New strategies and perspectives on managing IgA nephropathy

Abstract

IgA nephropathy is an inflammatory renal disease characterised by the deposition of IgA in the glomerular mesangium and is the most commonly reported primary glomerulonephritis worldwide. Thirty to forty percent of patients with the disease develop progressive renal function decline, requiring renal replacement therapy within two decades of diagnosis. Despite this, accurate individual risk stratification at diagnosis and predicting treatment response remains a challenge. Furthermore, there are currently no disease specific treatments currently licensed to treat the condition due to long standing challenges in the nature and prevalence of the disease. Despite this, there have been exciting recent advances in the field that may represent paradigm shifts in the way IgA nephropathy is managed in the near future. In this review, we explore the evidence base informing current approaches to management and explore new strategies and future directions in the diagnosis and management of IgA nephropathy.

Keywords: Berger’s disease; IgA nephropathy; Novel treatments; Repurposed therapy.

Fig. 1

Targets of novel/repurposed drugs. Target 1: B-lymphocyte activation results in the production IgA1 poorly O-glycosylated at the hinge region (gd-IgA1, highlighted in red). This results in the generation of auto-antibodies, which leads to the formation of immune complexes. The deposition of immune complexes in the mesangium will lead to varying degrees of inflammation and fibrosis. Atacicept, blisibimod, TRF-budesonide, bortezomib and microbiome modulation can modulate B-lymphocyte activity, which may theoretically lead to a reduction in the production of Gd-IgA1, the auto-antibodies and circulating immune complexes. Target 2: Acthar, avacopan, OMS721 and LNP023 all act in the kidney to suppress local inflammation and subsequent fibrosis, dampening the downstream consequences of immune complex deposition. Fostamatinib acts both at the level of the B-cell and directly in the kidney reducing the inflammatory response to IgA deposition. IgA1 proteases are capable of digesting both circulating and deposited IgA and IgA immune complexes