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Background Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways. Methods We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls. Results The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS. Conclusions The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. Graphical abstract

Objectives Cocaine and cocaine mixed with levamisole are increasingly used in the UK and result in significant direct nasal damage in addition to promoting vasculitis. Our aims were as follows: (1) to identify the main symptoms and presentation of cocaine-induced vasculitis; (2) to provide evidence regarding the best practice for the investigation and diagnosis of cocaine-induced vasculitis; and (3) to analyse the clinical outcomes of patients in order to understand the optimal management for the condition. Methods We performed a retrospective case series analysis of patients presenting with cocaine-induced midline destructive lesions or vasculitis compatible with granulomatosis with polyangiitis (GPA) from two large tertiary vasculitis clinics between 2016 and 2021. Results Forty-two patients (29 Birmingham, 13 London) with cocaine-induced midline lesions or systemic disease were identified. The median age was 41 years (range 23–66 years). Current cocaine use was common, and 20 of 23 samples provided were positive when routine urine toxicology was performed; 9 patients who denied ever using cocaine were identified as using cocaine based on urine toxicology analysis, and 11 who stated they were ex-users still tested positive. There was a high incidence of septal perforation (75%) and oronasal fistula (15%). Systemic manifestations were less common (27%), and only one patient had acute kidney injury. Fifty-six per cent of our patients were PR3-ANCA positive, with none testing positive for MPO-ANCA. Symptom remission required cocaine discontinuation even when immunosuppression was administered. Conclusion Patients with destructive nasal lesions, especially young patients, should have urine toxicology performed for cocaine before diagnosing GPA and considering immunosuppressive therapy. The ANCA pattern is not specific for cocaine-induced midline destructive lesions. Treatment should be focused on cocaine cessation and conservative management in the first instance in the absence of organ-threatening disease.

Objectives To investigate key factors that may contribute to the variability of rituximab-mediated peripheral and renal B cell depletion (BCD) in SLE. Methods We analysed: (i) CD19+ B cell counts in patients with SLE before and 1, 2, 3 and 6 months after treatment with rituximab, comparing them with RA patients; (ii) the presence of B cells in renal biopsies after rituximab therapy; (iii) whether the duration of BCD correlated with patient demographics and B cell expression of CD20 and FcγRIIb; and (iv) the effect of B cell activation factor (BAFF) on the efficiency of rituximab and obinutuzumab at inducing BCD in whole blood assays, in vitro. Results In SLE (n = 71), the duration of BCD was shorter compared with RA (n = 27). B cells were detectable in renal biopsy samples (n = 6) after treatment with rituximab in all patients with poor response while peripheral blood B cells remained low or undetectable in the same patients. There were no significant relationships between peripheral BCD and patient age, disease duration, serum C3 levels or the level of expression of B cell surface proteins CD20 and FcγRIIb. Obinutuzumab was more efficient than rituximab at inducing BCD in whole blood assays, regardless of excess BAFF. Conclusions BCD in SLE is less efficient than in RA. Renal B cell presence following rituximab treatment was associated with poor outcomes. No significant relationships between any measured B cell related, clinical or laboratory parameters and the efficiency of BCD by rituximab was found. Obinutuzumab was superior to rituximab at inducing BCD.

Adult nephrologists often look after patients who have been diagnosed with kidney disease in childhood. This does present unique challenges to the adult nephrologist, who may be unfamiliar with the underlying cause of kidney disease as well as the complications of chronic kidney disease (CKD) that may have accumulated during childhood. This review discusses common causes of childhood CKD, in particular congenital anomalies of the kidney and urinary tract (CAKUT), autosomal dominant tubulointerstitial kidney disease (ADTKD), polycystic kidney disease, hereditary stone disease, nephrotic syndrome and atypical haemolytic uraemic syndrome. The long-term consequences of childhood CKD, such as the cardiovascular consequences, cognition and education as well as bone health, nutrition and growth are also discussed.

Hematopoietic stem cell transplantation (HSCT) is increasingly used as first-line management in adults with aplastic anaemia even in the absence of a sibling donor. HSCT can be associated with a broad range of acute and chronic complications, including infections, graft versus host disease, and other immune complications. Renal complications are common following HSCT, including acute kidney injury (10%–70%), chronic kidney disease (7%–48%), and thrombotic microangiopathy and nephrotic syndrome (0.4%–4%).1 In addition, renal manifestations of both acute and chronic graft versus host disease (GvHD) have been described, including nephrotic syndrome, which usually occurs as a late complication most commonly due to membranous nephropathy.2, 3, 4 Post-transplant lymphoproliferative disorder (PTLD) post HSCT occurs in up to 3.2% of allogeneic transplant recipients and is almost exclusively Epstein-Barr virus (EBV) related.5 Management includes reduction of immunosuppression, rituximab, and/or chemotherapy in higher risk disease. Minimal change disease (MCD) complicates Hodgkin disease in approximately 0.4%, and less commonly non-Hodgkin lymphoma.6,7 We present, to our knowledge, the first reported case of MCD associated with EBV-driven PTLD following HSCT and demonstrate an excellent response to rituximab with remission of nephrotic syndrome, normalization of Epstein-Barr viremia, and full clinical remission of PTLD.

Subglottic stenosis (SGS) is a severe, life-threatening disease found in immune-mediated diseases such as granulomatosis with polyangiitis (GPA) and in rare cases of immunoglobulin G4 (IgG4)-relate...

Objectives To compare membranous lupus nephritis (MLN) and proliferative lupus nephritis (PLN) with respect to survival, demographic, clinical and laboratory characteristics; and to investigate predictors of renal and patient survival. Methods Single-centre retrospective observational study. Patients with biopsy-proven PLN, MLN and mixed lupus nephritis were included. Groups were compared using appropriate statistical tests and survival was analysed through the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of renal and patient survival. Results A total of 187 patients with biopsy-proven lupus nephritis (135 with PLN, 38 with MLN and 14 with mixed LN) were followed for up to 42 years (median 12 years). There was a higher proportion of MLN amongst Afro-Caribbeans than amongst Caucasians (31% vs 15%, P = 0.010). Patients with MLN had significantly lower anti-dsDNA antibodies (P = 0.001) and higher C3 levels (P = 0.018) at diagnosis. Cumulative renal survival rates at 5, 10, 15 and 20 years were 91, 81, 75 and 66% for PLN and 100, 97, 92 and 84% for MLN, respectively (P = 0.028). Cumulative patient survival at 5, 10, 15 and 20 years was 94, 86, 80 and 76%, with no difference between PLN and MLN. Urinary protein-creatinine ratio above 42 mg/mmol and eGFR below 76 ml/min/1.73 m2, one year after the diagnosis of LN, were the strongest predictors of progression to end-stage renal disease. eGFR below 77 ml/min/1.73 m2, at one year, development of end-stage renal disease and Afro-Caribbean ethnicity were associated with higher mortality. Conclusion Patients with MLN and PLN differ significantly regarding serological profiles and renal survival, suggesting different pathogenesis. Renal function at year one predicts renal and patient survival.

