Review
Presence of anti-GBM antibodies can be detected in blood of most patients, or by direct IF on a biopsy specimen. The typical finding on direct IF is a linear IgG staining along the GBM, which is often accompanied by some degree of complement deposition. 19 This finding by IF (as depicted in figure 1D) strink- ingly reveals the pathogenetic mechanism of anti-GBM disease because it represents binding of autoantibodies to the well char- acterised autoantigen expressed in the basement membrane. 20 By light microscopy, anti-GBM disease is characterised by a cres- centic glomerulonephritis which develops after destruction of the GBM due to the inflammatory response that evolves from IgG binding. Because this is an acute process by which the entire GBM of all glomeruli is being targeted in a relatively short time, typically, cellular crescents are present in the majority of glom- eruli in the renal biopsy. It is generally acknowledged that if 100% of glomeruli in a renal biopsy have crescents, outcome is poor. This rule of thumb is based on a series of 71 patients: in this study, no patient who required haemodialysis and had 100% crescents on kidney biopsy recovered renal function. 21 In a recent study of 123 patients, it was shown that there is some variability in the histological patterns of anti-GBM disease. For instance, younger patients in particular would still have a proportion of normal glomeruli in the biopsy, 22 and variation in the glomerular lesion also in relation to chronic lesions such as fibrous crescents and global glomerulosclerosis was encountered. In this study, dialysis independency at presentation, presence of normal glomeruli and a relatively mild interstitial infiltrate were associated with a favourable outcome. A variant of anti-GBM disease, ‘double positive’ disease marked by presence of circu- lating ANCA, directed predominantly to MPO is present in 10%–50% of patients with anti-GBM. While the renal presen- tation of these patients is similar to isolated anti-GBM disease, patients with ‘double positive’ disease often have a relapsing disease course akin to ANCA vasculitis and require maintenance immunosuppression. Unlike other diseases presenting with detectable antibodies (dsDNA in LN, ANCA in ANCA-GN), the titres of anti-GBM antibodies have a relevance in guiding immunosuppressive therapy. The ultimate therapeutic goal is reduction of circu- lating anti-GBM antibodies to a normal range or a range which is considered ‘non-toxic’, 23 the latter depending on the specific assay used to detect antibodies.
deposits which involve more than half of capillary loops of more than half of glomeruli with mesangial deposits. 13 Disease antigens have been identified in class V LN. Exostosin 1 and exostosin 2 are present in around a third of the patients, and these patients present at a younger age and with less severe chronic damage on kidney biopsy. 14 Another identified antigen is neural cell adhesion molecule 1, which is present in around 6.6% of cases with class V LN. 15 Cryoglobulinaemic glomerulonephritis Initial presentation of cryoglobulinaemic disease differs among patients, and spans from relatively mild cases to life-threatening disease with a rapid decline in kidney function. Organ manifesta- tions often result in significant morbidity and cumulative organ impairment. 16 Of the glomerular diseases that are discussed in this review, cryoglobulinaemic GN 17 is the only one for which EM is essential to the diagnosis. From a light microscopic perspec- tive, cryoglobulinaemic GN shares the most similarities with LN class IV. Lupus-like lesions such as pseudothrombi, and lesions similar to wire loops (figure 2E) are revealed by EM to consist of cryoglobulins, which show a microtubular substructure, rather than the more regular deposits that are found in LN. Endocap- illary and mesangial cell proliferation, thickening of the GBM and subendothelial deposits resembling a MPGN-pattern can be indicative of cryoglobulinaemic GN. A third of the biopsies also reveal vasculitis of small-sized and medium-sized arteries with fibrinoid necrosis. 18 From a clinical perspective, cryoglobulins have been subcategorised in types 1, 2 and 3, but all of these may contain IgG and/or IgM and lead to similar findings by EM. Types 1–3 are almost indistinguishable according to the findings in the biopsy, although characterisation by IF (figure 1C) may be helpful as type 1 characteristically should have a light chain restriction, type 2 an IgM kappa predominance, whereas type 3 has mixed immunoglobulins. Anti-GBM disease Anti-GBM disease presents with kidney disease in almost all patients, and is characterised by a rapid deterioration of kidney function. Many patients present with dialysis-dependency, and the presence of oliguria and especially anuria portends a risk factor for remaining on dialysis even after immediate treatment initiation.
Figure 5 The expanding spectrum of diseases summarised under the umbrella of glomerulonephritis. A subclassification is based on predominant histologic manifestation, that is, deposition of immune complexes. A minority of these diseases are under a shared care between rheumatologists and nephrologists, but often require an interdisciplinary approach (ie, amyloidosis with haematologists and cardiologists). ANCA, anti-neutrophil cytoplasmic antibody; GBM, glomerular basement membrane; MPO, myeloperoxidase; PR3, proteinase 3.
Kronbichler A, et al . Ann Rheum Dis 2023; 82 :585–593. doi:10.1136/annrheumdis-2022-222495
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