Pauci-immune Necrotizing Research Articles

Clinical Presentation and Treatment Outcomes of Renal Medullary Angiitis in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Single-Center Case Series.

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with renal involvement primarily affects the renal cortex and presents with key histopathologic findings of a pauci-immune necrotizing and crescentic glomerulonephritis. Infrequently reported and poorly characterized is renal medullary angiitis (RMA), a pathologic variant of AAV primarily involving the renal medulla. This study seeks to describe the presentation and treatment outcomes of RMA. In this single-center cohort, renal pathology samples classified as AAV with renal involvement underwent secondary review to determine if they met histopathologic criteria for RMA. Demographic, clinical, and laboratory data were obtained via electronic medical record review. Descriptive statistical analysis was performed on key variables. Of the 136 kidney biopsy samples classified as AAV with renal involvement, histopathologic features of RMA were present in 13 cases. The mean (SD) age at the time of RMA diagnosis was 65 (19) years, and 54% were female. Most cases presented with extrarenal manifestations of disease. Initial median (IQR) estimated glomerular filtration rate and proteinuria on presentation were 16 (10-19) mL/min/1.73 m2 and 1,100 (687-2,437) mg, respectively. The primary histologic features were high degrees of interstitial inflammation comprised leukocytes, neutrophils, plasma cells, and eosinophils along with either interstitial hemorrhage or necrosis. All patients were treated with glucocorticoids in combination with either cyclophosphamide, rituximab, or mycophenolate. All patients achieved disease remission. During a median (IQR) follow-up of 42 (14-68) months, 1 patient reached ESKD and 1 patient died. In this single-center case series, we identified the presence of RMA in 9.5% of AAV samples that underwent secondary review. RMA presented with severe impairment in renal function and multisystem disease. Standard of care immunosuppression for AAV was effective for remission induction in RMA. It remains unclear whether standard prognostication tools are useful in this population.

#4710 CYCLOPHOSPHAMIDE INDUCTION TREATMENT IN ANCA-ASSOCIATED VASCULITIS WITH RENAL AND PULMONARY INVOLVEMENT: OUTCOMES AND SIDE EFFECTS

Abstract Background and Aims ANCA associated vasculitis are necrotaizing vasculitis of small and medium vassels - which cause organ damage. They are relatively rare diseases with an estimated prevalence of 200–400 cases per million people [1]. Pauci-immune necrotizing and crescentic glomerulonephritis (GN) is a frequent component of ANCA-associated vasculitis that can cause rapidly progressive Acute Kidney Injury (AKI). Less frequently, it can cause low progressive Chronic Kidney Disease (CKD) [2]. Combination therapy of steroids and cyclophosphamide has improved 5-years survival up to 70-90% but it can cause serious side effects including infectious episodes [3], bone marrow suppression and myelodysplasia. We present a case highlighting treatment modalities and our decision making. Method Our retrospective study analyzes the case of a 63-year-old male presenting with progressive dyspnea and hemoptysis. A chest CT suggested diffuse alveolar hemorrhage. The blood tests showed onset of AKI with 7.68 mg/dl serum creatinine (normal values 0.72-1.25), mild proteinuria and hematuria. A kidney and pulmonary vasculitis was suspected and the c-ANCA serum value was elevated at >500 IU/ml. Three cycles of Plasma Exchange (PEX) were performed and methylprednisolone was given (500 mg for 3 days, 1 g on the 4th day) followed by cyclophosphamide boluses of 1 g/week for 4 weeks. Broad-spectrum antibiotics and antifungal therapy was administered to prevent secondary infections. Due to the further worsening of the renal function, three hemodialysis treatments and a cascade filtration were performed continuing with cyclophoshamide 1 g/day orally and methylprednisolone 60 mg/day. Cyclophosphamide therapy was discontinued due to thrombocytopenia and progressive leukopenia. Filgastrim 30MU/0.5 ml was administered for five days until the resolution of the pancytopenia when cyclophosphamide 50 mg 2cp+1cp was resumed. Results A one-month follow-up CT showed reduction in hemorrhagic opacities and the c-ANCA level was significantly reduced. Steroid dosing was progressively reduced and the patient was discharged with methylprednisolone 16mg 2cp+1/2cp tapering over 6 months and cyclophosphamide 50 mg 2cp+1cp. Serum creatinine levels improved from 2.64 mg% at discharge to 1.6 mg% at follow up. Conclusion When treating c-ANCA vasculitis with corticosteroids and cyclophosphamide, routine evaluation of complete blood count parameters is necessary to prevent bone marrow toxicity. We continued methylprednisolone and cyclophosphamide for six months, obtaining a total clinical remission despite side effects induced by the state of immunosuppression (oral cavity mycosis, bone marrow toxicity and CMV reactivation).