Membranous nephropathy (MN) is one of the most common causes of adult-onset nephrotic syndrome. We describe the cases of 2 young women in their 20s presenting with nephrotic syndrome due to antiphospholipase A2 receptor (anti-PLA2R)–negative MN, that was found to be associated with benign tumors. Both women had no extrarenal symptoms of a connective tissue disease, infection, or malignancy. They both had been previously healthy and were not receiving treatment with any drugs. Both had MN on kidney biopsy. Biopsies were negative for PLA2R antigen, and their serum did not demonstrate the presence of anti-PLA2R antibodies. Both were investigated for a secondary cause on the basis of negative anti-PLA2R serology and biopsy features supportive of secondary MN and were found to have benign tumors on radioimaging: a uterine leiomyoma and mesenteric fibromatosis, respectively. In both instances, the nephrotic syndrome remitted following resection of the tumors. To our knowledge, uterine leiomyoma and mesenteric fibromatosis have not previously been described in association with MN. These cases highlight the importance of pursuing a secondary cause of MN in patients without anti-PLA2R antibodies in serum or PLA2R antigen on kidney biopsy.

Vogt, Bruno/0000-0002-1548-6387; Dufek, Stephanie/0000-0002-6323-6673; Liu, Lili/0000-0002-2622-9669; Paczek, Leszek/0000-0003-0160-3009; Cui, Zhao/0000-0002-5837-1926; amoroso, antonio/0000-0002-9437-9407; Rosen, Raphael/0000-0003-1025-1965; Loos, Ruth/0000-0002-8532-5087; coenen, marieke/0000-0001-8796-2031; zanoni, francesca/0000-0001-9567-6713; CUCCA, Francesco/0000-0002-7414-1995; Ars, Elisabet/0000-0002-4118-4358; Hamilton, Patrick/0000-0001-6703-3745 WOS:000563559600001 PubMed ID: 32231244 Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk. National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) [RC2-DK116690, R01-DK105124, R01-DK097053, R01-DK108805]; National Institute on Minority Health and Health Disparities (NIMHD)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Minority Health & Health Disparities (NIMHD) [R01-MD009223]; Charles Woodson Clinical Research Fund; Nephrotic Syndrome Study Network Consortium (NEPTUNE) [U54-DK-083912]; Columbia University, Columbia Glomerular Center; Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); University of MichiganUniversity of Michigan System; NephCure Kidney International; Halpin Foundation; National Key Research and Development Program of China [2016YFC0904100]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81621092]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81870460, 81570598]; Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee [17441902200]; Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant [20152207]; Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project [DLY201510]; International Cooperation and Exchange Projects of Shanghai Science and Technology Committee [14430721000]; Outstanding Young Scholar Award [81622009]; Shanghai Health and Family Planning Committee Hundred Talents Program [2018BR37]; Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea - Ministry of Health and Welfare, Republic of Korea; MRCMedical Research Council UK (MRC) [MR/J010847/1]; Manchester Academic Health Science Centre [MAHSC 186/200]; Greater Manchester Local Clinical Research Network; Kidneys for Life Charity; David and Elaine Potter Charitable Foundation; St Peter's Trust for Kidney, Bladder and Prostate Research; Kids Kidney Research UKKidney Research UK (KRUK); Kidney Research UKKidney Research UK (KRUK); Italian Ministry of Health grantMinistry of Health, Italy [GR-2011-02350438]; Department of Excellence Grant 2018-2022 - Italian Ministry of Education for the Department of Medical Sciences of the University of Turin; Columbia University; Poznan University of Medical Sciences, Poland; German Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01ER0804]; KfH Foundation for Preventive Medicine; Bayer Pharma AG; German Research FoundationGerman Research Foundation (DFG) [CRC 1140, KO 3598/3-1, CRC 992]; European Research CouncilEuropean Research Council (ERC) [ERC-2012ADG_2012-0314, 322947]; 7th Framework Programme of the European Community contract [2012-305608]; National Research Agency grant MNaims [ANR-17-CE17-0012-01]; Dutch Kidney Foundation [OW08, KJPB11.021]; National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); NIMHD We are grateful to all study participants across multiple nephrology centres worldwide for their contributions to this work. This work was supported by the following institutions, grants and funding agencies in the US: Columbia University, Columbia Glomerular Center, National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) grants RC2-DK116690 (K.K., M.K.), R01-DK105124 (K.K.), R01-DK097053 (L.H.B., M.K.), R01-DK108805 (M.G.S.), and National Institute on Minority Health and Health Disparities (NIMHD) grant R01-MD009223 (K.K., A.G.G., A.B.). M.G.S. is additionally supported by the Charles Woodson Clinical Research Fund. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International and the Halpin Foundation. The recruitment and analysis of the Chinese cohorts were supported by the National Key Research and Development Program of China (2016YFC0904100), Natural Science Foundation of China to the Innovation Research Group (81621092), National Natural Science Foundation of China (No. 81870460, 81570598), Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (No.17441902200), Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant (No.20152207), Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project (No.DLY201510), International Cooperation and Exchange Projects of Shanghai Science and Technology Committee (No.14430721000), the Outstanding Young Scholar Award for Zhao Cui (No.81622009), and Shanghai Health and Family Planning Committee Hundred Talents Program for Jingyuan Xie (No.2018BR37). The recruitment of the Korean cohort was supported by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, financed by the Ministry of Health and Welfare, Republic of Korea. P.B. and P.H. acknowledge financial support from MRC project "Autoimmunity in Membranous Nephropathy", grant MR/J010847/1 which funded the sample collection from MN patients across the UK. P.B., P.H. and S.H. acknowledge support from Manchester Academic Health Science Centre (MAHSC 186/200), the Greater Manchester Local Clinical Research Network and Kidneys for Life Charity for supporting research in MN in Manchester. We are grateful to the MENTOR study (clinical trials no. NCT01180036), for contributing blood samples of trial participants. The UK cohort was supported in part by grants from the David and Elaine Potter Charitable Foundation (to S.H.P. and R.K.), St Peter's Trust for Kidney, Bladder and Prostate Research (to D.B., H.C.S., S.H.P. and R.K.), Kids Kidney Research UK and Kidney Research UK (to D.B. and R.K.). The Italian cohorts were supported by the Italian Ministry of Health grant GR-2011-02350438 (G.Z., S.G.) and the Department of Excellence Grant 2018-2022 funded by the Italian Ministry of Education for the Department of Medical Sciences of the University of Turin (A.A.).; The recruitment of Polish cases was sponsored by the Polish Kidney Genetics Network (POLYGENES), a collaborative effort between Columbia University and Poznan University of Medical Sciences, Poland. The full list of POLYGENES collaborators can be found in the Supplementary Materials. The GCKD (German Chronic Kidney Disease) study was funded by grants from the German Ministry of Education and Research (BMBF, No. 01ER0804) and the KfH Foundation for Preventive Medicine, with genotyping supported by Bayer Pharma AG. The list of GCKD investigators can be found in the Supplementary Materials. The work of M.W. and A.K. was funded by the CRC 1140 Initiative and by KO 3598/3-1 and CRC 992 (A.K.) of the German Research Foundation. The work of E.H. and R.A.K.S. was funded by the CRC 1192 from the German Research Foundation (Projects B1 and C1). P.R. is a recipient of European Research Council ERC-2012ADG_2012-0314 grant 322947, 7th Framework Programme of the European Community contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases), and the National Research Agency grant MNaims (ANR-17-CE17-0012-01). The Dutch studies were supported by grants from the Dutch Kidney Foundation to JMH and JFW (Nierstichting Nederland grant OW08 and grant KJPB11.021). We would like to thank the Population Architecture Using Genomics and Epidemiology (PAGE) consortium, funded by the National Human Genome Research Institute (NHGRI) with co-funding from the NIMHD, for providing population controls for this study. For full acknowledgment of the PAGE consortium, please see Supplementary Materials. The funding sources were not involved in the study design, collection, analysis, and interpretation of data, writing of the report, or in the decision to submit the paper for publication.

