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Background: Kidney involvement is common in anti-neutrophil cytoplasm antibody-associated vasculitis (AAV) and the prognosis is determined by the severity of kidney damage. This study focused on long-term kidney outcomes, defining possible risk factors and comparing the performance of three different histological classifications to predict outcomes for patients with AAV., Methods: The dataset included 848 patients with newly diagnosed AAV who participated in seven randomized controlled trials (RCTs) (1995-2012). Follow-up information was obtained from questionnaires sent to the principal investigators of the original RCTs., Results: The cumulative incidence of end-stage kidney disease (ESKD) at 5 and 10 years was 17% and 22%, respectively. Patients who developed ESKD had reduced patient survival compared with those with preserved kidney function (hazard ratio 2.8, P < .001). Comparing patients with AAV and kidney involvement with a matched general population, patients with AAV had poor survival outcomes, even in early stages of chronic kidney disease. The main cause of death was infection followed by cardiovascular disease in patients developing ESKD and malignancy in those who did not. Some 34% of patients with initial need for dialysis recovered kidney function after treatment. Thirty-five out of 175 in need of kidney replacement therapy (KRT) during follow-up received a kidney transplant with good outcome; there was 86% patient survival at 10 years.In the subcohort of 214 patients with available kidney biopsies, three scoring systems were tested: the Berden classification, the Renal Risk Score and the Mayo Clinic Score. The scores highlighted the importance of normal glomeruli and severe glomerulosclerosis on kidney survival (P < .001 and P = .001, respectively). The Renal Risk Score demonstrated a moderate prediction of kidney survival (area under the curve 0.79; standard error 0.03, 95% confidence interval 0.71-0.83)., Conclusions: Early diagnosis of AAV is extremely important. Even milder forms of kidney involvement have an impact on the prognosis. Patients in need of KRT had the lowest survival rates, but kidney transplantation has shown favorable outcomes for eligible AAV patients. The three histologic scoring systems were all identified as independent prognostic factors for kidney outcome., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Objective: ANCA-associated vasculitis (AAV) is a relapsing-remitting disease, resulting in incremental tissue injury. The gold-standard relapse definition (Birmingham Vasculitis Activity Score, BVAS>0) is often missing or inaccurate in registry settings, leading to errors in ascertainment of this key outcome. We sought to create a computable phenotype (CP) to automate retrospective identification of relapse using real-world data in the research setting., Methods: We studied 536 patients with AAV and >6 months follow-up recruited to the Rare Kidney Disease registry (a national longitudinal, multicentre cohort study). We followed five steps: (1) independent encounter adjudication using primary medical records to assign the ground truth, (2) selection of data elements (DEs), (3) CP development using multilevel regression modelling, (4) internal validation and (5) development of additional models to handle missingness. Cut-points were determined by maximising the F1-score. We developed a web application for CP implementation, which outputs an individualised probability of relapse., Results: Development and validation datasets comprised 1209 and 377 encounters, respectively. After classifying encounters with diagnostic histopathology as relapse, we identified five key DEs; DE1: change in ANCA level, DE2: suggestive blood/urine tests, DE3: suggestive imaging, DE4: immunosuppression status, DE5: immunosuppression change. F1-score, sensitivity and specificity were 0.85 (95% CI 0.77 to 0.92), 0.89 (95% CI 0.80 to 0.99) and 0.96 (95% CI 0.93 to 0.99), respectively. Where DE5 was missing, DE2 plus either DE1/DE3 were required to match the accuracy of BVAS., Conclusions: This CP accurately quantifies the individualised probability of relapse in AAV retrospectively, using objective, readily accessible registry data. This