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

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>0 associated with an increase in immunosuppressive treatment. ESRD was defined as an eGFR<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.

Antimyeloperoxidase and proteinase 3 antibodies for nephritis flare prediction in ANCA-associated-vasculitis

Background The value of myeloperoxidase and proteinase 3 antibodies titers in the assessment of renal disease activity and flare prediction in patients with ANCA-associated-vasculitis (AAV) is not well-known. Methods Retrospective study including 113 AVV patients with a renal biopsy-proven pauci-immune necrotizing glomerulonephritis from seven Spanish hospitals. The main inclusion criteria were assessment of MPO antibodies (MPOab) using multiplex flow immunoassay and PR3 antibodies (PR3ab) measurements using immunoassay chemiluminescence with an identical range of values for all participating centers. Results Serum MPOab, 3 ± 1.2 months before relapse, was higher in patients who relapsed (19.2 ± 12.2 vs 3.2 ± 5.1 AI, p < 0.001). The discrimination value of MPOab 3 months before renal relapse had an AUC of 0.82 (95%CI 0.73-0.92; p < 0.001). ΔMPOab (change in antibodies titration 6 months before relapse) was higher in patients who relapsed [8.3 ± 12 vs 0.9 ± 3.1 AI, p = 0.001) (AI; antibody index unit). The discrimination value of ΔMPO had an AUC of 0.76 (95%CI 0.63-0.88; p < 0.001). The positive predictive value of renal relapse in PR3 patients is 100% and the negative predictive value of renal relapse in patients with PR3 positive titers is 57.1%. Serum PR3ab was higher in patients who relapsed 2.8 ± 1.4 months before relapse (58.6 ± 24.6 vs 2.0 ± 0.6 AI, p < 0.001). Conclusions MPO antibody level monitorization using multiplex flow immunoassay and PR3 measurements using immunoassay chemiluminescence are useful and sensitive tools for the prediction of renal relapse in the follow-up of AAV patients with renal disease, and relevant surrogate markers of renal disease activity.

Life prognosis and renal relapse after induction therapy in Japanese patients with proliferative and pure membranous lupus nephritis

Objective We aimed to compare life prognosis and renal relapse after induction therapy in proliferative (PLN) and pure membranous LN (MLN). Methods We retrospectively analysed the cases of 140 of 172 patients with LN who underwent a renal biopsy at our hospital or community hospitals from 1993 to 2016. We determined the complete response (CR) rate at 12 months after the patients had started induction therapy, and we evaluated the predictive factors for CR, life prognosis and renal relapse in PLN and pure MLN. We defined PLN as International Society of Neurology and the Renal Pathology Society (ISN/RPS) Class III or IV and MLN as ISN/RPS Class V. Results The renal pathology of 99 (70.7%) patients was classified as PLN, and that of the other 41 (29.3%) patients as MLN. Fifty patients (50.5%) with PLN and 22 patients (53.7%) with MLN achieved a CR at 12 months. A multivariate analysis showed that a lower index of chronicity in PLN and a higher total haemolytic complement (CH50) level in MLN were predictive factors for achieving a CR at 12 months. A Kaplan–Meier analysis showed that the life prognosis (P = 0.93) and renal relapse (P = 0.52) were not significantly different between PLN and MLN. Conclusions The predictive factors for a CR at 12 months post-induction therapy were index of chronicity in PLN and CH50 level in MLN. There were no significant differences in life prognosis or renal relapse between PLN and MLN in the achievement of a CR at 12 months post-induction therapy.

MO038ANTIMYELOPEROXIDASE AND PROTEINASE 3 ANTIBODIES ARE A USEFUL MARKER AS NEPHRITIS FLARE PREDICTOR IN ANCA-ASSOCIATED VASCULITIS

