Proteinase 3-specific antineutrophil cytoplasmic antibody-associated vasculitis.

Proteinase 3 (PR3)-specific antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is one of two major ANCA-associated vasculitis variants and is pathogenically linked to granulomatosis with polyangiitis (GPA). GPA is characterised by necrotising granulomatous inflammation that preferentially affects the respiratory tract. The small vessel vasculitis features of GPA are shared with microscopic polyangiitis. Necrotising granulomatous inflammation of GPA can lead to PR3-ANCA and small vessel vasculitis via activation of neutrophils and monocytes. B cells are central to the pathogenesis of PR3-ANCA-associated vasculitis. They are targeted successfully by remission induction and maintenance therapy with rituximab. Relapses of PR3-ANCA-associated vasculitis and toxicities associated with current standard therapy contribute substantially to remaining mortality and damage-associated morbidity. More effective and less toxic treatments are sought to address this unmet need. Advances with cellular and novel antigen-specific immunotherapies hold promise for application in autoimmune disease, including PR3-ANCA-associated vasculitis. This Series paper describes the inter-related histopathological and clinical features, pathophysiology, as well as current and future targeted treatments for PR3-ANCA-associated vasculitis.

Keratin Expression in Podocytopathies, ANCA-Associated Vasculitis and IgA Nephropathy.

Keratins are the main components of the cell cytoskeleton of epithelial cells. Epithelial cells under stressful stimuli react by modifying their keratin expression pattern. Glomerular diseases are pathological conditions that may lead to loss of kidney function if not timely diagnosed and treated properly. This study aims to examine glomerular and tubular keratin expression in podocytopathies, ANCA-associated vasculitis, and IgA nephropathy and how this expression correlates to clinical outcomes. We included 45 patients with podocytopathies (minimal change disease and focal segmental glomerulosclerosis), ANCA-associated vasculitis, and IgA nephropathy, with or without crescentic lesions, and healthy controls. All tissues were assessed by photon microscopy and immunohistochemistry. Biopsy sections were examined for keratins 7, 8, 18, and 19 expression in the glomerular and tubulointerstitial areas separately. Moreover, we examined how keratin expression was correlated with long-term kidney function outcomes. All four studied keratins had significantly increased glomerular expression in patients with ANCA vasculitis compared to controls and MCD patients. Tubular expression of keratins 7, 8, and 19 was related to kidney outcome in all groups. Patients with crescents had higher expression of all keratins in both glomeruli and tubulointerstitium. The presence of tubular atrophy, interstitial fibrosis, mesangial hyperplasia, and interstitial inflammation did not affect keratin expression. Keratins, an abundant component of renal epithelial cells, have the potential to be featured as a biomarker for kidney function prognosis in patients with glomerular diseases.

Renal pathology in adult and paediatric population of Japan: review of the Japan renal biopsy registry database from 2007 to 2017.

BACKGROUND: The Japan Renal Biopsy Registry (J-RBR), a nationwide, web-based, registry system, started in 2007. This study aimed to summarise the epidemiology of biopsy-diagnosed kidney disease in Japan over 10 years. METHODS: We analysed the J-RBR database, from 2007 to 2017. Patients' clinical data collected at the time of biopsy and histopathological diagnoses were used for epidemiological and clinicopathologic analyses. RESULTS: The predominant renal biopsy diagnoses were immunoglobulin A nephropathy (39.2%), lupus nephritis (6.5%) and minimal change disease (6.0%) in younger adults (19-64 years), and membranous nephropathy (17.4%), antineutrophil cytoplasmic antibody-associated vasculitis or anti-glomerular basement membrane glomerulonephritis (13.0%), and immunoglobulin A nephropathy (12.5%) in older adults (≥ 65 years). The percentages of patients diagnosed with membranoproliferative glomerulonephritis and immunoglobulin A nephropathy decreased, whereas those with immunoglobulin A vasculitis and diabetic nephropathy increased over the decade. In paediatric patients (< 19 years), immunoglobulin A nephropathy (36.1%), minimal change disease (17.6%), and immunoglobulin A vasculitis (8.6%) were the predominant diagnoses. The percentage of patients diagnosed with immunoglobulin A vasculitis increased over the decade. Based on the sex distribution, minimal change disease and membranous nephropathy were predominant in men aged < 20 and > 40 years, respectively, whereas immunoglobulin A vasculitis and antineutrophil cytoplasmic antibody-associated vasculitis or anti-glomerular basement membrane glomerulonephritis were predominant in women in their 20s and 30s and aged < 50 years, respectively. Immunoglobulin A nephropathy was predominant in men at most ages and in women in their 20s to 40s. CONCLUSIONS: This study describes the distribution and changes in kidney biopsy diagnoses over 10 years in Japan and paves the way for future research on kidney diseases in adults and children.

