anti - glomerular basement membrane ( anti - gbm ) disease is a rare condition characterized by the production of auto - antibodies against the alpha-3 chain of type iv collagen . incidence and prevalence of anti - gbm disease is estimated to be one case per 1 million population . goodpasture 's ( pulmonary - renal ) syndrome is the most common presentation of anti - gbm disease , characterized by rapidly progressive glomerulonephritis and pulmonary hemorrhage . anti - gbm antibodies normally can be detected in the circulation by enzyme - linked immunosorbent assay ( elisa ) . typically , anti - gbm disease is a monophasic illness [ 4 , 5 ] . the disease has good prognosis after a typical treatment regimen consisting of plasma exchange , cyclophosphamide and prednisone : one study reports 100% patient survival and 95% renal survival at 1 year . we present the case of a woman who presented with three episodes of presumed anti - gbm disease and varying presence of anti - gbm antibodies on laboratory assays throughout her disease course . a 33-year - old woman with a history of tobacco use presented with gross hematuria in 2001 . as part of her outpatient workup for hematuria she underwent a renal biopsy , which showed crescentic glomerulonephritis with 25% crescents on light microscopy and linear deposition of igg along the gbm on immunofluorescence microscopy . at the time of diagnosis , serum anti - gbm , anti - nuclear antibody ( ana ) and anti - neutrophilic cytoplasmic antibody ( anca ) levels were undetectable and there was no evidence of pulmonary involvement . she was treated with plasmapheresis three times per week for seven occurrences , oral prednisone 60 mg daily for 6 months and cyclophosphamide 2 mg / kg / day for 6 months . in 2006 , 5 years after initial diagnosis , she presented with dyspnea , hemoptysis and gross hematuria . hemoglobin was 8.5 g / dl and serum creatinine was 0.8 mg / dl . a chest x - ray and computed tomography ( ct ) were obtained and showed evidence of diffuse alveolar filling consistent with alveolar hemorrhage ( figure  1 ) . serum anti - gbm antibody was 112 au / ml and serum anca was negative . renal biopsy was not performed but she was treated for a presumed relapse of anti - gbm disease with plasmapheresis for 7 days , methylprednisone 1 g intravenously ( iv ) daily for three doses followed by 40 mg oral prednisone for 2 months and 2 mg / kg / day cyclophosphamide . she remained on the 2 mg / kg / day cyclophosphamide for 32 months prior to being tapered and discontinued due to loss of follow - up to care . at the end of a 7-day plasmapheresis treatment , anti - gbm antibody levels had returned to 0 ua / ml . during this relapse , she was hospitalized for 5 days and required intensive care unit ( icu ) monitoring for 2 days due to hypotension and need for plasmapheresis . she required 4 l of supplemental oxygen on admission , but prior to discharge she showed no significant desaturations during a 6-min walk test . 1.chest ct without iv contrast during admission in 2006 revealed diffuse patchy bilateral ground glass opacities , which along with lab evidence of anemia , is consistent with alveolar hemorrhage . chest ct without iv contrast during admission in 2006 revealed diffuse patchy bilateral ground glass opacities , which along with lab evidence of anemia , is consistent with alveolar hemorrhage . in 2014 , 8 years after her relapse , she presented with epistaxis and hemoptysis . on presentation , hemoglobin was 12.0 g / dl and serum creatinine was 0.57 mg / dl . chest x - ray showed bilateral perihilar opacities consistent with diffuse alveolar hemorrhage ( figure  2 ) . during this admission , she was again treated as a presumed anti - gbm relapse with plasmapheresis for 7 days , cyclophosphamide 2 mg / kg / day for 3 months and methylprednisone 1 g iv daily for three doses followed by oral prednisone 60 mg / day for 2 months . during this most recent hospitalization , she was initially admitted to the icu for plasmapheresis then transferred to the general medicine service after 1 day due to stability . chest plain film x - ray during admission in 2014 revealed extensive perihilar opacities . in 2015 , she was seen in the outpatient nephrology clinic for follow - up . urine analysis showed no evidence of hematuria or proteinuria and labs revealed normal kidney function with a creatinine of 0.7 mg / dl and estimated glomerular filtration rate > 90 ml / min/1.73 m. the patient states that she has been smoking one to one and a half packs per day since 1984 but is now down to 12 cigarettes daily . despite her two nearly fatal relapses , repeated counseling for smoking cessation and discussions regarding future risk of relapse due to continued cigarette use , the patient continues to smoke cigarettes . in multiple provider notes between 2006 and 2015 , she states that she is not ready to quit due to stress at home and family responsibilities . other significant social history includes consumption of one to two alcoholic beverages daily and she denies illicit drug use . she has been a bartender for over 10 years and has no history of exposure to solvents or hydrocarbons . relapses are infrequent in anti - gbm disease but have been reported [ 712 ] . the present report is unique because the patient had three episodes of presumed anti - gbm disease with varying presence of anti - gbm antibody and negative anca and ana . our patient was only biopsied during her initial presentation . after each of the three episodes she recovered with a similar treatment regimen ( table  1 ) . table  1.summary of clinical presentations , anti - gbm antibodies , renal biopsy and treatmentyearclinical presentationanti - gbm antibodiesrenal biopsytreatment2001gross hematuria ; no pulmonary symptomsundetectablecrescentic glomerulonephritis with 25% crescents on light microscopy ; linear deposition of igg on immunofluorescence microscopy 
