Monocyte infiltration and cross-linked fibrin deposition in IgA nephritis and Henoch-Schoenlein purpura nephritis

To clarify the role of immune cell infiltration and fibrin deposition in glomerular injury, renal biopsy specimens taken from patients with primary IgA nephritis and Henoch-Sch?nlein purpura nephritis (HSPN) were evaluated using monoclonal antibodies specific to mononuclear cell surfaces and cross-linked fibrin (XFb). Monocytes/macrophages were the predominant cell type infiltrating glomeruli in IgA nephritis and HSPN. The intraglomerular monocyte population in both diseases was significantly higher than that in normals, mesangial proliferative (non-IgA) glomerulonephritis or minimal change nephrotic syndrome. In IgA nephritis, there was a clear correlation between glomerular monocyte accumulation and the degree of proteinuria. Although the monocyte influx tended to decline with time in HSPN, it remained unchanged in IgA nephritis. XFb deposition was found in the glomeruli of 27 out of 48 patients with IgA nephritis, and in 15 out of 20 with HSPN. The degree of XFb deposition in IgA nephritis correlated significantly with the degree of mesangial proliferation. These findings indicate a close relationship of monocyte/macrophage infiltration and XFb deposition with glomerular injury in IgA nephritis.     

Intraglomerular monocytes in human glomerulonephritis.

A total of 246 cases of 166 primary glomerulonephritis (GN) and 80 secondary GN were examined for the presence of intraglomerular monocytes using nonspecific esterase reaction of alpha-naphthyl butyrate methods. The high score of monocyte index (MI) as the numbers of monocytes per glomerulus was found in crescentic GN (n = 5, MI = 3.72 +/- 1.98), endocapillary proliferative GN (n = 8, MI = 2.17 +/- 2.13), lupus nephritis (n = 43, MI = 2.21 +/- 3.35), and cryoglobulinemia-related GN (n = 1, MI = 11.5). The intermediate score of MI was observed in IgA nephropathy (IgA-N, n = 64, MI = 0.63 +/- 0.42) and Henoch-Sch?nlein purpura nephritis (HSP-N, n = 11, MI = 1.09 +/- 0.87). Out of IgA-N and HSP-N, the scores of MI in patients with more severe proliferation and/or with segmental lesions were higher than those without this histological finding. However, there was not a significant correlation between the glomerular monocytic infiltration and clinical findings in each group. In primary GN including minor glomerular abnormalities, focal glomerular sclerosis and membranous GN, and in secondary renal diseases except for SLE, HSP, and cryoglobulinemia, the score of intraglomerular monocytic infiltration was of little value. The participation of monocytes was predominant in extra- and intracapillary GN, lupus nephritis, and cryoglobulinemia-related GN, as previously reported. Moreover, in some types of proliferative GN, especially IgA-N and HSP-N, some parts of glomerular hypercellularity result from the participation of monocyte-macrophage series, although the main parts of cell proliferation are intrinsic mesangial cells.     

Lessons learned from the Japanese nephritis screening study

A program of urine screening for asymptomatic hematuria and proteinuria in school children has been conducted since 1973 by the Ministry of Education in Japan with great success in the early detection of asymptomatic renal disease. In order to know whether this nationwide program during 13 years has contributed to understanding of the epidemiology of chronic glomerular disease in Japan, a multicenter survey of the patients was conducted. Between 70% and 80% of IgA and non-IgA mesangial proliferative glomerulonephritis and 65%–80% of membranoproliferative glomerulonephritis (MPGN) were detected by mass urine screening at school. Severe glomerular lesions were more frequently observed in children with chance proteinuria and hematuria, as well as IgA and non-IgA mesangial proliferative glomerulonephritis with significant proteinuria. Mild glomerular change was more frequent in patients with MPGN, IgA and non-IgA mesangial proliferative nephritis with minimal proteinuria who were detected by our screening program, rather than those seen with some of the nephritic signs and symptoms at diagnosis. The above evidence suggests that a screening program may open the way for the early management of these diseases, especially where treatment is alrealy established.     