An unusual form of kidney injury without glomerulonephritis in microscopic polyangiitis: a case report

BackgroundMicroscopic polyangiitis (MPA), a kind of antineutrophil cytoplasmic autoantibody associated vasculitis (AAV), predominantly affects small-sized vessels. MPA is a significant cause of the pulmonary-renal syndrome. Pauci-immune necrotizing and crescentic glomerulonephritis is the typical renal histological feature of AAV. Tubulointerstitial lesions may occur and mostly form with inflammatory cell infiltration in the interstitium. However, a few cases reported only tubulointerstitial involvement without glomerular lesions in patients with MPA.Case presentationWe present an MPA case, a 70-year-old male patient diagnosed with acute kidney injury accompanying the dialysis requirement. Only acute tubulointerstitial nephritis was revealed in kidney biopsy without evidence of glomerular injury. Also, interstitial pulmonary fibrosis was determined on computerized tomography, and myeloperoxidase antineutrophil cytoplasmic autoantibody was positive. Consequently, we have considered the main diagnosis as MPA. We did not prefer a standard tubulointerstitial nephritis treatment regimen due to the presence of life-threatening systemic vasculitis. Treatment was established like crescentic glomerulonephritis. Induction therapy consisted of pulse steroid, cyclophosphamide, and plasmapheresis. Unfortunately, severe SARS-CoV-2 infection caused death during induction therapy in this case.ConclusionsThe lack of glomerular injury and solely interstitial inflammation is atypical regarding AAV involvement in the kidney. This diversity might be initially considered as only a simple histological elaboration. However, it is a significant entity for guiding the treatment of AAV.

PS-R06-4: POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME TRIGGERED BY FLUID RETENTION AND HYPERTENSION AFTER STEROID INITIATION IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS

Objectives: Central nervous system (CNS) involvement in antineutrophil cytoplasmic antibody (ANCA) -associated vasculitis is common, with hypertrophic pachymeninges, cerebrovascular events, hypophysitis, or posterior reversible encephalopathy syndrome (PRES) being the most common CNS presentations. Design and Methods: Case report. Results: A 73-year-old Japanese woman presented with a fever and cough. The patient had no relevant medical history. Her c-reactive protein (CRP) level increased to 22.38 mg/dl, and meropenem was initiated; however, her fever and CRP levels did not improve. Furthermore, creatinine level increased from 0.83 to 3.44 mg/dl during hospitalization. She was transferred to our hospital for evaluation of renal function deterioration. Her consciousness level was alert, and her blood pressure was 140/80 mm Hg. A renal biopsy was performed, and histological examination of the kidneys revealed diffuse pauci-immune necrotizing and crescentic glomerulonephritis. Myeloperoxidase (MPO) -ANCA was 2.9 IU/mL and proteinase 3 (PR3) -ANCA was negative. On the basis of these findings, the patient was diagnosed with ANCA-associated vasculitis. On the fourth hospital day, she was treated with 500 mg intravenous methylprednisolone, once daily, for 3 days, followed by oral prednisolone (40 mg; 0.8 mg/kg). Although her fever and CRP levels improved after the initiation of immunosuppressive therapy, she required renal replacement therapy on the eighth hospital day. Rituximab (500 mg) was administered on the ninth hospital day. Her blood pressure subsequently increased, with the systolic blood pressure being 190 mmHg, and consciousness suddenly deteriorated on the 11th hospital day. Head fluid-attenuated inversion-recovery (FLAIR) MRI showed multiple lesions with high signal intensity, and she was diagnosed with PRES. After intravenous administration of nicardipine and fluid removal by hemodialysis, her blood pressure decreased and her consciousness dramatically improved. Conclusion: In addition to the vascular endothelial damage associated with vasculitis itself, steroid therapy, renal failure, elevated blood pressure, and administration of rituximab are related to an increased susceptibility of PRES. In particular, steroid administration increases blood pressure due to fluid retention and can be a risk factor for the development of PRES, suggesting the need for adequate fluid management during steroid administration.

