Pauci-immune Glomerulonephritis Research Articles

The expanding spectrum of renal diseases associated with antiphospholipid syndrome

Background:The association of thrombotic events and/or pregnancy complications with circulating antiphospholipid antibodies defines antiphospholipid syndrome (APS). In previous reports, renal involvement in APS consisted mainly of thrombotic vascular complications involving large vessels or intrarenal small-sized vessels (APS nephropathy). We report 9 cases of glomerulonephritis associated with APS. These cases are characterized by predominant pathological features distinct from vascular APS nephropathy. Methods:We reviewed consecutive renal biopsies examined in 2 French university hospitals between 1980 and 2002 and identified renal biopsies performed in patients with primary APS. Results:We identified 29 biopsies performed in patients with APS. Twenty biopsies showed characteristic features of APS nephropathy. In 9 cases, predominant pathological features distinct from vascular APS nephropathy were noted: membranous nephropathy (3 cases), minimal change disease/focal segmental glomerulosclerosis (3 cases), mesangial C3 nephropathy (2 cases), and pauci-immune crescentic glomerulonephritis (1 case). In 7 cases, the presentation of renal symptoms was subacute or chronic. Two patients experienced episodes of acute renal failure. At referral, median creatinine clearance was 50 mL/min (0.83 mL/s) (range, 18 to 117 mL/min [0.30 to 1.95 mL/s]). Proteinuria was noted in all cases (range, 1.5 to 15 g/d), with nephrotic syndrome in 4 cases. Lupus anticoagulant was present in all cases, and anticardiolipin antibodies, in 8 cases. Anti-DNA antibodies repeatedly were negative in all cases. Treatment consisted of antihypertensive therapy (6 cases), anticoagulant drugs (5 cases), steroids (4 cases), and antiplatelet drugs (3 cases). At last follow-up, renal function remained stable in 7 patients. Of 2 patients presenting with acute renal failure, 1 patient recovered normal renal function, whereas the other patient progressed to end-stage renal failure. Conclusion:The cases reported here represent a new aspect of the expanding spectrum of renal diseases encountered in association with APS.

New insights into the immunopathogenesis and treatment of small vessel vasculitis of the kidney.

Glomerulonephritis is an important manifestation of small vessel vasculitides such as Wegener granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Renal involvement in these diseases is characterized by a pauci-immune segmental necrotizing and crescentic glomerulonephritis that is strongly associated with circulating antineutrophil cytoplasmic autoantibodies. We will review recent advances in understanding the pathogenesis of antineutrophil cytoplasmic autoantibody-related renal vasculitides and innovative approaches to their treatment. An experimental milestone in antineutrophil cytoplasmic autoantibody research has been reached in the past year. Using an innovative mouse model, investigators from the University of North Carolina in Chapel Hill have recently acquired robust data supporting the pathogenic role of antineutrophil cytoplasmic autoantibodies in the glomerulonephritis and small vessel vasculitis, analogous to those seen in microscopic polyangiitis and Wegener granulomatosis. Novel immunosuppressive approaches have been examined including preliminary studies using biologic agents, such as antagonists of tumor necrosis factor and monoclonal antibodies to B lymphocytes. Recent insights into the pathogenesis of antineutrophil cytoplasmic autoantibody-related vascular injury and the availability of new biologic, immune response modifiers to complement standard chemical immunosuppressive agents offer exciting new prospects for investigation in the management of patients with small vessel renal vasculitides.

Indications of plasma exchanges for systemic vasculitides.

Indications of plasma exchanges for systemic vasculitides are well delineated according to the results of therapeutic trials undergone during the past decades. In combination with antiviral agents and/or immunosuppressants plasma exchanges appear to be essential in the treatment of HBV-related polyarteritis nodosa: pauci-immune glomerulonephritis, kidney-limited or as a feature of Wegener's granulomatosis or microscopic polyangiitis; Goodpasture's syndrome, and for some complications of cryoglobulinemia. In patients with HIV and HBV-associated vasculitides, for which immunosuppressants are deleterious, plasma exchanges are also helpful and have been shown to be effective, combined with an antiretroviral regimen. In polyarteritis nodosa without HBV infection, Wegener's granulomatosis, Churg-Strauss syndrome and in other systemic diseases vasculitides, plasma exchanges can help to control or attenuate the disease. We review herein these indications of plasma exchanges in the light of the results of major trials.

