Glomerular deposition of cross-linked fibrin in human kidney diseases

The immunofluorescent localization of cross-linked fibrin (XFb) in kidneys from 87 patients with renal diseases was evaluated using a monoclonal antibody that discriminates XFb from fibrinogen and its derivatives. Glomerular deposition of XFb, along the endothelial surface and in the mesangium, was frequently observed in patients with IgA nephropathy, Henoch-Sch?nlein purpura nephritis (HSPN), lupus nephritis, and hemolytic uremic syndrome (HUS), which was confirmed by immunoelectron microscopy. Dual-label immunofluorescent studies showed that XFb was deposited in limited areas among the sites reactive with anti-fibrinogen antibodies; XFb was not present in the crescents, Bowman's capsule or interstitium. The localization of XFb was generally discordant with that of the platelet membrane antigen and von Willebrand factor (factor VIII-related) antigen. Subendothelial co-deposition of XFb and immunoglobulins (IgA with or without IgG) occasionally accompanying C3 was found in the glomeruli of some of the patients with IgA nephropathy and HSPN. The distribution of XFb observed by immunoelectron microscopy was similar to that of electron dense deposits. The glomerular population of monocytes/macrophages in patients with XFb deposition was similar to that of those without deposition. Urinary XFb derivatives were detected by the latex agglutination test in three of the 16 patients with glomerular XFb deposition, and in two of the 18 patients without it. These data indicate that the coagulation system is activated in the kidney of patients with IgA nephropathy, HSPN, lupus nephritis and HUS, and support the concept that glomerular fibrin deposition is associated with endothelial/subendothelial and mesangial injury. The activation of the coagulation system in IgA nephropathy and HSPN seems to be mediated by immune complexes rather than monocytes/macrophages. Determination of urinary XFb derivatives is not helpful for assessing glomerular XFb deposition.     

Mesangial factor V expression colocalized with fibrin deposition in IgA nephropathy

BACKGROUND: Factor V in its active form (Va) plays a key role at the termination of the intrinsic coagulation pathway, serving as a membrane-bound cofactor for the conversion of prothrombin to thrombin by factor Xa. Cross-linked fibrin (XFb) is often observed in mesangial areas in active types of human glomerulonephritis. In this study, to clarify contribution of factor V in intramesangial coagulation, mesangial factor V expression and its relationship to mesangial proliferation and fibrin deposition in IgA nephropathy (IgAN) were investigated. METHODS: Twenty-two patients with IgAN were studied. XFb was detected in renal biopsy specimens using anti-d-dimer antibody combined with plasmin exposure, and factor V was detected with rabbit antibody against human factor V. Double-labeling immunohistochemistry was used to investigate the relationship of the glomerular distribution of factor V to XFb. The relationship of factor V staining to the activity index or XFb deposition was evaluated. The expression of factor V mRNA was assessed by in situ hybridization in relationship to the antigen staining of alpha-smooth muscle actin (alpha-SMA). The ultrastructural distribution of factor V in glomeruli was studied by immunoelectron microscopy. RESULTS: XFb and factor V were observed in the mesangium and along capillary loops in seven and nine specimens, respectively. Factor V had intense, frequent expression in the proliferating and necrotizing areas, showing a significant relationship to XFb (P < 0.05). Furthermore, XFb deposition and factor V expression were markedly correlated with disease activity (P = 0.005 and P = 0.008, respectively). By double-labeling experiments, XFb and factor V were often seen colocalized in mesangial areas of the glomeruli, which showed necrotizing lesions and/or intense cellular proliferation. By in situ hybridization, factor V mRNA was detected mainly in the mesangial cells, which were positive for alpha-SMA, and partly in the endothelial cells. By immunoelectron microscopy, factor V presence was confirmed in the mesangium and endothelium. CONCLUSION: The present findings suggest that factor V is strongly expressed in mesangial cells in active IgAN accompanied with mesangial proliferation and may exert procoagulant activity, leading to intramesangial coagulation.     

