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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2013  |  Volume : 24  |  Issue : 4  |  Page : 783-788
Double-positive Goodpasture's syndrome with concomitant active pulmonary tuberculosis


1 Section of Nephrology, Department of Medicine, Aga Khan University, Karachi, Pakistan
2 Section of Infectious Disease, Department of Medicine, Aga Khan University, Karachi, Pakistan
3 Section of Internal Medicine, Department of Medicine, Aga Khan University, Karachi, Pakistan

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Date of Web Publication24-Jun-2013
 

   Abstract 

Anti-glomerular basement membrane (anti-GBM) disease usually presents as rapidly progressive glomerulonephritis, and, when accompanied with pulmonary hemorrhage, it is called Goodpasture's syndrome. Anti-neutrophilic cytoplasmic antibodies (ANCA) may co-exist with anti-GBM antibodies. In most of these "double positive" cases, ANCA is specific for myeloperoxidase (p-ANCA). We report a rare case of a critically ill patient c-ANCA-associated double-positive Goodpasture's syndrome with concomitant tuberculosis that was successfully treated with immunosuppression, plasmapheresis and anti-tuberculous therapy (ATT). A 32-year-old gentleman with a 15 pack-year smoking history presented with massive hemoptysis, respiratory failure and oliguria. Laboratory investigation revealed anemia, elevated creatinine and active urinary sediment. Chest X-ray revealed bilateral pulmonary infiltrates. Broad-spectrum antibiotics and intravenous corticosteroids were started. Bronchoscopy showed alveolar hemorrhage and smears from bronchial lavage from both lungs were positive for acid fast bacillus (AFB). Vasculitis work-up revealed high titers of c-ANCA and anti-GBM antibodies. Kidney biopsy revealed crescents in >50% glomeruli on light microscopy. Immunofluorescence showed linear deposition of IgG and C3. The patient received pulse methylprednisone for three days followed by oral prednisone and ATT. In addition, he also underwent nine sessions of plasmapheresis. Oral Cyclophosphamide was added on Day 10. The patient showed remarkable recovery as his lung fields cleared and his kidney function got stabilized. Cyclophosphamide was continued for three months and then switched to azathioprine. At six months, the creatinine is 1.2 mg/dL, with minimal proteinuria and a normal chest X-ray. To the best of our knowledge, this is the only reported case of double-positive Goodpasture's syndrome (c-ANCA and anti GBM) with active tuberculosis treated successfully.

How to cite this article:
Kashif W, Yaqub S, Mahmood SF, Patel J. Double-positive Goodpasture's syndrome with concomitant active pulmonary tuberculosis. Saudi J Kidney Dis Transpl 2013;24:783-8

How to cite this URL:
Kashif W, Yaqub S, Mahmood SF, Patel J. Double-positive Goodpasture's syndrome with concomitant active pulmonary tuberculosis. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2019 Oct 24];24:783-8. Available from: http://www.sjkdt.org/text.asp?2013/24/4/783/113886

   Introduction Top


Anti-glomerular basement membrane (anti-GBM) antibody disease is a rare autoantibody-mediated disorder that usually presents as rapidly progressive glomerulonephritis (GN). [1],[2] When accompanied by pulmonary hemorrhage, it is called the Goodpasture's syndrome. [2] It has been reported that in a significant number of patients with anti-GBM antibodies, anti-neutrophil cytoplasmic antibodies (ANCA) may co-exist. [1],[3] In most of these "double positive" cases, ANCA is usually specific for myeloperoxidase (MPO-ANCA or p-ANCA), whereas antibodies to the proteinase-3 enzyme (c-ANCA or PR3-ANCA) are much rarer. [1],[3],[4],[5],[6],[7],[8],[9],[10] We report a patient with c-ANCA-associated double-positive Goodpasture's syndrome who also had active pulmonary tuberculosis and was successfully treated with immunosuppression, plasmapheresis and anti-tuberculous therapy (ATT).