Adult nephrologists often look after patients who have been diagnosed with kidney disease in childhood. This does present unique challenges to the adult nephrologist, who may be unfamiliar with the underlying cause of kidney disease as well as the complications of chronic kidney disease (CKD) that may have accumulated during childhood. This review discusses common causes of childhood CKD, in particular congenital anomalies of the kidney and urinary tract (CAKUT), autosomal dominant tubulointerstitial kidney disease (ADTKD), polycystic kidney disease, hereditary stone disease, nephrotic syndrome and atypical haemolytic uraemic syndrome. The long-term consequences of childhood CKD, such as the cardiovascular consequences, cognition and education as well as bone health, nutrition and growth are also discussed.

Background Despite the improvement in survival of patients with lupus nephritis (LN) over the last decades, LN is associated with progression to end-stage renal disease (ESRD) in a significant proportion of patients. We aimed to investigate the factors influencing renal survival in patients with LN. Methods Single-centre retrospective observational study. Patients with biopsy-proven proliferative, membranous or mixed LN were included. Individual clinical files were reviewed to obtain demographic, clinical, laboratory and pathological data. Cox regression analysis was performed to investigate predictors of progression to ESRD and Kaplan-Meier curves were obtained. Results We studied 187 LN patients (135 proliferative, 38 membranous and 14 mixed LN), followed for up to 42 years (mean 13±9 years). Cumulative renal survival rates at 5, 10, 15 and 20 years were 93%, 85%, 78% and 70%, respectively. In univariable analysis, urinary protein/creatinine ratio (uPCR) above 42 mg/mmol or estimated glomerular filtration rate (eGFR) below 76 mL/min/1.73m2, one year after the diagnosis of LN, were the strongest predictors of progression to ESRD, with hazard ratios (HR) of 8.081 [95%CI:1.856-35.179] and 4.985 [95%CI:1.964-12.651], respectively. HR for uPCR and eGFR at the time of diagnosis were considerably smaller (2.508 [95%CI:1.062-5.922] and 2.833 [95%CI:1.156-6.945] respectively). Other factors associated with increased risk of ESRD were Afro-Caribbean ethnicity (HR = 3.861 [95%CI:1.817-8.206]), proliferative LN (HR = 3.423 [95%CI:1.049-11.173]), not having taken antimalarials (HR = 2.180 [95%CI:1.089-4.363]) and poorly controlled diastolic blood pressure (HR = 1.016 [95%CI:1.001-1.030]). The effect of uPCR and eGFR at one year remained significant after adjusting for ethnicity, histological class, uPCR and eGFR at the time of diagnosis, use of antimalarials and diastolic blood pressure (Table 1). Conclusion uPCR above 42 mg/mmol and eGFR below 76 mL/min/1.73m2, one year after the diagnosis of LN, were the strongest predictors of progression to ESRD. Disclosures F. Farinha None. R.J. Pepper None. D.G. Oliveira None. T. McDonnell None. D.A. Isenberg None. A. Rahman None.

Background The pathogenesis of membranous lupus nephritis (MLN) is poorly understood. Our objectives were to investigate, in patients with MLN, the presence of antibodies to nucleosomes and histones, which have been linked to the pathogenesis of proliferative lupus nephritis (PLN); and antibodies against phospholipase A2 receptor (PLA2R), previously identified in patients with idiopathic membranous nephropathy (IMN). Methods Single-centre study, using banked serum samples from patients with biopsy-proven lupus nephritis (LN). For each patient, we aimed to identify two paired serum samples – one at the date of renal biopsy (active nephritis) and one when LN was quiescent. Antibodies were detected with indirect ELISA. Positivity cut-offs were 20 U/mL for anti-nucleosomes and PLA2R, and 40 U/mL for anti-histones antibodies. Levels of antibodies in paired active and quiescent LN samples were compared with a Wilcoxon signed-rank test, and a Kruskal-Wallis test was used to compare the levels between independent LN groups. Results Forty-nine active serum samples (13 pure MLN, 22 PLN and 14 mixed) and 41 paired quiescent samples were tested for anti-nucleosome and anti-PLA2R antibodies; and 44 active (13 pure MLN, 17 PLN and 14 mixed) and 38 paired quiescent samples were tested for anti-histones antibodies. Anti-nucleosome antibodies were present in 98% of active-LN patients. Total median level was 190.70 (IQR 681), with no significant difference between the three groups (p=0.730). During quiescent LN, levels dropped significantly in PLN but not in pure MLN patients (figure 1). Anti-histone antibodies were positive in 32% of active-LN patients, with no significant difference between groups (p=0.828); their levels showed a similar trend to that of anti-nucleosomes (figure 1). Antibodies to PLA2R were negative in all patients. Conclusions Anti-nucleosome and anti-histone antibody levels did not reflect disease activity in MLN. Anti-PLA2R antibodies were absent in these patients. None of these antibodies is likely to be playing a preponderant role in MLN pathogenesis.

