Chronic rheumatoid arthritis complicated by myeloperoxidase antineutrophil cytoplasmic antibody-associated nephritis.

We report a myeloperoxidase antineutrophil cytoplasmic antibody-positive rheumatoid arthritis patient who developed necrotizing crescentic glomerulonephritis. Steroid therapy was given combined with an immunosuppressant agent, and double-filtration plasmapheresis was started with the aim of removing antibodies from the blood. This therapeutic regimen was found to be useful.     

Expression of macrophage migration inhibitory factor in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

AIM AND METHODS: To investigate the relationship between macrophage migration inhibitory factor and clinical or pathological findings in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody MPO-ANCA-associated glomerulonephritis characterized by idiopathic necrotizing crescentic glomerulonephritis, renal biopsy specimens from 16 patients with MPO-ANCA-associated glomerulonephritis and 15 controls were stained using an enzyme antibody method to detect macrophage migration inhibitory factor and macrophages infiltrating the glomeruli. The relationship of this factor with various clinical parameters and with cellular crescents was determined. RESULTS: Macrophage migration inhibitory factor was detected in 11 out of 16 patients with MPO-ANCA-associated glomerulonephritis, but was not found in any of the controls. In the positive patients, the blood MPO-ANCA level was significantly higher than in the negative patients. Both cellular crescents and the number of macrophages infiltrating the glomeruli were significantly increased in the patients positive for macrophage migration inhibitory factor. CONCLUSION: Thus, macrophage migration inhibitory factor may be closely related to cellular crescent formation and disease activity in patients with MPO-ANCA-associated glomerulonephritis.     

Successful renal transplantation in a child with ANCA-associated microscopic polyangiitis

Crescentic glomerulonephritis (CGN) is a clinicopathologic entity which is characterized by severe renal dysfunction of rapid onset with glomerular crescents. Type III CGN is associated with the absence of glomerular immune complex deposition (pauci-immune) and is associated with antineutrophil cytoplasmic antibody (ANCA). Microscopic polyangiitis and idiopathic pauci-immune necrotizing glomerulonephritis (NCGN) are strongly associated with ANCA directed against myeloperoxidase (anti-MPO). We describe here an unusual pediatric patient with MPO-ANCA-associated rapidly progressive glomerulonephritis (RPGN), emphasizing the management and outcome of the disease.     

Antineutrophil cytoplasmic antibody-negative pauci-immune crescentic glomerulonephritis associated with rheumatoid arthritis: An unusual case report

Clinically relevant renal lesions in rheumatoid arthritis (RA) are not common. More often renal involvement is related to complications of therapy than the disease itself. The most common forms of primary renal disease in RA are membranous glomerulonephropathy and a pure mesangial proliferative glomerulonephritis. Some studies have described the association between crescentic glomerulonephritis (crescentic GN) and RA, but they were all found to be perinuclear antineutrophil cytoplasmic antibody (p-ANCA) positive. However, RA associated with ANCA negative pauci-immue crescentic GN has not been reported. This is a case report of a 37-year-old female with RA who initially presented with general oedema and acute deterioration of renal function. The renal biopsy revealed ANCA negative pauci-immune crescentic GN. The patient was treated with steroid pulse and plasmapheresis, but not cyclophosphamide because of severe urosepsis. Despite the use of aggressive therapy, her renal function was not improved and she underwent maintenance haemodialysis thereafter. Because ANCA negative crescentic GN may occur in RA patients without frank systemic vasculitis, but with severe clinical manifestation, a heightened suspicion for a relatively 'silent' crescentic GN would have led to the correct diagnosis and appropriate treatment.     

Renal artery stenosis modifies glomerular injury in antineutrophil cytoplasmic antibody-associated disease.

