substantially among the IgA1 molecules in a person, constituting microheterogeneity for the structure of the hinge region. The numbers below the position indicators show the frequency (percentage) of the compositional variations of an IgA1 myeloma protein that mimics the structure of poorly glycosylated IgA1 in patients with IgA nephropathy. As compared with healthy persons, patients with IgA nephropathy have more circulating IgA1 molecules with O-linked hinge-region glycans that do not include galactose (galactose-deficient IgA1). Panel B shows O-glycan variants of IgA1. Synthesis of the O-linked glycans proceeds in a stepwise manner, starting with attachment of N-acetylgalactosamine to some of the hinge-region serine or threonine amino acids. The glycan is normally extended by attachment of galactose. Sialic acid can be attached to N-acetylgalactosamine, galactose, or both. If sialic acid is attached to N-acetylgalactosamine before attachment of galactose, subsequent attachment of galactose is not possible. An imbalance in the activities or expression of specific glycosyltransferases in patients with IgA nephropathy accounts for the increased production of galactose-deficient O-linked glycans in the IgA1 hinge region with increased sialic acid residues. Cα denotes constant-region domain on alpha heavy chain, CL constant-region domain on light chain, VH variable region on heavy chain, and VL variable region on light chain. Squares indicate N-acetylgalactosamine, circles galactose, and diamonds sialic acid. T h e n e w e ngl a nd j o u r na l o f m e dic i n e 2406 n engl j med 368;25 nejm.org june 20, 2013 as C3b or the soluble form of CD89 — the IgA receptor on macrophages and neutrophils.26 In the mesangium, complexed galactose-deficient IgA1 may attach to fibronectin or type IV collagen in the extracellular matrix27 or the CD71 transferrin receptor or integrins on mesangial cells.28,29 Activated mesangial cells secrete components of extracellular matrix,20 enhance the expression of inducible nitric oxide synthase,30 and release various mediators of renal injury that are not unique to IgA nephropathy: angiotensin II,31 aldosterone,31 proinflammatory and profibrotic cytokines,20,31 and growth factors.30 The consequences of such events, if extended over prolonged periods, would be mesangial hypercellularity, apoptosis, oxidative stress, activation of complement, expansion of mesangial matrix, injury to podocytes and proximal tubule epithelial cells, increased glomerular permeability, and scarring in the glomerular and interstitial compartments (Fig. 3).20,31,32 Such renal injury will lead to hypertension, proteinuria, hematuria, and reduced renal clearance.20,31 Patients with Henoch–Schönlein purpura nephritis and those with IgA nephropathy have many of the same laboratory abnormalities (Table 1) and pathological features of renal-biopsy specimens. These similarities have led to proposals that the two entities represent opposite ends of the clinical spectrum characterizing a single disease process.12 It is unknown whether changes in the clinical expression of disease reflect fluctuating serum levels of galactose-deficient IgA1, variations in the composition or precise location of IgA1 hinge-region glycoforms, different binding affinities of anti-glycan antibodies, other factors influencing the formation of galactose-deficient IgA1–containing immune complexes, or variation in the extent of complement- or cytokine-mediated damage in glomeruli. Gene tic Fac t or s Genetic factors undoubtedly influence the pathogenesis of IgA nephropathy. The serum level of galactose-deficient IgA1 is a heritable trait in diverse racial or ethnic groups.34 About 75% of patients with IgA nephropathy have a serum galactose-deficient IgA1 level above the 90th percentile for healthy controls35; moreover, about 30 to 40% of first-degree relatives have similarly high levels.36 This pattern is not explained by differences in serum IgA levels.37 However, most relatives with elevated serum galactose-deficient IgA1 levels never have clinical manifestations of renal disease.36,38 Thus, other factors must be necessary for the expression of disease. Genomewide association studies have identified common susceptibility loci in the absence of a priori mechanistic hypotheses.39 A study involving patients with IgA nephropathy who were of white European ancestry showed an association with the major histocompatibility complex (MHC); the strongest signal was in the DQ locus.40 A study involving Han Chinese and Europeans identified five susceptibility loci: three on chromosome 6p21 in the MHC, one on chromosome 1q32 in the cluster of genes encoding complement factor H (CFH), and one on chromosome 22q12.41 The 6p21 loci include genes encoding components of the class I and class II MHC response. Products of CFH and the cluster of nearby CFH-related genes (CFHR) modulate activation of the alternative complement pathway, with the combined deletion of CFHR1 and CFHR3 conferring a reduced risk of IgA nephropathy. A single deletion in both CFHR1 and CFHR3 confers a 30% reduction in the risk of IgA nephropathy. Chromosome 22q12 encodes oncostatin M and leukemia inhibitory factor, cytokines that are implicated in mucosal immunity and inflammation. A meta-analysis with risk-score modeling in 12 cohorts of Asian,