Sclerotic Class Research Articles

Clinicopathological characteristics and renal outcomes of adult patients with pauci-immune necrotizing glomerulonephritis according to ANCA status.

Pauci-immune necrotizing glomerulonephritis (PING) is commonly associated with the presence of antineutrophilic cytoplasmic antibodies (ANCAs) but a significant number of patients do not have these antibodies. The significance of ANCA-negativity in the context of Berden's classification of PING is not known. A retrospective analysis was conducted on all patients with histopathological diagnosis of idiopathic PING irrespective of ANCA status diagnosed between January 1998 to December 2018 and followed up at renal clinic for > 12months. All biopsies were reclassified by Berden's classification. Clinicopathological characteristics and renal outcomes of ANCA-positive and ANCA-negative patients were compared. Out of 134 patients, 66 (49.5%) were ANCA-negative. The mean age was 34.76 ± 13.3years. Compared with the ANCA-positive patients, ANCA-negative patients had significantly greater prevalence of nephrotic-range proteinuria (74.23% Vs 57.9%, P = 0.036) with less extra-renal manifestations (P < 0.05)). On histology, focal and crescentic classes dominated with less number of globally sclerosed glomeruli (2.7% Vs 5.07%, P = 0.02) and more mesangial proliferation (22.7% Vs 4.41%, P = 0.002) in the ANCA-negative group, whereas sclerotic was predominant in the ANCA-positive group (P = 0.05). More patients achieved complete and partial recovery in ANCA-negative patients (42.4% Vs 20.5%, P < 0.05) with better renal survival (27.27% Vs 16.17%, log-rank test: P = 0.03) and less patient mortality (13.63% vs 30.8%, log-rank test: P = 0.04) at 2years. Our study confirms high prevalence of ANCA negativity among our cohort and this group presents with isolated renal involvement with better renal and patient survival. The ANCA-positive group showed significantly more patients in the sclerotic class, lower 2-year renal survival, and higher 2-year mortality as compared to the ANCA-negative group. However, the complete and partial responses to treatment were significantly better in the ANCA-negative group. Key Points • This study shows a high prevalence of ANCA negativity in cases of PING in Pakistani population, as almost half of patients in this study did not have these antibodies. • This negativity is more prevalent in the Asian populations but its significance in the context of Berden's classification of PING is unknown. • ANCA-negative group exhibited less severe phenotype and better outcomes compared with ANCA-positive group.

#675 Application of ANCA-associated vasculitis Histopathological Classification and Renal Risk Score for prediction of end-stage kidney disease

Abstract Background and Aims Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease predominantly characterized by inflammation of small-sized blood vessels along with the presence of circulating ANCA. The kidney is frequently involved and, even though immunosuppressive therapy has dramatically improved the outcome of AAV patients, a significant proportion of patients progress to end-stage kidney disease (ESKD). Therefore, establishing and validating tools to predict renal outcomes in patients with AAV is crucial. Here we analyzed the application of two tools in predicting kidney survival in a Portuguese single-center cohort with AAV. Method We conducted a retrospective cohort study at a tertiary-care hospital in Portugal (Hospital de São João, Porto), from December 2010 to June 2023. Patients with a kidney biopsy-proven AAV were included. Serological ANCA-negative patients and patients with overlap syndromes, such as AAV in combination with anti-glomerular basement membrane disease, were excluded. Based on electronic records, information on demographics and clinical variables were collected. Kidney biopsies were reviewed to calculate: Berden histopathological classification and the Brix Renal Risk Score (RRS). Kidney survival was defined as the time from diagnosis to the need for kidney replacement therapy. A Kaplan-Meier analysis was performed to compare kidney survival based on the mentioned classifications. Results Fifty-one patients were enrolled, 78% (n = 40) of whom were positive for myeloperoxidase (MPO). The majority were men (61%, n = 31) with a mean age of 65 (± 12) years and a mean serum creatinine of 4.59 mg/dL (± 2.74) at diagnosis. During a median follow-up of 39 (IQR, 7-84) months, 20 patients (39%) progressed to end-stage kidney disease (ESKD), 10 patients (20%) died with preserved renal function and 21 patients (41%) did not need hemodialysis. Concerning Berden classification, 13 patients with a crescentic class, 4 patients with a mixed class and 3 patients with a sclerotic class developed ESKD. After 48 months of follow-up, renal survival was 100%, 90%, 61% and 26.7% in the focal, mixed, crescentic and sclerotic class groups, respectively. Berden classification did not correlate with kidney survival (p = 0.211). Concerning RRS, 10 patients in the high-risk group and 5 patients in the medium-risk group developed ESKD. After 48 months of follow-up, renal survival was 100% in the low-risk group, 85.7% in the medium-risk group, and 41.6% in the high-risk group. A correlation was established between kidney survival and RRS score (p = 0.003). Conclusion In our cohort RRS was predictive of ESKD, contrary to Berden histopathological classification. The information derived from these risk models strongly add to standard biochemical and clinical data. Patients with higher risk of ESKD need close follow-up and a tailored treatment plan regarding preparation for renal replacement therapy.

