Review
elicit an inflammatory response that co-occurs with complement activation, by which inflammatory cells such as neutrophils will be attracted that will try to get rid of the deposits, but in the process, will destroy parts of the basement membrane through release of inflammatory enzymes. Because subepithelial deposits, and to some extent mesangial deposits are further removed from the immune system they will elicit a less severe inflammatory response than subendothelial deposits. For this review, we have focused on five renal diseases which are under the ‘shared care’ of rheumatologists and nephrol- ogists to show the many facets of ICGN and how they relate to our insights into the pathogenesis of disease, diagnosis and treatment. A selection of different glomerular lesions is given in figure 2A–F. HOW DO IMMUNE COMPLEXES/CELLS DAMAGE THE KIDNEY? The filtration barrier comprised of endothelium, GBM and podocytes which are the main target of inflammatory and non- inflammatory injury in glomerular disease. Most exogenous non- renal antigens collect in the subendothelial space and mesangial areas that are close to the circulation allowing antibody binding, production of anaphylatoxins and recruitment of inflammatory cells. 36 The complement system, neutrophil/macrophage stimu- lation and the induction of several cytokines/chemokines lead to tissue inflammation, and thus damage of kidney structures. 37 Additionally, mesangial cells and endothelial cells are activated by complement and deposition of membrane attack complex results in mesangial expansion, endothelial cell detachment and apoptosis. 38 ICGNs are histologically characterised by distinct patterns of deposition of immune deposits mostly accompa- nied by complement deposits, especially C3 and C1q. Immune deposits usually precede the appearance of histological evidence for glomerular lesions. 6 Among the many factors contributing to autoimmunity, neutrophil extracellular traps (NETs) have a prominent role in ICGN. NETs contain neutrophilic granules, histones and decon- densed chromatin which also contain autoantigens. NETosis, a process by which chromatin is released, uncovers enzymes and autoantigens to the extracellular circulation in an inflam- matory context (figure 6). Blood of patients with LN and AAV demonstrate increased numbers of unique low-density granulo- cytes which have high NET-generating capacity and also display impaired NET degradation due to the presence of DNase1 inhibitors or anti-NET antibodies. NETs colocalise with immune deposits and a failure to degrade NETs, either due to presence of DNase1 inhibitors or anti-NET antibodies, promotes develop- ment of LN. 7 At present, it is unclear if NETosis directly contrib- utes to disease pathogenesis or if it is a ‘bystander’ reaction of the inflammatory response. 39 Therapeutic trials with agents such as CIT-013 40 to inhibit NET formation and promote NET clear- ance will help to clarify the role of NETs in autoimmunity. Further important steps take place during the natural course of ICGN, leading to progression of kidney lesions. A decrease in Dnase1 gene transcription and an accumulation of activated caspase 3-positive cells in kidney coincides with transition from a mesangial to a membranoproliferative pattern of LN indica- tive of disease progression. 41 42 Among other factors, megsin, a serine protease inhibitor, is involved in mesangial matrix expansion. The increase of mesangial cells was also linked to an augmented deposition of immune complexes, immunoglob- ulins and complement components, as highlighted by the pres- ence of electron-dense deposits in transgenic mice as early as at
ANCA-associated vasculitis In ANCA-associated vasculitis, kidney disease is most frequent in microscopic polyangiitis (>80%), while less frequent in gran- ulomatosis with polyangiitis (around 60%) and in eosinophilic granulomatosis with polyangiitis (around 25%–30%). Kidney disease can present as slowly progressive 24 over time or as a rapidly progressive glomerulonephritis, characterised by a rapid deterioration of kidney function. 25 ANCA bind to peripheral neutrophil epitopes, which through a complex interaction between triggered neutrophils and the endothelium ensues in what we recognise as vasculitis. 26 If this damage occurs in glomeruli, the inflammatory process destroys the capillary loops resulting in fibrinoid necrosis, and conse- quently, inflammatory mediators will leak into the Bowman’s space, resulting in proliferation of parietal epithelial cells even- tually forming crescents (figure 2C). In ANCA-GN, however, antibodies succumb in the inflammation and only the bystander effect of complement activation is observed in some biopsies. ANCA-GN is characterised by the virtual absence of deposits (‘pauci-immune’, figure 1E). However, by EM, studies showed that immune complex deposits were found in half of the patients and a majority (87% of 126 patients) showed positive IF findings for at least one immunoglobulin or complement component, even though staining was in general subdued. 27 Patients with MPO-ANCA vasculitis and IgG deposits tend to have poorer kidney survival. 28 In-depth analysis found a variable degree of complement deposition reflecting involvement of the alternative complement pathway, with a higher frequency in MPO-ANCA vasculitis compared with PR3-ANCA vasculitis. 29 30 Glomerular C3d staining not only associated with severity of kidney func- tion impairment and lower response rates to therapy, 31 but also formation of cellular crescents. 29 Numerous other glomerulonephritides can be encountered by the nephrologist and are summarised according to the pres- ence of immune deposits/complexes in figure 5. Many of these, however, fall outside the realm of the rheumatologist. CIRCULATING IMMUNE COMPLEXES AND LOCATION OF IMMUNE DEPOSITS/COMPLEXES WITHIN GLOMERULAR STRUCTURES Once there are circulating immune complexes (CIC), it is likely that they will deposit in the kidney, and this process has been linked to disease pathogenesis in several autoimmune disor- ders. In SLE, the amount of CIC correlates with disease activity and kidney involvement, and changes of CIC levels predict therapy response. 32 In most cases with cryoglobulinaemia (especially types II and III), the cryoglobulins have rheuma- toid factor activity, that in turn enables them to form immune complexes. 33 In IgAV, IgA1-containing CICs are usually detected, which are larger in size compared with those detected in IgAN. 34 ANCA-associated vasculitis is considered an antibody- mediated disorder, and it remains obscure if there is a role of CICs, which has recently been reported in a small study from Japan. 35 Irrespective of the nature of the deposits, their loca- tion is closely associated with clinical symptoms, as depicted in figure 4. Mesangial deposits will lead to hypercellularity of mesangial fields and broadening of the mesangial matrix. This is clinically associated with haematuria: through expansion of mesangial areas, breaks in the basement membrane will ensue leading to loss of erythrocytes in Bowman’s space. Subepithelial deposits will eventually lead to spike formation: rearrangement of the basement membrane around the deposits that look similar to spikes in a silver staining. Only subendothelial deposits will
Kronbichler A, et al . Ann Rheum Dis 2023; 82 :585–593. doi:10.1136/annrheumdis-2022-222495
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