National Survey Report on Podocyte Infolding Glomerulopathy in Japan: Proposal for a Morphological Classification Based on Electron Microscopy

Podocyte Infolding Glomerulopathy (PIG) was first proposed as a disease concept in Japan in 2008, and its international recognition has been increasing in recent years. Joh et al. initially proposed a subtype classification based on electron microscopic findings; however, its application has been limited due to ambiguous morphological definitions.

To address this issue, the Japanese Society of Nephrology organized a working group (WG) to conduct a nationwide survey, and the preliminary findings are presented here. This study aimed to establish a morphological subclassification of PIG based on transmission electron microscopy (TEM) findings, to clarify its morphological characteristics, and to analyze the clinicopathological features associated with each subtype, thereby elucidating their pathological and clinical significance.

We conducted a nationwide, multicenter cohort study of patients diagnosed with, or suspected of PIG, with the support of collaborative members of the Japanese Society of Nephrology. Clinical data and TEM images were retrospectively collected and evaluated. PIG was defined as (i) infoldings of podocyte foot processes into at least two sites per glomerular tuft, extending to half the thickness of the glomerular basement membrane (GBM), or (ii) the presence of microsphere or microtubular structures within the GBM suggestive of podocyte origin. Morphological subclassifications based on TEM findings and clinical parameters were compared among subtypes using one-way ANOVA with Tukey–Kramer HSD post hoc tests and Pearson’s chi-square test.

Ninety-two cases from 73 institutions met the criteria for PIG. TEM analysis evaluated the presence of primary infoldings, microspheres, microtubules, electron-dense deposits (EDD), foot process effacement, GBM thickening, and clustering. Based on these findings, four subtypes were identified (Figure). Type A: Only podocyte primary infoldings without any fine structures within the GBM (n=21). Type B: Microsphere structures within the GBM (n=24), with clustering observed in 14 cases (58%). Type C: Microsphere and/or microtubular structures (n=37). Type D: Similar to Type B, but high-density clusters of microspheres on the epithelial side of the GBM, resembling membranous nephropathy (n=10).

Extensive foot process effacement and GBM thickening (dense layer ≥700 nm) were observed in all cases. EDDs were present in approximately 30% of all subtypes, with no significant differences among them. Clinical parameters revealed significant differences among subtypes. Age: Types A and D occurred more frequently in older patients, whereas Types B and C were more common in younger ones (p < 0.01). Sex: A male predominance (~70%) was observed in Types A and D, while only ~20% of patients with Types B and C were male (p < 0.01). SLE comorbidity: SLE was frequently observed in Types B and C, but not in Types A and D (p < 0.01).

This interim report proposes a refined TEM-based subclassification of PIG and clarifies its distribution in Japan. Types A and D are likely distinct morphological entities, while Types B and C may exhibit morphological polarity. Further studies incorporating immunofluorescence findings and detailed clinical data are planned to refine the clinicopathological characterization of each subtype and to establish standardized diagnostic criteria for PIG.