Management of ANCA-associated vasculitis: Current trends and future prospects

The antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are a spectrum of heterogeneous autoimmune diseases characterized by necrotizing small vessel vasculitis and the presence of ANCA. These chronic multisystem disorders may be life-threatening if there is major organ involvement, such as acute renal failure or pulmonary hemorrhage, and require significant initial immunosuppression and long-term maintenance treatment. Long-established protocols using cyclophosphamide and prednisolone have resulted in dramatically improved outcomes for patients since the 1970s. Subsequently, international collaboration has contributed to a growing evidence base and consensus in the management of these rare disorders. Modifications to traditional treatment protocols by the use of azathioprine or methotrexate rather than cyclophosphamide, and the introduction of newer agents, such as rituximab, has maintained outcomes whilst decreasing toxicity. However, the treatment limitations of incomplete efficacy, infection, and cumulative toxicity persist. These issues have continued to drive the search for safer and more effective modulation of the immune system using targeted immunotherapy. This review will explore the current evidence base for management of ANCA-associated vasculitis and future treatment prospects

Exaggerated renal fibrosis in P2X4 receptor-deficient mice following unilateral ureteric obstruction

Background The ATP-sensitive P2X7 receptor (P2X7R) has been shown to contribute to renal injury in nephrotoxic nephritis, a rodent model of acute glomerulonephritis, and in unilateral ureteric obstruction (UUO), a rodent model of chronic interstitial inflammation and fibrosis. Renal tubular cells, endothelial cells and macrophages also express the closely related P2X4 receptor (P2X4R), which is chromosomally co-located with P2X7R and has 40% homology; it is also pro-inflammatory and has been shown to interact with P2X7R to modulate its pro-apoptotic and pro-inflammatory effects. Therefore, we chose to explore the function of P2X4R in the UUO model of renal injury using knockout mice. We hypothesized that UUO-induced tubulointerstitial damage and fibrosis would also be attenuated in P2X4R−/− mice. Method P2X4R−/− and wild-type (WT) mice were subjected to either UUO or sham operation. Kidney samples taken on Days 7 and 14 were evaluated for renal inflammation and fibrosis, and expression of pro-fibrotic factors. Results To our surprise, the obstructed kidney in P2X4R−/− mice showed more severe renal injury, more collagen deposition (picrosirius red staining, increase of 53%; P < 0.05) and more type I collagen staining (increase of 107%; P < 0.01), as well as increased mRNA for TGF-β (increase of 102%, P < 0.0005) and CTGF (increase of 157%; P < 0.05) by Day 14, compared with the UUO WT mice. Conclusion These findings showed that lack of P2X4R expression leads to increased renal fibrosis, and increased expression of TGF-β and CTGF in the UUO mode

Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial.

BACKGROUND: Granulomatosis with polyangiitis (GPA, Wegener's) and microscopic polyangiitis (MPA) are small vessel vasculitides collectively referred to as anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). AAV is associated with high rates of morbidity and mortality due to uncontrolled disease and treatment toxicity. Small randomized trials suggest adjunctive plasma exchange may improve disease control, while observational evidence suggests that current oral glucocorticoid doses are associated with severe infections in patients with AAV. A randomized study of both plasma exchange and glucocorticoids is required to evaluate plasma exchange and oral glucocorticoid dosing in patients with AAV. METHODS/DESIGN: PEXIVAS is a two-by-two factorial randomized trial evaluating adjunctive plasma exchange and two oral glucocorticoid regimens in severe AAV. Five hundred patients are being randomized at centers across Europe, North America, Asia, and Australasia to receive plasma exchange or no plasma exchange, and to receive standard or reduced oral glucocorticoid dosing. All patients receive immunosuppression with either cyclophosphamide or rituximab. The primary outcome is the time to the composite of all-cause mortality and end-stage renal disease.PEXIVAS is funded by the National Institute of Health Research (UK), the Food and Drug Administration (USA), the National Institutes of Health (USA), the Canadian Institute of Health Research (Canada), the National Health and Medical Research Council (Australia), and Assistance Publique (France). Additional in-kind supplies for plasma exchange are provided by industry partners (TerumoBCT, Gambro Australia, and Fresenius Australia). DISCUSSION: This is the largest trial in AAV undertaken to date. PEXIVAS will inform the future standard of care for patients with severe AAV. The cooperation between investigators, funding agencies, and industry provides a model for conducting studies in rare diseases. TRIAL REGISTRATION: Current Controlled Trials: (ISRCTN07757494) and clinicaltrials.gov: (NCT00987389).RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Membranous Glomerulonephritis With Crescents.