 plasmapheresis 3 days / week  7 occurrencesprednisone 60 mg / day  6 monthscyclophosphamide 2 mg / kg / day  6 months2006dyspnea , hemoptysis , gross hematuria ; diffuse alveolar hemorrhage on chest plain film and ct112 au / mlnot obtained 
 plasmapheresis daily  7 daysmethylprednisone 1 mg iv  3 days followed by prednisone 40 mg  2 monthscyclophosphamide 2 mg / kg / day  32 months2014epistaxis , hemoptysis ; diffuse alveolar hemorrhage on chest plain film and microhematuria on urine analysisundetectablenot obtained 
 plasmapheresis daily  7 daysmethylprednisone 1 mg iv  3 days followed by prednisone 60 mg  2 monthscyclophosphamide 2 mg / kg / day  3 months summary of clinical presentations , anti - gbm antibodies , renal biopsy and treatment plasmapheresis 3 days / week  7 occurrences prednisone 60 mg / day  6 months cyclophosphamide 2 mg / kg / day  6 months plasmapheresis daily  7 days methylprednisone 1 mg iv  3 days followed by prednisone 40 mg  2 months cyclophosphamide 2 mg / kg / day  32 months plasmapheresis daily  7 days methylprednisone 1 mg iv  3 days followed by prednisone 60 mg  2 months cyclophosphamide 2 mg / kg / day  3 months it is interesting that our patient had variable findings of circulating anti - gbm antibodies with each recurrence . have estimated that seronegative anti - gbm disease may occur in 23% of patients in the uk . one possible explanation is that the inability to detect anti - gbm antibodies may reflect technical limitations of the routinely available assay ( indirect immunofluorescence , immunoblot and elisa ) rather than antibody negativity . another possible explanation is that smoking produces autoantibodies that react with a different antigen or epitope compared with typical anti - gbm antibodies , which react with two well - defined epitope regions of the nc1-domain of type iv collagen alpha-3-chains [ 1 , 14 ] . ohlsson et al . reported four young women with severe alveolar hemorrhage and favorable renal outcome who were found to have a predominance of igg4 autoantibodies that were not detected by routine anti - gbm antibody laboratory assays . they concluded that these antibodies might constitute a distinct subgroup of anti - gbm disease . another recent case series by serisier et al . has suggested that alveolar hemorrhage in anti - gbm disease that is seronegative by routinely available assays may be more common than previously appreciated . subjects in the case series were all smokers who presented with alveolar hemorrhage and minimal evidence of active renal involvement . it may be that subjects with very low levels of anti - gbm antibodies develop isolated pulmonary hemorrhage when exposed to the right precipitant such as volatile hydrocarbons or cigarette smoke . early anti - gbm disease and relatively low circulating antibodies who manifest pulmonary disease due to the direct effects of cigarette smoke on the alveolar walls . smoking has been linked to recurrent disease and could have been the trigger in this case , as she has continued to use tobacco since her initial diagnosis [ 15 , 16 ] . it is possible that smoking may even stimulate production of anti - gbm antibodies by allowing direct contact between the alveolar basement membrane and the immune system [ 1 , 8 ] . other environmental exposures that have been implicated in relapse include organic solvents , hydrocarbons [ 18 , 19 ] , chlorine gas   and hard metal exposure . some case reports have also suggested cocaine   and urinary tract infection   as triggers for relapse . this case emphasizes the need for awareness of the possibility of seronegative anti - gbm disease . several previous cases and case series have reported seronegative disease particularly in patients with recurrences , tobacco users and those with predominantly pulmonary symptoms . renal biopsy should be considered in a patient with diffuse alveolar hemorrhage with even minimal renal involvement   since early diagnosis of anti - gbm disease allows for earlier initiation of life - saving treatment . lastly , diagnosis of anti - gbm disease in such patients warrants greater emphasis on the importance of smoking cessation and close monitoring for disease recurrence .
anti - glomerular basement membrane ( gbm ) disease is commonly a monophasic illness . 
 we present the case of multiple recurrences of anti - gbm disease with varying serum anti - gbm antibody findings . a 33-year - old female tobacco user presenting with hematuria 
 was diagnosed with anti - gbm disease by renal biopsy . 
 five years later , she presented with alveolar hemorrhage and positive anti - gbm antibody . 
 she presented a third time with alveolar hemorrhage but undetectable anti - gbm antibody . with each occurrence , symptoms resolved with plasmapheresis , intravenous methylprednisone and oral cyclophosphamide . 
 the relationship between anti - gbm antibody findings and disease presentation is complex . 
 clinicians should be aware of the possibility of seronegative anti - gbm disease .