Histologic and immunohistologic study and clinical presentation of ANCA-associated glomerulonephritis with correlation to ANCA antigen specificity

Background: The major antigen specificities of antineutrophil cytoplasmic antibodies (ANCA) are for proteinase 3 (PR3) and myeloperoxidase (MPO). Only a limited number of studies have systematically assessed renal pathology with respect to ANCA antigen specificity. Methods: The authors evaluated renal biopsy light microscopy and immunofluorescence findings, clinical presentation, and outcome in 135 patients with ANCA-associated vasculitides. Results: Patients were divided into 3 groups: PR3-ANCA (n = 55), MPO-ANCA (n = 74), and ANCA of other specificities (n = 6). The mean duration of renal disease at biopsy was significantly longer in patients with MPO-ANCA than in those with PR3-ANCA (6.9 v 3.0 months). Immunofluorescence results showed mostly pauci-immune glomerulonephritis (n = 129) and rarely diffuse granular glomerular immune deposits suggesting immune complex deposition (n = 6). A focal form of crescentic glomerulonephritis was more frequent (P < 0.001), and glomerular necrosis was more prominent (P = 0.013) in the PR3-ANCA group, whereas diffuse crescentic glomerulonephritis, glomerulosclerosis, and interstitial fibrosis predominated in the MPO-ANCA group (P < 0.001). Extraglomerular vasculitis, present in 22.2%, and chronic vascular lesions indicative of previous vasculitis, present in 11.9% of patients, correlated with systemic involvement. Conclusion: The evolution of the pathologic lesions of PR3-ANCA and MPO-ANCA-associated glomerulonephritis seems to be similar. Differences in histopathology could be explained by the observation that in patients with PR3-ANCA, kidney biopsy was performed soon after renal involvement appeared, and focal active lesions were prevalent, whereas in patients with MPO-ANCA, kidney biopsy was done late in the course of the disease, and diffuse chronic sclerotic lesions predominated. Renal extraglomerular small vessel vasculitis appeared to be predictive of systemic involvement. Am J Kidney Dis 41:539-549. © 2003 by the National Kidney Foundation, Inc.

A man with backache and renal failure

Backache, a common symptom, is rarely caused by infection of the lumbar discs. The authors present the case of a 60-year-old man with a Staphylococcus aureus septicemia and associated lumbar discitis in whom a pauci immune crescentic glomerulonephritis and renal failure developed. Treatment with antibiotics and not immunosuppressive agents resulted in improved renal function with a discharge creatinine level of 1.87 mg/dL (165 μmol/L). This case highlights an association of pauci-immune crescentic glomerulonephritis with discitis that responded to antibiotic therapy alone. Am J Kidney Dis 41:E1. © 2003 by the National Kidney Foundation, Inc.

Glomerular diseases in the elderly in India.

Three hundred fifteen (315) elderly (> or = 60 years) patients with clinical renal diseases were evaluated for the evidence of glomerular diseases between November 1998 to June 2002. Glomerular diseases (GN) were observed in 20.6% (65/315) of the elderly patients. The age of the patients (male 56; female 9) ranged between 60-90 (mean 64.17 +/- 3.83) years. The clinical presentation of GN included: nephrotic syndrome 40 (61.5%), acute nephritic syndrome 19 (29.2%), rapidly progressive GN 4 (6.15%) and asymptomatic urinary abnormality 2 (3.0%). Overall, primary and secondary glomerular disease were seen in 47 (72.3%) and 18 (27.6%) elderly patients respectively. Idiopathic membranous nephropathy was the most common GN responsible for nephrotic syndrome in 11 (27.5%) of elderly patients. Diabetic Nephropathy related to type 2 diabetes mellitus was the second common cause 9 (22.5%) of nephrotic syndrome. Amyloidosis was noted in 6 (15%) patients. Nephrotic syndrome was related to leprosy in one patient. Amyloidosis occurred in association with multiple myeloma in 5 and carcinoma colon in 1 patient. Thus, primary and secondary GN were responsible for nephrotic syndrome in 60% and 40% of cases respectively. Endocapillary proliferative GN of post infectious etiology was the most prevalent (82.6%) form of acute GN in our elderly patients. Hypertension occurred in 78.2% of cases and edema in 69.5%. Pulmonary congestion (52.2%) and ARF (73.9%) were the dominant presenting feature of acute GN and 39% of patients required dialytic support. Glomerular crescents were seen in 4 (17.4%) patients with acute glomerulonephritis. Pauci-immune crescentic GN which is the commonest type of acute GN in the elderly in western countries was not observed in this study. Renal biopsy revealed mesangiocapillary GN (1) and mesangioproliferative GN (1) in two patients with asymptomatic urinary abnormalities. Thus, overall spectrum of glomerular disease in the Indian elderly population is similar to that of developed countries except in two ways: (1) post infectious endocapillary proliferative-GN was the commonest type of acute GN (2) rarity or absence of pauci-immune crescentic glomerulonephritis.

Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.

Antineutrophil cytoplasmic autoantibodies (ANCAs) are identified in the circulation of approximately 80% of patients with pauci-immune necrotizing and crescentic glomerulonephritis and systemic small vessel vasculitis, such as microscopic polyangiitis and Wegener granulomatosis. The most common antigen target for ANCAs is myeloperoxidase (MPO), which is found in neutrophils and monocytes. We report definitive experimental animal evidence that ANCAs are pathogenic. MPO knockout (Mpo(-/-)) mice were immunized with mouse MPO. Splenocytes from these mice or from control mice were injected intravenously into recombinase-activating gene-2-deficient (Rag2(-/-)) mice, which lack functioning B lymphocytes and T lymphocytes. All mice that received splenocytes developed mild to moderate glomerular immune deposits, but only mice that received 1 x 10(8) or 5 x 10(7) anti-MPO splenocytes developed severe necrotizing and crescentic glomerulonephritis, granulomatous inflammation, and systemic necrotizing vasculitis, including necrotizing arteritis and hemorrhagic pulmonary capillaritis. To test the pathogenic potential of antibodies alone, purified anti-MPO IgG or control IgG was injected intravenously into Rag2(-/-) mice and wild-type mice. Mice that received anti-MPO IgG but not mice that received control IgG developed focal necrotizing and crescentic glomerulonephritis with a paucity of glomerular Ig deposition. Thus, anti-MPO IgG alone was able to cause pauci-immune glomerular necrosis and crescent formation in the absence of functional T or B lymphocytes in Rag2(-/-) mice and in the presence of an intact immune system in wild-type C57BL/6J mice. This animal model offers strong support for a direct pathogenic role for ANCA IgG in human glomerulonephritis and vasculitis.

Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice

Antineutrophil cytoplasmic autoantibodies (ANCAs) are identified in the circulation of approximately 80% of patients with pauci-immune necrotizing and crescentic glomerulonephritis and systemic small vessel vasculitis, such as microscopic polyangiitis and Wegener granulomatosis. The most common antigen target for ANCAs is myeloperoxidase (MPO), which is found in neutrophils and monocytes. We report definitive experimental animal evidence that ANCAs are pathogenic. MPO knockout (Mpo–/–) mice were immunized with mouse MPO. Splenocytes from these mice or from control mice were injected intravenously into recombinase-activating gene-2–deficient (Rag2–/–) mice, which lack functioning B lymphocytes and T lymphocytes. All mice that received splenocytes developed mild to moderate glomerular immune deposits, but only mice that received 1 × 108 or 5 × 107 anti-MPO splenocytes developed severe necrotizing and crescentic glomerulonephritis, granulomatous inflammation, and systemic necrotizing vasculitis, including necrotizing arteritis and hemorrhagic pulmonary capillaritis. To test the pathogenic potential of antibodies alone, purified anti-MPO IgG or control IgG was injected intravenously into Rag2–/– mice and wild-type mice. Mice that received anti-MPO IgG but not mice that received control IgG developed focal necrotizing and crescentic glomerulonephritis with a paucity of glomerular Ig deposition. Thus, anti-MPO IgG alone was able to cause pauci-immune glomerular necrosis and crescent formation in the absence of functional T or B lymphocytes in Rag2–/– mice and in the presence of an intact immune system in wild-type C57BL/6J mice. This animal model offers strong support for a direct pathogenic role for ANCA IgG in human glomerulonephritis and vasculitis.