framework could be leveraged for other outcomes and relapsing diseases., Competing Interests: Competing interests: PAM declares the following disclosures: Consulting and Research Support: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Neutrolis, Takeda. Consulting only: Cabaletta, CSL Behring, Dynacure, EMDSerono, Immagene, Jannsen, Jubilant, Kiniksa, Kyverna, Magenta, MiroBio, Mitsubishi, Novartis, Pfizer, Q32, Regeneron, Sparrow, Vistera. Research Support only: Eicos, Electra, Sanofi, Star. Stock options: Kyverna. Royalties: UpToDate. All other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objectives: This study aims to describe the data structure and harmonisation process, explore data quality and define characteristics, treatment, and outcomes of patients across six federated antineutrophil cytoplasmic antibody-associated vasculitis (AAV) registries., Methods: Through creation of the vasculitis-specific Findable, Accessible, Interoperable, Reusable, VASCulitis ontology, we harmonised the registries and enabled semantic interoperability. We assessed data quality across the domains of uniqueness, consistency, completeness and correctness. Aggregated data were retrieved using the semantic query language SPARQL Protocol and Resource Description Framework Query Language (SPARQL) and outcome rates were assessed through random effects meta-analysis., Results: A total of 5282 cases of AAV were identified. Uniqueness and data-type consistency were 100% across all assessed variables. Completeness and correctness varied from 49%-100% to 60%-100%, respectively. There were 2754 (52.1%) cases classified as granulomatosis with polyangiitis (GPA), 1580 (29.9%) as microscopic polyangiitis and 937 (17.7%) as eosinophilic GPA. The pattern of organ involvement included: lung in 3281 (65.1%), ear-nose-throat in 2860 (56.7%) and kidney in 2534 (50.2%). Intravenous cyclophosphamide was used as remission induction therapy in 982 (50.7%), rituximab in 505 (17.7%) and pulsed intravenous glucocorticoid use was highly variable (11%-91%). Overall mortality and incidence rates of end-stage kidney disease were 28.8 (95% CI 19.7 to 42.2) and 24.8 (95% CI 19.7 to 31.1) per 1000 patient-years, respectively., Conclusions: In the largest reported AAV cohort-study, we federated patient registries using semantic web technologies and highlighted concerns about data quality. The comparison of patient characteristics, treatment and outcomes was hampered by heterogeneous recruitment settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab., Methods: This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months., Results: The study included 227 patients. IgG levels at 6 months were lower than baseline (P < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P = 0.004). Age [β (95% CI): -0.23 (-0.38, -0.08) per 10 years, P = 0.003], oral glucocorticoid dose at induction [β (95% CI): -0.37 (-0.51, -0.24) per sqrt-transformed mg prednisone, P < 0.001] and concomitant use of intravenous glucocorticoid pulses [β (95% CI): -0.88 (-1.73, -0.02), P = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P < 0.001]., Conclusions: In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Despite newer treatments with immunosuppressive agents, there still exists a considerable morbidity and mortality risk among patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Since 1994 the European Vasculitis Society (EUVAS) has aimed for an improved outcome for patients with AAV, conducting several prospective randomized controlled trials (RCTs). The aim for the present study was to further evaluate the long-term survival of patients with AAV included in seven RCTs conducted by the EUVAS as well as to identify potential prognostic factors., Methods: Long-term follow-up data were collected from questionnaires sent to the principal investigators of the original RCTs (1995-2012): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC, comprising 848 patients, all newly diagnosed with AAV. Relative survival estimates are presented for the study cohorts. Demographic, clinical and laboratory characteristics at trial entry were studied as potential prognostic factors in multivariable models., Results: A total of 478 (56%) patients had granulomatosis with