Classic and perinuclear anti-neutrophil cytoplasm antibodies and antimyeloperoxidase antibodies in rapidly progressive glomerulonephritis.

Classic anti-neutrophil cytoplasm antibodies (cANCA), perinuclear ANCA (pANCA) and antibodies directed against myeloperoxidase (MPO-Ab) were evaluated in 25 patients with either idiopathic or secondary rapidly progressive glomerulonephritis (RPGN). While cANCA were found almost exclusively in Wegener's granulomatosis, pANCA were detectable in several disorders, including microscopic polyarteritis (mPA), but also idiopathic RPGN. MPO-Ab were frequently found in sera from patients with all types of idiopathic but not of secondary RPGN. These results support the hypothesis that some cases of RPGN are early or limited forms of systematic vasculitis. We then looked for the presence of IgA-ANCA in Henoch-Schoenlein purpura (HSP): we found IgA-ANCA with immunoenzymatic assay but not with immunofluorescence in HSP, in primary IgA-GN and in membranous GN as well, thus suggesting the poor specificity of this type of ANCA. The possible pathologic implications of ANCA were examined in vitro. Serum samples from several patients with ANCA were assessed for their capacity to enhance chemiluminescence generation from resting or PMA-stimulated macrophages. Sera from RPGN and mPA patients displaying anti-MPO activity induced granulocytes to enhance the production of oxygen free radicals, thus suggesting a phlogistic effect of MPO-Ab positive sera.     

Plasmapheresis with immunosuppressive therapy vs immunosuppressive therapy alone for rapidly progressive anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis.

Sir, Rapidly progressive deterioration of kidney function is a commonand usually serious feature of anti-neutrophil cytoplasmic autoantibody(ANCA)-associated glomerulonephritis; it can lead to end-stagerenal failure (ESRF) within weeks. Rapidly progressive glomerulonephritis(RPGN) is a syndrome characterized by a sudden and relentlessdecline in renal function associated with extensive crescentformation involving most glomeruli [1]. The European VasculitisStudy Group reported recently that the glomerular filtrationrate and predominantly chronic renal lesions are potent predictorsof patient outcome in ANCA-associated RPGN [2]. Intensive immunosuppressivetherapy improves the outcome of patients with RPGN; RPGN progressesto ESRF in 90% of patients who do not undergo therapy [3].     

Thrombotic thrombocytopenic purpura in a patient with rapidly progressive glomerulonephritis with both anti-glomerular basement membrane antibodies and myeloperoxidase anti-neutrophil cytoplasmic antibodies

A 61-year-old Japanese woman with rapidly progressive glomerulonephritis exhibited both anti-glomerular basement membrane (GBM) antibodies (920 EU) and myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA; 66 EU). Multiple plasma exchanges with fresh frozen plasma preceded by 500 mg/day intravenous methylprednisolone and 30 mg/day oral prednisolone decreased anti-GBM antibody and MPO-ANCA antibody titers to 106 EU and below 10 EU (normal ranges), respectively. Thrombotic thrombocytopenic purpura (TTP) manifests itself as a moderate decrease in the activity of disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 13 (ADAMTS13) protein levels to 35% of normal; ADAMTS13 deficiency is only symptomatic when levels are less than 50%. This patient’s disease was resistant to extensive plasma exchange, leading to her death from respiratory distress and perforation of the alimentary tract secondary to cytomegalovirus infection. Autopsy demonstrated severe crescentic glomerulonephritis associated with linear IgG, IgA, IgM, and C3 deposits along the glomerular capillary walls. This case is an uncommon example of combined double antibody-positive crescentic glomerulonephritis and refractory TTP.     

