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%.     

MPO-ANCA-positive crescentic necrotizing glomerulonephritis and tubulointerstitial nephritis with renal eosinophilic infiltration and peripheral blood eosinophilia

We present the case of a 67-year-old woman with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive pauci-immune crescentic necrotizing glomerulonephritis and tubulointerstitial nephritis with renal eosinophilic infiltration and peripheral blood eosinophilia. Staining for eosinophil cationic protein indicated that activated eosinophils were involved in the tubulitis, as well as in the glomerular injury. Marked peripheral blood eosinophilia is uncommon in ANCA-positive crescentic necrotizing glomerulonephritis associated with tubulointerstitial nephritis, except in Churg-Strauss syndrome. However, our patient had no clinical history or signs of asthma, no other signs suggestive of allergic diseases, and no histologic findings of granulomas in the kidney, thus failing to fulfill the criteria for Churg-Strauss syndrome.     

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.     

Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis.

BACKGROUND: Treatment of rheumatoid arthritis with anti-tumour necrosis factor alpha (TNFalpha) agents may lead to autoantibody formation and flares of vasculitis, but renal complications are rare. METHODS: We report the clinical and pathologic findings in five patients with longstanding rheumatoid arthritis (duration of rheumatoid arthritis, 10-30 years; mean, 23 years) who developed new onset of glomerular disease after commencing therapy with anti-TNFalpha agents (duration of therapy, 3-30 months; median, 6 months). RESULTS: At presentation, three patients were receiving etanercept, one adalimumab and one infliximab. Two subjects presented with acute renal insufficiency, haematuria, nephrotic-range proteinuria, positive lupus serologies, and hypocomplementemia, and renal biopsies showed proliferative lupus nephritis. Two individuals presented with new onset renal insufficiency, haematuria and proteinuria, and renal biopsies showed pauci-immune necrotizing and crescentic glomerulonephritis. One of these subjects, who had anti-myeloperoxidase autoantibodies, also developed pulmonary vasculitis. The fifth patient presented with nephrotic syndrome and renal biopsy findings of membranous glomerulonephritis, associated with immune complex renal vasculitis. A pathogenic role for anti-TNFalpha therapy is suggested by the close temporal relationship with development of glomerular disease, and by the improvement in clinical and laboratory abnormalities after drug withdrawal and initiation of immunosuppressive therapy in most cases. CONCLUSIONS: Rheumatoid arthritis patients receiving anti-TNFalpha agents may develop glomerulonephritis via the induction of rheumatoid arthritis-related nephropathy or de novo autoimmune disorders.     

Fortuitous vasculitis

A 43-year-old man with a cardiac device for dilated cardiomyopathy presented with fever, night sweats, and weight loss. Investigations revealed pancytopenia, acute renal failure, abnormal lung function, and raised inflammatory markers. A renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis. He was diagnosed with pulmonary-renal antineutrophil cytoplasmic antibody-negative systemic small vessel vasculitis. He commenced immunosuppression with prednisolone and cyclophosphamide with recovery from pancytopenia and improvement in renal function 3 months later. Subsequently, a bone marrow culture grew Mycobacterium fortuitum. Isolation on repeat peripheral mycobacterial blood cultures prompted treatment with ciprofloxacin and clarithromycin. Four months later, he presented with neutropenic sepsis, influenza A/H1N1, and Aspergillus flavus pneumonia. Despite treatment he deteriorated. A transthoracic echocardiogram revealed a vegetation on the right ventricular pacing wire. The device was removed. The vegetation revealed acid and alcohol fast bacilli on Ziehl-Neelsen staining and grew M. fortuitum on culture, sensitive to ciprofloxacin and clarithromycin. Despite device removal and antimicrobial therapy, the patient succumbed to treatment-related complications. The association between glomerulonephritis and endocarditis is well known; however, this is the first case to our knowledge describing pauci-immune necrotizing crescentic glomerulonephritis in the context of M. fortuitum endocarditis. Clinicians should maintain a high index of suspicion for endocarditis in patients with a cardiac device who present with fever and pauci-immune necrotizing crescentic glomerulonephritis. Patients should be investigated with mycobacterial blood cultures, at least three sets of standard blood cultures and transthoracic and transesophageal echocardiography. Clinicians should beware the perils of immunosuppression in the face of an occult sepsis.     