polyangiitis (GPA) and 370 (44%) had microscopic polyangiitis (MPA) with a mean age at diagnosis of 58 ± 14 years. The median follow-up time was 8 years (interquartile range 2.9-13.6). During the observation period there were 305 deaths and the main causes were infections (26%), cardiovascular disease (14%) and malignancies (13%). When compared with a matched cohort (regarding country, age group and sex) from the background population there were 14.2% more deaths among our cohort of AAV patients at 5 years, 19.9% at 10 years, 28.8% at 15 years and 36.3% at 20 years. The excess mortality occurred in all age groups. The estimated median survival time (from diagnosis) was 17.8 years (95% confidence interval 15.7-20). Among variables measured at baseline, advanced age, male sex, low estimated glomerular filtration rate and low platelet count were identified as predictors of death in a multivariate Cox model., Conclusions: Patients with AAV still have an increased risk of mortality compared with the general population despite newer therapeutic regimens. Treatment complications and organ damage are the main causes of limited survival and infections remain the leading cause of mortality among patients with AAV., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Activity and chronicity of kidney involvement in ANCA-associated vasculitis (AAV) can be currently reliably evaluated only by kidney biopsy. In this study, we measured a panel of serum and urinary biomarkers collected at the time of kidney biopsy and hypothesized that they could reflect specific histopathological parameters in the biopsy and help to predict prognosis., Methods: We examined a cohort of 45 patients with AAV and 10 healthy controls. Biomarker levels (DKK-3, CD163, EGF, PRO-C6 and C3M) were measured in this study by ELISA. Biopsies were scored with a scoring system for AAV (focal x crescentic x sclerotic x mixed class) and interstitial fibrosis was quantified., Results: Levels of urinary DKK-3, CD163, EGF, PRO-C6 and C3M significantly differed among biopsy classes in AAV, with urinary DKK-3 and PRO-C6 levels being highest in the sclerotic class and lowest in the focal class, urinary CD163 levels highest in the crescentic class and urinary C3M levels highest in the focal class. Moreover, the urinary biomarkers were able to discriminate focal biopsy class from the other classes. Urinary DKK-3, EGF, PRO-C6 and C3M levels measured at the time of biopsy were also significantly related to the extent of fibrosis and to the final kidney function at the end of follow-up., Conclusions: This small pilot study suggests that selected urinary biomarkers of fibrosis and inflammation may reflect changes in the kidney biopsy and be prognostic of kidney outcome in patients with AAV., Competing Interests: NS, FG, and MK are full-time employees at Nordic Bioscience and FG and MK hold stocks. Nordic Bioscience is a privately-owned, small–medium-sized enterprise partly focused on the development of biomarkers and owns the patent for the uC3M and PRO-C6 ELISAs. No authors received fees, bonuses, or other benefits for the work described in the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Satrapova, Sparding, Genovese, Karsdal, Bartonova, Frausova, Honsova, Kollar, Suchanek, Koprivova, Rysava, Bednarova, Tesar and Hruskova.)

Efficacy of immunosuppressive treatment of Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is complicated by its toxicity. With the replacement of cyclophosphamide with rituximab, serious adverse events seem to be associated especially with high-dose corticosteroids. Activation of alternative complement pathway plays an important role in the pathogenesis of AAV. Avacopan (C5a receptor inhibitor) was demonstrated to have at least similar efficacy and better safety (in terms of corticosteroid-related adverse events) compared with high-dose corticosteroids in the induction treatment of AAV. Other modes of the inhibition of alternative complement pathway are currently tested in AAV or could be considered on the basis of the experience in other glomerular diseases., Competing Interests: VT was principal investigator in both CLEAR and ADVOCATE trials with avacopan. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tesar and Hruskova.)

