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Glomerulonephritis (GN) due to infective endocarditis (IE) is well documented, but most available data are based on old autopsy series. To update information, we now present the largest biopsy-based clinicopathologic series on IE-associated GN. The study group included 49 patients (male-to-female ratio of 3.5:1) with a mean age of 48 years. The most common presenting feature was acute kidney injury. Over half of the patients had no known prior cardiac abnormality. However, the most common comorbidities were cardiac valve disease (30%), intravenous drug use (29%), hepatitis C (20%), and diabetes (18%). The cardiac valve infected was tricuspid in 43%, mitral in 33%, and aortic in 29% of patients. The two most common infective bacteria were Staphylococcus (53%) and Streptococcus (23%). Hypocomplementemia was found in 56% of patients tested and ANCA antibody in 28%. The most common biopsy finding was necrotizing and crescentic GN (53%), followed by endocapillary proliferative GN (37%). C3 deposition was prominent in all cases, whereas IgG deposition was seen in

Antimyeloperoxidase antibodies can cause crescentic glomerulonephritis and pulmonary hemorrhage. Toll-like receptors (TLRs) respond to infectious agents activating host defenses, whereas infections potentially initiate disease and provoke relapses. Neutrophils were found to be key effector cells of injury in experimental models, as disease does not occur in their absence and injury is enhanced by lipopolysaccharide (LPS). In this study, highly purified LPS (a pure TLR4 ligand) acted with antimyeloperoxidase antibodies to synergistically increase kidney and lung neutrophil recruitment and functional injury; effects abrogated in TLR4-deficient mice. Increased kidney TLR4 expression after stimulation predominantly occurred in glomerular endothelial cells. Enhanced glomerular neutrophil recruitment correlated with increased kidney mRNA expression of CXCL1 and CXCL2 (homologs of human CXCL8), whereas their preemptive neutralization decreased neutrophil recruitment. Disease induction in bone marrow chimeric mice showed that TLR4 in both bone marrow and renal parenchymal cells is required for maximal neutrophil recruitment and glomerular injury. Further studies in human glomerular cell lines stimulated with LPS found that glomerular endothelial cells were the prominent sources of CXCL8. Thus, our results define a role for TLR4 expression in bone marrow-derived and glomerular endothelial cells in neutrophil recruitment and subsequent functional and histological renal injury in experimental antimyeloperoxidase glomerulonephritis. Kidney International (2010) 78, 1263-1274; doi:10.1038/ki.2010.327; published online 15 September 2010

Wegener's granulomatosis, microscopic polyangiitis, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis (NCGN) are strongly associated with antineutrophil cytoplasmic autoantibodies (ANCAs) directed against either proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO). This has led some investigators to prefer combining these diseases under the common heading of ANCA-associated vasculitides. However, it is increasingly recognized that there are characteristic differences between patients with anti-PR3 and those with anti-MPO-associated vasculitis. This review focuses on the clinical, histopathologic, and possibly pathophysiologic differences between anti-PR3- and anti-MPO-associated vasculitis. Although there is considerable overlap, the anti-PR3- and anti-MPO-associated vasculitides are each characterized by particular clinical and histopathological findings. Extrarenal organ manifestations and respiratory tract granulomas occur more frequently in patients with anti-PR3 than in those with anti-MPO. Anti-PR3-positive patients with NCGN generally have a more dramatic deterioration of their renal function compared with anti-MPO-positive patients. The term "ANCA-associated vasculitis" is considered as a useful concept in the presence of systemic vasculitis. Likewise, in the presence of vasculitis, the terms "anti-PR3-associated vasculitis" and "anti-MPO-associated vasculitis" are useful concepts.

Antiproteinase 3- and antimyeloperoxidase-associated vasculitis. Wegener's granulomatosis, microscopic polyangiitis, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis (NCGN) are strongly associated with antineutrophil cytoplasmic autoantibodies (ANCAs) directed against either proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO). This has led some investigators to prefer combining these diseases under the common heading of ANCA-associated vasculitides. However, it is increasingly recognized that there are characteristic differences between patients with anti-PR3 and those with anti-MPO-associated vasculitis. This review focuses on the clinical, histopathologic, and possibly pathophysiologic differences between anti-PR3- and anti-MPO-associated vasculitis. Although there is considerable overlap, the anti-PR3- and anti-MPO-associated vasculitides are each characterized by particular clinical and histopathological findings. Extrarenal organ manifestations and respiratory tract granulomas occur more frequently in patients with anti-PR3 than in those with anti-MPO. Anti-PR3-positive patients with NCGN generally have a more dramatic deterioration of their renal function compared with anti-MPO-positive patients. The term "ANCA-associated vasculitis" is considered as a useful concept in the presence of systemic vasculitis. Likewise, in the presence of vasculitis, the terms "anti-PR3-associated vasculitis" and "anti-MPO-associated vasculitis" are useful concepts.

