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Year : 2017  |  Volume : 4  |  Issue : 1  |  Page : 26-28

Atypical anti-glomerular basement membrane disease superimposed on IgA nephropathy

Institute of Nephrology, Rajiv Gandhi Government General Hospital, Madras Medical College, Chennai, Tamil Nadu, India

Date of Web Publication1-Mar-2017

Correspondence Address:
Jeyachandran Dhanapriya
Institute of Nephrology, Rajiv Gandhi Government General Hospital, Madras Medical College, Chennai - 600 003, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2394-2916.201277

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Anti-glomerular basement membrane (anti-GBM) disease is an autoimmune disorder characterized by crescentic glomerulonephritis, pulmonary hemorrhage, and the presence of circulating anti-GBM antibodies which bind to the α3 chain of Type IV collagen found in the GBM. IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. The simultaneous occurrence of atypical anti-GBM disease and IgAN has not been reported previously. We report here two female patients who presented with oliguria, hypertension, and renal failure. Renal biopsy revealed crescentic glomerulonephritis and bright linear IgG staining along glomerular capillary walls and mesangial IgA (3+) deposits in immunofluorescence. Serology was negative for anti-GBM antibodies both by ELISA and immunoblot assays. Hence, a diagnosis of atypical anti-GBM disease with superimposed IgAN was made. Both patients were treated with hemodialysis, intravenous steroids, and cyclophosphamide with the improvement of renal function in one patient and the other progressed to end-stage renal disease.

Keywords: Anti-glomerular basement membrane disease, hemodialysis, IgA nephropathy, renal biopsy

How to cite this article:
Balasubramaniyan T, Dhanapriya J, Dineshkumar T, Maasila AT, Arivazhagan S, Rajasekar D, Sakthirajan R, Gopalakrishnan N. Atypical anti-glomerular basement membrane disease superimposed on IgA nephropathy. J Integr Nephrol Androl 2017;4:26-8

How to cite this URL:
Balasubramaniyan T, Dhanapriya J, Dineshkumar T, Maasila AT, Arivazhagan S, Rajasekar D, Sakthirajan R, Gopalakrishnan N. Atypical anti-glomerular basement membrane disease superimposed on IgA nephropathy. J Integr Nephrol Androl [serial online] 2017 [cited 2023 Dec 2];4:26-8. Available from: http://www.journal-ina.com/text.asp?2017/4/1/26/201277

  Introduction Top

Anti-glomerular basement membrane (anti-GBM) disease is usually diagnosed by high titers of IgG autoantibodies to the noncollagenous (NC1) domain of α3 (Type IV) collagen in the circulation and/or renal biopsy.[1] Atypical anti-GBM nephritis is a rare variant, characterized by lung involvement, and undetectable circulating anti-GBM antibodies by conventional methods.[2] We report here two such patients with atypical anti-GBM disease and coexisting IgA nephropathy (IgAN). Early treatment with corticosteroids, plasmapheresis, and cyclophosphamide may prevent irreversible renal damage.

  Case Reports Top

Case 1

A 68-year-old postmenopausal female who was a known hypertensive for 2 years, presented to us with edema legs, dyspnea, and reduced urine output of 1-week duration. She denied any history of fever, rash, hemoptysis, or macroscopic hematuria. Examination revealed pulse rate of 80/min and blood pressure of 180/100 mmHg. System examination was normal. Investigations showed urinalysis: 4+ proteinuria; plenty of red blood cells/hpf; urine protein creatinine ratio (PCR): 10.2; blood hemoglobin: 9.7 mg/dL; blood urea: 160 mg/dL; serum creatinine: 8.9 mg/dL; corrected serum calcium: 8.1 mg/dL; serum phosphorus: 6.4 mg/day; serum uric acid: 7.8 mg/dL; serum sodium 141 mEq/L; serum potassium: 4.9 mEq/L; and serum lactate dehydrogenase: 200 U/L. Anti-GBM antibody (both ELISA and immunoblot assay), anti-nuclear and anti-double-stranded DNA antibodies, p-ANCA, c-ANCA, and cryoglobulins were negative. Complement levels were normal. HIV, hepatitis B and hepatitis C serologies were negative. Chest radiography was normal, and ultrasonography revealed normal sized kidneys with increased cortical echoes. Computed tomography of the chest ruled out alveolar hemorrhage. Renal biopsy revealed cellular crescents in 12 out of 17 glomeruli, increase in mesangial cellularity and matrix in all glomeruli, and segmental endocapillary proliferation seen in four glomeruli. Interstitium was edematous with scattered lymphoplasmacytic infiltrate. Immunofluorescence ( IF) revealed IgG (+3) linear positivity along the capillary walls [Figure 1]a and IgA (+3) in the mesangium [Figure 1]b.
Figure 1: (a) Immunofluorescence of renal biopsy showing IgG 3+ positivity over capillary walls. (b) Immunofluorescence of renal biopsy showing IgA 3+ positivity over mesangium

