CD36 regulates macrophage and endothelial cell activation and multinucleate giant cell formation in anti neutrophil cytoplasm antibody vasculitis.

OBJECTIVE: To investigate CD36 in ANCA-associated vasculitis (AAV), a condition characterized by monocyte/macrophage activation and vascular damage. METHODS: CD36 expression was assessed in AAV patients and healthy controls (HC). The impact of palmitic acid (PA) stimulation on multinucleate giant cell (MNGC) formation, macrophage, and endothelial cell activation, with or without CD36 knockdown, was examined. RESULTS: CD36 was overexpressed on AAV patients' monocytes compared to HC, regardless of disease activity. AAV patients exhibited elevated soluble CD36 levels in serum and plasma and PR3-ANCA patients' monocytes demonstrated increased MNGC formation following PA stimulation compared to HC. PA stimulation of macrophages or endothelial cells resulted in heightened CD36 expression, cell activation, increased macrophage migration inhibitory factor (MIF) production, and c-Myc expression, with attenuation upon CD36 knockdown. CONCLUSION: CD36 participates in macrophage and endothelial cell activation and MNGC formation, features of AAV pathogenesis. AAV treatment may involve targeting CD36 or MIF.

The leukotriene B4 /BLT1-dependent neutrophil accumulation exacerbates immune complex-mediated glomerulonephritis.

Crescent formation is the most important pathological finding that defines the prognosis of nephritis. Although neutrophils are known to play an important role in the progression of crescentic glomerulonephritis, such as anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, the key chemoattractant for neutrophils in ANCA-associated glomerulonephritis has not been identified. Here, we demonstrate that a lipid chemoattractant, leukotriene B4 (LTB4 ), and its receptor BLT1 are primarily involved in disease pathogenesis in a mouse model of immune complex-mediated crescentic glomerulonephritis. Circulating neutrophils accumulated into glomeruli within 1 h after disease onset, which was accompanied by LTB4 accumulation in the kidney cortex, leading to kidney injury. LTB4 was produced by cross-linking of Fc gamma receptors on neutrophils. Mice deficient in BLT1 or LTB4 biosynthesis exhibited suppressed initial neutrophil infiltration and subsequent thrombotic glomerulonephritis and renal fibrosis. Depletion of neutrophils before, but not after, disease onset prevented proteinuria and kidney injury, indicating the essential role of neutrophils in the early phase of glomerulonephritis. Administration of a BLT1 antagonist before and after disease onset almost completely suppressed induction of glomerulonephritis. Finally, we found that the glomeruli from patients with ANCA-associated glomerulonephritis contained more BLT1-positive cells than glomeruli from patients with other etiologies. Taken together, the LTB4 -BLT1 axis is the key driver of neutrophilic glomerular inflammation, and will be a novel therapeutic target for the crescentic glomerulonephritis.

A case of rapid avacopan-induced liver injury in pediatric granulomatosis with polyangiitis.

Children with anti-neutrophil cytoplasmic antibody-associated vasculitis benefit immensely from avacopan as it reduces the requirement for steroids. However, descriptions of adverse drug reactions in children are lacking, and the dosage and follow-up intervals are unclear. A 10-year-old boy with initial granulomatosis and polyangiitis presented with diffuse pulmonary hemorrhage. Rituximab and 30 mg avacopan were administered twice daily as induction therapy following methylprednisolone pulse therapy. However, sudden liver function test abnormalities were observed on day 31 of avacopan treatment, despite liver enzyme levels being within the normal range 5 days earlier. A drug-induced lymphocyte stimulation and various infectious disease tests yielded negative results. Discontinuation of rituximab and avacopan resulted in improved liver function; no change in the Birmingham Vasculitis Activity Score during liver function test abnormalities was observed. Avacopan-associated abnormalities in liver function tests suggest that drug-induced liver injury may occur rapidly in children, and appropriate dosing strategies should be reconsidered.

Detailed tracking of antigen and antibody levels during coronavirus disease 2019 treatment in an immunosuppressed patient with anti-neutrophil cytoplasmic autoantibody-associated vasculitis.