Migration of circulating leukocytes from the vasculature into the surrounding tissue is an important component of the inflammatory response. Among the cell surface molecules identified as contributing to leukocyte extravasation is VCAM-1, expressed on activated vascular endothelium, which participates in all stages of leukocyte–endothelial interaction by binding to leukocyte surface expressed integrin VLA-4. However, not all VLA-4-mediated events can be linked to VCAM-1. A novel interaction between VLA-4 and endothelial Lutheran (Lu) blood group antigens and basal cell adhesion molecule (BCAM) proteins has been recently shown, suggesting that Lu/BCAM may have a role in leukocyte recruitments in inflamed tissues. Here, we assessed the participation of Lu/BCAM in the immunopathogenesis of crescentic glomerulonephritis. High expression of Lu/BCAM in glomeruli of mice with rapidly progressive glomerulonephritis suggests a potential role for the local expression of Lu/BCAM in nephritogenic recruitment of leukocytes. Genetic deficiency of Lu/BCAM attenuated glomerular accumulation of T cells and macrophages, crescent formation, and proteinuria, correlating with reduced fibrin and platelet deposition in glomeruli. Furthermore, we found a pro-adhesive interaction between human monocyte α4β1 integrin and Lu/BCAM proteins. Thus, Lu/BCAM may have a critical role in facilitating the accumulation of monocytes and macrophages, thereby exacerbating renal injury.

The occurrence of focal fibrinoid necrosis of capillary loops in the very early stages of ANCA-associated necrotizing crescentic glomerulonephritis (NCGN) and the increased prevalence of this disease at older age suggest that renal ischemia may play an additional role in its pathophysiology. In the present study we investigated the contribution of renal ischemia to the induction of anti-myeloperoxidase (MPO) associated NCGN in a previously described rat model of this disease. The development of renal lesions is dependent on the presence of an anti-MPO immune response and the localization of a lysosomal extract containing lytic enzymes and MPO in combination with hydrogen peroxide (H2O2) along the glomerular basement membrane (GBM). The hypothesis tested whether perfusion of hydrogen peroxide (H2O2) could be replaced by ischemia/reperfusion (I/R) injury, as I/R injury activates endothelial cells to produce oxygen metabolites. I/R was induced by clamping the renal artery for 20 minutes in kidneys in which the circulation had been restored several minutes after perfusion with the lysosomal extract in MPO immunized rats. Rats developed lesions characterized by intra- and extracapillary cell proliferation, periglomerular infiltration, ruptures in Bowman's capsule, ischemic tubuli, and interstitial mononuclear infiltrate. Immune deposits, however, persisted for a longer time along the GBM after perfusion of lytic enzymes followed by I/R injury compared to previous studies in which H2O2 in conjunction with lytic enzymes were perfused in MPO-immunized rats. Control groups consisting of control immunized rats perfused with the lysosomal extract followed by I/R and MPO immunized rats perfused with the lysosomal extract developed minor lesions only. To further explore the possible mechanisms involved in the contribution of I/R to the development of NCGN, we studied the expression of ICAM-1 in renal tissue from the three experimental groups. Up-regulation of ICAM-1 occurred in MPO-immunized rats perfused with the lysosomal extract followed by I/R and also in both control groups, suggesting that up-regulation of ICAM-1 in itself is not sufficient to induce lesions. In conclusion, renal ischemia contributes to the development of experimental anti-MPO associated NCGN possibly by inducing endothelial cells to produce toxic oxygen metabolites.

