Inflammasomes in the Kidney.

Inflammasomes influence a diverse range of kidney disease, including acute and chronic kidney diseases, and those mediated by innate and adaptive immunity. Both IL-18 and in particular IL-1ß are validated therapeutic targets in several kidney diseases. In addition to leukocyte-derived inflammasomes, renal tissue cells express functional inflammasome components. Furthermore, a range of endogenous substances that directly activate inflammasomes also mediate kidney injury. Many of the functional studies have focussed on the NLRP3 inflammasome, and there is also evidence for the involvement of other inflammasomes in some conditions. While, at least in some disease, the mechanistic details of the involvement of the inflammasome remain to be elucidated, therapies focussed on inflammasomes and their products have potential in treating kidney disease in the future.

ANCA-Associated Vasculitis: Pathogenesis, Models, and Preclinical Testing.

Our understanding of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has developed greatly since the discovery of ANCA, directed against neutrophil components, in 1982. Observations in human disease, and increasingly sophisticated studies in vitro and in rodent models in vivo, have allowed a nuanced understanding of many aspects of the immunopathogenesis of disease, including the significance of ANCA as a diagnostic and monitoring tool as well as a mediator of microvascular injury. The mechanisms of leukocyte recruitment and tissue injury, and the role of T cells increasingly are understood. Unexpected findings, such as the role of complement, also have been uncovered through experimental studies and human observations. This review focusses on the pathogenesis of ANCA-associated vasculitis, highlighting the challenges in finding new, less-toxic treatments and potential therapeutic targets in this disease. The current suite of rodent models is reviewed, and future directions in the study of this complex and fascinating disease are suggested.

Cardiovascular risk is similar in patients with glomerulonephritis compared to other types of chronic kidney disease: a matched cohort study.

BACKGROUND: Patients with chronic kidney disease (CKD) due to glomerulonephritis (GN) are thought to be at high risk for cardiovascular disease (CVD). However, no study has examined whether GN directly contributes to CV risk beyond the effects conferred by pre-existing traditional risk factors and level of renal function. METHODS: Matched cohort study using the previously described prospective CanPREDDICT study cohort. 2187 patients with CKD (eGFR 15-45 ml/min/m2) from 25 Canadian centres were divided into GN vs non-GN cause of CKD. Patients on immunotherapy for GN were not included in the study. Standardized measures of CV risk factors, biomarkers and CV outcomes were recorded over 3 years of follow-up, with the primary outcome measure being time to first all-cause CV event. RESULTS: In the overall cohort, CV events occurred in 25 (8.7%) of the GN group and 338 (17.8%) of the non-GN group (HR 0.45, 95% CI 0.30-0.67, p < 0.01). In a Cox regression multivariable model that included age, sex, prior diabetes and CVD, baseline eGFR and onset of renal replacement therapy, the risk of CV events was similar in the GN and non-GN groups (HR 0.71, 95% CI 0.47-1.08, p = 0.11). GN and non-GN patients were matched by age and using a propensity score including sex, prior diabetes and CVD and baseline eGFR. In the matched group, the risk of CV events was similar in GN vs non-GN patients (N = 25/271 (9.2%) in both groups, HR 1.01, 95% CI 0.05-1.77, p = 0.9). An interaction analysis showed that CRP, ACR and troponin conferred differing amounts of CV risk in the GN and non-GN groups. CONCLUSIONS: Patients with advanced CKD due to GN have a high 8.7% absolute 3-year risk of CVD, attributable to prior CV risk factors and level of kidney function rather than the GN disease itself.

The Players: Cells Involved in Glomerular Disease.

Glomerular diseases are common and important. They can arise from systemic inflammatory or metabolic diseases that affect the kidney. Alternately, they are caused primarily by local glomerular abnormalities, including genetic diseases. Both intrinsic glomerular cells and leukocytes are critical to the healthy glomerulus and to glomerular dysregulation in disease. Mesangial cells, endothelial cells, podocytes, and parietal epithelial cells within the glomerulus all play unique and specialized roles. Although a specific disease often primarily affects a particular cell type, the close proximity, and interdependent functions and interactions between cells mean that even diseases affecting one cell type usually indirectly influence others. In addition to those cells intrinsic to the glomerulus, leukocytes patrol the glomerulus in health and mediate injury in disease. Distinct leukocyte types and subsets are present, with some being involved in different ways in an individual glomerular disease. Cells of the innate and adaptive immune systems are important, directing systemic immune and inflammatory responses, locally mediating injury, and potentially dampening inflammation and facilitating repair. The advent of new genetic and molecular techniques, and new disease models means that we better understand both the basic biology of the glomerulus and the pathogenesis of glomerular disease. This understanding should lead to better diagnostic techniques, biomarkers, and predictors of prognosis, disease severity, and relapse. With this knowledge comes the promise of better therapies in the future, directed toward halting pathways of injury and fibrosis, or interrupting the underlying pathophysiology of the individual diseases that lead to significant and progressive glomerular disease.

The NLRP3 inflammasome in kidney disease and autoimmunity.

The NLRP3 inflammasome is an intracellular platform that converts the pro-inflammatory cytokines interleukin (IL)-1ß and IL-18 to their active forms in response to 'danger' signals, which can be either host or pathogen derived, and mediates a form of inflammatory cell death called pyroptosis. This component of the innate immune system was initially discovered because of its role in rare autoinflammatory syndromes called cryopyrinopathies, but it has since been shown to mediate injurious inflammation in a broad range of diseases. Inflammasome activation occurs in both immune cells, primarily macrophages and dendritic cells, and in some intrinsic kidney cells such as the renal tubular epithelium. The NLRP3 inflammasome has been implicated in the pathogenesis of a number of renal conditions, including acute kidney injury, chronic kidney disease, diabetic nephropathy and crystal-related nephropathy. The inflammasome also plays a role in autoimmune kidney disease, as IL-1ß and IL-18 influence adaptive immunity through modulation of T helper cell subsets, skewing development in favour of Th17 and Th1 cells that are important in the development of autoimmunity. Both IL-1 blockade and two recently identified specific NLRP3 inflammasome blockers, MCC950 and ß-hydroxybutyrate, have shown promise in the treatment of inflammasome-mediated conditions. These targeted therapies have the potential to be of benefit in the growing number of kidney diseases in which the NLRP3 inflammasome has been implicated.

Renal leukocyte chemotactic factor 2 (LECT2) amyloidosis in First Nations people in Northern British Columbia, Canada: a report of 4 cases.

Leukocyte chemotactic factor 2 (LECT2) amyloidosis is a recently identified type of amyloidosis that may represent an underdiagnosed cause of chronic kidney disease. LECT2 amyloidosis typically is reported as being renal limited and, in the United States, more prevalent in Hispanic patients. We add to the epidemiologic data of this condition by describing 4 First Nations people from Northern British Columbia, Canada, who presented with slowly progressive chronic kidney disease that was found to be due to LECT2 amyloidosis.