   Case Report Top


A 32-year-old gentleman with a 15 pack-year cigarette smoking history was seen in the emergency room (ER) with massive hemoptysis, respiratory distress and low urine output for two days.

Three months prior to his presentation, the patient had complained of upper respiratory tract symptoms including cough with white sputum rarely streaked with blood along with arthralgia, weight loss and low-grade subjective fevers. He had received multiple courses of antibiotics during this time period for presumed respiratory tract infection without much benefit. A detailed work-up was done two weeks prior to his ER visit [Table 1], which revealed mild anemia, a positive rheumatoid factor and an elevated erythrocyte sedimentation rate; otherwise, his chest X-ray, serum creatinine and cell counts were all normal. Sputum for acid fast bacilli smear was also performed, and was reported negative in three samples.
Table 1: Laboratory investigations from 3 weeks prior to admission and in the emergency room.

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On physical examination in the ER, the patient was pale, anxious and in obvious respiratory distress. On examination, his BP was 120/70 mmHg and his pulse was 120/min, with a respiratory rate of 38/min. On chest auscultation, bilateral coarse crepitations could be heard; he had tachycardia but no gallop and his jugular venous pressure was not elevated. There was no edema, cyanosis or clubbing [Figure 1] and [Figure 2].
Figure 1: Chest X-ray on arrival.

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Figure 2: Chest X-ray 8 h later.

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Urine analysis was performed on a spontaneously voided specimen while the patient was in the ER. Dipstick revealed positivity for blood and 2+ proteinuria, but was otherwise normal. Urine microscopy revealed >20 red blood cells per high-power field, many granular casts and three red cell casts.

An autoimmune vasculitis work-up along with blood and urine cultures were sent in the ER and the patient was empirically started on Levofloxacin and Piperacillin-Tazobactam to treat a possible severe community-acquired pneumonia. Because of the high index of suspicion for a pulmonary-renal syndrome, 1 g methylprednisone was also given intravenously and the patient was electively intubated and transferred to the intensive care unit for a fiber-optic bronchoscopy.

Bronchoscopy findings were consistent with severe alveolar hemorrhage. The brochoalveolar lavage (BAL) specimen gram stain and fungal smears were negative, although the acid fast bacilli smear was reported positive on two separate specimens from both lungs.

At this point in time, a diagnosis of pulmonary renal syndrome with concomitant pulmonary tuberculosis was made and the patient was started on four-drug ATT consisting of standard doses of Isoniazid, Rifampin, Ethambutol and Pyrazinamide. Methylprednisone 1 g daily was also continued for three days [Table 2].
Table 2: Vasculitis work-up.

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There was significant clinical improvement in the patient's overall condition over the next few days. After three doses of pulse corticosteroids, the patient was started on 1 mg/kg/day of oral prednisone. Daily plasmapheresis with 2 L exchanges (FFP based) was initiated on Day 4 of hospitalization. Ultrasound-guided trans-cutaneous kidney biopsy was performed on Day 7 when the patient was out of the Intensive Care Unit.

Light microscopy [Figure 3] revealed crescents in more than 50% glomeruli, with advanced sclerosis in almost 20% glomeruli. There was mild to moderate tubular atrophy and fibrosis. Immunofluorescence revealed linear deposition of IgG and C3.
Figure 3: Light microscopy (H&E stain) showing crescent formation (magnified view).

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The patient received a total of nine sessions of plasmapheresis (seven sessions on consecutive days and two sessions on alternate days). Oral cyclophosphamide (1.5 mg/kg/day) was added on Day 11 and the patient was continued on prednisone 1 mg/kg/day along with the four-drug ATT. There was substantial improvement in the overall clinical status of the patient during his two-week stay in the hospital [Figure 4]. His kidney function stabilized with a serum creatinine of 2.7 mg/dL on discharge.
Figure 4: Chest X-ray on discharge.