#2257 Kidney outcomes in ANCA-associated vasculitis—application of Berden's Classification and ANCA Renal Risk Score in a single centre cohort

Abstract Background and Aims Anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis is the most common cause of rapidly progressive glomerulonephritis and is a life-threatening condition. The course of the disease is variable and disease prognostication remains challenging. Histological and clinical scores have been developed to predict kidney outcomes, to tailor treatment. The aim of this study is to apply Berden´s histopathological classification (BHC) and ANCA renal risk score (ARRS), proposed by Brix and co-workers, in a cohort of patients with ANCA-associated vasculitis and to analyse their performance in renal outcomes prediction. Method In this retrospective observational study, we included patients with biopsy proven ANCA-associated vasculitis, diagnosed at our centre between March 2011 and March 2023. We consulted the clinical records and the kidney biopsy reports. Biopsies were categorized according to both scores. Follow up time was up to 48 months since the date of diagnosis. In BHC patients were divided into 4 groups (focal, crescentic, sclerotic and mixed) according to normal glomeruli, cellular crescents and globally sclerosed glomeruli proportion. When applying the ARRS, patients were divided into 3 groups: low, medium or high risk. This is a histopathological and biochemical score that combines normal glomeruli and tubular atrophy and interstitial fibrosis (IFTA) percentages with estimated glomerular filtration rate (eGFR) at time of diagnosis. Factors related to renal survival were evaluated by Spearman Rank Correlation, Binary Logistic Regression analysis and Kaplan-Meier curves were used for assessing time between diagnosis and end stage kidney disease (ESKD). Results Our study included 31 patients, 54.8% were male, median age at diagnosis was 62 (IQR, 53-69) years, with a median eGFR of 8.3 (IQR, 6.2-13.3) mL/min/1.73 m2 and a median urine albumin to creatinine ratio (uACR) of 1.5 (IQR, 0.88-2.2) g/g. 19 patients (61.3%) were positive for myeloperoxidase and 5 (16.1%) were proteinase 3 positive. Median follow up time was 36 (IQR, 9-48) months. 10 patients (32%) developed ESKD and 9 patients (29%) died. Regarding BHC, 4 patients (13%) presented a focal class, 18 (58%) crescentic, 7 (23%) mixed and 2 (6%) sclerotic. Progression to ESKD occurred in 7 patients with crescentic class (38.9%), 2 patients with mixed (28.6%) and 1 patient with sclerotic (50%). None of the patients with focal class developed ESKD. There were no significant differences in kidney survival curves by BHC class (Log Rank p = 0.47) (Fig. 1a). In ARRS, 1 patient (3%) was in the low-risk group, 19 patients (61%) in the medium risk and 11 patients (35%) in the high risk. Characteristics of the population by ARRS score group and detailed score discrimination are specified in Table 1. Progression to ESKD, occurred in 5 patients of medium risk group (26.3%) and also in 5 patients in the high-risk group which represented 45.5% of this group. Kidney survival curves by ARRS score group had no statistic difference (Log Rank p = 0.46) (Fig. 1b). ESKD was positively associated with serum creatinine (sCr) at admission (p = 0.02), highest sCr (p = 0.001) and leukocyturia (p = 0.05). By multivariate analysis adjusted to gender, age, sCr at admission, leukocyturia and BHC or ARRS, the only factor associated with ESKD was sCr at admission (OR 1.45, CI 1.03-2.06, p = 0.05). Conclusion In our cohort of patients, sCr at patient hospital admission was the best predictor for progression to ESKD. By ARRS, just one patient had low risk, and as expected, kidney survival was higher in the medium risk group (68.5%) than in the high-risk group (53%), although not reaching statistical significance. BHC also had no association with kidney outcomes, although kidney survival was 100% in focal class and sclerotic class had the lowest survival (50%), yet crescentic class revealed a worse kidney survival (57.1%) than mixed class (71.4%). The small number of patients, overall and in each group, and the short follow up period can be pointed as limitations of this study.

Renal histopathological predictors of end-stage kidney disease in ANCA-associated vasculitis with glomerulonephritis: a single-centre study in Korea

This study investigated whether histopathological classification and histologic lesion scores could significantly and independently predict the progression to end-stage kidney disease (ESKD) in Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-glomerulonephritis (AAV-GN). This study included 113 patients with AAV-GN confirmed by kidney biopsy. The glomerular, tubulointerstitial, and vascular lesions were systematically assessed using a scoring system. The scoring system was adopted from the Banff scoring system but also the Oxford study and the revision of the ISN/RPS. For comparison, the scores were classified into two groups; the low, and the high, and the difference was investigated between ESKD and non-ESKD groups using Cox proportional analysis. At diagnosis, the median age was 59.0 years and 33.6% were males. Of 113 patients, 44.2% had ESKD progression during follow-up. There were significant differences in several kidney-, inflammation-, and AAV-pathogenesis-related variables between AAV-GN patients with ESKD and those without. The sclerotic class exhibited the worst renal prognosis among the four histopathological classes. Among histopathological features, high interstitial fibrosis, tubular atrophy and global glomerulitis scores were significantly associated with ESKD progression. Whereas multivariable Cox analysis revealed only a high global glomerulitis score which means global endocapillary hypercellularity in a larger number of glomeruli is an independent predictor of ESKD progression. Moreover, among clinical and histopathological features, a high global glomerulitis score could also predict ESKD progression in addition to serum blood urea nitrogen and creatinine. This study demonstrated the worst renal prognosis for the sclerotic class and first discovered that a high global glomerulitis score was an independent predictor of ESKD in patients with AAV-GN.

Comparison of Clinico-pathologic features and outcomes of ANCA negative and ANCA positive pauci immune crescentic glomerulonephritis: A single centre study.

