Biomarkers in IgA nephropathy: relationship to pathogenetic hits

Abstract

Introduction: IgA nephropathy, the most prevalent glomerular disease in the world, requires a renal biopsy for diagnosis. Reliable biomarkers are needed for the non-invasive diagnosis of this disease and to more fully delineate its natural history and risk for progression.

Areas covered: In this review, the authors examine serum levels of galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG and IgA autoantibodies that are integral to pathogenesis of IgA nephropathy. They also explore biomarkers related to alternative and lectin pathways of complement activation and serum and urinary peptide biomarkers detected by mass spectrometric methods. The literature search included review of all publications having IgA nephropathy in the title that were cited in PubMed and Scopus over the past 10 years and a non-systematic review of abstracts published for the annual meetings of the American Society of Nephrology and the International Symposia on IgA Nephropathy.

Expert opinion: Serum Gd-IgA1 level and glycan-specific autoantibody levels are prime candidates to become diagnostic biomarkers for IgA nephropathy because of their central role in the earliest stages of disease pathogenesis. Assays for serum levels of complement proteins C3 and factor H are readily available in clinical practice and deserve continued study, either alone or in tandem with total serum IgA or serum Gd-IgA1 levels, as prognostic biomarkers for patients with IgA nephropathy. Urinary peptidomic data are also reviewed because this approach can successfully differentiate patients with IgA nephropathy from healthy controls and from patients with other forms of renal disease.

Figure 1

A. The structure of monomeric IgA1. Three to six O-linked glycans are attached in the hinge region and two N-linked glycans are attached in CH2 and CH3 domains of the heavy chain. B. IgA1 hinge-region amino acid sequence. Amino acid residues are numbered to mark the six common sites of O-linked glycan attachment. Ser residues are in blue and Thr residues are in red. C. O-linked glycans of circulatory IgA1. The first two structures on the left are galactose-deficient O-linked glycans, whereas other structures represent galactosylated variants with or without sialic acid. GalNAc-specific lectin (HAA) reactivity with IgA1 O-glycan variants is shown. GalNAc that has sialic acid attached will not react with HAA unless the sample is treated with neuraminidase (+ neu), which removes the sialic acid residue. Symbols: white square, GalNAc; black circle, Gal; black diamond, sialic acid. Neu: Neuraminidase; HAA: Helix aspersa agglutinin.

Figure 2. This figure depicts the relationship between the four hits in the pathogenesis of IgA nephropathy [10] and the relative usefulness of a biomarker for diagnosis or prognosis of IgA nephropathy

We propose that the best diagnostic markers should be related to the earlier hits and that biomarkers related to later hits are more likely to serve as prognostic markers.