofluorescence [ 3 , 8 , 9 ]. Any discordance between immunoassay results and indirect immunofluorescence or a double-positive pattern (concomitant MPO- and PR3-ANCA positivity) warrant further consideration and might indicate drug-induced AAV [ 3 ]. It is important to stress that a negative assay does not exclude a diagnosis of AAV as around 10% of AAV patients are considered to have ANCA-negative disease [ 10 ]. Such patients can only be diagnosed by an indicatory biopsy.

Both MPO- and PR3-ANCA vasculitis can manifest with kidney disease, with reported frequencies of 70–95% and 50–78%, respectively. Children present more frequently with PR3-ANCA GN [ 1 , 11 ]. MPO-ANCA is associated with more severe kidney function compromise at baseline compared to PR3-ANCA [ 8 , 10 ]. Conversely, PR3-ANCA has consistently been associated with higher risk of relapse [ 3 ], further driving the risk of kidney function decline during follow-up. A specific risk factor for renal relapse is a 2-fold rise in ANCA titers [ 12 ]. Persistent MPO-ANCA positivity or reappearance of MPO-ANCA is associated with disease relapse [ 13 ], as well as a transition from a negative ANCA test to becoming positive again [ 5 ].

Kidney Biopsy as Diagnostic “Biomarker” in ANCA-GN

With the ANCA test becoming a widely used and reliable diagnostic test, of which the results offer a rapid indication whether or not a patient has AAV – and in case of kidney manifestations, probably also an ANCA-GN, the kidney biopsy has become second choice in clinical practice as a diagnostic tool. Only in situations where there is doubt about the diagnosis, e.g., in patients with a high clinical suspicion of AAV but with a negative test result on the ANCA test, a biopsy is performed. It is important to emphasize that not taking a kidney biopsy is also a choice for which a second chance may be less satisfactory. For instance, in those patients who undergo a kidney biopsy after therapy has been started, lesions may become nonspecific and will be described by the pathologist as mitigated. Similarly, kidney biopsies taken long after a suspicion for ANCA-GN, treated but without the expected results, will mostly show chronic lesions that are also nonspecific and therefore non-diagnostic. The preferred moment for taking a kidney biopsy is therefore the time of disease presentation – where it will also provide a good impression of the severity and aggressiveness of the disease by which it can be compared at a later time point. Similar to the situation in lupus nephritis, repeat kidney biopsies in ANCA-GN gain ground with respect to being an important tool for treatment maintenance decisions [ 14 ]. Moreover, the kidney biopsy taken at disease presentation may reveal unexpected findings that may have gone unnoticed otherwise. Examples are the co-occurrence of anti-GBM antibodies [ 15 ] or comorbidity by other kidney diseases such as diabetes with kidney disease, multiple myeloma, or tubulo-interstitial nephritis. Most interestingly, there are recent studies showing how the kidney biopsy tissue can be used for new purposes, e.g., in relation to therapy choice by performing new techniques such as spatial and single-cell transcriptome analysis [ 16 ]. Also, the relevance of histopathological findings for the response to plasma exchange in severe ANCA-GN was recently described [ 17 ]. Implementation of these study results in clinical practice may change the role of the kidney biopsy completely.

Hematuria and Proteinuria

ANCA-GN should be suspected in all patients with impaired kidney function, proteinuria, and hematuria. Proteinuria and hematuria improve following induction of remission treatment but persist during the remission phase in a significant proportion. Uncertainty exists how these parameters should be assessed in terms of disease activity, and the Birmingham Vasculitis Activity Score (BVAS), used in the assessment of disease activity in most trials, is imperfect when it comes to assessment of kidney disease.

Hematuria has been considered as a marker of ANCA-GN. A return of hematuria after initial resolution, when other common causes are excluded, is indicative of a potential renal relapse [ 18 – 20 ]. However, a recent study demonstrated that hematuria at the time of interval biopsy, i.e., a pre-specified biopsy performed to determine the histologic response in the kidney following induction therapy, did not discriminate between patients with inactive and active disease. Hematuria was common in both active and inactive disease, but 60% of patients with active disease on interval biopsy had no hematuria and 59% of patients with inactive disease had some degree of hematuria [ 14 ]. A subsequent study which examined the value of repeated biopsy, defined as biopsy on clinical indication, in ANCA-GN patients showed that active GN was present in 70% of patients with new-onset hematuria and 20% of patients with persistent hematuria [ 21 ]. It should be noted that in this study, aside from differences in the nature of re-biopsy, the time to biopsy was significantly longer (median 34 months vs. 130 days). However, these findings accentuate the importance of new-onset hematuria as opposed to persistent hematuria, which might be more indicative of damage rather than activity. Even more importantly, urinary sediment has not been used in most studies and might provide further value in assessing hematuria of glomerular origin and thus increase probability to detect renal relapses noninvasively.

Patients with ANCA-GN usually have proteinuria in a non-nephrotic range. A reduction in albuminuria of 63 and 70% has been observed in the ADVOCATE trial in the avacopan and prednisone arm at week 26 and reflects control of disease activity [ 22 ]. Persistence of residual proteinuria beyond week 26 generally hints toward chronic damage rather than active disease and has been shown to be adversely associated with death, ESKD, and renal relapse in some studies [ 18 , 20 ]. New-onset or re-emerging proteinuria should always be a cause to suspect relapse, new-onset concurrent GN, or other diagnosis and should warrant further work-up.

Other Diagnostic and Prognostic Biomarkers

Most patients with active ANCA-GN have high inflammatory markers, especially acute phase reactants, i.e., C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and platelets [ 23 – 25 ]. Two studies are notable for evaluating the role of ESR in ANCA-GN. One study showed that ESR might correlate with histologic type, with higher ESR associated with crescentic and sclerotic classes of the Berden classification (see below) [ 26 ]. Moreover, a very recent study enrolling 166 patients with biopsy-proven ANCA-GN and severe disease, defined as eGFR <15 mL/min per 1.73 m 2 at diagnosis or need for dialysis, showed that higher ESR was a predictor of kidney function recovery [ 27 ]. Given that the other two predictors of kidney function recovery were lower serum creatinine and minimal/mild chronic changes on kidney biopsy, ESR possibly identified the group of patients with active, more acute disease.

However, these biomarkers are nonspecific and do not provide information on underlying cause and therefore have limited relevance for use in clinical practice or research when patients are assessed during episodes of active disease. A summary is provided in Table 1 .

Experimental Biomarkers to Be Used in Special Scenarios

The hunt for specific experimental biomarkers has seen tremendous developments over the past decade. Some of these markers have been useful to discover targets for therapies, including complement inhibitors, and others have been used to evaluate treatment response in clinical trials.

