Myeloperoxidase-specific antineutrophil cytoplasmic antibody-associated vasculitis.

Myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-ANCA-associated vasculitis) is one of two major ANCA-associated vasculitis variants characterised by systemic necrotising vasculitis with few or no immune deposits. MPO-ANCA-associated vasculitis predominantly affects small blood vessels and, in contrast to its counterpart proteinase 3-ANCA-associated vasculitis, is generally not associated with granulomatous inflammation. The kidneys and lungs are the most commonly affected organs. The pathogenesis of MPO-ANCA-associated vasculitis is characterised by loss of tolerance to the neutrophil enzyme MPO. This loss of tolerance leads to a chronic immunopathological response where neutrophils become both the target and effector of autoimmunity. MPO-ANCA drives neutrophil activation, leading in turn to tissue and organ damage. Clinical trials have improved the therapeutic approach to MPO-ANCA-associated vasculitis. However, there remains substantial unmet need regarding relapse frequency, toxicity of current treatment, and long-term morbidity. In this Series paper, we present the current state of research regarding pathogenesis, diagnosis, and treatment of MPO-ANCA-associated vasculitis.

The use of belimumab in three cases of refractory lupus nephritis.

In recent trials for the treatment of systemic lupus erythematosus (SLE), belimumab (BLM), in addition to standard immunosuppression, has been shown to improve renal and nonrenal outcomes. We report our experience using BLM in three cases of refractory lupus nephritis (LN), where renal remission was not achieved using cyclophosphamide, mycophenolate mofetil and other immunosuppressive medications. In two of the three cases, BLM therapy led to a partial remission of LN, improvement in serological markers of SLE and disease activity, which permitted a reduction in prednisolone dosing. Treatment with efficacious therapies early in the course of LN is a desirable therapeutic strategy, to achieve early remission of proteinuria and curtail the development of irreversible chronic renal damage. Further studies are needed to provide information on the effectiveness of BLM for maintenance of remission, prevention of flares and monitoring for long-term complications of B-cell modulation.

Primary aldosteronism: an unsuspected culprit of hypertension in systemic lupus erythematosus?

Primary aldosteronism (PA) is the most common endocrine cause of secondary hypertension and is associated with a high risk of cardiovascular disease in the general population. Patients suffering from systemic lupus erythematosus (SLE), a multisystem and multifactorial autoimmune disease, experience a high burden of hypertension and cardiovascular disease. Importantly, cardiovascular disease is one of the leading causes of death in SLE. Very limited evidence suggests an increased proportion of autoimmune diseases such as SLE in patients with PA. However, studies evaluating the prevalence of PA in the SLE population are lacking. Despite the potential for curative or targeted treatments, guidelines for the management of hypertension in SLE do not currently recommend testing for PA. This review highlights PA as a potentially over-looked secondary cause of hypertension in SLE, and offers future directions in research to improve the detection of this highly modifiable cardiovascular risk factor in the SLE population.

Removal of the endothelial surface layer via hyaluronidase does not modulate monocyte and neutrophil interactions with the glomerular endothelium.

OBJECTIVE: The endothelial surface layer (ESL), a layer of macromolecules on the surface of endothelial cells, can both impede and facilitate leukocyte recruitment. However, its role in monocyte and neutrophil recruitment in glomerular capillaries is unknown. METHODS: We used multiphoton intravital microscopy to examine monocyte and neutrophil behavior in the glomerulus following ESL disruption with hyaluronidase. RESULTS: Constitutive retention and migration of monocytes and neutrophils within the glomerular microvasculature was unaltered by hyaluronidase. Consistent with this, inhibition of the hyaluronan-binding molecule CD44 also failed to modulate glomerular trafficking of these immune cells. To investigate the contribution of the ESL during acute inflammation, we induced glomerulonephritis via in situ immune complex deposition. This resulted in increases in glomerular retention of monocytes and neutrophils but did not induce marked reduction in the glomerular ESL. Furthermore, hyaluronidase treatment did not modify the prolonged retention of monocytes and neutrophils in the acutely inflamed glomerular microvasculature. CONCLUSIONS: These observations indicate that, despite evidence that the ESL has the capacity to inhibit leukocyte-endothelial cell interactions while also containing adhesive ligands for immune cells, neither of these functions modulate trafficking of monocytes and neutrophils in steady-state or acutely-inflamed glomeruli.

RORing toward immunoregulation in glomerulonephritis?