Leukocyturia and hematuria enable non-invasive differentiation of Bowman’s capsule rupture severity in PR3-ANCA glomerulonephritis

BackgroundRenal involvement is a common and severe complication of anti-neutrophil cytoplasmic antibody-(ANCA)-associated vasculitis potentially resulting in pauci-immune necrotizing and crescentic ANCA glomerulonephritis (GN) with rapid deterioration of kidney function, progression to end stage kidney disease or, if left untreated, lethal exitus. Analysis of the urinary sediment routinely supports clinical management of ANCA GN, but histopathological implications of aberrancies in the urinary sediment mostly remain elusive. Therefore, we aimed to systematically assess the correlation of aberrancies in the urinary sediment and clinico-pathologic findings.MethodsA total of 42 kidney biopsies with ANCA GN were retrospectively analyzed in a single-center observational study. Laboratory and histopathological parameters were systematically analyzed and correlated with findings of the urinary sediment.ResultsIn the overall ANCA GN cohort, leukocyturia and hematuria were associated among each other, and with markers for non-selective glomerular damage, respectively. Non-invasive measurement of leukocyturia indicated focal (but not extensive) Bowman’s capsule rupture (BCR) specifically in proteinase-3 (PR3)-ANCA GN, whereas hematuria correlated with extensive (but not focal) BCR. Concerning intrarenal immune cell infiltration, leukocyturia was associated with tubulointerstitial plasma cell infiltration in PR3-ANCA GN. Finally, none of these associations were detectable in myeloperoxidase-ANCA GN, implying different modes of kidney damage.ConclusionWe herein expand our current knowledge by providing evidence that leukocyturia and hematuria enable non-invasive differentiation of BCR severity specifically in PR3-ANCA GN.Graphical abstract

S760 Epidemiology of Glomerulonephritis as an Extraintestinal Manifestation of Inflammatory Bowel Disease: A Large Population-Based Study

Introduction: Inflammatory bowel disease (IBD), including both Crohn’s disease (CD) and Ulcerative colitis (UC), are known to cause many extraintestinal manifestations. There is limited data describing the association between IBD and renal manifestations. This study provides epidemiologic data to further understand the association between IBD and glomerulonephritis (GN). Methods: The aim of this study was to investigate if IBD is associated with GN. Data was collected from a commercial database (Explorys Inc, Cleveland, OH), an aggregate of EHR data from 27 integrated healthcare systems in the US between 1/2017-1/2022. We identified patients with CD and UC based on Systemized Nomenclature of Medicine – Clinical Terms. We compared the prevalence of GN at least 30 days post-CD or post-UC diagnosis to a control cohort without CD or UC. We excluded patients with a diagnostic predisposition for development of GN (Table). Results: Of the 34,063,760 patients, we identified 149,630 cases of CD and 127,300 cases of UC. There were 310 and 260 cases of glomerulonephritis at least 30 days after diagnosis of CD and UC, respectively. Overall prevalence of glomerulonephritis for CD and UC was 207/100000 persons and 203/100000 persons, whereas for the cohort without CD and UC was 72/100000 persons and 72/100000 persons. Prevalence ratios (PR) of developing glomerulonephritis after at least 30 days of a CD and UC diagnosis were 2.88 (95% CI, 2.57-3.22, p< 0.001) and 2.83 (95% CI, 2.51-3.20, p< 0.001), respectively. Figure shows prevalence and PR in CD and UC sub-categorized by demographics. Membranous GN was the most prevalent (CD 90, UC 90), followed by proliferative (CD 50, UC 50), mesangiocapillary (CD 30, UC20), diffuse (CD 10, UC 0) and focal membranoproliferative (CD 10, UC 10). Conclusion: In this large population-based study, glomerulonephritis was significantly more prevalent in patients with both CD and UC compared to those without IBD. Further studies are needed to understand the pathophysiological mechanism underlying renal involvement.Figure 1.: Prevalence and prevalence ratios of glomerulonephritis after at least 30 days post-CD and post-UC diagnosis. Table 1. - Diagnoses excluded prior to analysis Excluded diagnoses Systemic lupus erythematosus Goodpasture's syndrome Hereditary nephritis Post-infectious GN Granulomatosis with polyangiitis Allergic grandulomatosis angiitis Alport syndrome Human immunodeficiency virus Hepatitic B virus Hepatitis C virus Nephrotic syndrome with membranoproliferative glomerulonephritis Primary pauci-immune necrotizing and crescentic glomerulonephritis Berger's immunoglobulin A or immunoglobulin G nephropathy