The urinary compartment is particularly attractive to evaluate the role of biomarkers in ANCA-GN. Levels of monocyte chemoattractant protein-1 (MCP-1) in the urine predicted active renal vasculitis and preceded the improvement of kidney function by 2 weeks in a prospective study. Urinary MCP-1 levels correlated with macrophage infiltration of glomeruli of affected patients [ 28 ]. Longitudinal assessment of urinary biomarkers revealed that in relapsing patients with ANCA-GN, urinary MCP-1 offered the best discrimination among a set of marker molecules, and a 1.3-fold increase in MCP-1 had a 94% sensitivity and 89% specificity to predict active disease [ 29 ]. Analysis of patients with subtle renal activity revealed that urinary MCP-1 and soluble CD163, another marker indicating macrophage/monocyte activation, correlated marginally and combined assessment of both improves the positive likelihood ratio of active ANCA-GN to 19.2, with a negative likelihood ratio of 0.6, thus underlining the potential to diagnose active renal disease [ 30 ]. Analysis of urinary MCP-1 has been part of the road to the approval of avacopan in the management of AAV. In the phase 2 CLEAR trial, both avacopan treatment arms had a more rapid reduction of sCD163 in comparison to the control arm [ 31 ]. However, this treatment difference could not be confirmed in the larger phase 3 trial, ADVOCATE, where patients in the avacopan and prednisone arm had a urinary MCP-1 decrease of −73% and −71% from baseline. It is noteworthy that levels of uMCP-1 tend to decrease even beyond 26 weeks of follow-up as a further decline of 6% and 7% was observed from week 26 and 52 [ 22 ].

A first study investigating the role of urinary sCD163, a macrophage scavenger receptor for hemoglobin/haptoglobin complexes, found increased levels during phases of active ANCA-GN in an inception cohort and two large validation cohorts and compared these levels to patients with other GN forms and other causes of acute kidney injury. sCD163 in the urine was markedly increased in ANCA-GN in comparison to other disease forms [ 32 ]. Further studies confirmed the diagnostic utility of urinary sCD163, as it was shown that higher concentrations were present during episodes of renal flares, and it could discriminate AKI episodes of ANCA-GN from other potential causes. However, patients with active nephrotic syndrome had urinary soluble CD163 concentrations similar to patients with active ANCA-GN and well above the threshold of 250 ng/mmol, which has been set to detect renal activity of ANCA-GN [ 33 ]. These promising results were independently confirmed by others and reported a consistent high accuracy to predict renal relapses of ANCA-GN [ 34 ]. The establishment of sCD163 measurements in the urine might help to diagnose disease relapses in scenarios where diagnostic difficulties are present as it discriminated well between different causes of AKI.

Activation of the alternative complement pathways plays a crucial role in disease pathogenesis. Levels of Bb, C3a, C5a, and the soluble C5b-9 were significantly higher during phases of active disease in comparison to remission. Moreover, urinary Bb correlated with serum creatinine and inversely with the proportion of normal glomeruli [ 35 ], highlighting the potential of urinary Bb to aid predicting severity of kidney disease in scenarios where a kidney biopsy is not possible. More recently, urinary Ba and its value to predict renal relapses were tested in a well-defined cohort. A total of 21 patients (35%) had a renal relapse, and urinary Ba predicted flares with an area under the curve of 0.76, yielding a sensitivity of 76.2% and a specificity of 68.4% [ 36 ]. In line with significant regulation of complement fragments in the urine, blood levels of Bb, C3a, C5a, and soluble C5b-9 were higher in active disease, while plasma levels of properdin were lower. Again, the levels of Bb correlated with key elements in kidney biopsies, namely, cellular crescents, and also disease severity as measured by BVAS and ESR [ 37 ]. Significant differences in levels of alternative complement pathway constituents were recently confirmed in a Spanish cohort; moreover, the authors provided evidence that common genetic variants are associated with disease susceptibility and severity of kidney damage [ 38 ], providing further evidence that disruption of the alternative complement pathway has a therapeutic relevance.

Urinary T cells, as assessed by flow cytometry, have emerged as markers, which can distinguish active disease from the remission state. As such, CD3 + , CD4 + , and T reg counts were higher during episodes of active disease. Other markers of renal inflammation, such as sCD163, MCP-1, and complement C5a, in the urine were outperformed by CD3 + T cells [ 39 ]. In the PRE-FLARED study, the authors investigated whether measurement of urinary T cells is predictive of subsequent renal flares within 6 months of assessment. The authors found that urinary CD4 T cells at a cutoff of over 490 cells had a sensitivity of 60% and a specificity of 97.8% (AUC of 0.88) to predict a renal flare [ 40 ]. Findings like these are highly relevant but will need to be confirmed in larger studies and especially incorporated in clinical trials testing the prolonged use of immunosuppression in patients at high risk of disease relapse. The lack of validation of other promising markers, such as soluble immune checkpoints [ 41 ], and the costs to run these assays limits the widespread use of most of the discussed experimental biomarkers. Moreover, most of these markers must prove to be more accurate than changes of proteinuria and especially urinary red blood cells of glomerular origin (see Fig. 1 for an overview).

Prognostic Histopathological/Clinical Scores

Four major prediction models have been devised for the use in patients with ANCA-GN, which are based on different clinical and/or histopathologic aspects: the Berden classification based on glomerular pathology, ANCA Renal Risk Score (ARRS) and its revised version ANCA Kidney Risk Score (AKRiS) based on histopathologic and laboratory values, Mayo Clinic Chronicity Score (MCCS) focusing on chronic histologic changes only, and Percentage of ANCA Crescentic Score (PACS) based on crescents and sclerotic changes. This section will provide an overview of these four prognostic models along with their strengths and limitations and an overview of future perspectives.

Histopathologic (Berden) Classification

The histopathologic classification investigated the role of glomerular pathology in prognostication of ANCA-GN [ 42 ]. The classification consists of four categories: focal, crescentic, sclerotic, and mixed and applies a “rule of 50%.” The focal class is defined by the presence of ≥50% normal glomeruli ( Fig. 2 a–d, for normal and virtually normal glomeruli), the crescentic class by ≥ 50% cellular crescents ( Fig. 3 a, b, e, for examples of a cellular crescent formation), the sclerotic class by ≥50% globally sclerotic glomeruli ( Fig. 4 a–d, for examples), and the mixed class including all other biopsies. In the original cohort, patients with focal class had the best kidney survival, followed by crescentic, mixed, and sclerotic class.