Background Despite the improvement in survival of patients with lupus nephritis (LN) over the last decades, LN is associated with progression to end-stage renal disease (ESRD) in a significant proportion of patients. We aimed to investigate the factors influencing renal survival in patients with LN. Methods Single-centre retrospective observational study. Patients with biopsy-proven proliferative, membranous or mixed LN were included. Individual clinical files were reviewed to obtain demographic, clinical, laboratory and pathological data. Cox regression analysis was performed to investigate predictors of progression to ESRD and Kaplan-Meier curves were obtained. Results We studied 187 LN patients (135 proliferative, 38 membranous and 14 mixed LN), followed for up to 42 years (mean 13±9 years). Cumulative renal survival rates at 5, 10, 15 and 20 years were 93%, 85%, 78% and 70%, respectively. In univariable analysis, urinary protein/creatinine ratio (uPCR) above 42 mg/mmol or estimated glomerular filtration rate (eGFR) below 76 mL/min/1.73 m2, one year after the diagnosis of LN, were the strongest predictors of progression to ESRD (figure 1), with hazard ratios (HR) of 8.081 [95%CI:1.856–35.179] and 4.985 [95%CI:1.964–12.651], respectively. HR for uPCR and eGFR at the time of diagnosis were considerably smaller (2.508 [95%CI:1.062–5.922] and 2.833 [95%CI:1.156–6.945] respectively). Other factors associated with increased risk of ESRD were Afro-Caribbean ethnicity (HR=3.861 [95%CI:1.817–8.206]), proliferative LN (HR=3.423 [95%CI:1.049–11.173]), not having taken antimalarials (HR=2.180 [95%CI:1.089–4.363]) and poorly controlled diastolic blood pressure (HR=1.016 [95%CI:1.001–1.030]). The effect of uPCR and eGFR at one year remained significant after adjusting for ethnicity, histological class, uPCR and eGFR at the time of diagnosis, use of antimalarials and diastolic blood pressure (table 1). Conclusions uPCR above 42 mg/mmol and eGFR below 76 mL/min/1.73 m2, one year after the diagnosis of LN, were the strongest predictors of progression to ESRD.

Background Lupus Nephritis (LN) is one of the most severe manifestations of Systemic Lupus Erythematosus (SLE). We aimed to compare proliferative (PLN), membranous (MLN) and mixed LN regarding clinical and laboratory presentation, and serologic profiles. Previous work suggested that these groups differ in autoantibody profile and complement levels, but those reports mainly originate from single-centres. Methods Multicentre observational study, with retrospective analysis of a prospective cohort, using data from the Portuguese registry of rheumatic diseases–Reuma.pt. Patients with biopsy-proven PLN, MLN and mixed LN were included. The first renal biopsy showing one of these classes was considered, for each patient. Groups were compared using Pearson’s Chi-Square for categorical variables and One-Way ANOVA or Kruskal-Wallis for numerical variables. Results 232 patients were included (87% females; 88.5% White Europeans). Median follow-up was 7 years (IQR 10.75; maximum 35 years). As seen in table1, the level of proteinuria did not differ between groups; however, MLN patients presented with significantly lower creatinine. Levels of complement were reduced in PLN and mixed LN but were normal in MLN patients, and this difference was statistically significant. Groups also differed regarding the proportion of positivity for anti-dsDNA (higher in PLN) and anti-RNP antibodies (higher in MLN). There was a lower SLEDAI in MLN, probably linked with the lower prevalence of anti-dsDNA antibodies and complement consumption in this group. Conclusions Our results support previous findings from single-centre studies suggesting that MLN has a different serological profile than PLN, possibly reflecting different pathogenesis.

Juvenile systemic lupus erythematosus (JSLE) is characterised by onset before 18 years of age and more severe disease phenotype, increased morbidity and mortality compared to adult-onset SLE. Management strategies in JSLE rely heavily on evidence derived from adult-onset SLE studies; therefore, identifying biomarkers associated with the disease pathogenesis and reflecting particularities of JSLE clinical phenotype holds promise for better patient management and improved outcomes. This narrative review summarises the evidence related to various traditional and novel biomarkers that have shown a promising role in identifying and predicting specific organ involvement in JSLE and appraises the evidence regarding their clinical utility, focusing in particular on renal biomarkers, while also emphasising the research into cardiovascular, haematological, neurological, skin and joint disease-related JSLE biomarkers, as well as genetic biomarkers with potential clinical applications.

Background:Lupus nephritis (LN) is one of the most severe manifestations of Systemic Lupus Erythematosus.Objectives:1) To compare proliferative (PLN), membranous (MLN) and mixed LN regarding clinical and laboratory presentation. 2) To investigate predictors of progression to chronic kidney disease (CKD).Methods:Multicentre observational study, with retrospective analysis of a prospective cohort, using data from the Portuguese registry of rheumatic diseases – Reuma.pt. Patients with biopsy-proven PLN, MLN and mixed LN were included. Groups were compared using Pearson’s Chi-Square for categorical variables and One-Way ANOVA or Kruskal-Wallis for numerical variables. COX regression analysis was used to investigate predictors of CKD (defined as estimated glomerular filtration rate [eGFR] lower than 60 mL/min/1.73m2for at least 3 months) and Kaplan-Meier curves were drawn.Results:236 patients were included. Median follow-up was 8 years (IQR 11; maximum 35 years). As seen in table 1, the level of proteinuria did not differ between groups; however, MLN patients presented with significantly lower serum creatinine. Levels of complement C3 and C4 were reduced in PLN but normal in MLN patients, and there were fewer patients with positive anti-dsDNA antibodies in the MLN group (pTable 1.Comparative description of the Reuma.pt cohort of patients with proliferative, membranous and mixed LNPLNMLNMixedPTotal, N186428Females, N (%)157 (85)39 (95)4 (50)0.004EthnicityWhite European, N (%)163 (90)31 (78)7 (88)0.115Other, N (%)19 (10)9 (23)1 (13)Age LN diagnosis(y), median (IQR)30 (20)34 (16)42 (25)0.409SLEDAI at LN diagnosis, median (IQR)16 (9)10 (10)21 (17)0.006*uPCR at LN diagnosis, median (IQR)1675 (2598)1698 (2153)2160 (3320)0.629Creatinine at LN diagnosis, median (IQR)0.80 (0.32)0.70 (0.20)1.00 (0.95)0.006*eGFR at LN diagnosis, mean ± SD98 ± 33112 ± 1782 ± 450.019*Albumin at LN diagnosis, mean ± SD34 ± 734 ± 730 ± 60.390C3 at LN diagnosis, mean ± SD0.65 ± 0.260.90 ± 0.350.53 ± 0.30Positive anti-dsDNA LN diagnosis, N (%)115 (91)11 (48)6 (86)Use of antimalarials, N (%)166 (94)36 (92)8 (100)0.688Use of immunosuppressants, N (%)163 (94)33 (87)8 (100)0.245Use of corticosteroids, N (%)145 (84)33 (85)7 (100)0.511CKD after LN diagnosis, N (%)27 (15)1 (3)3 (38)0.018*ESRD, N (%)7 (4)1 (3)2 (25)0.016Deaths, N (%)14 (8)2 (5)00.610uPCR: urinary protein-creatinine ratio, mg/g; y: years; Creatinine presented in mg/dL, eGFR in mL/min/1.73m2,albumin in g/L and C3 in g/LNote: Baseline data (LN diagnosis) in grey; other data refer to the course of disease*Significant difference between the proliferative and membranous groupsFigure 1.Kaplan-Meir curves showing cumulative survival free of CKD in patients with PLN, MLN and mixed LNConclusion:Our results support previous findings from single-centre studies suggesting that MLN has a different serological profile than PLN, possibly reflecting different pathogenesis. Renal function at one year predicts long-term outcome in LN.Disclosure of Interests:Filipa Farinha: None declared, Sofia C Barreira: None declared, Maura Couto: None declared, Margarida Cunha: None declared, Diogo Fonseca: None declared, Raquel Freitas: None declared, Luís Inês: None declared, Mariana Luis: None declared, Carla Macieira: None declared, Ana Rita Prata: None declared, Joana Rodrigues: None declared, Bernardo Santos: None declared, Rita Pinheiro Torres: None declared, Ruth J. Pepper: None declared, Anisur Rahman: None declared, Maria Jose Santos Speakers bureau: Novartis and Pfizer