A 67-year-old woman with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis was not vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was on multiple immunosuppressive drugs. She was hospitalized because of interstitial shadowing in the lungs and diagnosed with persistent coronavirus disease 2019 (COVID-19). Despite treatment with a recombinant monoclonal antibody and antivirals, her symptoms persisted and she lacked a specific antibody response. She tested negative for SARS-CoV-2 antigen after the second antiviral treatment, and a subsequent chest radiograph showed improvement. However, the antibody levels did not change. This case highlights the importance of careful monitoring of the SARS-CoV-2 antigen and antibody levels during COVID-19 treatment in patients with immunosuppression.

Incidence of anti-neutrophil cytoplasmic antibody-associated renal vasculitis: a retrospective study in rural and regional Victoria, Australia.

BACKGROUND: The epidemiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) varies worldwide. Previous Australian studies described a higher incidence of AAV in rural areas; however, this has not yet been investigated in Victoria. AIMS: To calculate the incidence of AAV in rural and regional Victoria and characterise the demographics and clinical outcomes of this cohort. METHODS: We performed a retrospective review of patients with newly diagnosed AAV confirmed on renal biopsy at Bendigo Health between 2013 and 2021. Cases were classified according to the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria. Local disease incidence was calculated using Estimated Resident Population data for our catchment, the Loddon Mallee region. RESULTS: Twenty-eight cases of new AAV were identified; 17 were classified as microscopic polyangiitis (MPA) and the remainder as granulomatosis with polyangiitis (GPA). The median age at diagnosis was 68 years (interquartile range (IQR): 59-77). The incidence per million person-years was 9.3 for AAV overall (95% CI: 6.2-13.5), 5.7 for MPA (95% CI: 3.3-9.1) and 3.7 for GPA (95% CI: 1.8-6.6). With a median follow-up time of 3.3 years (IQR: 1.9-5.6), one-quarter of patients relapsed (n = 7, 25%), and six required ongoing renal-replacement therapy (21%). CONCLUSIONS: The calculated incidence of AAV in rural and regional Victoria is not higher than the reported incidence in most urban Australian cohorts. This study may underestimate the true local disease incidence as only patients with renal vasculitis were included.

Variation in approaches to acute ANCA-associated vasculitis in Australia and New Zealand: rituximab, plasma exchange and glucocorticoids.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare autoimmune disease which is managed by a range of specialities. There are limited data on treatment practices in Australia and New Zealand. AIMS: To understand current patterns of acute AAV treatment in Australia and New Zealand. METHODS: An online survey was conducted between July and October 2022 investigating physicians' views on the management of AAV, focusing on induction therapy. The survey contained questions pertaining to access to treatment and responses to clinical management scenarios. Eosinophilic granulomatosis with polyangiitis was not included. A chi-squared test of independence was performed for statistical analysis. RESULTS: From a total of 55 responses, plasma exchange was difficult to access for 44% of respondents, more so in rural centres, and they also had difficulty accessing infusion centres. New Zealand clinicians had more difficulty accessing rituximab, with only 44% reporting easy access compared with Australian clinicians (93%). With clinical management scenarios, there was variation in the dosing regimen of glucocorticoids and initiation of plasma exchange, with 42% of respondents prescribing a glucocorticoid regimen different from the standard of care, the 'reduced-dose' arm of the Plasma Exchange and Glucocorticoids for the Treatment of ANCA-Associated Vasculitis trial. The choice of cyclophosphamide or rituximab for induction therapy was based on patient characteristics and medical history. CONCLUSIONS: There is substantial variation in approaches to the acute management of AAV in Australia and New Zealand, including differences in resource availability. This variation in care demonstrates the need to implement current practice guidelines and institute contemporary monitoring of AAV management, to achieve best patient outcomes.

Diagnostic delays in systemic vasculitides.