Over the past years, the Berden classification has been validated in both adults and pediatric studies. However, it became apparent that the kidney prognosis of the crescentic and mixed classes is comparable. The focal class has consistently the best prognosis, while a sclerotic class on kidney biopsy indicates poor kidney survival [ 43 ]. An international validation study by the original investigators showed that 10-year kidney failure risk generally differs between the histopathologic classes. However, there was no significant difference in kidney failure risk between crescentic and mixed class (14% vs. 20%), even after adjusting to differences in populations, treatment, and interobserver agreement. When looking at changes from baseline within the first year of diagnosis and mean eGFR at 1 year, there was however a notable difference among classes with crescentic class having best recovery of eGFR (+21 ± 19 and mean eGFR of 37 ± 21 mL/min per 1.73 m 2 ), while the mixed class had an increase of +10 ± 15 and a mean eGFR of 38 ± 21 mL/min per 1.73 m 2 [ 44 ]. This in part explains that long-term prognosis of both classes is similar; however, those with a crescentic class have a greater potential of eGFR recovery.

The utility of the Berden classification has also been tested in repeat kidney biopsy studies. Hruskova et al. [ 45 ] reported on patients who underwent a protocolized repeat biopsy after a median of 13 months from diagnosis. The majority of patients changed their classes. Eleven of a total of 17 patients showed a change in classification, mostly with a shift from crescentic to mixed class. This was confirmed by a recent large single-center study, which performed an interval biopsy in 59 patients. After short follow-up, there was a shift in the proportion of patients belonging to the focal class from baseline to interval biopsy (21% vs. 36%), the sclerotic class (4% vs. 15%), mixed class (62% vs. 49%), while the authors reported a significant reduction in crescentic class (13% vs. 0%) [ 14 ].

The advantage of the Berden classification is the easy applicability and the good prediction of kidney function recovery when effective immunosuppressive therapies are introduced. It has more limited utility when it comes to ESKD prediction in comparison to other scores, especially the ARRS/AKRiS.

ANCA Renal Risk Score/ANCA Kidney Risk Score (Brix Score)

The score was implemented to identify predictors of ESKD and construct a score combining clinical and histopathologic data. The initial study of the ARRS included 115 patients in the training set and 90 patients in the validation cohort [ 46 ]. The study reported that scoring of percentage of normal glomeruli (N0 >25%, N1 10%–25%, and N2 <10%), IF/TA (T0 ≤25% and T1 >25%), and eGFR (G0 >15 mL/min per 1.73 m 2 ; G1 ≤15 mL/min per 1.73 m 2 ) stratifies patients into three differing risk groups: low, 0 points; medium, 2–7 points; high, 8–11 points. The groups carried significantly different risks of kidney survival at 36 months in both training and validation cohorts: low (100%), medium (83–84%), and high (22–32%).

The scoring system not only highlights the percentage of normal glomeruli as the factor with the highest weighting as patients with N2 have six points already but also underlines the importance of histology [ 47 ]. Interestingly, around half of the patients who were dialysis dependent on initial presentation achieved kidney function recovery, while all patients with a maximum score of 11 remained dialysis dependent on follow-up [ 46 ].

The ARRS was validated in several studies including different ethnicities, some of which used some modifications. Importantly, the ARRS was also validated in a cohort of patients with advanced CKD (eGFR of 21 mL/min/1.73 m 2 ) comprised mostly (86%) of patients in mixed and sclerotic classes. Likewise, 35% and 47% were considered high and medium risk according to ARRS. The 3-year kidney survival was 73% [ 48 ], indicating that even patients in the high-risk group still benefit from immunosuppressive therapy.

The literature has been consistent that the ARRS outperforms other risk predictors. Analysis of 214 kidney biopsies analyzed 10-year kidney outcome and showed superiority to the Berden classification and the MCCS. In the high-risk group, 59.5% of patients reached ESKD, compared with 22.8% and 3.6% in the moderate- and low-risk groups, respectively [ 49 ]. This is in line with other studies reporting superiority of the ARRS over the Berden classification in predicting ESKD [ 50 , 51 ]. However, the value of the ARRS has also been challenged. Analysis of 102 patients from the Maine-Anjou AAV registry found that eGFR at baseline had a higher C-index for ESKD prediction than the ARRS [ 52 ], also highlighting that subsequent adjustments to the score were required.

Such a modification has been recently published, the ANCA Kidney Risk Score (AKRiS). The changes were modification of IFTA to allow semiquantitative reporting, replaced eGFR with serum creatinine, and added a cutoff for kidney function (K0: <250 µmol/L = 0, K1: 250–450 µmol/L = 4, K2: >450 µmol/L = 11 points). The AKRiS subdivides patients into four risk groups: low (0–4 points), moderate (5–11), high (12–18), and very high (21). The revised version predicted 3-year kidney survival, which was 96%, 79%, 54%, and 19% in an analysis of 1,439 patients with ANCA-GN [ 53 ]. AKRiS has recently been validated in 164 German patients, with similar risk prediction at 36 months (90.2%, 70.9%, 37%, and 16.7%), but also reported a similar C-index to the ARRS [ 54 ]. This is in contrast to a study of 101 ANCA-GN patients from Mexico, which reported that the improved AKRiS showed best prediction in the risk of kidney failure and outperformed the ARRS (C-index of 0.817 vs. 0.782). The addition of peak eGFR post-therapy to the AKRiS improved its performance at all follow-up intervals [ 55 ].

The AKRiS is the best predictor of ESKD when clinical and histopathological data are incorporated. It outperforms other prediction tools and is derived from a large international cohort of patients. There is limited information on eGFR recovery of the different risk groups.

Mayo Clinic Chronicity Score

In 2017, a standardized scheme of classification and reporting for GN was established [ 56 ]. Grading of chronic changes on kidney biopsies was a key component of this system. Increasing evidence of the importance of chronic changes and their predictive value has led to being incorporated in several prognostic systems [ 57 , 58 ]. These changes, which are part of the MCCS, encompass all kidney compartments and include glomerulosclerosis, IF/TA, and arteriosclerosis.

Using this scoring system, global and segmental glomerulosclerosis, IF and TA are all scored separately from 0 to 3 according to percent of involvement of the compartment (<10, 10–25, 26–50, and >50%) and arteriosclerosis from 0 to 1 according to the degree of intimal thickening yielding a score from a minimum of 0 to maximum of 10. These are then grouped into four grades: minimal (0–1), mild (2–4), moderate (5–7), and severe (8–10) [ 56 ].

In a study, which analyzed 329 patients with available kidney biopsies and a diagnosis of ANCA-GN, 31% were classified as minimal, 32% as mild, 26% as moderate, and 11% as severe. The extent of chronic changes expressed as grade and higher degrees of individual MCCS components correlated with lower eGFR. A composite of kidney failure and death was more frequent in higher MCCS grades while kidney function recovery was less common [ 57 ]. In the abovementioned study from Mexico, the MCCS had a poor prediction of ESKD with a C-index of 0.606 [ 55 ]; thus, the score is not widely implemented in clinical routine.