Urinary transforming growth factor-β in patients with glomerular diseases

We measured the urinary levels of active transforming growth factor-β (TGF-β) by enzyme-linked immunosorbent assay in 12 healthy controls and 42 patients with various glomerular diseases, including mesangial proliferative (IgA nephritis, Henoch-Sch?nlein purpura nephritis, and IgA-negative mesangial proliferative glomerulonephritis) and non-proliferative (minimal change nephrotic syndrome and focal glomerulosclerosis) types. Urinary TGF-β, expressed as a ratio to urinary creatinine (ng/mg creatinine), was elevated in patients with IgA nephritis and focal glomerulosclerosis, and was significantly higher than in patients with other types of glomerular diseases and healthy controls. There was a significant correlation between urinary TGF-β levels and the grade of interstitial fibrosis. Among patients with proliferative-type disease, urinary TGF-β was significantly correlated with the grade of mesangial matrix increase and the magnitude of proteinuria. The relationship between urinary TGF-β levels and the immunostaining intensity of TGF-β in the glomeruli was not significant. These results indicated that urinary TGF-β reflects the grade of interstitial fibrosis in glomerular diseases and also the mesangial matrix increase in proliferative-type glomerulonephritis. Measuring TGF-β levels in the urine might be helpful in monitoring patients with some types of glomerular disease. Received November 20, 1995; received in revised form October 8, 1996; accepted October 18, 1996     

Histology and immunohistology of IgA nephropathy

IgA nephropathy is a histologically diverse glomerular disease characterized by mesangial or mesangial plus peripheral glomerular capillary immune complex deposits that contain IgA as the dominant or co-dominant immunoglobulin type. The most common histologic manifestation of IgA nephropathy is mesangial proliferative glomerulonephritis (GN), most often focal but not infrequently diffuse. However, the light microscopic appearance of IgA nephropathy spans the entire range from histologically normal to diffuse proliferative and crescentic glomerulonephritis, much as is the case with lupus nephritis. This review examines the histologic diversity as well as the immunohistologic features of IgA nephropathy.     

Epidemiologic data of renal diseases from a single unit in China: analysis based on 13,519 renal biopsies

Renal biopsy specimens of 13,519 cases were collected during the period of January 1979 to December 2002 from the Research Institute of Nephrology, Nanjing University School of Medicine, Nanjing, China. Analysis of the data of this group of patients showed that primary glomerulonephritis (GN) remained the most important and prevalent renal disease in China. The ratio of primary to secondary GN was 2.75:1. However, it is declining progressively in the past two decades with an increment in the incidence of diabetic nephropathy and nephrosclerosis. IgA nephropathy (IgAN) constituted 45.26% of the primary GN, while non-IgA mesangial proliferative lesions were 25.62%. Membranous nephropathy was 9.89% and minimal change disease was 0.93%, remarkably less. The most prevalent etiology of secondary GN was systemic lupus erythrematosus (SLE) (54.3%) followed by Henoch-Sch?nlein purpura (20.3%), diabetic nephropathy (6.6%), systemic vasculitides (4.0%), and amyloidosis (2.2%). Based on the study of biopsy materials obtained from 607 cases manifesting chronic renal failure, IgAN was identified as the most frequent cause (26.69%) of chronic renal failure.     