Neutrophil activation in vitro and in vivo in kidneys in Wegener's granulomatosis. The mechanisms underlying glomerular capillary wall injury in Wegener's granulomatosis (WG) are not well understood. Anti-neutrophil cytoplasmic antibodies (ANCA), present in sera from patients with WG, are known to stimulate respiratory burst and degranulation of primed polymorphonuclear neutrophils (PMN) in vitro. Experimental studies have shown that oxygen radical production and lysosomal enzymes are important mediators of glomerular capillary wall injury. In the present study we investigated the presence of activated PMN and the extracellular localization of lysosomal enzymes in 28 consecutive renal biopsies from patients with WG. The presence of activated PMN within the renal biopsies was compared with the capacity of ANC A, isolated from simultaneously drawn serum samples, to activate primed PMN obtained from a normal donor. Both parameters were also related to renal function. Renal biopsies were obtained from newly diagnosed WG patients before therapy had started. Activation of PMN in the biopsies was assessed by measuring hydrogen peroxide production in situ. The number of activated PMN in the biopsy correlated with the extent of impairment of renal function. Proteinase 3, myeloperoxidase, and elastase, all targets of ANCA, were localized extracellularly in renal tissue and were also found within tubular epithelial cells. All ANC A positive samples were capable of activating primed PMN. The amount of activation correlated with the ANCA titer in those samples. No correlation, however, was found between the in vitro capacity of ANCA-positive IgG fractions to activate primed PMN and the number of activated PMN present in the renal biopsy. We conclude that activated PMN producing toxic oxygen metabolites and releasing lysosomal enzymes, are present in renal biopsies from patients with WG. The amount of activated PMN present within the kidney, and not the capacity of the corresponding ANCA to activate PMN, correlates with renal tissue damage as assessed by serum creatinine levels.

Antibody blockade of TNF-α reduces inflammation and scarring in experimental crescentic glomerulonephritis. Background Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine produced by macrophages, and by renal mesangial and tubular epithelial cells. It stimulates the release of interleukin (IL)-1β, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-β (TGF-β). Blockade of TNF-α is currently used clinically in several autoimmune inflammatory diseases. We hypothesised that blocking TNF-α with a monoclonal antibody would prevent inflammation and renal fibrosis in crescentic glomerulonephritis. Methods Nephrotoxic nephritis was induced in Wistar Kyoto (WKY) rats by intravenous injection of rabbit antirat glomerular basement membrane (GBM) nephrotoxic serum (NTS). Anti-TNF-α monoclonal antibody or saline was given intraperitoneally three times per week in four protocols: experiment 1, days 0 to 7; experiment 2, days 0 to 14 and days 4 to 14; experiment 3, days 4 to 28; and experiment 4, days 14 to 28. Results In experiment 1, rats treated from disease induction had less glomerular fibrinoid necrosis and fewer glomerular macrophages at day 7. In experiment 2, rats treated from day 0 or day 4 showed improved renal function, as judged by serum creatinine, with a significant reduction in crescents. In experiment 3, anti-TNF-α treatment significantly reduced urine protein to creatinine ratio and urinary MCP-1 levels. Serum creatinine was preserved at both day 14 and day 28. Tubulointerstitial inflammation, glomerular and tubulointerstitial scarring, and markers of fibrosis [α-smooth muscle actin (α-SMA) and type IV collagen] were significantly less in treated rats at day 28. In experiment 4, serum creatinine was higher and tubulointerstitial scarring was less in delayed-treated animals. Conclusion Neutralization of endogenous TNF-α reduces glomerular inflammation, crescent formation, and tubulointerstitial scarring, with preservation of renal function, in experimental crescentic glomerulonephritis. TNF-α blockade is effective even when introduced at the time of maximum glomerular inflammation.

Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Background Patients have been described who have both anti-neutrophil cytoplasm antibodies (ANCA) and anti-glomerular basement membrane (GBM) antibodies. We have attempted to define the true prevalence of such "double positive" patients, and describe in detail their clinical features and outcome. Methods We have reviewed all serologic assays performed between 1990 and 2000 in a single institution, and the case notes of patients having sera positive for both ANCA and anti-GBM antibodies. During this time 20,392 sera were initially tested for ANCA, and 4808 sera tested for anti-GBM antibodies. Results Five percent of all ANCA-positive serum samples were also positive for anti-GBM antibodies, and 32% of all anti-GBM positive samples had detectable ANCA. Of 27 patients with both antibodies, 82% had anti-myeloperoxidase specific P-ANCA. Pulmonary hemorrhage occurred in 44%. Renal biopsy showed extensive glomerular cellular crescents in most patients. Patient and renal survival rates were 52% and 26%, respectively, at one year. Sixty-eight percent of patients were dialysis-dependent at presentation, and none of these recovered renal function, despite immunosuppression with or without plasma exchange. Conclusion Serologic evidence of double positivity for both ANCA and anti-GBM antibodies is common in patients with either antibody. In our study these patients have a poor prognosis when presenting with severe disease and initially behave more like anti-GBM disease than vasculitis. Recovery from severe renal failure is rare.