Percentage of ANCA Crescentic Score

The Berden classification, MCCS, and ARRS have recently been validated in a Japanese cohort of 221 patients with ANCA-GN, who were followed up for a median of 5 years [ 59 ]. All three scores showed good applicability, but the limited sample of crescentic class patients (5%) might limit the generalizability in this population. The study proceeded to develop a novel score utilizing percentage of each lesion in relation to total number of glomeruli, Percentage of ANCA Crescentic Score (PACS), i.e., comprising the sum of the percentages of cellular crescents, fibrocellular crescents ( Fig. 3 e), fibrous crescents ( Fig. 3 c, d, for specific examples), and sclerotic glomeruli ( Fig. 4 ) to total glomeruli. PACS, which focused exclusively on histologic and not clinical variables, showed similar accuracy in ESKD prediction to ARRS and both were superior to MCCS. Importantly, the study of 101 patients with ANCA-GN from Mexico with a high burden of ESKD events (36.6%) found a C-index of 0.801 for PACS [ 55 ]. In patients with severe CKD at baseline, the PACS score might be a good addition to the armamentarium of histopathologic scores based on their findings.

Future Perspectives

The prospect of prognostic tools will be a constant refinement based on developments, especially centered around more refined therapeutic options and a future focus on eGFR recovery as one of the main outcomes of clinical trials. These upcoming models will ideally be developed on larger, multi-national cohorts containing patients with a widely heterogeneous clinical presentation appreciating the wide clinical spectrum of ANCA-GN. Big data and international collaborations sharing datasets and other information are key to achieve this and artificial intelligence will most probably play a crucial role in this path.

Treatment

eGFR Recovery as a Relevant Outcome

A kidney-centered outcome in ANCA-GN would be the potential of therapies/therapeutic approaches to increase eGFR after initial diagnosis or relapse. Currently available measures to assess disease activity, such as the BVAS, are inapplicable to capture such relevant outcomes. Kidney function recovery has not been defined in ANCA-GN nor in other circumstances, but most investigations have used an eGFR-centered approach, i.e., reporting the eGFR increase on average or using a threshold of one GFR category (≥15 mL/min/1.73 m 2 ) [ 27 ]. Treatment response in patients with a low eGFR at baseline (median of 7.1 mL/min/1.73 m 2 ) included the independence of dialysis and eGFR >20 mL/min/1.73 m 2 as a threshold of kidney function recovery with no signs of active disease 4 months after kidney biopsy [ 60 ]. The recently published ADVOCATE trial and its sub-analysis based on eGFR at baseline have further increased interest in establishment of endpoints focusing on kidney function recovery. Fifty patients had a baseline eGFR ≤20 mL/min/1.73 m 2 . In those subjects, the exploratory endpoints at 52 weeks included proportion of patients who reached an eGFR >20, ≥30, ≥45, ≥60 mL/min/1.73 m 2 and those who had an eGFR increase, which was ≥2-fold from the baseline value. A clear difference in favor of the avacopan arm was observed for most exploratory endpoints [ 61 ]. In practice, a threshold of 15 mL/min/1.73 m 2 seems to be a relevant and meaningful endpoint when assessing kidney function recovery in patients presenting with an eGFR of ≤30 mL/min/1.73 m 2 . Of note, patients with a higher eGFR at baseline will not face a similar increase as has been reported in numerous clinical trials, such as the RAVE trial, and thus will require other considerations in reporting kidney function recovery [ 8 ].

Definition of Renal Response/Remission

Randomized controlled clinical trials of remission induction therapy in AAV have focused on remission utilizing the BVAS as the primary endpoint. Importantly, renal remission or response has not been a primary endpoint in these clinical trials. Although cardiovascular disease and infections are important contributors to premature death [ 62 – 64 ], the initial presence and the severity of kidney dysfunction is the most important predictor of mortality [ 64 – 66 ]. Currently, there is a lack of standardized criteria to define renal response. Based on recently endorsed surrogate markers for treatment response in other glomerular diseases, it is obvious that the focus should be turned toward defining treatment response based on standardized surrogate kidney markers associated with better long-term kidney and mortality outcomes. Stabilization of serum creatinine or eGFR and resolution of hematuria are markers that associate with control of kidney inflammation. However, the extent of kidney function recovery and the assessment time points thereof, which associates with long-term kidney outcome, is unclear. The KDIGO 2024 Clinical Practice Guideline for the Management of Glomerular Diseases on AAV defines renal remission as stable or improved eGFR, while the presence of hematuria and proteinuria may be considered as markers of active disease or chronic parenchymal damage [ 67 ]. An ongoing project endorsed by the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) is developing consensus response definitions for clinical trials but is not focusing on kidney responses.

A rise in serum creatinine, presence of hematuria and red blood cell casts, and the presence of proteinuria are all markers of disease activity in the BVAS. Kidney function impairment at the first presentation is a well-recognized predictor of long-term kidney outcomes. Similarly, the presence of persistent proteinuria and hematuria is associated with adverse long-term outcomes of ESKD, relapse, and death [ 18 ]. Unlike noninflammatory kidney diseases where treatment is aimed at slowing decline in kidney function over time, recovery of kidney function should be a key therapeutic goal in inflammatory glomerular diseases. Along the same lines, the therapeutic goal of using medications to quell inflammation should include resolution of hematuria and proteinuria. While the ideal way to define renal response should include combined clinical, histologic, and immunologic response, protocol or follow-up biopsies are seldom done in clinical practice and there is lack of validated biomarkers of immunologic remission for inflammatory glomerular diseases. Hence, renal response is defined based on improvements in kidney function and hematuria and proteinuria. In a post hoc analysis of the RAVE trial focusing on patients with ANCA-GN, renal remission was defined as stabilization or improvement in serum creatinine and resolution of hematuria [ 68 ], while changes in eGFR from baseline were the criteria to assess renal response to remission induction therapy in the majority of AAV trials [ 22 , 69 – 71 ]. Importantly, both in clinical practice and in clinical trials, glucocorticoid tapering continues despite the persistence of hematuria. In fact, in the analysis of patients with ANCA-GN in WGET and RAVE trials, over 40% of patients had persistent hematuria and proteinuria beyond 6 months, a time point for the primary outcome of remission [ 20 ]. Although the diagnostic value of positive ANCA serology is undisputed and several studies have associated negative ANCA status at remission with lower disease relapse risk [ 72 ], studies have not investigated the impact of kinetics of ANCA on kidney outcomes. While the therapeutic landscape of AAV has expanded, leading to improved patient survival, a substantial proportion of AAV patients continues to progress to ESKD. Standardized criteria to define response are urgently needed to incorporate in clinical trials of newer therapeutic agents to improve kidney outcomes.