A 68-year-old man presented with renal failure, heart failure, gastrointestinal bleeding, and a pulmonary infiltrate. Serologic evaluation revealed a perinuclear antineutrophil cytoplasmic antibody (ANCA) at a titer of 1:1280, which on immunoblot and enzyme immunoassay showed antimyeloperoxidase specificity. Autopsy showed microscopic polyarteritis based on the presence of necrotizing alveolitis and crescentic glomerulonephritis. The extent and activity of the glomerular disease was modified by a right renal artery stenosis (RAS). Twenty percent of glomeruli on the right and 82% glomeruli on the left contained crescentic lesions. Furthermore, predominantly active lesions were associated with renal artery stenosis, while the contralateral kidney contained mostly organized crescents. This observation suggests that hemodynamic factors or its sequelae can influence the onset and severity of ANCA-associated disease.     

Association of a novel complement factor H mutation with severe crescentic and necrotizing glomerulonephritis

Severe crescentic and necrotizing glomerulonephritis typically is associated with anti-glomerular basement membrane or antineutrophil cytoplasmic antibodies. In this report, we describe a 23-year-old man with severe crescentic and necrotizing glomerulonephritis. Both anti-glomerular basement membrane and antineutrophil cytoplasmic antibody titers were negative. Kidney biopsy showed bright C3 staining in the mesangium and along capillary walls and no staining for immunoglobulins. Electron microscopy showed waxy deposits (many mesangial; few intramembranous or subendothelial), prompting evaluation of the alternative pathway of complement. Alternative pathway evaluation showed a novel mutation in short consensus repeat (SCR) 19 of complement factor H. In addition, the patient carried complement factor H and C3 risk alleles. Prompt treatment with intravenous steroids followed by oral steroids resulted in symptom alleviation and improved kidney function. This case shows what is to our knowledge a unique and previously unpublished cause of severe crescentic and necrotizing glomerulonephritis. Furthermore, the case demonstrates an expanding spectrum of complement-mediated glomerulonephritis and shows that crescentic and necrotizing glomerulonephritis with solely complement deposits should be evaluated for abnormalities in the alternative pathway of complement.     

Analysis of mononuclear cells in urine using flow cytometry: a useful tool for monitoring disease activity of proliferative glomerulonephritis]

We investigated CD56+ cells (natural killer cells), CD14+ cells (macrophage) and CD3+ cells (pan T cells) in urine using flow cytometry in various renal diseases including idiopathic crescentic glomerulonephritis, IgA nephropathy, membranoproliferative glomerulonephritis membranous nephropathy, pyelonephritis and idiopathic renal hematuria. A remarkable increase of CD56 cells in urine was observed in glomerulonephritis with marked necrotizing/and or crescentic (NC) lesions. The ratio of CD56+ cells/CD3+ cells was correlated with the severity of NC lesions. The ratio of CD14+ cells/CD3+ cells was increased in glomerulonephritis with endocapillary proliferation. Using immunohistochemical methods, CD56+ cells were also observed to be present in cellular crescents in biopsy specimens. These observations suggest that an analysis of these cells in urine using flow cytometry may be a useful tool for monitoring disease activity in proliferative glomerulonephritis.     

Antigen-specific radioimmunoassays for anti-neutrophil cytoplasmic antibodies in the diagnosis of rapidly progressive glomerulonephritis.

Circulating anti-neutrophil cytoplasmic antibodies (ANCA) have been described in most patients with "pauci-immune" necrotizing and crescentic glomerulonephritis. A 29-kDa serine protease (p29 or proteinase 3) and myeloperoxidase are the two best characterized antigens recognized by ANCA. The study presented here was conducted to define the diagnostic value of assays for antibodies against these two antigens in rapidly progressive glomerulonephritis. Radioimmunoassays were developed for anti-p29 and anti-myeloperoxidase antibodies, with purified antigens, and the results of the radioimmunoassays were compared with those obtained by immunofluorescence tests for ANCA. We performed assays on serum samples from 123 patients with the syndrome of rapidly progressive glomerulonephritis, as well as from 200 blood bank donors and from 717 additional control patients. Without knowledge of the results of ANCA tests, the renal pathologic findings in the 123 patients with rapidly progressive glomerulonephritis were analyzed, and 42 were classified as pauci-immune necrotizing and crescentic glomerulonephritis, 18 were classified as anti-glomerular basement membrane nephritis and 63 were classified as other forms of renal disease. We found radioimmunoassays to be more reliable in the diagnosis of pauci-immune necrotizing and crescentic glomerulonephritis than immunofluorescence testing. By radioimmunoassay, ANCA were found in 40 of 42 patients (95% sensitivity) with pauci-immune necrotizing and crescentic glomerulonephritis (14 with anti-p29 and 26 with anti-myeloperoxidase antibodies). The tests for antibodies to p29 and myeloperoxidase were 99.9 and 99.5% specific for pauci-immune necrotizing and crescentic glomerulonephritis, respectively. In the setting of rapidly progressive glomerulonephritis, a positive radioimmunoassay for anti-p29 or anti-myeloperoxidase antibodies (together with a negative test for anti-GBM antibodies) gives a probability of pauci-immune necrotizing and crescentic glomerulonephritis of over 99%.     