Glomerular T cell and monocyte populations in patients with IgA nephropathy

Renal tissues from 19 patients with the minimal or slight stage of IgA nephropathy were examined for evidence of glomerular T cell or monocyte infiltration using monoclonal antibodies to identify T cells (OKT3, OKT11), T cell subsets (OKT4, OKT8), and monocytes and null cells (OKM1) by indirect immunofluorescence. Renal tissues from 12 patients at the same stage of mesangial proliferative glomerulonephritis without IgA deposition were also investigated by these procedures. Light microscopic examination of the same renal tissues was also performed. Reactive glomerular mononuclear cells were found to be numerous in patients with IgA nephropathy. The most prominent type of glomerular cells was OKT8 positive. T cell subsets and OKM1 positive cells in glomeruli from patients with IgA nephropathy were significantly increased as compared to those from patients with mesangial proliferative glomerulonephritis. Focal segmental proliferation of mesangial cells was observed in glomeruli which showed an accumulation of OKT8 positive cells. It is concluded that the immuno-regulatory mechanism involving T cells and/or monocytes might be one of the exacerbating factors in patients with IgA nephropathy.     

Role of β2 integrins in glomerular leucocytes in Henoch-Schoenlein purpura nephritis: an age-matched comparative study with immunoglobulin A nephropathy

SUMMARY: A comparative immunohistological study was performed for the glomerular deposition of complements (C1q and C3c), fibrin/fibrinogen‐related antigen (FRA), the expression of intercellular adhesion molecule‐1 (ICAM‐1), and the infiltration of leucocytes bearing β₂ integrins (leucocyte function associated antigen‐1 (LFA‐1), complement receptor 3 (CR3) and complement receptor 4 (CR4)) on renal biopsy specimens from 49 cases with Henoch‐Schoenlein purpura nephritis (HSPN), and 49 age‐matched cases with immunoglobulin A nephropathy (IgAN). the glomerular expression of ICAM‐1 was signifcantly correlated with the glomerular infiltration of leucocyte function associated antigen (LFA)‐1⁺ leucocytes in both diseases, and with that of CR3⁺ leucocytes in HSPN. the expression of ICAM‐1 was closely localized with the infiltration of LFA‐1⁺ leucocytes in the study with double immunostaining. the incidence and intensity of glomerular deposition of FRA were significantly higher in HSPN than in IgAN (P< 0.001), and those of C3c were significantly lower in HSPN than in IgAN (P< 0.001). the glomerular deposition of FRA was significantly correlated with the glomerular infiltration of CR4⁺ leucocytes in HSPN (P<0.05) but not in IgAN. In contrast, the glomerular deposition of C3c was significantly correlated with the glomerular infiltration of CR4⁺ leucocytes in IgAN (P<0.05), but not in HSPN. Studies with double immunostaining revealed a close association of CR4⁺ leucocytes with FRA deposition in HSPN and with C3c deposition in IgAN, respectively. the number of glomerular leucocytes bearing β₂ integrins was significantly correlated with urinary protein at the time of renal biopsy in both diseases. These results suggested the differential roles of β₂ integrins in the induction of glomerular injury in HSPN and IgAN. the ICAM‐1/LFA‐1 interaction may commonly be involved in the glomerular infiltration of leucocytes in both diseases. the ICAM‐1/CR3 interaction may be involved only in HSPN. Complement receptor 4 may function as a fibrin/fibrinogen receptor in HSPN, while CR4 may function as a complement receptor in IgAN.     

Glomerular distribution and gelatinolytic activity of matrix metalloproteinases in human glomerulonephritis.