Primary antiphospholipid antibody syndrome and mesangial IgA glomerulonephritis

The antiphospholipid antibody syndrome (APS) is characterized by recurrent thrombosis, fetal loss, multiorgan involvement, and the presence of lupus anticoagulant and/or anticardiolipin antibody. When not associated with systemic lupus erythematosus, other collagen diseases, or ingestion of medications, the condition is called primary APS. The kidney may be involved in the APS syndrome with acute nephritis and renal failure. The cases with renal biopsy studies have shown variable glomerular morphology, ranging from mild mesangial changes to a diffuse endocapillary proliferative glomerulonephritis. The most frequent lesion is thrombotic microangiopathy or features seen in the hemolytic uremic syndrome. Apart from fibrin thrombus deposition, only a few cases have shown focal and segmental deposits of IgG and/or IgM and/or C3. We describe a patient with primary APS who had thrombosis with lower limb amputation and acute renal failure. The renal biopsy specimen showed a focal proliferative glomerulonephritis with endothelial proliferation and damage, with diffuse heavy mesangial deposits of IgA and fibrinogen. This case with diabetes mellitus, but without diabetic nephropathy, represents the occurrence of primary APS and mesangial IgA nephropathy which potentiated the renal injury, leading to acute renal failure. The relationship to the Henoch-Sch?nlein syndrome is discussed.     

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.     

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.     

Specific changes in plasma concentrations of matrix metalloproteinase-2 and -9, TIMP-1 and TGF-beta1 in patients with distinct types of primary glomerulonephritis.

BACKGROUND: Dysregulated renal expression of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMP) and TGF-beta1 contribute to the development of tubulo-interstitial fibrosis characteristic of progressive forms of primary glomerulonephritis (GN). There is little information on the circulating levels of these proteins in human GNs. Here, we assessed whether different histopathological GN types could be associated with distinct plasma patterns of MMPs and regulatory proteins. METHODS: Protein levels of MMP-2, MMP-9, TGF-beta1 and TIMP-1 were measured by ELISA in plasma from venous blood of 108 untreated patients with various types of primary GN defined by kidney biopsy, namely IgAN (n=63), membranous GN (MN, n=26), minimal change nephrotic syndrome (MCNS, n=12) and focal and segmental glomerular sclerosis (FSGS, n=7), and were compared with levels in 50 healthy subjects. Plasma samples were assayed for gelatinolytic activity (zymography). RESULTS: Zymography detected the proforms of MMP-2 and MMP-9. Compared with controls, IgAN patients exhibited a significant, parallel decrease in plasma levels of MMP-2, MMP-9 and TGF-beta1. In MN patients, decreased MMP-9 level contrasted with a high MMP-2 level and a normal TGF-beta1 level. In the MCNS/FSGS group, increased MMP-2 level contrasted with unchanged MMP-9 and decreased TGF-beta1 levels. Plasma concentration of TIMP-1 was elevated in all GN groups. There was no correlation between baseline MMP-2/MMP-9/TIMP-1/TGF-beta1 levels and the degree of renal dysfunction or with progression toward ESRD. CONCLUSIONS: Plasma concentrations of MMP-2, MMP-9 and TGF-beta1 significantly differed between the various histopathological types of primary GNs, thus suggesting the involvement of different underlying mechanisms in the regulation of glomerular and tubulointerstitial fibrosis in these renal diseases.     

Clinicopathological correlation of young onset chronic glomerulonephritis

In a retrospective analytical study involving 98 children with primary glomerulonephritis who were seen by us at our hospital during a 2-year period from 1984 through 1985 and who had renal biopsy performed previously, attempts were made to correlate pathological findings with both clinical findings and prognosis. The results are summarized as follows: 1) Of 87 patients with asymptomatic chronic glomerulonephritis, glomerular findings were those of minimal change lesion, mesangial proliferative nephritis, MPGN, membranous nephropathy and FGS or sclerosing nephritis in 29.9%, 51.7%, 13.8%, 1.1% and 3.5%, respectively. Among the other 11 patients in whom the diagnosis was made after manifesting the nephritic symptoms, minimal change was noted less frequently and MPGN was detected more frequently than in the aforementioned asymptomatic group. IgA nephropathy was estimated to account for 44.2% of cases of asymptomatic chronic nephritis. 2) Mild mesangial proliferation was observed relatively frequently and severe mesangial proliferation or MPGN rather infrequently in hematuria cases without proteinuria while in those with severe proteinuria minimal change lesion was uncommon and severe mesangial proliferative changes, MPGN or FGS were relatively frequent. 3) In 22 patients with IgA nephropathy and 11 with non-IgA nephritis the severity of glomerular changes was related to the intensity of proteinuria at the time of renal biopsy. 4) A 3 to 5 years' follow-up study of patients with mesangial proliferative nephritis inclusive of IgA nephropathy disclosed that 26-28% of patients became free from urinary abnormalities, 27-37% had persistent hematuria without proteinuria and 24-32% still had proteinuria of 2 plus or above. Patients with milder glomerular changes had a definitely better prognosis than those with severe glomerular lesions.     