Fortuitous Vasculitis

A 43-year-old man with a cardiac device for dilated cardiomyopathy presented with fever, night sweats, and weight loss. Investigations revealed pancytopenia, acute renal failure, abnormal lung function, and raised inflammatory markers. A renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis. He was diagnosed with pulmonary–renal antineutrophil cytoplasmic antibody-negative systemic small vessel vasculitis. He commenced immunosuppression with prednisolone and cyclophosphamide with recovery from pancytopenia and improvement in renal function 3 months later. Subsequently, a bone marrow culture grew Mycobacterium fortuitum. Isolation on repeat peripheral mycobacterial blood cultures prompted treatment with ciprofloxacin and clarithromycin. Four months later, he presented with neutropenic sepsis, influenza A/H1N1, and Aspergillus flavus pneumonia. Despite treatment he deteriorated. A transthoracic echocardiogram revealed a vegetation on the right ventricular pacing wire. The device was removed. The vegetation revealed acid and alcohol fast bacilli on Ziehl–Neelsen staining and grew M. fortuitum on culture, sensitive to ciprofloxacin and clarithromycin. Despite device removal and antimicrobial therapy, the patient succumbed to treatment-related complications. The association between glomerulonephritis and endocarditis is well known; however, this is the first case to our knowledge describing pauci-immune necrotizing crescentic glomerulonephritis in the context of M. fortuitum endocarditis. Clinicians should maintain a high index of suspicion for endocarditis in patients with a cardiac device who present with fever and pauci-immune necrotizing crescentic glomerulonephritis. Patients should be investigated with mycobacterial blood cultures, at least three sets of standard blood cultures and transthoracic and transesophageal echocardiography. Clinicians should beware the perils of immunosuppression in the face of an occult sepsis.     

Diffuse alveolar hemorrhage in lupus nephritis complicated by microscopic polyangiitis

Diffuse alveolar hemorrhage (DAH) is a rare but fatal complication in patients with systemic lupus erythematosus (SLE). We describe a case of a 74-year-old woman who presented with DAH as an initial presentation of SLE. She also had microscopic polyangiitis clinically manifesting as crescentic glomerulonephritis and purpura with positive myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA). The patient transiently improved when treated with plasma exchange and methylprednisolone pulse therapy; however, she died of recurrent pulmonary hemorrhage and concurrent cryptococcal pneumonia. This case indicates that MPO-ANCA is associated with severe organ involvement such as pulmonary hemorrhage and crescentic glomerulonephritis in SLE.     

Lupus nephritis associated with positive MPO-ANCA in a patient with underlying autoimmune hemolytic anemia

A 19-year-old female was admitted with general malaise and systemic edema. She had been diagnosed as having autoimmune hemolytic anemia (AIHA) eight years earlier and was successfully managed with oral prednisolone. During the current admission, she was diagnosed as having systemic lupus erythematosus (SLE) based on the presence of renal involvement, hematological abnormalities, and antinuclear and anti-double-stranded DNA antibodies, along with a recurrence of AIHA; her serology revealed a high myeloperoxydase-antineutrophil cytoplasmic antibody (MPO-ANCA) titer. She was treated with prednisolone (50 mg day⁻¹), but her renal function started to deteriorate. She responded to treatment with hemodialysis, plasmapheresis, and methylprednisolone pulse therapy; her MPO-ANCA titer and renal function improved. Treatment with intravenous cyclophosphamide gradually suppressed her AIHA and SLE activity. A renal biopsy revealed a diffuse proliferative lupus nephritis (class IV-G (A)) with necrotizing crescentic glomerulonephritis that was presumed to be associated with MPO-ANCA. The association of MPO-ANCA with SLE in this refractory case is discussed.     

A case of silicosis with MPO-ANCA-associated glomerulonephritis and alveolar hemorrhage]

