SAT0259 ANCA-ASSOCIATED VASCULITIS WITH RENAL INVOLVEMENT: THE ROLE OF A COMBINED HISTOPATHOLOGICAL ASSESSMENT AS PREDICTOR OF PATIENTS’ PROGNOSIS

Background:Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis often affect the kidney and renal involvement has a considerable clinical impact on patient’s prognosis. Currently used histopathological classifications are basically focused on the glomerular damage and assessing chronic damage progression, but their prognostic role presented some limitations.Objectives:To combine the Berden Classification, the ANCA Renal Risk Score (ARRS) and the Mayo Clinic-Renal Chronicity Score (RCS) with the inflammatory interstitial infiltrate and to evaluate the prognostic value of the combined assessment in patients with AAVMethods:We included 19 AAV patients with renal involvement (mean age 63±13.2 years; disease duration 4.9±5.2 months) who underwent renal biopsy. Patients were classified according to age, sex, disease duration, ANCA positivity. The histopathological evaluation was performed assessing the Berden category, Risk group (low, medium, high) according to the ARRS and Chronicity class according to the RCS; we also assessed the % of inflammatory interstitial infiltrate. Each patient was followed-up for 12 months; we considered the stage IV (eGFR < 30 ml/min/m2) of theKDIGO CKDClassification as renal outcome.Results:8 (42.1%) AAV patients were p-ANCA and 11 (57.9%) c-ANCA. 12 months after renal biopsy, 8 patients (42.1%) had a GFR <30 ml/min. According to the ARRS, 10 (52.6%) patients were in low, 7 (36.8%) in medium and 2 (10.5%) in high risk group. According to the RCS, 2 (10.5%) biopsies had minimal, 10 (52.6%) mild and 7 (36.8%) moderate chronic changes, no one presented severe chronic changes. According to the Berden classification, 6 (31.6%) samples represented the focal, 2 (10.5%) the crescentic and 11 (57.9%) the mixed category, no one represented the sclerotic class. The mean % of inflammatory infiltrate was 37.4±25.2. The interstitial inflammatory infiltrate showed a direct correlation with the severity of the Berden category (R=0.51; p=0.025), the % of sclerotic glomeruli (R=0.6; p=0.007) and the number of fibrocellular crescents (0.46; p=0.05) and an inverse correlation with the GFR at 12 months (R=-0.48; p=0.045). A ROC curve study identified a 22.5% cut-off of inflammatory infiltrate to predict the outcome of GFR at 12 months < 30 ml/min (sensitivity 88%, specificity 97.5%). Patients in focal class developed less frequently a GFR<30 (χ2=9.1; p=0.003), but there were no differences in the outcomes between the crescentic and mixed class. ARRS could differentiate risk group with regard to the renal outcome stage IV (χ2=9.0 e p=0.01) as well as the chronicity Score (χ2=8.1; p=0.017). Finally, we built a matrix combining the different histopathological scores and the % of inflammatory infiltrate to predict the outcome; we found that an inflammatory infiltrate wider than 22.5% characterizes most of patients developing stage IV chronic renal failure at the 12th month. In fact, more than 75% of patients with eGFR < 30 ml/min had inflammatory infiltrate wider than 22.5% at biopsy, despite they were in the low risk class (ARRS) and in minimal changes class (RCS).Conclusion:Our results underline the importance of the inflammatory infiltrate in renal outcome and histology. Despite the limited number of patients, our data suggest that a combined histological score assessing the chronicity and activity of renal disease from both glomerular and interstitial perspective could better predict patients’ global and renal prognosis.References:[1]Berden, J Am Soc Nephrol, 2010 Berti, Nephrol Dial Transplant 2018 Brix, Kidney Int. 2018Disclosure of Interests:Laura Gigante: None declared, Pier Giacomo Cerasuolo: None declared, Gisella Vischini: None declared, Francesco Federico: None declared, Dario Bruno: None declared, Alessia Musto: None declared, Stefano Costanzi: None declared, Silvia Laura Bosello Speakers bureau: Abbvie, Pfizer, Boehringer, Elisa Gremese Speakers bureau: Abbvie, BMS, Celgene, Jannsen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB

THU0287 EVALUATION OF PREDICTIVE FACTORS OF WORSE PROGNOSIS IN LUPUS NEPHRITIS: FOCUS ON NEW PATHOGENETIC PATHWAYS

Background:cytokine dysregulation plays an important role in the pathogenesis of Lupus Nephritis (LN) representing an attractive field of research aiming to find new pathways for new targeted therapies. IL-17, IL-23 axis seems to have a great influence in the development of LN.Objectives:to evaluate the strongest prognostic factors in a cohort of patient with LN focusing on of the impact of IL-17, IL 23 axis as new pathogenetic pathway on renal outcome.Methods:91 patients with active LN at disease onset or disease flare were enrolled. Laboratory, immunological and disease activity data were collected at the baseline and at 6(T6),12(T12),24(T24) months and at the last follow-up(FU). 84 renal biopsies were evaluated according to ISN/RPS classification, assessing the activity and chronicity indexes and the active interstitial infiltrate using the BANFF score system. Baseline serum levels of IL-17 and IL-23 were assessed by ELISA in 37 patients.Results:among the 84 renal biopsies evaluated 77% belonged to class III and IV according to ISN/RPS; 41,8% of patients had an active interstitial infiltrate<5%, 35.2% between 5% and 25% and 15,4% above 25%. Regarding immunological data 35,2% of patients revealed a seropositivity for antiphospholipid antibodies(APL+). The median serum level of IL-17 and IL-23 were 0.12±0.15 pg/ml and 27.7±9.12 pg/ml respectively. Using the ROC curves analysis we found a cut off value of 25.89 pg/ml for IL-23 for remission at T6. Among the 10 patients with a IL-23 level above this cut-off none achieved remission at T6 and the univariate analysis shows that a serum level of IL-23 above the defined cut-off was associated with an active interstitial infiltrate>5% at renal biopsy and with the development of persistent proteinuria. The analysis of IL-17 could not let us to find a cut off value for renal damage progression since a too much high number of patients had a null value. Nevertheless patients with more elevated serum levels of IL-17 at the baseline showed more elevated level of interstitial infiltrate at renal biopsy and a worse renal outcome overall. Finally we conducted an univariate and multivariate analysis for each renal outcome considered. We found that an inflammatory interstitial infiltrate>5% at renal biopsy and APL+ were associated with worse renal outcome in terms of early and persistent remission, chronic damage, persistent proteinuria, and renal flare both in univariate and multivariate analysis. Higher serum level of IL-23 was associated with persistent proteinuria, renal flare and tended to be associated to chronic renal damage and persistent renal activity.Conclusion:interstitial inflammatory infiltrate and APL+ represent in our study the strongest predictors of worse renal outcome. An higher serum level of IL-23 was found to be a negative prognostic factor pointed out the possibility to consider the IL-17-IL 23 axis as a biomarkers of a more aggressive renal disease.Disclosure of Interests:None declared

