The association of tumor necrosis factor superfamily 13 with recurrence of immunoglobulin A nephropathy in living related kidney transplantation

Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis [1, 2], and a significant number of patients progress to end-stage renal disease (ESRD) requiring dialysis or kidney transplantation [3]. In cases of transplant recipients, recurrence of primary glomerulonephritis commonly affects graft and patient outcomes [2]. The recurrence rate of IgAN after kidney transplantation has been estimated to be 9 to 61%, with this wide variability likely to reflect differences in follow-up duration and biopsy policies across institutions [4, 5]. While the impact of the recurrence of IgA deposits on graft function has been debated, recurrent IgAN has been associated with unfavorable outcomes in long-term follow-up studies [2, 6‐8]. Unfortunately, however, there is no biomarker that can predict IgAN recurrence in these patients.

Tumor necrosis factor superfamily 13 (TNFSF13), also known as a proliferation inducing ligand (APRIL), is secreted from antigen-presenting cells and is engaged in adaptive and innate immune responses by binding to receptors on B and T cells [9, 10]. An in vivo analysis using TNFSF13 gene knockout mice showed impaired IgA antibody responses to mucosal immunization [11]. Conversely, TNFSF13 transgenic mice showed enhanced T-cell independent humoral responses [12]. The TNFSF13 locus has recently been identified as a susceptibility gene in a Han Chinese genome-wide association study of IgAN patients [13]. Furthermore, high serum TNFSF13 levels in IgAN patients could predict the progression of renal disease based on B cell stimulation [14]. The high recurrence rates after kidney transplantation in IgAN patients suggests an impaired host IgA immune system. Therefore, TNFSF13, which is known to be involved in B cell and immunoglobulin A immune system function, could affect recurrent IgAN. The objective of this study was to find an association between pre-transplant serum TNFSF13 levels and recurrent IgAN.

Several factors, including genetic and environmental factors, contribute to the pathogenesis of IgAN. Among the several factors involved in the pathogenesis of IgAN, abnormal mucosal immunity is an important factor for triggering IgAN. As previously noted, TNFSF13 is known to be involved in abnormal mucosal immunity via T-cell independent production of IgA- producing B cells and IgA1 to IgA2 class switching [9, 17‐20]. TNFSF13 levels can affect the etiology of recurrent IgAN, based on findings of various studies about the effect of TNFSF13 on the IgA mucosal immune system [11, 14]. It is well known that a longer follow-up period after transplantation and younger age of a recipient at transplantation increase the risk of IgAN recurrence [2]. A previous study reported a high recurrence rate of IgAN after kidney transplantation among recipients with zero-HLA mismatches [21]. In our study, we identified that a higher pre-transplant serum level of TNFSF13 was associated with IgAN recurrence on multivariate analysis among patients who received a graft from a living related donor after adjusting for the recipient’s age at transplantation, the length of follow up duration.

We could not elucidate why there was an association between the levels of TNFSF13 on the recurrent IgAN only in living related donor graft but not in entire subjects. Although the mechanism of increased recurrent IgAN in living related grafts is unclear, several explanations could be possible. First, TNFSF13 shown to be increased the overall IgA secretion, although not specific to Gd-IgA1 [14]. However, unfortunately, we could not confirm that TNFSF13 would affect recurrent IgAN via increasing the relative amount of Gd-IgA1 because there were no differences in the level of Gd-IgA1 between the groups. Second, the pathogenesis of IgAN requires several hits, and we carefully assume there was the role of TNFSF13 in the production of anti-glycan antibody. It is essential for the generation of anti-glycan IgG due to a defect of allorecognition to Gd-IgA1 in the pathogenesis of IgAN [22]. A recent study has shown that TNFSF13 also involved in adaptive immunity through influencing on memory T cells [23]. We could not measure anti-glycan antibodies in the present study; however, we carefully suggest that TNFSF13 would affect recurrent IgAN by engaging in alloantibody response. Third, the similar genetic background in the living related grafts with recipients would have affected the recurrent IgAN [24]. It can be inferred that the mesangial immune complex deposition of living related grafts is more likely to occur [25, 26]. TNFSF13 may have upregulated the production of systemic IgA or pathognomonic IgA1-immune complex, and these factors may be profound in living related donor grafts having the genetic susceptibility. This issue would be resolved by the further experimental investigation.

Although IgAN was traditionally considered as a benign disease, more recent evidence has demonstrated that recurrence of IgAN in renal allografts is associated with unfavorable outcomes in graft function [2, 8, 27, 28]. In this study, we observed only one event of graft failure due to the self-discontinuing steroid. Therefore, we did not find an association between serum TNFSF13 levels and graft outcome. Additionally, we did not identify an HLA-specific effect, as reported in previous studies, including a negative effect for HLA-B35 and DR4 and a protective effect for HLA-A2 [6, 29]. As the majority of the patients in our study group received anti-interleukin 2 for induction therapy, we were unable to demonstrate the protective role of antithymocyte globulin induction therapy on IgAN recurrence, as reported in a previous study [30].

According to Australia and New Zealand Dialysis and Transplant (ANZDATA) registry, which has accumulated data over 30 years, showed that recurrence of IgAN was 5.1, 15% at 5, 15 years after kidney transplantation [2]. The rate of IgAN recurrence in our study was 15.9% over a median follow up duration of 5.1 years, a rate which was higher than the rate based on the ANZDATA registry data but lower than recurrence rate of 29–61% reported in other studies [4, 29]. Differences in reported rates of IgAN recurrence might result from differences in biopsy policy between institutions and differences in the length of follow up. Further prospective studies with sufficient follow-up duration are needed to clarify the association between pre-transplant serum TNFSF13 levels and the recurrence rate and graft functionality in IgAN patients.

The present study has several limitations. The number of total subjects and events in the present study was too small to obtain the predictive value of TNFSF13 for recurrent IgAN. Relatively shorter follow up duration was also a limitation of the present study. TNFSF13 was only associated with living related transplantation, and the predictive value was not shown. Further studies in the sufficient number of cohorts are needed to confirm these findings and to show cut off values for the predictive value of TNFSF13.

In summary, we identified an association between pre-transplant serum TNFSF13 levels and IgAN recurrence among patients who received a graft from a living related donor. Our findings suggest that there may be a possible role of TNFSF13 in IgAN recurrence among patients who undergo living related donor graft transplantation.

This study provides evidence to suggest that pre-transplant serum TNFSF13 levels is associated with recurrent IgAN who had living related transplantation. Regarding the concern of recurrence of IgAN on graft function, these results require further studies to validate the role of TNFSF13 in the recurrence of IgAN.