A 63-year-old man was referred to our hospital for rapid deterioration of his renal function. He had worked as a metal founder for more than 40 years, and had been diagnosed as having silicosis. Laboratory data on admission showed severe anemia, thrombocytopenia, and end-stage renal failure (BUN 88.8 mg/dl, serum creatinine 9.0 mg/dl). Myeloperoxidase anti-neutrophil cytoplasmic antibody(MPO-ANCA) was also detected in his sera. On the next day after admission, he complained of sudden dyspnea and hemoptysis. Mechanical ventilation with pure oxygen was insufficient to improve hypoxia without concomitant use of percutaneous cardio-pulmonary support(PCPS) and continuous hemofiltration(CHF). We diagnosed his condition as MPO-ANCA-associated rapidly progressive glomerulonephritis with diffuse alveolar hemorrhage. Treatment with plasmapheresis, pulse methylprednisolone and pulse cyclophosphamide effectively improved his hemoptysis as well as chest X-ray findings and blood gas analysis. However on his later clinical course, he was complicated with superimposed complex infection and passed away. Autopsy findings showed crescentic glomerulonephritis in the kidneys and silica nodules in the lungs. Recently it has been postulated that some relationship exists between ANCA-associated(especially MPO-ANCA-associated) glomerulonephritis and silica exposure. The reported cases of glomerulonephritis in the patients with silica exposure showed a rapidly progressive clinical course and pauci-immune necrotizing crescentic glomerulonephritis in their histology. Gregorini et al. reported that 12 of 37 (32%) male patients with RPGN had either silicosis or significant silica exposure, and 7 of 8 patients examined were ANCA-positive(6 of 7 were MPO-ANCA-positive). Therefore silica seems to cause glomerulonephritis by disrupting the immune response. Including this case mentioned above, we have experienced 10 cases of MPO-ANCA-associated glomerulonephritis, at least 3 cases out of which had suffered from silicosis in the past(30%). These results indicate that silicosis should be considered a relevant pathogen of MPO-ANCA-associated glomerulonephritis beyond the race.     

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.     

Recurrent lupus nephritis in the second allograft of a patient with systemic lupus erythematosus

Lupus glomerulonephritis is a common and serious complication of systemic lupus erythematosus (SLE) affecting up to 50% of lupus patients. Recurrent lupus nephritis is rare, complicating as low as 1% of the lupus transplant population according to some authors. However, it may be underreported with more realistic recurrent rates oscillating from 2.8 to 8.7%. We report the case of a patient with SLE who lost her first allograft 4 years after transplantation with a diagnosis of de novo fibrillary glomerulopathy. She underwent a second renal transplantation and her renal function was stable for the past 5 years. She now presented with skin rash, arthralgias and positive lupus serologies. Her creatinine was slightly elevated and proteinuria was also noted. A renal biopsy performed revealed a recurrent focal proliferative lupus nephritis (WHO III). Retrospectively, we believe that her first allograft was also lost to recurrent lupus nephritis. This is a unique case of recurrent lupus nephritis in the second allograft of a patient with SLE.     

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.     

Pauci-immune necrotizing glomerulonephritis complicating rheumatoid arthritis

Necrotizing glomerulonephritis associated with rheumatoid arthritis typically occurs in the setting of frankly apparent systemic vasculitic signs and symptoms. We report two recent cases that differed from this paradigm. Both patients had rheumatoid arthritis and deteriorating renal function due to P-ANCA positive pauci-immune necrotizing crescentic glomerulonephritis, but minimal systemic symptoms. Delay in diagnosis and institution of appropriate therapy may have contributed to the dialysis dependence of one of these patients. We suggest that heightened suspicion of an aggressive necrotizing glomerulonephritis should be maintained in all patients with rheumatoid arthritis who present with acute renal insufficiency even in the absence of frank vasculitis.     

Coexistence of Fabry's disease and necrotizing and crescentic glomerulonephritis

The coexistence of Fabry's disease, an X-linked hereditary disease, and other renal diseases, has rarely been described in the same patient. Combined Fabry's disease and pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) is hitherto unreported. We present the clinical and pathologic data of two patients with combined Fabry's disease and NCGN. Both patients presented with fevers of unknown origin and progressive renal insufficiency, however, lacked any other pathognomic signs of Fabry's disease such as acroparesthesias, dyshidrosis, and cutaneous angiokeratomas. The possible pathogenic mechanisms and causal relationship between the two disease processes are discussed.     

Renal involvement in leprosy: report of progression from diffuse proliferative to crescentic glomerulonephritis

Renal involvement in leprosy has been reported rarely in the literature. Acute kidney injury in patients with leprosy is uncommon and may occur due to acute tubular necrosis, drug-induced interstitial nephritis and rarely crescentic glomerulonephritis. The latter with histologic confirmation of the diagnosis has been reported in very few cases of leprosy. A 25-year-old male, on therapy for multibacillary leprosy, was found to have deranged renal functions on evaluation for a history of nausea, vomiting, swelling and episode of haematuria. Kidney biopsy was performed twice over a period of 2 weeks, showing progression from diffuse proliferative glomerulonephritis to crescentic glomerulonephritis, pauci-immune in nature. The patient was treated aggressively with intravenous steroids, following which his renal functions stabilized. Crescentic glomerulonephritis, an extremely rare phenomenon in leprosy, should be considered in these patients presenting with features of acute kidney injury. Timely performed renal biopsy assists in accurate diagnosis and appropriate management of the patient, hence preserving renal parenchyma. Rapid progression from diffuse proliferative glomerulonephritis to crescentic glomerulonephritis in a patient with leprosy is described herein for the first time in the literature.     