Pauci-immune crescentic glomerulonephritis (PICN) is an important cause of rapidly progressive renal failure. 10-40% of PICN cases have ANCA (antineutrophil cytoplasmic antibody) negative serology. The present study compared clinico-pathologic features, Brix's renal risk score, Berden's histopathological classes and differences in outcome between ANCAnegative vs ANCA positive PICN patients. Sixty-one patients of biopsy-proven PICN were studied. Biochemical findings and ANCA serology were recorded. Renal biopsy slides were reviewed along with direct immunofluorescence. Clinical and histological features were compared between ANCA negative and positive PICN using the Man Whitney U test and Chi-square test. Patients were compared for distribution in Berden's histological classes and Brix's renal risk categories. Patient and renal survival were compared using Kaplan-Meier survival analysis. ANCA negative PICN patients were younger (44.9 ± 16.5 years vs 53.6 ± 15.1 years, P = 0.049). Nasal (0 vs 18%, P = 0.035) and pulmonary involvement (9% vs 38%, P = 0.014) were lower in ANCA negative group. Both ANCA groups had similar renal biochemical profiles, percentage normal glomeruli, 16.3 ± 18.2 vs 21.7 ± 20.4 and percentage glomeruli with crescents, 64.5 ± 28.1 vs 64.3 ± 27.1. Twenty-seven per cent of ANCA negative cases fell in the sclerotic class in Berden's classification vs just 2.5% in ANCA positive group (p = 0.037) without significant difference in Brix's renal risk categories (p = 0.329). Thirteen per cent of ANCA negative patients achieved complete remission on treatment compared to 33% in ANCA positive patients. Patient survival and overall probability of progressing to ESRD were similar in the two groups. ANCA negative PICN cases present at younger ages. Nasal and pulmonary involvement is uncommon in these patients. Patient survival and progression to ESRD are similar in both ANCA groups.

Changing Phenotypes and Clinical Outcomes Over Time in Microscopic Polyangiitis

Diagnosis and management of microscopic polyangiitis (MPA) have evolved considerably over the past decades, but it is unknown whether clinical and histological presentation and patient and renal outcomes have changed accordingly. We compared clinical and histopathological characteristic at diagnosis, risk of death, end-stage kidney disease (ESKD), and relapse rate in patients diagnosed with MPA between 1980 and 2022, after grouping them in 2 periods (p): p1980-2001 and p2002-2022. We compared the mortality rate between the 2 periods using Kaplan-Meier estimator and Cox-regression, and competing risks of ESKD and death using the Aalen-Johansen estimator, Fine-Gray multiple regression, and multistate models. Out of 187 patients, 77 were in p1980-2001 and 110 in p2002 to 2022. Patients in p2002 to 2022 were older (66.2 ± 14.0 SD vs. 57.7 ± 15.8; P< 0.001), had a better kidney function (estimated glomerular filtration rate [eGFR] 25.9 ± 24.8 vs. 21.5 ± 28.2 ml/min per 1.73 m2; P= 0.011) and a lower prevalence of the Berden sclerotic class (5.9 vs. 20.9%; P= 0.011). Despite a similar crude and adjusted patient survival, the risk of ESKD decreased during p2002 to 2022 (subdistribution hazard ratio [HR] 0.30, 95% confidence interval [CI]: 0.16-0.57; P< 0.001). The results remained significant after accounting for death after ESKD and after adjusting for potential confounders (HR 0.33 [95% CI: 0.18-0.63; P< 0.001]). The risk of relapse was numerically higher during p2002 to 2022 (subdistribution-HR 1.64 [95% CI: 0.95-2.83; P= 0.075]). MPA kidney involvement has become less severe over the past decades, leading to a reduced risk of ESKD and a higher relapse rate, despite a comparable risk of death.

#5906 THE PROGNOSTIC VALUE OF DIFFERENT HISTOPATHOLOGIC MODELS OF ANCA-ASSOCIATED VASCULITIDES: A PROSPECTIVE STUDY

Abstract Background and Aims Renal histology in ANCA-associated vasculitides-glomerulonephritis (AAV/GN) is characterized by active (inflammation, necrosis, crescents) and chronic lesions (sclerosis, fibrosis), and lately classified by Berden Classification (BC), ANCA renal risk (RRS) and Mayo Chronicity score (MCCS). We aimed to prospectively compare predictive ability of the three classification models in AVV. Method 27 AVV/GN patients, 17 females, were estimated at time of diagnosis (T0), based on renal biopsy, commenced on the same treatment protocol, cyclophosphamide+steroids, and followed for 6 months. BC, RRS and MCCS Classification models were initially applied on renal biopsies and results were correlated to renal function at T0, and accordingly, 3 (T3) and 6 (T6) months. Results Patients’ median age at presentation was 61.9(18-82) years, ratio of MPO/PR3/ANCA- was 17/7/3, eGFR was 19(19)mg/ml/1.73m2, and 11/27(40.7%) patients were hemodialysis-dependent (HD) at T0. Based to BC model, 5(18,5%), 9(33,3%), 8(29,7%), 5(18,5%) were classified as Focal, Crescentic, Mixed, Sclerotic, respectively, while according to RRS 7(26%), 10(37%), 10(37%) as Low, Medium, High, respectively and to MCCS 3(11%), 13(48%), 6(22%), 5(19%) as Minimal, Mild, Moderate, Severe, respectively. During follow up eGFR significantly increased from T0 towards T3 and T6, 19(19), 34(21), 38.5(26)mg/ml/1.73m2, respectively, p&amp;lt;0.0001. In RRS model, significant improvement was noticed in patients classified as low, eGFR from 37.5(55) vs. 57.5(39) vs. 57(22)mg/ml/1.73m2, p = 0.019) or medium risk group, 31(24) vs. 39(18) vs. 40(10)mg/ml/1.73m2, p = 0.047), at T0, T3, T6, respectively. In BC, a significant increase of eGFR was evident in sclerotic class, 18(9) vs. 32(17) vs. 38(21)mg/ml/1.73m2, respectively p = 0.05. RRS showed important results regarding HD dependence. At T0, from the 11 HD patients 1/3/7 were classified as low/medium/high risk, p = 0.04, the ratio changed to 0/1/5, respectively, p = 0.02 at T3 and 0/1/4, p = 0.04 at T6. No patient with low risk RRS remained on HD, while, 7/10 patients with high RRS, were still on HD at T6. BC and MCCS could not predict end stage renal function either at 3 or 6 months of follow up. Conclusion In the short term follow up, ANCA renal risk could better predict renal function outcome compared to Berden Classification and Mayo Chronicity Score, with high RRS frequently leading to HD. Instead, the sclerotic class in BC was not predictive of poor outcome.