Predicting Outcome in Patients with Anti-GBM Glomerulonephritis

Background and objectivesLarge studies on long-term kidney outcome in patients with anti-glomerular basement membrane (anti-GBM) GN are lacking. This study aimed to identify clinical and histopathologic parameters that predict kidney outcome in these patients.Design, setting, participants, & measurementsThis retrospective analysis included a total of 123 patients with anti-GBM GN between 1986 and 2015 from six centers worldwide. Their kidney biopsy samples were classified according to the histopathologic classification for ANCA-associated GN. Clinical data such as details of treatment were retrieved from clinical records. The primary outcome parameter was the occurrence of ESRD. Kidney survival was analyzed using the log-rank test and Cox regression analyses.ResultsThe 5-year kidney survival rate was 34%, with an improved rate observed among patients diagnosed after 2007 (P=0.01). In patients with anti-GBM GN, histopathologic class and kidney survival were associated (P<0.001). Only one of 15 patients with a focal class biopsy sample (≥50% normal glomeruli) developed ESRD. Patients with a sclerotic class biopsy sample (≥50% globally sclerotic glomeruli) and patients with 100% cellular crescents did not recover from dialysis dependency at presentation. In multivariable analysis, dialysis dependency at presentation (hazard ratio [HR], 3.17; 95% confidence interval [95% CI], 1.59 to 6.32), percentage of normal glomeruli (HR, 0.97; 95% CI, 0.95 to 0.99), and extent of interstitial infiltrate (HR, 2.02; 95% CI, 1.17 to 3.50) were predictors of ESRD during follow-up.ConclusionsDialysis dependency, low percentage of normal glomeruli, and large extent of interstitial infiltrate are associated with poor kidney outcome in anti-GBM GN. Kidney outcome has improved during recent years; the success rate doubled after 2007.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_11_21_CJASNPodcast_18_1_v.mp3

Interstitial Immunostaining and Renal Outcomes in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis

Background: Immunopathologic features predict renal function at baseline and follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). The interstitial infiltrate consists predominantly of T lymphocytes, but their pathophysiologic significance is unclear, especially in light of the success of B-cell-directed therapy. Methods: Renal biopsies from 33 patients treated with cyclophosphamide (CYC; n = 17) or rituximab (RTX; n = 16) in the RTX in ANCA-associated vasculitis (RAVE) trial were classified according to the new ANCA GN classification. T- and B-cell infiltration in the interstitium was assessed by immunostaining for CD3 and CD20. Correlations of clinical and histologic parameters with renal function at set time points were examined. Results: The mean (SD) baseline estimated glomerular filtration rate was 36 (20) mL/min/1.73 m2. ANCA GN class distribution was 46% focal, 33% mixed, 12% sclerotic and 9% crescentic. The interstitial infiltrate consisted of >50% CD3 positive cells in 69% of biopsies, but >50% CD20 positive cells only in 8% of biopsies. In a multiple linear regression model, only baseline glomerular filtration rate (GFR) correlated with GFR at 6, 12, and 18 months. Interstitial B- and T-cell infiltrates had no significant impact on long-term prognosis, independent of the treatment limb. A differential effect was noted only at 6 months, where a dense CD3 positive infiltrate predicted lower GFR in the RTX group and a CD20 positive infiltrate predicted higher GFR in the CYC group. Conclusions: In ANCA-associated GN, the interstitial infiltrate contains mainly T lymphocytes. However, it is neither reflecting baseline renal function nor predictive of response to treatment, regardless of the immunosuppression regimen employed.

Select Opportunistic Infections in Adult Patients With HIV

•Risk factors: Ubiquitous organism; CD4 count <200/mcL; chronic corticosteroid or other immunosuppressive drug therapy•Clinical disease• Exertional dyspnea, fever, nonproductive cough, and chest discomfort that gets worse over days to weeks• Hypoxemia; chest radiographs vary (most commonly show diffuse bilateral, symmetrical interstitial infiltrate but may be relatively normal early in course and can have atypical presentation)...

Gaucher Disease and LGL Proliferations: Provocative Commonality?