Characteristics and Diagnostic Challenge of Antineutrophil Cytoplasmic Antibody Positive Infective Endocarditis

ObjectiveAntineutrophil cytoplasmic antibody (ANCA) has been reported in patients with infective endocarditis. Whether ANCA is associated with certain characteristics of infective endocarditis is unclear. The principal aim of this study is to investigate the clinical implications of ANCA in infective endocarditis and highlight the diagnostic challenge in ANCA-positive patients with infective endocarditis. MethodsA retrospective study was conducted in a tertiary hospital in China from August 2012 to December 2021. Patients with a diagnosis of infective endocarditis and available ANCA results were included in the study. The clinical and pathological characteristics were compared between ANCA-positive and ANCA-negative patients. ResultsA total of 237 patients were included. Forty three (18.1%) were ANCA-positive, predominantly c-ANCA/anti-PR3. Compared to ANCA-negative patients, ANCA-positive patients had longer disease duration (P = .004), more frequent purpura (P = .015), macrohematuria (P = .002), proteinuria (P = .043), acute kidney injury (P = .004), and rapidly progressive glomerulonephritis (P = .010). Histologic findings of 8 patients with infective endocarditis-associated glomerulonephritis were reviewed. Two ANCA-positive patients with infective endocarditis presented with pauci-immune necrotizing and crescentic glomerulonephritis. A total of 18.6% of ANCA-positive patients with infective endocarditis were misdiagnosed as ANCA-associated vasculitis. ConclusionsANCA is detected in a substantial proportion of patients with infective endocarditis. The presence of ANCA in infective endocarditis is associated with longer disease duration, more frequent purpura, and kidney involvement. ANCA-positive infective endocarditis may mimic ANCA-associated vasculitis, and the differential diagnosis is challenging. Whether ANCA is pathogenic in infective endocarditis-associated small vessel vasculitis requires further study.

Neutrophils associate with Bowman’s capsule rupture specifically in PR3-ANCA glomerulonephritis