#6470 PATIENT SURVIVAL IN AN ASSOCIATED VASCULITIS COHORT – DATA FROM A REFFERAL CENTER

Abstract Background and Aims Patients with ANCA associated vasculitis (AAV) have variable survival rates depending on disease activity, complications and sometimes the choice of treatment. Still today there are a lot of differencies between various cohorts regardless of similarities in clinical presentation, serology or histology. Understanding risk factors for various outcomes in cohorts from different geographical areas might help build better and more uniform prediction models. We present data on patient survival from our refferal center. Method This study included 106 consecutive AAV patients with biopsy proven renal involvement in the period from 2007-2017. We analyzed clinical, laboratory and pathohistological data as predictors for death of the patients. Survival univariate analysis was performed using Kaplan-Meier method and log-rank (Mantel-Cox) test. Variables that had p&amp;lt;0,1 in univariate analysis were alongside age and gender included in multivariate Cox proportional hazard model. Results The study included 106 AAV patients with renal involvement: 66 (61,1%) MPA, 20 (18,5%) GPA, 20 (18,5%) RLV. There were 14 (13%) PR3-ANCA positive patients, 57 (52,8%) MPO ANCA positive, 5 (4,6%) PR3-ANCA+MPO-ANCA and 32 (29,6%) ANCA negative patients. Average SCr was 316,5 μmol/l (IQR 207,0-548,5), 24-hour proteinuria median was 1,7g/24h (IQR 0,8-2,8). Histologicaly (Berden classification) 43 (39,8%) patients had crescentic, 19 (17,6%) focal, 34 (31,5%) mixed and 12 (11,1%) sclerotic class. Follow up time was 1 to 127 months with median 21 months (IQR = 7 - 44) and medium follow up time of 28,6 months (SD = 26,6). All the patients recieved the same induction treatment (cyclophosphamide and glucocorticoids +/- acute haemodialysis and plasma exchange treatment) and remission maintenance treatment (azathioprine). During the follow up 21 patient (19,8%) died. Out of those 13 were females. Main causes of death were either infections or cardiovascular diseases. In follow up period patient survival was 83,9-81,2-79-74,7% at 12-24-36-60 months. There were no differences in survival rates between clinical, histological or serological phenotypes. In univariate analysis significant predictors for death of patients were: age (&amp;gt;68 years; p = 0,002), anaemia (Haemoglobin &amp;lt;96 g/l; p = 0,001), increased CRP levels (CRP &amp;gt; 63mg/l; p = 0,001), lower serum C3 levels (p = 0,001), BVAS &amp;gt; 18 (p = 0,003) and the need for dialysis (p = 0,06). In multivariate analysis however significant predictors for the death of patients were age (HR = 1,059, 95% CI = 1,001-1,120; p = 0,046), anaemia (HR = 0,952, 95% CI = 0,908-0,998; p = 0,040) and BVAS (HR = 1,093, 95% CI = 1,030-1,159; p = 0,003). Interestingly in additional analysis PLEX was, alongside acute haemodialysis, significant predictor in combined ESRD/death outcome (as well as for ESRD and relapse rate) but not for death alone. Conclusion In our data disease activity as defined by BVAS and anaemia alongside the patient age are predictors for the patient survival. Anaemia is not included either in BVAS or in other disease activity scores or prediction models. Considering its potential impact on multiple organ functions perhaps anaemia levels should be included either in BVAS or perhaps in VDI though anaemia itself is mostly not autoimmune phenomenon in AAV patients. Also in our cohort PLEX wasn't a significant predictor for patient survival.

#3756 HISTOLOGICAL SUBTYPING OF INTERSTITIAL INFILTRATES AND CORRELATION WITH RENAL PROGNOSIS IN ANCA-ASSOCIATED GLOMERULONEPHRITIS

Abstract Background and Aims Interstitial inflammatory infiltrates in ANCA associated glomerulonephritis (AAGN) are frequently observed but their correlation to clinicopathological parameters remains elusive. Method Retrospective study of 40 patients with newly diagnosed AAGN. Histological assessments using the presence of interstitial inflammatory cells were performed. Biopsy tissues were investigated by CD3, CD20, CD4, CD8, CD68+ (PG-M1), CD138 immunohistochemical staining. We assessed the presence of inflammatory cells in terms of clinical, histopathological parameters as well as the renal prognosis in a large follow-up period [47.87 months (12-216)]. Results The interstitial infiltrates were consisted of lymphocytes (CD3 T cell&amp;gt; CD 20 B cell) at 83%, followed by plasma cells at 43%, neutrophils at 43%, macrophages at 40% and eosinophils at 20% of the biopsies. CD8 T cells dominated the interstitial area in focal and sclerotic class, while CD8 and CD4 tended to have different expression patterns in the interstitial area (figures 1,2). Interestingly, we reported that the presence of macrophages was correlated with higher chronicity index [interstitial fibrosis (39% vs 24%, p = 0.015) and creatinine at diagnosis (4.4 vs 2.6 mg/dL, p = 0.01)], while the presence of neutrophils, lymphocytes and eosinophils was correlated with higher activity index [cellular crescents (37% vs 6%, p&amp;lt;0.001, 26% vs 9%, p = 0.021, 49% vs 24%, p = 0.021, respectively)]. In terms of short-term renal prognosis, only the macrophages were correlated with worst renal function at the 1st year (Cre 3.2 vs 1.8 mg/dL, p = 0.042). Regarding the long-term renal prognosis, we validated as the most reliably predictive score, amongst Berden classification and Mayo Clinic chronicity score, the ANCA renal risk score (AUC 0.694, p = 0.05) and we found that the low-risk group tended to present less severe inflammation (p = 0.029), while the presence of macrophages and eosinophils was less often present (p = 0.03 and 0.05, respectively) compared to the higher risk groups. Conclusion Identifying the differences in histopathological subtypes, in yet underestimated active tubulointerstitial lesions, could be the first step toward improving our understanding of distinct pathophysiological mechanisms and anticipating to specific treatment regimens.