[Pharmacological and clinical profiles of avacopan (TAVNEOS® capsule), a selective C5a receptor antagonist].

Avacopan (TAVNEOS® capsules) is an orally available selective C5a receptor (C5aR) antagonist. It has been approved in Japan since 2021 for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), the two major subtypes of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current standard therapy combining glucocorticoids (GC) and immunosuppressants has greatly improved the prognosis of AAV, however, issues such as side effects associated with GC use remain to be resolved. Avacopan suppresses priming of neutrophils induced by the complement component C5a, a process deeply involved in the pathogenesis of AAV. In pre-clinical studies, avacopan inhibited chemotaxis and priming of neutrophils induced by C5a-C5aR signaling. It also significantly suppressed nephritis and renal damage in an ANCA-induced glomerulonephritis mouse model. In the global phase 3 study "ADVOCATE", avacopan achieved both primary endpoints being 1) non-inferior to prednisone in inducing remission at week 26 and 2) superior in sustained remission at week 52 for MPA and GPA patients. Additionally, with avacopan, GC toxicity score was significantly lower and fewer adverse events possibly related to GC were observed. Furthermore, avacopan increased estimated glomerular filtration rate (eGFR) more than prednisone indicating improved renal function. Thus, the novel mechanism of avacopan targeting the complement system is a promising new therapeutic option for AAV with fewer GC-related side effects and better improvement of renal function.

The intricate relationship between autoimmunity disease and neutrophils death patterns: a love-hate story.

Autoimmune diseases are pathological conditions that result from the misidentification of self-antigens in immune system, leading to host tissue damage and destruction. These diseases can affect different organs and systems, including the blood, joints, skin, and muscles. Despite the significant progress made in comprehending the underlying pathogenesis, the complete mechanism of autoimmune disease is still not entirely understood. In autoimmune diseases, the innate immunocytes are not functioning properly: they are either abnormally activated or physically disabled. As a vital member of innate immunocyte, neutrophils and their modes of death are influenced by the microenvironment of different autoimmune diseases due to their short lifespan and diverse death modes. Related to neutrophil death pathways, apoptosis is the most frequent cell death form of neutrophil non-lytic morphology, delayed or aberrant apoptosis may contribute to the development anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). In addition, NETosis, necroptosis and pyroptosis which are parts of lytic morphology exacerbate disease progression through various mechanisms in autoimmune diseases. This review aims to summarize recent advancements in understanding neutrophil death modes in various autoimmune diseases and provide insights into the development of novel therapeutic approaches for autoimmune diseases.

Occurrence and localization of FOXP3 + cells in kidney biopsies in lupus nephritis and ANCA-associated vasculitis.