Therapies Used for Induction of Remission

AAV is a potentially recurrent condition, with relapse rates of 15% within the first year of disease, approaching about 50% over the first 5 years (depending on serotype and initial mode of therapy) [ 73 ]. Therefore, two phases of treatment can be discerned: induction of remission (the first 3–6 months), with the aim of halting the inflammatory process and preventing further, potentially irreversible organ damage, and remission maintenance. As kidney disease usually portends a poor prognosis, virtually all patients with ANCA-GN qualify for combined immunosuppressive therapy, the backbone of which consisted of glucocorticoids and cyclophosphamide for many years, before rituximab emerged as an equivalent alternative to the latter in most circumstances.

Glucocorticoids have been a key component of induction immunosuppression since the 1960s [ 74 ]. Intravenous high-dose methylprednisolone, in total doses of 1–3 g, administered over 1–3 days, is usually chosen for the initial therapy of severe disease (i.e., patients presenting with rapid decline in kidney function and/or diffuse alveolar hemorrhage [DAH]). First reports about the efficacy of such “pulses” date back several decades [ 75 ], and their use remains well established, as illustrated by recent studies such as PEXIVAS and ADVOCATE (see below). However, this practice is not backed by high level evidence and likely contributes to overall toxicity, as acknowledged in recent recommendations and guidelines [ 7 , 76 ]. Oral glucocorticoids were subsequentially continued at a dose of 1 mg/kg per day (maximum 60–80 mg per day), until PEXIVAS demonstrated the non-inferiority of a reduced-dose regimen (60 mg in week 1 [50–75 kg body weight], reduced to 30 mg per day in week 2, reaching a dose of 7.5 mg per day by 3 months). Notably, only 15% of patients in this study received rituximab for induction, and there was a trend in favor of the higher steroid dose in this group [ 77 ]. LoVAS, a trial from Japan, reported similar results with a glucocorticoid regimen of 0.5 mg/kg per day in conjunction with rituximab, in an older, predominantly MPO-ANCA-positive cohort; however, it needs to be acknowledged that both groups had an eGFR of >50 mL/min at baseline [ 78 ]. The reduced dose-tapering regimen used in PEXIVAS, aiming for a daily dose of less than 30 mg by week 3, is now recommended for most patients with ANCA-GN, mirroring the trend to reduce glucocorticoid use in other autoimmune conditions [ 7 ].

Following the introduction of oral cyclophosphamide (at a dose of 2 mg/kg per day, with adjustments) in the treatment regimen some 50 years ago, this agent (in combination with glucocorticoids) represented the standard therapy for decades, and no major changes occurred until the early 2000s. The CYCLOPS trial was an important addition, as it established a clear schedule for the parenteral treatment with cyclophosphamide at a dose of 15 mg/kg every 2–3 weeks for 3–6 months, thereby reducing overall cyclophosphamide exposure by about 50%, while achieving comparable remission rates [ 69 ]. Like steroids, cyclophosphamide carries substantial toxicity (in particular, malignancies and infertility) and alternative immunosuppressives have been tested as induction agents. The MYCYC trial compared intravenous cyclophosphamide (CYCLOPS regimen) to mycophenolate mofetil (MMF; 2 g/day) in a cohort of patients with milder disease (patients with an eGFR <15 mL/min were excluded, and median eGFR was 51 mL/min); both groups received the same oral glucocorticoid regimen. MMF was found to be non-inferior, but relapse rate was higher, particularly in patients with PR3-ANCA serotype [ 71 ], and MMF usage is nowadays limited to selected low risk patients, especially with MPO-ANCA serology, if other treatment options are deemed unsuitable.

Rituximab has established itself as a true alternative to cyclophosphamide in most situations and continues to gain in popularity. Two key studies (RAVE and RITUXVAS), published in 2010, showed rituximab’s efficacy as induction agent, when added to glucocorticoids. RITUXVAS included 44 patients with de novo disease and severe kidney involvement (median eGFR was 18 mL/min/1.73 m 2 , including 9 patients requiring dialysis at entry). Rituximab was administered at a dose of 375 mg per square meter weekly for 4 weeks; in addition, two cyclophosphamide pulses were added (15 mg/kg, given in week 1 and 3) [ 70 ]. The RAVE trial enrolled 197 patients, about half of them with relapsing disease. This cohort had a better kidney function, with a mean creatinine clearance greater than 50 mL/min. Rituximab schedule was identical to RITUXVAS, but no concurrent cyclophosphamide was given [ 79 ], while oral cyclophosphamide (combined with glucocorticoids) was the comparator in RAVE. In all, these studies proved non-inferiority of rituximab to cyclophosphamide, with RAVE demonstrating superiority in relapsing disease; rates of adverse events were similar. However, questions remained as to whether rituximab should be chosen in very severe disease with characteristics not included in these trials. In particular, there remains uncertainty about the efficacy of rituximab in patients with severe kidney impairment as a creatinine of 4 mg/dL was an exclusion criterion in the (larger) RAVE trial. This has led some experts to advocate a combination therapy for patients with severe disease. For instance, a combination of rituximab and (low-dose intravenous) cyclophosphamide was proposed by Pepper et al. [ 80 ] as a means of achieving “steroid-free” induction in a cohort with severe disease. Forty-nine patients were included in this prospective study (90% with de novo disease and almost all with kidney disease including 3 with dialysis dependency at enrollment). Notably, intravenous methylprednisolone was given initially and oral prednisolone for up to 2 weeks, amounting to a net median steroid dose of 1,000–1,235 mg. The authors reported similar efficacy in comparison to earlier studies but a reduced infection rate. The key message this trial provides is that a “steroid-avoidance” (or rather minimization) regimen is feasible in patients with severe ANCA-GN. This trial was published in 2019, well before ADVOCATE (discussed later). A later publication [ 81 ] corroborated these findings in a retrospective cohort ( n = 64) who additionally underwent plasma exchange for severe disease (about half of the patients with concomitant dialysis dependency or DAH, respectively).