BackgroundRenal involvement is a common and severe complication of ANCA (antineutrophil cytoplasmic antibody) associated vasculitis (AAV) potentially resulting in a pauci-immune necrotizing and crescentic antineutrophil cytoplasmic antibody (ANCA) glomerulonephritis (GN) with acute kidney injury (AKI), end-stage renal disease (ESRD) or death. We recently described that Bowman’s capsule rupture links glomerular damage to tubulointerstitial inflammation in ANCA-associated glomerulonephritis. Herein we provide a comprehensive histological subtyping of immune cell infiltrates in association with Bowman’s capsule rupture in ANCA GN.MethodsA total of 44 kidney biopsies with ANCA GN were retrospectively included in a single-center observational study. Within a renal biopsy specimen, each glomerulus was scored separately for the presence of extensive and focal Bowman’s capsule rupture in injured glomeruli. Infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the area of total cortical inflammation.ResultsExtensive Bowman’s capsule rupture was associated with tubulointerstitial inflammation containing infiltrates of neutrophils, eosinophils and plasma cells. A similar association was observed for the presence of focal Bowman’s capsule rupture, correlating with tubulointerstitial inflammation containing neutrophils, eosinophils and plasma cells. Multiple logistic regression confirmed that extensive Bowman’s capsule rupture correlated with tubulointerstitial inflammation containing neutrophils, and focal Bowman’s capsule rupture correlated with neutrophil and plasma cell infiltration. Furthermore, this association was specifically observed in PR3-ANCA GN.ConclusionTo our knowledge, this is the first report linking Bowman’s capsule rupture directly to tubulointerstitial inflammation by immune cell subtypes. This underscores a pathomechanistic link between tubulointerstitial and glomerular lesions in ANCA GN and needs further investigation.Graphical abstract

Acute Kidney Injury and Proteinuria in a Man With Hemoptysis

Acute Kidney Injury and Proteinuria in a Man With Hemoptysis

Consideration of Therapeutic Plasma Exchange in Association With Inflammatory Lesions in ANCA-Associated Glomerulonephritis: A Real-World Retrospective Study From a Single Center

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Pathogenic ANCAs trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN). Standard therapeutical regimens include aggressive immunosuppressive therapy. Since some patients require renal replacement therapy (RRT) despite intensive immunosuppressive therapy, additional therapeutic plasma exchange (PEX) to deplete pathogenic ANCAs has been recommended but its value has recently been questioned. Because therapeutic decision making is crucial in these critically ill patients, we here aimed to identify inflammatory lesions in association with PEX consideration in a retrospective study from a single center tertiary hospital in a real-world population of 46 patients with severe AAV requiring intensive care treatment. The decision to consider PEX was more likely in patients with need for intensive care treatment and severe renal dysfunction. In contrast, short-term outcomes did not depend on clinical, or laboratory characteristics assessed at admission. Histopathological analysis confirmed active disease reflected by increased glomerular necrosis and crescents, but these histopathological findings did not associate with short-term outcome either. Interestingly, only increased global glomerular sclerosis in renal biopsies associated with a detrimental short-term outcome. In conclusion, our study investigated determinants for the consideration of therapeutic PEX in patients with severe AAV requiring intensive care treatment. This aspect underscores the need for renal biopsy and requires further investigation in a prospective controlled setting for therapeutic decision making especially in patients with severe AAV requiring intensive care treatment, especially important for treating intensivists.

MO279DETERMINANTS TO CONSIDER THERAPEUTIC PLASMA EXCHANGE FOR TREATMENT OF SEVERE ANCA-ASSOCIATED VASCULITIS: A RETROSPECTIVE STUDY FROM A SINGLE CENTER