Background: Renal fibrosis is the hallmark of chronic kidney disease (CKD) and is characterized by an imbalanced extracellular matrix remodelling. Endotrophin (ETP) is a signalling molecule released from collagen type VI (COL VI). ETP can be measured by the PRO-C6 assay, which quantifies the levels of COL VI formation. ETP levels were previously associated with mortality and disease progression in patients with CKD. We hypothesized that serum and urinary ETP levels correlate with the degree of interstitial fibrosis in kidney biopsies from patients with immunoglobulin A nephropathy (IgAN) and patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)., Methods: We examined a cohort of 49 IgAN and 47 AAV patients. A validation cohort of 85 IgAN patients was included. ETP was measured in serum (S-ETP) and urine (U-ETP/Cr) samples, taken on the same day before renal biopsy was performed, using the enzyme-linked immunosorbent assay PRO-C6. The biopsies were evaluated for interstitial fibrosis and tubular atrophy according to the Banff and MEST-C scores., Results: S-ETP and U-ETP/Cr levels correlated with kidney function, increased CKD severity, correlated with the extent of interstitial fibrosis and gradually increased with increasing degree of interstitial fibrosis and tubular atrophy. ETP outperformed the known fibrosis biomarker Dickkopf-3 for discrimination of patients with high fibrotic burden. The association of S-ETP and U-ETP/Cr with the level of kidney fibrosis was confirmed in the validation cohort., Conclusions: We demonstrated that high levels of circulating and excreted ETP are not only indicative of lower kidney function, but also reflect the burden of fibrosis in the kidneys., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) represents an autoimmunity disease characterized by high mortality. For successful treatment, the detailed knowledge of its complex pathogenesis and the set of biomarkers for differential diagnostics are desired. Analysis of molecular content of small urinary extracellular vesicles (uEV) offers the possibility to find markers in the form of microRNAs (miRNAs) and study the pathways involved in pathogenesis. We used next-generation sequencing in the first preliminary study to detect the miRNAs with altered expression in uEVs of patients with AAV in comparison with age-matched controls. We confirmed the results using single-target quantitative polymerase chain reaction tests on different sets of samples and found five miRNAs (miR-30a-5p, miR-31-3p, miR-99a-5p, miR-106b-5p, miR-182-5p) with highly elevated levels in uEVs of patients. We performed the comparison of their targets with the differentially expressed proteins in uEVs of patients included in the first phase. We realized that upregulated miRNAs and proteins in uEVs in AAV patients target different biological pathways. The only overlap was detected in pathways regulating the actin cytoskeleton assembly and thus potentially affecting the glomerular functions. The associations of upregulated miRNAs with pathways that were neglected as components of complex AAV pathogenesis, e.g., the epidermal growth factor receptor signaling pathway, were found.

ANCA-associated vasculitis (AAV) is a rare, but potentially severe autoimmune disease, even nowadays displaying increased mortality and morbidity. Finding early biomarkers of activity and prognosis is thus very important. Small extracellular vesicles (EVs) isolated from urine can be considered as a non-invasive source of biomarkers. We evaluated several protocols for urinary EV isolation. To eliminate contaminating non-vesicular proteins due to AAV associated proteinuria we used proteinase K treatment. We investigated the differences in proteomes of small EVs of patients with AAV compared to healthy controls by label-free LC-MS/MS. In parallel, we performed an analogous proteomic analysis of urine samples from identical patients. The study results showed significant differences and similarities in both EV and urine proteome, the latter one being highly affected by proteinuria. Using bioinformatics tools we explored differentially changed proteins and their related pathways with a focus on the pathophysiology of AAV. Our findings indicate significant regulation of Golgi enzymes, such as MAN1A1, which can be involved in T cell activation by N-glycans glycosylation and may thus play a key role in pathogenesis and diagnosis of AAV. SIGNIFICANCE: The present study explores for the first time the changes in proteomes of small extracellular vesicles and urine of patients with renal ANCA-associated vasculitis compared to healthy controls by label-free LC-MS/MS. Isolation of vesicles from proteinuric urine samples has been modified to minimize contamination by plasma proteins and to reduce co-isolation of extraluminal proteins. Differentially changed proteins and their related pathways with a role in the pathophysiology of AAV were described and discussed. The results could be helpful for the research of potential biomarkers in renal vasculitis associated with ANCA., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is the leading cause of rapidly progressive glomerulonephritis, which may follow an unfavorable disease course. Despite therapeutic advances, a number of patients with AAV will eventually develop end-stage renal disease (ESRD). Renal transplantation (RTx) is associated with a survival benefit and improves quality of life in patients with ESRD., Summary: In recent years, RTx has been increasingly used also in patients with vasculitis. The posttransplant patient- and graft-survival rates in AAV were at least comparable to other diagnoses in most studies. Prior to transplantation, patients should be in stable remission for 12 months. Persistent ANCA positivity does not exclude patients from the waiting list. Even though