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GOODPASTURES SYNDROME WITH CONCOMITANT
IMMUNE COMPLEX MIXED MEMBRANOUS AND
PROLIFERATIVE GLOMERULONEFRITIS
VESNA JURČIĆ1 ANDREJA ALEŠ RIGLER2
INSTITUTE OF PATHOLOGY FACULTY OF MEDICINE UNIVERSITY OF LJUBLJANA
SLOVENIA 2CLINICAL DEPARTMENT OF NEPHROLOGY UNIVERSITY CLINICAL CENTRE
LJUBLJANA SLOVENIA
A CASE REPORT
A 21-year-old woman presented to her local hospital in July
2006 with a one week history of flue-like illness chest
pain dyspnoe and blood-streaked sputum
Chest radiography showed bilateral patchy lung opacities
interpreted as possible atypical pneumonia which
regressed after treatment with azythromycin
No results of urinalysis
The patient was free of symptoms until the end of October
2006
OCTOBER 2006
Haemoptysis dyspnoe generalized oedema
Radiologic findings consistent with diffuse alveolar
haemorrhage
Severe anaemia
Nephrotic syndrome with erythrocyturia
Normal renal function
Urinalysis
proteinuria 63 gd erythrocyturia 209 leukocyturia 78 (x10⁶L)
Blood tests
blood urea nitrogen 120 mgdL (43 mmolL)
serum albumin 23 gdL (23 gL)
haemoglobin 92 gdL (92 gL)
Immunoserology
anti-GBM antibodies negative by standard ELISA
Hep ndash 2 ANA 1320 (speckled pattern)
Other immunoserology negative also in further follow-up
ENA anti-dsDNA anticardiolipin IgG and IgM
p-ANCA c-ANCA MPO-ANCA PR3-ANCA
Cryoglobulins
C3 and C4
all normal
LABORATORY FINDINGS
THE FIRST BIOPSY
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
IgM
THE FIRST BIOPSY
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
A CASE REPORT
A 21-year-old woman presented to her local hospital in July
2006 with a one week history of flue-like illness chest
pain dyspnoe and blood-streaked sputum
Chest radiography showed bilateral patchy lung opacities
interpreted as possible atypical pneumonia which
regressed after treatment with azythromycin
No results of urinalysis
The patient was free of symptoms until the end of October
2006
OCTOBER 2006
Haemoptysis dyspnoe generalized oedema
Radiologic findings consistent with diffuse alveolar
haemorrhage
Severe anaemia
Nephrotic syndrome with erythrocyturia
Normal renal function
Urinalysis
proteinuria 63 gd erythrocyturia 209 leukocyturia 78 (x10⁶L)
Blood tests
blood urea nitrogen 120 mgdL (43 mmolL)
serum albumin 23 gdL (23 gL)
haemoglobin 92 gdL (92 gL)
Immunoserology
anti-GBM antibodies negative by standard ELISA
Hep ndash 2 ANA 1320 (speckled pattern)
Other immunoserology negative also in further follow-up
ENA anti-dsDNA anticardiolipin IgG and IgM
p-ANCA c-ANCA MPO-ANCA PR3-ANCA
Cryoglobulins
C3 and C4
all normal
LABORATORY FINDINGS
THE FIRST BIOPSY
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
IgM
THE FIRST BIOPSY
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
OCTOBER 2006
Haemoptysis dyspnoe generalized oedema
Radiologic findings consistent with diffuse alveolar
haemorrhage
Severe anaemia
Nephrotic syndrome with erythrocyturia
Normal renal function
Urinalysis
proteinuria 63 gd erythrocyturia 209 leukocyturia 78 (x10⁶L)
Blood tests
blood urea nitrogen 120 mgdL (43 mmolL)
serum albumin 23 gdL (23 gL)
haemoglobin 92 gdL (92 gL)
Immunoserology
anti-GBM antibodies negative by standard ELISA
Hep ndash 2 ANA 1320 (speckled pattern)
Other immunoserology negative also in further follow-up
ENA anti-dsDNA anticardiolipin IgG and IgM
p-ANCA c-ANCA MPO-ANCA PR3-ANCA
Cryoglobulins
C3 and C4
all normal
LABORATORY FINDINGS
THE FIRST BIOPSY
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
IgM
THE FIRST BIOPSY
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
Urinalysis
proteinuria 63 gd erythrocyturia 209 leukocyturia 78 (x10⁶L)
Blood tests
blood urea nitrogen 120 mgdL (43 mmolL)
serum albumin 23 gdL (23 gL)
haemoglobin 92 gdL (92 gL)
Immunoserology
anti-GBM antibodies negative by standard ELISA
Hep ndash 2 ANA 1320 (speckled pattern)
Other immunoserology negative also in further follow-up
ENA anti-dsDNA anticardiolipin IgG and IgM
p-ANCA c-ANCA MPO-ANCA PR3-ANCA
Cryoglobulins
C3 and C4
all normal
LABORATORY FINDINGS
THE FIRST BIOPSY
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
IgM
THE FIRST BIOPSY
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE FIRST BIOPSY
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
IgM
THE FIRST BIOPSY
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
IgM
THE FIRST BIOPSY
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE FIRST BIOPSY
IgG
THE FIRST BIOPSY
IgG
IgM
THE FIRST BIOPSY
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE FIRST BIOPSY
IgG
IgM
THE FIRST BIOPSY
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE FIRST BIOPSY
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE FIRST BIOPSY
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE FIRST BIOPSY ACTIVE LESIONS
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE FIRST BIOPSY 814 (57) CRESCENTS
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE DIAGNOSIS
Anti-GBM glomerulonephritis with concomitant immune