Abstract Background and Aims Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Pathogenic ANCAs trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN). Standard therapeutical regimens include aggressive immunosuppressive therapy. Since some patients require RRT despite intensive immunosuppressive therapy, additional therapeutic plasma exchange (PEX) to deplete pathogenic ANCAs has been recommended but its value has recently been questioned. Because therapeutic decision making is crucial in these critically ill patients, we here aimed to identify determinants for PEX consideration in a retrospective study from a single center tertiary hospital in a real-world population of 46 patients with severe AAV requiring intensive care treatment. Method A total number of 46 patients with biopsy-proven AAV at the University Medical Center Göttingen were retrospectively included between 2015 till 2020. While no formal approval was required for the use of routine clinical data, a favorable ethical opinion was granted by the local Ethics committee. Medical records were used to obtain data on age, sex, diagnosis (MPO or PR3) and laboratory results (serum creatinine, C-reactive protein/CRP, urinary albumin/creatinine ration). The estimated glomerular filtration rate (GFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. A renal pathologist (SH) evaluated all biopsies. Within a renal biopsy specimen, each glomerulus was scored separately for the presence of necrosis, crescents and global sclerosis. Consequently, the percentage of glomeruli with any of these features was calculated as a fraction of the total number of glomeruli in each renal biopsy. Apart from these categories, the degree of interstitial fibrosis/tubular atrophy (IF/TA) was quantified. Based on these scorings, histopathological subgrouping according to Berden et al (focal, crescentic, mixed or sclerotic class) and ARRS according to Brix et al (low, medium or high risk) were performed. Results The decision to consider PEX was more likely in patients with need for intensive care treatment and severe renal dysfunction. In contrast, short-term outcomes did not depend on clinical or laboratory characteristics assessed at admission. Histopathological analysis confirmed active disease reflected by increased glomerular necrosis and crescents, but these histopathological findings did not associate with short-term outcome either. Interestingly, only increased global glomerular sclerosis in renal biopsies associated with a detrimental short-term outcome. Conclusion In conclusion, our study investigated determinants for the consideration of therapeutic PEX in patients with severe AAV requiring intensive care treatment. This aspect underscores the need for renal biopsy and requires further investigation in a prospective controlled setting for therapeutic decision making especially in patients with severe AAV requiring intensive care treatment, especially important for treating intensivists.

Should PLEX Be Used for Severe AKI and/or Pulmonary Hemorrhage in ANCA-Associated Vasculitis (AAV)? COMMENTARY.

“To plasmapherese (PLEX) or not to PLEX” is a question in the induction therapy for patients with ANCA-associated vasculitis (1). Drs. Glassock and Derebail present differing yet sometimes overlapping conclusions to this question in their virtual debate. Their erudite analysis carefully examines the available literature from their respective pro or con positions. To focus the issues, let us consider three real-life patients who illustrate the quandary of when, or whether, PLEX should be used. A 32-year-old mother of three is coughing up blood in the emergency room, complaining of worsening fatigue over the past 3 weeks. Physical examination 7 months prior was unremarkable; hemoglobin was 12.8 mg/dl, and serum creatinine was 0.7 mg/dl. Urinalysis was not performed. She describes new, dark, “tea-colored” urine over the past 2 days. Urinalysis shows numerous red blood cells and red cell casts. Kidney biopsy reveals pauci-immune necrotizing and crescentic glomerulonephritis (GN) with necrosis and crescents in three of seven glomeruli. There is minimal or no interstitial infiltrate, fibrosis, or tubular atrophy. Myeloperoxidase (MPO) ANCA is positive at a titer of 93 (normal <20). High-resolution chest computed tomography reveals diffuse alveolar infiltrates with minimal bronchial abnormalities involving multiple lung lobes. Oxygen saturation is 88% on 2 L of oxygen. The diagnosis is MPO ANCA with diffuse alveolar hemorrhage and necrotizing and crescentic GN. In addition to glucocorticoids and intravenous cyclophosphamide/rituximab, would you order plasmapheresis? Dr. Derebail would argue that this patient should receive plasmapheresis. Dr. Glassock specifies that no randomized, controlled trials of PLEX as therapy for diffuse alveolar hemorrhage are available and concludes that “PEXIVAS is not very informative regarding the utility of PLEX …

Proteinuria Indicates Decreased Normal Glomeruli in ANCA-Associated Glomerulonephritis Independent of Systemic Disease Activity

