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correlated with each other and reflect immunological activity contributing to kidney involvement. 59 This would allow to reduce the number of kidney biopsies, which is not well accepted by most patients. A further step towards prediction of kidney disease and specific lesions is a machine learning approach. Combination of RNA sequencing with demographic and labo- ratory parameters had an accuracy of 81.7% to predict active LN as compared with patients without LN, and this model was influenced by dsDNA titers, age, male sex and the expression of the PTPRO and IL10RA genes. 60 Disease flares of LN could be predicted by six variables, including partial remission, presence of endocapillary hypercellularity (at baseline biopsy), age, serum albumin, dsDNA and serum complement C3, 61 thus machine learning approaches might also displace the need for repeated kidney biopsies in LN. Treatment approaches of immune-mediated diseases should aim to immediately abrogate the transition to irreversible damage. Uncertainty, however, exists if resolution of immune deposits on initiation of immunosuppression plays a role in this context. In repeated kidney biopsies of patients with membra- nous LN, the resorption of immune deposits was seen more frequently in patients treated with rituximab compared with conventional immunosuppression, and this was associated with a favourable treatment response. 62 The utility of repeat kidney biopsies to evaluate the role of persistent immune deposits together with the histological alterations in particular in rela- tion to chronicity, clearly warrants further study. Novel methods may allow prediction of progression of specific lesions, and will incorporate multiple ‘omics’ approaches and machine learning algorithms. NEW THERAPEUTIC AVENUES Newer substances specifically tackling inflammatory pathways are needed to mitigate the transition of acute changes to chronic damage seen on repeat kidney biopsies. Imlifidase (IdeS, IgG-degrading enzyme of Streptococcus pyogenes ) is capable to cleave IgG from circulation within minutes 63 and thus is a therapeutic option for IgG antibody- mediated diseases, such as anti-GBM disease, renal transplan- tation, but also Guillain-Barre syndrome. Imlifidase was tested in a mouse model of anti-GBM disease. Kidney-bound IgG was cleaved by IdeS by approximately 93.4%, and this also reduced the glomerular influx of leukocytes by 62% and the staining of C3 and C1q. 64 A phase IIa trial in anti-GBM disease recruiting 15 patients with severely impaired kidney function found that 10 patients at 6 months were free of dialysis with a median GFR of 27 mL/min/1.73 m 2 . 23 65 A phase III trial in anti-GBM disease is in the set-up phase. Some of the patients in the phase IIa trial were double-positive (anti-GBM and ANCA), and imli- fidase led to a similar complete disappearance of ANCA after therapy. A single case report of a patient with severe respiratory compromise due to AAV was treated with imlifidase and weaned off venovenous extracorporeal membrane oxygenation after therapy. 66 Further developments in antibody-mediated diseases might be expected. Avacopan, which blocks the C5aR1, ameliorated the forma- tion of crescents in a mouse model of MPO-ANCA vasculitis in a dose-dependent fashion. In addition, significant reductions of haematuria and proteinuria were reported. 67 In the phase II trial CLEAR both avacopan groups had a more rapid decline in albu- minuria and overall disease activity. 68 The phase III trial ADVO- CATE randomised 331 patients to either avacopan plus standard of care or prednisone plus standard of care. The composite
primary endpoint of remission at week 26 and sustained remis- sion at week 52 were reached by 72.3% versus 70.1% and 65.7% versus 54.9% participants in the avacopan and predni- sone groups, respectively. Patients in the avacopan group had higher albuminuria values at baseline and a significant decrease of albuminuria by week 4, but there was no difference of albu- minuria change between groups at week 52. A significant differ- ence in change of eGFR between groups was observed at week 26 and week 52, with an increase of 7.3 mL/min/1.73 m 2 in the avacopan and 4.1 mL/min/1.73 m 2 in the prednisone arm at week 52, respectively. 69 The C5aR1 not only primes neutrophils for activation by ANCA, it further perpetuates the generation of ANCA, but also leads to neutrophil retention and reactive oxygen species bursts within glomerular capillaries. 70 The C5aR1 is expressed by other inflammatory cells with relevance in ANCA-GN, such as monocytes and macrophages. 71 Informa- tion about histology and especially repeat biopsies, which was optional in the ADVOCATE trial, are not published thus far. Other complement inhibitors, such as iptacopan, an oral factor B inhibitor, are under investigation in several glomerular diseases, and it seems that targeting complement pathways will revolu- tionise management strategies in kidney diseases. However, it is unclear so far if these therapies also reduce immune deposits in kidney tissue. CONCLUSION In summary, immune deposits in the kidney are a key feature of manifestations of autoimmune kidney diseases. There is, however, still limited data to support their pathogenetic evidence, but in general the location, the density and the property of deposits predict clinical presentation and disease severity. Experimental therapies have not specifically been developed to tackle immune deposits. Ultimately, future research will need to involve protocol kidney biopsies, multi- omics approaches and artificial intelligence to assess time- dependent changes of immune deposits potentially indicating response to therapy. Correction notice This article has been corrected since it published Online First. The third author affiliation has been updated. Contributors All four authors have contributed to the manuscript. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests AK received consulting fees from Vifor Pharma, Otsuka, Alexion, UriSalt, Delta4 and Catalyst Biosciences. IB received consulting fees from Boehringer-Ingelheim, Novartis, Catalyst Biosciences and Toleranzia. DG received consulting fees from ChemoCentryx. MS received consulting fees from Astra Zeneca, Boehringer-Ingelheim, Novartis and Otsuka. Patient consent for publication Not applicable. Ethics approval Not applicable. Provenance and peer review Not commissioned; externally peer reviewed. ORCID iDs REFERENCES 1 Mayadas TN, Tsokos GC, Tsuboi N. Mechanisms of immune complex-mediated neutrophil recruitment and tissue injury. Circulation 2009;120:2012–24. 2 Suurmond J, Diamond B. Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity. J Clin Invest 2015;125:2194–202. 3 Pickering MC, D’Agati VD, Nester CM, et al . C3 glomerulopathy: consensus report. Kidney Int 2013;84:1079–89. 4 Peruzzi L, Coppo R. Iga vasculitis nephritis in children and adults: one or different entities? Pediatr Nephrol 2021;36:2615–25. 5 Pillebout E, Sunderkötter C. Iga vasculitis. Semin Immunopathol 2021;43:729–38. Andreas Kronbichler http://orcid.org/0000-0002-2945-2946 Marcus Säemann http://orcid.org/0000-0003-2316-449X
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