CD4+ T cells that express forkhead box protein 3 are important in maintaining tolerance and restraining effector responses. Herrnstadt et al. use a model of rapidly progressive glomerulonephritis to examine the nature and role of forkhead box protein 3-positive and retinoid acid-related orphan receptor γt-positive regulatory T cells. These cells are prominent in experimental glomerulonephritis, both locally and systemically, and are present in kidneys of people with anti-neutrophil cytoplasmic antibody-associated vasculitis. Functionally, despite their expression of retinoid acid-related orphan receptor γt, associated with T-helper cell 17 cells, they regulate cellular immunity, both systemically and within the kidney.

The five types of glomerulonephritis classified by pathogenesis, activity and chronicity (GN-AC).

Glomerulonephritis (GN) is a diverse group of immune-mediated disorders. Currently, GN is classified largely by histological patterns that are difficult to understand and teach, and most importantly, do not indicate treatment choices. Indeed, altered systemic immunity is the primary pathogenic process and the key therapeutic target in GN. Here, we apply a conceptual framework of immune-mediated disorders to GN guided by immunopathogenesis and hence immunophenotyping: (i) infection-related GN require pathogen identification and control; (ii) autoimmunity-related GN, defined by presence of autoantibodies and (iii) alloimmunity-related GN in transplant recipients both require the suppression of adaptive immunity in lymphoid organs and bone marrow; (iv) autoinflammation-related GN, e.g. inborn errors of immunity diagnosed by genetic testing, requires suppression of single cytokine or complement pathways; and (v) Monoclonal gammopathy-related GN requires B or plasma cell clone-directed therapy. A new GN classification should include disease category, immunological activity to tailor the use of the increasing number of immunomodulatory drugs, and chronicity to trigger standard chronic kidney disease care including the evolving spectrum of cardio-renoprotective drugs. Certain biomarkers allow diagnosis and the assessment of immunological activity and disease chronicity without kidney biopsy. The use of these five GN categories and a therapy-focused GN classification is likely to overcome some of the existing hurdles in GN research, management and teaching by reflecting disease pathogenesis and guiding the therapeutic approach.

International Society of Nephrology first consensus guidance for preclinical animal studies in translational nephrology.

Preclinical tests in animal models are key steps in early drug development. Consequently, the International Society of Nephrology held a consensus meeting that connected experts in the global kidney community in order to provide guidance on optimal management of translational animal studies for the development of new drugs to treat kidney disease, entitled "TRANSFORM; TRAnslational Nephrology Science FOR new Medications." The meeting covered various themes, including the following: (i) selection of disease model; (ii) pharmacokinetics; (iii) interventions in late preclinical models; (iv) choice of animal; (v) statistical power; (vi) organoids and organ-on-a-chip models; and (vii) reporting of results. This guidance is the first to be provided on the optimal conduct of translational animal studies for the development of new drugs to treat kidney disease. These recommendations are designed to accelerate development of new drugs for efficacious treatment of kidney diseases, and to improve the prognosis and quality of life of patients with a variety of kidney diseases.

Glomerulonephritis: immunopathogenesis and immunotherapy.

'Glomerulonephritis' (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney (the glomeruli). These disorders are currently classified largely on the basis of histopathological lesion patterns, but these patterns do not align well with their diverse pathological mechanisms and hence do not inform optimal therapy. Instead, we propose grouping GN disorders into five categories according to their immunopathogenesis: infection-related GN, autoimmune GN, alloimmune GN, autoinflammatory GN and monoclonal gammopathy-related GN. This categorization can inform the appropriate treatment; for example, infection control for infection-related GN, suppression of adaptive immunity for autoimmune GN and alloimmune GN, inhibition of single cytokines or complement factors for autoinflammatory GN arising from inborn errors in innate immunity, and plasma cell clone-directed or B cell clone-directed therapy for monoclonal gammopathies. Here we present the immunopathogenesis of GN and immunotherapies in use and in development and discuss how an immunopathogenesis-based GN classification can focus research, and improve patient management and teaching.

Toll-like Receptor 9 Induced Dendritic Cell Activation Promotes Anti-Myeloperoxidase Autoimmunity and Glomerulonephritis.

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.

T-cell receptor αß+ double-negative T cells in the kidney are predominantly extravascular and increase in abundance in response to ischemia-reperfusion injury.

