Therapeutic Mechanism of Glucocorticoids on Cellular Crescent Formation in Patients With Antiglomerular Basement Membrane Disease

Abstract Background The detection of leukocyte-derived CD11b (α subunit of integrin Mac-1) and CD163 (scavenger receptor) in urine may reflect renal inflammation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The objective of this study was to evaluate the clinical significance of urinary CD11b (U-CD11b) and CD163 (U-CD163) in ANCA-GN. Methods U-CD11b and U-CD163 were examined using enzyme-linked immunosorbent assay in ANCA-GN urine samples from our institutional cohort (n = 88) and a nationwide cohort (n = 138), and their association with renal histology was subsequently analyzed. Logistic regression analyses were performed on a nationwide ANCA cohort to determine the associations of the two urinary molecules with renal remission failure at 6 months or with yearly estimated glomerular filtration rate (eGFR) slope over a 24-month observation period. Results U-CD11b and U-CD163 were significantly associated with cellular crescent formation and leukocyte accumulation in glomerular crescents. With regard to interstitial inflammation, both levels of U-CD11b and U-CD163 at diagnosis remarkably increased in ANCA-GN compared with the levels observed in nonglomerular kidney disorders including nephrosclerosis, immunoglobulin G4-related disease and tubulointerstitial nephritis; however, the presence of U-CD11b alone was significantly correlated with tubulointerstitial leukocyte infiltrates. Although neither U-CD11b nor U-CD163 at diagnosis was associated with remission failure at 6 months, multivariate analysis demonstrated that the baseline U-CD11b levels were significantly associated with the increase in eGFR following immunosuppressive therapy. Conclusions Although both U-CD11b and U-CD163 reflect renal leukocyte accumulation, U-CD11b at diagnosis provides additional clinical value by predicting the recovery rate after the treatment of ANCA-GN.

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Ovine Mesangiocapillary Glomerulonephritis Type I and Crescent Formation

Veterinary Pathology ◽

10.1177/030098589002700104 ◽

1990 ◽

Vol 27 (1) ◽

pp. 26-34 ◽

Cited By ~ 10

Author(s):

P. F. Frelier ◽

D. L. Armstrong ◽

J. Pritchard

Keyword(s):

Basement Membrane ◽

Glomerular Basement Membrane ◽

Inflammatory Cells ◽

Suitable Model ◽

Type I ◽

Human Beings ◽

Crescent Formation ◽

Mesangiocapillary Glomerulonephritis ◽

Bowman's Capsule

Morphologic examination of four Finnish Landrace mixed-breed lambs, 27 to 35 days of age, affected with mesangiocapillary glomerulonephritis type 1, demonstrated a progressive glomerulonephritis. By 27 days of age, three lambs had crescents in 58 to 93% of glomeruli. These three lambs were also uremic. The accelerated rate of crescent formation was attributed to infiltrating polymorphonuclear leukocytes and monocytes, the result of discontinuities (gaps) in the glomerular basement membrane, and to the loss of the integrity of Bowman's capsule. In the three lambs, platelets were identified adjacent to the endothelium or denuded glomerular basement membrane. Two distinctly different types of crescents were noted, apparently dependent on the integrity of Bowman's capsule. One type resulted from the influx of inflammatory cells and dissociation of parietal epithelial cells from Bowman's capsule. The other type was more extensive and contained collagen and was associated with damage to Bowman's capsule resulting in cellular infiltration from the interstitium and sclerosis. Based on morphologic similarities, ovine mesangiocapillary glomerulonephritis is a suitable model for studying the pathogenesis and treatment of mesangiocapillary glomerulonephritis type 1 in human beings.

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Growth Differentiation Factor 15 Ameliorates Anti-Glomerular Basement Membrane Glomerulonephritis in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21196978 ◽

2020 ◽

Vol 21 (19) ◽

pp. 6978

Author(s):

Foteini Moschovaki-Filippidou ◽

Stefanie Steiger ◽

Georg Lorenz ◽

Christoph Schmaderer ◽

Andrea Ribeiro ◽

...

Keyword(s):

T Cells ◽

Basement Membrane ◽

Glomerular Basement Membrane ◽

Transforming Growth Factor ◽

Protective Effects ◽

Crescent Formation ◽

Activated T Cells ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Deficient Mice

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis.