Systemic vasculitides are among the less common disorders encountered in routine rheumatology practice. The low incidence and heterogeneous presentation at onset can potentially lead to delayed diagnosis. Not recognizing these in the early phase may prove detrimental, as some vasculitis may progress to a catastrophic course with major morbidity or mortality. The causes of diagnostic delay may vary among different types of vasculitis and may also be disease-, patient-, or physician-related. Disease-related factors include the myriad presentations with diverse and non-specific symptoms, mimicking other conditions like infections. In addition, some forms have prolonged prodromal phases before evident organ damage. Limited awareness among healthcare professionals, particularly outside rheumatology, and a lack of readily available diagnostic tools contribute to missed diagnoses. Delays in seeking care due to non-specific symptoms or lack of access to specialist care can worsen outcomes. The economic burden also increases with delayed diagnosis and damage accrual when the disease remains unrecognized or untreated for prolonged periods. Although the causes of vasculitis are numerous, including secondary causes, in this review, we focus on diagnostic delays in primary vasculitides and suggest potential steps to identify and treat these diseases early. These include educating both healthcare professionals and the public about the signs and symptoms of vasculitis; expanding the rheumatology workforce and facilitating timely referrals; implementing readily available and reliable tests for early detection; and streamlining care and diagnostic pathways. Such measures have the potential to improve the overall outcomes of the disease, with prolonged remission, minimal damage accrual, and improved quality of life.

Use of mesna prophylaxis in patients with cyclophosphamide-treated ANCA-associated vasculitis: cross-sectional survey of practitioners.

BACKGROUND: There may be some diversity in the practice of co-prescribing 2-mercaptoethane sodium sulfonate (mesna) with cyclophosphamide (CYC) for ANCA-associated vasculitis (AAV). OBJECTIVES: To assess the practice of prescribing mesna prophylaxis for CYC-treated patients with AAV. METHODS: We invited authors of publications on AAV referenced in MEDLINE over the previous 10 years to participate in an anonymous online survey. Respondents were eligible if they were involved in CYC treatments for AAV. The survey asked about the characteristics of the respondents and their practice in using CYC and mesna to treat AAV and the underlying rationale. We compared 18 variables between mesna prescribers and their counterparts to identify factors associated with mesna use. RESULTS: In total, 139 eligible individuals completed the survey. The participants were from 34 countries and were essentially physicians (98%). Overall, 68%, 19% and 13% of respondents prescribed mesna systematically, never, or on a selective basis. As compared with never/selective-prescribers, systematic-prescribers were more often ≤ 39 years old (P = 0.008), more often used intermittent pulse therapy as the exclusive/predominant CYC administration scheme (P < 0.001), were more frequently based in France/Germany/Italy than in England/United States (P < 0.001), and more often indicated adherence to local standards (P = 0.003) or (inter)national guidelines for AAV (P < 0.001) as a rationale for their mesna practice. Never/selective-prescribers more commonly reported that their mesna prescription pattern had changed as compared with their former practice (P < 0.001). CONCLUSIONS: Systematic co-prescription of mesna is the prevailing practice for CYC treatments for AAV. The practice seems to involve practicability considerations and differs between generations.

IgG4-related kidney disease: Clinicopathologic features, differential diagnosis, and mimics.

IgG4-related kidney disease (IgG4-RKD) encompasses all forms of kidney disease that are part of IgG4-related disease (IgG4-RD). First recognized as IgG4-related tubulointerstitial nephritis (IgG4-TIN), and then IgG4-related membranous glomerulonephritis (IgG4-MGN), we now recognize additional patterns of interstitial nephritis, glomerular disease, and vascular disease that can be seen as part of IgG4-RKD. The clinical presentation is variable and can include acute or chronic kidney injury, proteinuria or nephrotic syndrome, mass lesion(s), and obstruction. While usually associated with other organ involvement by IgG4-RD, kidney-alone involvement is present in approximately 20 % of IgG4-RKD. Compared to IgG4-RD overall, patients with IgG4-RKD are more likely to show increased serum IgG4 or IgG, and more likely to have hypocomplementemia. In this review, we extensively cover other types of autoimmune and plasma cell-rich interstitial nephritis, mass forming inflammatory diseases of the kidney, and other mimics of IgG4-TIN, in particular ANCA-associated disease.

