Laminin-521: a novel target for pathogenic autoantibodies in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is typically characterized by autoimmunity against the α3 chain of type IV collagen. Rarely, circulating autoantibodies are not detected. These atypical cases follow a more indolent clinical course, and underlying mechanisms, including alternative target antigens, require investigation. In this issue of Kidney International, Kuang et al. describe a case of anti-GBM disease with autoantibodies against the GBM component laminin-521 and demonstrate that laminin-521 is pathogenic in a rat model of anti-GBM glomerulonephritis.

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.

Recurrent membranous nephropathy after transplantation: donor antigen and HLA converge in defining risk.

Membranous nephropathy, like many forms of glomerulonephritis, is an HLA-associated autoimmune disease that can recur in the transplanted kidney. In this issue of Kidney International, Berchtold and colleagues publish an intriguing and important paper on risk factors for recurrent post-transplant membranous nephropathy due to autoimmunity to PLA2R1. They found that the genetics of both the autoantigen and donor HLA are important determinants of the risk of recurrent disease in the graft.

Tertiary lymphoid tissue in kidneys: understanding local immunity and inflammation.

Tertiary lymphoid tissues are peripheral foci of immune activity that develop in kidneys and other peripheral organs in the context of chronic inflammation. In this issue of Kidney International, Sato and colleagues present a detailed characterization of tertiary lymphoid tissues in mouse and human kidneys in the context of acute kidney injury, chronic pyelonephritis, aging, and chronic kidney disease, showing the importance of nontraditional roles of B cells in the inflamed kidney microenvironment.

Glomerular Disease Education Experience across Nephrology Fellowship Programs: An International Survey.

Introduction: Glomerulonephritis (GN) education is an important, albeit a challenging, component of nephrology fellowship training. We hypothesized that trainee experience varies widely across programs, leading to differences in self-reported competency levels in the diagnosis and management of glomerular diseases. Methods: The Glomerular Disease Study & Trial Consortium (GlomCon) conducted an anonymous online survey to determine the educational experience of nephrology trainees. We used multiple-choice questions to obtain data about (a) curriculum-based education, (b) dedicated specialty clinic, and (c) exposure to pathology. We leveraged a visual analog scale of 1-100 (with a higher number indicating a higher comfort level) to assess self-reported levels of clinical competency. The survey was disseminated via email to the subscribing members of GlomCon and through Twitter. Results: In total, there were 109 respondents to our survey, and 56% were from training programs in the USA. Exposure to a specialized GN clinic was reported by 45%, while 77% reported the presence of an onsite nephropathologist at their training program. Self-reported competency scores were 59 ± 25 and 52 ± 25 for diagnosis and treatment of glomerular diseases, respectively. Days spent in a GN clinic per year, years of fellowship, and dedicated nephropathology didactics were associated with higher diagnosis and treatment competency scores. Conclusion: Trainees report a wide variation in glomerular disease education across fellowship programs. A lack of nephropathology exposure and a dedicated GN curriculum was associated with lower scores in self-reported clinical competency in caring for patients with glomerular disease.

PD-L1- and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease.

Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA323-339 and calcitriol targeted dLN PD-L1hi DCs of immunized mice and reduced their MHC class II expression. OVA323-339/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3+ and IL-10+ peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture's vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.

HLA and kidney disease: from associations to mechanisms.

Since the first association between HLA and diseases of native kidneys was described almost 50 years ago, technological and conceptual advances in HLA biology and typing, together with better case ascertainment, have led to an improved understanding of HLA associations with a variety of renal diseases. A substantial body of evidence now supports the existence of HLA genetic associations in the field of renal disease beyond the role of HLA in allogeneic responses in transplant recipients. Allomorphs of HLA have emerged as important risk factors in most immune-mediated renal diseases, which, together with other genetic and environmental factors, lead to loss of tolerance and autoimmune-mediated renal inflammation. HLA associations have also been described for renal diseases that are less traditionally seen as autoimmune or immune-mediated. Here, we review essential concepts in HLA biology and the association of HLA with diseases of the native kidneys, and describe the current understanding of the epistatic and mechanistic bases of HLA-associated kidney disease. Greater understanding of the relationship between HLA and kidney function has the potential not only to further the understanding of immune renal disease at a fundamental level but also to lead to the development and application of more effective, specific and less toxic therapies for kidney diseases.

Thrombotic microangiopathy associated with intravenous injection of extended-release oxycodone.

We describe the case of a 35-year-old man presenting with thrombotic microangiopathy (TMA) and renal impairment following, as he later disclosed, intravenous injection of oral formulation tamper-resistant extended-release oxycodone hydrochloride (Oxycontin). Recurrent misuse of this agent was associated with relapsing TMA despite treatment with terminal complement inhibitor eculizumab. Cases of TMA have been reported in the USA in association with intravenous misuse of extended-release oxymorphone (Opana ER) after the introduction of a new non-crushable formulation in 2012. There are two reported accounts of TMA associated with tamper-resistant Oxycontin, which became available in Australia in 2014. This is the first documented case in which eculizumab was used. This case illustrates the practical diagnostic challenges in identifying TMA disorders, and the importance of a detailed drug history. It also highlights the need to clarify what role, if any, eculizumab therapy has in cases of drug-associated TMA.