Objective S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV.Methods Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained.Results Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n=37), PR3-ANCA without relapse (n=56), myeloperoxidase (MPO)-ANCA with relapse (n=6), and MPO-ANCA without relapse (n=45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group (P=0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 (P=0.0043) and baseline and month 6 (P=0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse (P=0.028).Conclusion An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment.

Background Familial Mediterranean Fever (FMF) is caused by mutations in MEFV. The protein product pyrin is expressed in monocytes, neutrophils and eosinophils. Acute inflammatory attacks are accompanied by a dramatic hepatic acute phase response. S100A8/A9 is damage associated molecular pattern and a TLR4 ligand expressed in neutrophils, monocytes and early infiltrating macrophages. We aimed to investigate S100A8/A9 in 39 patients with FMF, 45 healthy carriers and wild type controls. Objectives To measure S100A8/9 in patients with FMF, carriers and healthy controls. Methods All patients were genotyped. Patients and healthy controls (HC) serum S100A8/A9 levels, cell surface expression on monocytes and neutrophils as well as intracellular peripheral blood mononuclear cells (PBMC) expression were measured by flow cytometry (FACS). CD14 cells were isolated and following overnight incubation with or without LPS, S100A8/A9 was measured in the supernatants by ELISA. Patient and HC monocyte apoptosis was compared. Results Serum levels were measures in 84 samples from 31 patients with homozygous or compound mutations (median 9061ng/ml [range 500-38470], 79 samples from 39 symptomatic patients who were MEFV heterozygotes (median 9394ng/ml [range 1744-38119], 80 samples from 45 individuals with MEFV variants but without clinical features of FMF (median 10939ng/ml [range 2447->40000]. There was no difference in calprotectin concentrations between the different mutations. All the groups described had significantly higher levels than healthy controls (n=16 median 2836ng/ml [range 1058-6175])(p Conclusion Patients with pyrin mutations both with and without clinical disease have greatly elevated serum S100A8/A9 levels without detectable cell surface expression in well-controlled disease with a trend to an increased monocyte intracellular expression. Upon monocyte stimulation with LPS, increased S100A8/A9 is secreted. The exact mechanism by which these patients, especially those with mutations but no clinical disease, demonstrate sustained elevated serum S100A8/A9 remains to be elucidated but does not appear to result in a significant clinical sequelae. Disclosure of Interests Ruth J. Pepper: None declared, Mathew Hutchinson: None declared, S.R. Henderson: None declared, S.K. Todd: None declared, Alan D. Salama: None declared, Philip N Hawkins: None declared, Helen J. Lachmann Grant/research support from: SOBI, Novartis, Consultant for: Novartis, Takeda, Speakers bureau: SOBI. Novartis

Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.

OBJECTIVES: Glucocorticoids (GCs) are a mainstay of treatment for patients with ANCA-associated vasculitis (AAV) but are associated with significant adverse effects. Effective remission induction in severe AAV using extremely limited GC exposure has not been attempted. We tested an early rapid GC withdrawal induction regimen for patients with severe AAV. METHODS: Patients with active MPO- or PR3-ANCA vasculitis or ANCA-negative pauci-immune glomerulonephritis were included. Induction treatment consisted of two doses of rituximab, 3 months of low-dose CYC and a short course of oral GC (for between 1 and 2 weeks). Clinical, biochemical and immunological outcomes as well as adverse events were recorded. RESULTS: A total of 49 patients were included, with at least 12 months of follow-up in 46. All patients achieved remission, with decreases observed in creatinine, proteinuria, CRP, ANCA level and BVAS. Three patients requiring dialysis at presentation became dialysis independent. Two patients required the introduction of maintenance GC for treatment of vasculitis. Overall outcomes were comparable to those of two matched cohorts (n = 172) from previous European Vasculitis Society (EUVAS) trials, but with lower total exposure to CYC and GCs (P < 0.001) and reduced rates of severe infections (P = 0.02) compared with the RITUXVAS (rituximab versus cyclophosphamide in AAV) trial. We found no new cases of diabetes in the first year compared with historic rates of 8.2% from the EUVAS trials (P = 0.04). CONCLUSION: Early GC withdrawal in severe AAV is as effective for remission induction as the standard of care and is associated with reduced GC-related adverse events.

Background Although the prognosis has improved in the last decades, Lupus patients still have a 3-fold increase in mortality, compared with the general population.1Lupus nephritis (LN) is one of the most severe manifestations of this complex systemic disease, occurring in up to 60% of patients. Objectives 1) To obtain the overall and renal survival curves for a LN cohort; 2) To investigate factors affecting survival; 3) To identify the causes of death in this cohort. Methods Single-centre retrospective observational study, including all patients with biopsy-proven LN, followed at UCLH Rheumatology department from 1975 to 2017. Individual clinical files were reviewed to obtain demographic, clinical, laboratory and pathological data. We also recorded data on treatment with corticosteroids, immunosuppressants and antimalarials. We analysed overall survival and renal survival through the Kaplan-Meier method. COX regression analyses were conducted to investigate possible predictors of shorter survival. Significance level was defined at 0.05. Results 209 patients were included (table 1). Cumulative survival at 5, 10, 15 and 20 years after the diagnosis of LN was 92%, 86%, 81% and 76%, respectively. Main causes of death were infection (29%), malignancy (21%) and cardiovascular (21%). Regarding progression to end-stage renal disease (ESRD), cumulative renal survival at 5, 10, 15 and 20 years was 94%, 86%, 79% and 72%, respectively. Table 2 shows the predictors of shorter survival identified for this cohort. Image 1 represents the Kaplan-Meier curves according to the factors affecting renal survival. Conclusions Cumulative survival rates and causes of death for this cohort are comparable with other cohorts of LN. ESRD confers the higher risk for death; African or Caribbean ethnicities and not taking antimalarials predict shorter overall and renal survival among these patients. Reference [1] Yurkovich M, Vostretsova K, Chen W, Avina-Zubieta JA. Overall and cause-specific mortality in patients with systemic lupus erythematosus: a meta-analysis of observational studies. Arthritis Care Res (Hoboken)2014;66(4):608–16. Disclosure of Interest None declared

