Haemodialysis facilities have a large environmental impact due to high energy, water and consumable usage by haemodialysis equipment. As climate change and natural resource scarcity escalate, all the while the number of people requiring dialysis increases, there is an urgent need for dialysis facilities that meet care needs while minimising environmental impact. To address this, the Australian and New Zealand Society of Nephrology engaged an environmental sustainability consulting practise to develop a best practise guide for the environmentally sustainable design and operation of haemodialysis facilities. Four opportunity areas were considered, namely energy, water, waste and resource recovery, and additional sustainability. A total of 28 environmental improvement initiatives were identified. The majority (n = 23) were general measures that could be applied across all healthcare settings, while five were specific to haemodialysis facilities. Recommendations were made regarding specific measures that should be undertaken and/or standards that must be met to achieve the intent of each initiative. These were stratified to enable their application to both existing dialysis facilities and new builds. The lifecycle stage of a haemodialysis facility to which each initiative applied was highlighted, as was its potential impact. This guide provides a tailored and comprehensive resource for the kidney care community to enable the integration of best practise sustainability considerations into both existing and new facilities. If broadly implemented, it has the potential to markedly improve the environmental impact of haemodialysis provision.

ANCA-associated vasculitis (AAV) is intricately linked with infections. Toll-like receptors (TLR) provide a potential link between infection and anti-myeloperoxidase (MPO) autoimmunity. TLR9 ligation has been shown to promote anti-MPO autoimmunity and glomerular vasculitis in murine MPO-AAV. This study investigates dendritic cell TLR9 ligation in murine experimental anti-MPO glomerulonephritis. We analyzed autoimmune responses to MPO following transfer of TLR9 stimulated, MPO pulsed dendritic cells and kidney injury following a sub-nephritogenic dose of sheep anti-mouse glomerular basement membrane globulin. TLR9 ligation enhanced dendritic cell activation upregulating CD40 and CD80 expression, promoting systemic anti-MPO autoimmunity and T cell recall responses and exacerbating kidney injury. CD40 upregulation by TLR9 was critical for the induction of nephritogenic autoimmunity. The presence of DEC205, which transports the TLR9 ligand to TLR9 located in the endosome, also promoted kidney injury. This confirms TLR9 mediated dendritic cell activation as a mechanism of anti-MPO autoimmunity in AAV and further defines the link between infection and the generation of MPO specific autoimmune inflammation.

Background In Australia, Lupus Nephritis (LN) affects a culturally diverse population of patients. We established the Lupus Nephritis Australian Registry (LUNAR) to better understand the population of patients receiving Myfortic and other immunosuppressants, and to analyse the safety and efficacy of the treatments they received. Methods A non-interventional, multicentre, registry of patients with biopsy-proven ISN/RPS class III, IV or V LN, treated with Myfortic or other immunosuppressants, was established. We collected baseline demographic and 6-monthly follow-up data over a 5-year period (2013–2018), including clinical data, laboratory tests and safety outcomes. Results 149 patients were enrolled in LUNAR across 8 sites, with 83.7% female and a mean age of 38.8 years. Most patients were Caucasian (45.2%) – patients of Asian ethnicity (29.6%) and Aboriginal/Torres Strait Islander or Maori/Pacific Islander descent (10.4%) were significantly over-represented compared to the general population. The mean and median duration of SLE was 8.6 and 6 years, respectively (range 0–42 years), and of LN was 5.4 and 3.9 years, respectively (range 0–30 years). Most patients had class IV LN on their initial kidney biopsy (59.3%), with 21.5% having class III and 11.1% having class V LN. Immunosuppressants used prior to screening included corticosteroids (68.9%), mycophenolate mofetil ((MMF) 61.5%), Myfortic (41.5%) and cyclophosphamide (32.6%). At enrolment or during the study, most patients were treated with Myfortic (76.3%), MMF (65.2%) and/or hydroxychloroquine (67.4%). Rituximab and azathioprine were each started in 8.9% of patients during the study period. Kidney function was stable/improved for most patients over the study period and mycophenolate-based therapy was well-tolerated. Conclusions LUNAR is the first study outlining the demographics, outcomes and practice patterns in the management of patients with LN in Australia. Acknowledgements Supported by funding from Novartis Pharmaceuticals.