The study aims to increase the understanding regarding the role of regulatory T cells (Tregs) in lupus nephritis (LN) and ANCA-associated vasculitis (AAV) by comparing their localization in renal tissue and changes following immunosuppressive therapy. Kidney biopsies from 12 patients with LN and 7 patients with AAV were examined. Kidney biopsies had been performed both at active disease and following immunosuppressive treatment. Clinical data was collected at both biopsy occasions. Expression of Forkhead Box P 3 (Foxp3) in renal tissue was assessed by immunohistochemistry. An arbitrary scale was used to estimate the number of Foxp3+ cells. In LN, 8/12 (67%) had positive tissue staining for Foxp3 at baseline, most pronounced in inflammatory infiltrates, but also interstitially and in a peri-glomerular pattern. At second biopsies, after immunosuppressive treatment, 4/12 (33%) still had detectable Foxp3+ cells, found in persisting inflammatory infiltrates and some in the interstitium. Patients with a good clinical response to treatment had high grade of Foxp3+ cells in first biopsies. In AAV, only 2/7 (29%) had positive staining for Foxp3 at baseline, in inflammatory infiltrates and to a lesser extent in the interstitium, despite large areas of inflammatory infiltrates in all patients. At follow-up, 2/7 (29%) biopsies were positive for Foxp3. Our data show a higher presence of Foxp3+ cells in renal tissue from LN patients compared to AAV, suggesting that Tregs may be differently involved in the control of inflammatory mechanisms in these diseases. These findings could have further implication for therapeutic approaches aiming at restoring the immunological tolerance. Key Points • Foxp3+-cells are present in larger amount in renal tissue in lupus nephritis vs. ANCA-associated vasculitis. • Our data suggest that Foxp3+ regulatory T cells are involved in the control of inflammatory processes in lupus nephritis.

Image findings of anti-neutrophil cytoplasmic antibody-associated vasculitis involving the skull base.

AIM: To investigate computed tomography (CT) and magnetic resonance imaging (MRI) features of skull bases involving anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). MATERIALS AND METHODS: A retrospective review was undertaken to identify an institutional historical cohort of 17 patients with confirmed AAV who underwent CT or MRI and had skull base involvement between 2002 and 2021. Two radiologists reviewed the extent and features of the lesions, bone changes, and other MRI findings. RESULTS: A total of 17 patients (12 men; mean age ± standard deviation, 46.5 ± 17.1 years) were selected. AAV presented as infiltrative lesions with involvement at various sites. Most cases involved the paranasal sinuses (PNS; 88%, 15/17), nasopharynx (88%, 15/17), pterygopalatine fossa (82%, 14/17), and parapharyngeal space (82%, 14/17), frequently accompanied by mucosal irregularity of the PNS and nasopharynx (71%, 12/17). Central skull base and temporal bone involvement were seen in 53% (9/17) and 38% (6/16) of cases, respectively. On T1-weighted imaging (WI) and T2WI MRI, all lesions (15/15) showed predominant signal iso-intensity to grey matter. CONCLUSIONS: Although radiological findings of AAV are non-specific and skull base involvement is less common, AAV may be considered if infiltrative lesions predominantly involving the PNS, nasopharynx, pterygopalatine fossa, and parapharyngeal space with combined bone changes of skull base are seen.

Biomarkers of fibrosis, kidney tissue injury and inflammation may predict severity and outcome of renal ANCA - associated vasculitis.

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.

The role of anti-eosinophilic therapies in eosinophilic granulomatosis with polyangiitis: a systematic review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, mostly affecting small-sized arteries and usually occurring in patients with an allergic background. Eosinophils seem to play a significant role in the pathogenesis of the disease and, therefore, biologics targeting interleukin 5 (IL5), a cytokine tightly linked to eosinophils, have emerged as a promising therapeutic tool. A systematic review of Medline was conducted from 2007 to 2022 to search for data regarding the use of anti-IL5 therapies in patients with EGPA. Ongoing or unpublished trials were also searched in ClinicalTrials.gov and the World Health Organization trials portal. The efficacy and safety of mepolizumab, an anti-IL5 monoclonal antibody (mAb), was confirmed by a randomized controlled trial (RCT), although a significant proportion of patients did not respond to this treatment. Other studies showed that both doses of 100 mg and 300 mg of mepolizumab are almost equally effective in EGPA. Benralizumab, an anti-IL5 receptor mAb has preliminary promising results and an RCT is planned to be conducted. Apart from their clinical efficacy in EGPA, anti-IL5 therapies may have steroid-sparing properties. Anti-IL5 therapies seem to be effective and safe in patients with refractory/relapsing EGPA and can be used as a steroid-sparing treatment. Nevertheless, more research is needed to clarify the pathophysiology of the disease; this may potentially lead to the identification of biomarkers to pinpoint patients most likely to respond to anti-IL5-blockade.

