Recurrent IgA nephropathy is predicted by altered glycosylated IgA, autoantibodies and soluble CD89 complexes

Abstract

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, frequently leads to end-stage renal disease and kidney transplantation. However, disease recurrence often occurs after transplantation. Here we evaluated the predictive value of three markers for IgAN recurrence: the presence of galactose-deficient IgA1, IgG anti-IgA autoantibodies, and IgA-soluble (s) CD89 complexes. This was analyzed in 38 kidney transplant recipients with IgAN recurrence and compared with 22 patients transplanted for IgAN but without recurrence and with 17 healthy controls. Pre-transplantation galactose-deficient IgA1 serum levels were significantly higher in the recurrence compared with the no recurrence or control groups. IgA-IgG complexes were significantly elevated in the recurrence group. Both the recurrence and no recurrence groups had increased values of IgA-sCD89 complexes compared with healthy controls, but values were significantly lower in patients with recurrence compared with no recurrence. Areas under the receiver operating curve of the markers in pre-transplantation sera were 0.86 for galactose-deficient-IgA, 0.82 for IgA-IgG, and 0.78 for sCD89-IgA; all significant. Disease recurrence was associated with decreased serum galactose-deficient IgA1 and appearance of mesangial-galactose-deficient IgA1 deposits, whereas increased serum IgA-sCD89 complexes were associated with mesangial sCD89 deposits. Thus, galactose-deficient-IgA1, IgG autoantibodies, and IgA-sCD89 complexes are valuable biomarkers to predict disease recurrence, highlighting major pathogenic mechanisms in IgAN.

Immunoglobulin A nephropathy: a pathophysiology view

“…As a consequence, cleavage of the extracellular domain of FcaRI is induced, leading to the formation of circulating IgA/FcaRI immune complexes, which are found in mesangial deposits. IgA/FcaRI immune complexes have been implicated in disease exacerbation through the release of pro-inflammatory cytokines, secretion of chemokines and the resultant migration of macrophages into the kidney [40,[89][90][91].…”

Biomarkers and targeted new therapies for IgA nephropathy

“…In conclusion, high levels of Gd-IgA1 are necessary for the development of IgAN, but not sufficient for the full clinical expression of the renal damage, and in most reports this biomarker is not associated with signs of progressive disease with proteinuria and glomerular filtration rate (GFR) decline [10,11,15]. However, higher levels of Gd-IgA1 are present in a subset of IgAN with severe clinical and renal features and predict a poor prognosis, and in recurrent IgAN after transplantation [21]. We observed that patients with IgAN present with markers of oxidative stress (advanced oxidation protein products, AOPP) [22].…”

“…1 Multi-hit pathogenetic steps of IgA nephropathy and focused new therapeutic proposals.MALT mucosaassociated lymphoid tissue, MEST mesangial proliferation, endocapillary hypercellularity, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis can activate the transferrin receptors on mesangial cells, leading to the development of IgAN. Both receptors have been reported to be biomarkers of the presence and activity of IgAN[21,23].…”

Histopathological findings in transplanted kidneys

“…Predictors of active IgAN recurrence include young age, rapid progression of the original disease, and high serum levels of galactose-deficient IgA1 and IgA-IgG complexes [137][138][139]. Risk factors associated with recurrent IgA vasculitis include shorter duration of the original disease, a living related donor, and necrotizing/crescent glomerulonephritis of the native kidneys [140].…”