Background and Aims The diagnostic utility of ANCA antibodies in ANCA associated-vasculitis (AAV), antiproteinase 3 (PR3) and myeloperoxidase (MPO) testing is now undisputed, but the clinical utility of serial MPO/PR3 testing to predict relapses, remain controversial. The aim of this study was to analyze the relevance of serum MPO and PR3 antibody level assessment in the management of AAV. We sought to determine whether MPO and PR3 antibody levels correlated with renal disease activity, and whether an increase could predict a nephritis flare. Method Retrospective multicenter study including AAV-patients with renal involvement from 7 nephrology departments belonging to the Spanish Glomerular Study Group (GLOSEN). The main inclusion criteria were that MPO antibodies were detected by ELISA (Multiplex assay) and PR3 using chemioluminescence immunoassay. For statistical purpose a continuous variable were calculated, called delta MPO/PR3(ΔMPO y ΔPR3) that reflects change in antibodies levels 6 months before renal flare. Clinical data were recorded since complete remission of first nephritis diagnosis flare until second renal relapse. Results 113 AAV-patients with pauci-inmune necrotizing glomerulonephritis were included, 59 (52.2%) women, mean age (64.3±14.8 years), 85 patients (75.2%) MPO-AAV and 28 (24.8%) PR3-AAV, after a mean follow-up of 5±4.8 years, 54 renal relapses occurred in 40 (52,6%) MPO-AAV patients and in 14 (57.1%) PR3-AAVpatients. Serum MPO levels were significant higher in relapser-patients compared with non- relapser patients, 3±1.2 months before nephritis relapse [(n=32) 19.2±12.2 IA vs (n=38) 3.2±5.1 IA, p<0.001)]. Δ MPO levels were significant higher in relapse-patients compared with non-relapser patients [(n=32) 8.3±12 IA vs (n=38) 0.9±3.1.1 IA, p=0.001). The discrimination value of the MPO antibody levels 3 months before renal relapse were established by means of a ROC curve: AUC of 0.82 (95% CI 0.73 to 0.92; p<0.001) and the MPO cut-off value predicting renal relapse were established in 8.3 IA. The discrimination value of the ΔMPO were established by means of ROC curve: AUC of 0.76 (95% CI 0.63 to 0.88; p<0.001), ΔMPO cut-off value were established in an increase of MPO levels of 3.7 IA. Serum PR3 levels were significant higher in relapser-patients 2.8±1.4 months before relapse [(n=14) 58.6±6.6 IA vs (n=7) 2.0±0.6 IA, p<0.001)] and Δ PR3 levels were significant higher in relapse-patients compared with non-relapser patients [(n=14) 57.5±28.5 IA vs (n=7) 0.8±0.2. IA, p<0.001)]. The discrimination value of the PR3 3 months before flare and Δ PR3 antibody levels were established by means of ROC curve: AUC 1. Conclusion Our results show that MPO antibodies, measured by Multiplex assay, could be a useful predictor of glomerulonephritis flare in AAV-patients. MPO levels 3 months before renal flare seems a good marker confirmed by ROC curve results, MPO cut-off value with the best sensitivity and specificity in predicting renal relapse was established in 8.3 IA. Δ MPO levels show that increase in titers ≥ 3.7 IA 6 months before renal flare, predict nephritis relapse However, PR3 antibodies are not a useful predictor marker, rise in antibodies level indicate renal vasculitis activity.

