Histopathology · 2026
Glomerular plasmalemma vesicle-associated protein-1 as an endothelial remodelling marker complementing C4d in chronic active antibody-mediated rejection.
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Igarashi Yuto, Shimokawa Mayu, Kawanishi Kunio, Hirai Toshihito, Seino Hiroshi, Shimizu Tomokazu, Ishida Hideki, Takagi Toshio
Аннотация
AIMS: Chronic active antibody-mediated rejection (caABMR) is a major cause of late kidney allograft failure, yet reliable histological indicators of microvascular injury and therapeutic response remain insufficient. Complement C4d deposition reflects complement activation but does not fully capture endothelial remodelling, particularly in ABO-incompatible transplantation. Plasmalemma vesicle-associated protein-1 (PV-1), encoded by PLVAP and normally absent from glomerular endothelium, is upregulated during endothelial remodelling. We investigated whether glomerular PV-1 complements C4d in identifying active endothelial injury in caABMR.
METHODS AND RESULTS: A total of 429 allograft biopsies from 126 patients with caABMR and 345 surveillance biopsies from 94 stable recipients were analysed. Glomerular PV-1 and C4d immunofluorescence intensities were quantified and correlated with histopathological lesions, renal function, and donor-specific antibodies, with stratification by ABO compatibility. Both PV-1 and C4d were associated with microvascular inflammation and transplant glomerulopathy. While C4d reflected cumulative complement activation and showed staining in ABO-incompatible grafts, PV-1 specifically identified endothelial remodelling, particularly in lesions with double-contour formation, and demonstrated dynamic reduction following B-cell-directed therapy. Low-vacuum scanning electron microscopy correlated with the presence of de novo PV-1 expression in glomerular endothelial cells. In multivariable Cox models incorporating ΔPV-1 and ΔC4d with clinical covariates, ΔPV-1 remained independently associated with death-censored graft survival, whereas ΔC4d did not.
CONCLUSIONS: Glomerular PV-1 functions as a dynamic marker of endothelial remodelling that complements the static C4d footprint of complement activation. Combined assessment of PV-1 and C4d captures distinct dimensions of microvascular pathology and may refine histopathological evaluation of injury and treatment response in caABMR.
METHODS AND RESULTS: A total of 429 allograft biopsies from 126 patients with caABMR and 345 surveillance biopsies from 94 stable recipients were analysed. Glomerular PV-1 and C4d immunofluorescence intensities were quantified and correlated with histopathological lesions, renal function, and donor-specific antibodies, with stratification by ABO compatibility. Both PV-1 and C4d were associated with microvascular inflammation and transplant glomerulopathy. While C4d reflected cumulative complement activation and showed staining in ABO-incompatible grafts, PV-1 specifically identified endothelial remodelling, particularly in lesions with double-contour formation, and demonstrated dynamic reduction following B-cell-directed therapy. Low-vacuum scanning electron microscopy correlated with the presence of de novo PV-1 expression in glomerular endothelial cells. In multivariable Cox models incorporating ΔPV-1 and ΔC4d with clinical covariates, ΔPV-1 remained independently associated with death-censored graft survival, whereas ΔC4d did not.
CONCLUSIONS: Glomerular PV-1 functions as a dynamic marker of endothelial remodelling that complements the static C4d footprint of complement activation. Combined assessment of PV-1 and C4d captures distinct dimensions of microvascular pathology and may refine histopathological evaluation of injury and treatment response in caABMR.