goodpasture syndrome ( gps ) was first identified in 1959 by drs stanton and tange , with the description of nine patients with renal failure and pulmonary hemorrhage , all of whom eventually died .
subsequently , the molecular basis of this disease was found to be auto - antibodies formed against the 3 and 5 domains within the non - collagenous part of type iv collagen present in basement membranes of glomeruli and alveoli .
left untreated , gps carries a poor prognosis . conventional treatment for anti - glomerular basement membrane
however , because of the infrequent nature of anti - gbm disease , there is a paucity of randomized clinical trial data with which to inform and optimize therapy .
nonetheless , a small , randomized trial in 1985 of 17 subjects revealed the superiority of immunosuppressive therapy in combination with plasma exchange versus immunosuppression alone .
it is this trial that forms the basis of current treatment recommendations for this disease .
following infusion , rapid b - cell lysis occurs with consequent decline in antibody production , antigen presentation and activation of t - cells and macrophages .
we present a case of concurrent anti - gbm disease and membranous nephropathy , which was resistant to conventional therapy , yet treated successfully with rituximab .
a 24-year - old caucasian male , without a significant past medical history , presented with a 2-week history of hematuria and occasional expectoration of blood - tinged sputum .
he reported a smoking history of 1 pack per day for the past 5 years .
physical examination revealed the following vital signs : temperature of 36.5c , heart rate of 78 bpm , blood pressure of 131/82 mmhg and respiratory rate of 18 per minute with 99% saturation on room air .
laboratory evaluation showed the following values : hemoglobin 1.7 mmol / l ( 11.0 g / dl ) , hematocrit 32.4% , wbc 10.5 k/l , platelets 227 k/l , sodium 138 mmol / l , potassium 4.3 mmol / l , chloride 100 mmol / l , serum creatinine ( scr ) 247.35 mol / l ( 2.8 mg / dl ) and a glucose level of 5.49 mmol / l ( 99 mg / dl ) .
the scr rose to 379.86 mol / l ( 4.3 mg / dl ) over 4 days despite volume expansion with intravenous fluids .
his initial urine albumin - to - creatinine ratio ( acr ) was 1004 mg / g .
he had normal complement levels with c3 and c4 levels of 160 mg / dl ( normal range , 90230 ) and 29 mg / dl ( normal range , 1051 ) , respectively .
other negative tests included the following : antinuclear antibody , anti - neutrophilic cytoplasmic antibody , anti - dna antibody , rheumatoid factor , human immunodeficiency virus antibody , hepatitis c antibody and hepatitis b surface antigen .
anti - gbm titers were pending at the time of kidney biopsy . the kidney biopsy ( figure 1 ) revealed a crescentic glomerulonephritis with 54% of 13 glomeruli demonstrating cellular crescents and linear igg staining of the glomerular capillary basement membrane characteristic of anti - gbm disease , along with faint capillary loop granular staining .
electron microscopy confirmed the presence of occasional small epimembranous and intramembranous electron dense deposits characteristic of membranous nephropathy . 

1.hematoxylin and eosin staining of renal biopsy specimen from a patient with concurrent diagnoses of anti - gbm disease and idiopathic membranous nephropathy that demonstrates a glomerular crescent ; original magnification 200 ( a ) .
linear immunofluorescent staining of gbm by anti - human rabbit immunoglobulin g ; original magnification 400 ( c ) .
electron - dense epimembranous deposits shown by arrows ; original magnification 15 750 ( d ) .
hematoxylin and eosin staining of renal biopsy specimen from a patient with concurrent diagnoses of anti - gbm disease and idiopathic membranous nephropathy that demonstrates a glomerular crescent ; original magnification 200 ( a ) .
linear immunofluorescent staining of gbm by anti - human rabbit immunoglobulin g ; original magnification 400 ( c ) .
electron - dense epimembranous deposits shown by arrows ; original magnification 15 750 ( d ) .
daily apheresis treatments were initiated and were reduced to a thrice - weekly regimen after three consecutive treatments .
he was transitioned to prednisone 60 mg daily by mouth , after 3 intravenous pulse doses of 1 g methylprednisolone and oral , daily cyclophosphamide ( cyc ) 250 mg ( 2.5 mg / kg ) that was soon reduced to 150 mg daily after adjustment for renal function . approximately 2 weeks after admission , he was discharged on prednisone 60 mg daily , cyc 150 mg daily and thrice - weekly apheresis treatments . at discharge ,
mol / l ( 5.2 mg / dl ) and the anti - gbm titer was 86 units .