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Cyclophosphamide was continued for three months, after which it was switched to azathioprine. At six months follow-up, he is doing well on tapering doses of steroids and azathioprine. His serum creatinine is 1.2 mg/dL and he has no proteinuria. His chest X-ray is normal and his ATT has been switched to a maintenance two-drug regime. We were however unable to isolate Mycobacterium tuberculosis on cultures of the BAL fluid, possibly due to the concurrent quinolone use when the samples were sent. Moreover, as the smears were positive, nucleic amplification testing had not been performed on the original sample. Nonetheless, given his rapid improvement and tapering immunosuppression, we plan to continue ATT for nine to 12 months. He will also remain on Pneumocystis carnii (PCP) prophylaxis with Trimethoprim- sulphamethoxazole while he continues azathioprine and steroids.


   Discussion Top


Anti-GBMis a rare but well-described cause of rapidly progressive GN. It is characterized by the presence of autoantibodies directed at specific antigenic targets within the glomerular basement membrane. When anti-GBM disease occurs in conjunction with lung hemorrhage, it is referred to as "Goodpasture's syndrome."

A large number of diseases have been associated with Goodpasture's syndrome; however, the most consistently reported associations are with membranous nephropathy [11],[12] and ANCA-associated vasculitis. [1],[3] When ANCA and anti-GBM antibodies co-exist, it is known as "double positive" disease. The overall frequency of ANCA in Goodpasture's syndrome is ~30%, whereas patients with ANCA-positive vasculitis develop anti-GBM antibodies in approximately 10% of the cases. [1],[3] Immunofluorescence (IF) of the glomerular basement membrane helps determine the primary culprit. Patients with anti-GBM disease with co-existing ANCA show a linear pattern of deposition of antibodies along the glomerular basement membrane while those with ANCA-associated vasculitis with concurrent anti-GBM antibodies exhibit a pauciimmune pattern on IF. Most of these double-positive cases exhibit a perinuclear pattern of ANCA (p-ANCA or MPO-ANCA) with myeloperoxidase as the target antigen. [1],[3],[4],[5],[8],[9],[10] Very few cases having anti-GBM antibodies with coexistent c-ANCA with specificity against PR-3 enzyme (PR-3 ANCA or c-ANCA) have been reported in the literature, but, where they were

found, patients had similar disease severity to those with p-ANCA double-positive disease. [4],[6],[7] The clinical significance of dual positivity in humans is still under deliberation, with some authors suggesting a better prognosis [5],[8] whereas others predicting a worse patient and renal outcome as compared with isolated anti-GBM disease. [4],[5],[8],[13],[14],[15]

Bosch et al suggested that patients with MPO-ANCA and anti-GBM antibodies responded better to therapy than patients with isolated anti-GBM antibodies, and reported better outcomes. [5] A Swedish study in 29 patients also reported a better outcome in patients with both anti-GBM and MPO-ANCA. [8] However, Bonsib et al and Denton et al reported that most patients with double-positive disease died or remained dialysis dependent. [4],[13] Rutgers et al showed that renal survival in double-positive patients was not better than in isolated anti-GBM-positive patients, and was worse compared with patients with MPO-ANCA only. [15] Levy et al also suggested that double-positive patients respond poorly to therapy and are associated with poor renal outcomes despite receiving plasma exchange in addition to immunosuppression. [14] However, they also showed that regardless of the serum creatinine provided, the patient was not dialysis dependant on presentation and that the patient survival was 100% at one year. On the other hand, survival at one year was only 35% if the patient was dialysis dependant at the time of presentation. Renal outcomes were dependant on the presenting serum creatinine, as 75% of the patients recovered their renal function if their serum creatinine was less than 500 μmol/L at presentation, as opposed to no renal recovery if the serum creatinine was more than 500 μmol/L at presentation. [14]

Our patient had presented with pulmonary hemorrhage, acute kidney injury and active urinary sediment. He had anti-GBM antibodies and was also found to have co-existent c-ANCA. Immunofluorescence studies of the renal biopsy revealed a linear pattern of deposition of antibodies along the glomerular basement membrane; thus, he had c-ANCA-positive Goodpasture's syndrome (double-positive disease). Interestingly, he was found to have concurrent smear-positive active pulmonary tuberculosis. ANCA positivity alone has been reported in patients with pulmonary tuberculosis. [16],[17] Whether the ANCA was related to tuberculosis or the glomerular disease cannot be ascertained.