#4683 CHARACTERISTICS AND OUTCOMES OF MPO VERSUS PR3 ANCA ASSOCIATED GLOMERULONEPHRITIS: A REPORT FROM AN AUSTRALIAN POPULATION-BASED STUDY

Abstract Background and Aims ANCA-associated vasculitis is a group of autoimmune vasculitides of unknown aetiology that predominantly affect small blood vessels among different organ systems, with different phenotypic manifestations. Myeloperoxidase (MPO) and Proteinase 3 (PR3) have emerged as two main serological subtypes and growing evidence has shown there are differences between their disease characteristics [1,2]. We investigate into the difference in histological presentation, disease manifestation and progression, as well as mortality rate in patients with biopsy confirmed ANCA associated glomerulonephritis (AAGN). Method This retrospective study was performed at the Royal Brisbane and Women's Hospital, a major tertiary hospital that service a population of 1,030,006 in North Brisbane, Australia. The 2012 Chapel Hill Consensus Conference definitions was used to identify renal predominant ANCA vasculitis. Patients with pauci-immune glomerulonephritis confirmed on kidney biopsy between 1st January 2005 to 1st October 2021 were selected for review. Biopsies were categorised according to Berden's histopathologic classification. Clinical data were collected via medical records. Results Of 80 cases of AAGN identified during the study period, 53 cases were MPO/pANCA positive and 21 cases were PR3/cANCA positive, there were 5 ANCA negative cases and one indeterminate case due to unavailable serology results. There was no statistical significant difference between gender and ANCA subtype (Male MPO 53% and Male PR3 48%, p=0.57). Lung involvement was the most common extra-renal manifestation of AAGN. Similar rates were found between MPO and PR3 positive diseases, 30% (16/53) and 29% (6/21), respectively. PR3 AAGN were much more likely to have sinus involvement, 14% (3/21) vs 4% (2/53) (Relative Risk 3.8, p=0.13). Berden classification was used to classify renal biopsy results (Table 1). There were more cases of sclerotic AAGN within the MPO group whereas crescentic AAGN cases were more common in the PR3 group (Fisher Exact test, p=0.43) Estimated Glomerular Filtration Rate (eGFR) were measured at time of AAGN diagnosis compared to at 3 years. In the MPO group, 45% cases had recovery of eGFR by at least 5mls/min, compared to 62% in PR3 group (P = .30). In addition, 91% (40/44) had improvement of MPO titre following induction treatment, compared to 83% (15/18) in PR3 group had improvement in their titre (p=0.40). Eighteen percent (14/80) of AAGN cases died during the study period. The crude mortality rate for MPO, PR3 and ANCA negative cases were 21% (11/53), 10% (2/21) and 20% (1/5) respectively (p=0.33). Conclusion In our cohort, MPO AAGN was more prevalent (RR 2.5), more likely to have sclerotic class on biopsy (i.e. typically carries the worst prognosis), less likely to have eGFR recovery following treatment and had a higher mortality rate. This is despite the MPO group having a higher titre response rate. Both MPO and PR3 are associated with lung involvement but sinus involvement was significantly more common in PR3 disease. ANCA negative pauci-immune GN remains an uncommon, recognised subtype. Allowing for rarity of disease, larger longitudinal cohort studies are desirable to further define the disease characteristics between AAGN subtypes.

#5028 CHANGING PATTERNS IN CLINICAL-HISTOLOGICAL PRESENTATION AND OUTCOMES OVER THE LAST FOUR DECADES IN PATIENTS WITH MICROSCOPIC POLYANGIITIS (MPA)

Abstract Background and Aims Recent data seem to indicate an increasing age of patients affected by MPA over the last decades, which may result from the wider availability of anti-neutrophil cytoplasmic antibody (ANCA) testing and to a greater awareness of the disease. It is not known whether the changing MPA has been mirrored by a change in the pattern of clinical outcomes. We aimed at assessing the changes in demographic, clinical and histological presentation, and outcomes of MPA patients over a 42-year period. Method We performed a multicenter retrospective cohort study. Patients diagnosed with MPA between 1980 and the 31st of January 2022 were grouped in two periods (p), based on the year of diagnosis: p1980–2001 and p2002–2022. We tested the baseline differences using the Mann-Whitney test and the Fisher's exact. We estimated the crude patient survival using the Kaplan-Meier estimator and the cumulative incidence of competing events death/dialysis using Aalen-Johansen estimator. The probability of end-stage kidney disease (ESKD) and death at each time point since MPA diagnosis was estimated through a multistate model, which accounted for patients who died after starting dialysis. We used Cox proportional hazards, Fine-Gray regression, and multistate regression models to adjust for potential confounding factors such as age, kidney function and clinical symptoms at the time of diagnosis. Results Out of 201 patients, 187 had non-missing follow-up to ESKD and/or death and could be included in the study. There were 77 patients in p1980-2001, and 110 patients in p2002-2022. Compared to p1980-2001, patients in p2002-2022 were older (66.2 (14.0) vs 57.7 (15.8) vs; P&amp;lt;0.001) and had better kidney function (eGFR (MDRD), mL/min/1.73m2 25.9 (24.8) vs 21.5 (28.2); P = 0.011). The prevalence of the sclerotic class according to the Berden histopathological classification was lower in p2002-2022 (4.8 vs 18.2%; P = 0.006). There were mild differences in the pattern of clinical symptoms, with a lower prevalence of constitutional symptoms (83.6 vs 94.8%; P = 0.021) and a higher prevalence of pulmonary disease (40 vs 20.8%; P = 0.040) and peripheral neuropathy (17.3 vs 5.2%; P = 0.013) in p2002-2022. Crude and adjusted patient survival was similar. However, the risk of ESKD decreased during p2002-2022 compared to p1980-2001 (Figure 1; crude Subhazard ratio of ESKD: 0.30 [95%CI: 0.16 to 0.57; P&amp;lt;0.001]). The difference in the probability of ESKD remained significant even after accounting for death after ESKD (Figure 2), and after adjusting for potential confounders (Hazard ratio of ESKD since MPA diagnosis in multistate models: 0.33 [95%CI: 0.18 to 0.63; P&amp;lt;0.001]). Conclusion Clinical presentation of MPA has become less severe in the last decades, leading to a reduced risk of ESKD, despite a comparable risk of death. Older age, changing clinical patterns and better kidney function at the time of diagnosis do not fully account for the reduction in ESKD, which may be instead related to new induction and maintenance therapies as well as to a greater awareness of the disease.