The hemoglobin level was 8.8 g/dL with normal indices. The CASE PRESENTATION erythrocyte sedimentation rate was 70 mm/hr. C-reactive proA 62-year-old white woman presented to another hospital tein was 30 mg/L (normal 10 mg/L), and she had a positive with a five-week history of profound malaise and small joint antineutrophil cytoplasmic antibody (ANCA) test to a titer of arthralgia. Initially she had noticed a mild sore throat that set1:400 serum dilution by indirect immunofluorescence with a tled spontaneously. She had transient redness of her left conperinuclear pattern. Subsequent antigen-specific ELISA conjunctiva. One week after the onset of symptoms, she had a firmed reactivity to myeloperoxidase (MPO), denoting MPOsingle episode of macroscopic hematuria for which she received ANCA (Fig. 1). The ANA, anti-DNA, and anti-GBM antibody antibiotics from her family doctor. She denied dysuria or uritests were negative. Complement C3 and C4 levels were nornary frequency. For one week prior to admission, she had mal, and cryoglobulins were not detectable. Hepatitis B and suffered nausea and vomiting without abdominal pain or bowel C serologies were negative. After control of blood pressure, a disturbance. She had lost one stone (14 pounds) in weight. She renal biopsy was performed; the tissue contained eight glomerhad been hypertensive five years previously, but she had had uli. Of these, one was globally sclerosed, three were normal, no other antecedent illnesses. There was no family history of and four contained acute segmental lesions of various sizes renal disease, hypertension, or rheumatic complaints. She had with thrombosis, tuft disruption, and a few cells in Bowman’s four adult children, all of whom were well. Medication on space (Fig. 2). Tubules were acutely damaged, with blood in admission comprised a beta blocker (atenolol, 100 mg daily) a few. A patchy infiltrate of chronic inflammatory cells was for hypertension. She did not smoke cigarettes and drank less present. Small arteries and arterioles appeared virtually northan three units (24 g) of alcohol per week. She was a poultry mal. Immunoperoxidase study revealed no significant immunofarmer and lived in a rural setting. protein deposition within glomeruli. Clinical examination revealed that she was pale and dehyThe clinical history, renal biopsy findings, and blood serology drated. She had no rash, no active synovitis, and no lymphadewere consistent with an acute vasculitic (pauci-immune) glonopathy. Her temperature was 37.2 C; pulse, 70 beats/min; merulonephritis of the microscopic polyangiitis type. An assessand blood pressure, 160/90 mm Hg lying and 145/80 mm Hg ment of vasculitic activity showed a Birmingham Vasculitis Acstanding. Her jugular venous pressure was not elevated and she tivity Score (BVAS) of 13 and a Vasculitis Damage Index (VDI) had no sacral or ankle edema. The heart sounds were normal score of 0. Therapy with prednisolone, 1 mg/kg/day, and oral

Efficacy of galectins in the amelioration of nephrotoxic serum nephritis in Wistar Kyoto rats. Background Galectins are characterized by specific affinity for β-galactoside sugars, and they play a role in diverse biological processes, including cell adhesion, cell proliferation, and apoptosis. Galectin-1, -3, and -9 have been implicated in modulating the immune response. Methods Nephrotoxic serum nephritis, which is characterized by crescent formation and glomerular influx of CD8 + cells into glomerular capillaries, was induced in Wistar Kyoto (WKY) rats by injecting rabbit antiglomerular basement membrane serum. Following induction, the rats were treated either with phosphate-buffered saline or dexamethasone, galectin-1, galectin-3, or galectin-9 on alternate days and were sacrificed at day 14. At day 8, splenic lymphocytes were isolated and employed for terminal deoxytransferase-mediated uridine triphosphate nick end-labeling (TUNEL) assay to assess the degree of apoptosis, and the kidneys were utilized to determine the extent of influx of CD4 + and CD8 + cells and glomerular damage. Results Dexamethasone induced a marked apoptosis of splenic CD4 + and CD8 + cells, and it inhibited the production of anti-rabbit IgG and the influx of CD8 + cells and macrophages into the renal glomeruli. Crescent formation and excretion of urinary proteins were also reduced. Galectin-9 failed to induce apoptosis in the CD4 + cells; however, it induced apoptosis in the CD8 + cells and inhibited the infiltration of CD8 + cells. Although galectin-1 and -3 did not induce the apoptosis in the T cells, they inhibited the accumulation of macrophages in the renal glomeruli. Like dexamethasone, the galectins also reduced the crescentic formation, proliferation of glomerular cells, and excretion of urinary proteins. Conclusions Galectin-9 selectively induces apoptosis of the activated CD8 + cells, while the macrophage influx into the kidney is modulated by all three galectins. This finding raises an interesting possibility for the utility of galectins in the modulation of macrophages that are involved in immune-mediated glomerular diseases.