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Diagnosis of crescentic glomerulonephritis with linear IgG staining consistent with “Anti-glomerular basement membrane disease” superimposed on IgAN was made. She received three days of intravenous (IV) pulse methylprednisolone treatment (1000 mg/day), followed by oral prednisolone (1 mg/kg/day at the start and tapered slowly) and monthly IV 500 mg cyclophosphamide for 6 months. She is currently on follow-up with serum creatinine of 1.5 mg/dL.

Case 2

A 26-year-old female presented to us with leg swelling, facial puffiness, and decreased urine output of 2 weeks duration. Her blood pressure was 190/110 mmHg. Examination revealed edema legs and blood pressure of 190/110 mmHg. Laboratory investigations revealed urine PCR: 8.5 and active urinary sediments. Her serum creatinine was 14.5 mg/dL. All investigations were negative similar to the previous patient. Anti-GBM antibodies by IF and ELISA (titers - 8.09 RU and > 20 RU is considered positive) were all negative.

Renal biopsy showed endocapillary and mesangial proliferation along with fibrocellular crescents in all viable glomeruli (10/14) [Figure 2]. IF showed IgA (+3) and C3 (+1) over the mesangium and IgG (+3) linear positivity over the capillary walls. Patient was treated with hemodialysis, and three doses of IV pulse methylprednisolone followed by oral steroids and cyclophosphamide. Patient was not responding to treatment and became dialysis dependent.
Figure 2: Renal biopsy showing endocapillary and mesangial proliferation with fibrocellular crescents (H and E, 100X magnification)

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  Discussion Top

Anti-GBM disease accounts for 20% of all rapidly progressive glomerulonephritis (RPGN). It occurs in all age groups, with peak incidences during the third decade in men and in the sixth decade affecting men and women equally.[3] Atypical anti-GBM disease is characterized by bright, linear immunoglobulin deposition along GBM in patients who lacked anti-GBM antibodies by conventional testing (ELISA, Western blot, or indirect immunofluorescence) and who had a relatively benign course. Standard ELISA employs denatured recombinant NC1 portion of the α3 (IV) collagen, and the Western blots use collagenase digests of normal GBM, which contain NC1 from α3 (IV), α4 (IV), and α5 (IV) collagen chains. The sensitivity of ELISA in detecting these antibodies is 87–90%, when combined with Western blot it increases to 95–99%. All these tests detect IgG antibodies; hence, patients with IgA- or IgM-mediated disease remain undetected.[1]

First report of anti-GBM disease and mesangial IgA deposits was described in 1998 in renal transplant recipients after 12 years.[4] Gao et al.[5] described a 38-year-old female with similar presentation. Anti-GBM disease combined with IgA granular deposition in the mesangial area, complicated with reversible posterior leukoencephalopathy syndrome with circulating anti-GBM antibodies in a young male was reported recently.[6] A rare form of anti-GBM glomerulonephritis mediated by IgA autoantibodies has also been described in literature.[7] When compared to classical IgG-related anti-GBM disease, the prognosis of IgA-related anti-GBM disease is poor.