Background Lupus nephritis (LN) is currently classified according to the 2003 International Society of Nephrology/Renal pathology Society (ISN/RPS) classification system, which is based on histology. Most patients have proliferative lupus nephritis (PLN), which has been the most studied type of LN. Membranous lupus nephritis (MLN) is less frequent, accounting for 10%–20% of the cases. In some patients there is a combination of the two types. Objectives To compare MLN and PLN with respect to demographic, clinical and laboratory characteristics. Methods Single-centre retrospective observational study. All patients with biopsy-proven proliferative (class III and IV), membranous (class V) and mixed (class III or IV+V) LN (according to the 2003 ISN/RPS classification), followed at UCLH Rheumatology department from 1975 to 2017, were included. Individual clinical files were reviewed to obtain demographic, clinical, laboratory and pathological data. We also recorded data on treatment with corticosteroids, immunosuppressants and antimalarials. We compared groups using Pearson’s chi-squared test for qualitative variables and Mann-Whitney test for quantitative variables. Renal survival was analysed through the Kaplan-Meier method. Significance level was defined at 0.05. Results 187 patients were included (table 1). Age at diagnosis was not significantly different between groups (p=0.474). The groups differ regarding ethnicity – higher proportion of Caucasians with PLN versus higher proportion of Afro-Caribbeans with MLN. Patients with MLN present with higher C3 levels and significantly lower anti-dsDNA levels than the ones with proliferative changes. Thirty-four patients with PLN, 3 with MLN and 2 with mixed nephritis, progressed to end-stage renal disease. Cumulative renal survival rates at 5, 10, 15 and 20 years were 91, 81, 75% and 66% for PLN and 100, 97, 92% and 84% for MLN, respectively (Image 1). Conclusions In spite of presenting in the context of the same autoimmune systemic disease, PLN and MLN appear to be very different entities, showing significant differences regarding serologic profiles and renal survival. Disclosure of Interest None declared

Glomerulonephritis is a common cause of end-stage renal disease. Infiltrating leukocytes interacting with renal cells play a critical role during the initiation and progression of glomerulonephritis, but the exact mechanisms are not clearly defined. By using the murine model of nephrotoxic nephritis, we investigated the role of S100A8/A9 [myeloid-related protein (MRP) 8/14, calprotectin] in promoting glomerulonephritis. In nephrotoxic nephritis, wild-type (WT) mice with glomerulonephritis have elevated serum levels of S100A8/A9, whereas mice deficient in MRP14 (S100a9(-/-)), and hence S100A8/A9, are significantly protected from disease. By using bone marrow transplants, we showed that MRP14 deficiency is required in both the hemopoietic and intrinsic cells for the protective effect. In vitro, both the WT bone marrow-derived macrophages and renal mesangial cells stimulated with S100A8/A9 secrete IL-6, CXCL1, and tumor necrosis factor α; however, Mrp14(-/-) cells exhibit significantly blunted proinflammatory responses. The interaction of WT bone marrow-derived macrophages with renal microvascular endothelial cells results in increased levels of monocyte chemotactic protein 1, IL-8, and IL-6 cytokines, which is attenuated in Mrp14(-/-) bone marrow-derived macrophages. Data shows that S100A8/A9 plays a critical role during glomerulonephritis, exerting and amplifying autocrine and paracrine proinflammatory effects on bone marrow-derived macrophages, renal endothelial cells, and mesangial cells. Therefore, complete S100A8/A9 blockade may be a new therapeutic target in glomerulonephritis.

Objectives: B cells are central to the pathology of ANCA-associated vasculitis (AAV), a disease characterized by autoantibodies and effectively treated by rituximab. In addition to promoting inflammation, a subset of B cells act to suppress harmful autoimmune responses (Breg). The balance of effector and regulatory B cell subsets in AAV is not known. This study was conducted to assess the relative frequency of these subsets during different states of disease activity. / Methods: B memory (Bmem), naive (Bnaive) and regulatory (Breg) subsets were defined by their relative expression of CD24 and CD38. Function was assessed by cytokine production and suppressive action on CD4(+) Th1 activation evaluated in a co-culture system. / Results: Compared with healthy controls, the frequency of Breg (CD24(hi)CD38(hi)) was significantly reduced during disease remission in both proteinase 3 (PR3)- and MPO-ANCA patients and during acute disease in PR3-ANCA patients, while the frequency of memory cells (CD24(hi)CD38(lo)) was reduced during active disease and restored during remission. Breg cell frequency showed a positive correlation, while Bmem had an inverse correlation with IL-10 production in vitro. B and T cell co-cultures revealed that memory and naive B cell subsets augmented Th1 activation in vitro, which was prevented by Breg, and this pattern did not differ between remission AAV patients and controls. / Conclusion: In remission there is a numerical, but not functional, deficiency in Breg and preservation of Bmem associated with reduced IL-10 production and increased Th1 activation in vitro. This imbalance may contribute to the high rate of relapse observed in AAV, especially in PR3-ANCA patients.

OBJECTIVES Rituximab is effective in inducing remission in ANCA-associated vasculitis (AAV), with randomized evidence to support its use as four infusions of 375 mg/m(2) (the conventional lymphoma dosing schedule). As B cell depletion (BCD) appears to occur very rapidly after the first dose, we questioned the need for repeat dosing and adopted a standard single-dose protocol of 375 mg/m(2) to treat active AAV. METHODS All consecutive cases with newly diagnosed or relapsing AAV for whom conventional immunosuppression was contraindicated or ineffective were enrolled. All were rituximab naive. Circulating CD19(+) B cells and clinical and serological markers of disease activity were recorded at regular intervals. Complete remission (CR) was defined as the absence of clinical features of AAV with a prednisolone dose 500 μM). Eight (42%) were on additional immunosuppression at the time of rituximab treatment. Satisfactory BCD (

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). All current treatment regimens include oral steroids, which are associated with severe adverse events and long-term damage. We have piloted a steroid-avoiding protocol (rituxilup) for the treatment of biopsy-proven active International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV, or class V LN.We report the findings from the first 50 consecutive patients, treated with 2 doses of rituximab (1 g) and methyl prednisolone (500 mg) on days 1 and 15, and maintenance treatment of mycophenolate mofetil. Patients on maintenance steroids or with life-threatening SLE or requiring dialysis were excluded. Renal remission was defined as serum creatinine no greater than 15% above baseline; complete biochemical remission (CR) was defined as urine protein : creatinine ratio (PCR)50 mg/mmol or partial remission (PR) if PCR50 mg/mmol but non-nephrotic and50% reduction.A total of 45 (90%) patients achieved CR or PR by a median time of 37 weeks (range 4-200). Overall, 72% (n=36) achieved CR (median time 36 weeks (11-58)) and a further 18% (n=9) achieved persistent PR (median time 32 weeks (19-58)). By 52 weeks, CR and PR had been achieved in 52% (n=26) and 34% (n=17) respectively. In all, 12 relapses occurred in 11 patients, at a median time of 65.1 weeks (20-112) from remission. A total of 6/50 patients had systemic flares. Of the 45 responders, only 2 required2 weeks of oral steroids. Adverse events were infrequent; 18% were admitted, 10% for an infective episode.The rituxilup cohort demonstrates that oral steroids can be safely avoided in the treatment of LN. If findings are confirmed, it could mark a step change in the approach to the treatment of LN.

