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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2014  |  Volume : 25  |  Issue : 3  |  Page : 634-637
ANCA-mediated crescentic glomerulonephritis with linear deposition of IgG along the glomerular basement membrane

1 Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
2 Department of Pathology, The Methodist Hospital, Houston, Texas, USA

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Date of Web Publication9-May-2014


Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides is an important cause of rapidly progressive glomerulonephritides (RPGN), and they are classically described as pauci-immune diseases as evidenced by the absence of immune deposits on immunofluoresence microscopy of the kidney biopsy. We report two patients with RPGN, pulmonary-renal syndrome, positive ANCA serology and linear Immunoglobulin G (IgG) staining on glomerular basement membrane in the absence of detectable anti-glomerular basement membrane (anti-GBM) antibodies in the serum.

How to cite this article:
Sangsiraprapha W, Truong L, Mandayam S. ANCA-mediated crescentic glomerulonephritis with linear deposition of IgG along the glomerular basement membrane. Saudi J Kidney Dis Transpl 2014;25:634-7

How to cite this URL:
Sangsiraprapha W, Truong L, Mandayam S. ANCA-mediated crescentic glomerulonephritis with linear deposition of IgG along the glomerular basement membrane. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2022 Aug 7];25:634-7. Available from: https://www.sjkdt.org/text.asp?2014/25/3/634/132221

   Introduction Top

Crescentic glomerulonephritis is traditionally classified into pauci-immune, immune-mediated and anti-GBM antibody-mediated types. Vasculitis associated with circulating antineutrophil cytoplasmic antibody (ANCA) directed against either myeloperoxidase (MPO) or proteinase-3 (PR3) usually presents as a pauci-immune crescentic glomerulonephritis. Pauci-immune glomerulonephritis is characterized by minimal immune deposits by immunofluorescence (IF). [1]

We report two cases of crescentic glomerulonephritis associated with positive ANCA and linear IgG deposition in the glomerular basement membrane (GBM) in the absence of anti-GBM antibodies in serum.

   Case Reports Top

Case 1

A 51-year-old woman with a history of hypertension and osteoarthritis presented with hypoxic respiratory failure. Physical examination showed coarse breath sound at lung bases and oxygen saturation of 66% on room air. Laboratory studies showed hemoglobin 4.9 g/dL, hematocrit 14.2%, platelets 327 K/uL, BUN 45 mg/dL and serum creatinine (Cr) 3.5 mg/dL. Chest radiograph showed extensive bilateral pulmonary infiltrates suspicious of pulmonary hemorrhage. Urinalysis showed RBC casts with proteinuria. Renal sonogram showed normal-sized kidneys with slightly increased cortical echogenicity. Serologic studies revealed ANA titer >640 with speckled pattern, normal complement levels and positive MPO ANCA (titer of >100 EU/mL); however, PR3 ANCA, anti-dsDNA antibody and anti-Sm antibody were all negative. Multiple samples for anti-GBM anti-body performed by enzyme immunoassay (EIA, Laboratory Corporation of America) were negative. She was treated with broad-spectrum anti-biotics, blood transfusion and hemodialysis.

An ultrasound-guided kidney biopsy was performed, and it showed six glomeruli with fibro-cellular crescent in one, fibroid necrosis with crescents in two and global sclerosis in one [Figure 1]A. There was mild interstitial edema and focal acute tubular injury with mild interstitial inflammation composed of mononuclear and plasma cells. Immunofluorecence showed five glomeruli with global linear GBM staining for IgG [Figure 1]B, kappa and lambda light chains. Electron microscopic examination did not show electrondense deposits in the glomeruli. The renal biopsy diagnosis was crescentic glomerulonephritis with linear IgG deposition on GBM. However, multiple repeated tests for anti-GBM antibodies were negative.
Figure 1: (A) A glomerulus with crescent formation. There is marked chronic tubulointerstitial injury. (B) Linear deposition of IgG along the glomerular basement membrane.

