Biomarkers for IgA nephropathy on the basis of multi-hit pathogenesis

Abstract

IgA nephropathy (IgAN) is the most prevalent glomerular disease worldwide and is associated with a poor prognosis. Development of curative treatment strategies and approaches for early diagnosis is necessary. Renal biopsy is the gold standard for the diagnosis and assessment of disease activity. However, reliable biomarkers are needed for the noninvasive diagnosis of this disease and to more fully delineate the risk of progression. With regard to the pathogenesis of IgAN, the multi-hit hypothesis, including production of galactose-deficient IgA1 (Gd-IgA1; Hit 1), IgG or IgA autoantibodies that recognize Gd-IgA1 (Hit 2), and their subsequent immune complexes formation (Hit 3) and glomerular deposition (Hit 4), has been widely supported by many studies. Although the prognostic values of several biomarkers have been discussed, we recently developed a highly sensitive and specific diagnostic method by measuring serum levels of Gd-IgA1 and Gd-IgA1-containing immune complexes. In addition, urinary Gd-IgA1 may represent a disease-specific biomarker for IgAN. We also confirmed that there is a significant correlation between serum levels of these effector molecules and disease activity, suggesting that each can be considered a practical surrogate marker of therapeutic response. Thus, these disease-oriented specific serum and urine biomarkers may be useful for screening of potential IgAN with isolated hematuria, earlier diagnosis, disease activity, and eventually, response to treatment. In this review, we discuss these concepts, with a focus on potential clinical applications of these biomarkers.

The Role of IgA in the Pathogenesis of IgA Nephropathy

“…Therefore, reliable biomarkers are desirable for the noninvasive diagnosis of primary IgAN and/or for evaluating the risk for IgAN progression. However, despite numerous studies investigating underlying molecular mechanisms of IgAN and a number of proposed IgAN-specific serologic or urinary biomarkers (i.e., serum levels of Gd-IgA1, Gd-IgA1 specific autoantibodies, IgA-IgG immune complexes, urinary Gd-IgA1, CD89, CD71, miRNA) [72][73][74], it is important to be aware that all these proposed biomarkers have not been evaluated yet. Thus, their clinical value in predicting risk of IgAN and guiding clinical decision regarding IgAN diagnosis is currently not known.…”

Galactose-deficient IgA1 in skin and serum from patients with skin-limited and systemic IgA vasculitis

“…After we have provided evidence that Gd-IgA1 is deposited at vessels of systemic and skin-limited IgAV, we believe it is reasonable to extrapolate the IgAN multi-hit hypothesis [25][26][27][28] to IgAV as shown in Figure 3. We detected co-deposition of IgG (as in IgAN) in 2 cases of skin-limited IgAV consistent with the presence of IgA-IgG immune complexes [29].…”

A proliferation‐inducing ligand increase precedes IgA nephropathy recurrence in kidney transplant recipients

“…Although kidney biopsy is the gold standard for diagnosis and prognosis of IgAN it cannot be used to assess disease activity due to associated procedural risks. Non‐invasive biomarkers are needed to assess activity that can also allow an early diagnosis.…”