myeloperoxidase ( mpo)-anti - neutrophil cytoplasmic antibody ( anca ) is frequently detected in cases of microscopic polyangiitis ( mpa ) and renal - limited vasculitis , while those directed against proteinase 3 ( pr3-anca ) are commonly seen in granulomatosis with polyangiitis . these conditions are collectively referred to as anca - associated vasculitis ( aav ) , which is a life - threatening autoimmune disease characterized by pulmonary - renal involvement . a recent nationwide survey showed that mpo - anca was positive in 88.1 and 91.8% of patients with renal - limited vasculitis and mpa , respectively , among rapidly progressive glomerulonephritis patients in japan . thus , circulating anca is now widely used as diagnostic markers for several forms of idiopathic systemic vasculitis and rapidly progressive glomerulonephritis [ 1 , 3 ] . there is also growing evidence for their pathogenicity , per se , in in vitro and in vivo studies . however , paradoxically , elevation of serum anca titers has also been observed in diverse conditions such as rheumatic diseases [ 3 , 5 ] , inflammatory bowel diseases [ 3 , 5 ] , infectious disorders [ 5 , 6 ] , and drug - induced syndromes , which creates a clinical puzzle . here , we describe a hemodialysis ( hd ) patient who developed pulmonary hemorrhage as long as 10 years after detection of circulating mpo - anca . despite our concern about aav , the preexisting pulmonary disease ( thought to be pneumoconiosis and tuberculosis ; tb ) and renal disease ( biopsy - proven focal segmental glomerulosclerosis ; fsgs ) limited a definite diagnosis and administration of potent immunosuppressive therapy . this case provides deep insights into the appropriate clinical management of patients with circulating anca . a 50-year - old male visited our hospital in october 1996 because of abnormalities detected in a medical checkup . urinary protein and occult hematuria had been documented in medical checkups over the previous few years , with marked proteinuria of up to 3.8 g / day being a prominent feature of his clinical presentation . renal biopsy performed in december 1996 revealed segmental sclerosis in 1 of 7 glomeruli and deposition of immunoreactive substances into glomeruli , including igm and complement . therefore , a diagnosis of fsgs was made on the basis of the results of a renal biopsy . also , chest computed tomography ( ct ) delineated interstitial changes accompanied by cystic lesions in the lung and pleural thickening ( fig . 1a ) , along with chest x - ray abnormalities that had been noted in a past medical checkup . he had worked as a demolition worker and smoked approximately 30 cigarettes a day since he was 18 years old . work- and smoking - related lung conditions were therefore the most likely causes of the pulmonary lesions . an annual chest ct showed little change over several years , in contrast to progression of the renal disorder . pleural thickening strongly suggested concomitant tb based on epidemiological reports showing a strong association of tb with pneumoconiosis , although mycobacterium species were not detected by sputum culture tests that were repeatedly performed over a couple of years . cyclosporine a ( csa ) was administered at doses of 50100 mg per day under therapeutic drug monitoring ( the trough level was usually around 50 ng / ml ) in lieu of steroid therapy   to reduce the risk of excessive immunosuppression , but the serum creatinine ( cr ) level showed a rapid elevation in 2000 , at approximately 3 years after biopsy ( fig . he had presented with persistent microscopic hematuria , which is inconsistent with the clinical presentation of fsgs , since the first visit . by contrast , a temporary decrease in proteinuria ( down to 1.3 g / day ) was observed afterward , unlike with treatment - resistant fsgs . rapidly progressive glomerulonephritis was suspected despite the biopsy findings , and circulating anca was measured ( this test has been clinically available since 1998 in japan ) . elevation of the mpo - anca titer ( 168 eu ) was found , along with an altered clinical presentation . however , potent immunosuppressive therapies such as glucocorticoids were still withheld due to the possibility of an underlying infection ( tb ) . apheresis was alternatively conducted in an effort to avoid decreased immune competence , but initiation of hd was required in september 2001 because of end - stage renal disease ( esrd ) . thrice - weekly hd was performed uneventfully for several years , and there were also no changes in pulmonary signs . in contrast , circulating mpo - anca had ranged from 10.5 to 32.5 u / ml , even in the dialysis period , indicating possible aav ( fig . however , steroid therapy was postponed due to the unconfirmed diagnosis , presumed tb , and lack of problematic clinical events . abruptly , the patient developed gross hemoptysis accompanied by severe cough at night in bed and was transported to our facility by ambulance in october 2010 . steroid therapy comprising 3-day intravenous infusion of 500 mg methylprednisolone followed by daily oral administration of 20 mg prednisolone ( psl ) was launched . as expected , the hemorrhagic shadows almost disappeared as early as 2 days after hospitalization ( fig . 1d ) , and the serum mpo - anca titer subsequently fell to normal ( fig . at present , psl has slowly been tapered to a daily dose of 5 mg , but there has been little change over time in the serum mpo - anca level and follow - up ct . the main features of the present case can be summarized as ( 1 ) sustained elevation of serum mpo - anca , of which the significance was uncertain ; ( 2 ) the result of a renal biopsy and presumed pulmonary disease , which were different from aav , and ( 3 ) delayed onset of pulmonary hemorrhage . however , in our case , the pathological findings of renal biopsy , including deposition of immunoreactive substances ( igm and complement ) into glomeruli and a lack of glomerular crescent formation , were entirely different from those commonly observed in aav patients ( pauci - immune necrotizing crescentic glomerulonephritis ) . the clinical features , such as heavy proteinuria ( up to 3.8 g / day ) , agreed well with those of fsgs , whereas interstitial changes in the inferior lobes of the lungs and the