Therapy of IgA nephropathy with mycophenolate mofetil--report of 3 cases

Mycophenolate mofetil is an immunosuppressive agent in transplantation which inhibits the purin neogenesis. Proliferating lymphocytes are suppressed and antibody production is decreased. Many cases of successful therapy in different kidney diseases are reported, such as diffuse proliferative lupus nephritis, pauci-immune necrotizing glomerulonephritis, focal segmental glomerular sclerosis and IgA nephropathy. We report 3 patients with IgA nephropathy who were treated with mycophenolate mofetil for more than 1 year. In all patients, proteinuria decreased significantly and the renal function remained stable. In 2 patients, kidney biopsy was repeated after 12 months and 18 months, respectively. There were no histological signs of progression of the disease. Two patients developed infections during treatment. One patient had a pneumonia, and a second patient an infection with varizella zoster. Based on our data, mycophenolate mofetil can be a potential treatment of IgA nephropathy. Further controlled studys are warranted to investigate the role of mycophenolate mofetil in IgA nephropathy.     

Enterococcal endocarditis associated with crescentic glomerulonephritis

Glomerulonephritis secondary to infective endocarditis (IE) is an uncommon diagnosis and is usually associated with cardiac valvular infection by blood-culture-positive bacteria. We report a case of necrotizing glomerulonephritis associated with culture-positive endocarditis caused by Enterococcus faecalis. The patient presented with renal abnormalities and was further investigated by renal biopsy. He had immune complex-mediated necrotizing and crescentic glomerulonephritis with mesengial and capillary deposition of immunoglobulin M (Ig M), Ig G, and complement 3 (C3). He was treated with antibiotics, including ampicillin and gentamicin. In addition, steroid and cyclophosphamide were administered. The patient died of renal failure 48 days after hospital admission. In conclusion, glomerulonephritis caused by Enterococcus faecalis endocarditis is an immune-complex-mediated disease characterized by necrotizing and crescentic glomerular lesions that can be fatal despite aggressive antimicrobial and immunosuppressive therapy.     

Hydralazine-Induced ANCA-Positive Pauci-immune Glomerulonephritis: A Case Report and Literature Review

We report a case of hydralazine-induced alveolar hemorrhage and anti-neutrophil cytoplasmic antibody (ANCA)-positive pauci-immune glomerulonephritis, with serum anti-histone antibodies present, features not previously described in the literature with this drug. A 50-year-old Caucasian female had hypertension treated with hydralazine 75mg TID for three years, and a lung nodule followed up periodically with chest-computed tomographies. She was admitted to the hospital for hemoptysis and newly discovered diffuse pulmonary ground-glass opacities. Transbronchial lung biopsy showed alveolar hemorrhage. Serum creatinine was 3.5 mg/dL and urinalysis showed 2+blood, 30-50RBC/hpf and red blood cell casts. ANCA against myeloperoxidase were present. Anti-double-stranded DNA, ANA, and anti-histone antibodies were positive. Serum complements were normal. Renal biopsy revealed focal crescentic necrotizing glomerulonephritis with negative immunofluorescence, consistent with pauci-immune ANCA-positive vasculitis. Serum creatinine returned to baseline three days after hydralazine was discontinued, and the hemoptysis resolved after treatment with cyclophosphamide and prednisone was started. We concluded that this case represents a hydralazine-induced small vessel vasculitis rather than an idiopathic one. The possibility of hydralazine-induced vasculitis should be considered when patients treated with hydralazine develop a pulmonary-renal syndrome. Anti-histone antibodies may be present in the absence of full classification criteria of drug-induced lupus.     

Anti-neutrophil cytoplasmic autoantibodies in a child with pauci-immune necrotizing and crescentic glomerulonephritis

We report a case of pauci-immune, necrotizing and crescentic glomerulonephritis in a 10-year-old child initially thought to have Henoch-Schönlein purpura. The diagnosis of a Wegener's granulomatosis-microscopic polyarteritis disorder was made on the basis of clinical presentation and a positive anti-neutrophil cytoplasmic auto-antibody (ANCA). This case illustrates the usefulness of the ANCA in the diagnosis and management of childhood vasculitides.