Antineutrophil cytoplasmic antibodies and associated diseases: A review of the clinical and laboratory features. There have been a number of recent advances in this field. First, the “International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA)” has been developed to optimize ANCA testing. It requires that all sera are tested by indirect immunofluorescent (IIF) examination of normal peripheral blood neutrophils and, where there is positive fluorescence, in enzyme-linked immunosorbent assays (ELISAs) for antibodies against both proteinase 3 (PR3) and myeloperoxidase (MPO). Testing will be further improved when international standards and common ELISA units are available. Second, new diagnostic criteria for the small vessel vasculitides that take into account ANCA-positivity and target antigen specificity as well as histologic features are currently being produced. Third, we understand that the complications associated with treatment of the ANCA-associated vasculitides are often more hazardous than the underlying disease, and regimens that use effective but less toxic agents are being evaluated. The factors associated with increased risk of relapse, however, remain incompletely understood. Finally, ANCA with specificities other than PR3 and MPO are present in many nonvasculitic autoimmune diseases. Their clinical significance is still largely unclear, and some of the target antigens are present in other cells as well as neutrophils and thus are not strictly “ANCA.”

Keywords: nephrotic syndrome, membranous glomerulonephritis, IgA nephropathy, crescentic glomerulonephritis, minimal change disease, amyloidosis, immunotactoid glomerulopathy, monoclonal immunoglobulin deposition disease, POEMS syndrome, Castleman's disease

Renal ischemia/reperfusion injury contributes to renal damage in experimental anti-myeloperoxidase-associated proliferative glomerulonephritis. The occurrence of focal fibrinoid necrosis of capillary loops in the very early stages of ANCA-associated necrotizing crescentic glomerulonephritis (NCGN) and the increased prevalence of this disease at older age suggest that renal ischemia may play an additional role in its pathophysiology. In the present study we investigated the contribution of renal ischemia to the induction of anti-myeloperoxidase (MPO) associated NCGN in a previously described rat model of this disease. The development of renal lesions is dependent on the presence of an anti-MPO immune response and the localization of a lysosomal extract containing lytic enzymes and MPO in combination with hydrogen peroxide (H2O2) along the glomerular basement membrane (GBM). The hypothesis tested whether perfusion of hydrogen peroxide (H2O2) could be replaced by ischemia/reperfusion (I/R) injury, as I/R injury activates endothelial cells to produce oxygen metabolites. I/R was induced by clamping the renal artery for 20 minutes in kidneys in which the circulation had been restored several minutes after perfusion with the lysosomal extract in MPO immunized rats. Rats developed lesions characterized by intra- and extracapillary cell proliferation, periglomerular infiltration, ruptures in Bowman's capsule, ischemic tubuli, and interstitial mononuclear infiltrate. Immune deposits, however, persisted for a longer time along the GBM after perfusion of lytic enzymes followed by I/R injury compared to previous studies in which H2O2 in conjunction with lytic enzymes were perfused in MPO-immunized rats. Control groups consisting of control immunized rats perfused with the lysosomal extract followed by I/R and MPO immunized rats perfused with the lysosomal extract developed minor lesions only. To further explore the possible mechanisms involved in the contribution of I/R to the development of NCGN, we studied the expression of ICAM-1 in renal tissue from the three experimental groups. Up-regulation of ICAM-1 occurred in MPO-immunized rats perfused with the lysosomal extract followed by I/R and also in both control groups, suggesting that up-regulation of ICAM-1 in itself is not sufficient to induce lesions. In conclusion, renal ischemia contributes to the development of experimental anti-MPO associated NCGN possibly by inducing endothelial cells to produce toxic oxygen metabolites.

