Nov 2021 Edition
The latest edition of the ISN Journals eDigest, a companion to the October issues of Kidney International (KI) and Kidney International Reports (KI Reports), presents articles from both journals on ANCA and its associated conditions.
Articles from KI include the KDIGO guideline and executive summary for the management of glomerular diseases, a study of ANCA-associated glomerulonephritis complicating treatment with hydralazine, the role of endothelial cells in glomerular diseases, and a conceptual framework linking immunology, pathology, and clinical features in primary membranous nephropathy.
The first paper in KI Reports discusses the significance of glomerular C3 deposition in patients with ANCA-associated glomerular nephritis, while the other reveals results from an audit of the clinical practices of physicians in teaching hospitals who treated patients with ANCA-associated vasculitis.
KIDNEY INTERNATIONAL ARTICLES
Developed to assist clinicians caring for patients with glomerulonephritis while being mindful of implications for policy and cost, the guideline, also presented as an executive summary, provides practical, evidence-based recommendations and useful infographics based on input from relevant experts to guide diagnosis, prognosis, treatment, and special situations. It also offers research recommendations for areas where there are gaps in knowledge.
This survey, published as a companion paper to the KDIGO clinical practice guideline for the management of glomerular diseases, and Executive Summary, sought to establish a consensus-derived set of critically important outcomes in future trials. Four priorities were defined: confronting death and compounded suffering, focusing on specific targets in glomerular disease, preserving meaning in life, and fostering self-management.
Retinoic Acid Receptor Responder1 Promotes Development of Glomerular Diseases via the Nuclear Factor-KB Signaling Pathway
This study is another example of the role of endothelial cells in glomerular diseases. The investigators found that in diabetic kidney disease, ANCA-vasculitis, and IgA nephropathy, retinoic acid receptor responder 1 (Rarres1) was preferentially localized in glomerular and peri-tubular endothelial cells. To examine the role of endothelial Rarres1, the protein was either overexpressed or knocked out in renal endothelial cells. Mice overexpressing endothelial Rarres1 and given nephrotoxic serum had more severe podocyte damage than control mice, and conversely, podocytes were better preserved after induction of nephrotoxic nephritis in Rarres1 knockout mice. These data suggest Rarres1 in the glomerular microvasculature may be a mediator of podocyte injury and open up new therapeutic approaches.
This study is perhaps the largest and most detailed investigation of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) occurring in the setting of hydralazine use. Hydralazine has also been associated with lupus-like syndromes, and several of the patients described here seemed to have features of both AAV and lupus. Given the array of effective and possibly less toxic anti-hypertensive medications available today, an informal poll among nephrology colleagues showed considerable variation in use worldwide. We suspect that cases of hydralazine-associated AAV will continue to be found, and it will be important for nephrologists to keep this in mind as we consult our cardiology colleagues.
A Conceptual Framework Linking Immunology, Pathology, and Clinical Features in Primary Membranous Nephropathy
This excellent review sheds light on current knowledge on the development and time course of changes in the serum levels of autoantibodies against PLA2R, proteinuria, and histological findings that underlie the pathophysiology of primary membranous nephropathy. The authors make the important point that evaluation of risk of disease progression is a dynamic process. Monitoring of PLA2R antibodies together with proteinuria should now drive indications and adjustment of therapy as recommended by the recently published KDIGO clinical practice guideline for the management of glomerular diseases.
Circulating complement factor H (FH) is a key regulator of the alternative complement pathway. The authors interrogated the role of FH locally produced by endothelial cells. Using cultured kidney FH-deficient murine and human endothelial cells, they found that in the absence of FH, the cells’ cytoskeleton was remodeled, cellular energy metabolism was altered, and proliferation increased. These changes could be reversed by FH repletion. Additionally, in the absence of FH, murine kidney endothelial cells initiated a pro-inflammatory gene program. These data suggest that endothelial FH is important in maintaining endothelial integrity.
KIDNEY INTERNATIONAL REPORTS ARTICLE
This study discusses the clinicopathologic and prognostic significance of glomerular C3 deposition in the renal histopathology of patients with ANCA-associated glomerular nephritis (GN). Recent studies have revealed the pivotal role of complement activation in the development of ANCA-GN. Researchers in Tokyo retrospectively compared clinicopathologic features and long-term outcomes in 142 patients with and without C3 deposition. Patients with glomerular C3 deposition were found to have worse renal outcomes and lower survival rates.
A team in the Netherlands from the Arthritis Research and Collaboration Hub study group conducted an investigative audit of the clinical practices of physicians in nine teaching hospitals who treated 233 patients with ANCA-associated vasculitis (AAV) from 2010-2018. The team retrospectively collected data on clinical variables, medications, and outcomes.
Physicians most frequently used oral cyclophosphamide for induction therapy. Azathioprine was most commonly administered for maintenance therapy. The most prevalent adverse outcomes included major infection and relapse.