Association of the podocyte phenotype with extracapillary hypercellularity in patients with diabetic kidney disease

Extracapillary hypercellularity was recently identified as a poor prognostic factor for diabetic kidney disease (DKD), but its nature, pathogenesis, and relationship with glomerular sclerosis are still unclear. We retrospectively studied 107 patients with biopsy-proven DKD, recruited from January 2018 through December 2020. We compared the clinicopathologic characteristics of 25 patients with extracapillary hypercellularity lesions (the extracapillary hypercellularity group) to those of 82 patients without extracapillary hypercellularity (the control group). Multiple cell-specific markers were used for immunohistochemical staining to analyse the types of cells that exhibited extracapillary hypercellularity. Podocyte phenotype changes were evaluated via immunohistochemical staining for Synaptopodin and Nephrin, and foot process width was measured via transmission electron microscopy. Patients with extracapillary hypercellularity lesions had more severe clinical features than patients without extracapillary hypercellularity in DKD, as indicated by elevated proteinuria and serum creatinine levels, and decreased serum albumin. Pathologically, extracapillary hypercellularity was accompanied by increased mesangial hyperplasia and interstitial fibrosis. Severe obliterative microvascular disease was observed more frequently in the extracapillary hypercellularity group than in the control group. At cell type analysis, 25 patients in the DKD-extracapillary hypercellularity group showed that a mixture of cells expressed either Wilm’s tumor-1 or paired box protein 2. Furthermore, DKD-extracapillary hypercellularity patients had significant loss of podocyte phenotype and severe foot process effacement. Cells in extracapillary hypercellularity had increased hypoxia-induced factor-1 alpha expression. Extracapillary hypercellularity is associated with severe renal dysfunction and renal sclerosis. Vascular damage is closely related to severe podocyte hypoxia injury and requires additional attention in future research.