ESRD Develops in 20–40% of patients by 20 yr after biopsy Develops in 1 to 3% of children, with higher risk if clinical onset in adulthood Transplantation Macroscopic hematuria rare; histologic recurrence in 50–60% of patients by 5 yr Extrarenal manifestations rare; recurs as IgA nephropathy (frequency not well defined) * CIC denotes circulating immune complexes, eGFR estimated glomerular filtration rate, and ESRD end-stage renal disease. † The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines address specific glomerular diseases. 33 medical progress n engl j med 368;25 nejm.org june 20, 2013 2409 have a relative with biopsy-confirmed IgA nephropathy, microscopic hematuria, or proteinuria. The mode of inheritance is usually autosomal dominant with incomplete penetrance, suggesting a major gene with a large effect.34 Linkage studies of multiplex families have linked several chromosomal loci, distinct from those identified in genomewide association studies, in these families.34 The mutations may be identified by means of genome-sequencing approaches. Biom a r k er s Although the serum level of galactose-deficient IgA1 is frequently elevated in patients with IgA nephropathy,35 the sensitivity and specificity of this laboratory finding are insufficient for the test to replace kidney biopsy as the diagnostic standard. The serum level of glycan-specific IgG antibodies is correlated with the level of urinary protein excretion25 and the risk of progression to end-stage renal disease (ESRD) or death.4 This biomarker may prove useful for monitoring disease progression or the response to therapy. Increased urinary excretion of epidermal growth factor,45 podocytes,46 low-molecular-mass proteins,47 and mannose-binding lectin48; increased plasma levels of activated complement C3,49 advanced oxidative protein products,50 and fibroblast growth factor 2351; an increased serum level of uric acid,52,53 and decreased serum levels of CD89–IgA complexes26 are associated with severe histologic changes, severe proteinuria, or a poor clinical outcome. However, these findings may not be unique to IgA nephropathy. Urinary proteomic analysis can identify patterns of excreted peptides that are unique to diseases, without a priori assumptions about pathogenesis. Analysis of urinary samples by means of capillary electrophoresis coupled with mass spectrometry has differentiated patients with IgA nephropathy from healthy controls and patients with minimal-change disease or IgA–immune-complex nephritis due to chronic hepatitis C infection, even in association with nonpathologic proteinuria.54,55 Furthermore, the urinary proteomic profile predicts the response to treatment with an angiotensin-converting–enzyme (ACE) inhibitor.56 Additional studies are needed to determine the potential and cost-effectiveness of urinary proteomic analysis in establishing the diagnosis of IgA nephropathy and making decisions about treatment. Demo gr a phic a nd Epidemiol o gic Ch a r ac ter is tics The prevalence of IgA nephropathy relative to other glomerular diseases is generally inferred from the proportion of cases in biopsy series, but the true prevalence of IgA nephropathy is unknown because diagnosis requires kidney biopsy. The prevalence of clinically silent IgA nephropathy may be surprisingly high; in a Japanese study, 16% of donor kidneys had glomerular IgA deposits and nearly 2% exhibited mesangioproliferative changes with C3 deposits characteristic of IgA nephropathy.57 Although data from biopsy series regarding the prevalence of IgA nephropathy in the total population should be interpreted cautiously, several observations are noteworthy. In the United States, IgA nephropathy is the most frequently diagnosed primary glomerular disease in adults and the leading primary glomerular disease causing ESRD in young white adults.58 Limited data from population-based studies in the United States indicate that the annual incidence of biopsydocumented IgA nephropathy is about 1 case per 100,000 persons,14,59 representing a lifetime risk of about 1 in 1400. In New Mexico, from 2000 to 2005 the incidence was highest among Native Americans, intermediate among Hispanics, and lowest among non-Hispanic whites.59 The annual incidence among children in the United States is about 0.5 cases per 100,00014; however, in Japan, the incidence is 10 times as high.60 Clinic a l Ou t comes The clinical course of IgA nephropathy is variable. Estimates of renal survival are often biased because many patients have stage 3 or 4 chronic kidney disease at biopsy or the data are censored for death before patients reach the primary outcome measure of ESRD or percent decrease in the estimated glomerular filtration rate (GFR).15,61-63 The likelihood of dialysis or death was recently estimated with the use of three risk factors that are documented at biopsy: urinary protein excretion of more than 1 g per day, hypertension (>140/90 mm Hg), and severe histologic lesions on the basis of glomerular, vascular, tubular, and interstitial features.64 The 20-year predicted survival without the need for dialysis was 96% among patients with no risk factors versus 36% among T h e n e w e ngl a nd j o u r na l o f m e dic i n e 2410 n engl j med 368;25 nejm.org june 20, 2013 those with three factors. The 10-year