Targeting immune checkpoints in anti-neutrophil cytoplasmic antibodies associated vasculitis: the potential therapeutic targets in the future.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) is a necrotizing vasculitis mainly involving small blood vessels. It is demonstrated that T cells are important in the pathogenesis of AAV, including regulatory T cells (Treg) and helper T cells (Th), especially Th2, Th17, and follicular Th cells (Tfh). In addition, the exhaustion of T cells predicted the favorable prognosis of AAV. The immune checkpoints (ICs) consist of a group of co-stimulatory and co-inhibitory molecules expressed on the surface of T cells, which maintains a balance between the activation and exhaustion of T cells. CD28, inducible T-cell co-stimulator (ICOS), OX40, CD40L, glucocorticoid induced tumor necrosis factor receptor (GITR), and CD137 are the common co-stimulatory molecules, while the programmed cell death 1 (PD-1), cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), T cell immunoglobulin (Ig) and mucin domain-containing protein 3 (TIM-3), B and T lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA), T-cell Ig and ITIM domain (TIGIT), CD200, and lymphocyte activation gene 3 (LAG-3) belong to co-inhibitory molecules. If this balance was disrupted and the activation of T cells was increased, autoimmune diseases (AIDs) might be induced. Even in the treatment of malignant tumors, activation of T cells by immune checkpoint inhibitors (ICIs) may result in AIDs known as rheumatic immune-related adverse events (Rh-irAEs), suggesting the importance of ICs in AIDs. In this review, we summarized the features of AAV induced by immunotherapy using ICIs in patients with malignant tumors, and then reviewed the biological characteristics of different ICs. Our aim was to explore potential targets in ICs for future treatment of AAV.

Interstitial Lung Disease and Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Review.

Interstitial lung disease is a common complication of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). It is seen most commonly in microscopic polyangiitis owing to the pathogenic effect of myeloperoxidase in the lung. Oxidative stress, neutrophil elastase release, and expression of inflammatory proteins by neutrophil extracellular traps result in fibroblast proliferation and differentiation and therefore fibrosis. Usually, interstitial pneumonia pattern fibrosis is common and associated with poor survival. Treatment for patients with AAV and interstitial lung disease lacks evidence, and those with vasculitis are treated with immunosuppression, whereas those with progressive fibrosis may well benefit from antifibrotic therapy.

C-Reactive Protein Levels Are Associated with Complement C4 Deposits and Interstitial Arteritis in ANCA-Associated Renal Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis in case of kidney involvement, representing a major denominator of AAV mortality. Innate immunity with complement system activation is increasingly recognized in the pathogenesis of AAV and as an attractive therapeutic target. Although C-reactive protein (CRP) was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self-determinants. Elevated baseline CRP at disease onset of AAV has already been described as a determinant of poor long-term outcomes. However, its clinical implications at disease onset of AAV, with respect to vasculitis manifestations and complement system activation that might also affect long-term outcomes, remain elusive. CRP levels were retrospectively analyzed in 53 kidney-biopsy-confirmed cases of ANCA-associated renal vasculitis; a total of 138 disease controls were also evaluated. Univariate and multivariate regression analysis was performed on clinicopathological parameters associated with CRP levels in ANCA-associated renal vasculitis. Results: Compared to disease controls, CRP elevation was common in ANCA-associated renal vasculitis and associated with de novo disease (p = 0.0169), critical illness (p = 0.0346), and severe deterioration of kidney function (p = 0.0167), independent of extrarenal disease manifestations. As confirmed by multiple regression analysis, CRP levels were correlated with active lesions predominated by interstitial arteritis in renal vasculitis, specifically with MPO-ANCA seropositivity (p = 0.0017). Based on analysis of systemic complement system activation and intrarenal complement deposits, CRP elevation was correlated specifically with complement C4 deposits in interstitial arteries in the subgroup with myeloperoxidase (MPO)-ANCA seropositivity (p = 0.039). Finally, this association was independent of systemic complement system activation, as reflected by the consumption of respective complement components. Here, we expand our current understanding of CRP in ANCA-associated renal vasculitis not only as an inflammatory marker, but potentially also as being involved in the pathogenesis of kidney injury by interaction with the complement system.