Investigation of Clinical Features and Association between Vascular Endothelial Injury Markers and Cytomegalovirus Infection Associated with Thrombotic Microangiopathy in Patients with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis: Case-Based Research.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) can occasionally trigger thrombotic microangiopathy (TMA). Cytomegalovirus (CMV) may be reactivated during intensive immunosuppressive therapy for AAV and cause TMA. Therefore, we aimed to evaluate the clinical features of and the association between vascular endothelial injury markers and TMA due to CMV in patients with AAV. A 61-year-old female was diagnosed with AAV and severe kidney injury. Immunosuppressive therapy gradually improved her symptoms and laboratory findings. However, 2 weeks after induction therapy initiation, she exhibited altered consciousness, a significant decrease in platelet count, and hemolytic anemia, resulting in a TMA diagnosis. Plasma exchange did not improve TMA findings and routine screening test revealed CMV infection. Ganciclovir injection improved the infection and TMA findings. Consequently, we diagnosed her with CMV-induced TMA. Both AAV and CMV may induce severe vascular endothelial injury, potentially leading to TMA development. CMV-induced TMA should be considered when TMA develops during induction therapy against AAV. Moreover, of the three serum markers of vascular injury-serum sulfatides, soluble thrombomodulin, and pentraxin 3-serum sulfatides may be associated with the development of TMA, and a high level of soluble thrombomodulin may be associated with the development of CMV viremia during the clinical course of AAV.

Serum Uric Acid Associates with Systemic Complement C3 Activation in Severe ANCA-Associated Renal Vasculitides.

Involvement of the complement system is key to the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis, but immunometabolic implications, especially on serum uric acid (UA) levels, still need to be elucidated. A total of 34 patients with biopsy-proven ANCA-associated renal vasculitis between 2015 and 2020 were retrospectively enrolled. Serum UA levels were correlated with clinical and histopathological characteristics, separated for critically ill (CI, n = 19), myeloperoxidase (MPO)-ANCA (n = 21) and proteinase 3 (PR3)-ANCA (n = 13) subgroups. We here identified inverse correlations of serum UA levels and complement C3 levels in the total cohort (p = 0.005) and the CI subgroup (p < 0.001). Intrarenal complement C4d deposition in venules correlated with serum UA levels in the total cohort (p = 0.007) and in the CI subgroup (p = 0.016). Significant associations of serum UA levels and tubulitis in areas of scarred cortex (t-IFTA) were identified in the total cohort (p = 0.008), and both subgroups of CI (p = 0.034) and MPO-ANCA (p = 0.029). In PR3-ANCA, interstitial fibrosis (ci) was observed as the strongest association with serum UA levels (p = 0.022). Our observations broaden our current understanding of contributory metabolic factors that influence the initial disease course in ANCA-associated renal vasculitis.

Neutrophil extracellular trap formation in anti-neutrophil cytoplasmic antibody-associated and large-vessel vasculitis.

Levels of neutrophil extracellular traps (NETs) were measured in plasma of healthy controls (HC, n = 30) and patients with granulomatosis with polyangiitis (GPA, n = 123), microscopic polyangiitis (MPA, n = 61), Takayasu's arteritis (TAK, n = 58), and giant cell arteritis (GCA, n = 68), at times of remission or activity and correlated with levels of the platelet-derived thrombospondin-1 (TSP-1). Levels of NETs were elevated during active disease in patients with GPA (p < 0.0001), MPA (p = 0.0038), TAK (p < 0.0001), and GCA (p < 0.0001), and in remission for GPA, p < 0.0001, MPA, p = 0.005, TAK, p = 0.03, and GCA, p = 0.0009. All cohorts demonstrated impaired NET degradation. Patients with GPA (p = 0.0045) and MPA (p = 0.005) had anti-NET IgG antibodies. Patients with TAK had anti-histone antibodies (p < 0.01), correlating with presence of NETs. Levels of TSP-1 were increased in all patients with vasculitis, and associated with NET formation. NET formation is a common process in vasculitides. Targeting NET formation or degradation could be potential therapeutic approaches for vasculitides.

