Immune characteristics of renal allograft donors with mesangial IgA deposition
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.
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Participants and healthy controls
According to regulations, only blood-related kidney transplantation is performed in our center. Fifty living blood-related donors who had provided material for kidney transplantation at Peking University First Hospital from August 2016 to June 2019 were included in this study. Donors were defined as cases with IgA deposition who were both positive by immunofluorescence microscopy and electron microscopy. We randomly selected donors (1:1) without mesangial IgA deposition as control group using
Baseline demographic and clinical characteristics
Overall, 50 blood-related living donors seen at Peking University First Hospital from 2016 to 2019 were enrolled in this study. There were 16 male donors (32%), and the study population had a mean age of 50.9 (6.8) years at the time of donation. The mean eGFR was 90.4 (18.1) ml/min/1.73 m2(CKD-EPI). The mean value for systolic BP was 129(13) mmHg, and the mean diastolic BP was 80 (8) mmHg. Seven donors had mild hematuria at the time of donation with median urine RBC count of 4 (range 3–5) per
Discussion
In this study, we observed a high prevalence of latent mesangial IgA deposition in 26% of healthy donors. This finding was confirmed by both IF and EM. A systematic evaluation of an immune biomarker specific for IgAN demonstrated that donors with IgA deposition had high levels of plasma IgA1 and galactose-deficient IgA1 compared to those without IgA deposition or healthy controls. In addition, using a Gd-IgA1-specific monoclonal antibody, KM55, we showed glomerular deposition of Gd-IgA1. These
Conclusion
From our single center’s experience, 26% blood-related donors had Gd-IgA1 contained mesangial IgA deposition. Healthy donors with IgA deposition showed lower levels of IgG anti-glycan antibodies than patients with IgA nephropathy, suggesting IgG anti-glycan antibodies may play a pivotal role in the manifestation of IgA nephropathy.
Statement of Ethics
Our study is a retrospective study. This study was approved by the Ethics Committee of Peking University First Hospital without obtaining additional informed consent (approval number: 2020–345).
Author contributions
ZW conducted the whole experiment and drafted the manuscript. ZX and GZY helped with ELISA detection, MLW assisted in double immunofluorescent staining. ZWY and XX helped with clinical data collection and allografts biopsy samples collection. XJZ and HZ provided valuable guidance in experiment design. WKH and JCL reviewed the data and guided writing the manuscript.
Supportive foundations
This work was supported by Chinese Academy of Medical Sciences Research Unit (No. 2019RU023), the National Natural Science Foundation of China (81670649), the Natural Science Foundation for Innovation Research Groups of China (81621092), the National Key Research and Development Program of China (2018YFC1314004), the Capital Health Development Research Project of China (2018–2-4073), Capital of Clinical Characteristics and the Applied Research Fund (Z161100000516005).
CRediT authorship contribution statement
Zi Wang: Conceptualization, Investigation, Writing - original draft, Writing - review & editing. Xue Zhang: Methodology, Validation. Wenke Han: Conceptualization, Project administration. Guizhen Yu: Methodology. Zewei Ying: Resources. Xin Xu: Resources. Manliu Wang: Methodology. Xujie Zhou: Resources, Validation. Jicheng Lv: Conceptualization, Project administration, Supervision, Funding acquisition. Hong Zhang: Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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