T-cell receptor+ CD4- CD8- double-negative (DN) T cells are a population of T cells present in low abundance in blood and lymphoid organs, but enriched in various organs including the kidney. Despite burgeoning interest in these cells, studies examining their abundance in the kidney have reported conflicting results. Here we developed a flow cytometry strategy to clearly segregate DN T cells from other immune cells in the mouse kidney and used it to characterize their phenotype and response in renal ischemia-reperfusion injury (IRI). These experiments revealed that in the healthy kidney, most DN T cells are located within the renal parenchyma and exhibit an effector memory phenotype. In response to IRI, the number of renal DN T cells is unaltered after 24 h, but significantly increased by 72 h. This increase is not related to alterations in proliferation or apoptosis. By contrast, adoptive transfer studies indicate that circulating DN T cells undergo preferential recruitment to the postischemic kidney. Furthermore, DN T cells show the capacity to upregulate CD8, both in vivo following adoptive transfer and in response to ex vivo activation. Together, these findings provide novel insights regarding the phenotype of DN T cells in the kidney, including their predominant extravascular location, and show that increases in their abundance in the kidney following IRI occur in part as a result of increased recruitment from the circulation. Furthermore, the observation that DN T cells can upregulate CD8 in vivo has important implications for detection and characterization of DN T cells in future studies.

Predictors of infection requiring hospitalization in patients with systemic lupus erythematosus: a time-to-event analysis.

OBJECTIVES: To evaluate the predictors of serious infection in patients with systemic lupus erythematosus (SLE). METHODS: Serious infections were identified in SLE patients in a prospectively-followed single centre cohort. Associations of serious infection with disease-related variables and medication use were analysed using Cox and related regression models. RESULTS: 346 patients were followed for a mean (SD) of 6.6 (3.7) years. 86 episodes of serious infection were observed, with an incidence rate of 3.8 episodes per 100 person-years. Patients who had serious infection had higher baseline SLE Damage Index (SDI) and Charlston Comorbidity Index (CCI); they were also more likely to have high disease activity status (HDAS), and higher disease activity in multiple clinical domains, higher flare rates, higher time-adjusted prednisolone dose exposure, and less time in lupus low disease activity state (LLDAS). Patients who have received cyclophosphamide, rituximab and mycophenolate were more likely to have experienced serious infection. After multivariable adjustment in Cox regression analysis, cyclophosphamide, higher SDI score, and higher disease activity were associated with an increased hazard of first serious infection. History of previous serious infection conferred the highest risk. Lymphopenia was also a modest but statistically significant predictor of serious infection. CONCLUSION: History of previous serious infection was the strongest predictor of serious infection in our SLE cohort. This study also suggests that clinical factors such as damage accrual, disease activity, and choice of immunosuppressant, can each have an independent risk in predicting serious infection particularly the first episode.

A Focus Group Study of Self-Management in Patients With Glomerular Disease.

INTRODUCTION: Patients with glomerular disease experience symptoms that impair their physical and mental health while managing their treatments, diet, appointments and monitoring general and specific indicators of health and their illness. We sought to describe the perspectives of patients and their care partners on self-management in glomerular disease. METHODS: We conducted 16 focus groups involving adult patients with glomerular disease (n = 101) and their care partners (n = 34) in Australia, Hong Kong, the United Kingdom, and United States. Transcripts were analyzed thematically. RESULTS: We identified the following 4 themes: empowered in autonomy (gaining confidence through understanding, taking ownership of disease and treatment, learning a positive health approach); overwhelmed by compounding treatment burdens (financially undermined and depleted, demoralized by side effects and harms, frustrated by fragmented and inflexible care, fear of possible drug harms); striving for stability and normalcy (making personal sacrifices, maximizing life participation, attentiveness to bodily signs, avoiding precarious health states, integrating medicines into routines); and necessity of health-sustaining relationships (buoyed by social support, fulfilling meaningful responsibilities, sharing and normalizing experiences, seeking a trusting and respectful alliance). CONCLUSION: Patients with glomerular disease and their care partners value their capacity for autonomy and disease ownership, stability of their health, and relationships that support self-management. Strategies directed at strengthening these factors may increase self-efficacy and improve the care and outcomes for patients with glomerular disease.

Ageing enhances cellular immunity to myeloperoxidase and experimental anti-myeloperoxidase glomerulonephritis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is an autoimmune disease characterized by small blood vessel inflammation, commonly affecting the kidneys and respiratory tract. It is unclear why the incidence of this condition increases with age. Previous studies in a passive antibody transfer system in aged mice have implicated innate effectors. To test the hypothesis that autoimmunity to myeloperoxidase (MPO), an autoantigen responsible for AAV, increases with age, anti-MPO autoimmunity was studied in murine models of active autoimmunity and disease induced by cellular immunity. METHODS: Young (8 weeks) and aged (either 15 or 22 months) mice were immunized with whole proteins or peptides from ovalbumin, as a model foreign antigen, or MPO protein or peptides. Mice were subjected to a model of active anti-MPO glomerulonephritis. Cellular and humoral immune responses, and tissue inflammation were assessed. RESULTS: While cellular immunity to ovalbumin was diminished in aged mice, cellular autoimmunity to MPO and its immunodominant CD4+ and CD8+ T cell epitopes was increased after immunization with either MPO peptides or whole MPO protein, assessed by peptide and antigen-specific production of the pro-inflammatory cytokines IFN-γ and IL-17A. MPO-ANCA titres were not increased in aged mice compared with young mice. In experimental anti-MPO glomerulonephritis, cell-mediated injury was increased, likely due to CD4+ and CD8+ T cells, innate immunity and the increased vulnerability of aged kidneys. CONCLUSION: Heightened cellular immunity to MPO develops with ageing in mice and may contribute to the increased incidence and severity of AAV in older people.