Von Willebrand factor antigen as a marker of disease activity in childhood-onset antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Von Willebrand Factor (VWF) antigen plays a role in vascular inflammation and thrombosis, both important in the pathogenesis of Antineutrophil Cytoplasmic Antibody-associated vasculitis (AAV). Previous work found that VWF correlates with disease activity in childhood-onset primary CNS vasculitis. We sought to determine the relationship between VWF and disease activity over time in children with AAV. METHODS: AAV patients with more than one VWF level measured were included in this retrospective stuy, and the relationship between active vasculitis, VWF and other disease measures were analyzed. Generalized estimating equations (GEE) analysis was used to account for repeated VWF measurements within a patient. Repeated measures correlation was used to determine associations of paired laboratory observations. Diagnostic performance was evaluated using receiver operating curve (ROC) analysis. RESULTS: 732 total VWF measurements were collected in 33 AAV patients. VWF antigen levels were higher during active disease (median = 2.03 IU/ml, IQR = [1.35, 2.55]) compared with inactive disease (median = 1.18 IU/ml, IQR = [0.94, 1.53). VWF antigen was the only variable that was significantly associated with active disease (OR 3.01, p< 0.001, 95CI [2.3, 3.93]). The effect of VWF did not show a substantial difference between the disease subtypes. There was a moderate positive correlation between VWF antigen and disease activity, with an acceptable sensitivity and specificity rates. CONCLUSION: Increased VWF antigen levels correlate with active vasculitis in this paediatric-onset AAV cohort and may be used as an additional biomarker in childhood AAV.

A microRNA sponge, LINC02193, promotes neutrophil activation by upregulating ICAM1 and is correlated with ANCA-associated vasculitis.

OBJECTIVE: To investigate the pathogenic role and underlying mechanisms of lncRNAs in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). METHODS：: RNA-sequencing (RNA-seq) was applied to screen the expression profile of lncRNAs in peripheral leukocytes from 5 AAV patients and 5 healthy controls (HC). Candidate lncRNAs were preliminarily verified in peripheral leukocytes from 46 AAV patients and 35 HC by qRT-PCR. Then, the identified LINC02193 was further validated in peripheral neutrophils from 67 AAV patients, 45 HC and 64 disease controls. Correlation between LINC02193 levels and disease activity was analyzed. Then, a loss-of-function study was conducted to investigate the role of LINC02193 in neutrophils activation. Furthermore, bioinformatics analysis, dual luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to explore the mechanism of LINC02193 regulating neutrophils activation. RESULTS: A total of 467 upregulated and 412 downregulated lncRNAs were identified in AAV patients. From top 5 upregulated lncRNAs, an elevation of LINC02193 was validated in a larger sample of AAV patients, and positively correlated with disease activity. Knockdown of LINC02193 inhibited ROS and NO production, NETs release and adhesion to endothelial cells of differentiated human promyelocytic leukaemia HL­60 cells (dHL-60), whereas overexpression of ICAM1 counteracted these effects. Mechanistic analysis demonstrated that LINC02193 acted as a miR-485-5p sponge to relieve the repressive effect of miR-485-5p on ICAM1, thus promoting ICAM1 expression. CONCLUSION: LINC02193, a novel lncRNA identified in AAV could function as competing endogenous RNAs (ceRNA) for miR-485-5p to promote ICAM1 expression and neutrophils activation, suggesting its potential as a therapeutic target of AAV.

Eosinophilic granulomatosis with polyangiitis and severe cardiac involvement in a patient surviving for 34 years.