Fatal hemoperitoneum due to rupture of the left gastric artery in a patient with microscopic polyangiitis

Microscopic polyangiitis is a vasculitis which primarily affects capillaries, venules or arterioles. Involvement of small and medium-sized arteries may also occur. A 70-year-old Japanese female with a fever and cough was diagnosed with pneumonia and antibiotics were administered. Her symptoms initially improved, but her fever recurred and she experienced malaise and loss of appetite. Her renal function gradually worsened and she was positive for myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA). She was referred to our hospital on the suspicion of ANCA-associated glomerulonephritis. However, her depressive mental symptoms did not allow her to undergo a renal biopsy. She was clinically diagnosed with ANCA-associated glomerulonephritis, and oral corticosteroids and intravenous methylprednisolone were administered. Her symptoms and renal function were improved, but she died suddenly 15 days after admission. An autopsy disclosed approximately 700 mL bloody ascites. Coagulation adhered to the lesser curvature of the stomach, but the source of hemorrhage could not be detected macroscopically because the gastric mucosa did not show abnormal findings. The histological findings revealed that the left gastric artery showed necrotizing angiitis and rupture. In the kidneys, cellular crescents were found in approximately 10%, fibrous crescents were found in approximately 10%, sclerosis and collapse were found approximately 30% of the glomeruli, and necrotizing angiitis was observed in interlobular arteries and arterioles. From these findings, she was finally diagnosed with microscopic polyangiitis. Microscopic polyangiitis is an extremely rare cause of spontaneous intraperitoneal bleeding, but it must be carefully considered in the differential diagnosis for the appropriate management of such patients.     

Azurocidin-specific-ANCA-related idiopathic necrotizing crescentic glomerulonephritis

An 80-year-old woman who had rapidly progressive glomerulonephritis unaccompanied by systemic vasculitis is described. On renal biopsy, she showed necrotizing crescentic glomerulonephritis by light microscopy and pauci-immune glomerular lesions by immunofluorescent study. No dense deposits were present on electronmicroscopic study. On serum examination, indirect immunofluorescent study showed perinuclear pattern antineutrophil cytoplasmic antibody (ANCA), but myeloperoxidase-ANCA and proteinase 3-ANCA were both negative. Her serum reacted only to azurocidin excluding other ANCA antigens: bactericidal permeability-increasing protein, cathepsin G, elastase, lactoferrin, or lysozyme. Serum creatinine level decreased, and C-reactive protein turned negative after steroid therapy. Azurocidin-ANCA also turned negative. It is suggested that azurocidin-ANCA might have been related to the inflammatory process of pauci-immune necrotizing crescentic glomerulonephritis in this patient.     

Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases

BACKGROUND: Necrotizing and crescentic glomerulonephritis related to antineutrophil cytoplasmic autoantibodies (ANCA) is typically referred to as "pauci-immune"; however, it is not unusual for renal biopsies in such cases to exhibit some immune complex deposition within glomeruli on immunofluorescence and/or electron microscopic study. The composition and intraglomerular localization of such deposits in ANCA-glomerulonephritis has not been widely studied, and their potential pathologic and clinical significance is not clear, although a possible synergistic effect between immune complexes and ANCA in producing more severe glomerulonephritis is suggested by some human and animal studies. METHODS: Electron micrographs from 126 renal biopsies showing necrotizing/crescentic glomerulonephritis characterized by positive ANCA serology [C-ANCA, anti-proteinase 3 (anti-PR3), or anti-myeloperoxidase (MPO)] or necrotizing arteritis in the absence of known ANCA results were examined for the presence, quantity, and location of electron-dense deposits. The presence or absence of such deposits was correlated with histologic findings (fraction of glomeruli with crescents and segmental necrotizing lesions, mesangial and endocapillary hypercellularity), immunofluorescence findings, and clinical data, including serum creatinine and 24-hour urine protein levels at the time of biopsy. RESULTS: Sixty-eight (54%) of these biopsies showed glomerular immune complex deposits on electron microscopy; 87% of the latter also showed positive immunofluorescence findings for at least one immunoglobulin or complement component, although staining was relatively mild in most instances (< or =2+ on a 0 to 4+ scale in all but eight cases). Nearly half of biopsies negative for deposits by electron microscopy also showed positive immunofluorescence findings, though even more so than in cases with deposits on electron microscopy the intensity of immunofluorescence staining in these biopsies was typically very weak (trace or trace to 1+ in most cases, none >2+). Hypercellularity within the glomerular tuft was seen in 50% of biopsies with deposits on electron microscopy but only 14% of those without deposits; in each group this was usually mild and mesangial. Notably, the presence of deposits on electron microscopy was associated with a higher median level of proteinuria (3.2 versus 1.3 g/24 hours, P < 0.0001) and a higher median percentage of glomeruli with crescents (62.5% versus 44.0%, P= 0.06). CONCLUSION: Immune complex deposits were found on electron microscopy in just over half of renal biopsies with crescentic glomerulonephritis associated with positive ANCA serology and/or necrotizing arteritis. Clinical correlations suggest that these immune complex deposits may somehow potentiate the effect of ANCA in producing glomerulonephritis.     

Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in children

Two cases of anti-neutrophil cytoplasmic antibody (ANCA)-associated necrotizing and crescentic glomerulonephritis are reported. A 12-year-old girl and a 10-year-old boy presented with polyarthritis, anaemia, haematuria, proteinuria, impaired renal function, anorexia, nausea, marked loss of weight and lethargy. The boy also had a vasculitic rash and anterior uveitis. Both children had diffuse cytoplasmic ANCA identified by indirect immunofluorescence and confirmed by specific enzyme-linked immunosorbent assay. Renal biopsies showed severe focal and segmental necrotizing glomerulonephritis with 100% crescents. They were treated with plasma exchange, prednisolone, cyclophosphamide and heparin. Within 1 month of commencing treatment, both had normal serum creatinine concentrations and ANCA was not detectable. Renal biopsies 6 weeks following commencement of treatment revealed quiescent disease, although up to 40% of glomeruli were sclerosed or had fibrous crescents. Following cessation of cyclophosphamide and heparin after 7 months and reduction in steroid dose, a biopsy at 10 months in the boy revealed quiescent disease, but the girl had recurrent disease associated with reappearance of a low titre of ANCA and small cellular crescents in 20% of the glomeruli. These cases reflect the potential usefulnes of ANCA determination for categorizing paediatric patients, helping in the selection of therapy and as a possible marker of disease activity, similar to the experience in adults.     

MPO-ANCA-positive anti-glomerular basement membrane antibody disease successfully treated by plasma exchange and immunosuppressive therapy