Abstract 1100 Large granular lymphocytes(LGL)which may be of T or NK phenotype, normally account for 10–15% of peripheral blood(PB)lymphocytes. T-LGL leukemia is a clonal expansion of antigen-primed competent cytotoxic-T-lymphocytes(CTL)which is unique in that these cells retain many phenotypic and functional properties of normal cytotoxic effector T cells. Sphingolipid-mediated signaling has been shown to have a role in long-term survival of CTLs. The diagnosis of T-LGL leukemia requires proof of clonality, yet clonal T-LGL proliferations may occur in normal individuals with autoimmune diseases, viral infections, B cell lymphoproliferations and post bone marrow transplantation rendering the differentiation of malignant (leukemic) from benign LGL expansions at times difficult. It has been suggested that T-LGL proliferations with polyclonal or oligoclonal TCR gene rearrangement may be a response to a stimulus before the emergence of a dominant clone. Gaucher disease (GD)is a lysosomal storage disease caused by mutations in the gene encoding acid β-glucocerebrosidase, leading to the accumulation of glucocerebroside in tissue macrophages (Gaucher cells) and resulting in hepatosplenomegaly, cytopenias and skeletal involvement. GD and T-LGL leukemia share strikingly similar clinical features, including cytopenias, splenomegaly, B cell dyscrasias, arthralgias, pulmonary hypertension (PHT), and increased association with neoplasms and autoimmune disorders. The etiology of PHT, B cell dyscrasias, and the increased frequency of neoplasms in GD remains unclear. Table 1 describes the characteristics of 4 GD patients suffering from severe cytopenias relative to the overall phenotype of their GD in whom LGL were found to comprise the majority of the PB lymphocytes. Patient #1: 31year-old female suffering from severe GD with massive splenomegaly and severe cytopenias but refuses Gaucher-specific therapy; Patient #2: 31year-old female has suffered from severe Gaucher disease since childhood, was splenectomized, has unexplained anemia and known LGL expansion for 7 years but clonality studies continue to be negative; Patient #3: 45 year-old female with severe GD, splenectomized, suffered from AVN, bone crisis autoimmune hemolytic anemia, PHT, and B cell dyscrasia; and Patient #4: 72 year-old male has asymptomatic GD with progressive pancytopenia who was diagnosed with myelodysplastic syndrome(MDS),T-LGL proliferation and monclonal gammopathy of unknown origin(MGUS). LGL cells comprised 70% of PB lymphocytes in addition there was severe trilineage dysplastic changes, TCR rearrangement was positive. Interestingly, 8 months after the start of enzyme replacement therapy(ERT),counts improved and the number of PB LGL was reduced to <10% of lymphocytes. In a cohort of 55 consecutive GD patients, 38% had LGL expansions in the PB smears. Since both conditions may be asymptomatic for many years, their co-existence can easily be missed.Table 1:Patient characteristics1234Age at diagnosis31314572GenderFemaleFemaleFemaleMaleSplenectomyNoYesYesNoBony diseaseAVNBone crisis, AVN, osteomyelitisNo?Pulmonary HypertensionNoNoYesNoAutoimmune phenomenonNoNoAIHANoB cell dyscrasiasYesNoPolyclonal hypergammagloblulinemiaMGUSOther neoplasmsNoNoNoMDSLeucocyte count (×10/ul)2.213.36.62.9LGL percent of lymphocytes52%62%30%70%LGL absolute count (×10/ul)0.55.111.10.532LGL phenotypeCD3+,CD8+, CD56+, CD16−, CD57−, TCR αβ+CD3+, CD8+, CD16−, CD56−, TCR αβ+?CD3+, CD8+, CD16−, CD56−, TCR αβ+2 populationsa) CD3+, CD8+, CD56+, TCR αβ+9.3g/dlb) CD3−,CD56+,CD4−, CD8−Hemoglobin (g/dl)4.911.311.4Platelet count (x10/ul)111779630TCR rearrangementNegativeNegativePositivePositiveBone marrow pattern of involvementMild interstitial infiltrate of small lymphocytes CD8+TMild interstitial infiltrate of small lymphocytes CD8+TERTNoYesYesYesERT: improvement of cytopeniasUntreatedNoNoYes The co-existence of two hematological pathologies in more than one patient and the possibility that therapy for one may impact the other, is provocative. We suggest that LGL expansions in GD may be reactive to glucocereborside accumulation in Gaucher cells, and may play a pathogenic role in the development of some of the features of GD as well as induce/exacerbate some associated disorders. Disclosures: Zimran: Actelion: Honoraria.