Biochemical and Biophysical Research Communications
Difference in IgA1 O-glycosylation between IgA deposition donors and IgA nephropathy recipients
Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Indeed, it is now regarded as more serious than previously believed because 20–40% of such patients reach end-stage renal disease within 20 years [1]. IgAN is considered as a systemic disease because it often recurs following renal transplantation. The recurrence rate has been found to range from 8% to 53%, and the graft loss rate due to recurrence has been observed to range from 2% to 16% [2].
Pathologically, IgAN is characterized by IgA deposits in the kidney, including mesangial cell proliferation, extracellular expansion, and inflammation. Human IgA can be classified into two subclasses: IgA1 and IgA2. In the present focus, the IgA1 subclass is more critical in the pathogenesis of IgAN because most of the IgA deposited in the kidney comprises IgA1 [3,4]. As Novak et al. [5] published, Fig. 1(A) shows schematic view of the O-glycosylation of IgA. It is recognized that IgA1 contains a hinge region (HR) between the Fab and Fc areas, which is enriched in serine (Ser) and threonine (Thr) residues and that in healthy subjects, up to six of these sites are susceptible to O-glycans [6]. IgA1 O-glycans comprise N-acetylgalactosamine (GalNAc) with a β1,3-linked galactose (Gal), and sialic acid (NeuAc) may be attached to GalNAc by a α2,6- or α2,3-linkage [7]. Because IgA2 lacks this HR, it is not O-glycosylated. There have been several reports analyzing the structural varieties of O-glycans in the HR of serum IgA1 in IgAN. Glycosylation studies have revealed aberrancies in the O-glycans of IgA1 in the circulation of patients with IgAN. Specifically, some IgA1 molecules shows galactose-deficient (Gd-IgA1), i.e., consisting of terminal GalNAc or sialylated GalNAc [8]. In addition, this Gd-IgA1 is recognized by glycan-specific antibodies of IgG or IgA, which form immune complexes [9] bound to mesangial cells, and can induce mesangial inflammations. Therefore, Gd-IgA1 has been identified as one of the most convincing key mediators in the pathogenesis of IgAN.
On the other hand, in healthy populations, latent IgA deposition (IgAD) in the kidney without urinary abnormality and renal insufficiency is occasionally observed. Prevalence of IgAD in normal populations has been previously investigated, and asymptomatic IgAD in 4%–30% of renal specimens via necropsy of patients [[10], [11], [12]]. In particular, Suzuki et al. reported that 16.2% of renal transplantation donors showed latent IgAD without glomerular inflammatory changes [13]. These IgA deposits from donor kidneys simply disappear within a few months after engraftments into recipients without IgAN [14]. In addition, we previously reported that the subclass of IgA deposited in the mesangium of IgAD donors were also IgA1 [15].
However, there have not been any reports analyzing of the O-glycan structures of serum IgA1 from IgAD patients, and the mechanism why IgAD does not progress to IgAN remains unclear. We have reported the measurement of the site-occupancy of O-glycans in IgA patients using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI–TOF MS) [16]; this method facilitated the investigation of the heterogeneity of the O-glycan structures in the IgA1 HR. For the current study, we examined the measurement of the O-glycans of IgA1 in IgAN recipients, IgAD donors, and non-IgAD healthy donors using MALDI–TOF MS.
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Patients
We recruited 169 consecutive pairs of living renal transplant recipients and donors; 108 of these renal transplants were performed at Hyogo Prefectural Nishinomiya Hospital (Nishinomiya, Japan) between May 2011 and December 2017, whereas 61 were performed at Osaka University Hospital (Osaka, Japan) between November 2015 and December 2017. In all cases, we performed a pre-implant (zero-hour) graft biopsy before reperfusion. Eight donors were excluded because there was no glomerulus in the
Prevalence of IgAN in the renal transplant patients
Baseline characteristics of our recipients and donors are presented in Table 1. The primary cause of end-stage renal disease was biopsy-proven IgAN in 37 (21.9%) of the transplant recipients. Ages at ESRD and transplants of the IgAN recipients were significantly younger than those of the recipients with other kidney diseases (OKDs). Notably, there were no significant differences in terms of donor sex and age at transplant between the IgAN and OKDs recipients. Regarding donor relationships,
Discussion
In this cohort study, we examined the correlation between IgAN and IgAD. IgAD was observed in 13.0% of the renal transplant donors in our population. In addition, the frequency of IgAD significantly differed between the IgAN-related and non-related donors. In other words, the IgAD donors tended to involve relatives of IgAN recipients (28.6% in relatives vs. 9.8% in non-relatives, respectively; p = 0.0073). Although the prevalence of IgAD in normal populations has been previously investigated,
Author contributions
S.N. and R.I. designed the research, performed the research, analyzed the data, and wrote the paper. R.I., H.I., M.T., and Y.W. supervised the study. T.N. and K.O. evaluated the pathology of renal biopsy. N.N. designed the research and edited the paper. M.K., T.K., T.A., K.Y., M.U., H.K., K.N. discussed the data.
Funding
This study was supported by a Japan Society for the Promotion of Science KAKENHI Grant-in-Aid for Young Scientists KAKENHI (16K20132).
Conflicts of interest
All authors declare that they have no financial interests relevant to this study.
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