A 64-year-old gentleman initially presented with nephrotic syndrome and membranous nephropathy with positive staining for C1q, which was suspicious for lupus membranous nephritis. Investigation led to the simultaneous diagnosis of colorectal cancer (CRC). The CRC was surgically excised and the patient's nephrotic syndrome resolved. The patient subsequently presented with classic systemic lupus erythematosus (SLE) including positive serological markers, mouth-ulcers and a photosensitive maculopapular rash. Two months later the patient represented with an SLE flare encompassing the full-hand of renal-pulmonary syndrome and vasculitic-neuropathy, importantly at this presentation occult recurrence of CRC was proven with tissue biopsy. Major histocompatibility class II haplotyping demonstrated HLA-DRB1*03, a known predisposition for SLE. This case depicts the scenario of tumour transformation triggering SLE development in a predisposed individual after an initial paraneoplastic manifestation in the form of membranous nephropathy (plus C1q). This supports the potential role of tumourgenesis in the development of SLE in a primed individual.

The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti-myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C5aR1 in these responses has not been described. Here, we use murine models to dissect the role of C5aR1 in the generation of anti-myeloperoxidase autoimmunity and the effector responses resulting in renal injury. The genetic absence or pharmacological inhibition of C5aR1 results in reduced autoimmunity to myeloperoxidase with an attenuated Th1 response, increased Foxp3(+) regulatory T cells and reduction in generation of myeloperoxidase-ANCA. These changes are mediated by C5aR1 on dendritic cells, which promotes activation, and thus myeloperoxidase autoimmunity and glomerulonephritis. We also use renal intravital microscopy to determine the effect of C5aR1 inhibition on ANCA induced neutrophil dysfunction. We found that myeloperoxidase-ANCA induce neutrophil retention and reactive oxygen species burst within glomerular capillaries. These pathological behaviors are abrogated by C5aR1 inhibition. Thus, C5aR1 inhibition ameliorates both autoimmunity and intra-renal neutrophil activation in ANCA-associated vasculitis.

In antineutrophil cytoplasmic antibody-associated vasculitis (AAV), Toll-like receptors (TLRs) may be engaged by infection-associated patterns and by endogenous danger signals, linking infection and innate inflammation with this autoimmune disease. This study examined intrarenal TLR2, TLR4, and TLR9 expression and renal injury in AAV, testing the hypothesis that increased TLR expression correlates with renal injury. Patients with AAV exhibited both glomerular and tubulointerstitial expression of TLR2, TLR4, and TLR9, with TLR4 being the most prominent in both compartments. Glomerular TLR4 expression correlated with glomerular segmental necrosis and cellular crescents, with TLR2 expression correlating with glomerular segmental necrosis. The extent and intensity of glomerular and tubulointerstitial TLR4 expression and the intensity of glomerular TLR2 expression inversely correlated with the presenting estimated glomerular filtration rate. Although myeloid cells within the kidney expressed TLR2, TLR4, and TLR9, TLR2 and TLR4 colocalized with endothelial cells and podocytes, whereas TLR9 was expressed predominantly by podocytes. The functional relevance of intrarenal TLR expression was further supported by the colocalization of TLRs with their endogenous ligands high-mobility group box 1 and fibrinogen. Therefore, in AAV, the extent of intrarenal TLR4 and TLR2 expression and their correlation with renal injury indicates that TLR4, and to a lesser degree TLR2, may be potential therapeutic targets in this disease.

To define the incidence of AKI post cardiac surgery.

Myeloperoxidase (MPO) is an important neutrophil lysosomal enzyme, a major autoantigen, and a potential mediator of tissue injury in MPO-ANCA-associated vasculitis (MPO-AAV) and glomerulonephritis. Here we examined MPO deposition in kidney biopsies from 47 patients with MPO-AAV. Leukocyte accumulation and fibrin deposition consistent with cell-mediated immunity was a major feature. Tubulointerstitial macrophage, CD4+ and CD8+ T-cell, and neutrophil numbers correlated with low presenting eGFR. MPO was not detected in kidneys from patients with minimal change or thin basement membrane disease, but was prominent in glomerular, periglomerular, and tubulointerstitial regions in MPO-AAV. Extracellular MPO released from leukocytes was pronounced in all MPO-AAV patients. Similar numbers of neutrophils and macrophages expressed MPO in the kidneys, but colocalization studies identified neutrophils as the major source of extracellular MPO. Extraleukocyte MPO was prominent in neutrophil extracellular traps in the majority of patients; most of which had traps in half or more glomeruli. These traps were associated with more neutrophils and more MPO within glomeruli. Glomerular MPO-containing macrophages generated extracellular trap-like structures. MPO also localized to endothelial cells and podocytes. The presence of the most active glomerular lesions (both segmental necrosis and cellular crescents) correlated with intraglomerular CD4+ cells and MPO+ macrophages. Thus, cellular and extracellular MPO may cause glomerular and interstitial injury.