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Given pulmonary renal syndrome and the renal biopsy findings, the patient was treated with an aggressive immunosuppressive protocol typically used for anti-GBM disease with plasma exchange, intravenous cyclophosphamide and intravenous methylprednisolone, followed by oral prednisone. After three cycles of intravenous cyclophosphamide, she recovered sufficient renal function (serum Cr of 1.2 mg/dL) to discontinue dialysis. Her respiratory status has stayed significantly improved and she is ambulatory without a need for supplemental oxygen.

Case 2

A 65-year-old man with history of hypertension and migratory arthritis presented with increasing dyspnea on exertion, non-productive cough and fever. Physical examination revealed coarse breath sounds and occasional wheeze at lung bases with oxygen saturation of 97% on 50% oxygen mask. Laboratory studies revealed Cr 3.9 mg/dL, hemoglobin 7.3 g/dL, WBC 17 K/dL, platelet 620 K/dL and bilateral pulmonary infiltrates on chest X-ray. Urinalysis showed multiple RBCs, RBC casts and granular casts with proteinuria. Renal sonogram showed normal-sized kidneys with normal echogenicity. Serology was negative for ANA, rheumatoid factor, HIV and viral hepatitis. The serum complement levels were normal. PR3 ANCA was positive (>30 EU/mL); however, anti-GBM antibody performed by multi-analyte fluorescent detection (MAFD, ARUP Laboratories) was negative.

An ultrasound-guided renal biopsy was performed. A kidney biopsy showed 12 glomeruli, with global sclerosis in two and segmental endocapillary cell proliferation with cellular or fibrocellular crescents in six [Figure 2]A. There were foci of chronic tubule-interstitial injury characterized by tubular atrophy, interstitial fibrosis and severe interstitial inflammation. IF revealed seven glomeruli with global, diffuse IgG [Figure 2]B and C3 linear staining of the GBM. Electron microscopic studies did not show electron-dense deposits in the glomeruli. The kidney biopsy diagnosis was crescentic glomerulonephritis with linear IgG deposition on GBM. However, anti-GBM antibody was negative.
Figure 2: (A) A glomerulus showing endocapillary cell proliferation and fibinoid necrosis, associated with a cellular crescent. There is marked chronic tubulointerstitial injury. (2B) Linear deposition of IgG along the glomerular basement membrane.

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The patient was treated with an immunosuppressive protocol consisting of plasma exchange, intravenous cyclophosphamide and intravenous methylprednisolone, followed by oral prednisone. His systemic symptoms resolved, but renal function did not improve with treatment and required chronic hemodialysis therapy.

   Discussion Top

Cresentic glomerulonephritis is generally divided into three immunopathological categories: (1) glomerulonephritis (GN) with antibodies directed against the GBM as observed in Goodpasture's syndrome, characterized by linear staining by IF for IgG and usually C3 along the glomerular capillary loops; (2) immune complex-mediated GN that represents a severe form of various types of glomerulonephritis such as post-infectious glomerulonephritis, IgA nephropathy and lupus nephritis, with superimposed crescent formation, characterized by granular glomerular staining for immunoglobulins and/ or complement components by IF and multiple electron-dense deposits by electron microscopy; and (3) pauci-immune GN, which is characterized by mild or absent glomerular staining for immunoglobulins and/or complement components by IF, and absence of electron-dense deposits by electron microscopy. [1] Approximately 80-85% of cases of pauci-immune crescentic GN are associated with ANCA. Recent studies show that ANCA, mainly MPO-ANCA, is involved in the pathogenesis of both glomerulonephritis and small-vessel vasculitis. [2],[3]

Exposure to environmental stimuli, drug or infection has been shown to trigger cross-reactive autoimmunity to ANCA antigen, which is contained in the same vesicles that harbor MPO and PR3. ANCA in collaboration with a synergistic pro-inflammatory cytokine promotes neutrophil adhesion to the endothelium and activates neutrophils to release toxic granule enzymes and oxygen radicals, causing injury to the endothelium. ANCA also promotes neutrophil secretion of pro-inflammatory cytokines and activates complement factors. [2],[3] Although ANCA-associated vasculitides usually have mild or no glomerular tuft staining, immune deposits have been shown in a previous report. [1] This suggests a possible role of ANCA-mediated antibody injury to vascular endothelium, similar to that observed in anti-GBM-associated GN.