Despite continuous efforts to limit overall steroid exposure, toxicity inherent to their use has been considered inevitable for a long time. To this end, the glucocorticoid toxicity index (GTI) was developed in 2017 and has quickly established itself as a valuable instrument for addressing steroid-related side effects in a structured fashion [ 82 ]. However, new compounds, such as complement-directed therapies, may render essentially steroid-free induction an achievable aim. In the ADVOCATE trial, avacopan, an oral C5a receptor antagonist (at a dose of 30 mg twice daily and in conjunction with either rituximab, oral or intravenous cyclophosphamide), was non-inferior at 26 weeks for achieving remission (and no glucocorticoid use in the preceding 4 weeks) and superior at 52 weeks for sustained remission. The trial enrolled 331 patients with newly diagnosed (70%) or relapsing (30%) disease and led to the FDA approval of avacopan as an adjunctive agent to standard therapy for patients with severe disease in 2021. Although the avacopan group also received a short course of glucocorticoids early in the trial (upfront randomization or as pretreatment for rituximab infusion), the cumulative dose was about 45% of the standard group (mean total dose 1.7 mg vs. 3.8 g, respectively) [ 22 ]. No Neisseria meningitides infections occurred, and there is no requirement for antibiotic prophylaxis or vaccination. GTI was used in this trial and demonstrated convincingly the clinical benefits of steroid minimization [ 83 ]. Of note, in the subgroup receiving rituximab (approximately two-thirds of the entire cohort), this compound was not re-dosed after 6 months, which, by now, is standard of care. This lack of rituximab maintenance hampers the interpretation of the results of the ADVOCATE trial somewhat as differences in relapse rate have been observed at week 52, a difference driven by the rituximab-treated patients [ 84 ]. In a post hoc analysis involving a subgroup with an eGFR ≤20 mL/min per 1.73 m 2 ( n = 50), kidney function improved more in the group treated with avacopan than with prednisone [ 61 ]. While ADVOCATE did not include patients with severe kidney impairment (eGFR <15 mL/min per 1.73 m 2 as an exclusion criterion), a recent retrospective real-world evidence study, including 92 patients, found avacopan to be safe in a subgroup with CKD stage 5 ( n = 21, including 9 persons on kidney replacement therapy) [ 85 ]. Likewise, a small case series of patients with severe kidney involvement ( n = 4) reported recovery in kidney function [ 86 ].

Plasma exchange is considered as an adjunct to induction therapy in cases of severe kidney disease and/or DAH. It leads to a rapid decline in ANCA and was shown to result in improved outcomes in the MEPEX trial. This study included 137 patients with a new diagnosis of ANCA-GN, confirmed by biopsy, and a “severe renal” subgroup (as per EUVAS criteria; serum creatinine >5.8 mg/dL). One group received plasma exchanges (7 sessions), while the other group was treated with pulse steroids (3 g in total); all patients also received concomitant oral cyclophosphamide and steroids. The rate of kidney function recovery at 12 months was higher in the plasma exchange arm; notably, no difference in mortality was observed [ 87 ]. However, the PEXIVAS trial, which included 704 patients with either DAH or ANCA-GN, did not find a reduction in ESKD or death after a longer median follow-up (almost 3 years) in the group receiving plasma exchange (7 sessions). Of note, kidney disease present in 691 patients was less severe than in MEPEX (median serum creatinine, 3.7 mg/dL), with just about 30% of patients presenting with a creatinine >5.8 mg/dL; another substantial limitation was the lack of renal histology. A subsequent retrospective French study tried to identify a subgroup of patients who might derive most benefit from plasma exchange and proposed a score incorporating clinical, serological, and histology data [ 17 ]. Most points were derived from creatinine levels and renal histopathology, with creatinine values >6.8 mg/dL and crescentic class (Berden classification) impacting risk reduction with plasma exchange the most. To conclude, apart from clear indications (individuals with concomitant anti-GBM autoantibodies [“double-positive” serology]), the role of plasma exchange in the treatment of ANCA-GN is debated. There is the overall impression that a subgroup of patients with severe kidney disease and active inflammation on histology as well as patients presenting with severe pulmonary hemorrhage may derive benefit, but there is also consensus that strict risk-benefit assessment is warranted, particularly as infections frequently complicate treatment. From a practical point of view, it may be prudent to initiate plasma exchange when a patient presents with severe pulmonary-renal syndrome until a presumptive or definitive diagnosis (by autoimmune serology or histology, respectively) can be established. Prophylaxis against Pneumocystis jirovecii pneumonia with low-dose trimethoprim/sulfamethoxazole is an important component during essentially all forms of remission induction [ 88 , 89 ].

Conclusions

Rituximab has reached equal indication as an induction agent for newly diagnosed and relapsing disease and the KDIGO 2024 clinical practice guideline recommends a combination of cyclophosphamide or rituximab with glucocorticoids as initial treatment of new-onset AAV and the potential to combine cyclophosphamide and rituximab in those with a serum creatinine ≥4 mg/dL [ 7 ]. Several agents are now available, which – in various combinations – allow for individualized remission induction, dependent on severity of presentation, type of organ involvement, age, and comorbidities. Plasma exchange may still be indicated in patients presenting with severe, active disease. The role of avacopan is likely to evolve in the near future.

Therapies Used for Maintenance of Remission

The vast majority of ANCA-associated GN patients requires a maintenance regimen after attaining remission [ 78 ]. Basic requirements for maintenance regimens are to prevent further damage and potential relapse but also to have low toxicity [ 90 ]. A minority of patients with MPO-ANCA vasculitis who achieved complete remission and ANCA negativity have a subsequent low risk of relapse and might be followed up and monitored without specific maintenance therapy. Given an inherently higher risk of relapse, this a priori excludes patients who were PR3-ANCA positive [ 3 ]. This section will provide an overview of trials informing about current maintenance therapy approaches, optimal dosing, and duration of therapy.

Azathioprine- versus Rituximab-Based Maintenance of Remission

Evidence for rituximab’s efficacy as a maintenance agent stems from several randomized controlled trials. The results of the first trial, MAINRITSAN1, led to the FDA approval of rituximab as a maintenance agent. A total of 115 patients were enrolled; rituximab was compared to azathioprine as maintenance therapy after achieving remission with an induction regimen comprising cyclophosphamide and glucocorticoid. A significantly higher risk of relapse after 28 months of follow-up was reported in patients receiving azathioprine as relapse occurred in 29% of these patients versus 5% of those receiving rituximab with no difference in safety profile [ 91 ]. Long-term follow-up of these patients showed that rituximab has a higher relapse-free survival at 60 months compared to azathioprine (72% vs. 49%) with a better overall survival (100% vs. 93%) [ 92 ].

MAINRITSAN2 was designed to evaluate if tailored administration of rituximab, either due to B-cell reappearance or ANCA titer rise, in comparison to a fixed 5-dose regimen affects risk of relapse. The trial included 162 patients who achieved complete remission after induction therapy [ 93 ]. The trial was underpowered to detect a significant difference between the treatment arms, but fewer patients had a relapse: 8/81 (9.9%) in the standard arm versus 14/81 (17.3%) in the experimental arm. Major guidelines/recommendations are therefore not recommending the use of a tailored arm to maintain remission [ 94 ].

