Circulating IgM Does Not Target Common Chemical Adducts in Recurrent FSGS

To the Editor:

Recurrent primary focal segmental glomerulosclerosis (FSGS) after kidney transplantation remains a major cause of early graft dysfunction and loss.¹ Increasing evidence implicates natural IgM antibodies and complement activation in disease pathogenesis. Although glomerular IgM deposition was traditionally considered nonspecific, recent studies suggest natural IgM may recognize neoepitopes exposed during cellular stress and contribute to tissue injury.²

Natural IgM antibodies are polyreactive and commonly recognize altered self-antigens, generated during oxidative stress.³ We therefore hypothesized that circulating IgM in recurrent FSGS recognizes chemically modified self-antigens within injured glomeruli. To test this, we profiled circulating IgM reactivity against 93 chemically modified antigens in kidney transplant recipients with and without recurrent FSGS.⁴

In a discovery cohort of 23 subjects, including kidney transplant recipients with recurrent FSGS (n = 7), nonrecurrent FSGS (n = 6), transplant controls without previous FSGS (n = 5), and healthy controls (n = 5), we measured serum IgM reactivity at transplantation using an enzyme-linked immunosorbent assay-based platform normalized by within-subject z-scores (Supplementary Table S1). Overall, IgM reactivity profiles were similar across groups (Figure 1a). Principal component analysis showed no separation among groups, and no adduct differed significantly after multiple-testing correction (Figure 1b; Supplementary Tables S2, S3).

Figure 1.

Serum IgM reactivity: (a) Heatmap and (b) PCA analysis of serum IgM reactivity to 93 adducts in the various groups of the discovery cohort. (c) ΔZ-Score between recurrent & nonrecurrent FSGS for each adduct. The dashed line represents the SD. (d) IgM reactivity against the top 8 candidate adducts in the TANGO cohort. Kruskal-Wallis test and Pairwise Wilcoxon with Benjamini Hochberg correction did not show significant differences (P < 0.05) between the groups for any antigen. FSGS, focal segmental glomerulosclerosis; RecFSGS, recurrent FSGS; nonrecFSGS, nonrecurrent FSGS; Kidney Tx, kidney transplant recipients without a diagnosis of FSGS; HD, healthy donors.

Nonetheless, exploratory analysis identified eight candidate adducts with relatively increased IgM reactivity in recurrent FSGS (Figure 1c). Therefore, we tested these candidate targets, in an independent validation cohort from the TANGO Consortium enriched for early post-transplant recurrence (Supplementary Table S1). However, across all tested adducts, IgM reactivity was not associated with recurrence status (Figure 1d; Supplementary Tables S4–S6).

These findings do not support broad recognition of chemically modified self-antigens by circulating IgM in recurrent FSGS. Instead, IgM deposition may reflect alternative mechanisms, including recognition of tissue-restricted or conformational epitopes not captured by linear antigen assays, binding to lipid-protein complexes, or low-affinity polyreactive interactions.⁵ IgM binding may also occur secondary to complement activation or endothelial injury rather than primary antigen recognition.

Our study has limitations. First, the sample size is modest. Although this reflects the rarity of recurrent FSGS and the inclusion of 2 independent cohorts, it limited statistical power to detect differences, if present. Second, the discovery and validation cohorts differed in age distribution— the discovery cohort included pediatric cases, whereas the validation cohort included adults. Therefore, we cannot exclude the possibility that a larger, age-matched pediatric or adult cohort might detect antiadduct IgM reactivity in a subset of patients with FSGS.

Despite these limitations, our data argue against a generalized modified self-recognition model and support alternative mechanisms of IgM-mediated injury in recurrent FSGS.

Disclosure

All the authors declared no conflicting interests.

Patient Consent

All patients provided written informed consent.

Supplementary Material

Supplementary File (PDF)

Supplementary Methods. Table S1. Patients’ characteristics. Table S2. Normalized OD data of the discovery cohort. Table S3. Intra-individual Z-scores of the discovery cohort. Table S4. OD Data of the validation cohort. Table S5. Results of the pairwise Wilcoxon test with BH correction. Table S6. Results of the Kruskal-Wallis tests. Table S7. ELISA material.