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the development of glomerular injury in rat experimental glomerulonephritis (GN). However, the significance of MMPs in human GN remains obscure. In order to evaluate the role of MMPs in human GN, we examined the glomerular distribution and gelatinolytic activities of MMP-2 and MMP-9 in human GN. METHODS: We performed immunohistochemistry with polyclonal anti-MMP-2 and MMP-9 antibodies, and analysed gelatin zymograms of five isolated glomeruli from various types of human renal disease. The renal specimens investigated were from normal kidneys (n=5), IgA nephritis (n=20), Henoch-Sch?nlein nephritis (n=4), non-IgA mesangial proliferative GN (n=9), lupus nephritis (n=6), acute poststreptococcal GN (APSGN) (n=4) and diabetic nephropathy (DN) (n=4). RESULTS: MMP-2 immunoreactivity was not detected in normal controls or in any type of GN. MMP-9 staining, which was almost negative in normal glomeruli, was increased mainly in the mesangial region and corresponded to the level of glomerular cell proliferative changes in mesangial proliferative GN (IgA nephritis, Henoch-Sch?nlein nephritis, non-IgA mesangial proliferative GN and lupus nephritis). Positive but weak staining for MMP-9 was observed in mesangial areas in DN. In addition, double immunostaining showed that MMP-9 is colocalized in scattered neutrophils within diseased glomeruli in APSGN. MMP-9 gelatinolytic activity in five normal glomeruli was weakly detected. Consistent with the levels of immunostaining, MMP-9 glomerular activity was dramatically increased in nephritic glomeruli with IgA nephritis, lupus nephritis and DN. The gelatinolytic activity of MMP-2 was occasionally detectable in nephritic glomeruli. CONCLUSION: These results strongly suggest that MMP-9 plays an important role in abnormal mesangial proliferative changes in human GN.     

Polymorphs infiltrate glomeruli in mesangial IgA glomerulonephritis

During episodes of macroscopic hematuria, patients with IgA nephropathy commonly have polymorphonuclear neutrophils (PMNs) as well as fibrin and mononuclear cells in glomerular capillaries. We quantitated PMN and macrophage infiltration in glomeruli of 54 patients with IgA nephropathy in whom renal biopsies were obtained within 30 days of macroscopic hematuria. Control biopsies (N = 22) were from patients with IgA nephropathy and urinary erythrocyte counts below 50,000/ml. PMN monocyte/macrophages were quantitated using the monoclonal antibodies FMC10 and HAM56, respectively. In patients with heavy hematuria, 45.9 +/- 3.4% (mean +/- SE) of glomeruli were positive for PMNs (control 10.5 +/- 2.8%, P = 0.001) with a mean PMN count/glomerulus of 1.10 +/- 0.20 (control 0.13 +/- 0.03, P = less than 0.001). 65.6 +/- 9.7%. Of the glomeruli were positive for monocytes in the heavy hematuria group (control 40.0 +/- 8.4, P less than 0.05) with the mean monocyte count per glomerulus being 1.6 +/- 0.2 (control 0.6 +/- 0.1, P less than 0.01). We conclude that, in the acute phase of mesangial IgA nephropathy, PMN and monocytes are present and presumably participate in glomerular injury.     

Significance of mononuclear phagocytes in IgA nephropathy

To clarify the significance of mononuclear phagocytes in IgA nephropathy, renal biopsied materials from 45 patients with the disease were examined by the indirect immunoperoxidase method using anti-human monoclonal antibodies and by ultrastructural peroxidase (PO) cytochemistry. The monoclonal antibodies were FMC32, S-100 (alpha), My4, and LeuM5 for detection of mononuclear phagocytes and HLA-DR for Ia antigens. Mesangial hypercellularity in IgA nephropathy was divided into three grades. The number of monocyte/macrophages per glomerulus differed significantly among the grade of mesangial hypercellularity. In the capillary lumen, monocytes were more numerous in the group with slight mesangial hypercellularity. By contrast, macrophages were often found in the Bowman's space and mesangial area of the glomeruli in the advanced group. In the renal interstitium, the number of monocyte/macrophages per 100 interstitial cells differed significantly among the degree of interstitial damage, and they were observed mainly around sclerotic glomeruli. Ultrastructural PO cytochemistry revealed infiltration of monocytes, exudate macrophages, and/or PO-negative macrophages. Clinicopathological study showed a relationship between the number of monocyte/macrophages per glomerulus and the number of glomerular crescents and the degree of proteinuria. The constancy of the percentage of exudate macrophages and polymorphonuclear leukocytes were observed irrespective of the grade of mesangial hypercellularity. On the other hand, the increasing percentage of PO-negative macrophages and decreasing percentage of monocytes were observed over the grade. These results suggest that mononuclear phagocytes might play an important role in the pathogenesis of mesangial hypercellularity, and irreversible glomerular damage and interstitial tissue injury in IgA nephropathy.     