the recurrence risk is generally low with modern posttransplant immunosuppression, including mycophenolate mofetil and tacrolimus, patients with AAV, particularly those with positive antiproteinase-3 ANCA who may have increased risk of relapse or recurrence of the disease, require constant surveillance. Similar to treatment of relapsing disease in the nontransplant setting, rituximab may become treatment of choice for posttransplant recurrences. Key Messages: RTx is the preferred renal replacement therapy of choice for AAV patients with ESRD. It is recommended that patients should be in remission for about 12 months prior to proceeding with RTx. ANCA positivity alone is not a contraindication for transplantation. The risk of relapse posttransplantation is minimal with currently used posttransplant immunosuppressive regimen., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Introduction: ANCA-associated vasculitis (AAV) is a rare but potentially life-threatening disease. Currently used induction treatment (cyclophosphamide or rituximab with high-dose corticosteroids) has significantly improved outcome of AAV, but is associated with high toxicity. Alternative complement pathway activation was shown to play a role in the pathogenesis of AAV, thus providing rationale for the use of avacopan, a selective inhibitor of C5a receptor, in the treatment of AAV. Areas covered: Pharmacokinetic and pharmocodynamic properties of avacopan, clinical efficacy and safety and tolerability of avacopan in so far performed clinical trials in patients with AAV are reviewed and discussed. Expert opinion: Avacopan was shown to have at least similar efficacy compared to high dose corticosteroids in patients with active AAV with renal involvement, while there were no major safety issues reported. Replacement of corticosteroids should decrease the corticosteroid-related toxicity and improve long-term outcome of patients with AAV even though this still needs to be confirmed in a larger trial. Data on long-term outcome of avacopan-treated patients are currently lacking and will be eagerly awaited. In the future, avacopan could replace corticosteroids not only in the induction phase, but also in the maintenance treatment of AAV.

Background: Rapidly progressive glomerulonephritis (RPGN) is characterized by a rapid deterioration of renal function and by extracapillary proliferation in >50% of glomeruli. The most common type of RPGN is "pauci-immune" glomerulonephritis caused by anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV)., Summary: The incidence of AAV increases with age and pauci-immune glomerulonephritis is the most common diagnosis found in renal biopsies in the elderly population. Age was identified as an independent negative risk factor for both death and end-stage renal disease in AAV, and the mortality of older patients was uniformly higher than in younger patients in all retrospective studies. Early diagnosis may be difficult particularly in elderly patients with renal-limited disease but is important for the good outcome of the patients. Immunosuppressive treatment options include cyclophosphamide or rituximab combined with corticosteroids with or without plasma exchange in case of severe disease. Data from randomized trials are completely missing for patient aged >75 years. Based on retrospective studies, elderly patients seem to respond to immunosuppressive drugs just as younger patients are able to, but they are at a higher risk of adverse events. Key Messages: RPGN is relatively common in the elderly patients. Immunosuppressive treatment in older patients with AAV or RPGN may be useful but needs to be strictly individualized with all the risks taken into consideration. Further studies are needed to examine the role of novel therapeutic options in the elderly population with RPGN., (© 2018 S. Karger AG, Basel.)

Background: The prognostic value of the anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis (GN) classification has been demonstrated in several cohorts with sclerotic class having the worst renal outcome. Relevant published data on factors predicting outcomes in sclerotic ANCA GN is limited., Methods: Sclerotic ANCA GN patients were recruited from 5 centers worldwide for this retrospective cohort study. We describe the clinical characteristics of this cohort and evaluate predictors of 1-year glomerular filtration rate (GFR) and end-stage renal disease (ESRD). Kidney function at 12 months as measured by Modification of Diet in Renal Disease estimated GFR (eGFR) was modeled by simple and multiple linear regression analyses. We used Cox proportional hazards regression modeling to evaluate ESRD-free survival., Results: Of the 50 patients, 92% were Caucasian and 60% male with a mean age of 61 years. While 72% had renal limited disease, 82% were MPO ANCA positive. Kidney biopsies contained a median of 20 (interquartile range [IQR] 15-34) glomeruli with 96% showing moderate to severe interstitial fibrosis. Overall, 96% of patients received immunosuppressive drug therapy and 16% received plasmapheresis. Treatment response was achieved in all but 1 patient. The median (IQR) eGFR at entry was 14.5 (9-19) mL/min/1.73 m2. Over a median (IQR) follow-up of 33.5 (17-82) months, 26 patients reached ESRD. Ten patients died with 6 of the deaths occurring within the first year of diagnosis. The hazard of progression to ESRD was significantly higher in those with lower GFR at study entry (p = 0.003) and with higher degree of tubular atrophy (p = 0.043)., Conclusions: Renal recovery is rare among sclerotic ANCA GN patients requiring dialysis at entry and 12% of patients died in the first year. Entry GFR and tubular atrophy were significant predictors of GFR at 12 months and renal survival in patients with sclerotic class ANCA GN., (© 2018 S. Karger AG, Basel.)