Detection and clinical implication of anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis and rapidly progressive glomerulonephritis

The specificity of anti-neutrophil cytoplasm antibodies (ACPA/ANCA) was investigated in patients suffering from Wegener's granulomatosis (WG), various forms of systemic diseases including vasculitides (non-WG), and different types of biopsy-proven glomerulonephritides. In particular, the diagnostic significance of ACPA/ANCA was assessed in patients affected by rapidly progressive glomerulonephritis with and without systemic manifestations. From 25 patients with active Wegener's granulomatosis 22 showed the classical diffuse finely granular cytoplasmic staining of neutrophils as did 4/31 patients with idiopathic rapidly progressive glomerulonephritis. One patient with biopsy confirmed Wegener's granulomatosis, six patients with microscopic polyarteritis and 3/31 patients with idiopathic rapidly progressive glomerulonephritis showed a focal cytoplasmic staining exhibiting a rosette-like pattern. One further patient with Wegener's granulomatosis displayed a prominent fluorescence of the outer nuclear membrane as well as a punctate-diffuse nuclear staining resembling that of granulocyte specific antibodies. Another patient with active Wegener's granulomatosis did not react in the ACPA/ANCA-test. These findings demonstrate different staining patterns of neutrophils which are related to different clinical entities within the spectrum of small vessel vasculitis. Moreover, they point out that different antigens are involved in the various types of vasculitis. In classical cases of Wegener's granulomatosis, but not in other forms of vasculitis, the titer of ACPA/ANCA showed a close relationship to the number of organs involved.     

Study of five patients with myeloperoxidase anti-neutrophil cytoplasmic antibody-positive rapidly progressive glomerulonephritis during the course of interstitial pneumonitis

Five patients with rapidly progressive glomerulonephritis (RPGN) that developed during the management of interstitial pneumonitis at our hospital in the past 5 years were studied. In these patients, chronic interstitial pneumonitis preceded the onset of nephritis by periods of 0 to 11 years. All patients had a high titer of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) when RPGN was diagnosed. One patient had anti-proteinase-3 antibodies and another had anti-glomerular basement membrane antibodies. Renal biopsy was performed in all patients. All patients showed necrotizing and crescentic glomerulonephritis, without the deposition of immunoglobulins, and were diagnosed as having pauci immune RPGN. The relationship between MPO-ANCA-related RPGN and chronic interstitial pneumonitis remains unclear. Our present findings indicate that interstitial pneumonitis is important as a preceding condition in some patients with MPO-ANCA-related RPGN. Four patients were older than 70 years. Therefore, particular attention should be paid to the possibility of MPO-ANCA-related RPGN in elderly patients with chronic interstitial pneumonitis. Received: November 9, 2000 / Accepted: November 17, 2001     

Mast cells in rapidly progressive glomerulonephritis.

The role of mast cells (MC) in tubulointerstitial damage in glomerulonephritis (GN) is not fully understood. The distribution of MC was compared in renal biopsies from 50 patients with different stages of rapidly progressive GN (RPGN) and in 20 control samples. The immunoreactivity of renal MC with anti-tryptase and anti-chymase antibodies was studied. Interstitial myofibroblasts were stained with anti-alpha-smooth muscle actin (alpha-SMA) antibody, and inflammatory cells were identified by anti-CD3, -CD20, and -CD68 monoclonal antibodies. Positively stained cells were counted, and the relative interstitial and fractional areas of anti-alpha-SMA-stained cells were measured. MC were rarely found in control samples. In contrast, samples showing crescentic GN contained numerous tryptase-positive MC (MC(T)) (43.7+/-4.65 versus 7.14+/-1.3/mm2) and fewer tryptase- and chymase-positive MC (MC(TC)) (13.8+/-1.86 versus 1.89+/-0.86/mm2) in the renal interstitium but never in the glomerulus. Double immunostaining demonstrated the presence of both phenotypes of MC. Accumulation of MC was significantly correlated with the numbers of T lymphocytes (MC(T), r = 0.67) and interstitial macrophages (MC(T), r = 0.455). There was also a significant correlation between the number of MC(T) and the relative interstitial area. The number of MC(TC) was well correlated with the fractional area of alpha-SMA-positive interstitium (r = 0.749) and the percentage of the interstitial fibrotic area (r = 0.598). There was also a significant negative correlation between interstitial MC(TC) accumulation and creatinine clearance (r = 0.661). The density of MC(TC) was higher (1.4-fold) in advanced forms of GN associated with fibrocellular crescents and interstitial fibrosis. These results show the potential involvement of MC in the fibroproliferative process in the renal interstitium of patients with RPGN. The results indicate that these cells constitute part of the overall inflammatory cell accumulation in RPGN.     

