GOODPASTURE'S SYNDROME WITH CONCOMITANT IMMUNE COMPLEX MIXED MEMBRANOUS AND PROLIFERATIVE GLOMERULONEFRITIS

Transcription

1 GOODPASTURE'S SYNDROME WITH CONCOMITANT IMMUNE COMPLEX MIXED MEMBRANOUS AND PROLIFERATIVE GLOMERULONEFRITIS VESNA JURČIĆ 1, ANDREJA ALEŠ RIGLER 2, INSTITUTE OF PATHOLOGY, FACULTY OF MEDICINE, UNIVERSITY OF LJUBLJANA, SLOVENIA 2 CLINICAL DEPARTMENT OF NEPHROLOGY, UNIVERSITY CLINICAL CENTRE, LJUBLJANA, SLOVENIA

2 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.

3 OCTOBER 2006 Haemoptysis, dyspnoe, generalized oedema Radiologic findings consistent with diffuse alveolar haemorrhage Severe anaemia Nephrotic syndrome with erythrocyturia Normal renal function

4 LABORATORY FINDINGS Urinalysis: proteinuria 6.3 g/d, erythrocyturia 209, leukocyturia 78 (x10⁶l). Blood tests: blood urea nitrogen 12.0 mg/dl (4.3 mmol/l) serum albumin 2.3 g/dl (23 g/l) haemoglobin 9.2 g/dl (92 g/l) Immunoserology: anti-gbm antibodies negative by standard ELISA Hep 2 ANA 1:320 (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

5 THE FIRST BIOPSY

6 THE FIRST BIOPSY IgG

7 THE FIRST BIOPSY IgG

8 THE FIRST BIOPSY IgG IgM

9 THE FIRST BIOPSY

10 THE FIRST BIOPSY

11 THE FIRST BIOPSY ACTIVE LESIONS

12 THE FIRST BIOPSY 8/14 (57%) CRESCENTS

13 THE DIAGNOSIS Anti-GBM glomerulonephritis with concomitant immune complex membranous and proliferative glomerulonephritis (mesangioproliferative and segmental endocapillary proliferative pattern)

14 TREATMENT (NOVEMBER 2006 JULY 2007) Plasmapheresis Metylprednisolone pulses i.v. Cyclophosphamide The symptoms of respiratory insufficiency and haemoptysis disappeared. Maintenance therapy with metylprednisolone because of persistent proteinuria ANA 1:80

15 AUGUST 2007 THE FIRST RECURRENCE Recurrence of nephrotic proteinuria and erythrocyturia, no pulmonary involvement. ANA 1:320

16 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)

17 THE SECOND BIOPSY

18 THE SECOND BIOPSY

19 THE SECOND BIOPSY

20 THE SECOND BIOPSY

21 THE DIAGNOSIS Anti-GBM glomerulonephritis (10/20 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 focal and segmental changes)

22 TREATMENT Metylprednisolone Mycophenolate mofetil (MMF) In December 2007 nephrotic syndrome remitted, but proteinuria persisted 1.5 g/d (partial remission). ANA 1:80

23 AUGUST 2009 SECOND RECURRENCE In August 2009: pulmonary involvement with haemoptysis and radiologic signs of diffuse alveolar haemorrhage without renal involvement ANA 1:320 Anti-GBM antibodies by standard ELISA were negative, but now positive by indirect immunofluorescence on normal kidney 1:10, and on α3 col IV biochip 1:10 Treatment: methylprednisolone pulses and MMF continued Haemoptysis disappeared

24 LAST FOLLOW-UP IN DECEMBER 2009 Laboratory results within normal ranges, but persistent proteinuria (1.2 g/d) December ? She failed to attend subsequent outpatient appointments and became lost to follow-up.

25 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 : Not so extensive crescentic GN with normal renal function: only about 50% crescents, small to medium sized, with not much glomerular destruction and necrosis Concurrent immune complex membranous and proliferative GN (MEZ, ENDO and MPGN in the second biopsy)

26 CONCLUSIONS Anti-GBM antibodies detected only by more sensitive methods Persistent proteinuria Recurrent course

27 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 membrane 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.

28 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 full-house immune deposits, no extraglomerular granular immune deposits, no tubuloreticular inclusions or fingerprints by EM. However, this patient probably had an autoimmune syndrome, associated with the production of more than one type of antibodies.

29 Clin Nephrol Mar;81(3): Goodpasture's syndrome with concomitant immune complex mixed membranous and proliferative glomerulonephritis. Jurčić V, Vizjak A, Rigler Aleš A, Jeruc J, Wieslander J, Ferluga D