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Int J Nephrol Renovasc Dis. 2018 Apr 12;11:137-148. doi: 10.2147/IJNRD.S129227. eCollection 2018.

Primary IgA nephropathy: current challenges and future prospects.

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Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK.


IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, exhibiting a variable clinical and pathological course and significantly contributing to the global burden of chronic kidney disease and end-stage renal disease. Current standards of care focus on optimization of antihypertensive and antiproteinuric therapies (typically renin- angiotensin system blockade) to reduce disease progression. Much recent attention has focused on whether additional immunosuppression confers better outcomes than supportive management alone, and indeed, several trials have demonstrated renoprotective effects following the use of oral corticosteroids. However, results have been inconsistent, and perceived benefits must be balanced against risks and adverse effects associated with generalized immunosuppression, as highlighted by the high-profile STOP-IgAN and TESTING clinical trials. Recent translational research in vitro and animal models of IgAN have generated greater insight into potential therapeutic targets for this complex autoimmune disease. Deeper understanding of the roles of the mucosal immune barrier, complement activation and deposition, T-cell dependent and independent mechanisms of B cell activation, and of the deposition and downstream inflammatory signaling pathways of nephritogenic polymeric IgA1 complexes (e.g., signaling of immune receptors via spleen tyrosine kinase) has formed the rationale for the development of novel agents and clinical trials of more targeted therapies. However, translating findings into clinical practice is challenging, with many immunopathological features of IgAN specific to humans. Recent comprehensive reviews outline current understanding of mechanisms of IgAN as well as ongoing and future clinical trials; it is not our aim to replicate this here. Instead, we take a mechanistic approach to current treatment strategies, outlining advantages and limitations of each before exploring ongoing research with potential translation into future targeted therapies for this complex disease.


IgA nephropathy; Syk; chronic kidney disease; complement; glomerulonephritis; immunosuppression

Conflict of interest statement

Disclosure M Prendecki is supported by a Medical Research Council (UK) Clinical Research Training Fellowship. S McAdoo is supported by NIHR Clinical Lectureship. FWK Tam is supported by the Diamond Fund from Imperial College Healthcare Charity, Ken and Mary Minton Chair of Renal Medicine, and Make Every Kidney Count programme grant from Kidney Research UK. He has received research project grants from AstraZeneca Limited, Baxter Biosciences, Boehringer Ingelheim, and MedImmune and is the Principal Investigator of an ongoing international clinical trial of a Syk inhibitor in IgA nephropathy ( NCT02112838), funded by Rigel Pharmaceuticals. He has consultancy agreements with Rigel Pharmaceuticals, Novartis, and Baxter Biosciences. RS Penfold reports no conflicts of interest in this work.

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