INTRODUCTION: Many studies have reported a poor prognosis for eosinophilic granulomatosis with polyangiitis (EGPA) patients with cardiac involvement. CASE STUDY: A woman developed EGPA at 37 years of age, with weight loss, numbness in the right upper and lower extremities, muscle weakness, skin rash, abdominal pain, chest pain, an increased peripheral blood eosinophil count (4165/µL), and necrotizing vasculitis on peroneal nerve biopsy. The patient was treated with prednisolone, immunosuppressants, intravenous immune globulin, and mepolizumab, but she experienced many relapses, with chest pain, abdominal pain, numbness, and paralysis, over a long period. The patient died from aspiration pneumonia at 71 years of age after undergoing left total hip arthroplasty for left hip neck fracture. RESULTS: Autopsy showed bronchopneumonia in the lower lung lobes on both sides, as well as infiltration of inflammatory cells, including neutrophils and lymphocytes. There was no evidence of active vasculitis in either the lung or colon. At autopsy the heart showed predominantly subendocardial fibrosis and fatty infiltration, but no active vasculitis or eosinophilic infiltration. CONCLUSION: To our knowledge, there have been no autopsy reports of EGPA patients who have survived for 34 years with recurrent cardiac lesions. In this case, the cardiac involvement (active vasculitis and eosinophilic infiltration) had improved by the time of death.

Prognostic value of proteinuria monitoring in anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To determine the prognostic significance of proteinuria monitoring in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We retrospectively analyzed the data of kidney biopsy-confirmed patients with AAV. Proteinuria was evaluated by a urine dipstick test. Poor renal outcome was defined as stage 4/5 chronic kidney disease (CKD) (estimated glomerular filtration rate < 30 mL/min/1.73 m2). RESULTS: We enrolled 77 patients with a median follow-up duration of 36 months (interquartile range, 18-79) in this study. Excluding 8 patients on dialysis at 6 months, 59/69 (85.5%) achieved remission after induction therapy. Patients were then divided into two groups according to the presence of proteinuria at 6 months after induction therapy (n = 29 with proteinuria, 40 without proteinuria). There was no significant difference in the rate of relapse or death according to the presence of proteinuria (p = 0.304 relapse, 0.401 death). In contrast, patients with proteinuria had significantly lower kidney function than those without proteinuria (41 vs. 53.5 mL/min/1.73 m2, p = 0.003). Multivariate analysis revealed that eGFR values at 6 months (hazard ratio [HR] 0.925; 95% CI 0.875-0.978, p = 0.006) and proteinuria at 6 months (HR 4.613; 95% CI 1.230-17.298, p = 0.023) were significantly associated with stage 4/5 CKD. CONCLUSION: The presence of proteinuria at 6 months after induction therapy and low renal function was significantly associated with a higher risk of stage 4/5 CKD in patients with AAV. Monitoring for proteinuria after induction therapy may help predict poor renal outcomes in patients with AAV.

Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges.

BACKGROUND: Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX. METHODS: We performed a multicenter, retrospective study on 188 patients with AAV and AKI treated with PLEX and 237 not treated with PLEX. The primary outcome was mortality or KRT at 12 months (M12). RESULTS: No significant benefit of PLEX for the primary outcome was found. To identify patients benefitting from PLEX, we developed a model predicting the average treatment effect of PLEX for an individual depending on covariables. Using the prediction model, 223 patients had a better predicted outcome with PLEX than without PLEX, and 177 of them had >5% increased predicted probability with PLEX compared with without PLEX of being alive and free from KRT at M12, which defined the PLEX-recommended group. Risk difference for death or KRT at M12 was significantly lower with PLEX in the PLEX-recommended group (-15.9%; 95% CI, -29.4 to -2.5) compared with the PLEX not recommended group (-4.8%; 95% CI, 14.9 to 5.3). Microscopic polyangiitis, MPO-ANCA, higher serum creatinine, crescentic and sclerotic classes, and higher Brix score were more frequent in the PLEX-recommended group. An easy to use score identified patients who would benefit from PLEX. The average treatment effect of PLEX for those with recommended treatment corresponded to an absolute risk reduction for death or KRT at M12 of 24.6%. CONCLUSIONS: PLEX was not associated with a better primary outcome in the whole study population, but we identified a subset of patients who could benefit from PLEX. However, these findings must be validated before utilized in clinical decision making.

De Novo ANCA-Negative Pauci-Immune Crescentic Glomerulonephritis After COVID-19 mRNA Vaccination: A Case Report.