former job of the patient ( demolition worker ) strongly indicated pneumoconiosis , including asbestosis and silicosis . incidentally , csa might be regarded as an exacerbating factor for renal impairment . however , csa nephrotoxicity was less likely in the present case , based on the treatment duration and the use of therapeutic drug monitoring . in fact , we have recently reported that patients who were treated for minimal change nephrotic syndrome with csa for at least 2 years experienced no deterioration in renal function . we were also concerned about subsequent infection by mycobacterium tuberculosis since an increased risk of this infection has been reported in populations with similar features to our patient . renal function was already impaired ( cr clearance 45.3 ml / min ) when circulating anca was noted . thus , the pre - existing lesions described above were important hurdles in defining the clinical strategy . however , based on suspicion of latent aav , an annual ct was performed , and the serum kl-6 level , a good monitoring approach for diagnosis and follow - up of interstitial pneumonia in aav patients as with other rheumatic diseases , was measured every month even after progression to esrd . however , despite our effort at preclinical detection of aav , no radiographic changes were observed over time , and serum kl-6 remained normal . there was also no evidence for other sites of involvement , including gastrointestinal , neural , or otological symptoms . furthermore , there was no significant change in serum c - reactive protein or signs of possible pulmonary infection prior to the hemoptysis . the radiographic findings at the time of hemoptysis were compatible with alveolar hemorrhage , which is the most frequent manifestation of lung involvement in mpa . although other possibilities such as infectious disorders , organized pneumonia , and overt tb can not be completely excluded , the bilaterality , rapid response to steroid therapy , and follow - up normalization of serum anca were eloquent indicators of aav . it has been well described that there are some differences in characteristics of japanese aav patients compared with those in europe . for instance , mpa and mpo - anca are more common in japan , and granulomatosis with polyangiitis and pr3-anca are more common in the uk . in light of the japanese prospective multi - center study with mpo - associated vasculitis , the clinical practice guideline for aav ( a japanese - language publication ) was published for japanese patients in 2011 . according to this guideline , in cases of focal ( < 30% ) lung hemorrhage ( severe form ) , steroid therapy should be launched and combined with cyclophosphamide within 4 weeks . hence , as a result of the rapid improvement , monotherapy of corticosteroids was conducted in the present case . positive anca test results have been reported in many diseases other than systemic vasculitis , including rheumatic diseases [ 3 , 5 ] , inflammatory bowel diseases [ 3 , 5 ] , infectious disorders [ 5 , 6 ] , and drug - induced syndromes . with regard to antecedent infection , flores - surez et al .   found that 18 of 45 tb patients ( 40% ) were anca positive by enzyme - linked immunosorbent assay ( elisa ) and concluded that a positive anca test must be carefully interpreted as indicative of systemic vasculitis , especially when there are no signs of extrapulmonary involvement . also highlighted the high prevalence of autoantibodies among very old people ( centenarians ) in whom mpo- and pr3-anca were positive in 10.8 and 7.2% , respectively . .   found that the positive predictive value was only 54% for anca testing , indicating that a positive result on an anca test ( elisa ) is not a definitive diagnostic indicator of aav . however , in the present case , clinical manifestation of these autoimmune diseases was not observed and antithyroid agents had not been used . the studies described above suggest that circulating anca is not only a diagnostic clue for aav but also a critical issue in clinical practice . knight et al .   found that 18 of 74 subjects with a positive test for cytoplasmic- or pr3-anca did not present with clinical evidence supportive of or insufficient to support a diagnosis of systemic vasculitis , but presented with a range of other diseases including ankylosing spondylitis , sarcoidosis , and ulcerative colitis . in particular , it was concluded that anca - positive subjects with no vasculitis at the time of the test had only a small risk of subsequent development of vasculitis , since none of the 18 patients developed vasculitis during a mean follow - up period of 6.8 years . in the present case , alveolar hemorrhage occurred at 10 years after an initial positive anca test . thus , our experience strongly suggests that long - term care should be provided to patients with positive circulating anca , even in a case with an undetermined diagnosis .
detection of circulating anti - neutrophil cytoplasmic antibody ( anca ) provides a powerful clue in the diagnosis of vasculitis , but the clinical interpretation of the results is difficult in some cases . here , we describe the case of a 65-year - old man who underwent hemodialysis due to focal segmental glomerulosclerosis and abruptly developed hemoptysis 14 years after a renal biopsy . at the time of the biopsy , computed tomography ( ct ) showed interstitial shadows in the lungs and pleural thickening , indicating pneumoconiosis that was accompanied by tuberculosis . circulating myeloperoxidase - anca ( 10.532.5 u / ml ) was subsequently noted , but the significance of this observation was unclear due to the preexisting disorders in the lungs and kidneys . 
 potent immunosuppressive therapies were avoided because of the pulmonary lesions and decreased renal function . 
 there were few changes noted on follow - up ct , but infiltrative shadows emerged in the bilateral lungs , consistent with hemoptysis . 
 the hemorrhagic shadows completely disappeared shortly after initiation of steroid therapy , with normalization of the serum anca level . 
 herein , we report this case , with an emphasis on the clinical dilemma faced in deciding the appropriate treatment . 
 the findings in the case provide deep insights into clinical management of anca - positive patients .