Background: Renal involvement is a common and severe complication of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), potentially resulting in a pauci-immune necrotizing and crescentic ANCA glomerulonephritis (GN) with acute kidney injury (AKI), end-stage renal disease (ESRD) or death. There is recent evidence that the degree of proteinuria at diagnosis is associated with long-term renal outcome in ANCA GN. Therefore, we here aimed to systematically describe the association between proteinuria and clinicopathological characteristics in 53 renal biopsies with ANCA GN and corresponding urinary samples at admission. Methods: A total number of 53 urinary samples at admission and corresponding renal biopsies with confirmed renal involvement of AAV were retrospectively included from 2015 to 2021 in a single-center study. Results: Proteinuria correlated with myeloperoxidase (MPO) subtype, diagnosis of microscopic polyangiitis (MPA) and severe deterioration of kidney function. Proteinuria was most prominent in sclerotic class ANCA GN and ANCA renal risk score (ARRS) high risk attributed to nonselective proteinuria, including both glomerular and tubular proteinuria. Finally, there was no association between proteinuria and systemic disease activity, suggesting that proteinuria reflected specific renal involvement in AAV rather that systemic disease activity. Conclusions: In conclusion, proteinuria correlated with distinct clinicopathological characteristics in ANCA GN, mostly attributed to a reduced fraction of normal glomeruli. Furthermore, proteinuria in ANCA GN reflected specific renal involvement in AAV rather than systemic disease activity. Therefore, urinary findings could further improve our understanding of mechanisms promoting kidney injury and progression of ANCA GN.

Spectrum of Kidney Involvement in Patients with Myelodysplastic Syndromes

IntroductionMyelodysplastic syndromes (MDS) are characterized by a high prevalence of associated autoimmune manifestations. Kidney involvement has been rarely reported in MDS patients. We report on the spectrum of kidney pathological findings in MDS patients.MethodsWe retrospectively identified MDS patients who had undergone a kidney biopsy between 2001 and 2019 in nine Swiss and French nephrology centres.ResultsNineteen patients (median age 74 years [63-83]) were included. At the time of kidney biopsy, eleven (58%) patients had extra-renal auto-immune manifestations and sixteen (84%) presented with acute kidney injury. Median serum creatinine at diagnosis was 2.8 mg/dL [0.6-8.3] and median urinary protein to creatinine ratio was 1.2 g/g [0.2-11]. Acute tubulo-interstitial nephritis (TIN) was present in seven (37%) patients. Immunofluorescence study in one patient with acute TIN disclosed intense IgG deposits along the tubular basement membrane and Bowman’s capsule. Other kidney pathological features included ANCA-negative pauci-immune necrotizing and crescentic glomerulonephritis (n = 3), membranous nephropathy (n = 2), IgA nephropathy (n = 1), IgA vasculitis (n = 1), immunoglobulin-associated membrano-proliferative glomerulonephritis type I (n=1), crescentic C3 glomerulopathy (n = 1), fibrillary glomerulonephritis (n = 1) and minimal change disease (n = 1). Eleven (58%) patients received immunosuppressive treatments, among whom one developed a severe infectious complication. After a median follow-up of 7 month [1-96], nine (47%) patients had chronic kidney disease stage 3 (n = 6) or 4 (n = 3) and five (26%) progressed to end-stage kidney disease. Three patients died.ConclusionsMDS are associated to several autoimmune kidney manifestations, predominantly acute TIN. MDS are to be listed among the potential causes of autoimmune TIN.

Circulating B Cells, Plasma Cells, and Treg Associate with ANCA Levels in ANCA-associated Vasculitis

Circulating B Cells, Plasma Cells, and Treg Associate with ANCA Levels in ANCA-associated Vasculitis

98 Granulicatella Adiacens Endocarditis-Induced ANCA-Negative Pauci-Immune Necrotizing and Crescentic Glomerulonephritis Successfully Treated with Aortic Valve Replacement

98 Granulicatella Adiacens Endocarditis-Induced ANCA-Negative Pauci-Immune Necrotizing and Crescentic Glomerulonephritis Successfully Treated with Aortic Valve Replacement

Renal Involvement in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is the most common cause of rapidly progressive glomerulonephritis. ANCAs play an important role in the pathogenesis and diagnosis of AAV. The classic renal lesion in AAV is a pauci-immune necrotizing and crescentic glomerulonephritis. Treatment is divided into 2 phases: (1) induction of remission to eliminate disease activity and (2) maintenance of remission to prevent disease relapse. AAV patients with end-stage renal disease require modification of immunosuppressive strategies and consideration for kidney transplantation. An improved understanding of disease pathogenesis has led to new treatment strategies being tested in clinical trials.

