Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients

Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such ‘double-positive’ cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies. Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such ‘double-positive’ cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies. Anti-glomerular basement membrane (GBM) disease and the anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are rare conditions, with estimated incidences in Europe of 1 and 20 per million population per year, respectively.1Pusey C.D. Anti-glomerular basement membrane disease.Kidney Int. 2003; 64: 1535-1550Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 2Watts R.A. Mahr A. Mohammad A.J. et al.Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.Nephrol Dial Transplant. 2015; 30: i14-i22Crossref PubMed Scopus (165) Google Scholar The concurrence of both ANCA and anti-GBM antibodies in individual patients, however, is well-recognized, and occurs at a much higher frequency than would be expected by chance alone. This phenomenon was first reported within a few years of the first description of ANCA in the 1980s,3O’Donoghue D.J. Short C.D. Brenchley P.E. et al.Sequential development of systemic vasculitis with anti-neutrophil cytoplasmic antibodies complicating anti-glomerular basement membrane disease.Clin Nephrol. 1989; 32: 251-255PubMed Google Scholar, 4Jayne D.R. Marshall P.D. Jones S.J. et al.Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis.Kidney Int. 1990; 37: 965-970Abstract Full Text PDF PubMed Scopus (234) Google Scholar and has been observed in several series from around the world over the subsequent 30 years.5Levy J.B. Hammad T. Coulthart A. et al.Clinical features and outcome of patients with both ANCA and anti-GBM antibodies.Kidney Int. 2004; 66: 1535-1540Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 6Rutgers A. Slot M. van Paassen P. et al.Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis.Am J Kidney Dis. 2005; 46: 253-262Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 7Zhao J. Yang R. Cui Z. et al.Characteristics and outcome of Chinese patients with both antineutrophil cytoplasmic antibody and antiglomerular basement membrane antibodies.Nephron Clin Pract. 2007; 107: c56-c62Crossref PubMed Scopus (27) Google Scholar, 8J DEZ Taylor D. Thein H. et al.Incidence and features of dual anti-GBM-positive and ANCA-positive patients.Nephrology. 2011; 16: 725-729Crossref PubMed Scopus (28) Google Scholar It is clear that the 2 antibody populations associated with these diseases are antigenically distinct,9Short A.K. Esnault V.L. Lockwood C.M. Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis.Am J Kidney Dis. 1995; 26: 439-445Abstract Full Text PDF PubMed Scopus (94) Google Scholar and that this phenomenon is not due to cross-reactivity, although the mechanisms of the association are not fully understood. Several studies have reported the outcomes of these patients who are double positive, although with conflicting findings; some have observed better outcomes compared with those with single-positive anti-GBM disease,4Jayne D.R. Marshall P.D. Jones S.J. et al.Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis.Kidney Int. 1990; 37: 965-970Abstract Full Text PDF PubMed Scopus (234) Google Scholar, 10Bosch X. Mirapeix E. Font J. et al.Prognostic implication of anti-neutrophil cytoplasmic autoantibodies with myeloperoxidase specificity in anti-glomerular basement membrane disease.Clin Nephrol. 1991; 36: 107-113PubMed Google Scholar, 11Segelmark M. Hellmark T. Wieslander J. The prognostic significance in Goodpasture's disease of specificity, titre and affinity of anti-glomerular-basement-membrane antibodies.Nephron Clin Pract. 2003; 94: c59-c68Crossref PubMed Scopus (105) Google Scholar while others have suggested that patients who are double positive have comparable or worse outcomes.5Levy J.B. Hammad T. Coulthart A. et al.Clinical features and outcome of patients with both ANCA and anti-GBM antibodies.Kidney Int. 2004; 66: 1535-1540Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 6Rutgers A. Slot M. van Paassen P. et al.Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis.Am J Kidney Dis. 2005; 46: 253-262Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 12Weber M.F. Andrassy K. Pullig O. et al.Antineutrophil-cytoplasmic antibodies and antiglomerular basement membrane antibodies in Goodpasture’s syndrome and in Wegener's granulomatosis.J Am Soc Nephrol. 1992; 2: 1227-1234PubMed Google Scholar, 13Lindic J. Vizjak A. Ferluga D. et al.Clinical outcome of patients with coexistent antineutrophil cytoplasmic antibodies and antibodies against glomerular basement membrane.Ther Apher Dial. 2009; 13: 278-281Crossref PubMed Scopus (37) Google Scholar, 14Srivastava A. Rao G.K. Segal P.E. et al.Characteristics and outcome of crescentic glomerulonephritis in patients with both antineutrophil cytoplasmic antibody and anti-glomerular basement membrane antibody.Clin Rheumatol. 