Clinicopathological study of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

AIMS: To investigate the potential prognostic factors for myeloperoxidase anti-neutrophil cytoplasmic antibody- (MPO-ANCA) associated glomerulonephritis. MATERIALS: The clinical and pathological findings were reviewed in 17 patients with this type of glomerulonephritis. METHODS: The relationship between the outcome and various clinical and pathological factors were assessed. The relationship between the blood MPO-ANCA level and cellular crescent formation was also investigated. RESULTS: Patients who died had a significantly lower serum albumin and creatinine clearance than those who survived, but there were no differences of age, blood MPO-ANCA, urinary protein, and serum creatinine levels or cellular crescent formation between the two groups. There was a close relationship between blood MPO-ANCA levels and cellular crescent formation. CONCLUSIONS: Hypoalbuminemia and renal dysfunction may be indicators of a poor prognosis in MPO-ANCA-associated glomerulonephritis. Patients with high blood levels of this antibody and increased cellular crescent formation appear to have active disease, but these factors are not statistically associated with a fatal outcome. Therefore, aggressive treatment may be indicated in patients with active disease initially.     

Antineutrophil cytoplasmic antibody-positive rapidly progressive glomerulonephritis caused by propylthiouracil: A case report

Propylthiouracil, which is used as an antithyroid drug, is associated with many side effects. Vasculitis is a rare complication of this drug. Recently, antineutrophil cytoplasmic antibodies (ANCA) have been described in association with vasculitic disorders, including rapidly progressive glomerulo-nephritis. We report a case of ANCA-positive rapidly progressive glomerulonephritis caused by propylthiouracil administration. Although renal function was improved by discontinuation of the drug and initiation of steroid therapy, assay results for ANCA to myeloperoxidase remained positive throughout the clinical period.     

Cellular composition of crescents in human rapidly progressive glomerulonephritis identified using monoclonal antibodies

The relative contributions of glomerular epithelial cells, macrophages, and other cell types to the formation of cellular crescents characteristic of human rapidly progressive glomerulonephritis remain controversial. To identify and quantitate the cell types present during different stages of glomerular crescent formation, immunoperoxidase labelling of cryostat sections from renal biopsies with cellular (n = 9) or sclerosed (n = 3) crescents was performed using monoclonal antibodies to cell-specific antigens of leucocytes, epithelial cells, and other glomerular cell types. Fresh cellular crescents consisted of macrophages (34.5 +/- 7.0%; mean +/- SEM) plus lesser proportions of polymorphs (12.8 +/- 4.7%) and epithelial cells (10.4 +/- 1.5%). Sclerosed crescents contained fewer macrophages (5.1 +/- 1.0%), but similar proportions of polymorphs (11.1 +/- 2.9%) and epithelial cells (11.5 +/- 2.1%). Lymphocytes were not detected within crescents. Many of the remaining unlabelled cells morphologically resembled fibroblasts and expressed surface fibronectin, though fibroblast-specific cell markers were not available. These results show that macrophages and not epithelial cells constitute the major cell type within cellular crescents. Therapeutic manoeuvres directed against macrophages may, therefore, be of clinical value in the management of human crescentic rapidly progressive glomerulonephritis.     

D-penicillamine therapy associated with rapidly progressive glomerulonephritis.

A 55-year-old woman with advanced rheumatoid arthritis developed rapidly progressive glomerulonephritis with epithelial crescents and pulmonary hemorrhage following treatment with D-penicillamine. D-penicillamine was then withdrawn and a pulse therapy with methylprednisolone halted the progression of kidney and lung damage. We review the other cases previously reported and discuss pathogenesis and treatment of this rare condition.     