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The correlation of urinary podocytes and podocalyxin with histological features of lupus nephritis

Lupus ◽

10.1177/0961203317734918 ◽

2017 ◽

Vol 27 (3) ◽

pp. 484-493 ◽

Cited By ~ 6

Author(s):

D Ikuma ◽

K Hiromura ◽

H Kajiyama ◽

J Suwa ◽

H Ikeuchi ◽

...

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Activity Index ◽

Sandwich Elisa ◽

Characteristic Analysis ◽

Crescent Formation ◽

Class V ◽

Histological Features ◽

Cellular Crescent ◽

Class Iv

Objectives The objective of this study was to test the correlation of urinary podocyte number (U-Pod) and urinary podocalyxin levels (U-PCX) with histology of lupus nephritis. Methods This was an observational, cross-sectional study. Sixty-four patients were enrolled: 40 with lupus nephritis and 24 without lupus nephritis (12 lupus nephritis patients in complete remission and 12 systemic lupus erythematosus patients without lupus nephritis). Urine samples were collected before initiating treatment. U-Pod was determined by counting podocalyxin-positive cells, and U-PCX was measured by sandwich ELISA, normalized to urinary creatinine levels (U-Pod/Cr, U-PCX/Cr). Results Lupus nephritis patients showed significantly higher U-Pod/Cr and U-PCX/Cr compared with patients without lupus nephritis. U-Pod/Cr was high in proliferative lupus nephritis (class III±V/IV±V), especially in pure class IV (4.57 (2.02–16.75)), but low in pure class V (0.30 (0.00–0.71)). U-Pod/Cr showed a positive correlation with activity index ( r=0.50, P=0.0012) and was independently associated with cellular crescent formation. In contrast, U-PCX/Cr was high in both proliferative and membranous lupus nephritis. Receiver operating characteristic analysis revealed significant correlation of U-Pod/Cr with pure class IV, class IV±V and cellular crescent formation, and the combined values of U-Pod/Cr and U-PCX/Cr were shown to be associated with pure class V. Conclusions U-Pod/Cr and U-PCX/Cr correlate with histological features of lupus nephritis.

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THE GLOMERULUS IN EXPERIMENTAL RENAL DISEASE IN RATS AS OBSERVED BY LIGHT AND ELECTRON MICROSCOPY

Journal of Experimental Medicine ◽

10.1084/jem.102.5.573 ◽

1955 ◽

Vol 102 (5) ◽

pp. 573-580 ◽

Cited By ~ 31

Author(s):

Carolyn F. Piel ◽

Luther Dong ◽

F.W.S. Modern ◽

Joseph R. Goodman ◽

Roger Moore

Keyword(s):

Electron Microscopy ◽

Endothelial Cells ◽

Basement Membrane ◽

Light Microscopy ◽

Light And Electron Microscopy ◽

Electron Microscopic ◽

Crescent Formation ◽

Colloidal Iron ◽

Narrow Channels ◽

Glomerular Capillary

Nephrotoxic serum disease in rats has been studied by light and electron microscopy from 1 hour to 10 weeks after production of the disease. By light microscopy leucocytic infiltration of the glomerular capillary was observed between the 3rd and 6th hour. At 6 hours an increase in colloidal iron-positive material was observed coating the extraluminal surface of the capillaries. Also at this time swelling of the endothelial cells becomes prominent. By 72 hours, thickening of the basement membrane was observed. Glomerular capillary thrombi were observed in approximately half the tissue examined in the first 2 weeks of disease. 50 per cent of the animals showed severe chronic lesions, exudation into the capsular space, crescent formation, and obliteration of glomeruli. At 1 hour electron microscopic pictures showed that osmophilic material may line the foot processes of the epithelial cells and obliterate all but narrow channels of the space between the feet. By 6 hours thickening of the basement membrane was prominent. This change persisted throughout 10 weeks of observation. The tissue from animals which had severe chronic alterations by light microscopy revealed changes which could not be interpreted at this time.

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Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

AJP Renal Physiology ◽

10.1152/ajprenal.00018.2014 ◽

2014 ◽

Vol 307 (9) ◽

pp. F1023-F1032 ◽

Cited By ~ 11

Author(s):

Junhua Mao ◽

Zhifeng Zeng ◽

Zhuo Xu ◽

Jiangzhong Li ◽

Lei Jiang ◽

...