The patient is a 45-yr-old Caucasian man with no significant past medical history, who in December 2006 developed arthralgias affecting both shoulders and hips and subsequently noticed shortness of breath with a cough, and a lower limb rash. These symptoms did not improve with diclofenac or with a course of antibiotic therapy prescribed by his general practitioner. The patient presented to his local hospital when he developed hemoptysis, epistaxis, and sinusitis, as well as a worsening of his shortness of breath, rash. and arthralgias. He had lost 3.5 kg in weight during the course of his illness. He was on no medication except for diclofenac, prescribed in the previous month, and a course of amoxicillin. His family history included rheumatoid arthritis and lung cancer in two family members, both of whom were heavy smokers. He was originally from Ireland but had been living in the United Kingdom for the previous 25 yr. He had a partner and three children and was an ex-smoker. At the local hospital, examination was unremarkable except for a lower limb vasculitic rash. Initial blood tests (Table 1) revealed significant renal impairment with a serum creatinine of 345 μmol/L (normal range 50 to 110 μmol/L) and an acute inflammatory response with a C-reactive protein (CRP) of 204 mg/dl and a serum albumin of 31 g/L. He was treated with antibiotics for a presumed chest infection and with intravenous fluids. On the sixth day of admission, creatinine had increased to 563 μmol/L and he was acidotic with serum bicarbonate 18 mmol/L, at which point he was admitted to the intensive care unit for hemofiltration. Hemoglobin had fallen to 9 from 12 g/L on admission. Further investigations revealed an antineutrophil cytoplasm antibody (ANCA) by immunofluorescence and an anti-PR3 antibody concentration of 728 IU/ml (normal range 0 to 19 …

Large-bore dual lumen in-dwelling venous catheters are used in hemodialysis. These catheters are usually locked with heparin after the treatment. This study addressed the underappreciated postdialysis coagulopathy that can result. Thirty-six patients were included: 7 dialyzed through arterio-venous fistulae, 29 through in-dwelling venous catheters. The latter group was further subdivided according to whether they received heparin or heparin-free dialysis. To assess the heparin lock, a full-dose heparin lock as well as a much weaker heparin lock and a citrate lock were used. To assess the coagulopathy, blood was taken 1 hr after dialysis. The activated partial thromboplastin time (APTT) and anti-Xa level was measured. Additionally, 6 venous catheters were removed and the amount of fluid expelled upon locking with saline was measured. Clotting from the patient group with arterio-venous fistulae was normal following dialysis. The patients with in-dwelling venous catheters and heparin locks had significantly deranged clotting; 6 out of 10 patients had abnormal APTT results. All patients with catheters, heparin-free dialysis, and heparin locks had deranged clotting (7 out of 7). The rate decreased significantly when heparinized saline was used as a lock. A subset of patients had a citrate lock rather than a heparin lock; the clotting results normalized in all but one patient. An in vitro study demonstrated immediate leakage of fluid from the end of the ports upon locking. Significant postdialysis anticoagulation can occur after dialysis, which can be attributed to the heparin line locks. This risk is considerably reduced when a citrate lock is used instead.

Discovery of the role of the IL-1 inflammasome in CAPS has revolutionised treatment, and anti-IL-1 therapies have successfully switched off disease activity in many patients. More than 110 CAPS patients (including 24 children) in the UK have been treated with drugs targeting IL-1, over 90% of these have had complete resolution of disease.

OBJECTIVE To determine the incidence and treatment of lymphoceles after retropubic radical prostatectomy (RP). PATIENTS AND METHODS Up to January 2004, 260 patients who had a retropubic RP in one institution by one surgeon were assessed retrospectively, using the patients’ notes or the computerized results system to determine whether a lymphocele was suspected and then confirmed by imaging studies (computed tomography or ultrasonography). RESULTS Nine patients developed symptomatic lymphoceles; eight of these were detected by imaging. Four lymphoceles required intervention while the remainder regressed spontaneously. No complications were reported in the group that was treated. CONCLUSION The rate of symptomatic lymphocele formation was low after RP, with an overall incidence of 3.5%. Ultrasonography was effective in detecting lymphoceles and ultrasonographically guided percutaneous drainage an effective treatment.

BACKGROUND Soluble Flt1 (sFlt1) is a potent inhibitor of vascular endothelial growth factor, secreted mainly by the placenta, endothelial cells and monocytes. Increased sFlt1 serum levels correlate with endothelial dysfunction and cardiovascular complications in dialysis patients. However, the impact of dialysis by itself on sFlt1 serum levels remains unknown. METHODS We assessed sFlt1 kinetics during dialysis and the impact of different dialysis techniques [high-flux haemodialysis (HD), haemodiafiltration (HDF)] and heparinization procedures on sFlt1 serum levels in 48 patients on regular dialysis. RESULTS sFlt1 serum levels increased as early as 1 min after the start of dialysis and peaked at 15 min before returning to baseline at 4 h [mean peak level 2551 pg/mL, versus 102 before dialysis (P < 0.0001)]. sFlt1 kinetics were similar with two different dialysis membranes. In contrast, when unfractionated heparin (UH) and low-molecular-weight heparin (LMWH) were omitted during dialysis (HD or pre-dilution HDF), no significant increase in sFlt1 levels occurred. Conversely, delayed administration of LMWH (after 30 min of a heparin-free HD) induced a sharp increase in sFlt1. Similarly, when UH and LMWH were omitted and citrate-based dialysate or a heparin-coated membrane was used, sFlt1 levels remained unchanged. When heparinization procedures were the same, no difference in sFlt1 levels was noted between HD and HDF. In vitro, UH and LMWH failed to induce sFlt1 release by monocytes from controls or HD patients. These findings suggest that priming of monocytes on the extracorporeal circuit is required for heparin-induced sFlt1 release or that endothelial cells contribute to this increase. CONCLUSIONS Our results indicate that heparin-based HD induces a major sFlt1 release, which may exacerbate the anti-angiogenic state and thus endothelial dysfunction, commonly found in dialysis patients.