A clinico-pathologic study of crescentic glomerulonephritis in 50 children. A report of the Southwest Pediatric Nephrology Study Group. In this study, we have evaluated 50 children (30 girls and 20 boys; mean age, 10.1 years) with a variety of renal diseases in whom renal biopsy specimens showed crescents in ≥ 50% of glomeruli. Initial clinical features included edema in 61%; hypertension in 51%; gross hematuria in 73%; 3 to 4+ proteinuria in 78%; and severely decreased GFR ( 2 ) in 66%. When the total number of patients was divided into those with 50 to 79% crescents (N = 18) and those with 80 to 100% crescents (N = 32), no significant difference in outcome could be demonstrated, with endstage renal disease (ESRD) being seen in 44 and 52% of the two groups, respectively. Pathologic features associated with a poor prognosis included predominance of large crescents (P = 0.004) or fibrous crescents (P = 0.03); increased frequency of gaps in Bowman's capsule (P = 0.004); global glomerular sclerosis (P = 0.05); glomerular IgM (P = 0.003); interstitial fibrosis (P = 0.03); and tubular atrophy (P = 0.04). At followup, GFR was normal in all patients with poststreptococcal GN, but low in 60% of patients with other conditions. The study permits the following conclusions: (1) Approximately 50% of children with crescents in 50% or more glomeruli progress to ESRD; (2) a poor prognosis is associated with (a) a high percentage of large crescents, (b) increased frequency of gaps in Bowman's capsule, and (c) evidence of chronic histologic changes, but not with the percentage of crescents per se; and (3) the underlying type of glomerulonephritis is considered a helpful prognostic indicator. This study also suggests that gaps in Bowman's capsule may play a role in the fibrous transformation of the glomerular crescents. Une etude anatomo-clinique de la glomerulonephrite a croissants chez 50 enfants. Un rapport du Southwest Pediatric Nephrology Study Group. Dans cette etude, nous avons evalue 50 enfants (30 filles et 20 garcons; âge moyen, 10,1 ans) atteints de diverses maladies renales, chez lesquels des specimens biopsies renales ont montre des croissants dans 50% des glomerules. Les caracteristiques cliniques initiales comprenaient des oedemes chez 61%; une hypertension chez 51%; une hematurie macroscopique chez 73%; une proteinurie 3 a 4+ chez 78%; et une GFR severement diminuee ( 2 ) chez 66%. Lorsque le nombre total de malades etait divise en ceux ayant 50 a 79% de croissants (N = 18) et ceux ayant 80 a 100% de croissants (N = 32), aucune difference significative dans le devenir ne pouvait etre demontree, une insuffisance renale terminale (ESRD) etant observee chez 44 et 52% des deux groupes, respectivement. Les caracteristiques anatomo-pathologiques associees a un mauvais pronostic comprenaient la predominance de grands croissants (P = 0,004), ou de croissants fibreux (P = 0,03); une augmentation de frequence de lacunes dans la capsule de Bowman (P = 0,004); une sclerose glomerulaire globale (P = 0,05); des IgM glomerulaires (P = 0,003); fibrose interstitielle (P = 0,03); et une atrophie tubulaire (P = 0,04). Lors du suivi, GFR etait normale chez tous les malades atteints de GN post-streptococcal, et basse chez 60% des malades ayant d'autres atteintes. Cette etude autorise les conditions suivantes: (1) approximativement 50% des enfants ayant des croissants dans 50% ou plus des glomerules evoluent vers l'ESRD; (2) un mauvais pronostic est associe a (a) un fort pourcentage de grands croissants, (b) une augmentation de frequence de lacunes dans la capsule de Bowman, et (c) la preuve de modifications histologiques chroniques, mais non au pourcentage de croissants per se; et (3) le type de glomerulonephrite sous-jacente est considere comme un indicateur pronostique utile. Cette etude suggere aussi que les lacunes de la capsule de Bowman pourraient jouer un role dans la transformation fibreuse des croissants glomerulaires.