Keyword(s):

Mammalian Target Of Rapamycin ◽

Hypoxia Inducible Factor ◽

Target Of Rapamycin ◽

Crescent Formation ◽

Glomerular Diseases ◽

Mtorc1 Signaling ◽

Cellular Crescent ◽

Underlying Mechanisms ◽

Mtorc1 Activation ◽

Glomerular Tuft

Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19 ± 3.86% of total glomeruli in knockouts vs. 0% in control littermates, n = 12–36, P = 0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92 ± 11.961% of total glomeruli in knockouts vs. 0% in control littermates, n = 4–7, P = 0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.

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Fibronectin mRNA in the developing glomerular crescent in rabbit antiglomerular basement membrane disease.

Journal of the American Society of Nephrology ◽

10.1681/asn.v5122087 ◽

1995 ◽

Vol 5 (12) ◽

pp. 2087-2090

Author(s):

S P Sady ◽

M Goyal ◽

P E Thomas ◽

B L Wharram ◽

R C Wiggins

Keyword(s):

Wound Healing ◽

In Situ Hybridization ◽

Basement Membrane ◽

Matrix Protein ◽

Crescent Formation ◽

Plasma Phase ◽

Two Phases ◽

Fibronectin Mrna ◽

In Cells

Fibronectin is a multifunctional matrix protein important in wound healing that is markedly increased in glomerular crescents. A previous report established two phases of fibronectin metabolism in crescent formation in an anti-glomerular basement membrane model of crescentic nephritis in the rabbit. Phase I was associated with increased glomerular fibronectin content from plasma. Phase II was associated with increased fibronectin mRNA in glomeruli. To examine the hypothesis that fibronectin is synthesized in the developing crescent, rabbit fibronectin cDNA was cloned, sense and antisense riboprobes were prepared and their specificity under the conditions to be used was validated and in situ hybridization studies were performed in the model. The results showed that the cells in the developing glomerular crescent express an intense fibronectin mRNA signal at Day 7 and that this signal persisted in cells of the crescent at Day 14. This result shows that fibronectin synthesis does indeed take place in cells of the developing crescent in this model and supports the hypothesis that fibronectin may be an important agent regulating crescent formation and fibrosis.

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(Pro)renin receptor promotes crescent formation via the ERK1/2 and Wnt/β-catenin pathways in glomerulonephritis

AJP Renal Physiology ◽

10.1152/ajprenal.00250.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. F571-F578

Author(s):

Maki Urushihara ◽

Shuji Kondo ◽

Yukiko Kinoshita ◽

Natsuko Ozaki ◽

Ariunbold Jamba ◽

...

Keyword(s):

Cell Proliferation ◽

Basement Membrane ◽

Glomerular Basement Membrane ◽

Mesangial Cells ◽

Macrophage Infiltration ◽

Crescent Formation ◽

Sirna Treatment ◽

Extracellular Signal ◽

Parietal Epithelial Cells

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active β-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active β-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the β-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/β-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.

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Membranous nephropathy followed by anti-glomerular basement disease: A case report and review of clinical presentation and treatment

SAGE Open Medical Case Reports ◽

10.1177/2050313x18807621 ◽

2018 ◽

Vol 6 ◽

pp. 2050313X1880762

Author(s):

Claudius Speer ◽

Matthias Martin Gaida ◽

Rüdiger Waldherr ◽

Christian Nusshag ◽

Florian Kälble ◽

...

Keyword(s):

Basement Membrane ◽

Glomerular Basement Membrane ◽

Membranous Nephropathy ◽

Clinical Presentation ◽

Rapidly Progressive Glomerulonephritis ◽

Renal Vein Thrombosis ◽

Simultaneous Occurrence ◽

Rapid Decline ◽

Crescent Formation ◽

Vein Thrombosis

Membranous nephropathy is a common cause of nephrotic syndrome in adults and can be primary or secondary through autoimmune disease, medication, infection, or malignancy. Rapidly progressive glomerulonephritis with crescent formation is rare in patients with membranous nephropathy. Thus, in cases with rapid decline in renal function, after excluding complications such as malignant hypertension, acute hypersensitivity interstitial nephritis, and bilateral renal vein thrombosis, the simultaneous occurrence of a superimposed glomerulonephritis should be considered. We report a 55-year-old man suffering from a biopsy-confirmed primary membranous nephropathy, who developed rapidly progressive glomerulonephritis with anti-glomerular basement membrane antibodies after being affected with membranous nephropathy for 8 years. The kidney biopsy revealed a concurrence of membranous nephropathy and anti-glomerular basement membrane disease. Clinical presentation and treatment of membranous nephropathy followed by anti-glomerular basement membrane disease are discussed based on our observation with promising follow-up.

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