Many forms of glomerular disease are immune mediated and are therefore treated with immunosuppression. The particular regimen that is used may vary depending on the underlying condition, but many protocols are based on combination therapy using glucocorticoids and a second agent, which has historically often been cyclophosphamide. With the introduction of newer immunosuppressive agents, including biologics, these protocols have been modified for different conditions and, in only some cases, tested in randomised controlled trials. Certain protocols are based on oral therapies and can easily be delivered safely as outpatients; others require infusions which necessitate careful co-ordination of day case admissions and outpatient monitoring to allow early recognition of potential adverse events. Regardless of the actual regimen used, there are some general principles that apply to delivering a safe immunosuppressive service. In this chapter, we discuss practical issues surrounding immunosuppression in glomerular disease.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) commonly results in glomerulonephritis, in which neutrophils and monocytes have important roles. The heterodimer calprotectin (S100A8/S100A9, mrp8/14) is a Toll-like receptor-4 ligand found in neutrophils and monocytes and is elevated in inflammatory conditions. By immunohistochemistry of renal biopsies, patients with focal or crescentic glomerular lesions were found to have the highest expression of calprotectin and those with sclerotic the least. Serum levels of calprotectin as measured by ELISA were elevated in patients with active AAV and the levels decreased but did not normalize during remission, suggesting subclinical inflammation. Calprotectin levels in patients with limited systemic disease increased following treatment withdrawal and were significantly elevated in patients who relapsed compared with those who did not. As assessed by flow cytometry, patients with AAV had higher monocyte and neutrophil cell surface calprotectin expression than healthy controls, but this was not associated with augmented mRNA expression in CD14(+) monocytes or CD16(+) neutrophils. Thus, serum calprotectin is a potential disease biomarker in patients with AAV, and may have a role in disease pathogenesis.

Histopathological classification systems have been applied to a number of renal conditions, to allow clinicians to make useful predictions regarding patient and kidney outcome and to aid in comparing similar lesions across clinical trials and cohorts. This has been successful for lupus nephritis, focal segmental glomerulosclerosis and more recently for both IgA disease (the Oxford classification) [1] and anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) [the Berden or European vasculitis study group (EUVAS) classification] [2]. In IgA disease, numerous follow-up studies have now been published validating the classification, in different age groups and across different countries and ethnicities. The paper in Nephrology Dialysis Transplantation by Chang et al. [3] attempts to re-evaluate the Berden/EUVAS ANCA-associated glomerulonephritis classification in a Chinese population, and it therefore represents an important first step in assessing the general utility of the classification. AAV frequently causes a focal segmental necrotizing glomerulonephritis, and renal involvement exerts a profound influence on patient morbidity and mortality. Indeed, disease severity in AAV is mostly assessed by the severity of renal involvement. A significant proportion of patients present with advanced renal failure and require dialysis. With modern treatment protocols, ~50–60% of those dialysis-dependant patients who survive the first year recover independent renal function. Previous studies by EUVAS investigators had demonstrated the prognostic value of the renal biopsy by defining lesions that were associated with favourable renal outcome and treatment response. They demonstrated that those patients recovering independent renal function had less glomerulosclerosis, arteriosclerosis and tubular atrophy while they were more likely to have received plasmaphaeresis as adjunctive treatment [4]. Additionally, by combining presenting renal function measurement (estimated glomerular filtration rate; eGFR0) with histological parameters, they devised better predictors of renal function at 18 months than eGFR alone [5]. They found that the most inflammatory glomerular lesions, containing fibrinoid necrosis or cellular crescents, were the ones most likely to respond to treatment, being associated with the greatest improvement in renal function following 18 months of follow-up. By contrast, established sclerotic glomerular lesions were most predictive of final renal function at 18 months. These findings relied on assessment of cohorts who were treated in a relatively homogeneous manner (recruited from various EUVAS clinical trials), with pathologists who had demonstrated high degrees of concordance in defining the histopathological lesions [6]. However, despite the prognostic value of the biopsy, a formal histological classification system had been lacking, until recently. The Berden/EUVAS histopathological classification of AAV was proposed in 2010 [2] by an international group of renal pathologists and was validated in 100 patients from two large multicentre European vasculitis trials (CYCAZAREM and MEPEX, which recruited patients with ANCA-associated glomerulonephritis of differing severities). Renal histology from patients originating in nine European countries, with at least 1-year follow-up, and including both MPO-ANCA and PR3-ANCA were analysed. Importantly, patients with other co-morbid conditions, such as concurrent anti-glomerular basement membrane disease, were excluded. The classification system was based on glomerular pathology assessed by light microscopy. Interestingly, tubulointerstitial fibrosis and tubular atrophy, generally predictive of long-term renal outcomes for many diseases, did not add any prognostic value and were thus excluded. The key aspect of the classification was that it was simple and was defined by four separate glomerular categories: focal, crescentic, mixed and sclerotic. Biopsies in the focal category were defined by having 50% normal glomeruli. Crescentic biopsies were those with 50% glomeruli with cellular crescents. Mixed referred to biopsies having

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis exhibits endothelial damage, but the capacity for vessel repair in this disorder is not well understood. Here, we observed a marked increase in serum levels of soluble Flt1 (sFlt1), a potent inhibitor of vascular endothelial growth factor, in patients with active ANCA-associated vasculitis compared with patients during remission and other controls. Serum levels of sFlt1 correlated with C5a, an anaphylatoxin released after complement activation. Serum from patients with acute ANCA-associated vasculitis disrupted blood flow in the chicken chorioallantoic membrane assay, suggesting an antiangiogenic effect. Preincubation with excess human vascular endothelial growth factor prevented this effect. Anti–proteinase-3 (PR3) mAb and serum containing PR3-ANCA from patients with active vasculitis both induced a significant and sustained release of sFlt1 from monocytes, whereas anti-myeloperoxidase (MPO) mAb or polyclonal antibodies did not. However, the serum containing polyclonal PR3-ANCA did not induce release of sFlt1 from cultured human umbilical vein endothelial cells. In summary, these data suggest that anti-PR3 antibodies, and to a much lesser extent anti-MPO antibodies, increase sFlt1 during acute ANCA-associated vasculitis, leading to an antiangiogenic state that hinders endothelial repair.

Objectives To determine a role for antineutrophil cytoplasmic antibody (ANCA)-activated neutrophils in promoting B cell survival through the release of B lymphocyte stimulator (BLyS). Methods Neutrophil BLyS expression was measured by flow cytometry. Concentrations of BLyS in cell supernatants and donor serum samples were measured by ELISA. Cell survival assays were carried out using an L3055 cell line and viability measured by flow cytometry. Results Tumour necrosis factor α and formyl-Met-Leu-Phe (fMLP) treatment of non-primed neutrophils and treatment of primed neutrophils with anti-PR3 ANCA IgG resulted in a significant increase in surface expression of BLyS within 30 min which returned to basal levels by 2 h. Supernatants from ANCA-stimulated neutrophils were shown to contain increased levels of BLyS and to promote the survival of the centroblast cell line L3055. Serum BLyS concentrations are increased in patients with active ANCA-associated systemic vasculitis and these levels are increased further following 1–3 months of treatment with rituximab. Conclusions ANCA specifically causes the release of BLyS from activated neutrophils which can support B cell survival in vitro. The presence of serum BLyS in active disease and its increase following B cell depletion suggest it is an important factor in disease pathogenesis and may facilitate disease relapse.