The existence of a protracted course in crescentic glomerulonephritis. We describe a spectrum of clinical and morphologic features which may occur in idiopathic crescentic glomerulonephritis. Of note are patients who pursue a more indolent course to renal failure in contrast to typical rapidly progressive glomerulonephritis (RPGN). Patients following this protracted course have an insidious presentation with hematuria and renal insufficiency, and at the time of renal biopsy (usually after many months of clinical illness) show less extensive involvement with crescents, which are often in both cellular and fibrous stages. This form of crescentic glomerulonephritis is further distinguished from RPGN by frequent hypertension and the nephrotic syndrome, the absence of oligo-anuria and progression to renal failure over many months or even years.

De novo glomerular osteopontin expression in rat crescentic glomerulonephritis. Osteopontin (OPN) is a secreted acidic glycoprotein that has potent monocyte chemoattractant and adhesive properties. Up-regulation of tubular OPN expression is thought to promote interstitial macrophage infiltration in experimental nephritis; however, the role of OPN in glomerular lesions, particularly crescent formation, is unknown. The present study used Northern blotting, in situ hybridization and immunohistochemistry to examine OPN expression in a rat model of accelerated anti-GBM glomerulonephritis. Osteopontin mRNA and protein is expressed by some parietal epithelial cells, thick ascending limbs of Henle and medullary tubules and collecting ducts in normal rat kidney. De novo OPN mRNA and protein expression was evident in glomerular visceral and parietal epithelial cells in anti-GBM glomerulonephritis. Glomerular OPN expression preceded and correlated with macrophage infiltration in the development of hypercellularity, focal and segmental lesions and, notably, crescent formation. There was marked up-regulation of OPN expression by tubular epithelial cells that also preceded and correlated with interstitial macrophage (r = 0.93, P < 0.001) and T-cell infiltration (r = 0.85, P < 0.001). Both glomerular and tubular OPN expression correlated significantly with proteinuria (P < 0.001) and a reduction in creatinine clearance (P < 0.01). In addition, double immunohistochemistry showed co-expression of osteopontin and one of its ligands, CD44, in intrinsic renal cells. CD44 and OPN expression by parietal epithelial cells was evident in crescent formation, while virtually all OPN-positive tubules expressed CD44. Infiltrating macrophages and T-cells were CD44-positive, but only a small proportion of T-cells and few macrophages showed OPN expression. Interestingly, strong OPN mRNA and protein expression was seen in macrophage multinucleated giant cells. In summary, this study suggests that OPN promotes macrophage and T-cell infiltration in the development of renal lesions in rat anti-GBM glomerulonephritis, including glomerular crescent and multinucleated giant cell formation.

Podocyte involvement in human immune crescentic glomerulonephritis. Background The role of podocytes in human crescentic glomerulonephritis (GN) has been underestimated. This may be due to the confounding fact that "dysregulated" podocytes are able to proliferate, lose their markers, and acquire new epitopes. Moreover, in experimental anti glomerular basement membrane (GBM) crescentic GN, podocytes participate in the crescent formation. The aim of this study was to investigate the involvement of podocytes in human immune crescentic GN. Methods Renal biopsies from 12 patients with anti GBM disease and 14 with class IV lupus GN were studied by immunohistochemistry for the following markers: ( 1 ) synaptopodin, GLEPP1, podocalyxin, podocin, α actinin 4, and vimentin for podocyte identification; ( 2 ) PCNA, Ki 67, and p57 for cell cycle assessment; ( 3 ) cytokeratins for identifying epithelial cells but not normal podocytes; ( 4 ) CD68 for tagging a macrophagic epitope; ( 5 ) alpha smooth muscle actin (α SMA), a phenotypic marker of myofibroblasts. Results "True" (capsular) crescents lining Bowman's capsule and (tuft) "pseudocrescents" covering the glomerular tuft with a persistent patent urinary space were present in the 2 types of crescentic GN in similar percentages. Several features indicated that podocytes were involved in the formation of the both crescent types. Identifiable podocytes expressed proliferation markers. Podocyte cytoplasmic expansions and racket like podocytes bridged between the tuft and Bowman's capsule. True and pseudocrescents contained labeled podocytes. In addition, podocytes located outside of the crescents had often lost their markers (dedifferentiation) and acquired new epitopes (cytokeratins and CD68). Conclusion In human immune crescentic GN, podocytes undergo proliferation and dysregulation that are indicative of a podocytopathy. Podocytes contribute to crescent formation.