Streptococcal origin of a case of Henoch-Schoenlein purpura nephritis

We report the case of a 25-year-old man with abdominal pain, purpura on the legs and proteinuria occurring 2 weeks after acute tonsillitis, and admitted to our hospital with suspected Henoch-Sch?nlein purpura nephritis (HSPN). He had increased anti-streptolysin O (ASO) titer and hypocomplementemia. A renal biopsy specimen showed endocapillary proliferative changes, which are typical of acute poststreptococcal glomerulonephritis (APSGN). However, immunofluorescence study revealed predominant IgA and C3 deposits in mesangial lesions, indicating a diagnosis of HSPN. Because of massive proteinuria initially, the treatment with a combination of prednisolone, cyclophosphamide, dipyridamole and warfarin was started along with 3 plasma exchanges. Angiotensin-converting enzyme inhibitor was also given. Response to the treatment was favorable. A follow-up biopsy was performed 8 months after the first biopsy. The renal biopsy specimen showed a figure of typical HSPN. To further investigate the cause of glomerular changes in our patient, an immunofluorescent study of nephritogenic nephritis-associated plasmin receptor (NAPlr) of group A, beta-hemolytic streptococci was performed. NAPlr was significantly positive in the glomeruli in the first biopsy specimen, but not in the second. His clinical course and pathological findings suggest that NAPlr may be related to the pathogenesis in a part of patients with HSPN, especially in patients with high ASO titer and hypocomplementemia.     

Soluble fibrin formation in the mesangial area of IgA nephropathy

Background Fibrin monomer and its derivatives in blood are found in an early stage of thrombosis. When they are produced in blood, they form complexes with fibrinogen, and they exist as soluble complexes named soluble fibrin (SF). As final insoluble products, cross-linked fibrin (XFb) is often observed in mesangial areas in active types of human glomerulonephritis. To clarify the mechanisms of mesangial SF production and its relationship to XFb deposition in IgA nephropathy (IgAN), an immunohistochemical study was conducted. Methods Nineteen patients with IgAN were studied. XFb was detected in renal biopsy specimens using anti-d-dimer antibody combined with plasmin exposure. SF was detected with a monoclonal antibody (IF-43), and factor V was detected with a specific rabbit antibody. The relationships of SF staining to the disease activity index, XFb deposition, and factor V staining was evaluated. Results XFb, factor V, and SF were observed in the mesangium in 14, 11, and 8, respectively, of a total of 19 specimens. SF had frequent staining in the proliferating areas, showing a significant relationship to XFb or factor V (P < 0.05). Furthermore, XFb, factor V, and SF depositions were markedly correlated with disease activity (P < 0.001 in each case). Conclusions These findings suggest that SF is formed in the mesangial area in active IgA nephropathy accompanied by mesangial proliferation, in particular, in its early stage.     

Tissue factor production by cultured rat glomerular epithelial cells

It is well known that fibrin deposition in Bowman's space inassociation with crescent formation may play an important rolein progressive glomerular injury in crescentic glomerulonephritis.Recent reports describe the presence of a procoagulant activity(PCA) in the glomeruli and its increased expression in humanand experimental nephritis. The cells that synthesize PCA havenot yet been identified. We attempted to determine if glomerularepithelial cells (GEC), one of the prominent cell populationsin the crescent, can produce PCA. The PCA of cultured rat GECwas measured by clotting and amidolytic assays. The culturedGEC yielded PCA with the characteristics of a tissue factor,and this PCA was stimulated by interleukin 1, tumour necrosisfactor-alpha, and lipopolysaccharide. We concluded that GEC produce tissue-factor-like PCA and therebymay contribute to fibrin deposition, which, along with macrophageor monocyte infiltration, leads to crescent formation in crescenticglomerulonephritis.     

Glomerulonephritis in Henoch-Schöenlein purpura without mesangial IgA deposition

Ten patients with Henoch-Schöenlein purpura (HSP) were selected for study because their early renal biopsies showed focal and segmental hypercellularity, with IgA present only in deposits at the periphery of the lobules. Mesangial deposits of IgA were absent. All had laboratory evidence of nephrotic syndrome and/or renal compromise. The glomerular hypercellularity was largely the result of the infiltration of monocytes whose cytoplasm often contained tubular lysosomes and wrapping lysosomal membranes, evidence of monocyte activation. Mean levels of C3 were normal but those of C4 and properdin significantly depressed. This complement profile, as well as a glomerular monocytic infiltrate, are also seen in essential cryoglobulinemia in the adult. Of follow-up biopsies in six patients, the glomeruli were normal in three, with no IgA deposition. In the other three, mesangial deposits of IgA typical of HSP were present. The initial focal-segmental glomerulitis of these patients appeared to be the benign first phase of a disease which had the potential to culminate in mesangial IgA deposition. Patients like the three who escaped mesangial IgA would be among those responsible for the observed dissociation between severity of the initial illness and ultimate prognosis.     

