Background: The etiology of minimal change disease (MCD) remains a mystery as the only hallmark findings are the diffuse effacement of foot processes by electron microscopy (EM). Punctate IgG staining floating outside of glomerular capillary loops have recently been identified as autoimmune antibodies against nephrin in podocytes from a set of MCD cases (Watts AJB et al., JASN 2022;33:238-252). The corresponding ultrastructural findings by EM, however, of the autoimmune antibodies are not yet described. We hypothesized that budding ballooning clusters (BBC) seen in EM may be correlated with the punctate IgG staining granules. Design: We identified 7 patients with MCD cases showing punctate IgG staining and were evaluated for BBC using EM images (15-20 images per case). We concurrently examined 8 primary focal segmental glomerulosclerosis (FSGS) cases, 12 negative controls (either unremarkable cases or tubulointerstitial diseases), and 5 diabetic nephropathy/vascular nephropathy cases by EM. Results: Light microscopy was not remarkable in MCD (Figure 1A, PAS staining). In 7 out of 8 cases of MCD (case 2a unavailable), there were positive punctate IgG staining particles outside of the glomerular basement membranes (GBM) (Figure 1B, indicated by arrows) along with concurrent punctate staining for C3, kappa, and lambda as well (Table 1). By EM, all 8 (100%) MCD cases revealed BBC that were characterized with ballooning foot processes ranging from 1 to 6 µm and were either budding or detached from the GBM in 3 – 7 clusters; no electron dense materials were seen in BBC (Figure 1C and 1D with arrows). BBC were also seen in 3 out of 8 (38%) primary FSGS, but in only 1 of 12 (8%) negative controls and none of the 5 (0%) diabetic/vascular nephropathy cases. Additional EM review of our archival MCD caselog revealed the presence of BBC in 12 of 20 (60%) of cases. Conclusions: Our data suggest that BBC are EM structures that are most likely correlated with punctate IgG staining seen in some cases of MCD in terms of their microscopic locations and sizes. Future studies using the immunogold labeling technique may be useful to confirm IgG staining in the BBC.
Mahalingam V, Fatemi S, Li W, Kanaan H, Zhang P. Ultrastructural findings of budding ballooning clusters are best correlated with punctate autoimmune antibodies seen by immunofluorescence in minimal change disease. Lab Invest. 2023 Mar;103(3 Suppl.1):S1442-S1443. doi:10.1016/j.labinv.2023.100096