NEW NEPHROPATHY
IgA Nephropathy Robert J. Wyatt, M.D., and Bruce A. Julian, M.D. From the Children’s Foundation Research Institute at Le Bonheur Children’s Hospital and the Department of Pediatrics, University of Tennessee Health Science Center, Memphis (R.J.W.); and the Department of Medicine, University of Alabama at Birmingham, Birmingham (B.A.J.). Address reprint requests to Dr. Wyatt at Rm. 520, Children’s Foundation Research Institute, 50 North Dunlap, Memphis, TN 38103, or at rwyatt@uthsc .edu. N Engl J Med 2013;368:2402-14. DOI: 10.1056/NEJMra1206793 Copyright © 2013 Massachusetts Medical Society. I gA nephropathy is the most prevalent primary chronic glomerular disease worldwide.1 However, the requirement of a kidney biopsy for diagnosis hinders delineation of the full consequences of this disease. Since IgA nephropathy was last reviewed in the Journal more than a decade ago,2 advances in analytic approaches have provided better insight into the molecular mechanisms of this disease. These advances offer the potential for the development of noninvasive tests for diagnosis and monitoring of disease activity and an opportunity to envision disease-specific therapy. Pathol o gic a l Fe at ur es The diagnostic hallmark of IgA nephropathy is the predominance of IgA deposits, either alone or with IgG, IgM, or both, in the glomerular mesangium (Fig. 1). The frequency of IgA without IgG or IgM varies greatly, from 0 to more than 85% across centers.3,4 Complement C3 and properdin are almost always present. C4 or C4d,5 mannose-binding lectin,6 and terminal complement complex (C5b–C9)7 are frequently detected, whereas C1q is usually absent. These findings suggest involvement of the alternative and lectin pathways of complement activation (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The mesangial IgA is exclusively of the IgA1 subclass and is deficient in galactose,8-10 a biochemical feature of central importance in the pathogenesis of IgA nephropathy. The features of IgA nephropathy on light microscopy may vary greatly among patients and within the individual biopsy sample. An increase in mesangial matrix and hypercellularity are common; other glomerular lesions may include focal necrosis (affecting a minority of glomeruli), segmental scarring (affecting only a portion of a glomerulus), and crescents in Bowman’s space. An international panel of nephrologists and nephropathologists developed the Oxford classification of IgA nephropathy to standardize the grading of features on light microscopy.11 Electron microscopy usually shows electron-dense material corresponding to immune deposits on immunofluorescence microscopy. These are generally observed in mesangial and paramesangial areas but are occasionally present in subepithelial and subendothelial portions of glomerular basement membranes.3 Renal histologic features of Henoch–Schönlein purpura nephritis are strikingly similar to those of IgA nephropathy.12 The diagnosis of Henoch–Schönlein purpura nephritis rests on the concurrent presence of palpable purpura due to leukocytoclastic vasculitis with IgA in the walls of dermal capillaries. Clinic a l Pr esen tation In North America, about 75% of children and young adults with IgA nephropathy present with macroscopic hematuria during an upper respiratory or gastrointesti- medical progress n engl j med 368;25 nejm.org june 20, 2013 2403 A B C D E F G Figure 1. Pathological Characteristics of IgA Nephropathy. Panel A (periodic acid–Schiff stain) shows mesangial hypercellularity, with four or more cells per mesangial area (arrow). Panel B (periodic acid–Schiff stain) shows segmental endocapillary proliferation with occlusion of the capillary lumen (arrow). Panel C (periodic acid–Schiff stain) shows segmental glomerulosclerosis and adhesion, with focal accumulation of hyaline and obliteration of the capillary lumen (arrow). Panel D (trichrome stain) shows tubular atrophy and interstitial fibrosis, with severe interstitial scarring and loss of tubules (arrow). Panel E (periodic acid–Schiff stain) shows a glomerular crescent; a circumferential layer of epithelial cells surrounds the glomerular tuft (arrow). Panel F (immunofluorescence stain with fluorescein-conjugated anti-IgA antibodies) shows diffuse mesangial staining for IgA (arrow). In Panel G, an electron micrograph of a glomerular capillary tuft in a specimen fixed in osmium tetroxide shows electron-dense material in the mesangial area (arrow), a finding that is consistent with the accumulation of immune complexes. T h e n e w e ngl a nd j o u r na l o f m e dic i n e 2404 n engl j med 368;25 nejm.org june 20, 2013 nal illness.3,13 Evidence of acute kidney injury may be present. Older adults usually present with proteinuria, microscopic hematuria, or hypertension, alone or in combination.3,14,15 In the United States, more than 50% of adults older than 30 years of age at diagnosis have chronic kidney disease at stage 3 to 5.14,15 In North American cohorts, the male-to-female ratio is about 2:1 for children and adults,3,13,14 whereas the ratio is