Induction of urokinase receptor expression in nephrotoxic nephritis.

The urokinase receptor (uPAR) is a multifunctional molecule involved in pericellular, fibrinolytic, and proteolytic activities, as well as in cell adhesion and chemotaxis and may play a role in the pathogenesis of tissue remodeling occurring during glomerulonephritis. We analyzed sequentially the expression of uPAR by immunohistochemistry and in situ hybridization in an accelerated model of nephrotoxic nephritis in rats. A strong induction of uPAR mRNA expression was observed in glomeruli as soon as 1 h after nephrotoxic serum injection. The intensity of glomerular uPAR mRNA and antigen expression increased and peaked at 24 h. At that time, numerous glomerular fibrin deposits, monocyte/marcrophage infiltration, and heavy proteinuria were observed. Fibrin deposition was detected at 6 h, peaked at 24 h, and progressively declined over the next 3 weeks, while uPAR antigen expression remained elevated until the end of the study (3 weeks). By double labeling, we showed that the expression of uPAR was mediated by both intrinsic glomerular cells and infiltrating macrophages. Severe podocytic lesions developed within 3 days after antiserum injection, and glomerulosclerosis rapidly progressed within 2-3 weeks. These results show that glomerular uPAR expression is induced in nephrotoxic nephritis and suggest that uPAR may promote local proteolysis and also tissue remodeling, leading to the late development of glomerulosclerosis.     

Autoantibodies against glomerular mesangial cells and their target antigens in lupus nephritis

Mesangial proliferation and deposition of immunoglobulins and complement components within glomerular mesangium was one of the important pathological features of lupus nephritis. Autoantibodies against human mesangial cells could be detected in the sera of patients with IgA nephropathy (IgAN) and Henoch-Sch?enlein nephritis. We speculated that autoantibodies against human glomerular mesangial cells might play a role in the development of lupus nephritis. OBJECTIVE: To screen autoantibodies against human glomerular mesangial cells in sera from patients with lupus nephritis and to identify their target antigens. METHODS: Sera were collected from 96 patients with lupus nephritis as well as 25 patients with IgAN and 20 patients with idiopathic membranous nephropathy (IMN). Cell lysates of in vitro cultured human glomerular mesangial cells were used as antigens in Western-blot analysis to detect autoantibodies against human mesangial cells in sera from patients with lupus nephritis as well as IgAN and IMN. The clinical and pathological significance of the autoantibodies were further investigated. RESULTS: Autoantibodies against human mesangial cells could be detected in 94/96 (97.9%) of the sera from patients with lupus nephritis in Western-blot analysis. Twelve protein bands could be blotted by the sera from patients with lupus nephritis. The prevalence of autoantibodies against human mesangial cells in IgAN was 14/25 (56.0%) and only seven protein bands could be blotted. Five autoantibodies (anti-18, 24, 36, 46, and 91 kD) could be detected only in sera from patients with lupus nephritis. In patients with lupus nephritis, some autoantibodies might have some relationship with gender, hematuria, ANA, anti-dsDNA or anti-ENA antibodies. CONCLUSIONS: There are autoantibodies directly against heterogeneous antigens of human glomerular mesangial cells in sera from patients with lupus nephritis, and some of them might be associated with different clinical manifestations.     

IgA nephritis associated with plasminogen abnormalities

Two patients with IgA nephritis associated with hereditary plasminogen abnormalities are described. One patient had dysplasminogenemia and the other had plasminogen deficiency. In both patients, renal biopsy specimens showed significant arteriosclerotic changes in addition to mesangial proliferation. Increased fibrinopeptide A concentration in their plasma suggested increased thrombin generation. In one patient, no systemic arteriosclerosis coexisted, judging from normal optic fundi and the absence of neurological and cardiac abnormalities. In IgA nephritis, renal vascular hyalinosis is often observed, probably resulting from vascular injury. Thus, it was suggested that the decreased fibrinolysis and renal vascular injury of these patients synergistically induced more fibrin thrombi and accelerated arteriosclerosis of the kidney. These cases imply the important role of fibrinolytic disorders in the progression of IgA nephritis.     