Une vascularite associant une atteinte rénale et pulmonaire au cours d’une maladie de Basedow traitée par le benzylthiouracile

Introduction. – Vasculitis is a rare complication of antithyroid drugs reported with propylthiouracil, carbimazol, methimazol and we discribe the first case with benzylthyouracil. Renal involvement during thyroid auto-immune diseases and during vasculitis as complication of antithyroid drugs will be discussed. Exegesis. – We present a case study of 28-year-old female patient with Graves' disease diagnosed in 1996 and treated by benzylthiouracil for 2 years. The thyroid function was poorly controlled, so surgical treatment was indicated in May 1998. One month later, she developed vasculitis with pulmonary and renal involvement. Her renal function deteriorated rapidly. On admission, the additional laboratory findings showed hematuria, proteinuria of 1,44 g/day and serum creatinine level at 1000 μmol/l. She had myeloperoxidase-anti neutrophil cytoplasmic antibody, antithyroglobuline and antimicrosome antibodies. A renal biopsy revealed pauci-immune crescentic glomerulonephritis with 75% sclerous crescents. Chest-X-ray showed unilateral alveolar shadowing and a bronchio-alveolar lavage revealed lymphocytic alveolitis. She was treated with high dose of prednisolone and cyclophosphamide. After a follow-up of 18 months, the serum creatinine level decreased at 186 μmol/l and chest-X-ray returned to normal. Conclusion. – some cases of vasculatis associated with anti-thyroid drug treatment are reported

Using antineutrophil cytoplasmic antibody testing to diagnose vasculitis: can test-ordering guidelines improve diagnostic accuracy?

Antineutrophil cytoplasmic antibodies (ANCAs) are strongly associated with Wegener granulomatosis, Churg-Strauss angiitis, microscopic polyangiitis, and pauci-immune glomerulonephritis, referred to collectively as ANCA-associated vasculitis (AAVs). It is unclear how accurate ANCA measurement is for diagnosing AAV in diverse populations or whether proposed ANCA test-ordering guidelines improve test performance. We assembled a retrospective case series of hospitalized and ambulatory patients from 2 academic medical centers to assess the diagnostic accuracy of ANCA measurement by enzyme-linked immunosorbent assay in identifying cases of AAV. In addition, we assessed the effect of applying proposed ANCA test-ordering guidelines on test performance. For ANCA testing, sensitivity was 81%; specificity, 98%; positive predictive value, 54%; and negative predictive value, 99%. There were no significant changes in operating characteristics after applying the guideline criteria. Using guidelines would have decreased ANCA test ordering by 23% and would have decreased the false-positive rate by 27%. No cases of AAV would have been missed if only patients fulfilling the guidelines were ANCA tested. A positive result on an enzyme-linked immunosorbent assay ANCA test, as it is currently ordered, is not a definitive diagnostic indicator of AAV. Compliance with guidelines for ANCA testing would decrease the number of false-positive results and has the potential to reduce total test expenditures.

A REPEAT BIOPSY STUDY IN SPONTANEOUS CRESCENTIC GLOMERULONEPHRITIS MICE

Background: Spontaneous crescentic glomerulonephritis (SCG)/Kj mice are a candidate for suitable animal model of human pauci-immune crescentic glomerulonephritis (GN). In the present study, we used renal biopsy technique and analyzed time sequence correlations among crescent formation and glomerular neutrophil infiltration in SCG/Kj mice. Methods: We observed the progress of GN in SCG/Kj mice according to the urinary abnormalities, and performed the serial renal biopsies. The kinetics of histopathology and glomerular neutrophil influx corresponding disease stage were examined by enzyme-histochemistry and immunohistochemistry. Results: We divided natural course of GN into three periods in view of urinalysis: a proteinuria-negative/hematuria-negative (P− H−) period, followed by a proteinuria-positive/hematuria-negative (P+ H−) period, and finally a proteinuria-positive/hematuria-positive (P+ H+) period. Endocapillary proliferation phase existed in P+ H− period, whereas crescent formation occurred and extended in P+ H+ period. In P+ H− period, prominent glomerular neutrophil infiltration was observed, while these numbers decreased with the progression of crescent formation. Conclusion: These observations suggest that there is a good correlation between urinalysis and histopathological events of SCG/Kj mice, and that endocapillary proliferation, which contains neutrophil infiltration, may contribute to the subsequent crescent formation in these mice.