A modified renal risk score for Chinese patients with antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: The renal risk score (RRS) is a useful tool to predict end-stage renal disease (ESRD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to validate the predictive performance of RRS and to further modify this model in Chinese AAV patients. METHODS: Two hundred and seventy-two patients diagnosed with AAV confirmed by renal biopsies were retrospectively enrolled from a single center. The RRS was calculated based on 3 categorical variables, i.e., the proportion of normal glomeruli, the proportion of interstitial fibrosis and tubular atrophy (IF/TA), and eGFR at biopsy, classifying these patients into low-, medium-, and high-risk groups. In addition, a modified model was developed based on the RRS and was further validated in another independent cohort of 117 AAV patients. The predictive performance of each model was evaluated according to discrimination and calibration. RESULTS: Patients were classified by the RRS into low- (26.5%), medium- (46.7%), and high-risk (26.8%) groups, with 120-month renal survival rates of 93.3%, 57.2%, and 18.4%, respectively (P < 0.001). The RRS showed good discrimination but less satisfactory calibration. Therefore, a modified model with improved discrimination and calibration was developed in Chinese AAV patients, with eGFR, proportion of normal glomeruli (both as continuous variables), and IF/TA (< 25%, 25-50%, > 50%) included. Internal and external validation of the modified model were performed. Finally, an online risk prediction tool was developed based on the modified model. CONCLUSIONS: The RRS was an independent predictor of ESRD of AAV patients. The modified model could predict the probability of ESRD for AAV patients with improved performance in Chinese AAV patients.

Association between Loss of Immune Checkpoint Programmed Cell Death Protein 1 and Active ANCA-Associated Renal Vasculitis.

Immune checkpoint inhibitors (ICIs) have made an important contribution to the survival of patients with certain cancers. ICIs interrupt co-inhibitory signaling pathways mediated by programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen (CTLA-4) that result in the elimination of cancer cells by stimulating the immune system. However, immune-related adverse events have also been described and attributed to an enhanced immune system activation. Recent observations have suggested a dysregulation of immune checkpoints in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We here analyzed intrarenal PD-1 and PD-L1 by immunostaining in a total of 15 kidney biopsies with ANCA-associated renal vasculitis in correlation with glomerular and tubulointerstitial lesions. For independent validation, publicly available datasets were analyzed for PD-1 expression (encoded by PDCD1). We here observed a predominant tubulointerstitial expression of PD-1 that is decreased in ANCA-associated renal vasculitis. Moreover, loss of tubulointerstitial PD-1 correlated with active ANCA-associated renal vasculitis. Consistent with the observed association with active glomerular and tubulointerstitial lesions, we identified that interstitial PD-1 correlated with tubular and/or glomerular PD-L1 positivity. Finally, PD-1 was associated with decreased local synthesis of complement factor B. Interestingly, we did not observe a correlation between PD-1 and complement C5 or its C5a receptor. Combined with our observations, this may implicate a link between impaired PD-1/PD-L1 signaling, complement factor B and active ANCA-associated renal vasculitis. These findings could be of relevance because experimental data have already described that PD-1 agonism can be used therapeutically to attenuate autoimmunity in multiple disease models. Furthermore, targeted therapy against a complement C5/C5a receptor and factor B are both available and currently evolving in the treatment of AAV. Therefore, this pilot study expands our current knowledge and describes a potential interplay between immune checkpoints and the alternative complement pathway in active ANCA-associated renal vasculitis.

Selective deficiency of UCP-1 and adropin may lead to different subtypes of anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that is prone to respiratory and renal failures. Its major target antigens are serine protease 3 (PR3) and myeloperoxidase (MPO), but the determinants of PR3 and MPO subtypes are still unclear. Uncoupling protein-1 (UCP-1) and adropin (Adr) regulate mutually and play an important role in endothelial cell injury. In this study, adropin and UCP-1 knockout (AdrKO and UCP-1-KO) models were established on the basis of C57BL/6 J mice. The results showed that UCP-1-KO and AdrKO mice similar to AAV: significant inflammatory cell infiltration, vascular wall damage, and erythrocyte extravasation. The pathological basis of AdrKO was that endothelial cells adhered and activated neutrophils to release MPO, and the core gene was peroxisome proliferator-activated receptor gamma (PPARG). However, UCP-1-KO induced PR3 release, and the accumulation and expression of tissue factor on the vascular wall, and the core gene was peroxisome proliferator-activated receptor delta (PPARD). The present study verified that the subtypes of AAV may be genetically different diseases and it also provide novel experimental evidence for clinical differentiation of the two subtypes.