Calcific uraemic arteriolopathy (CUA) or calciphylaxis is most commonly seen in end‐stage renal disease and is associated with significant morbidity and mortality. The aim of this study was to determine whether hyperbaric oxygen therapy (HBOT) is effective in healing calciphylaxis lesions and to determine if there are any patient factors that can predict wound healing and patient survival.

BACKGROUND:A predictive histologic classification recently was proposed to determine the prognostic value of kidney biopsy in patients with antineutrophil cytoplasmic antibody-associated renal vasculitis (AAV).STUDY DESIGN:A dual-purpose retrospective observational cohort study to assess the reproducibility of the new classification and clinical variables that predict outcomes.SETTING & PARTICIPANTS:169 consecutive patients with AAV were identified; 145 were included in the reproducibility study, and 120, in the outcomes study.PREDICTOR:Kidney biopsy specimens were classified according to the predominant glomerular lesion: focal, mixed, crescentic, and sclerotic. An assessment of tubular atrophy also was performed.OUTCOMES:The primary outcome was time to end-stage kidney disease or all-cause mortality, modeled using Cox regression analysis.MEASUREMENTS:Estimated glomerular filtration rate, requirement for renal replacement therapy.RESULTS:For the reproducibility study, the overall inter-rater reliability of the classification demonstrated variability among 3 histopathologists (intraclass correlation coefficient, 0.48; 95% CI, 0.38-0.57; κ statistic=0.46). Although agreement was high in the sclerotic group (κ=0.70), it was less consistent in other groups (κ=0.51, κ=0.47, and κ=0.23 for crescentic, focal, and mixed, respectively). For the clinical outcomes study, patients with sclerotic patterns of glomerular injury displayed the worst outcomes. Patients with focal (HR, 0.26; 95% CI, 0.12-0.58; P=0.001), crescentic (HR, 0.33; 95% CI, 0.16-0.69; P=0.003), and mixed (HR, 0.39; 95% CI, 0.18-0.81; P=0.01) patterns of injury had lower risk of the primary outcome. Tubular atrophy correlated with outcome, and advanced injury was associated with worse outcomes (HR, 5.9; 95% CI, 2.25-15.47; P<0.001). Level of kidney function at presentation strongly predicted outcome (HR per 10-mL/min/1.73m(2) increase in estimated glomerular filtration rate, 0.63; 95% CI, 0.46-0.81; P<0.001).LIMITATIONS:Data availability, given the retrospective nature of the study.CONCLUSIONS:Reproducibility of the classification was seen only in patients with sclerotic patterns of glomerular injury. Sclerotic pattern of glomerular injury, advanced chronic interstitial injury, and decreased kidney function all predicted poor outcomes.

Abstract Although in vitro observations indicate that long noncoding RNAs (lncRNAs) regulate innate immune responses, their effect upon immune tolerance in vivo has not been defined. We have identified a novel gene of unknown function for which sequence variation is associated with autoimmune diabetes in the nonobese diabetic (NOD) mouse strain. Bioinformatics and expression analyses indicate this gene encodes a lncRNA that is induced by Toll-like receptor (TLR) activation, localizes to the nucleus and cytoplasm of dendritic cells, and binds to proteins within these cellular compartments. Moreover, sequence variation for this gene is associated with altered TLR-mediated cytokine production. Hence this gene was named Apics for Attenuator of Pattern recognition receptor-Induced Cytokine Secretion. To further investigate the function of this lncRNA, we established a C57BL/6 (B6) knockout mouse strain for Apics and discovered that Apics-deficient dendritic cells exhibit enhanced TLR-mediated cytokine production. Apics-deficient B6 mice also exhibit increased susceptibility to autoimmunity in two disease models: experimental autoimmune encephalomyelitis and experimental anti-neutrophil cytoplasmic antibody-associated vasculitis. Our study suggests that lncRNAs, such as Apics, can serve as TLR-inducible repressors that regulate the magnitude of innate immune responses to reduce the risk for developing autoimmune disease.