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

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. 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. 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. 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.

MO253: Interstitial Fibrosis in Anca-Associated Vasculitis: MPO Versus PR3-A Single-Center Experience

Abstract BACKGROUND AND AIMS Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a necrotizing vasculitis characterized by inflammation of small blood vessels, being the kidney one of the most frequently affected organs. AAV has a high morbidity and mortality, developing rapidly progressive renal failure that could lead to end-stage renal disease (ESRD). The pathogenesis is complex and multifactorial; macrophages have turned out to be a key element in inflammation and also in fibrosis. As already described in previous publications, PR3-AAV and MPO-AAV show clinical-demographic differences and different renal phenotypes on kidney biopsy. Histopathological subgrouping into four classes (focal, crescentic, mixed and sclerotic, as defined by Berden et al.) was proposed to predict long-term renal survival rates, poorest in the sclerotic class. This classification, validated by our group and multiple others, is still under review. The aim of this study is to demonstrate whether interstitial fibrosis in AAV is at least as important as glomerular sclerosis in renal prognosis, being a differentiating element between MPO and PR3 vasculitis. METHOD We performed a retrospective single-center study of 95 AAV-patients (78 MPO-AAV and 17 PR3-AAV) diagnosed by renal biopsy from 1991 to 2021 and at least 1-year follow-up. Clinical and laboratory variables, presence and type of ANCA, immunosuppressant therapy and renal/patient survival were evaluated. Sixty-two kidney biopsy samples have been analyzed: histomorphometric quantification has been carried out using MetaMorph® software on trichrome-stained slides in order to measure the degree of fibrosis. Continuous variables were described using measures of central tendency and dispersion (mean and standard deviation), and categorical variables using frequency tables and percentages. Student's t-tests or Mann–Whitney U tests, as appropriate, were performed to evaluate differences in mean values, and chi-squared tests were used to evaluate differences in qualitative variables. Statistical significance was defined as P-values &amp;lt;.05. All P-values were two-sided. RESULTS PR3-AAV population was predominantly male (70%) with a mean age at diagnosis of 62 years and a mean follow-up of 54 months, while MPO-AAV population was mainly female (65.8%), mean age 66 years and follow-up 65 months. There were no statistically significant differences in renal function between MPO and PR3-AAV at diagnosis. However, our data showed that MPO-AAV had worse renal function than PR3-AAV at the end of follow-up (P = .01). Furthermore, it should be highlighted that renal function improved throughout the follow-up (P &amp;lt; .01 and P = .05 in MPO and PR3-AAV, respectively). From a histological point of view: MPO-AAV manifests more interstitial fibrosis at diagnosis than PR3-AAV (P = .01). However, there were no statistically differences in the amount of glomerular sclerosis. It is noteworthy that PR3-AAV showed more crescentic proliferation at diagnosis (P = .03) but less fibrotic crescents than MPO-AAV (not reaching statistical significance). CONCLUSION The method we used allows a quantitative assessment of renal fibrosis. Our data confirm that renal prognosis is better in PR3-AAV than in MPO-AAV, which could be explained by a greater interstitial fibrosis, as well as more fibrotic crescentic in MPO-AAV at diagnosis.

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

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. 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). 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%. 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.

Serum Sulfatide Levels as a Biomarker of Active Glomerular Lesion in Patients with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Single Center Pilot Study.

Sulfatides are glycosphingolipids that are associated with coagulation and platelet aggregation. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) activates platelet function and often leads to thrombotic complications. These facts suggest an association between serum sulfatides and AAV. We aimed to clarify the significance of serum sulfatide levels in patients with AAV. We conducted a retrospective, single-center, observational pilot study that included 35 patients who developed AAV and 10 control patients who were candidates for living-donor kidney transplantation. We compared serum sulfatide levels between the control and AAV patients. We analyzed the differences in serum sulfatide levels among four classes (focal, crescentic, mixed, and sclerotic class) of glomerular lesions that were categorized by histopathologic classification of ANCA-associated glomerulonephritis. Serum sulfatide levels in patients with AAV were significantly lower than those in the controls. Serum sulfatide levels were significantly different between the four classes. Additionally, serum sulfatide levels in the crescentic class were significantly lower than those in the other classes. Serum sulfatide levels were significantly correlated with albumin, cholesterol, C-reactive protein, and pentraxin 3. In conclusion, serum sulfatide levels are significantly correlated with inflammation, reflecting crescentic glomerulonephritis, which is an active glomerular lesion in AAV patients.