THU0274 RENAL CHARACTERISTICS AND OUTCOME OF LUPUS NEPHRITIS ACCORDING TO ITS TIME OF ONSET

Background:Lupus nephritis (LN) usually develops within 5 years of systemic lupus erythematosus (SLE) onset. It is unclear whether the course and outcome of LN differ between patients who initially had LN at SLE onset (initial-onset LN) and those who developed LN within 5 years after SLE onset (early-onset LN).Objectives:To compare clinical characteristics and renal outcomes between SLE patients with initial-onset LN and SLE patients with early-onset LN.Methods:SLE patients with biopsy-proven LN were retrospectively reviewed. The clinical parameters and renal outcomes were compared between initial-onset LN and early-onset LN groups. We used Cox regression analysis to estimate risk of worse renal outcome, according to the onset time of LN.Results:Of the total 136 LN patients, 92 (67.6%) and 44 (32.4%) patients were classified into the initial-onset and early-onset LN groups, respectively. The initial-onset LN group had higher prevalences of impaired renal function (34.8% vs. 11.4%, p=0.004) and microscopic hematuria (73.9% vs. 54.5%, p=0.024), and higher urine protein/creatinine ratio (4626.1 [2180.0–6788.3] vs. 2410.0 [1265.0–5168.5] mg/g, p=0.006) at LN diagnosis. Renal relapse (46.3% vs 25.7%, p=0.039) and progression to chronic kidney disease (CKD) or end-stage renal disease (ESRD) were more common (24.4% vs. 8.3%, p=0.042) in the initial-onset LN group. In the multivariable Cox regression analysis, initial-onset LN group had higher risk of renal relapse (adjusted hazard ratio [HR] 2.938, 95% confidence interval [95% CI] 1.344–6.426, p=0.007) and progression to CKD or ESRD (adjusted HR 4.642, 95% CI 1.107–19.458, p=0.036), compared with early-onset LN group.Conclusion:Patients with LN at SLE onset may have more severe renal presentations and worse renal outcome than those who develop LN within 5 years.References:Not applicableTable.Hazard ratios for renal relapse and progression to CKD/ESRD according to onset time of LNUnivariable analysisMultivariable analysisaHR (95% CI)pHR (95% CI)pRenal relapseEarly-onset LN1.000 (reference)1.000 (reference)Initial-onset LN2.734 (1.315–5.686)0.0072.938 (1.344–6.426)0.007Progression to CKD/ESRDEarly-onset LN1.000 (reference)1.000 (reference)Initial-onset LN4.201 (1.249–14.132)0.0204.642 (1.107–19.458)0.036aAdjusted for age, ISN/RPS class, activity index, chronicity index, GFR, UPCR, hematuria and use of HCQLN, lupus nephritis; CKD, chronic kidney disease; ESRD, end-stage renal disease; ISN/RPS, International Society of Nephrology/Renal Pathology Society (ISN/RPS); GFR, glomerular filtration rate; UPCR, urine protein/creatinine ratio; HCQ, hydroxychloroquine; HR, hazard ratio; CI, confidence intervalAcknowledgments:None.Disclosure of Interests:None declared

P0362ROLE OF REPEATED RENAL BIOPSY IN ANCA VASCULITIS

Background and Aims Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a systemic disease characterized by inflammation of small vessels and presence of ANCA. Pauci-immune necrotizing crescentic glomerulonephritis is a severe renal complication of AAV. Despite immunosuppressive therapy, relapses are frequent during the course of the disease, affecting up to 50% of the patients. Kidney biopsy is routinely used to diagnose AAV at initial presentation and to predict renal prognosis. Although the activity of renal AAV is not easily evaluated by plasma or urine biomarkers, kidney biopsy is rarely performed when relapse is suspected. We herein analyze the clinical, laboratory and renal pathology data from patients who underwent repeated kidney biopsies during the course of AAV. Method We retrospectively reviewed data from 37 patients who underwent at least 2 kidney biopsies in our centre, between 2002 and 2018. The first renal biopsy (B1) was constantly performed at diagnosis. A follow-up biopsy (B2) was performed for purpose, either for suspicion of refractory disease or confirmation of renal relapse. Modifications of renal pathology between B1 and B2 were studied, by comparing presence of active and chronic lesions. Active lesions were defined by the presence of cellular crescents and/or fibrinoid necrosis. Chronic lesions were quantified by the percentage of globally sclerotic glomeruli and the percentage of interstitial fibrosis / tubular atrophy (IF/TA). Results Median age at diagnosis was 57 years, M/F ratio was 21/16. ANCA specificity was anti-MPO in 65% of cases, anti-PR3 in 32%. The median delay between B1 and B2 was 3,3 [0,9-5,8] years. B2 was done for suspicion of refractory disease (n=8) or of renal relapse (n=29). Causes of B2 were : persistence or reappearance of haematuria in 78% of cases, increase of creatinine in 43%, increase of ANCA titer in 67%. Systemic AAV activity was more important at B1 vs B2 (median BVAS 18 vs 9), as well as renal dysfunction (median sCreat 200 vs 156 μmol/l). Active glomerulonephritis was constantly found at B1 but was present in only 35% of B2. Presence of cellular crescents decreased from 71,4 to 29,7% (p = 0,002), whereas fibrinoid necrosis decreased from 80,6 to 35,1% (p = 0.0003). Five factors were significantly associated with the presence of active lesions : presence of at least one extra-renal AAV manifestation (p = 0.0006), increase of ANCA titer (p = 0.0022), CRP>30mg/l (p = 0.001), absence of IF/TA (p=0,02) and high percentage of normal glomeruli (p=0,014) at B1. Interestingly, level of proteinuria and persistence of hematuria were not associated with histological activity at B2 (p =0,64 and 0,22 respectively). In contrast, chronic lesions such as glomerulosclerosis and IF/TA were more severe at B2 compared to B1 (p <0,0001 and 0,014 respectively). The worsening of fibrotic lesions was not associated with ANCA specificity (anti-MPO vs -PR3). Conclusion This is the largest cohort reporting on repeated renal biopsy in AAV. Despite several clinical and laboratory signs suggesting active renal AAV, B2 revealed no relapse in 2/3 of cases, allowing avoidance of a new immunosuppressive induction treatment. Our results suggest that rebiopsy is crucial when renal relapse is suspected, as proteinuria and hematuria do not predict active disease, suggesting that their persistence could be explained by glomerular scarring.