2013; 32: 1317-1322Crossref PubMed Scopus (33) Google Scholar, 15Alchi B. Griffiths M. Sivalingam M. et al.Predictors of renal and patient outcomes in anti-GBM disease: clinicopathologic analysis of a two-centre cohort.Nephrol Dial Transplant. 2015; 30: 814-821Crossref PubMed Scopus (69) Google Scholar, 16Cui Z. Zhao J. Jia X.Y. et al.Anti-glomerular basement membrane disease: outcomes of different therapeutic regimens in a large single-center Chinese cohort study.Medicine (Baltimore). 2011; 90: 303-311Crossref PubMed Scopus (88) Google Scholar These studies, however, have generally been limited by small size (many describing fewer than 20 cases) and variations in the severity of disease at presentation, with between 0% and 100% of patients being dependent on dialysis at DEZ Taylor D. Thein H. et al.Incidence and features of dual anti-GBM-positive and ANCA-positive patients.Nephrology. 2011; 16: 725-729Crossref PubMed Scopus (28) Google Scholar, 15Alchi B. Griffiths M. Sivalingam M. et al.Predictors of renal and patient outcomes in anti-GBM disease: clinicopathologic analysis of a two-centre cohort.Nephrol Dial Transplant. 2015; 30: 814-821Crossref PubMed Scopus (69) Google Scholar in the series to from Chinese fewer than of patients with and the of the to European patients with different therapeutic regimens is J. Yang R. Cui Z. et al.Characteristics and outcome of Chinese patients with both antineutrophil cytoplasmic antibody and antiglomerular basement membrane antibodies.Nephron Clin Pract. 2007; 107: c56-c62Crossref PubMed Scopus (27) Google Scholar, 16Cui Z. Zhao J. Jia X.Y. et al.Anti-glomerular basement membrane disease: outcomes of different therapeutic regimens in a large single-center Chinese cohort study.Medicine (Baltimore). 2011; 90: 303-311Crossref PubMed Scopus (88) Google Scholar The of the study is to the clinical features and long-term outcomes of a contemporary cohort of patients with double-positive ANCA and anti-GBM the of these patients, we have cases from large European comparable treatment for these and have compared clinical features and outcomes to those for single-positive AAV and single-positive anti-GBM patients with double-positive disease more those with single-positive anti-GBM disease at presentation, we have compared and treatment in these 2 groups. and a of cases at in 568 patients with single-positive 41 with single-positive anti-GBM disease, and 37 patients who double positive for anti-GBM antibodies and ANCA and double-positive The of double-positive to single-positive anti-GBM cases was similar in all however, patients who double positive a variable of the AAV cases to The features of the cohort are in The single-positive anti-GBM the age distribution of this disease, whereas patients who double positive had age distribution similar to patients with AAV was in between the groups. 1 patient in the double-positive had a of and AAV 2 years to with double-positive clinical and of for a of ANCA for patients on for patients on for anti-neutrophil cytoplasm estimated glomerular glomerular basement renal of of as median between by with to between individual or by for a of ANCA for patients on in a anti-neutrophil cytoplasm estimated glomerular glomerular basement renal of of as median between by with to between individual or by 1 clinical features and at presentation. The duration of to a was similar in the AAV and double-positive and this was longer than in single-positive anti-GBM patients Despite duration of the severity of as for in patients who not by or anti-GBM patients was similar to that of patients who double The frequency of hemorrhage was similar in anti-GBM and double-positive in of patients. disease and lung in patients with in approximately of who double positive had disease features and a of anti-GBM during the study and at different by as of the of for who double positive to have of anti-GBM antibodies than anti-GBM patients who positive, although the between was not similar of patients in both these for anti-GBM these was evidence of on renal in the of in with of anti-GBM the AAV the of patients who positive for antibody was approximately However, in the double-positive was a of patients with antibodies patient in the double-positive was positive for and anti-GBM this patient had a of and was positive for a of and to ANCA over the of the was not to of ANCA the anti-GBM and double-positive had similar disease severity at presentation, we more analysis to and therapeutic in these 2 of patients in both renal as in The severity of renal disease in those who biopsy was similar in both and to the severity of renal disease in the that biopsy be and comparable between groups. It was not however, to retrospectively the renal biopsy was not in all patients. some this was due to the for treatment with and others for with the age between the the age in the of patients who biopsy was in the anti-GBM compared with the double-positive age at at for patients on for patients on estimated glomerular glomerular basement renal as median