A follow-up trial, MAINRITSAN3, which enrolled 97 patients who successfully completed MAINRITSAN2 without major relapses and were in complete remission for 18 months, aimed to investigate the efficacy and safety of rituximab for further 18 months [ 5 ]. Patients were randomized to receive rituximab or placebo every 6 months for an additional 18 months and a total of 4 doses. At 28 months, 96% of patients receiving rituximab versus 74% receiving placebo remained relapse free with no differences in safety events. Based on these findings, the EULAR recommendations highlight that therapy can be continued for 48 months and even longer if patients have a significant risk of relapse and wish to continue therapy [ 76 ].

RITAZAREM was the first therapy, which tested rituximab as both induction and maintenance therapy [ 95 , 96 ]. This was an open-label RCT, which enrolled 170 patients with relapsing AAV in complete remission, which was achieved by 90.4% after induction therapy with rituximab. Patients were randomized to receive either rituximab or azathioprine. After 20 months of follow-up, 13% of patients receiving rituximab relapsed compared with 38% of patients receiving azathioprine. RITAZAREM confirmed the superiority of rituximab over azathioprine to reduce disease relapses with a reported 59% lower risk of relapse in the rituximab group. In addition, a good safety profile of rituximab and no differences in hypogammaglobulinemia and infection were reported [ 96 ].

Discussions about frequency of rituximab administration are ongoing. Beyond results of MAINRITSAN2, there are data from the recently published MAINTANCAVAS trial, which compared two remission maintenance strategies in patients who completed at least 2 years of fixed-scheduled rituximab. Repeated administration was either offered when B-cell repopulation was detected or when a significant rise in ANCA levels was measured. The trial enrolled 115 patients and showed that 4.1% had a clinical relapse in the B-cell monitored arm compared to 20.5% in the ANCA level monitored arm [ 6 ]. The study reported a higher number of COVID-19-related serious adverse events and a higher exposure to rituximab (3.6 g vs. 0.5 g) in the B-cell monitored group, clearly highlighting an inequity in rituximab administration. An ANCA-based strategy should not be pursued based on these results.

In azathioprine-treated patients, the REMAIN trial investigated whether continuation of azathioprine beyond 18–24 months prevents disease relapses. Among 110 patients, fifty-nine were randomized to a continuation of azathioprine for another 30 months and 51 patients who stopped azathioprine 3 months after randomization. Moreover, steroids were stopped after 2 years and 4 months, respectively. An almost 6-fold increased risk of disease relapse was reported in the discontinuation group (63% vs. 22%) and a positive ANCA test at randomization emerged as additional risk factor for relapse (51% vs. 29%). No significant difference in severe adverse events was observed [ 97 ]. The underpowered AZA-ANCA trial randomized a total of 45 c-ANCA positive patients to extended azathioprine (full dose of azathioprine up to 4 years after diagnosis, subsequent tapering) or “standard,” which initiated tapering after 1 year after diagnosis already. The relapse rate of patients was 24% versus 46% in the extended and standard therapy arm and fell short of statistical significance [ 98 ].

Alternative Maintenance Therapies

MMF was compared to azathioprine in the IMPROVE trial [ 99 ]. This open-label RCT included 156 patients randomized to either MMF or azathioprine and followed patients for a median of 39 months. Relapses were more frequent in the MMF arm (55% vs. 38%) with no differences in severe adverse events. A systematic review and meta-analysis including 10 trials, 6 of which included MMF in remission maintenance therapy, showed that overall estimated remission maintenance at end of follow-up ranged between 51% and 91%, being on the higher end of this in studies including patients with kidney involvement [ 100 ].

The WEGENT trial aimed to assess if methotrexate was safer than azathioprine [ 101 ]. A total of 126 patients who achieved remission were randomized to receive either oral azathioprine or methotrexate. Methotrexate was not safer than azathioprine and, while this was a primarily a study powered to detect differences in safety signals, there were also no differences in relapse rate. Long-term follow-up of WEGENT showed similar 10-year overall and relapse-free survival rates between methotrexate and azathioprine [ 102 ].

Conclusions

Rituximab has replaced other immunosuppressive strategies as first-line therapy to maintain remission. The efficacy has been shown for mainly newly diagnosed patients who received cyclophosphamide as induction therapy and for relapsing patients who received a rituximab-based induction therapy. Long-term use of rituximab exhibits a risk to develop hypogammaglobulinemia [ 103 ] and therefore some patients will require alternative immunosuppressive therapies. In such a scenario, we would consider azathioprine as a second-line therapy, as in ANCA-GN the use of methotrexate might have a narrow window of use. The ideal duration and requirement of administration of rituximab or other effective immunosuppressants needs further study in future clinical trials (see Fig. 5 for an overview).

Transplantation of Patients with ANCA-Associated GN

A significant proportion of patients with ANCA-GN eventually develop ESKD. In an extended follow-up of participants included in RCTs conducted by the EUVAS, the incidence of ESKD was 22% at 10 years [ 104 ].

In parallel to the general ESKD population, kidney transplantation is the treatment of choice for patients with ANCA-GN. An analysis of patients with ESKD due to PR3-positive vasculitis in the United States Renal Data System (USRDS) registry showed that transplant recipients had an improved survival compared with those who remained on the waiting list. This difference was largely driven by a 90% reduction in cardiovascular deaths [ 105 ]. However, patients with AAV are less likely to be listed for transplantation or have a longer preceding dialysis vintage [ 106 , 107 ], suggesting that there are several barriers to transplantation.

One barrier to transplantation is uncertainty about the optimal timing of transplantation. It is generally accepted that patients should achieve clinical remission followed by a relapse-free period before transplantation can be safely undertaken [ 108 ]. In addition, the immunosuppressive effects that persist early after induction treatment could lead to an excessive risk of posttransplant infection when standard therapeutic regimens are added. Therefore, it is prudent to include an observation period after remission is achieved to allow for partial recovery of immune competence while monitoring for potential relapse of AAV. However, this observation period must also be weighed against the excess cardiovascular morbidity and reduced quality of life associated with prolonged dialysis treatment, and clinicians must strike an optimal balance.

There is a paucity of evidence regarding the ideal time point for transplantation. In a cohort of 102 patients with AAV, kidney transplantation within the first year after remission was associated with a higher risk of mortality [ 109 ]. This reference has been used to suggest a 1-year disease-free interval before transplantation [ 108 , 110 ], while a 6-month interval was suggested by KDIGO [ 7 ].