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.     

2型糖尿病合并非糖尿病肾病的临床及病理分析

目的：回顾性分析2型糖尿病合并非糖尿病肾病的临床表现及病理特征。方法：回顾性分析2004年1月～2009年12月临床疑为合并非糖尿病肾病的110例2型糖尿病患者的肾活检资料。根据肾活检结果分为单纯糖尿病肾病（DN）组和糖尿病肾病合并非糖尿病肾病（NDRD）组,并对临床和病理资料进行分析。结果：110例2型糖尿病肾病患者中,50例（45.5%）合并非糖尿病肾病。糖尿病肾病合并非糖尿病肾病组蛋白尿、血尿发生率高于单纯糖尿病肾病组,但糖尿病视网膜病变发生率低于单纯糖尿病肾病组。两组年龄、糖尿病病程、高血压、血肌酐和肾小球滤过率差异无统计学意义。所有合并的非糖尿病肾病中,IgA肾病的比率最高为34%,其他依次为膜性肾病22.0%,系膜增殖性肾小球肾炎14%,HBV相关性肾小球肾炎8.0%,微小病变型肾小球肾炎10%,高血压肾小球硬化4.0%,FSGS4.0%,新月体肾小球肾炎2.0%,狼疮性肾炎2.0%。结论：2型糖尿病肾病合并非糖尿病肾病发生率45.5%,IgA肾病最常见。血尿、蛋白尿同时缺乏糖尿病视网膜病变强烈提示合并非糖尿病肾病。对于临床表现不典型的患者,肾活检是一项排除糖尿病肾脏病变的重要手段。     

Role of mast cell tryptase in renal interstitial fibrosis.

Renal interstitial fibrosis is characterized by increased proliferation of fibroblasts and excessive accumulation of extracellular matrix. Mast cell tryptase has been implicated in the development of tissue fibrosis in skin and lungs. However, the significance of mast cell tryptase in human renal diseases has not been investigated. The potential role of mast cell-derived tryptase in the development of renal fibrosis was studied using immunohistochemical techniques and cultured human renal fibroblast cell lines. Semiquantitative immunostaining analysis of samples from 70 patients with several renal diseases, including IgA glomerulonephritis (GN) (n = 30), non-IgA GN (n = 5), membranous GN (n = 5), focal segmental glomerulosclerosis (n = 4), minor glomerular abnormalities (n = 5), lupus nephritis (n = 3), and acute or chronic tubulointerstitial nephritis (n = 18), revealed that the degree of renal interstitial fibrosis was well correlated with the number of infiltrating tryptase-positive mast cells (P < 0.01). Mast cells could not be detected in damaged glomeruli in any form of renal disease. [(3)H]Thymidine uptake experiments demonstrated that DNA synthesis by cultured renal fibroblasts was increased with the concentration of tryptase (0.5 to 5 nM) coincubated with heparin and was suppressed by coincubation with the protease inhibitors leupeptin and benzamidine hydrochloride. Tryptase alone also increased DNA synthesis by fibroblasts but exhibited less effectiveness, compared with the combination of tryptase and heparin. Conversely, heparin alone suppressed DNA synthesis by fibroblasts. Metabolic [(35)S]methionine-labeling experiments with cultured renal fibroblasts indicated that tryptase increased the synthesis of fibronectin and collagen type I, in a dose-dependent manner. These findings suggest that mast cell tryptase plays a role in the proliferation and extracellular matrix protein production of renal interstitial fibroblasts and thus contributes to the development of renal interstitial fibrosis.     