Silica exposure in anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and lupus nephritis

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitis (SVV) and systemic lupus erythematosus (SLE) are rare diseases with unknown causes. Silica dust exposure has been suggested to be an environmental factor that may increase the risk of developing these and other autoimmune disorders. This is a report of two case-control studies to determine whether silica dust exposure is independently associated with ANCA-SVV with glomerulonephritis and SLE nephritis. Patients were screened through a collaborative network of 225 private practice and university nephrologists (the Glomerular Disease Collaborative Network). Patients with ANCA-SVV or SLE, all with biopsy-proven renal involvement, were included. Control subjects were patients without ANCA-SVV or SLE who had been referred to the same renal clinics and were matched for gender, race, and age (within 5 yr). Exposures to silica, exposures to other environmental agents, and smoking histories were evaluated using a self-administered questionnaire. Enrollment consisted of 65 patients with ANCA-SVV and 51 patients with SLE nephritis. Silica dust exposure was reported by 46% of patients with ANCA-SVV, compared with 20% of control subjects (P = 0.001). The odds ratio of silica dust exposure was 4.4 times greater for patients with ANCA-SVV, compared with control subjects (95% confidence interval, 1.36 to 13.4; P = 0.013). The odds ratios for silica dust exposure were similar for patients with ANCA-SVV with lung or sinus vasculitis (odds ratio, 4.5; 95% confidence interval, 0.99 to 20.83; P = 0.054) and those without lung or sinus vasculitis (odds ratio, 4.7; 95% confidence interval, 1.34 to 16.24; P = 0.016). Silica dust exposure was reported by 12% of patients with SLE nephritis, compared with 25% of control subjects (P = 0.047). The odds ratio for exposure to silica dust was not statistically different for patients with SLE nephritis, compared with control subjects (odds ratio, 0.001; 95% confidence interval, <0.01 to >100; P = 0.993). Activities and environments known to cause high levels of exposure to silica dust were associated with ANCA-SVV but not with SLE nephritis.     

Methylprednisolone therapy for acute crescentic rapidly progressive glomerulonephritis

In the last 10 years we have evaluated 63 patients with acute crescentic rapidly progressive glomerulonephritis (AC-RPGN), 46 of whom received pulse methylprednisolone (PM). The groups consisted of patients with no immune deposits, immune complexes, vasculitis, and antiglomerular basement membrane (anti-GBM) disease. Seventy-nine percent of non-anti-GBM patients improved versus 25% of unpulsed, p less than 0.005; 70% stopped dialysis (D) versus none of unpulsed, p less than 0.009; creatinine decreased from 8.6 before to 2.7 mg/dl after PM, p less than 0.05. Percent crescents and oligoanuria did not influence PM results, but did with conventional therapy (prednisone, cytotoxics, anticoagulants, supportive treatment). Seventeen percent of anti-GBM patients improved, none stopped D. In anti-GBM patients, serum creatinine less than 6 mg/dl was associated with a favorable response to PM, p = 0.045. Twenty-one percent of responding patients lost function at 19.8 months. The long-term response for non-anti-GBM patients was 62%. Patients with low chronicity on biopsy had shorter duration of disease (p = 0.006) and 92% initial, 85% long-term improvement; those with high chronicity had an immediate 71%, and 36% long-term response rate, p less than 0.02. Thus, PM is effective and appears superior to conventional therapy in treatment of non-anti-GBM AC-RPGN.     

Association of idiopathic retroperitoneal fibrosis, rapidly progressive glomerulonephritis and antiproteinase 3 antineutrophil cytoplasmic antibodies (anti PR3-ANCA)

We report a case of idiopathic retroperitoneal fibrosis and rapidly progressive glomerulonephritis with serum antiproteinase 3 antineutrophil cytoplasmic antibodies (anti-PR3-ANCA), without clinical or histological signs of Wegener's granulomatosis, in a 46-year-old man. Our case and previously reported cases showing the same association support the hypothesis that the association is not fortuitous, but reflects a common immunological mechanism.