Kidney biopsy in patients with antineutrophil cytoplasmic antibody-associated vasculitis with mild renal abnormality.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic inflammation of small or medium blood vessels that includes microscopic polyangiitis. A diagnosis of ANCA-associated vasculitis can be aided by histological identification of vasculitis, and identification of renal impairment can help predict outcomes. However, kidney biopsy is not generally indicated in the absence of renal findings. We report two cases of ANCA-associated vasculitis diagnosed by kidney biopsy despite the absence of remarkable urinary abnormality and renal impairment. These patients had fever of unknown origin and were positive for myeloperoxidase (MPO)-ANCA but showed few findings that would suggest small-vessel vasculitis in the kidney. Nevertheless, kidney biopsies revealed small-vessel arteritis, necrotizing glomerulonephritis, and interstitial nephritis. Immunofluorescent antibody tests performed using samples of glomeruli were all negative, suggesting microscopic polyangiitis. Therefore, kidney biopsy may be useful in confirming the diagnosis, even if patients have completely normal urinary findings in the absence of other organ lesions.

Modified histopathological classification with age-related glomerulosclerosis for predicting kidney survival in ANCA-associated glomerulonephritis.

BACKGROUND: The histopathological classification of ANCA-GN divides patients into four groups based on signs of glomerular injury. However, this classification did not consider age-related glomerulosclerosis. In this study, we aimed to compare the prediction of renal survival between Berden's ANCA-GN histopathological classification and ANCA-GN histopathological classification modified with age-related glomerulosclerosis. METHODS: Between January 2004 and December 2019, 65 patients diagnosed with ANCA-GN were enrolled. Demographic, laboratory, and histopathologic findings were retrospectively analyzed. Renal survival analyses were compared according to classical and modified ANCA-GN histopathological classifications. Multivariate Cox regression analysis for the factors affecting renal survival was performed. RESULTS: In Berden's ANCA-GN histopathological classification, 15 patients were in the focal group, 21 in the crescentic, 21 in the sclerotic, and 8 in the mixed group. The ANCA-GN histopathological classification model generated statistically significant predictions for renal survival (p = 0.022). When the histopathological classification was modified with age-related glomerulosclerosis, eight of the nine patients previously classified in the sclerotic group were classified in the mixed and one in the crescentic groups. Modification of histopathological classification with age-related glomerulosclerosis increases the statistical significance in renal survival analysis (p = 0.009). The multivariate Cox regression analysis showed that the disease-related global sclerotic glomeruli percentage and serum creatinine level were significant independent factors. CONCLUSION: Modification of Berden's ANCA-GN histopathological classification model with age-related glomerulosclerosis may increase the statistical significance of the histopathological classification model.