Anti-glomerular basement membrane (GBM) antibody disease is clinically manifested as rapidly progressive glomerulonephritis (RPGN) with crescentic changes. The renal prognosis is poor. We report here the case of a 61-year-old woman with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive anti-GBM antibody disease. This patient was referred to our hospital because of RPGN. Anti-GBM antibody was positive with a titer of 38 EU. The MPO-ANCA titer was 65 EU. Chest imaging examination revealed pulmonary multiple nodules. ANCA-associated vasculitis was suspected. Renal pathology revealed cellular crescents in 13 out of 17 glomeruli. Immunofluorescence with anti-IgG antibody, anti-C3 antibody, and anti-fibrin antibody showed linear staining along the glomerular capillary walls. Based on these findings, the patient was diagnosed with anti-GBM antibody disease. Hemodialysis was started because of uremic syndrome with elevated serum creatinine (6.84 mg/dL). In addition, treatment with plasma exchange using 3.6 L (90 mL/kg) of fresh frozen plasma combined with an oral dose of 40 mg of prednisolone was initiated. Within 3 weeks, both types of autoantibodies became undetectable. Subsequently, this patient achieved dialysis independence and remission of glomerulonephritis. No adverse effects were observed. In patients with MPO-ANCA-positive anti-GBM antibody disease, intensive therapy predominantly with plasma exchange might be operative, even though renal function is less likely to recover.     

ANCA-positive crescentic glomerulonephritis associated with minocycline therapy

Minocycline is an oral antibiotic widely used for the long-term treatment of acne and rheumatoid arthritis. A few patients develop antineutrophil cytoplasmic antibodies (ANCAs) during minocycline therapy. In this report, the authors describe a case of severe pauci-immune crescentic and necrotizing glomerulonephritis associated with positive cytoplasmic ANCA (C-ANCA) titers and proteinase 3 (PR3) levels after minocycline therapy. Discontinuation of minocycline and initiation of immunosuppressive treatment resulted in improvement of renal function and decline in C-ANCA titers and PR3 levels. A high degree of suspicion, testing for ANCA titers, prompt discontinuation of the drug, and initiation of immunosuppressive treatment are crucial to the diagnosis and treatment of drug-induced ANCA-associated glomerulonephritis.     

Transformation from tubulointerstitial nephritis to crescentic glomerulonephritis: an unusual presentation of ANCA-associated renal vasculitis

A 44-year-old man with acute renal failure and antineutrophil cytoplasmic antibodies (ANCA) positivity was described. The first renal biopsy specimen showed tubulointerstitial nephritis (TIN) with normal glomeruli. However, delayed recovery of renal function with low-dose steroid treatment for TIN prompted a second renal biopsy 1 month later; and the specimen demonstrated a dramatically different morphology, with necrotizing and crescentic glomerulonephritis. Improvement in renal function occurred, together with reduction of ANCA titers, following intensive immunosuppressive therapy. This case illustrates an unusual presentation of TIN in ANCA-associated renal vasculitis. The possible pathogenetic mechanism are discussed.     

Transformation from Tubulointerstitial Nephritis to Crescentic Glomerulonephritis: An Unusual Presentation of ANCA-Associated Renal Vasculitis

A 44-year-old man with acute renal failure and antineutrophil cytoplasmic antibodies (ANCA) positivity was described. The first renal biopsy specimen showed tubulointerstitial nephritis (TIN) with normal glomeruli. However, delayed recovery of renal function with low-dose steroid treatment for TIN prompted a second renal biopsy 1 month later; and the specimen demonstrated a dramatically different morphology, with necrotizing and crescentic glomerulonephritis. Improvement in renal function occurred, together with reduction of ANCA titers, following intensive immunosuppressive therapy. This case illustrates an unusual presentation of TIN in ANCA-associated renal vasculitis. The possible pathogenetic mechanism are discussed.     

Recurrence of Wegener's granulomatosis 13 years after renal transplantation

Wegener's granulomatosis (WG) can cause renal failure, requiring long-term renal replacement therapy. Renal transplantation in patients with WG is successful, but the risk for recurrence of the disease necessitates continued vigilance. We report a patient that originally presented with acute renal failure secondary to a pauci-immune focal necrotizing crescentic glomerulonephritis. Subsequent nasal involvement and serologic tests for antineutrophil cytoplasmic antibodies suggested a diagnosis of WG. © 2001 by the National Kidney Foundation, Inc.     