We treated our patient aggressively with steroids, plasma exchange and oral cyclophosphamide with concomitant ATT. One of the interesting features of our case is that it highlights the role of early aggressive immunosuppressive therapy along with plasmapheresis as being potentially lifesaving, and should not be delayed while simultaneously treating a concomitant active infection such as tuberculosis.

After three months of therapy, once remission was achieved, he was switched over from oral cyclophosphamide to azathioprine. There is no consensus on the optimal duration of therapy in anti-GBM disease. Spontaneous cessation of autoantibody formation can take six to nine months, or longer. It has been suggested that, after remission is induced, maintenance therapy with less-toxic drugs, such as low-dose prednisone and azathioprine, should be given for six to nine months. [18]

We found only one case report describing the role of mycophenolate mofetil (MMF) in Goodpasture's syndrome. Remission was induced in a patient with relapsing Goodpasture's syndrome using MMF, who failed to achieve remission with plasma exchange, methylprednisolone and cyclophosphamide. [19]

Our patient's course was further complicated with superimposed TB. While we were unable to grow the organism (likely due to prior and concomitant quinolone use), given the clinical presentation and the excellent response, we opted to treat him with the full regime of ATT. The length of therapy of ATT in patients with on-going immunosuppressive therapy is not well defined; however, generally, no change is recommended in such patients. Nonetheless, we have opted to treat him for a slightly longer period of nine months (as opposed to six months), keeping in mind that his immunosuppressive therapy would be minimal at this point as will his Goodpasture's, decreasing his risk of a relapse. Finally, as the patient was on cytotoxic therapy as well as on more than an equivalent of 20 mg of prednisolone daily for more than one month, the patient was also placed on PCP prophylaxis.

This, to the best of our knowledge, is the only case of double-positive Goodpasture's syndrome (c-ANCA and anti-GBM) with active pulmonary tuberculosis reported in the literature. After initial aggressive therapy with high-dose corticosteroids, daily plasma exchange, oral cyclophosphamide and concomitant four-drug ATT, our patient improved and went home two weeks after presenting in a critical condition with life-threatening massive hemoptysis and acute kidney injury. At six months after the initial presentation, his creatinine is 1.2 mg/dL, with minimal proteinuria on alternate day steroids, low-dose azathioprine and two-drug maintenance ATT.

 
   References Top

1.Jayne DR, Marshall PD, Jones SJ, Lockwood CM. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int 1990;37:965-70.  Back to cited text no. 1
    
2.Wilson CB, Dixon FJ. Anti-glomerular basement membrane antibody-induced glomerulonephritis. Kidney Int 1973;3:74-89.  Back to cited text no. 2
    
3.Hellmark T, Niles JL, Collins AB, McCluskey RT, Brunmark C. Comparison of anti-GBM antibodies in sera with or without ANCA. J Am Soc Nephrol 1997;8:376-85.  Back to cited text no. 3
    
4.Bonsib SM, Goeken JA, Kemp JD, Chandran P, Shadur C, Wilson L. Coexistent anti-neutrophil cytoplasmic antibody and antiglomerular basement membrane antibody associated disease - report of six cases. Mod Pathol 1993;6:526-30.  Back to cited text no. 4
    