between by or by for patients on in a estimated glomerular glomerular basement renal as median between by or by The median of in biopsy was was in the of crescentic between the 2 groups. however, a tendency for more to be observed in patients who double positive the of to be more observed in patients with anti-GBM disease in patients who double was a in the of and between these 2 with more evidence of chronic in double-positive cases those cases in was for all cases 1 single-positive for and all with anti-GBM had of by analysis of the was detectable between single-positive anti-GBM and double-positive with to treatment the of with 100% in double-positive and anti-GBM and patients not for the double-positive patients not 2 dialysis dependent at with 100% on and in the of lung was These patients and for the patients, had hemorrhage or required and treatment was of those with AAV. the single-positive anti-GBM 1 patient was dialysis dependent with on and treatment was 1 patient had renal and was for to treatment and was not and 1 patient was and to of patients who double positive treatment with or with with and with whereas of patients with single-positive anti-GBM disease of and and renal survival for all at and is in patient survival was similar in all at both survival was in the AAV at both although was in the of patients who required dialysis in the anti-GBM and double-positive at The of patients who with dialysis-dependent renal and who renal and at 1 was different between from in patients with single-positive anti-GBM disease to in patients who double positive and in AAV 2 this was due in to from dialysis to and within the double-positive in a renal in the first of follow-up in patients who was in age or of between those patients and who double-positive and who and those who although those who renal to have of anti-GBM antibodies of the patients who double-positive who renal renal and was not to of treatment and renal survival at and after at 1 of patients requiring at who with renal at 1 of for for anti-neutrophil cytoplasm glomerular basement renal between by for of patients requiring at who with renal at 1 in a anti-neutrophil cytoplasm glomerular basement renal between by The median duration of follow-up was 4.8 years patient and renal survival is in and No in overall patient survival was observed during the study survival was in the AAV compared with both the anti-GBM and the double double-positive who double positive to have better renal survival than those who positive with anti-GBM disease, although this was not in analysis in AAV patients and all patients with anti-GBM disease and double the follow-up of patients with AAV and of 37 patients who double positive had a patients with single-positive anti-GBM disease had early of anti-GBM antibodies requiring treatment in the first diagnosis, we disease than disease No patients with single-positive anti-GBM disease evidence of or recurrent antibodies long-term a approximately of the surviving patients who double positive recurrent disease These to to first and the of in patients with ANCA against in with the of AAV. patients had associated with and 1 patient had a of both and anti-GBM in patient who ANCA positive, and the of associated with a in ANCA of more than or from to ANCA-positive in the to of the clinical features of and to the of patients not maintenance treatment than at the of in the frequency of in the double-positive cohort was comparable to that in AAV cases whereas in the anti-GBM patients who double positive have renal To disease to ANCA or anti-GBM disease has been in the renal of double-positive patients with to at of for treatment treatment anti-neutrophil cytoplasm glomerular basement years. in a anti-neutrophil cytoplasm glomerular basement years. in age, of patients requiring renal and of patients with lung hemorrhage at between patients with anti-GBM disease, and double analysis to of and renal disease in all patients, for these in of and renal or for of for of for of at at at or for of for of for of at at at anti-neutrophil cytoplasm double renal basement membrane lung renal for of in a anti-neutrophil cytoplasm double renal basement membrane lung renal of included at lung hemorrhage and age not at and age The of lung hemorrhage at while had of to included lung hemorrhage at and at was not associated with to at and the of to The of was in anti-GBM disease compared with AAV the in patients who double positive those with AAV was not different intermediate of in patients who double and lung hemorrhage at had on to of a outcome of or to included age at and lung hemorrhage at at and age associated with to or hemorrhage at was not associated with to or or to was similar between double-positive and single-positive anti-GBM disease However, patients with AAV had a of to or compared with patients who double positive of included and at was associated with a of analysis was not due to the small of This is the series to the outcomes of patients with both ANCA and anti-GBM autoantibodies