Background: Rituximab (RTX) is approved for remission induction in ANCA associated vasculitis (AAV). However, data on use of RTX in patients with severe renal disease is lacking., Methods: We conducted a retrospective multi-center study to evaluate the efficacy and safety of RTX with glucocorticoids (GC) with and without use of concomitant cyclophosphamide (CYC) for remission induction in patients presenting with e GFR less than 20 ml/min/1.73 m(2). We evaluated outcomes of remission at 6 months (6 M), renal recovery after acute dialysis at diagnosis, e-GFR rise at 6 M, patient and renal survival and adverse events., Results: A total 37 patients met the inclusion criteria. The median age was 61 years. (55-73), 62 % were males, 78 % had new diagnosis and 59 % were MPO ANCA positive. The median (IQR) e-GFR at diagnosis was 13 ml/min/1.73 m(2) (7-16) and 15 required acute dialysis. Eleven (30 %) had alveolar hemorrhage. Twelve (32 %) received RTX with GC, 25 (68 %) received RTX with GC and CYC and seventeen (46 %) received plasma exchange. The median (IQR) follow up was 973 (200-1656) days. Thirty two of 33 patients (97 %) achieved remission at 6 M and 10 of 15 patients (67 %) requiring dialysis recovered renal function. The median prednisone dose at 6 M was 6 mg/day. The mean (SD) increase in e-GFR at 6 months was 14.5 (22) ml/min/m(2). Twelve patients developed ESRD during follow up. There were 3 deaths in the first 6 months. When stratified by use of concomitant CYC, there were no differences in baseline e GFR, use of plasmapheresis, RTX dosing regimen or median follow up days between the groups. No differences in remission, renal recovery ESRD or death were observed., Conclusions: This study of AAV patients with severe renal disease demonstrates that the outcomes appear equivalent when treated with RTX and GC with or without concomitant CYC.

Despite major advances in the management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) achieved in the last decades, a large proportion of AAV patients still develop end-stage renal disease. The survival of AAV patients dependent on dialysis is significantly worse compared with dialysis-independent AAV patients, but is comparable to other non-diabetic patients requiring dialysis. Renal transplantation (RTx) is the method of choice among renal replacement therapies and there has been increasing evidence that it is a suitable method with favorable patient- and graft-survival also in AAV patients. It is recommended to perform RTx after ≥12 months of remission, and ANCA positivity at the time of RTx is generally not considered a contraindication. Even though the risk of relapse after RTx is relatively low with current post-transplant immunosuppressive regimens, disease recurrence may occur. Besides cyclophosphamide, rituximab might become a therapeutic alternative for post-transplant AAV recurrence in the near future but its efficacy and safety in this setting needs to be confirmed in larger studies., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Introduction: Antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) is a group of autoimmune diseases characterized by the necrotizing inflammation of small vessels and associated with the antineutrophil cytoplasmic antibodies. Treatment of AAV can be divided into the induction phase aimed at achieving remission of the disease and the maintenance phase aimed at prevention of relapses. Long-term outcome of AAV dramatically improved with the introduction of cyclophosphamide. Recent clinical studies resulted in the reduction of the cumulative dose of cyclophosphamide and introduction of new treatment options, namely B-cell-depleting antibody rituximab, into both induction and maintenance treatment. This paper aims to evaluate the current role of the conventional induction and maintenance treatment in view of the gradually increasing use of rituximab., Areas Covered: This paper provides an overview of the main clinical studies in induction and maintenance treatment of adult patients with AAV, treatment of relapses of AAV and shortly comments also on the treatment of refractory AAV, treatment of different subgroups of AAV (based on the age, renal function, clinical presentation and type of autoantibody), long-term outcome of patients with AAV, adverse events of treatment and treatment of end-stage renal disease in AAV., Expert Opinion: Our analysis demonstrates that although the introduction of rituximab modified the approach to both the induction and maintenance treatment of AAV, more conventional induction and maintenance treatment with standard immunosuppressive drugs still retains its importance as we need more data on long-term efficacy and safety of biologic treatment, and also its cost-effectiveness still remains an open issue.