his scr increased to 644.88 mol / l ( 7.3 mg / dl ) and his anti - gbm titer rose to 132 units . the patient also became volume overloaded .
he received 17 apheresis treatments during his second hospitalization , on a near daily basis .
he also received four hemodialysis treatments that were eventually stopped due to substantial improvement in his kidney function .
mol / l ( 4.5 mg / dl ) with a creatinine clearance of 26 ml / min/1.73 m determined by a 24-h urine collection .
although the scr declined to 362.19 mol / l ( 4.1 mg / dl ) , the anti - gbm titer was persistently elevated .
the patient remained apheresis - dependent and attributable to the lack of response to conventional therapy , b - cell depletion with rituximab was attempted to eliminate antibody production .
approximately 2 months after his initial presentation , the patient received a single , 1000 mg dose of rituximab .
subsequently , the patient 's anti - gbm titer normalized ( figure 2 ) , and the patient was maintained on cyc and prednisone .
prednisone was slowly reduced and ultimately discontinued over a 6-month time period . presently , his scr is 181.98 mol / l ( 2.06 mg / dl ) and the acr is 366 mg /
3.acr , albumin - to - creatinine ratio ; cyc , cyclophosphamide ; d , day ; m , month ; p , prednisone ; scr , serum creatinine ( mg / dl ) ; titer reported in units .
acr , albumin - to - creatinine ratio ; cyc , cyclophosphamide ; d , day ; m , month ; p , prednisone ; scr , serum creatinine ( mg / dl ) ; titer reported in units .
our patient experienced a rapidly progressive course typical of anti - gbm disease eventuating in hemodialysis .
the treating care providers opted initially for a treatment regimen consisting of apheresis , cyc and prednisone .
the cyc plus prednisone approach has been one of the main regimens to treat membranous nephropathy , and initially , we felt that this approach would provide efficacious treatment of both glomerulopathies .
a review published in 2011 reported a case of concurrent anti - gbm disease and membranous nephropathy and reviewed 25 previously reported cases .
more recently , the etiopathogenesis of idiopathic membranous nephropathy has been characterized and determined to result from auto - antibodies directed against the podocyte - related antigen , phospholipase a2 [ 810 ] .
previously , basford et al .   hypothesized that concurrent disease resulted from the induction of one disorder from the other .
it is also possible that a biclonal autoimmune response is responsible for the simultaneous occurrence of anti - gbm disease and membranous nephropathy .
biclonality is a rare but established phenomenon and has been described in multiple myeloma and lymphomas .
the index patient demonstrated a clear correlation between his anti - gbm titers and his kidney function ( figure 2 ) .
our patient 's initial presenting anti - gbm titers were highly elevated ( nine times the reference range ) but minimally responsive to conventional therapy ( cyc and prednisone ) .
since he was apheresis - dependent and required renal replacement therapy , conventional therapy was considered a failure .
given the persistence of the anti - gbm titer , the alternative anti - cd20 b - cell depletion treatment represented a plausible and rational option in this disorder .
there has been increasing evidence that rituximab is effective for the treatment of membranous nephropathy [ 1214 ] , and this treatment has been efficacious in six of seven isolated cases of anti - gbm disease ( table 1 ) [ 1519 ] .
this report represents the seventh successful instance of rituximab treatment of anti - gbm disease and the second case where independence from renal replacement therapy was achieved .
moreover , this is the first case where rituximab has been used as simultaneous treatment of coexistent membranous nephropathy and anti - gbm disease . 