Event Abstract Back to Event Glomerular deposition of myeloperoxidase and NETS in human ANCA associated vasculitis correlates with DTH effector cell accumulation Kim M. O'Sullivan1*, Sharon L. Ford1, Camden Lo2, Shaun A. Summers1, 3, A. R. Kitching1, 3 and Stephen R. Holdsworth1, 3 1 Monash University, Department of Medicine, Australia 2 Monash University, Monash Micro Imaging, Australia 3 Monash Medical Centre, Department of Nephrology, Australia Myeloperoxidase (MPO) autoimmunity underlies most cases of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis and glomerulonephritis. We sought evidence for the hypothesis that glomerular injury is initiated by ANCA induced neutrophil accumulation, degranulation and NET formation. This is substantially exacerbated by anti MPO CD4 T cells recognising extracellular MPO then directing DTH effector macrophages. Forty eight renal biopsies from ANCA MPO positive patients with clinically active glomerulonephritis were examined by confocal microscopy for leukocytes and MPO. A significant infiltration of MPO+CD15+ neutrophils and MPO+CD68+monocytes/macrophages was present in all biopsies. Significant correlation was found for simultaneous glomerular infiltration of CD4 T cells and MPO expressing cells (P<0.05), and simultaneous infiltration of CD15 and MPO positive cells, and CD68 and MPO positive cells ( P=0.004, P=0.035 respectively). Interstitial CD15 positive cells and the total number of MPO positive cells correlated inversely with estimated glomerular infiltration rate at time of biopsy and at 1 year (P<0.05 and, P<0.01, respectively.) Extracellular MPO was found in 93% of all glomeruli and made up 23% of the total proportion of MPO observed within glomeruli and 31% of all the MPO in the interstitium. Neutrophil extracellular traps (NETs) were present in 61.3% of MPO-ANCA biopsies and there was a significantly more CD15 cells, total MPO expression and extracellular MPO in the glomeruli of patients with the presence of NETs (P< 0.05). This study provides evidence to support the hypothesis that neutrophil derived extracellular MPO acts as a planted autoantigen in glomeruli inducing T cell mediated DTH type injury. Keywords: human ANCA vasculitis, Myeloperoxidase (MPO), Neutrophils, monocytes/macrophages, neutrophil extracellular traps (NETs), T cells Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: O'Sullivan KM, Ford SL, Lo C, Summers SA, Kitching AR and Holdsworth SR (2013). Glomerular deposition of myeloperoxidase and NETS in human ANCA associated vasculitis correlates with DTH effector cell accumulation. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00685 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Ms. Kim M O'Sullivan, Monash University, Department of Medicine, Melbourne, Victoria, 3134, Australia, kim.osullivan@monash.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Kim M O'Sullivan Sharon L Ford Camden Lo Shaun A Summers A. R Kitching Stephen R Holdsworth Google Kim M O'Sullivan Sharon L Ford Camden Lo Shaun A Summers A. R Kitching Stephen R Holdsworth Google Scholar Kim M O'Sullivan Sharon L Ford Camden Lo Shaun A Summers A. R Kitching Stephen R Holdsworth PubMed Kim M O'Sullivan Sharon L Ford Camden Lo Shaun A Summers A. R Kitching Stephen R Holdsworth Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Highly sensitised patients are at increased risk for antibody mediated rejection (AMR) and reduced graft survival. Highly sensitive assays for detecting recipient preformed anti-HLA antibodies have been developed and identify high immunological risk donors. A 62yo male with end stage renal failure secondary to glomerulonephritis received a T-cell crossmatch negative, deceased donor, renal transplant mismatched at 3 of 6 HLA loci. A donor specific antibody (DSAb) to DR17 (MFI 2073) was present. Given his advancing age, multiple medical comorbidities and broad HLA sensitisation the transplant was accepted, however, shortly before transplantation two atypical results were made available. Firstly a B-cell crossmatch was performed and found to be negative in current serum but strongly positive in peak serum, secondly a further potential DSAb was predicted based on linkage disequilibrium with known donor HLA typing. The donor HLA typing would not be clarified until after the transplant. Despite the increased risk of AMR the transplant proceeded with pre-emptive plasma exchange. The patient developed severe AMR requiring extensive therapy. Incomplete prospective donor HLA typing can generate uncertainty in the interpretation of the virtual crossmatch performed for deceased donor transplants. This may result in clinically relevant sequelae. Advances in antibody detection techniques need to be matched by timely donor HLA typing for its full benefit to be realised.