Relevance of Complement C4 Deposits Localized to Distinct Vascular Compartments in ANCA-Associated Renal Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis affecting multiple organ systems, including the kidney. Small vessels in the kidney include small-sized arteries, capillaries, and venules. Intrarenal C4 deposits are now increasingly recognized as a potential marker and pathogenic mechanism of autoantibody-mediated tissue damage in ANCA-associated renal vasculitis. We here describe the relevance of complement C4 deposits localized to distinct vascular compartments in a cohort of biopsy-proven ANCA-associated renal vasculitis. A cohort of 43 biopsy-proven cases of ANCA-associated renal vasculitis with myeloperoxidase (MPO) or proteinase 3 (PR3) seropositivity were retrospectively enrolled in a single-center observational study. Univariate and multivariate regression analysis was performed to identify parameters associated with intrarenal C4 deposits in ANCA-associated renal vasculitis. We here show that C4 deposits localize to distinct vascular compartments in ANCA-associated renal vasculitis, and provide evidence for an association with better short-term survival (p = 0.008), implicating that this subgroup had a superior response to remission induction therapy. Second, C4 deposits in interlobular arteries were associated with eosinophilic infiltrates in renal vasculitis with MPO-ANCA seropositivity (p = 0.021). In renal vasculitis positive for MPO-ANCA, the absence of C4 deposits in the glomerular tuft was associated with sclerotic class ANCA-associated renal vasculitis (p < 0.001), and tubular RBC casts (p = 0.024). Fourth, complement C4 in interlobular arteries is associated with tubular atrophy specifically in renal vasculitis with PR3-ANCA seropositivity (p = 0.006). Finally, complement C4 deposits in peritubular capillaries associated specifically with hyaline casts in cases positive for PR3-ANCA (p = 0.025), implicating a role in tubular injury. Interestingly, C4 deposits were localized to distinct vascular compartments independent of the systemic activation of the complement system, reflected by the consumption of respective serum complement molecules in ANCA-associated renal vasculitis. In summary, we here show that C4 deposits localize to distinct vascular compartments in ANCA-associated renal vasculitis, and provide evidence for an association with survival and distinct histopathological lesions. Considering recent advances in AAV therapy with the emergence of new therapeutics that inhibit complement activation, we here provide novel insights into complement C4 as a potential marker to identify patients who may benefit most from these drugs. Thus, our results may contribute to a more personalized treatment approach of AAV depending on the relevance of distinct intrarenal complement deposits.

CX3CL1-induced CD16+ monocytes extravasation in myeloperoxidase-ANCA-associated vasculitis correlates with renal damage.

Background: Monocytes are involved in the pathogenesis of ANCA-associated vasculitis (AAV). Monocyte/macrophages are the dominant infiltrating cells in the glomeruli of patients with myeloperoxidase-AAV (MPO-AAV). However, how human monocyte subsets extravasate to the kidney in MPO-AAV with renal damage is unclear. Methods: 30 MPO-AAV patients with renal damage and 22 healthy controls were enrolled in this study. Monocyte subsets and monocyte-related chemokines in the blood and kidneys of MPO-AAV patients were detected. The chemoattractant activity of the CX3CL1-CX3CR1 axis on CD16+ monocytes was observed. The effect of MPO-ANCA on the migration of CD16+ monocytes to human glomerular endothelial cells (HGECs) was detected by flow cytometry and transwell migration assay. Results: Compared with controls, CD16+ monocytes were significantly decreased in the blood and increased in the glomeruli of MPO-AAV patients with renal damage. The level of CX3CL1, but not CCL2, was significantly increased in the plasma of MPO-AAV patients. CX3CL1 co-localized with glomerular endothelial cells in MPO-AAV patients with renal damage. Moreover, we initially found that MPO-ANCA promotes an increase of the chemokine CX3CL1 on HGECs, imposing recruitment on CD16+ monocytes. Finally, the percentage of CD16+ monocytes in the blood was found to be positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with urinary protein creatinine ratio in MPO-AAV patients with renal damage. Furthermore, the urinary protein creatinine ratio was positively correlated with the infiltrating of CD14+ and CD16+ cells in the kidneys. Conclusion: Enhanced extravasation of CD16+ monocytes to the kidney via the CX3CL1-CX3CR1 axis may be involved in renal damage in MPO-AAV.

Remission of Granulomatosis with Polyangiitis Only After Resection of a Pulmonary Nodule.

Granulomatosis with polyangiitis (GPA) is characterized by necrotizing granulomatous lesions and is classified as ANCA-associated vasculitis (AAV). We herein report a case of GPA that was remitted by resection of a pulmonary lesion without immunosuppressive therapy. We detected activated neutrophils and neutrophil extracellular traps (NET) formation in resected lung tissue by immunofluorescence. Activated neutrophils and NETs might be involved in the pathophysiology of AAV and induce the vicious cycle of ANCAs and NETs. In cases of GPA with no other severe lesions, the reevaluation of the disease activity after diagnostic resection is crucial for considering the need for immunosuppressive therapy.