To prevent the spread of the coronavirus disease 2019 (COVID-19) pandemic, vaccines have been authorized for emergency use and implemented worldwide. We present a case of de novo glomerulonephritis (GN) after use of the COVID-19 mRNA vaccine BNT162b2. A 48-year-old man with no relevant medical history was referred for sudden and persistent worsening of renal insufficiency 1.5 months after the second vaccine dose. He had arthralgia and skin rash a week after vaccination. Abdominal pain and diarrhea started 2 weeks later, and he was admitted to the hospital for enteritis treatment. Colonoscopy showed multiple ulcerations and petechiae suggestive of vasculitis in the terminal ileum. After prednisolone therapy, his gastrointestinal symptoms improved, but his renal function continued to deteriorate. Based on kidney biopsy findings and nephrotic-range proteinuria (5,306 mg/24 hours), he was diagnosed with anti-neutrophil cytoplasmic autoantibody (ANCA)-negative pauci-immune crescentic GN (CrGN). He received high-dose steroid pulse therapy and oral cyclophosphamide, and then, gradually underwent steroid tapering, with improvement in proteinuria and renal function over several weeks. Several cases of GN suspected to be related to COVID-19 vaccines have been reported. To our knowledge, this is the first case report of ANCA-negative pauci-immune crescentic CrGN with extrarenal involvement after COVID-19 mRNA vaccination. Our finding expands the spectrum of COVID-19 vaccine-associated GN.

Serum Complement C4 Levels Are a Useful Biomarker for Predicting End-Stage Renal Disease in Microscopic Polyangiitis.

This study aimed to evaluate the risk factors for end-stage renal disease (ESRD) in microscopic polyangiitis (MPA). In total, 74 patients with MPA were enrolled, and we compared the baseline clinical characteristics and disease activity between MPA patients who have progressed to ESRD and those without ESRD to select predictive factors for ESRD. Out of 74 patients, 12 patients (16.2%) had ESRD during follow-up. Serum C4 levels were significantly higher in MPA patients who have progressed to ESRD than in those without ESRD (p = 0.009). Multivariate analyses revealed that high serum creatinine levels (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.25-15.5) and high serum C4 levels (OR 1.24, 95% CI 1.03-1.49) were risk factors for ESRD. Using receiver operating characteristic analysis, the cut-off value for initial serum C4 levels and serum creatinine levels were 29.6 mg/dL and 3.54 mg/dL, respectively. Patients with MPA with a greater number of risk factors (serum C4 levels > 29.6 mg/dL and serum creatinine levels > 3.54 mg/dL) had a higher ESRD progression rate. Serum C4 levels were significantly positively correlated with serum creatinine levels and kidney Birmingham vasculitis activity score (p = 0.02 and 0.04, respectively). These results suggest that serum C4 levels are useful tools for assessing renal disease activity and prognosis in MPA.

Antiphospholipid antibody positivity and the thrombotic risk in Japanese patients with anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: It has been reported that 21.0-51.7% of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) patients were antiphospholipid antibody (aPL)-positive. However, the clinical significance of aPL positivity in AAV is not fully understood. METHODS: We retrospectively assessed patients with AAV diagnosed from 2013 to 2020 at our hospital. Positivity of aPL was defined as positivity of anti-cardiolipin antibody, anti-cardiolipin ß2 glycoprotein 1 complex antibody, and/or lupus anticoagulant at least one time during the follow-up periods. The thrombotic risk of aPL positivity was examined by multivariate analyses with the Cox regression model. RESULTS: A total of 93 patients with a median age of 71.9 years were included in the study. The median follow-up period was 35.4 months. Thirty-one patients (33.3%) were aPL-positive. Twenty-two thrombotic events occurred in 17 patients (18.3%). Thrombotic events occurred more frequently in aPL-positive patients than in aPL-negative patients (P = 0.011). Multivariate analyses with two different models identified aPL positivity as a thrombotic risk factor (hazard ratios 4.302 and 5.956, 95% confidence intervals 1.546-11.968 and 1.940-18.281, respectively). CONCLUSIONS: The proportion of aPL-positive patients was 33.3%, and aPL positivity increased the thrombotic risk in Japanese patients with AAV.