Lupus-like nephritis in an HIV-positive patient: report of a case and review of the literature

The most common manifestation of HIV/AIDS in the kidney is the collapsing variant of focal segmental glomerular sclerosis, HIV-associated nephropathy (HIVAN). Other forms of renal disease in HIV-infected patients include mesangial proliferative glomerulonephritis (GN), membranoproliferative GN, IgA nephropathy, minimal change disease and proliferative immune-complex GN. We present the case of a 42-year-old Caucasian male with HIV infection, treatment associated peripheral neuropathy, nephrotic syndrome and progressive renal failure. The initial and subsequent kidney biopsies showed diffuse proliferative glomerulonephritis resembling diffuse proliferative (WHO class IV) lupus nephritis. There was no clinical or serological evidence of systemic lupus erythematosus (SLE). Proteinuria improved with ACE-inhibitors, and renal function remained relatively stable while receiving highly active antiretroviral therapy (HAART). A precipitous decline in renal function to end-stage renal disease followed a brief period of withdrawal from potent antiretroviral therapy during which the viral load rebounded. Considering previously reported cases, it appears that lupus-like nephritis is a rare but well-defined pattern of immune-complex-induced renal injury seen in HIV-infected patients. It appears to be markedly responsive to HAART.     

Binding sites for carrier-immobilized carbohydrates in the kidney: implication for the pathogenesis of Henoch-Sch?nlein purpura and/or IgA nephropathy.

BACKGROUND: Henoch-Sch?nlein purpura is a common vasculitis of childhood affecting the skin, joints, gastrointestinal tract, and kidney. The mesangial deposition of IgA1 is the most critical factor for the prognosis of patients with this disease. The aberrant glycosylation of the IgA1 subclass with the absence of terminally located galactose and presence of only alpha-N-acetylgalactosamine in O-linked oligosaccharides in the hinge region of IgA1 represents a prominent difference from the normal IgA1. These alterations prompt the supposition that the sugar part may guide IgA deposition by recognition of endogenous lectins on the mesangium. METHODS: Owing to the limited knowledge about the expression of carbohydrate-binding sites in the human kidney we initiated the study of this aspect with a class of tools which are suitable to map the lectinome of cells. Employing biotinylated neoglycoconjugates, glycosaminoglycans, and sulphated polysaccharides we monitored the presence of accessible carbohydrate-binding sites in control kidneys represented by tumour-free areas of kidneys with Grawitz tumour and in biopsies from patients with Henoch-Sch?nlein purpura-associated IgA nephropathy. RESULTS: Using frozen sections, no expression of any tested carbohydrate-binding site(s) was observed in the endothelial and the mesangial cells in glomeruli of the control kidneys as well as in the biopsies from Henoch-Sch?nlein purpura IgA nephropathic kidneys, in contrast to the tubules. The N-acetylgalactosamine-binding sites were expressed only in the inner layer of Bowman's capsule of 20% of glomeruli of the control kidney from one patient with Grawitz tumour and one biopsy from a patient with Henoch-Sch?nlein purpura-associated IgA nephropathy. However, the macrophages in the glomeruli of patients with IgA nephropathy and interstitial macrophages from both studied groups, i.e. without and with IgA nephropathy, harbour capacity to recognize carrier-immobilized alpha-N-acetylgalactosamine. Access to this binding site for the neoligand conjugate can be blocked by the monoclonal antibody MEM-18 recognizing CD14 antigen. CONCLUSION: The possibility for a participation of macrophage deposition of IgA1 in mesangium via a lectin mechanism involving this binding capacity warrants further studies.     

Renal expression of matrix metalloproteinases in human ANCA-associated glomerulonephritis.