INTRODUCTION: Membranous glomerulonephritis (MGN) is rarely associated with necrotizing and crescentic glomerulonephritis (NCGN). METHODS: We report the clinical and pathologic findings in 15 patients with MGN and NCGN associated with anti-neutrophil cytoplasm antibodies (ANCAs), anti-glomerular basement membrane (GBM), or anti-phospholipase A2 receptor (PLA2R) antibodies. RESULTS: The cohort consisted of 15 patients: 7 males and 8 females with a median age of 63 years (range: 18-79). In 12 of 15 patients, MGN and NCGN were diagnosed at the time of the biopsy, and in 3 cases, MGN predated the NCGN. ANCA was positive in 7 cases (6 MPO myeloperoxidase (MPO)-ANCA and 1 PR3-ANCA), anti-GBM antibodies were detected in 5 cases, and anti-PLA2R antibodies were found in 2 cases. One case was negative for all antibodies. Microscopic hematuria was present in all but one patient who was anuric, and median urinary protein-to-creatinine ratio was 819.5 mg/mmol (range: 88-5600). Pathologic evaluation revealed MGN and NCGN with crescents involving 28% of glomeruli (median; range: 5%-100%). Follow-up was available for all 15 patients; all were treated with steroids; 10 with cyclophosphamide, and 6 also received rituximab. At a median follow-up of 72 months, 9 had stabilization or improvement of renal function, 6 had progressed to end-stage renal disease, and 4 died during the follow-up period. CONCLUSION: MGN with crescents associated with ANCAs or anti-GBM antibodies is a rare dual glomerulopathy. Patients present with heavy proteinuria, microscopic hematuria, and acute kidney injury and should be treated for a rapidly progressive glomerulonephritis. Prognosis is variable, and 40% of patients progress to end-stage renal disease

Local IL-17 Production Exerts a Protective Role in Murine Experimental Glomerulonephritis

IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of glomerulonephritis and IL-17 deficient mice are protected from nephrotoxic nephritis. However, a regulatory role for IL-17 has recently emerged. We describe a novel protective function for IL-17 in the kidney. Bone marrow chimeras were created using wild-type and IL-17 deficient mice and nephrotoxic nephritis was induced. IL-17 deficient hosts transplanted with wild-type bone marrow had worse disease by all indices compared to wild-type to wild-type bone marrow transplants (serum urea p<0.05; glomerular thrombosis p<0.05; tubular damage p<0.01), suggesting that in wild-type mice, IL-17 production by renal cells resistant to radiation is protective. IL-17 deficient mice transplanted with wild-type bone marrow also had a comparatively altered renal phenotype, with significant differences in renal cytokines (IL-10 p<0.01; IL-1β p<0.001; IL-23 p<0.01), and macrophage phenotype (expression of mannose receptor p<0.05; inducible nitric oxide synthase p<0.001). Finally we show that renal mast cells are resistant to radiation and produce IL-17, suggesting they are potential local mediators of disease protection. This is a novel role for intrinsic cells in the kidney that are radio-resistant and produce IL-17 to mediate protection in nephrotoxic nephritis. This has clinical significance as IL-17 blockade is being trialled as a therapeutic strategy in some autoimmune diseases

P2X7 receptor‐mediated Nlrp3‐inflammasome activation is a genetic determinant of macrophage‐dependent crescentic glomerulonephritis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141169/1/jlb0127-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141169/2/jlb0127.pd

Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy

IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression

Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background

The link between mutations in collagen genes and the development of Alport Syndrome has been clearly established and a number of animal models, including knock-out mouse lines, have been developed that mirror disease observed in patients. However, it is clear from both patients and animal models that the progression of disease can vary greatly and can be modifed genetically. We have identifed a point mutation in Col4a4 in mice where disease is modifed by strain background, providing further evidence of the genetic modifcation of disease symptoms. Our results indicate that C57BL/6J is a protective background and postpones end stage renal failure from 7 weeks, as seen on a C3H background, to several months. We have identifed early diferences in disease progression, including expression of podocyte-specifc genes and podocyte morphology. In C57BL/6J mice podocyte efacement is delayed, prolonging normal renal function. The slower disease progression has allowed us to begin dissecting the pathogenesis of murine Alport Syndrome in detail. We fnd that there is evidence of diferential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an infammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function

Experimental crescentic glomerulonephritis:a new bicongenic rat model

SUMMARY Crescentic glomerulonephritis (CRGN) is a major cause of human kidney failure, but the underlying mechanisms are not fully understood. Wistar Kyoto (WKY) rats are uniquely susceptible to CRGN following injection of nephrotoxic serum, whereas Lewis (LEW) rats are resistant. Our previous genetic studies of nephrotoxic nephritis (NTN), a form of CRGN induced by nephrotoxic serum, identified Fcgr3 and Jund as WKY genes underlying the two strongest quantitative trait loci for NTN phenotypes: Crgn1 and Crgn2, respectively. We also showed that introgression of WKY Crgn1 or Crgn2 individually into a LEW background did not lead to the formation of glomerular crescents. We have now generated a bicongenic strain, LEW.WCrgn1,2, in which WKY Crgn1 and Crgn2 are both introgressed into the LEW genetic background. These rats show development of NTN phenotypes, including glomerular crescents. Furthermore, we characterised macrophage function and glomerular cytokine profiles in this new strain. Additionally, we show that LEW.WCrgn1,2 rats are resistant to the development of glomerular crescents that is usually induced following immunisation with recombinant rat α3(IV)NC1, the specific Goodpasture autoantigen located in the glomerular basement membrane against which the immune response is directed in experimental autoimmune glomerulonephritis. Our results show that the new bicongenic strain responds differently to two distinct experimental triggers of CRGN. This is the first time that CRGN has been induced on a normally resistant rat genetic background and identifies the LEW.WCrgn1,2 strain as a new, potentially valuable model of macrophage-dependent glomerulonephritis