LAUSR

Almost 50 years have passed since the initial description of IgA nephropathy by Berger and Hinglais. IgA nephropathy is the most common chronic glomerulonephritis in the world. A renal biopsy is required for diagnosis but not regularly performed early in the course of the disease in some regions. Clearly, many people with this disease go undiagnosed, as shown by marked differences in populationbased incidences for European and North American cohorts. Variation exists even within a single country, as evidenced by 70% more kidney biopsies being performed in the Tayside region of Scotland compared with Greater Glasgow. This disparity is undoubtedly due to differences in criteria for proceeding with a renal biopsy, either on the part of the referring practitioner or nephrologist. In North America, many patients who present with end-stage renal disease are not diagnosed and more than half of the patients have an estimated glomerular filtration rate of less than 60 mL/min per 1·73 m2 at diagnosis. Many patients are past the point of no return when diagnosed, with chronic IgA nephropathy with serum creatinine of 2·5–3·0 mg/dL, after which progression to end-stage renal disease is inevitable. Also, a significant association between a lower incidence and poor survival is highly likely. Clearly, identified cases represent only the tip of the iceberg of clinically apparent IgA nephropathy. Advances in the understanding of pathogenesis of IgA nephropathy have led to a multi-hit hypothesis. Most individuals who develop IgA nephropathy have increased circulating levels of poorly galactosylated IgA1 (often referred to as galactose-deficient IgA1; Gd-IgA1). Gd-IgA1 has some hinge region of N-acetygalactosamine residues exposed—ie, not galactosylated—and thus becomes an autoantigen recognised by IgG, or IgA1 autoantibodies, or both. Immune complexes are then generated, some of which deposit in the glomerular mesangium, resulting in mesangial-cell activation and inflammation that can damage and ultimately destroy the glomerulus. Until now, treatment strategies for IgA nephropathy have focused on attenuation of glomerular injury, the final hit. This approach includes reduction of injury with systemic corticosteroids and sometimes other immunosuppressive agents, as well as decreasing proteinuria by renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In The Lancet, Bengt FellstrÖm and colleagues offer a new approach to the treatment of IgA nephropathy. The NEFIGAN study investigators should be congratulated for screening sufficient patients from 62 European centres in 1 year to enroll the 149 who were randomised and treated with placebo or a targeted-release formulation of a corticosteroid, TRF budesonide. Targeted-release formulation (TRF) budesonide delivers the agent to the distal ileum with minimal systemic absorption. The premise for this approach is a postulated role for the mucosal immune system in the pathogenesis of IgA nephropathy: mucosal B lymphocytes of Peyer’s patches primed to produce Gd-IgA1. Thus, TRF budesonide targets the initial hit of the 4-hit hypothesis. As described in this report, TRF budesonide significantly reduces serious side-effects typically seen with systemically absorbed corticosteroids. In my opinion, this is the most important treatment trial conducted to date for IgA nephropathy. The results will potentially change treatment strategy for an important subset of patients with IgA nephropathy. Optimal RAS blockade before randomisation (as used in this study) should be required for all future treatment trials for patients with IgA nephropathy. The primary endpoint in the study is urinary protein to creatinine Published Online March 28, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30820-6