Background: Histopathological lesions in renal biopsy (RB) at presentation of ANCA-associated vasculitis (AAV) have been described in depth but repeat protocolized renal biopsies are seldomly performed in AAV. In this study, we present a group of AAV patients with repeat protocolized biopsies, and we evaluate their clinical significance., Methods: A total of 17 consecutive patients diagnosed between 1991 and 1995 with AAV and renal involvement confirmed by biopsy at presentation in a single center underwent a protocol planned rebiopsy in remission after a median of 13 months (range 11-28) from diagnosis. Biopsies were assessed by two independent pathologists, blinded to patient data. Clinical data were collected retrospectively., Results: Patients were followed-up for a median of 189 months from diagnosis. Renal relapse was observed in eight patients (47.1%), seven patients died, three patients reached end-stage renal failure. There was a significant decrease in the percentage of acute lesions (cellular crescents, fibrinoid necrosis, P < 0.001) and a significant increase in chronic lesions (glomerulosclerosis, interstitial fibrosis, P ≤ 0.01) in the repeat RB compared with the first RB. This resulted in a class change over the biopsies within most patients. The percentage of normal glomeruli in the first biopsy positively correlated with estimated GFR at the end of follow-up (rs = 0.509, P = 0.05)., Conclusions: This is the first study on protocolized repeat biopsies in AAV, giving insight into disease activity under immunosuppressive treatment. Apparently, many AAV patients have grumbling disease with ongoing activity, eventually leading to an increased amount of chronic lesions., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Introduction of the standard immunosuppressive treatment has dramatically changed the outcome of patients with both ANCA-associated vasculitis and lupus nephritis, transforming them from incurable diseases with very high short-term mortality to chronic debilitating diseases with much lower short-term, but still relatively high long-term, morbidity/mortality. Long-term morbidity with damage accumulating partly due to the adverse events of the available treatment (namely gonadal toxicity, malignancy, bone disease, cataracts, diabetes, and thromboembolic and cardiovascular disease) has become a major concern. Although cyclophosphamide-based regimens have been partly replaced by newer agents in both ANCA-associated vasculitis and lupus nephritis (namely rituximab or mycophenolate, respectively) their short-term and medium-term adverse events may not be significantly less frequent and we can only hope that new treatments will translate into better long-term outcomes including better long-term safety., (© 2014 S. Karger AG, Basel.)

ANCA-associated vasculitis (AAV) is a potentially life-threatening disease with frequent and often severe kidney involvement which may result in end-stage renal disease. Anti-PR3 and anti-MPO disease are genetically distinct diseases and may have a different pathogenesis. Recent discovery of new autoantibodies (anti-LAMP-2) and the role of complement activation in the pathogenesis of AAV could result in better monitoring of the activity of the disease and identification of new treatment targets. The outcome of patients with AAV has dramatically improved, but long-term mortality still remains relatively high partly due to effective but relatively toxic immunosuppressive treatment. Recent studies demonstrated that B-cell depletion with rituximab is comparable to cyclophosphamide as induction treatment in newly diagnosed AAV patients and better than cyclophosphamide in relapsing patients. Rituximab-based maintenance treatment is superior to standard treatment with azathioprine. The use of more targeted treatment will hopefully be translated into a better long-term outcome of AAV patients., (Copyright © 2013 S. Karger AG, Basel.)