Two considerations can be made about this. First, given the high degree of heterogeneity between patients with AAV in terms of disease presentation, clinical course, and treatment intensity, it may be more appropriate to tailor the optimal timing of transplantation to the individual patient rather than opting for a fixed period. To guide this decision, noninvasive biomarkers are needed to assess the level of immunocompetence, which would correlate positively with the risk of relapse and negatively with the risk of infection. Recently, Torque Teno viral load in patients treated for AAV has been associated with treatment intensity and the occurrence of early relapse [ 111 ]. Further research is needed to define a personalized optimal time point for transplantation in patients with ANCA-GN, taking into account various infectious, immunological and cardiovascular factors. Second, it is not always straightforward to distinguish residual vasculitis activity from damage resulting from previous disease activity [ 112 ]. Follow-up in expert vasculitis clinics should therefore be considered even in dialysis patients, especially in those with previous extrarenal manifestations [ 113 ].

Posttransplant outcomes for patients with ANCA-GN were similar or better than other causes of ESKD in registry studies of the ERA, USRDS, and UNOS, with 10-year patient survival rates of 70–90% and graft survival rates of 50–70% [ 106 , 107 , 114 ]. In contrast, patient and graft survival rates were lower in patients with MPO-ANCA vasculitis in the ANZDATA registry (68% and 50%, respectively) [ 115 ]. Similarly, a recent French multicentric study found inferior graft outcomes in patients with ANCA-GN compared to matched recipients, with a trend toward worse patient survival [ 116 ].

The risk of relapse of AAV after transplantation is considered to be low and has continued to decrease over the past few decades, with an estimated incidence rate of 0.01–0.03 events per patient per year in recent studies [ 117 , 118 ]. This evolution is likely related to the introduction of potent immunosuppressive regimens that are not only more effective in preventing rejection but also help to maintain remission of ANCA-GN. In previous case series, allograft involvement was present in 55% of posttransplant relapses, while the remaining 45% of cases had exclusively extrarenal manifestations [ 118 , 119 ]. Risk factors for posttransplant relapse include a history of PR3-positive vasculitis and persistent antibodies at transplantation [ 116 , 118 – 121 ], although this signal is not consistent across studies [ 109 ]. To further improve our understanding, larger multicentric studies are needed to investigate the granular associations between allograft outcomes and ANCA specificities, titers, and kinetics. In summary, given the low incidence of relapse and the uncertain prognostic value of persistent antibodies, ANCA positivity is not considered as a contraindication to transplantation [ 7 ]. Nevertheless, individualized risk stratification and careful follow-up of ANCA-positive patients are warranted.

The diagnosis of relapse after transplantation can be challenging due to the heterogeneous presentation of AAV, which may mimic infection or other complications related to immunosuppression [ 113 ]. In addition, the use of posttransplant immunosuppression may attenuate the rapid and aggressive pattern of a classic vasculitis flare, further complicating the diagnosis. Therefore, clinicians should maintain a high level of vigilance to detect relapses at an early stage. As rising ANCA titers tend to precede a clinical disease flare after transplantation [ 119 , 121 ], regular monitoring of ANCA may be of interest, although the therapeutic implications in case of rising titers remain unclear. Interestingly, persistent or recurrent MPO-ANCA positivity has been associated with poor renal outcomes in native kidney disease, suggesting a smoldering disease phenotype [ 122 ]. A similar mechanism may explain the worse allograft outcome after transplantation in MPO-ANCA vasculitis, as observed in the ANZDATA registry [ 115 ]. To further investigate this aspect and to detect subclinical inflammation, protocol biopsy studies in transplant recipients with prior AAV could be of relevance.

Given the increased burden of malignancies and infections in patients with AAV [ 88 , 123 ], the additional immunosuppression after transplantation may further increase this risk. Indeed, retrospective studies have found an increased risk of solid and hematological malignancies in patients with GN as the cause of ESKD who received pretransplant immunosuppression, particularly cyclophosphamide or rituximab, compared with those transplanted for other reasons [ 124 , 125 ]. This suggests that specific attention should be paid to malignancy surveillance in this patient population. Surprisingly few studies exist on the risk of posttransplant infectious diseases in patients with underlying GN. In contrast to the increased risk of malignancy, a recent retrospective analysis found no increased risk of bacterial or viral infections (BK and CMV) in transplant recipients with prior immunosuppression for GN, although the occurrence of opportunistic infections such as mycobacterial, fungal, and P. jirovecii infections was not examined [ 126 ]. To what extent the risks of malignancy and infection can be modulated by personalizing the immunosuppressive regimen remains to be studied, for example, by comparing induction therapy with either basiliximab or thymoglobulin to no induction. As suggested by others, assessing the “net state of immunosuppression” at the time of transplantation could be a very interesting tool to optimize the balance between (1) preventing rejection or vasculitis relapse and (2) avoiding excessive risk of malignancy and infection [ 127 ].

Conclusion

The management of ANCA-GN has been revolutionized over the past decade, with implementation of new histopathological/clinical scores predicting renal outcome, the detection of experimental biomarkers aiming to detect renal relapses earlier than established marker molecules. In the treatment, established therapies have been adjusted to contemporary needs; the implementation of newer therapies and the most recent approval of avacopan led to substantially reduce glucocorticoid exposure. Inhibition of the alternative complement pathway had a significant impact on eGFR recovery in comparison to the prednisone group in the ADVOCATE trial, indicating that avacopan has a greater kidney function potential and thus is a milestone in the management of ANCA-GN. A significant gap in knowledge exists when it comes to kidney transplantation in patients with AAV, as more efforts are needed to delineate the ideal timing of transplantation, predictors of disease relapse, and factors influencing long-term graft survival.

Conflict of Interest Statement

Martin Windpessl received consulting and speaking fees from AstraZeneca, Boehringer Ingelheim, CSL Vifor, Delta 4, GlaxoSmithKline, Novartis, and Otsuka. Duvuru Geetha received consulting fees from Amgen, Calliditas, ChemoCentryx, Otsuka, and Vera Therapeutics.

Ingeborg Bajema received consulting fees from Alentis, Amgen, Aurinia, CSL Vifor, GlaxoSmithKline, Hansa Biopharma, Novartis, Otsuka, and Vera Therapeutics. She is owner and director of BiPath. Sayna Norouzi received consulting fees from Boehringer Ingelheim, Calliditas, Novartis, and Otsuka.

Andreas Kronbichler received grant support from CSL Vifor and consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, CSL Vifor, Delta4, GlaxoSmithKline, Novartis, Novo Nordisk, Otsuka, Roche, Sobi, and Walden Biosciences. He serves as an associate editor of Glomerular Diseases and as an editor of Nephrology Dialysis Transplantation . Vanja Ivkovic, Ilay Berke, and Jasper Callemeyn declare no conflict of interests.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

V.I., M.W., I.B., D.G., J.C., S.N., I.M.B., and A.K. contributed to writing the article. I.B. and I.M.B. created the figures. All authors revised the initial draft and approved submission.

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