Monitoring of serum hepatitis C virus RNA level during steroid therapy for hepatitis C virus-positive antineutrophil cytoplasmic antibody-related glomerulonephritis: report of two cases

We report on two adult patients with hepatitis C virus-positive antineutrophil cytoplasmic antibody-related glomerulonephritis. These patients had a renal-limited form of crescentic glomerulonephritis with high levels of serum hepatitis C virus RNA. We investigated the efficiency and transition of the serum levels of creatinine, hepatitis C virus RNA, and hepatic enzymes during corticosteroid therapy in the two patients. Corticosteroid therapy consisted of intravenous high-dose methylprednisolone for 3 days, followed by oral prednisolone without cyclophosphamide. During this course of treatment, renal function in both patients recovered remarkably. A marked increase in the level of hepatitis C virus RNA, however, was observed with or without an increase in serum levels of hepatic enzymes. It seems that steroid therapy for patients who have antineutrophil cytoplasmic antibody-related pauci-immune crescentic glomerulonephritis and high levels of hepatitis C virus RNA is efficient and relatively safe, although serum levels of hepatitis C virus RNA and liver function need to be carefully monitored.

ANCA-associated renal vasculitis

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

Native and recombinant proteins to analyze auto-antibodies to myeloperoxidase in pauci-immune crescentic glomerulonephritis

The prevalence of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) directed against myeloperoxidase (MPO) in pauci-immune necrotizing crescentic glomerulonephritis (NCGN) is dependent on the assay(s) used. We investigated the frequency of MPO–ANCA as detected by different assays for MPO–ANCA in a large cohort of patients with biopsy-proven pauci-immune NCGN. Sera from 121 consecutive untreated patients presenting with pauci-immune NCGN were tested for ANCA directed to proteinase-3 (PR3) at diagnosis. PR3–ANCA negative sera were tested by direct ELISA using recombinant or native MPO and by capture ELISA using two different specific monoclonal antibodies directed to MPO and three different antigenic sources. Sera from 80 relevant disease controls were tested to explore the specificity of the different assays. Thirty-eight out of 121 patients (31%) with pauci-immune NCGN did not have PR3–ANCA. Sufficient amounts of serum from 30 of these 38 PR3–ANCA negative patients were available for further testing. Recombinant and native MPO were recognized by similar numbers of sera in a direct ELISA (recombinant MPO: 93%, native MPO: 93%) and a capture ELISA (recombinant MPO: 77–87%, native MPO: 93%). Sera of patients with PR3–ANCA positive pauci-immune NCGN and disease controls were less frequently positive for MPO–ANCA in a capture ELISA (recombinant MPO: 3–7%, native MPO: 6–7%) than in a direct ELISA (recombinant MPO: 25%, native MPO: 13%). Both direct and capture ELISA assays using either native or recombinant MPO are sensitive techniques to detect MPO–ANCA in patients with pauci-immune NCGN. A capture ELISA performs better than a direct ELISA because it combines a higher specificity with a comparable sensitivity. Recombinant MPO is a good alternative for native MPO when used as antigen in a capture ELISA, but not when used in a direct ELISA because of lower specificity in this latter assay.

The role of metals in autoimmune vasculitis: epidemiological and pathogenic study

Background: A possible relationship between Silica (Si) exposure and antineutrophil cytoplasm antibodies (ANCA)-associated vasculitis has been reported. Furthermore, tuberculosis (TBC) has been frequently described in patients with silicosis, and TBC infection shares with ANCA-associated vasculitis the formation of granulomas. Therefore, an intriguing network including Silica, Vasculitis, TBC and ANCA might be hypothesized. The aim of this work was to further investigate these correlations using both epidemiological and pathogenic approaches. Methods: Study I — epidemiological study. A case–control study to compare the occupational histories of 31 cases of biopsy proven vasculitis (18 pauci-immune crescentic glomerulonephritis, 9 microscopic polyangitis, 4 Wegener's granulomatosis) with those of 58 age, sex and residence-matched controls (affected by other kidney diseases), was performed. Occupational Health physicians designed an appropriate questionnaire in order to evaluate a wide spread of exposures and calculate their entity by the product of Intensity×Frequency×Duration. Study II — tuberculosis association. A case–control study to evaluate the frequency of a previous history of tuberculosis (TBC) in 45 patients with vasculitis and 45 controls were performed. Study III — ANCA positivity. A case–control study to evaluate the presence of ANCA was performed by testing blood samples of 64 people with previous professional exposure and 65 sex/age matched patients hospitalized in a General Medicine Unit. Furthermore, the same evaluation was made in a pilot study in 16 patients with ongoing or previous TBC. Study IV — experimental study. The oxygen free radicals (OFR) and IL-12 production (both involved in the pathogenesis of vasculitis) from human phagocytic cells stimulated with an amorphous (diatomaceous earth) and a crystalline (quartz) form of Si at the doses of 10 and 100 μg ml −1 was evaluated. Results: Study I — a positive history of exposure to Si resulted in significantly more present in cases (14/31=45%) than in controls (14/58=24%, P=0.04, OR=2.4) and no other significant exposure association was found (including asbestos, mineral oil, formaldehyde, diesel and welding fumes, grain and wood dust, leather, solvents, fungicides, bitumen, lead and paint). Study II — past TBC infection was significantly more present in patients with vasculitis (12/45=26%) than in controls (4/45=8%, P<0.05). Study III — ANCA was present in 2/64 exposed people (vs. 0/65 controls, P=NS) and 0/16 patients with TBC. Study IV — both amorphous and crystalline Si forms represented a stimulus for OFR and IL-12 production, but quartz resulted as a greater inductor. Conclusions: We conclude that Si exposure might be a risk factor for ANCA-associated vasculitis, possibly enhancing endothelial damage by phagocyte generation of oxygen free radicals and Th1 differentiation by an excessive IL-12 phagocyte production. Frequency of TBC was significantly higher in vasculitis patients. ANCA was not frequent in the preliminary examination of people with previous professional exposure or patients with TBC, but the number of samples evaluated is too small to allow conclusions.