Patients with ANCA-Associated Glomerulonephritis and Connective Tissue Diseases: A Comparative Study from the Maine-Anjou AAV Registry

Background and objectives: The overlap between antineutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis (ANCA-GN) and connective tissue diseases (CTD) has been reported mainly as case series in the literature. Frequency of this association, as well as presentation and outcomes are unknown. Materials and Methods: Patients from the Maine-Anjou ANCA-associated vasculitides (AAV) registry with ANCA-GN diagnosed between 01/01/2000 and 01/01/2018, ANCA positivity, and at least six months of follow-up, were included. Results: 106 out of 142 patients fulfilled the inclusion criteria and were analyzed. CTD was present at ANCA-GN diagnosis in 16 (15.1%) patients. The most common CTD were rheumatoid arthritis, Sjogren syndrome and systemic sclerosis. Compared to the control group, females were more represented in the CTD group (75%, p = 0.001). Renal presentation was comparable between groups, including the pathological analysis of renal biopsies. Patients of CTD group presented a higher rate of non-renal relapse (25% versus 7.7%, p = 0.037), and experienced more frequently a venous thrombotic event (31.2% versus 10%, p = 0.021). No difference between groups was observed according to major outcomes. Conclusion: Association between CTD and ANCA-GN is not a rare condition and predominantly affects females. While AAV presentation is not significantly different, CTD patients experience more frequently non-renal relapse and venous thrombotic events.

Improvement of Outcomes in Patients with Lupus Nephritis: Management Evolution in Chinese Patients from 1994 to 2010

Objective.To assess how the longterm outcomes have changed over the past decades in Chinese patients with lupus nephritis (LN). The trends in patient manifestation at presentation, treatment pattern, and therapeutic effects were evaluated.Methods.A cohort of biopsy-proven patients with LN (n = 1945) from January 1994 to December 2010 was analyzed. Treatment regimens, treatment response, renal relapse, and renal outcome were compared at different time periods (1994–1998, 1999–2004, and 2005–2010).Results.Patients in the later periods had shorter duration of disease, lower serum creatinine value and chronicity at biopsy, and more frequent followup. They were more likely to receive standard-of-care therapies, which included cyclophosphamide, mycophenolate mofetil, and combination therapy. Patients in the later periods had higher probabilities of achieving remission (p < 0.001) and lower probabilities of experiencing renal flare (p = 0.007). The 5-year renal survival rates were 92.6%, 90.6%, and 94.3% in 1994–1998, 1999–2004, and 2005–2010, respectively. The 5-year risk of endstage renal disease (ESRD) did not differ between 1994–1998 and 1999–2004, but was significantly lower in 2005–2010 (HR 0.40, 95% CI 0.19–0.85 vs 1999–2004). In multivariable Cox analysis, standard therapy was independently associated with lower risk of ESRD (adjusted HR 0.72, 95% CI 0.52–0.98, p = 0.04). Variables of renal damage at biopsy (renal function, activity index, and chronicity index) were independently associated with poor outcome.Conclusion.The outcomes of Chinese patients with LN have improved from 1994 to 2010. With the increased use of standard therapies, the remission rates have increased and renal relapse has decreased.