with patients with single-positive AAV and anti-GBM several the phenomenon of double is common, these patients the early and of anti-GBM disease, and the long-term of of AAV. who are double positive for approximately of all anti-GBM disease cases at and over of AAV patients with renal at the over the The of AAV cases was variable at the in at of patients with and in of to or variations in disease a study reported that more than of patients with anti-GBM disease had autoantibodies to of who had antibodies to by study this and the to the antibody in all cases of or anti-GBM this large we observed comparable severity of disease at between single-positive anti-GBM and double-positive with approximately of patients requiring renal at presentation, and lung in both groups. analysis that is these severe disease than per that overall patient and are in patients with anti-GBM disease and those who are double positive than in this that anti-GBM disease is the early disease in double-positive These patients, however, clinical features of such as older age a longer of systemic and features of chronic on renal biopsy of would be expected for the age between analysis that patients who are double positive have intermediate of to compared with single-positive AAV or anti-GBM This be to the that more than of the surviving patients who double positive and required dialysis at renal by This to renal was more in with AAV than anti-GBM disease, renal from dialysis is J.B. A.J. C.D. outcome of anti-glomerular basement membrane antibody disease with and PubMed Scopus Google Scholar and with some of double-positive D.R. Marshall P.D. Jones S.J. et al.Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis.Kidney Int. 1990; 37: 965-970Abstract Full Text PDF PubMed Scopus (234) Google Scholar, 10Bosch X. Mirapeix E. Font J. et al.Prognostic implication of anti-neutrophil cytoplasmic autoantibodies with myeloperoxidase specificity in anti-glomerular basement membrane disease.Clin Nephrol. 1991; 36: 107-113PubMed Google Scholar, 11Segelmark M. Hellmark T. Wieslander J. The prognostic significance in Goodpasture's disease of specificity, titre and affinity of anti-glomerular-basement-membrane antibodies.Nephron Clin Pract. 2003; 94: c59-c68Crossref PubMed Scopus (105) Google Scholar patients who double positive had this tendency to renal and intermediate long-term renal more chronic renal on biopsy and more advanced age at presentation, is to have of anti-GBM that have been early in the of anti-GBM disease, or that have a of are several of of anti-GBM disease, by severe renal than is A. O. et and crescentic glomerulonephritis with renal in patients with underlying disease: a 2015; PubMed Scopus Google Scholar, H. et anti-glomerular basement membrane antibodies with of and in anti-glomerular basement membrane J Kidney Dis. Full Text Full Text PDF PubMed Scopus Google Scholar, et clinicopathologic characteristics and outcome of anti-glomerular basement membrane Int. Full Text Full Text PDF PubMed Scopus (69) Google Scholar in antibody or in or specificity for these variable to patients who are double positive, 1 study that had a of anti-GBM antibodies and to than patients who R. Hellmark T. Zhao J. et and specificity of anti-glomerular basement membrane antibodies in patients with disease with or anti-neutrophil cytoplasmic Am Soc Nephrol. 2007; PubMed Scopus Google Scholar although study not report in T. et of anti-GBM antibodies in with or Am Soc Nephrol. PubMed Google Scholar It is that in or specificity for the in treatment in however, we to this in in a we have been to of a of studies have that the of crescentic and in anti-GBM disease is of J.B. A.J. C.D. outcome of anti-glomerular basement membrane antibody disease with and PubMed Scopus Google Scholar, D.J. Anti-glomerular basement membrane a study of J Clin PubMed Scopus (37) Google Scholar and a prognostic on has been for ANCA-associated et of ANCA-associated Am Soc Nephrol. PubMed Scopus Google Scholar, A. et outcome of anti-neutrophil cytoplasm of the and prognostic Dial Transplant. 2015; 30: PubMed Scopus Google Scholar It is however, these to patients who are double the overall of anti-GBM disease, a analysis of in these cases is in to prognostic such that while patients who are double positive those with anti-GBM disease, a of patients who are dialysis dependent at be more to and aggressive treatment be in some The of AAV by patients who are double positive is a of disease The long-term follow-up by study that of surviving patients who are double positive disease at some at a frequency comparable to that observed in single-positive AAV be these more in patients who positive, and associated with in ANCA 1 patient with both ANCA and anti-GBM These that while the early disease in these patients is anti-GBM disease, patients with anti-GBM disease these cases long-term follow-up and consideration of maintenance 1 of patients had of AAV to with a double-positive that anti-GBM antibodies be in AAV is evidence of renal The