Semin Immunopathol (2014) 36:431–442 DOI 10.1007/s00281-013-0411-7
REVIEW
New insights into the pathogenesis of IgA nephropathy Jürgen Floege & Ivan C. Moura & Mohamed R. Daha
Received: 22 November 2013 / Accepted: 26 November 2013 / Published online: 18 January 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract IgA nephropathy (IgAN) is the most common diagnosis amongst primary glomerular diseases in most countries where renal biopsies are regularly performed. Only a fraction of these patients is at high risk of losing glomerular filtration rate (GFR) in particular those with high grade proteinuria, uncontrolled hypertension or already impaired GFR at diagnosis, and those with renal scars in the renal biopsy. Genetic modifiers of IgAN onset and/or course are emerging. Spontaneous animal models of IgAN are problematic given considerable species differences between the rodent and human IgA system. However, new transgenic models help to better understand the pathogenesis. A key pathogenetic role appears to be played by underglycated IgA1 as well as autoantibodies to these IgA glycoforms and IgA receptors such as CD89 and transferrin receptor 1. Once IgA and/or IgAcontaining immune complexes are deposited or formed in the mesangium, secondary effector mechanisms become important including complement activation, release of mesangial growth factors (in particular platelet-derived growth factor),
This article is a contribution to the special issue on Immunopathology of Glomerular Diseases - Guest Editors: P. Ronco and J. Floege J. Floege (*) Division of Nephrology, RWTH University Hospital Aachen, 52057 Aachen, Germany e-mail:
[email protected] I. C. Moura INSERM U699, Paris, France e-mail:
[email protected] I. C. Moura Université Paris Diderot, Sorbonne Paris Cité, Paris, France M. R. Daha Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands e-mail:
[email protected]
and finally non-IgAN-specific events that culminate in glomerular and subsequently renal tubulointerstitial scaring. Here, we review these processes and describe potential novel therapeutic targets in IgAN. Keywords IgA nephropathy . Mesangium . IgA receptor . Complement . PDGF . CD89 . Transferrin receptor-1
Introduction IgA nephropathy (IgAN) presently can only be diagnosed by immunohistological examination of a kidney biopsy. It is usually characterized by mesangioproliferative changes in glomeruli with deposition of IgA in the mesangium although the light microscopical pattern may vary widely (Fig. 1). IgAN is the most prevalent pattern of glomerular disease in most countries where renal biopsy is widely used as an investigative tool. Its estimated frequency is at least 2.5 cases per year per 100,000 adults. However, the apparent frequency strongly depends on the local biopsy policy. For example, most nephrologists agree not to perform a kidney biopsy in patients with persistent glomerular microhematuria, lowgrade proteinuria (i.e.,
