This study demonstrated that Gd-IgA1 can be used as a biomarker to predict the risk of IgAN recurrence in a population of patients receiving kidney transplants in China. The risk prediction worked well through the first 2 years post-transplantation. A Gd-IgA1 level ≥ 4.2 (mg/mL) at 1–6 months post-transplantation was independently associated with an increased risk of IgAN recurrence.
The differences in post-transplantation serum Gd-IgA1 levels between recurrent and non-recurrent IgAN recipients was influenced by two factors. First, most patients with recurrence showed higher Gd-IgA1 levels than those without recurrence before transplantation. Second, while Gd-IgA1 levels in most patients with recurrence remained high, it dropped immediately in most recipients without recurrence after transplantation, even if they were at higher levels before transplantation. There are several explanations for this. For those without recurrence, the serum Gd-IgA1 and related immune complexes were subject to more efficient absorption and degradation once circulated inside the healthy donor kidney. In patients with recurrence, the donor kidneys were not capable of absorbing or degrading circulating Gd-IgA1 and related immune complexes. Further, patients with lower risk might be more responsive to IS treatment, resulting in reduced Gd-IgA synthesis within first year of transplant, while patients with high risk could be less responsive to IS treatment and continue to produce higher amounts of serum Gd-IgA1. The discrepancy in Gd-IgA1 levels between patients with and without recurrence seemed to diminish after 24 months, indicating that the accumulated risk of IgAN recurrence may manifest as the precipitation of Gd-IgA1 immune complexes in the glomerular mesangium rather than solely as the serum Gd-IgA1 concentration.
In 2015, Berthelot et al. first reported the usefulness of serum Gd-IgA1 levels in predicting IgAN recurrence post-KT and that patients with recurrence had significantly higher pre-transplant serum Gd-IgA1 levels than those without recurrence (15). However, Berthoux et al. showed that pre-transplant serum Gd-IgA1 levels could not predict the IgAN recurrence risk (16). Temurhan and Park investigated the correlation between post-kidney transplantation biomarker levels and IgAN recurrence, discovering that, at the time of the biopsy, patients with recurrence exhibited significantly higher levels of Gd-IgA1 than those without recurrence (17, 18). A meta-analysis also supported the relationship between post-KT Gd-IgA1 levels and IgAN recurrence while finding no association between pre-transplant Gd-IgA1 levels and the risk of recurrence (19).
We also investigated whether serum APRIL, BAFF, and sCD89 concentrations could predict the risk of recurrence. Genome-wide association studies have provided significant support for the role of APRIL in the pathogenesis of IgAN (20–25). APRIL can increase the production of Gd-IgA1 in the lymphocytes of patients with IgAN (26, 27). According to Martín-Penagos et al., APRIL levels in serum 6 months post-KT and the average levels within 3 years after KT were significantly higher in patients with IgAN recurrence compared to those without recurrence (28). Our data confirmed the difference in APRIL levels between patients with and without recurrence 1–6 months post-transplantation, but no differences were observed in later time periods. This suggests that, in patients with high risk, elevated APRIL levels in the early stages might contribute to maintaining elevated levels of Gd-IgA1, thereby increasing the risk of IgAN recurrence.
BAFF, which shares high homology with the APRIL protein, is integral to the conversion and expression of IgA1 antibodies. Several studies have implicated high levels of BAFF in the development of IgAN (29–31). Conversely, another report showed lower BAFF levels in patients with IgAN (32). This was also observed in the present study; patients in the IgAN recurrence group had significantly lower levels of BAFF at 1–6 months and 6–12 months post-transplantation than patients without recurrence. Serum BAFF ≥ 933 pg/mL at 1–6 months post-transplantation was identified as a protective factor against IgAN recurrence. We do not have a good explanation for this observation, and we would like to emphasise that more data are required to validate this.
CD89, also known as IgA Fc receptor, is expressed in human bone marrow cells but not in glomerular cells. sCD89 is the soluble free form of the CD89 receptor shed by myeloid cells, and it can bind to IgA and form an immune complex. Studies have indicated that the serum sCD89 concentration can predict disease progression in IgAN (33, 34), while IgA-sCD89 complexes can predict the IgAN recurrence risk after kidney transplantation (15). However, our data did not reveal any association between sCD89 levels and the risk of IgAN recurrence. All patients showed a significant decrease in serum sCD89 levels post-transplantation with no differences between the recurrent and non-recurrent groups. This general decrease in sCD89 levels after kidney transplantation might be caused by the effects of immune suppressors. However, in this study we did not analyse the levels of serum immune complexes of Gd-IgA1-sCD89 or Gd-IgA1-IgG, which might better reflect the IgAN recurrence risk.
This study has some limitations. Firstly, being a retrospective study, there is a possibility of introducing patient selection bias. Secondly, since the sample size was considerably small, the conclusions require further validation in a larger patient cohort through prospective studies. Thirdly, the follow-up duration of our study was relatively short for a disease that progresses as slowly as IgAN. Longer follow-up might affect the findings. Lastly, since all patients were of Han Chinese descent, further validation is necessary to apply these findings to other populations.