Immune cell behaviour and dynamics in the kidney - insights from in vivo imaging.

The actions of immune cells within the kidney are of fundamental importance in kidney homeostasis and disease. In disease settings such as acute kidney injury, anti-neutrophil cytoplasmic antibody-associated vasculitis, lupus nephritis and renal transplant rejection, immune cells resident within the kidney and those recruited from the circulation propagate inflammatory responses with deleterious effects on the kidney. As in most forms of inflammation, intravital imaging - particularly two-photon microscopy - has been critical to our understanding of immune cell responses in the renal microvasculature and interstitium, enabling visualization of immune cell dynamics over time rather than statically. These studies have demonstrated differences in the recruitment and function of these cells from those in more conventional vascular beds, and provided a wealth of information on the actions of blood-borne immune cells such as neutrophils, monocytes and T cells, as well as kidney-resident mononuclear phagocytes, in a range of diseases affecting different kidney compartments. In particular, in vivo imaging has furthered our understanding of leukocyte function within the glomerulus in acute glomerulonephritis, and in the tubulointerstitium and interstitial microvasculature during acute kidney injury and following transplantation, revealing mechanisms of immune surveillance, antigen presentation and inflammation in the kidney.

Animal models of vasculitis.

PURPOSE OF REVIEW: Vasculitis describes a wide spectrum of rare, inflammatory, multisystem disorders. These heterogenous diseases all have inflammation of blood vessels as a central feature. However, they differ in terms of their genetic and environmental risk factors, disease pathogenesis, clinical presentations and treatment strategies. Many animal models of vasculitis exist, each resembling a different human clinical phenotype. This review provides an overview of recently published findings from experimental animal models of vasculitis. RECENT FINDINGS: Several new animal models have been described during the review period. New insights gleaned from existing animal models regarding cause, disease effector mechanisms and novel treatments identified in established animal models are discussed. SUMMARY: Animal models continue to be an important tool for understanding disease pathogenesis, especially in rare and complex diseases such as vasculitis. They also provide an invaluable platform for development and preclinical testing of new treatments.

A Core Outcome Set for Trials in Glomerular Disease: A Report of the Standardized Outcomes in Nephrology-Glomerular Disease (SONG-GD) Stakeholder Workshops.

BACKGROUND AND OBJECTIVES: Outcomes reported in trials in adults with glomerular disease are often selected with minimal patient input, are heterogeneous, and may not be relevant for clinical decision making. The Standardized Outcomes in Nephrology-Glomerular Disease (SONG-GD) initiative aimed to establish a core outcome set to help ensure that outcomes of critical importance to patients, care partners, and clinicians are consistently reported. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We convened two 1.5-hour workshops in Melbourne, Australia, and Washington, DC, United States. Attendees were identified purposively with 50 patients/care partners and 88 health professionals from 19 countries; 51% were female. Patients and care partners were from the United States, Australia, and Canada, and had experience of a glomerular disease with systemic features (n=9), kidney-limited nephrotic disease (n=9), or other kidney-limited glomerular disease (n=8). Attendees reviewed the results of the SONG-GD Delphi survey and aims of the workshop and then discussed potential core outcomes and their implementation in trials among moderated breakout groups of eight to 12 people from diverse backgrounds. Transcripts of discussions were analyzed thematically. RESULTS: Three themes were identified that supported the proposed core outcomes: limiting disease progression, stability and control, and ensuring universal relevance (i.e., applicable across diverse populations and settings). The fourth theme, preparedness for implementation, included engaging with funders and regulators, establishing reliable and validated measures, and leveraging existing endorsements for patient-reported outcomes. CONCLUSIONS: Workshop themes demonstrated support for kidney function, disease activity, death, life participation, and cardiovascular disease, and these were established as the core outcomes for trials in adults with glomerular disease. Future work is needed to establish the core measures for each domain, with funders and regulators central to the uptake of the core outcome set in trials.