Clinical features and outcomes of anti-neutrophil cytoplasmic autoantibody-associated vasculitis in Chinese childhood-onset patients

Data on anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are limited in children. This study is to determine the clinical features and outcomes of childhood-onset AAV. A retrospective study was performed on patients who were diagnosed with AAV before 18years old in Xiangya Hospital. Their medical records were analyzed by retrospective review. Sixteen patients were diagnosed with AAV before 18years old in the past 9years, with an average age of 13.3 ± 3.3years and 13 of them were female. There were 15 patients with microscopic polyangiitis (MPA) and 1 with Wegener's granulomatosis. The interval between onset of disease and diagnosis of AAV was 2 (1.5-3) months. Most patients (15/16, 93.8%) had multi-organ involvement, and all patients had renal involvement with 7 (43.8%) patients requiring dialysis at presentation. Eleven patients underwent a renal biopsy, of which mixed class and sclerotic class were the most two common histological types. All patients received immunosuppressive therapy for induction therapy including intravenous administrations of methylprednisolone (MP) pulse therapy for 8 patients. 8 patients (50%) achieved remission after induction therapy. After a median follow-up of 46.3 ± 36.1months, nine (56.3%) patients progressed to end-stage renal disease (ESRD) and 5 (31.3%) patients died. Childhood-onset AAV showed similar clinical and pathological features compared to those of adults, except that it usually occurs in girls. The most commonly involved organ was the kidney, and it had a high risk of progression to ESRD. Early diagnosis and initiation of appropriate immunomodulatory therapy would be important to improve outcomes.

Kidney Pathology and Outcomes in ANCA-Associated Vasculitis: Retrospective Analysis of 85 Patients

ANCA-associated vasculitis (AAV) poses a significant risk of kidney failure; kidney biopsy remains a key prognostic tool. The histopathologic classification of AAV glomerulonephritis (GN) developed by Berden et al. showed correlation between GN classes and kidney outcomes; ANCA Renal Risk Score (ARRS) included tubular atrophy and interstitial fibrosis (TA/IF) as an additional parameter for risk assessment. We aimed to evaluate kidney survival across AAV GN classes and ARRS groups. A single-center retrospective study included 85 adult patients with biopsy-proven AAV kidney disease followed in the period of 2000–2020. Primary outcome was kidney survival at the end of 18 (5; 66) months follow-up, and kidney death was considered as stage 5 CKD. We found significant differences in kidney survival for sclerotic, mixed, crescentic and focal AAV GN classes: 19%, 76.2%, 91.7% and 100%, respectively (p = 0.009). Kidney survival was 0%, 75.6% and 100% for the high-, medium- and low-risk ARRS groups, respectively (p &lt; 0.001); TA/IF analysis showed kidney survival at 49.6% vs. 87.7% for widespread and mild TA/IF, respectively (p = 0.003). Kidney survival was significantly lower in anti-MPO-ANCA versus anti-PR3-ANCA carriers (50.3% and 78.1%, respectively, p = 0.045). We conclude that unfavorable AAV kidney outcomes are associated with sclerotic GN class by Berden’s classification, ARRS high risk group, and anti-MPO-ANCA subtype.

MO245OUTCOME OF DIFFERENT INDUCTION REGIMENS IN ANCA-ASSOCIATED GLOMERULONEPHRITIS ACCORDING TO THE HISTOPATHOLOGICAL CHARACTERISTICS: THE REASSESS STUDY*

Abstract Background and Aims Renal involvement in ANCA-associated vasculitis (AAV) impacts significantly on patients’ prognosis. The role of different induction regimens on remission rates and long-term renal outcomes according to renal histological characteristics has not been explored yet. Method AAV patients with biopsy-proven renal involvement were collected retrospectively from eleven centers and stratified according to the induction regimen employed: Rituximab (RTX), Cyclophosphamide (CYC) or both (RTX-CYC). Kidney biopsies were classified according to the Berden and Brix classifications. Renal remission rate was assessed 6 months after the induction regimen and defined as a renal Birmingham Vasculitis Activity Score (BVAS) of 0. Among patients who achieved remission at 6 months, renal relapse was defined as a renal-BVAS&amp;gt;0 associated with an increase in immunosuppressive treatment. ESRD was defined as an eGFR&amp;lt;15 ml/min/1,73m2, need for dialysis or renal transplant. Results 323 patients were identified and followed-up for a median time of 36 months (IQR 18-72). The cohort included 38% patients with GPA and 62% with MPA, 53% patients were MPO-ANCA and 41% PR3-ANCA positive. The median baseline eGFR in the overall cohort was 19 ml/min/1,73m2 (IQR 12- 34). 58% of patients were treated with CYC, 24% with RTX-CYC and 18% with RTX. According to the Berden classification, 24% biopsies were classified as Focal, 31% as Crescentic, 33% as Mixed and 12% as Sclerotic. The Brix score was assessable in 270/323 (84%) patients: 17%, 52% and 31% were respectively in the Low, Medium and High-risk class. The overall renal remission at 6 months was 90%; according to the Berden classification, 94% patients achieved remission in the Focal, 88% in the Crescentic, 91% in the Mixed and 86% in the Sclerotic class. According to the Brix risk score, 88% patients achieved remission in the High risk, 91% in the Medium and 96% in the Low-risk class. According to induction regimen employed, 91%, 90% and 90% patients achieved remission in the RTX, CYC and RTX plus CYC group respectively. In a logistic regression model adjusted for sex, age, ANCA type, AAV diagnosis, creatinine and proteinuria at onset, the induction regimen employed was not predictive of renal remission at 6 months, neither in Berden Focal plus Crescentic and Mixed plus Sclerotic classes, nor in Brix High and Low plus Medium risk classes. Of the 185 patients with at least 6 months of follow-up available after remission, 25% experienced a renal relapse. In a Cox regression model adjusted for sex, age, ANCA type, AAV diagnosis, creatinine and proteinuria at onset, the induction regimen or histological score were not predictive of renal relapse. In the unadjusted survival analysis with the Kaplan-Maier curve, patients in the Crescentic group treated with RTX had a shorter ESRD-free survival compared to the CYC group (p=0.033) and the RTX-CYC group (p=0.044); figure 1: This was confirmed also with a Cox regression analysis adjusted for sex, age, ANCA type, AAV diagnosis, creatinine and proteinuria when comparing the RTX group with the CYC one (HR 8.30 [95% CI 1.64 to 42.01], p=0.011); figure 2: While the eGFR changes over time in the Focal plus Crescentic and Mixed plus Sclerotic classes showed a similar trend between treatment groups, in the Crescentic class the median eGFR values in the RTX group tended to be lower compared to the CYC and the RTX-CYC ones; figure 3: The rate of severe infections in the RTX, CYC and RTX-CYC group was respectively 6.3, 8.5 and 8.8 per 100 patient-years during the first 12 months. Conclusion in a retrospective multicenter survey, response rates and relapse risk after different induction regimens in AAV patients with renal involvement were comparable in the overall cohort and in the different histopathological subgroups. Although in a small subset of patients, the ESRD-free survival in the Crescentic class was shorter in the RTX group compared to the CYC one.

