Review Novel aspects in the pathophysiology and diagnosis of glomerular diseases Andreas Kronbichler , 1,2 Ingeborg Bajema, 3 Duvuru Geetha, 4 Marcus Säemann 5,6
Renal pathologists mostly use combinations of findings by immunofluorescence (IF) staining and electron microscopy (EM) to determine the nature and location of all kinds of deposits in a kidney biopsy. This enables the distinction between an enormous variety of deposits sharing characteristics by either one technique but are different by mutual exclusion. For example, in C3 glomerulonephritis, C3 is the dominant staining by IF, but the variant dense deposit disease can only be recognised by EM. 3 For this review, we have chosen to focus on five kidney diseases that are commonly encountered by the rheumatologists: IgA vasculitis (IgAV), lupus nephritis (LN), cryoglobulinaemia, anti-glomerular basement membrane (GBM) disease and anti- neutrophil cytoplasm-antibody glomerulonephritis (ANCA-GN). For the latter, its denotation as an ICGN may be questioned as indicated already by its other name ‘pauci-immune glomerulonephritis’. However, recent evidence highlights the importance of deposition of especially complement fragments in kidney biopsy specimens of patients with ANCA- GN. We also include it in this review because of its relevance for the rheumatologist. Most importantly, whereas pathogenesis of the five diseases that are the focus of our review may differ, they share the important clinical threat of turning into chronic kidney disease (CKD) and frequently require a shared care by rheumatologists and nephrologists. CLINICAL PHENOTYPES The discussed diseases not only differ among each other in terms of organ manifestations (table 1), also within their own spectrum marked differences are apparent, for instance in their clinical presen- tation, treatment response and outcomes. Kidney disease clinically presents as nephritic syndrome in IgAV, cryoglobulinaemia, anti-GBM disease and ANCA-GN, while patients with LN present with different degrees of nephrosis (although often as non-nephrotic proteinuria, and might also present with a degree of haematuria and thus nephritis). The differences in symptoms between nephritic syndrome and nephrosis are highlighted in table 2. Assessment of kidney function (serum creatinine, estimated glomerular filtration rate (eGFR)) and urinalysis, both at diagnosis and follow-up visits, is needed to detect overt kidney involvement in cases with a mainly extra-renal initial manifestation. Early referral to nephrology to verify kidney involvement and establish a therapeutic concept directed to limit the extent of kidney damage (ie, sclerosis) is needed as part of a shared care between specialties.
ABSTRACT Immune deposits/complexes are detected in a multitude of tissues in autoimmune disorders, but no organ has attracted as much attention as the kidney. Several kidney diseases are characterised by the presence of specific configurations of such deposits, and many of them are under a ’shared care’ between rheumatologists and nephrologists. This review focuses on five different diseases commonly encountered in rheumatological and nephrological practice, namely IgA vasculitis, lupus nephritis, cryoglobulinaemia, anti-glomerular basement membrane disease and anti-neutrophil cytoplasm-antibody glomerulonephritis. They differ in disease aetiopathogenesis, but also the potential speed of kidney function decline, the responsiveness to immunosuppression/immunomodulation and the deposition of immune deposits/complexes. To date, it remains unclear if deposits are causing a specific disease or aim to abrogate inflammatory cascades responsible for tissue damage, such as neutrophil extracellular traps or the complement system. In principle, immunosuppressive therapies have not been developed to tackle immune deposits/complexes, and repeated kidney biopsy studies found persistence of deposits despite reduction of active inflammation, again highlighting the uncertainty about their involvement in tissue damage. In these studies, a progression of active lesions to chronic changes such as glomerulosclerosis was frequently reported. Novel therapeutic approaches aim to mitigate these changes more efficiently and rapidly. Several new agents, such as avacopan, an oral C5aR1 inhibitor, or imlifidase, that dissolves IgG within minutes, are more specifically reducing inflammatory cascades in the kidney and repeat tissue sampling might help to understand their impact on immune cell deposition and finally kidney function recovery and potential impact of immune complexes/ deposits. INTRODUCTION The term immune-complex glomerulonephritis (ICGN) is used in connection with specific disease entities and denotes a pattern of disease in which an immune-mediated process resulting in glomer- ular deposits has led to kidney injury. The huge complexity behind the term could easily be under- estimated: there are numerous kidney diseases that are characterised by the presence of deposits; but not all deposits are immune deposits, and not all immune deposits are immune complexes. 1 However, regardless of the nature of the deposits, they are considered to initiate and perpetuate an inflammatory response and further abrogate toler- ance mechanisms of both B and T cells, 2 critical in the pathogenesis of autoimmunity.
Handling editor David S Pisetsky 1 Department of Medicine, University of Cambridge, Cambridge, UK 2 Vasculitis and Lupus Service, Addenbrooke’s Hospital, Cambridge, UK 3 Department of Pathology, Leiden University Medical Center, Leiden and Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands 4 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 5 6th Medical Department, Nephrology and Dialysis, Clinic Ottakring, Vienna, Austria 6 Medical Faculty, Sigmund Freud University, Vienna, Austria
Correspondence to Dr Andreas Kronbichler, Department of Medicine, University of Cambridge, Cambridge, UK; a k2283@cam.a c.uk
AK and IB contributed equally.
Received 16 March 2022 Accepted 9 December 2022 Published Online First 19 December 2022
© Author(s) (or their employer(s)) 2023. No
commercial re-use. See rights and permissions. Published by BMJ.
To cite: Kronbichler A, Bajema I, Geetha D, et al . Ann Rheum Dis 2023; 82 :585–593.
Kronbichler A, et al . Ann Rheum Dis 2023; 82 :585–593. doi:10.1136/annrheumdis-2022-222495
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