Involvement of endothelial cell adhesion molecules in the development of anti-Thy-1 nephritis

To study an involvement of glomerular endothelial cells in the development of anti-Thy-1 nephritis, we examined the expression of endothelial cell adhesion molecules during the course of this model. Ribonuclease protection assay elucidated that expression of mRNA for intercellular adhesion molecule-1 (ICAM-1) was markedly enhanced in the glomeruli with a peak at 2 h (6.5-fold, p < 0.05) after the anti-Thy-1 antibody injection when mesangial cell lysis was recognized and IL-1beta mRNA expression was induced in the glomeruli. The glomerular ICAM-1 was predominantly localized in the endothelial cells and was intensely immunostained at day 1 in the glomerular endothelial cells. In contrast, platelet endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial-cadherin mRNA expression increased gradually with a peak at day 6 (2.6-fold (p < 0.05) and 4.2-fold (p < 0.05), respectively) in the glomeruli with mesangial proliferative lesion. PECAM-1 was also immunolocalized in the glomerular endothelial cells and the immunoreactivity was greatly enhanced at day 6. Glomerular expression of vascular cell adhesion molecule-1 and endothelial leukocyte adhesion molecule-1 (E-selectin) was unchanged at a low level during the course of anti-Thy-1 nephritis. Blocking of ICAM-1 by administration of anti-ICAM-1 antibody showed significant decrease in the number of polymorphonuclear leukocytes accumulating in the glomeruli by 45.7% (9.4 +/- 0.2 vs. 5.1 +/- 0.1 per glomerular cross section, p < 0.01) at 2 h. These results suggest a significant involvement of glomerular endothelial cells in the development and repair of anti-Thy-1 nephritis via direct or indirect intercellular interactions between mesangial cells and glomerular endothelial cells.     

Pathogenesis of Henoch-Schönlein purpura nephritis

The severity of renal involvement is the major factor determining the long-term outcome of children with Henoch-Schönlein purpura (HSP) nephritis (HSPN). Approximately 40% children with HSP develop nephritis, usually within 4 to 6 weeks after the initial onset of the typical purpuric rashes. Although the pathogenetic mechanisms are still not fully delineated, several studies suggest that galactose-deficient IgA1 (Gd-IgA1) is recognized by anti-glycan antibodies, leading to the formation of the circulating immune complexes and their mesangial deposition that induce renal injury in HSPN.     

中性粒细胞细胞外网络与B淋巴细胞在狼疮肾炎患者肾组织的表达及其意义

目的 探讨中性粒细胞细胞外网络(NET)在狼疮肾炎(LN)患者肾组织中的表达与狼疮活动的关系.方法 采用免疫组织化学技术,分别检测NET(以瓜氨酸化的组蛋白H3为标志)在20例LN、8例微小病变(MCD)患者和3例健康对照的肾组织的表达,同时检测相应部位B淋巴细胞(CD19标志)的浸润.分析LN患者肾组织活动指数和慢性指数评分,以及它们与NET的关系.结果 LN患者肾小球中NET表达显著高于健康对照组和MCD组(1.056±0.985比0±0、0±0,均P＜0.01).在中、重度增生的系膜细胞、细胞新月体、有炎性细胞浸润的肾小管间质,NET表达显著上调;系膜细胞中、重度增生肾小球的NET表达显著高于其他类型肾小球,差异均有统计学意义(均P＜0.01).中、重度系膜细胞增生肾小球的平均NET阳性细胞数与LN病理活性指数呈正相关(r=0.620,P=0.004);与SLE-DAI评分呈正相关(r=0.492,P=0.027);与肾小管中NET阳性细胞数呈正相关(r=0.558,P=0.011).肾间质NET阳性细胞数与肾间质阳性B淋巴细胞数呈正相关(r=0.573,P=0.008);与LN病理慢性指数呈正相关(r=0.645,P=0.002).结论 NET在LN患者肾组织广泛表达,肾小球中浸润的NET可能参与了LN患者肾组织的活动性损伤.     