Moulis et al.[8] described five cases of atypical cases of anti-GBM disease, in which three patients were tested negative for anti-GBM antibodies by conventional assays. Nasr et al.[9] reported twenty cases of atypical anti-GBM disease characterized by linear GBM immunoglobulin deposition in renal biopsy, negative for serum anti-GBM antibodies by conventional testing. In contrast to typical anti-GBM disease, glomerular pathology was heterogeneous, few had crescents, there was little C3 deposition, and only 27% developed end-stage renal disease (ESRD).

The possible explanations for the negative serology include: (1) the autoantibodies in such patients may be directed against α4NC1 of Type IV collagen instead of α3NC1, hence not detected by conventional assays. (2) Antibodies in atypical cases may be deficient in provoking inflammation such as IgG4 antibodies instead of IgG1, which are weak and have no capacity to fix complement. (3) The autoantibodies because of high avidity for the glomeruli can be at low levels in circulation. The association between these two entities is unclear. Most probable mechanism was asymptomatic IgA-related immune complex deposits along GBM with the release of inflammatory resulted in conformation changes, thereby exposing the cryptic antigen sites and led to the production of anti-GBM antibodies.[2],[10]

Both of our patients presented with RPGN and renal biopsy showed crescentic glomerulonephritis. Both the patients tested negative for anti-GBM antibodies by conventional methods hence named atypical. Both received steroids and cyclophosphamide, the first patient responded well to treatment and the second one progressed to ESRD. The difference in response to treatment between these two patients could not be explained except for second patient who became dialysis dependent had c3 positivity and more interstitial infiltrates. Literature regarding atypical anti-GBM disease and superimposed IgAN is sparse. Kidney biopsy will be of great use in diagnosing atypical cases and combined renal lesions.


We would like to thank Dr. Anila Abraham Kurien, MD, Renopath, Chennai, for her help in evaluating renal biopsy.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Kluth DC, Rees AJ. Anti-glomerular basement membrane disease. J Am Soc Nephrol 1999;10:2446-53.  Back to cited text no. 1
Rosales IA, Colvin RB. Glomerular disease with idiopathic linear immunoglobulin deposition: A rose by any other name would be atypical. Kidney Int 2016;89:750-2.  Back to cited text no. 2
Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Mechanisms of disease: Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med 2003;348:2543-56.  Back to cited text no. 3
Trpkov K, Abdulkareem F, Jim K, Solez K. Recurrence of anti-GBM antibody disease twelve years after transplantation associated with de novo IgA nephropathy. Clin Nephrol 1998;49:124-8.  Back to cited text no. 4
Gao B, Li M, Xia W, Wen Y, Qu Z. Rapidly progressive glomerulonephritis due to anti-glomerular basement membrane disease accompanied by IgA nephropathy: A case report. Clin Nephrol 2014;81:138-41.  Back to cited text no. 5
Ge YT, Liao JL, Liang W, Xiong ZY. Anti-glomerular basement membrane disease combined with IgA nephropathy complicated with reversible posterior leukoencephalopathy Syndrome: An unusual case. Am J Case Rep 2015;16:849-53.  Back to cited text no. 6
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. 7
Moulis G, Huart A, Guitard J, Fortenfant F, Chauveau D. IgA-mediated anti-glomerular basement membrane disease: An uncommon mechanism of Goodpasture's syndrome. Clin Kidney J 2012;5:545-8.  Back to cited text no. 8
Nasr SH, Collins AB, Alexander MP, Schraith DF, Herrera Hernandez L, Fidler ME, et al. The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis. Kidney Int 2016;89:897-908.   Back to cited text no. 9
Troxell ML, Houghton DC. Atypical anti-glomerular basement membrane disease. Clin Kidney J 2016;9:211-21.  Back to cited text no. 10


  [Figure 1], [Figure 2]

This article has been cited by
1 Atypical Anti-Glomerular Basement Membrane Disease With Diffuse Crescentic Membranoproliferative Glomerulonephritis: Case Report and Review of Literature
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Qatar Medical Journal. 2020; 2020(1)
[Pubmed] | [DOI]


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