Endothelial cell injury in acute and chronic glomerular lesions in patients with IgA nephropathy.

Endothelial cell injury may contribute to the progression of various glomerular diseases. In the present study, we examined glomerular capillary injury in acute and chronic glomerular lesions in patients with Immunoglobulin A nephropathy (IgAN). We selected renal biopsy samples of IgAN (n = 200), and glomerular capillary injury in the acute and chronic glomerular lesions was assessed using immunohistochemistry for CD34 and electron microscopy. We examined the correlations between acute and chronic glomerular lesions and proteinuria, hematuria, and the renal function. The injured glomerular capillaries in the acute glomerular lesions were characterized morphologically by the separation of CD34+ endothelial cells from the glomerular basement membrane and the loss of glomerular endothelial cells and capillaries, together with inflammatory cell infiltration, fibrin exudation, rupture of the glomerular basement membrane, and/or crescent formation. In addition, the injured capillaries in the chronic glomerular lesions were characterized by the loss of CD34+ glomerular endothelial cells and capillaries exhibiting segmental and global glomerular sclerosis with or without fibrous crescents. In the acute glomerular lesions, the presence of endocapillary hypercellularity, fibrinoid necrosis, and cellular and fibrocellular crescents correlated significantly with hematuria, with or without proteinuria. In the chronic glomerular lesions, a significant relationship was evident between segmental or global sclerosis and proteinuria and/or the serum creatinine level. In conclusion, injuries of glomerular capillaries and the loss of endothelial cells occurred in the acute and chronic glomerular lesions in IgAN and may contribute to the development of hematuria, proteinuria, and renal dysfunction.

Kusano T ，Takano H ，Kang D ，Nagahama K ，Aoki M ，Morita M ，Kaneko T ，Tsuruoka S ，Shimizu A ... -  《-》

Glomerular capillary and endothelial cell injury is associated with the formation of necrotizing and crescentic lesions in crescentic glomerulonephritis.

Fujita E ，Nagahama K ，Shimizu A ，Aoki M ，Higo S ，Yasuda F ，Mii A ，Fukui M ，Kaneko T ，Tsuruoka S ... -  《-》

Analysis of glomerular anionic charge status in children with IgA nephropathy using confocal laser scanning microscopy.

The proteinuria resulting from IgA nephropathy is secondary to altered charge-selective and/or size-selective properties of the glomerular capillary walls. However, the functional changes occurring within the glomerular capillary network which lead to proteinuria are still poorly understood. In this study, we analyzed the participation of charged components in the glomerular capillary and their role with respect to proteinuria in childhood IgA nephropathy. We examined glomerular anionic charge in renal biopsy specimens with confocal laser scanning microscopy using FITC-conjugated poly-L-lysine as a cationic tracer. The renal specimens investigated were from 9 children with IgA nephropathy (IgAN(+)) associated with detectable proteinuria in a morning urine specimen, 8 children with IgA nephropathy (IgAN(-)) and 11 children with thin basement membrane disease (TBMD) with no detectable proteinuria. The labeling intensity of glomerular fixed anionic sites from IgAN(+) was significantly lower than that of IgAN(-) and TBMD. Staining the serial sections following methylation treatment revealed that the labeling intensity for fixed anionic sites in TBMD was significantly higher than that of both IgAN(+) and IgAN(-). On the other hand, saponification treatment resulted in significantly more intensive fluorescence in TBMD and IgAN(-) than in IgAN(+). Furthermore, statistical analysis demonstrated a significant correlation between 24-hour protein excretion and the intensity of fixed anionic sites in all patients with IgA nephropathy at pH 7.0 and following staining with saponification treatment. These findings suggest that a reduction of glomerular anionic charge might be causally associated with the development of proteinuria in childhood IgA nephropathy. Furthermore, sulfate components such as heparan sulfate proteoglycan might be involved initially followed by carboxyl components such as sialoglycoproteins in the glomeruli of patients with IgA nephropathy contributing to the occurrence of proteinuria. We suggest that this method represents a straightforward approach to dissect the participation of charged components in the pathogenesis of childhood IgA nephropathy and their relationship to the development of glomerular proteinuria.

Sakagami Y ，Nakajima M ，Takagawa K ，Ueda T ，Akazawa H ，Maruhashi Y ，Shimoyama H ，Kamitsuji H ，Yoshioka A ... -  《nephron clinical practice》

An important role of glomerular segmental lesions on progression of IgA nephropathy: a multivariate analysis.

Katafuchi R ，Oh Y ，Hori K ，Komota T ，Yanase T ，Ikeda K ，Omura T ，Fujimi S ... -  《CLINICAL NEPHROLOGY》

M2 macrophage infiltrates in the early stages of ANCA-associated pauci-immune necrotizing GN.

This study examined kidney biopsies with focal segmental glomerular fibrinoid necrosis to identify early features of pauci-immune necrotizing GN and the primary effector cells mediating initial capillary injury. Seventeen consecutive kidney biopsies with focal pauci-immune necrotizing GN, obtained over a 6-year period (2007-2012), were studied. Neutrophils and CD68(+), CD163(+), CD3(+), CD56(+), and CD20(+) cells were scored in paraffin sections counterstained with periodic acid-Schiff. Electron microscopy was performed in 15 of 17 biopsies and additional examples of pauci-immune necrotizing GN (n=25). Biopsies with thin basement membrane nephropathy (n=5) served as immunohistologic normal controls. Biopsies with pauci-immune necrotizing GN had a mean of 10 (range=3-25) normal-appearing glomeruli, a mean of 2 (range=1-5) glomeruli with segmental fibrinoid necrosis, and a mean of 2 (range=1-11) glomeruli with cellular crescents. CD68(+) and CD163(+) macrophages predominated at sites of fibrinoid necrosis in pauci-immune necrotizing GN, exceeding the quantity of neutrophils and T cells (mean scores [SD]=2.5 [0.7] and 2.2 [0.75] versus 0.6 [0.5] and 0.1 [0.3], respectively; P<0.001). B and natural killer cells were rare. Normal-appearing glomeruli in pauci-immune necrotizing GN had significantly more CD68(+) and CD163(+) macrophages than the controls (CD68(+), 0.9 [0.3] versus 0.4 [0.3]; CD163(+), 1 [0.4] versus 0.4 [0.3]; P<0.001). The quantity of other glomerular infiltrates did not differ from controls. The serum creatinine level at biopsy correlated with the glomerular CD68 and neutrophil scores (r=0.74 and r=0.71, respectively; P=0.001) but did not correlate with the extent of fibrinoid necrosis (r=0.36). Macrophages were localized at minute perforations and attenuations of the capillary basement membrane by electron microscopy. Early pauci-immune necrotizing GN is characterized by a selective localization of CD163(+) M2 macrophages at sites of glomerular fibrinoid necrosis and in normal-appearing glomeruli. These observations indicate that alternatively activated macrophages are positioned as potential effectors of glomerular injury in the early stages of pauci-immune necrotizing GN and may be potential targets for therapeutic intervention.

Zhao L ，David MZ ，Hyjek E ，Chang A ，Meehan SM ... -  《-》