Osteopontin expression in human crescentic glomerulonephritis

Osteopontin expression in human crescentic glomerulonephritis. BACKGROUND: Osteopontin is a molecule with diverse biological functions, including cell adhesion, migration, and signaling. The expression of osteopontin has been demonstrated in a number of models of renal injury in association with accumulations of monocyte/macrophages, including recent reports of osteopontin expression in glomerular crescents in a rat model of anti-glomerular basement membrane glomerulonephritis. METHODS: Glomerular expression of osteopontin in biopsies of human crescentic glomerulonephritis (N = 25), IgA nephropathy with crescents (N = 2), and diffuse proliferative lupus glomerulonephropathy with crescents (N = 1) was studied by immunohistochemistry, in situ hybridization, and combined immunohistochemistry/in situ hybridization. Additionally, antibodies to cell-specific phenotypic markers were used to identify cellular components of the glomerular crescent, which express osteopontin protein and mRNA. RESULTS: All of the crescents present in the biopsies studied contained a significant number of cells that expressed osteopontin protein and mRNA, demonstrated by immunohistochemistry and in situ hybridization, respectively. Using replicate tissue sections and combined immunohistochemistry/in situ hybridization, we showed that the majority of the strongly osteopontin-positive cells are monocyte/macrophages. In addition to the very strong and cell-associated localization, a weaker and more diffuse pattern of osteopontin protein and mRNA expression could be seen in a number of crescents. None of the osteopontin mRNA-expressing cells could be identified as parietal epithelial cells, CD3-positive T cells, or alpha-smooth muscle actin-positive myofibroblasts. Interstitial monocyte/macrophages did not express osteopontin, except when located in a periglomerular inflammatory infiltrate. CONCLUSIONS: Macrophages present in the human glomerular crescent express osteopontin protein and mRNA at a high level. This expression supports a role for osteopontin in the formation and progression of the crescentic lesion via chemotactic and signaling properties of the molecule.     

Sjögren's syndrome with ANCA-associated crescentic extramembranous glomerulonephritis

A 49-year-old woman with a 1-year history of Sjögren's syndrome was diagnosed with cutaneous leukocytoclastic vasculitis and necrotizing crescentic membranous glomerulonephritis. Antineutrophil cytoplasmic antibodies targeting myeloperoxidase were found. She reported a transient episode of nephritis 4 years earlier. This pattern of kidney disease is not typical of Sjögren's syndrome. Methylprednisolone boluses followed by oral glucocorticoid therapy were given in combination with mycophenolate mofetil. Renal function stabilized after 2 months, and tests for anti-myeloperoxidase reverted to negative.     

Antineutrophil cytoplasmic autoantibody-associated glomerulonephritis in children.

Aretrospective investigation was conducted by members of the Japanese Society for Pediatric Nephrology from 1990 to 1997 to define the clinical features and outcome of antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis in children. Thirty-four ANCA-seropositive Japanese pediatric patients with biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis were identified. Of these, 3 cases associated with Wegener's granulomatosis were excluded because of the small sample size. Among the 31 patients studied, 10 had a diagnosis of necrotizing crescentic glomerulonephritis alone and 21 had microscopic polyangiitis. Females predominated (87%), and the median age at onset was 12 yr. Twenty-six patients received treatment with cyclophosphamide and corticosteroids, and five patients received treatment with corticosteroids alone; 84% of patients achieved remission, and 39% of responders relapsed in a median of 24 mo. ANCA titers correlated with response to treatment and disease activity, with some exceptions. Patients were followed for a median of 42 mo (range, 3 to 96 mo). Nine of 31 patients (29.0%) progressed to end-stage renal disease, 6 (19.4%) had reduced renal function, and 15 (48.4%) had normal renal function at the last observation. One patient (3.2%) died from cytomegalovirus infection 3 mo after initiation of therapy. Life-table analysis showed 75% renal survival at 39 mo. Patients who subsequently developed end-stage renal disease (n = 9) had significantly higher average peak serum creatinine levels and more chronic pathologic lesions at diagnosis compared with patients with favorable renal outcome (n = 15). In conclusion, our clinical experience suggests that the clinical disease spectrum of ANCA-associated glomerulonephritis is similar in pediatric and adult patients, but there is a female predominance in children.