Pauci-immune ANCA-positive crescentic glomerulonephritis associated with metastatic adenocarcinoma of the lung

A 66-year-old woman developed rapidly progressive renal failure several days after she was diagnosed with non–small cell carcinoma of the lung. Antineutrophil cytoplasmic antibody test performed as an indirect immunofluorescence assay was positive with a perinuclear pattern of staining (pANCA). The patient did not improve with hemodialysis treatment and died on the second day after admission to the hospital. A complete autopsy was performed and showed metastatic adenocarcinoma of the lung and pauci-immune crescentic glomerulonephritis. A literature search showed only 7 previously reported cases of malignant tumors associated with ANCA-positive pauci-immune crescentic glomerulonephritis. The clinicopathologic findings of the current and all previously reported cases and possible relationship between ANCA-positive glomerulonephritis and malignancy are discussed.

Acute non-proliferative glomerulitis: a cause of renal failure unique to children.

Over a 31-year period, we have encountered 13 children with a disease entity not reported by other clinics that leads to rapidly progressive crescentic glomerulonephritis. Gross hematuria, rapidly declining renal function, and a serum C3 level at the lower limit of normal or slightly depressed usually characterized the disease onset; hypertension and nephrotic syndrome were absent. Glomerular IgG was absent, but large C3-containing subepithelial deposits on the paramesangial basement membrane (GBM) were always present. Because of these deposits and because dense alteration of the GBM was found in 3 patients, the disease may resemble membranoproliferative glomerulonephritis type II, but is distinguishable on other morphological and clinical grounds. The absence of anti-neutrophil cytoplasmic antibody, tested for in 5 of 13 patients, is one of several ways the disease differs from the pauci-immune glomerulonephritis of adults. Clinically and by glomerular morphology, it also differs from severe poststreptococcal acute glomerulonephritis. Treatment with high-dose corticosteroids has been highly successful. Because in this series the disease occurred only in children under age 12 years and the amount of silver-positive mesangial matrix was normal, indicating absence of mesangial proliferation, it has been designated juvenile acute non-proliferative glomerulitis.

“pauci-immune” proliferative and necrotizing glomerulonephritis with thrombotic microangiopathy in patients with systemic lupus erythematosus and lupus-like syndrome

In the glomerulonephritides of systemic lupus erythematosus (SLE), the number of subendothelial deposits, when present, generally corresponds to the degree of light microscopic glomerular hypercellularity; only very rarely are no or few such deposits present in cases of focal (WHO class III) or diffuse (WHO class IV) proliferative lupus nephritis. We have recently encountered five cases of active diffuse proliferative glomerlonephritis with no subendothelial and few or no mesangial deposits and thrombotic microangiopathy (TMA) in four patients with SLE and one patient with lupus-like syndrome. Three of the five patients were tested for circulating lupus anticoagulants or anticardiolipin antibodies, and two were positive. All five patients tested negatively for antineutrophil cytoplasmic antibodies (ANCA). Three patients responded to steroid and cyclophosphamide treatment, although one of them died of acute bacterial bronchopneumonia. One patient was lost to follow-up. We conclude that “pauci-immune” proliferative lupus nephritis is rare and should be treated as proliferative lupus nephritis with a proportionate number of subendothelial deposits. The negative ANCA suggests that these cases do not represent incidental ANCA-associated pauci-immune necrotizing and crescentic glomerulonephritis in patients with SLE. Of particular interest is that, in patients with SLE, if associated with TMA, an active proliferative necrotizing glomerulonephritis may be present even in the absence of significant glomerular immune complex deposition.