Primary Vasculitis in Childhood: GPA and MPA in Childhood.

Childhood onset anti-neutrophilic cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a rare group of primary systemic vasculitides affecting medium and small blood vessels. AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and renal limited ANCA vasculitis. These disorders are associated with severe clinical manifestations, frequent relapses and a high cumulative morbidity, and often present with multisystem involvement. Renal involvement is common in the pediatric age group, characterized by pauci-immune necrotizing and crescentic glomerulonephritis which frequently progresses to chronic kidney disease in adulthood. ANCAs against proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO) (MPO-ANCA) remain the hallmark of AAV and are integral to the disease pathogenesis. Newer understanding of neutrophil extracellular traps and complement activation have provided better insights into disease pathogenesis. A pediatric vasculitis working group has developed and validated childhood vasculitis classification criteria and disease activity and damage scores. No specific pediatric treatment recommendations exist due to rare nature of the illness in pediatric population. Smaller case series have been published on the efficacy of adult treatment regimens in pediatric patients. The prognosis often remains guarded with frequent relapses and a high cumulative morbidity. The aim of this article is to provide a comprehensive review on pediatric AAV with a focus on recent observations regarding epidemiology, disease pathogenesis, treatment, and prognosis.

ANCA Glomerulonephritis and Vasculitis.

ANCA vasculitis has an associated autoimmune response that produces ANCAs that induce distinct pathologic lesions. Pauci-immune necrotizing and crescentic GN is a frequent component of ANCA vasculitis. ANCA vasculitis is associated with ANCA specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). A diagnosis of ANCA vasculitis should always specify the serotype as MPO-ANCA positive, PR3-ANCA positive, or ANCA-negative. To fully characterize a patient, the serotype also should be accompanied by the clinicopathologic variant if this can be determined: microscopic polyangiitis, granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or renal-limited vasculitis. ANCA vasculitis is most prevalent in individuals >50 years old. There are racial/ethnic and geographic influences on the prevalence, serotype frequencies, and clinicopathologic phenotypes. There is clinical, in vitro, and animal model evidence that ANCAs cause disease by activating neutrophils to attack small vessels. Immunomodulatory and immunosuppressive therapies are used to induce remission, maintain remission, and treat relapses. Over recent years, there have been major advances in optimizing treatment by minimizing toxic therapy and utilizing more targeted therapy.

Complement activation in pauci-immune necrotizing and crescentic glomerulonephritis: results of a proteomic analysis.

Complement activation plays an important role in the pathophysiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although it remains unclear which pathway is activated. Whether pauci-immune necrotizing crescentic glomerulonephritis (pauci-immune GN) with negative ANCA serology is part of the spectrum of AAV or a different disease entity is essentially unknown. We used proteomic analysis to delineate the complement profile in a series of 13 kidney biopsies of patients with pauci-immune GN, with either proteinase 3 (PR3) (five patients) or myeloperoxidase (MPO) antibodies (four patients) or with consistently negative ANCA serology (four patients). Immunofluorescence staining of glomeruli was essentially negative in the PR3-ANCA and MPO-ANCA groups, while a mild staining for C3 was seen in the ANCA-negative cases. No electron-dense deposits were found in the PR3-ANCA and MPO-ANCA groups, but mesangial and few subepithelial deposits were clearly present in the ANCA-negative specimens. Mass spectrometry revealed low spectra numbers for C3 and immunoglobulins in both PR3-positive and MPO-positive patients with minimal or no C4 and C9. In contrast, larger spectra numbers for C3, moderate spectra numbers for C9, complement factor H-related protein-1 and low spectra numbers for C4, C5 and immunoglobulins were found in the ANCA-negative cases. While complement activation is noted in AAV, the complement activation appears to be more prominent in the ANCA-negative glomerulonephritis. The larger amount of C3 and moderate amount of C9 in the ANCA-negative glomerulonephritis implies activation of the alternate and terminal pathway of complement, suggesting that this entity may be caused or promoted by a genetic or acquired defect in the alternative pathway.