complex membranous and proliferative
glomerulonephritis (mesangioproliferative and segmental
endocapillary proliferative pattern)
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
TREATMENT (NOVEMBER 2006 ndash JULY 2007)
Plasmapheresis
Metylprednisolone pulses iv
Cyclophosphamide
The symptoms of respiratory insufficiency and haemoptysis
disappeared
Maintenance therapy with metylprednisolone because of
persistent proteinuria
ANA 180
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
AUGUST 2007
THE FIRST RECURRENCE
Recurrence of nephrotic proteinuria and erythrocyturia no
pulmonary involvement
ANA 1320
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
AUGUST 2007
THE FIRST RECURRENCE
Immunoserology anti-GBM antibodies negative by standard tests
but positive by more sensitive detection methods
1) ELISA test for IgG subclasses revealed low titre of IgG4 antibodies
2) anti-GBM antibodies positive by IIF on biochips containing purified GP antigen (NC1 domain of alpha 3 collagen IV)
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE SECOND BIOPSY
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE SECOND BIOPSY
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE SECOND BIOPSY
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
THE DIAGNOSIS
Anti-GBM glomerulonephritis (1020 ndash 50 crescents)
with concomitant immune complex proliferative
glomerulonephritis (in this biopsy also
membranoproliferative)
Due to SED and SEP deposits it may be classified as
membranoproliferative glomerulonephritis type III
(atypical ndash focal and segmental changes)
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
TREATMENT
Metylprednisolone
Mycophenolate mofetil (MMF)
In December 2007 nephrotic syndrome remitted but
proteinuria persisted ndash 15 gd (partial remission)
ANA 180
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
AUGUST 2009
SECOND RECURRENCE
In August 2009 pulmonary involvement with haemoptysis
and radiologic signs of diffuse alveolar haemorrhage
without renal involvement
ANA 1320
Anti-GBM antibodies by standard ELISA were negative but
now positive by indirect immunofluorescence on normal
kidney 110 and on α3 col IV biochip 110
Treatment methylprednisolone pulses and MMF continued
Haemoptysis disappeared
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
LAST FOLLOW-UP IN DECEMBER 2009
Laboratory results within normal ranges but persistent
proteinuria (12 gd)
December 2009 ndash 2014 She failed to attend subsequent
outpatient appointments and became lost to follow-up
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
CONCLUSIONS
Classical GP syndrome is monophasic disease clinically
presented as RPGN and histologically characterized by
diffuse crescentic glomerulonephritis without significant
mesangial proliferation
The majority of patients have circulating anti-GBM
antibodies detectable with standard anti-GBM ELISA
OUR PATIENT
bull Not so extensive crescentic GN with normal renal
function only about 50 crescents small to medium
sized with not much glomerular destruction and
necrosis
bull Concurrent immune complex membranous and
proliferative GN (MEZ ENDO and MPGN in the second
biopsy)
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
CONCLUSIONS
bull Anti-GBM antibodies detected only by more sensitive
methods
bull Persistent proteinuria
bull Recurrent course
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
CONCLUSION
It is not clear which pathogenetic mechanisms was the
initial the anti-GBM or immune-complex mediated
Both possibilities (case reports and experimentally) initial
disease (anti-GBM or MGN) exposes or changes antigens
of the glomerular basement membranerarr another types of
autoantibodies are formed
In our patient temporal relation can not be determined the
patient had chronic lesions already in the first biopsy
and initial clinical data are lacking
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
CONCLUSION
The patient had a persistently positive ANA and ANA titres
corresponded with relapses of the disease Whether ANA
have a pathogenetic role in her disease is unclear
The patient did not fulfill criteria for the diagnosis of SLE
Furthermore there were no ldquofull-houserdquo immune
deposits no extraglomerular granular immune deposits
no tubuloreticular inclusions or bdquofingerprintsldquo by EM
However this patient probably had an autoimmune
syndrome associated with the production of more than
one type of antibodies
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
Clin Nephrol 2014 Mar81(3)216-23
Goodpastures syndrome with concomitant immune
complex mixed membranous and proliferative
glomerulonephritis
Jurčić V Vizjak A Rigler Aleš A Jeruc J Wieslander J Ferluga D
![CONCOMITANT SYMPTOMS & REMEDIEShomoeopathybooks.com/Repertory of Concomitant Symptoms-1/Repe… · CONCOMITANT SYMPTOMS & REMEDIES :- GRAPH., KALI FACE :[ABDOMEN] : ... aconite if](https://img.pdfslide.net/doc/110x75/5aac6f627f8b9a8f498d0756/concomitant-symptoms-reme-of-concomitant-symptoms-1repeconcomitant-symptoms.jpg)