of association between AAV and anti-GBM disease in in that of the antibody the severity of renal disease in of vasculitis or anti-GBM K. T. T. of by antibodies.Kidney Int. 1995; Full Text PDF PubMed Scopus Google Scholar, P. E. et al.Autoantibodies to myeloperoxidase glomerular injury in the J Google Scholar, et of anti-glomerular basement membrane antibodies and glomerular neutrophil on glomerulonephritis in cytoplasmic antibody vasculitis.Nephrol Dial Transplant. PubMed Scopus Google Scholar however, these in studies have on the development of both antibody or on the in in clinical clinical study by and from the of suggested that the of patients with anti-GBM disease had detectable ANCA to the development of anti-GBM in the development of clinical disease, that AAV as for anti-GBM et autoantibodies with anti-glomerular basement membrane Am Soc Nephrol. 2011; PubMed Scopus Google Scholar this patients who double positive had the age of AAV a longer of systemic to diagnosis, and more features of on renal that glomerular and to the development of anti-GBM disease, by the of the O. et of the in anti-GBM of PubMed Scopus Google Scholar This to the of in a in a anti-GBM has been that of as a of neutrophil to the development of D. A. et and of neutrophil of neutrophil in a of myeloperoxidase antineutrophil cytoplasmic 64: PubMed Scopus Google Scholar and that neutrophil are in anti-GBM et in severe Am Soc Nephrol. 2015; 26: PubMed Scopus Google Scholar Thus, is that glomerular neutrophil and in anti-GBM disease to the development of The that a high of patients with anti-GBM disease have autoantibodies to of this as to as a of and by anti-GBM Cui Z. J. et al.Autoantibodies against of myeloperoxidase in anti-glomerular basement membrane disease.Clin J Am Soc Nephrol. PubMed Scopus Google Scholar or to both antibodies is The of both anti-GBM disease and AAV are van D. et in ANCA-associated a Dis. PubMed Scopus Google Scholar, Zhao et in the of anti-glomerular basement membrane J Nephrol. 32: PubMed Scopus Google Scholar and both have with both have reported with and a small study observed a in of the patients who double positive that M. et with Goodpasture’s disease have two the of the Dial Transplant. 2004; PubMed Scopus Google Scholar this we have been to the or and features of of however, large follow-up years for patients, the of all single-positive anti-GBM and AAV cases by of and that is from that comparable treatment several clinical that while anti-GBM disease is the disease in these patients, ANCA be a be more to and have a of requiring careful long-term follow-up and This is a analysis of patients with anti-GBM disease, and double-positive ANCA and anti-GBM antibody disease from European and patients between and with at 1 of follow-up included in with a of systemic vasculitis with the et of 2013; PubMed Scopus Google Scholar and positive ANCA included in the AAV disease was by the of anti-GBM antibodies in association with clinical of hemorrhage rapidly progressive or crescentic glomerulonephritis with of the GBM in the of as or The double-positive cohort included patients who this of anti-GBM disease and in had positive ANCA anti-GBM antibodies between and over at included or GBM and ANCA was by or by or ANCA who are ANCA positive by ANCA specificity to myeloperoxidase or patients who positive by by those with a to the and those with a cytoplasmic to the of the and to on of clinical presentation, and outcomes. from clinical to at was by the for dialysis during the first was by a for that not recover during follow-up or before was estimated by the in J.B. et more to glomerular from a of in PubMed Scopus Google Scholar by or in disease requiring we renal biopsy by the of or was by the of glomerular in the whereas a of or and those with included in the of included those with or or compared clinical features and long-term outcomes between all we more of and treatment in the single-positive anti-GBM and double-positive groups. as of and with than 2 to between individual groups. of between was was to survival and as analysis was to of associated with outcomes and or as a included in the analysis included diagnosis, age, at presentation, and lung hemorrhage at presentation. the in the was the as a with double-positive as the The analysis was with AAV as the to between AAV and anti-GBM was for included in the are as and analysis and this was a study and all treatment to was not required for this the The reported in at the and ANCA in in and at the of in in is in of a for a This work was by the The are those of the and not those of the the or the of from at ANCA in anti-GBM disease: a clinical et that patients with both antiglomerular basement membrane antibody and antineutrophil cytoplasm antibody a that between that of single-positive antiglomerular basement membrane disease and antineutrophil cytoplasm be a of that have a more to These with of antiglomerular basement membrane disease, to antiglomerular basement membrane disease as a and better clinical PDF