MO282EARLY RENAL RECOVERY AFTER A FIRST FLARE OF PAUCI IMMUNE GLOMERULONEPHRITIS

Abstract Background and Aims Renal involvement is a severe manifestation of ANCA-associated vasculitis. Patients often progress to end-stage renal disease. The potential for renal recovery after a first flare has seldom been studied. Our objectives were to describe the evolution of the estimated glomerular filtration rate (eGFR) and identify factors associated with the change in eGFR between diagnosis and follow-up at 3 months (ΔeGFRM0–M3) in a cohort of patients with a first flare of pauci-immune glomerulonephritis. Methods This was a retrospective study over the period 2003–2018 of incident patients in the Nord-Pas-de-Calais (France). Patients were recruited if they had a first histologically-proven flare of pauci immune glomerulonephritis with at least 1 year of follow up. Kidney function was estimated with MDRD-equation and analysed at diagnosis, 3rd, 6th and 12th months. The primary outcome was ΔeGFRM0–M3. Factors evaluated were histological (Berden classification, interstitial fibrosis, percentage of crescents), clinical (extra-renal manifestations, sex, age) or biological (severity of acute kidney injury, dialysis, ANCA subtype). Results One hundred and seventy-seven patients were included. The eGFR at 3 months was significantly higher than at diagnosis (mean ± standard deviation, 40 ± 24 vs 28 ± 26 ml/min/1.73 m2, p &amp;lt; 0.001), with a ΔeGFRM0–M3 of 12 ± 19 ml/min/1.73 m2. The eGFR at 12 months was higher than at 3 months (44 ± 13 vs 40 ± 24 ml/min/1.73m2, p = 0.003). The factors significantly associated with ΔeGFRM0–M3 in univariate analysis were: sclerotic class according to Berden classification, percentage of interstitial fibrosis, percentage of cellular crescents, acute tubular necrosis, neurological involvement. The factors associated with ΔeGFRM0–M3 in multivariate analysis were the percentage of cellular crescents and neurological involvement. The mean increase in eGFR was 2.90 ± 0.06 ml/min/1.73m2 for every 10-point gain in the percentage of cellular crescents. ΔeGFRM0–M3 was not associated with the risks of end-stage renal disease or death in long-term follow-up. Conclusions Early renal recovery after a first flare of pauci-immune glomerulonephritis occurred mainly in the first three months of treatment. The percentage of cellular crescents was the main independent predictor of early renal recovery.

MO083SYSTEMATIC HISTOLOGICAL SCORING OF TUBULOINTERSTITIAL LESIONS CORRELATE WITH CLINICAL PARAMETERS IN ANCA-ASSOCIATED GLOMERULONEPHRITIS

Abstract Background and Aims Renal involvement is a common and severe complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We have previously reported that severe deterioration of kidney function is associated with necrotizing and crescentic ANCA glomerulonephritis (GN), classified into Berden’s crescentic class or ANCA renal risk score (ARRS) high risk. However, tubulointerstitial inflammation associated with either histopathological subgrouping or ARRS remains elusive. Furthermore, clinical and laboratory markers of AAV disease severity or deterioration of kidney function in association with inflammatory findings in the kidney have not been described yet. Since aggressive immunosuppressive therapy is recommended for remission induction especially in severe cases of AAV, we here aimed to expand our current knowledge with regard to histopathological classification of tubulointerstitial injury and inflammatory findings analogous to the Banff classification. Method A total number of 50 renal biopsies with confirmed renal involvement of AAV were retrospectively included between 2015 till 2020 in a single-center observational study. Renal biopsies were evaluated for either focal, crescentic, mixed or sclerotic class (according to Berden et al.) and ARRS low, intermediate or high risk (according to Brix et al.). Inflammatory and fibrotic tubulointerstital alterations were evaluated analogous to Banff scoring system for allograft pathology. Results We here show that distinct inflammatory lesions are associated with glomerular findings classified into either histopathological subgrouping or ARRS. Furthermore, interstitial inflammation and tubulitis correlate with disease severity and decline of kidney function in AAV. Finally, we provide data that tubulointerstitial injury and inflammatory findings correlate with short-term outcome in response to aggressive immunosuppression and remission induction therapy. Conclusion In summary, we here provide evidence that a systematic scoring of inflammatory and degenerative tubulointerstitial lesions correlate with severe renal impairment and short-term response to remission induction therapy. Since aggressive immunosuppressive therapy is recommended for remission induction especially in severe cases of AAV, systematic histopathological scoring of tubuloinsterstital lesions could further improve our current knowledge of ANCA GN progression.