Angiopoietin correlates with glomerular capillary loss in anti-glomerular basement membrane glomerulonephritis . Background Emerging evidence suggests that endothelial turnover occurs in several glomerular diseases and correlates with resolution or progression of glomerular lesions. We hypothesized that the growth factors modulating embryonic kidney endothelial cell survival and capillary morphogenesis may be implicated in capillary loss that occurs in immune-mediated glomerulonephritis (GN). Methods GN was induced in C57BL/6 mice by intravenous administration of sheep anti-mouse glomerular basement membrane (GBM) globulin and assessed with markers of vascularity in glomerular lesions, correlating these with expression of specific vascular growth factors. Results As assessed by periodic acid Schiff staining, 14 ± 4% (mean ± SD) glomeruli were affected by sclerosis at 14 days after globulin administration, and 33 ± 5% were affected at 21 days. By 21 days, a significant increase of plasma creatinine and urinary protein occurred. P-selectin expression was increased in glomerular capillaries 14 days after disease induction, and capillary loss, as assessed by immunohistochemistry for platelet-endothelial cell adhesion molecule, vascular endothelial growth factor (VEGF) receptor 2 and the angiopoietin (Ang) receptor Tie-2, was recorded at 14 and 21 days in glomeruli affected by proliferative crescents and/or sclerosis. VEGF-A immunostaining, evident in control glomeruli, was qualitatively diminished in glomeruli with lesions. Ang-1 immunostaining was detected in control glomeruli and was diminished at 14 days after administration of anti-mouse GBM globulin; instead, Ang-1 was immunolocalized to distal tubules. In contrast, Ang-2 immunostaining was barely detectable in control glomeruli but was prominent in disease glomeruli. In GN mice, rare apoptotic glomerular endothelia were detected by electron microscopy and in situ end-labeling, but such cells were not seen in controls. Conclusions Loss of glomerular capillaries during the course of anti-GBM GN in mice was temporally associated with decreases in endothelial survival molecules VEGF-A and Ang-1, and with up-regulation of Ang-2, an antagonist of Ang-1. A changing balance of these growth factors may contribute to decreased glomerular vascularity in crescentic GN.

Migration of circulating leukocytes from the vasculature into the surrounding tissue is an important component of the inflammatory response. Among the cell surface molecules identified as contributing to leukocyte extravasation is VCAM-1, expressed on activated vascular endothelium, which participates in all stages of leukocyte–endothelial interaction by binding to leukocyte surface expressed integrin VLA-4. However, not all VLA-4-mediated events can be linked to VCAM-1. A novel interaction between VLA-4 and endothelial Lutheran (Lu) blood group antigens and basal cell adhesion molecule (BCAM) proteins has been recently shown, suggesting that Lu/BCAM may have a role in leukocyte recruitments in inflamed tissues. Here, we assessed the participation of Lu/BCAM in the immunopathogenesis of crescentic glomerulonephritis. High expression of Lu/BCAM in glomeruli of mice with rapidly progressive glomerulonephritis suggests a potential role for the local expression of Lu/BCAM in nephritogenic recruitment of leukocytes. Genetic deficiency of Lu/BCAM attenuated glomerular accumulation of T cells and macrophages, crescent formation, and proteinuria, correlating with reduced fibrin and platelet deposition in glomeruli. Furthermore, we found a pro-adhesive interaction between human monocyte α4β1 integrin and Lu/BCAM proteins. Thus, Lu/BCAM may have a critical role in facilitating the accumulation of monocytes and macrophages, thereby exacerbating renal injury.

The recruitment of leukocytes during host defense and inflammation is a complex process involving the coordinated interactions of leukocyte adhesion molecules and chemoattractants1,2,3,4. Included among the latter chemoattractant molecules are the chemokines, a superfamily of small (8–13 kD) secreted cytokines3,4. The characterization of key molecular determinants of leukocyte trafficking in renal disease has already identified a range of attractive new therapeutic targets in glomerulonephritis, tubulointerstitial nephritis, ischemic acute renal failure and allograft rejection2,4. Several agents that block chemokine and adhesion molecule expression or function have already been shown to confer impressive protection in experimental models of renal inflammation2,4. It is clear, however, that many important players have yet to be defined and that, in an environment where there is frequently overlap of function, the hierarchy of mediators has yet to be fully established.