table 1.summary of anti - gbm cases reporting the use of rituximabcaselung involvementanti - gbm titer before treatmenttreatmentanti - gbm titer after treatmentoutcomeweschler et al.55-year - old male with hivno symptomatic lung involvement8.6 eu / dl ( nl < 5)p , mmf , ivig , 375 mg / m rituximab 4 weekly dosesnegative for 16 months of follow - upscr 1.2 mg / dl at 16 months follow - uparzoo et al.73-year - old female with gps relapse after 1-year remissionclinical lung involvement51 iu / dlplex , p and cyc , followed by rituximab 375 mg / m , 6 weekly doses , followed by azathioprine maintenance after 4th cyclenegativein remission after 10 monthsshah et al.54-year - old male , anti - gbm disease dialysis - dependent at outsetovert lung hemorrhage>680 u / mlpmp , plex , cyc that was switched to rituximab 375 mg / m 4 weekly dosesnegativedialysis - dependent and on transplant listshah et al.64-year - old male , anti - gbm disease , p - anca positive , required dialysis , initial scr 6.37 mg / dl ( 536 mol / l)49 u / mlhigh - dose steroids , plex , cyc converted to rituximab 375 mg / m , 4 weekly dosesnegativedialysis - independent with scr 2.94 mg / dl ( 260 mol / l)shah et al.17-year - old maleanti - gbm disease , initial scr 3.08 ( 272 mol / l)clinical lung involvement131 u / l(nl < 3)four doses of pmp , plex , and 2 weekly doses of rituximab 375 mg / mnegativescr 1.13 mg / dl after 33 monthssyeda et al.68-year - old female dialysis - dependent , scr 11.3 mg / dl , p - anca positive developed ttpno lung involvementanti - gbm ab > 1:160,nl < 1:20plex , p , cyc ( 5 days ) , 4 doses of rituximab 375 mg / mnegativedialysis - dependentsauter m. et al.29-year - old , male status post - ddkt because of goodpasture 's , presented with aki 16 mo post - transplantno symptomatic lung disease after recurrence95.5 iu / dl ( nl < 4)plex , mmf dose escalation to 3 g / d , and pafter 2 weeks mmf substituted by cycrituximab 375 mg/ for 3 weekly dosesloss of renal graft , patient on rrtab , antibody ; acr , albumin - to - creatinine ratio ; anca , antineutrophil cytoplasmic antibody ; cyc , cyclophosphamide ; ddkt , deceased donor kidney transplant ; gbm , glomerular basement membrane ; gps , goodpasture syndrome ; hiv , human immunodeficiency virus ; ivig , intravenous immunoglobulin ; mo , month(s ) ; mmf , mycophenolate mofetil ; nl , normal ; p , prednisone ; plex , plasma exchange ; rrt , renal replacement therapy ; scr , creatinine ( mg / dl ) ; ttp , thrombotic thrombocytopenic purpura ; wk , week(s ) ; u , antibody titer units
. summary of anti - gbm cases reporting the use of rituximab ab , antibody ; acr , albumin - to - creatinine ratio ; anca , antineutrophil cytoplasmic antibody ; cyc , cyclophosphamide ; ddkt , deceased donor kidney transplant ; gbm , glomerular basement membrane ; gps , goodpasture syndrome ; hiv , human immunodeficiency virus ; ivig , intravenous immunoglobulin ; mo , month(s ) ; mmf , mycophenolate mofetil ; nl , normal ; p , prednisone ; plex , plasma exchange ; rrt , renal replacement therapy ; scr , creatinine ( mg / dl ) ; ttp , thrombotic thrombocytopenic purpura ; wk , week(s ) ; u , antibody titer units .
the index patient , formerly dialysis- and apheresis - dependent , is now apheresis - independent and completed cyc and prednisone therapies after just a single rituximab treatment .
the proteinuria nearly completely resolved and the scr stabilized at 181.98 mol / l ( 2.06 mg / dl ) .
we contend that rituximab has induced a coincident and complete remission of his two separate glomerulopathies .
lastly , given the positive outcomes of this case and the pathobiology of anti - gbm disease , we suggest b - cell depletion therapy as an alternative treatment modality in refractory anti - gbm disease .
 antibody - mediated anti - glomerular basement membrane ( anti - gbm ) disease occurs rarely in the presence of another b - cell disorder , membranous nephropathy . 
 the coexistence of these two autoimmune disorders would be anticipated to require differing , specific therapies targeted to each disease process . 
 we describe a case of concomitant membranous nephropathy and anti - gbm disease in which conventional therapy , including steroids , plasmapheresis and cyclophosphamide , failed to attenuate the anti - gbm disease , yet responded to an alternative treatment of rituximab . 
 this b - cell directed , monoclonal , chimeric antibody treatment substantially reduced anti - gbm antibody titers and led to discontinuation of plasmapheresis , while maintaining the remission of membranous nephropathy and anti - gbm disease . 