Anti-GBM antibody tests of our case 1 were performed by the LabCorp of America (USA). The anti-GBM test performed on the sample was an enzyme immuno assay (EIA) called INOVA. The anti-GBM antibody test of case 2 was performed at Arup Laboratories (USA) using a multi-analyte fluorescent detection (MAFD) system for the IgG. Both assays have 100% sensitivity and are highly specific for antibodies against human noncollagenous-1 (NC1) domain of alfa-3 chain of type IV collagen.

Our patients presented with pulmonary-renal syndrome with renal immunohistology, similar to patient with Goodpasture's syndrome. Interestingly, repeated testing for anti-GBM anti-bodies was negative throughout the disease course. This finding may be due to complete absorption of the anti-GBM antibody by glomerular capillaries, resulting in a very low and undetectable level of these antibodies in the circulation or these patients that may have anti-GBM antibody against antigens other than the NC1 domain as mentioned in a previous report. [4] A rare case of anti-GBM disease mediated by IgA antibody, which was not specific for the NC1 antigen, rather than the usual IgG antibody, has been reported by Ho et al. [5] However, this is unlikely in our cases as IgA deposition on GBM was not detected in either of our kidney biopsies. There is a case report by Sepandj et al [6] with similar pathological findings in a patient with MPO-ANCA positive, anti-GBM-negative GN with a linear staining pattern; however, there was no evidence of pulmonary involvement in that case.

The exact role of the ANCA in the deposition of immunoglobulin in the GBM and its pathogenicity is yet to be determined. Further studies focusing on the roles of ANCAs are necessary and accumulation of similar cases may unravel the pathogenesis of this interesting disease and help develop treatment protocols.

In conclusion, we reported two cases of pulmonary-renal syndrome in the context of ANCA vasculitis (both anti-MPO and anti-PR3) and associated with linear GBM immunoglobulin staining in the absence of circulating anti-GBM antibodies by serology.

   References Top

1.Haas M, Eustace JA. Immune complex deposits in ANCA-associated crescentic glomerulonephritis: A study of 126 cases. Kidney Int 2004;65:2145-52.  Back to cited text no. 1
2.Kallenberg CG, Heeringa P, Stegeman CA. Mechanisms of Disease: Pathogenesis and treatment of ANCA-associated vasculitides. Nat Clin Pract Rheumatol 2006;2:661-70.  Back to cited text no. 2
3.Gomez-Puerta JA, Bosch X. Anti-neutrophil cytoplasmic antibody pathogenesis in small-vessel vasculitis: An update. Am J Pathol 2009; 175:1790-8.  Back to cited text no. 3
4.Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003;63:1164-77.  Back to cited text no. 4
5.Ho J, Gibson IW, Zacharias J, Fervenza F, Colon S, Borza DB. Antigenic heterogeneity of IgA anti-GBM disease: New renal targets of IgA autoantibodies. Am J Kidney Dis 2008;52: 761-5.  Back to cited text no. 5
6.Sepandj F, Cohen B, Gupta R. Pathogenic significance of ANCA in a patient with crescentic glomerulonephritis, bone marrow granulomata, and linear staining pattern along the glomerular basement membrane with ANCA by indirect immunofluorescence. Nephrol Dial Transplant 1997;12:2698-702.  Back to cited text no. 6

Correspondence Address:
Dr. Sreedhar Mandayam
Department of Medicine, Baylor College of Medicine, Houston, TX 77030
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.132221

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