BACKGROUND: Expression of matrix metalloproteinases (MMPs) by infiltrating and intrinsic renal cells is increased in inflammatory conditions, and may correlate with disease activity of glomerulonephritis. We analysed renal expression of MMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1) and markers of neutrophil and monocyte infiltration in renal biopsies of patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: Immunohistochemical expression of MMP-2, -3, -9, TIMP-1, the neutrophil- and monocyte-derived MMP activators cathepsin G, neutrophil elastase and myeloperoxidase (MPO), and the monocyte marker CD14 was determined in renal biopsies of active proteinase 3 (PR3)-ANCA (n = 7) and MPO-ANCA (n = 6) associated glomerulonephritis, and in normal renal tissue (n = 4). Double labelling experiments of MMPs and TIMP-1 were performed with MPO and CD68, labelling neutrophils and macrophages. RESULTS: MMP-2-, MMP-3-, MMP-9- and TIMP-1-positive cells were detected in ANCA-associated glomerulonephritis in glomeruli with active inflammation (cellular crescents or fibrinoid necrosis), only occasionally in normal appearing glomeruli, and not in sclerotic glomeruli and positive cells were found in the tubulo-interstitium. MMPs and TIMP-1 were expressed predominantly by MPO-and CD68-positive cells. In normal renal tissue, no expression was detected, with the exception of weak mesangial staining for MMP-2. In ANCA-associated glomerulonephritis, glomerular MMP-2, -9 and TIMP-1 correlated with glomerular cathepsin G expression, while the number of MMP-9-expressing cells per glomerulus correlated with the percentage of crescentic glomeruli. Tubulo-interstitial expression of MMPs correlated with all markers of neutrophil and monocyte infiltration, and interstitial MMP-9 and TIMP-1 expression correlated with renal function at the time of renal biopsy. CONCLUSIONS: Expression of glomerular and interstitial MMP-2, -3, -9 and TIMP-1 is increased in active ANCA-associated glomerulonephritis and correlates with inflammatory activity.     

Enhanced expression of the CD71 mesangial IgA1 receptor in Berger disease and Henoch-Schönlein nephritis: association between CD71 expression and IgA deposits

ABSTRACT. IgA nephropathy (IgA-N) that comprises Berger disease and Henoch-Sch?nlein Purpura (HSP) nephritis is defined by mesangial IgA deposits. Recently, this group has characterized a new receptor for IgA, the transferrin receptor (CD71), expressed on mesangial cells. To assess whether CD71 was involved in the pathogenesis of IgA-N, its expression was analyzed together with IgA deposits on 16 kidney biopsies from 16 patients with Berger disease (n = 4) or HSP (n = 12). These biopsies were compared with 17 kidney biopsies of a group of 15 patients (control group) with other glomerulonephritis, including systemic lupus erythematosus, poststreptococcal acute glomerulonephritis, membranoproliferative glomerulonephritis, steroid-sensitive minimal change nephrotic syndrome, steroid-resistant idiopathic nephrotic syndrome with focal and segmental glomerulosclerosis, and persistent and isolated proteinuria with minimal change on kidney biopsy. In this control group, IgA deposits could be observed in eight kidney biopsies of seven patients. These biopsies were also compared with normal kidney specimens (normal group). In normal kidney, it was found that CD71 was linearly expressed on tubular epithelium but was either not expressed or very dimly in glomeruli. In contrast, CD71 was strongly expressed in 105 of the 107 glomeruli of the kidney biopsies from the IgA-N group. For the control group, it was found that expression of CD71 in glomeruli was correlated to the presence of IgA deposits. Indeed, among the 87 glomeruli of nine kidney biopsies (eight patients) without IgA fixation, 78 exhibited no CD71 expression and nine exhibited a very dim one. On the other hand, all 49 glomeruli of the eight kidney biopsies (seven patients) in which IgA deposits were detected exhibited CD71 expression (P < 10(-4)). Performance of dual-labeling studies with confocal microscopy on kidney biopsies of IgA-N patients demonstrated that most of the IgA deposits co-localized with CD71. It was also demonstrated that the intensity of the expression of CD71 was not linked to the intensity of clinical or biologic findings but to the intensity of cellular proliferation in both IgA-N and control groups. These results show that mesangial CD71 expression is not specific to IgA-N. However, the association between IgA deposits and CD71 expression and their co-localization in the mesangium provide strong evidence that CD71 is a major IgA receptor on mesangial cells.