5.Bosch X, Mirapeix E, Font J, et al. Prognostic implication of anti-neutrophil cytoplasmic auto-antibodies with myeloperoxidase specificity in anti-glomerular basement membrane disease. Clin Nephrol 1991;36: 107-13.  Back to cited text no. 5
    
6.Kalluri R, Meyers K, Mogyorosi A, Madaio MP, Neilson EG. Goodpasture syndrome involving overlap with Wegener's granulomatosis and anti-glomerular basement membrane disease. J Am Soc Nephrol 1997;8:1795-800.  Back to cited text no. 6
    
7.Neary P, Kadlubowski M, Thomson D, Cavaye M, Cumming AD. Antiglomerular basement membrane disease with cANCA positivity without pulmonary involvement. Nephrol Dial Transplant 1996;11:693-5.  Back to cited text no. 7
    
8.Segelmark M, Hellmark T, Wieslander J. The prognostic significance in Goodpasture disease of specificity, titer and affinity of anti-glomerular-basement-membrane antibodies. Nephron Clin Pract 2003;94: c59-68.  Back to cited text no. 8
    
9.Short AK, Esnault VL, Lockwood CM. Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: Two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis. Am J Kidney Dis 1995;26:439-45.  Back to cited text no. 9
    
10.Weber MF, Andrassy K, Pullig O, Koderisch J, Netzer K. Antineutrophil-cytoplasmic antibodies and antiglomerular basement membrane antibodies in Goodpasture syndrome and in Wegener's granulomatosis. J Am Soc Nephrol 1992;2:1227-34.  Back to cited text no. 10
    
11.Klassen J, Elwood C, Grossberg AL, et al. Evolution of membranous nephropathy into anti-glomerular-basement-membrane glomerulonephritis. N Engl J Med 1974;290: 1340-4.  Back to cited text no. 11
    
12.Kurki P, Helve T, von Bonsdorff M, et al. Transformation of membranous glomerulonephritis into crescentic glomerulonephritis with glomerular basement membrane antibodies. Serial determinations of anti-GBM before the transformation. Nephron 1984; 38:134-7.  Back to cited text no. 12
    
13.Denton M, Magee C, Niles J. Rapidly progressive glomerulonephritis. Ann Intern Med 2002;137(5 Part 1):W1.  Back to cited text no. 13
    
14.Levy JB, Hammad T, Coulthart A, Dougan T, Pusey CD. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney Int 2004;66:1535-40.  Back to cited text no. 14
    
15.Rutgers A, Slot M, van Paassen P, van Breda Vriesman P, Heeringa P, Tervaert JW. Co-existence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCA in crescentic glomerulonephritis. Am J Kidney Dis 2005;46:253-62.  Back to cited text no. 15
    
16.Flores-Suarez LF, Cabiedes J, Villa AR, van der Woude FJ, Alcocer-Varela J. Prevalence of Anti-neutrophil cytoplasmic autoantibodies in patients with tuberculosis. Rheumatology (Oxford) 2003;42: 223-9.  Back to cited text no. 16
    
17.Pradhan VD, Badakere SS, Ghosh K, Pawar AR. Spectrum of anti-neutrophil cytoplasmic antibodies in patients with pulmonary tuberculosis overlaps with that of Wegener's granulomatosis. Indian J Med Sci 2004;58:283-8.  Back to cited text no. 17
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18.Jindal KK. Management of idiopathic crescentic and diffuse proliferative glomerulonephritis: Evidence-based recommendations. Kidney Int Suppl 1999;70: S33-40.  Back to cited text no. 18
    
19.Garcia-Canton C, Toledo A, Palomar R, et al. Goodpasture's syndrome treated with mycophenolate Mofetil. Nephrol Dial Transplant 2000; 15:920-2.  Back to cited text no. 19
    

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Correspondence Address:
Waqar Kashif
Department of Medicine, Aga Khan University, P. O. Box 3500, Stadium Road, Karachi
Pakistan
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DOI: 10.4103/1319-2442.113886

PMID: 23816731

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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