Clinical significance of renal biopsies showing mixed mesangial and global proliferative lupus nephritis

Renal biopsies of 70 children with systemic lupus erythematosus were categorized, according to the World Health Organization classification, as normal (five, 7%), mesangial (23, 33%), focal segmental proliferative (11, 16%), diffuse global proliferative (20, 29%) (ie, greater than or equal to 80% of glomeruli showing mesangioendothelial cell proliferation and/or deposition of immune complexes along the subendothelial margin of glomerular capillaries), and membranous (six, 8%) lupus nephritis (LN). In addition, five (7%) biopsies showed global proliferative LN in less than 80% of glomeruli and mesangial LN in the others. We assessed the renal status of these five patients at the time of renal biopsy and at outcome following prednisone treatment, with or without azathioprine. Four patients improved and later had either a normal urinalysis or only trace proteinuria. A low chronicity index was calculated on the biopsies of these patients. The fifth patient, whose condition did not improve, demonstrated a high chronicity index on renal biopsy. Overall, the renal status at outcome in the patients showing mixed mesangial and global proliferative LN more closely resembled that of patients with mesangial than diffuse global proliferative LN.     

Correlations among expression of glomerular intercellular adhesion molecule 1 (ICAM-1), levels of serum soluble ICAM-1, and renal histopathology in patients with IgA nephropathy.

The purpose of the present study was to evaluate the correlations among expression of intercellular adhesion molecule 1 (ICAM-1) in glomeruli, levels of soluble ICAM-1 (sICAM-1) in sera, and renal injuries in patients with IgA nephropathy. The levels of sICAM-1 in sera from 27 patients with IgA nephropathy and 7 healthy controls were measured by the human soluble ICAM-1 immunoassay. The expression of ICAM-1 in glomeruli was detected by indirect immunofluorescence. We observed marked expression of ICAM-1 in glomerular capillary walls and mesangial areas in patients with advanced-stage, but not in those with mild IgA nephropathy. Since the histopathological changes in the advanced stage of this disease were characterized by diffuse mesangial cell proliferation and tubulointerstitial injury, the expression of ICAM-1 in the glomeruli may be of value in evaluating the degree of renal lesions in patients with IgA nephropathy. However, there was no significant change in the levels of serum sICAM-1 among mild-stage and advanced-stage patients and healthy controls. It appears that the measurement of serum sICAM-1 is not useful in evaluating the degree of renal injuries in patients with IgA nephropathy.     

Abnormal IgA glycosylation in Henoch-Schonlein purpura restricted to patients with clinical nephritis

Background: Glomerular deposition of IgA1 is a common feature of Henoch-Schonlein purpura, and is indistinguishable from that seen in IgA nephropathy. Serum IgA1 is abnormally O-glycosylated in IgA nephropathy, and this may contribute to mesangial IgA1 deposition and the development of glomerular injury. This altered O-glycosylation of IgA1 can be detected by its increased binding to the lectin Vicia villosa. Methods: To investigate whether IgA1 is abnormally glycosylated in Henoch-Schonlein purpura, the binding of Vicia villosa lectin to serum IgA1 was studied in the following subject groups: IgA nephropathy; adults and children with Henoch-Schonlein purpura and nephritis; children with clinically diagnosed Henoch-Schonlein purpura but no renal involvement; adults and children with non-IgA associated glomerulonephritis; and matched controls. Results: The abnormality of lectin binding seen in IgA nephropathy was also found in both adults and children with Henoch-Schonlein purpura with nephritis. However the lectin binding of serum IgA1 from children with Henoch-Schonlein purpura lacking renal involvement did not differ from controls, and similarly no abnormality of lectin binding was seen in patients with non-IgA associated glomerulonephritis. Conclusions: These data indicate that the abnormality of IgA1 O-glycosylation seen in IgA nephropathy is also found in Henoch Schonlein purpura, but only in those subjects with renal involvement, while IgA1 O-glycosylation is normal in patients with other forms of renal disease. These findings lend strong support to a role for altered IgA1 O-glycosylation in the pathogenesis of IgA-associated glomerular disease.