European, and African ancestry confirmed all five loci.42 The IgA nephropathy risk alleles at these five loci have opposing effects on other immune-mediated disorders, including multiple sclerosis, inflammatory bowel disease, and type 1 diabetes mellitus. An independent genomewide association study involving Han Chinese replicated four of the five loci.43 The 1q32 signal was not detected, probably because this protective allele is rare in Asians. In a study using a genetic risk score based on the five loci, disease risk varied by a factor of 10 between persons with no protective alleles and those with five or more protective alleles.44 The frequency of risk alleles paralleled the known ethnic variation in the prevalence of IgA nephropathy: higher in Chinese than Europeans and lowest in blacks. Thus, common genetic variants influence the risk of IgA nephropathy across ethnically diverse populations and implicate adaptive immunity in the pathogenesis. These loci contain many genes, medical progress n engl j med 368;25 nejm.org june 20, 2013 2407 and fine-mapping studies are needed to uncover the causal genetic variants underlying the signals found in the genomewide association studies. Variations in disease prevalence among populations may also result from the modulation of genetically determined influences by environmental factors such as hygiene or infection. About 5% of patients with IgA nephropathy COLOR FIGURE AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Please check carefully Draft 4 06/04/12 3 SBL Author Wyatt Fig # Title ME DE Artist Issue date Figure 3. Induction of Glomerular and Tubulointerstitial Injury by Pathogenic IgA1-Containing Immune Complexes. Galactose-deficient IgA1 may accumulate in the glomerular mesangium by either of two routes: galactose-deficient IgA1 is bound by glycan-specific antibodies in circulating immune complexes that pass through large fenestrae in the glomerular capillary network, or uncomplexed galactose-deficient IgA1 passes through glomerular capillary fenestrae to be “planted” in the mesangium and subsequently targeted by circulating anti-glycan antibodies of the IgG or IgA1 isotype. Attachment of galactose-deficient IgA1 in immune complexes to mesangial cells stimulates the cells to proliferate; secrete various proinflammatory and profibrotic cytokines, components of the extracellular matrix, and growth factors; activate the alternative and lectin complement pathways; and release reactive oxygen species. These mediators activate neighboring mesangial cells and also enter the urinary space, damaging podocytes and proximal tubular epithelial cells (PTECs). Injury to podocytes compromises the filtration-barrier function of the glomerular basement membrane, allowing circulating proteins and IgA1-containing immune complexes to enter the urinary space, and leads to sclerosis of the glomerular tuft. Injury to PTECs causes tubular atrophy and interstitial fibrosis, which is the component of the MEST (mesangial hypercellularity, endocapillary proliferation, segmental glomerulosclerosis or adhesion, and tubular atrophy and interstitial fibrosis) score that is most strongly associated with renal-function outcome. T h e n e w e ngl a nd j o u r na l o f m e dic i n e 2408 n engl j med 368;25 nejm.org june 20, 2013 Table 1. Comparative Features of IgA Nephropathy and Henoch–Schönlein Purpura Nephritis (HSPN).* Feature IgA Nephropathy HSPN Presentation Incidence per 1 million 5–50 among children, 10–40 among adults 15–70 among children, 4–13 among adults Macroscopic hematuria More common, coincident with mucosal infection Less common, sometimes after resolution of the Henoch–Schönlein purpura syndrome Renal histologic findings Immunofluorescence More staining for lambda than kappa light chains Equal staining for lambda and kappa light chains Light microscopy Rare glomerular crescents More crescents or glomerular-tuft necrosis Electron microscopy Rare glomerular capillary-loop deposits More subendothelial immune deposits Extrarenal involvement IgA in dermal capillaries Rare (clinically normal skin) Common in purpuric lesions Gastrointestinal vasculitis Rare Common Arthralgia Occasional Frequent Pathogenesis Serum IgA1 CICs Contain galactose-deficient IgA1 Contain galactose-deficient IgA1; complexes are larger Serum galactose-deficient IgA1 High level High level Serum anti-glycan antibodies Increased level Increased level Complement activation Alternative and lectin pathways Alternative and lectin pathways Genetic features Identical twins, case report One child with clinical phenotype of IgA nephropathy Second child with clinical phenotype of HSPN Familial disease 5% of family members with IgA nephropathy or hematuria; IgA nephropathy and HSPN may occur in same family Familial disease less common; HSPN and IgA nephropathy may occur in same family Serum galactose-deficient IgA1 Heritable trait Heritable trait Genomewide association studies Several loci associated with disease No studies Familial linkage studies Several loci linked with disease No studies Treatment of native-kidney disease KDIGO guidelines† Same, except that for patients with crescents and the nephrotic syndrome, treatment can be the same as that for crescentic IgA nephropathy Outcome Clinical remission Common Very common