Immune characteristics of renal allograft donors with mesangial IgA deposition

Highlights

• Our data showed that 26% blood-related donors had mesangial IgA deposition.

• IgA deposited in healthy donors contains galactose-deficient IgA1.

• Levels of serum IgG anti-glycan antibodies in donors with IgA deposition were between healthy control and patients with IgAN.

Abstract

Background

There are few studies describing the prevalence and immune features of people with subclinical mesangial immunoglobulin A (IgA) deposition in the Chinese population. We sought to investigate the prevalence of mesangial IgA deposition among kidney donors and the immune characteristics of donors with mesangial IgA deposition.

Methods

Fifty blood-related living donors with zero-hour allograft biopsies obtained at Peking University First Hospital were enrolled. Galactose-deficient IgA1 (Gd-IgA1) in glomerular deposits was examined by double immunofluorescent staining using the specific monoclonal antibody KM55. Plasma IgA, IgA1, Gd-IgA1 and antibodies directed against Gd-IgA1 were measured using enzyme-linked immunosorbent assay.

Results

Thirteen of 50 (26%) donors had mesangial IgA deposition, which was confirmed by both immunofluorescence and electron microscopy. The levels of plasma IgA, IgA1 and Gd-IgA1 were all increased in donors with IgA deposition compared with those without IgA deposition (mean ± SD, 3.54 ± 0.505 versus 2.356 ± 0.265 mg/ml, p = 0.049; 3.003 ± 0.4048 versus 2.356 ± 0.265 mg/ml, p = 0.057; and 4.719 ± 0.4357 versus 3.356 ± 0.4707 ug/ml, p = 0.0440, respectively). Colocalized IgA1 and Gd-IgA1 indicated that there were galactose-deficient IgA1 deposits in the glomerular mesangium. While donors with IgA deposition showed lower levels of IgG anti-glycan antibodies than patients with IgA nephropathy (37.71 ± 8.886 versus 78.86 ± 5.155 units/ml, p = 0.001).

Conclusions

The immune features of donors with IgA deposition, including IgA1 and Gd-IgA1 deposition, were similar to those of patients with IgA nephropathy, but donors with IgA deposition had lower levels of antiglycan antibodies, which may explain the subclinical status of IgA deposition in donors. Mesangial IgA deposition was common in the Chinese blood related donors cohort, further large study with both living and cadaveric donor kidneys was still needed to confirm these findings.

Introduction

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and an important cause of end-stage kidney disease (ESKD) in young adults [1]. It is characterized by mesangial IgA deposition often accompanied by the presence of C3 and histologically with lesions featuring mesangial cell proliferation and matrix expansion. The prevalence of mesangial IgA deposition in the general population has been observed to be 4–16% via assessment of renal specimens obtained through necropsy of patients without any manifestation of renal disease [2], [3], [4]. The phenomenon of mesangial IgA deposition in donor kidneys at transplantation, although not always related to glomerular inflammatory changes, has been linked to a worse outcome in terms of allograft survival [5], [6]. The frequency of IgA deposition in standard biopsies of living or cadaveric donor kidneys is reported to be as high as 16% in Japan [7], [8]. The incidence of latent IgA deposition in other populations is still not unclear. Additionally, in most studies, IgA deposition is not confirmed by electron microscopy (EM).

The IgA deposited in the mesangial zones of patients with IgAN is exclusively of the IgA1 subclass. IgA1 is one of the very few serum proteins with O-glycosylation. The O-glycans in the hinge region of IgA1 consist of N-acetylgalactosamine, galactose, and sialic acid. It is now firmly established that serum IgA1 molecules are poorly O-galactosylated in IgAN, which features predominantly Gd-IgA1. Additionally, anti-glycan antibodies targeting Gd-IgA1 lead to the formation of immune complexes, which then deposit in the glomerular mesangium. Elevated circulating IgA1, Gd-IgA1 and anti-glycan antibodies have been identified among the key effector molecules in the pathogenesis of IgAN. While the pathogenesis of latent IgA deposition in the kidney remained unclear. Oka et al. [9] found that donors with mesangial IgA deposition is IgA1 dominant. Nakazawa et al also demonstrated that the numbers of GalNAc and Gal and the Gal/GalNAc ratio in the HR of the IgAN recipients were significantly lower comparing to the IgAD and non-IgAD healthy donors [8]. Until now, the immune characteristics have not been systematically investigated in donors with latent IgA deposition.