IgA Nephropathy: An Interesting Autoimmune Kidney Disease

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is a leading cause of chronic kidney disease and progresses to end-stage kidney disease in up to 40% of patients about 20 years after diagnosis. Additionally, IgAN is associated with significant mortality. The diagnosis currently necessitates a kidney biopsy, as no biomarker sufficiently specific and sensitive is available to supplant the procedure. Patients display significant heterogeneity in the epidemiology, clinical manifestations, renal progression, and long-term outcomes across diverse racial and ethnic populations. Recent advances in understanding the underlying pathophysiology of the disease have led to the proposal of a four-hit hypothesis supporting an autoimmune process. To date, there is no disease-specific treatment but, with a better understanding of the disease pathogenesis, new therapeutic approaches are currently being tested in clinical trials. In this review, we examine the multiple facets and most recent advances of this interesting disease.

Keywords: Autoimmune disease; Galactose-deficient IgA1; Glomerulonephritis; IgA nephropathy; IgA vasculitis.

Figure 1.. Pathological Characteristics of IgAN.

Panel A (Periodic acid-Schiff Hematoxylin stain x40) shows a glomerulus with increased mesangial matrix and cellularity (> 3 cells in a mesangial area), without endocapillary proliferation or crescent formation. Panel B (Jones silver stain x40) shows a glomerulus with early fibrocellular crescent (asterisks) and segmental sclerotic lesions with obliterated capillary lumina (arrows) that are entrapped within the circumferential crescent. Panel C (immunofluorescence stain with fluorescein-conjugated anti-IgA antibodies x40) shows near global, granular, staining for IgA limited to the mesangium. Panel D is an electron micrograph of a mesangial area with large electron-dense immune complex deposits in the expanded mesangium (asterisks).

Figure 2.. Structure of Human IgA1 and O-glycosylation of the IgA1 Hinge Region.

IgA exists in several molecular forms in the circulation: monomers, dimers, trimers, large polymers, secretory IgA, as well as bound in immune complexes. The figure depicts an IgA1 monomer. Each heavy chain has a N-linked (attached to a nitrogen molecule in asparagine) glycan (carbohydrate) side chains (orange) in the second and third constant-region domains (Cα2 and Cα3) and clustered O-glycans (attached to an oxygen molecule in serine or threonine; blue) in the hinge region between the first and second constant-region domains (Cα1 and Cα2). This hinge region in the IgA1 molecule has 9 threonine and serine residues to some of which a glycan can attach. The composition and number of the O-glycans vary considerably among the IgA1 molecules in an individual, creating microheterogeneity for the hinge region structure. The IgA1 hinge region usually has 3 to 6 O-linked glycans. When compared with healthy individuals, patients with IgAN have more of circulating IgA1 molecules with less galactose (galactose-deficient IgA1). The monomer depicted has five O-linked glycans at each of the two hinge regions. (A) O-linked glycan synthesis proceeds in a stepwise fashion, starting with attachment of N-acetylgalactosamine to a hinge-region serine or threonine amino acid. (B) The glycan is typically extended by attachment of galactose to N-acetylgalactosamine by the core 1 β1,3-galactosyltransferase (C1GALT1) enzyme whose activity is stabilized by a molecular chaperone, C1GALT1C1 (also called COSMC). (C, D) Sialic acid (N-acetylneuraminic acid) can be attached to N-acetylgalactosamine, galactose, or both. (E) If sialic acid is attached to N-acetylgalactosamine prior to attachment of galactose, subsequent attachment of galactose is not possible. An imbalance in the activities or expression of specific glycosyltransferases in IgA1-producing cells of patients with IgAN accounts for the increased production of galactose-deficient O-linked glycans in the IgA1 hinge region. 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. Fab, fragment antigen-binding; Fc, fragment crystallizable region, GalNAc, N-acetylgalactosamine; Gal, galactose; Pro, proline; Val, valine; Ser, serine; Thr, threonine; Cys, cysteine.

Figure 3.. Multi-Hit Hypothesis for Pathogenesis of IgAN.

Increased levels of circulatory galactose-deficient IgA1 (Hit 1) are recognized as an autoantigen by autoantibodies (either IgG or IgA, but mostly of the IgG subclass; Hit 2) that leads to formation of pathologic immune complexes (Hit 3), some of which accumulate in the glomeruli and induce kidney injury (Hit 4).