Etiologies and outcome of acute renal insufficiency in older adults: A renal biopsy study of 259 cases

Acute renal insufficiency is a common problem, yet one that is frequently reversible with proper diagnosis and treatment. Although it has been argued that a renal biopsy is not needed for diagnosis in most cases of acute renal failure in the elderly, other studies have shown frequent disagreements between clinical and renal biopsy diagnoses in such cases. To investigate the causes of acute renal insufficiency in patients aged at least 60 years who underwent a renal biopsy and possible correlations between biopsy findings and renal survival, we first identified all native renal biopsy specimens from patients aged 60 years or older processed at The University of Chicago Medical Center (Chicago, IL) from 1991 through 1998 and reviewed the clinical records to determine the indication for the biopsy. We then reviewed again the records of those patients who underwent biopsy because of acute renal insufficiency, recorded the primary renal biopsy diagnosis in each of these cases, and obtained follow-up information for patients who underwent biopsy before July 1996. During the study period, 1,065 of 4,264 biopsy specimens (25.0%) received were obtained from patients aged 60 years or older, and acute renal insufficiency was the indication for biopsy in 259 of these patients (24.3%). The most frequent primary diagnoses on these latter biopsy specimens were pauci-immune crescentic glomerulonephritis (GN) with or without arteritis, 31.2% of biopsy specimens; acute interstitial nephritis, 18.6%; acute tubular necrosis (ATN) with nephrotic syndrome, 7.5%; atheroemboli, 7.1%; ATN alone, 6.7%; light chain cast nephropathy (LCCN), 5.9%; postinfectious GN, 5.5%; anti–glomerular basement membrane antibody nephritis, 4.0%; and immunoglobulin A (IgA) nephropathy and/or Henoch-Schönlein nephritis, 3.6%. Eight biopsy specimens (3.2%) showed only benign nephrosclerosis without an apparent cause of acute renal insufficiency, and another six specimens were inadequate. The renal biopsy diagnosis was in agreement with the prebiopsy clinical diagnosis (or differential diagnosis) in 107 of the 161 cases (67%) in which such information was provided. The distribution of diagnoses was similar in patients in the age groups of 60 to 69, 70 to 79, and 80 years or older, although younger age correlated significantly with improved renal and patient survival. The relative risk for progression to end-stage renal disease (ESRD) also increased according to diagnostic categories: LCCN (greatest risk) > GN other than pauci-immune > atheroemboli ≅ pauci-immune crescentic GN > tubulointerstitial diseases other than LCCN (the latter category including ATN with nephrotic syndrome). Development of ESRD correlated significantly with decreased patient survival. In summary, renal biopsy in patients aged 60 years or older with acute renal insufficiency uncovered the cause in greater than 90% of the cases and provided clinically useful information with respect to expectation for renal survival and potential treatment options.

Granulomatous Pneumocystis carinii pneumonia in Wegener′s granulomatosis

This study reports on a first case of granulomatous Pneumocystis carinii pneumonia (PCP) in a human immunodeficiency virus-negative patient with antineutrophil cytoplasmic antibody-positive Wegener's granulomatosis whilst receiving immunosuppressive treatment. The patient presented with diffuse alveolar haemorrhage, pauci-immune rapid progressive glomerulonephritis and leukocytoclastic vasculitis of the skin. Granulomatous Pneumocystis carinii pneumonia developed under immunosuppressive treatment with cyclophosphamide and prednisone. At the time Pneumocystis carinii pneumonia developed, there was a marked lymphopenia with a very low CD8+ cell count in the blood. Grocott staining in bronchoalveolar lavage fluid revealed no Pneumocystis carinii. The diagnosis was made via a video-assisted thoracoscopic lung biopsy which showed granulomas containing high numbers of Pneumocystis carinii cysts.