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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 71-74

Takayasu arteritis with ANCA associated vasculitis and anti-GBM antibodies

1 Department of Pediatrics, All India Institute of Medical Sciences, Raebareli, Uttar Pradesh, India
2 Department of Radiodiagnosis, Sikund Diagnostic Centre, Dehradun, Uttarakhand, India
3 Department of Renal Pathology, National Reference Laboratory, Dr Lal Path labs Ltd, New Delhi, India
4 Department of Pediatrics, SGRR Institute of Medical Sciences, Dehradun, Uttarakhand, India

Date of Submission08-May-2020
Date of Decision19-Jul-2020
Date of Acceptance27-Nov-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Mritunjay Kumar
Department of Pediatrics, All India Institute of Medical Sciences, Raebareli - 229 405, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2589-9309.305901

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Vasculitides are conventionally classified according to the size of the vessels involved and characteristic clinical and histopathological findings. Anti-neutrophil cytoplasmic antibodies (ANCAs) and other serologies help characterizing small vessel vasculitis. While few cases of large vessel involvement are reported in association with ANCA-associated vasculitis, these reports were in adult patients and lacked typical large vessel involvement. We describe an adolescent girl with focal necrotizing glomerulonephritis and positive serologies for p-or myeloperoxidase ANCA, as well as large vessel arteritis and presence of anti-glomerular basement membrane antibodies. This report highlights the diagnostic difficulties in rare patients presenting with overlap in clinical and serological features of different forms of systemic vasculitis.

Keywords: Anti-glomerular basement membrane, anti-neutrophil cytoplasmic antibody, children, takayasu, vasculitis

How to cite this article:
Kumar M, Sumbul M, Sharma A, Singh R. Takayasu arteritis with ANCA associated vasculitis and anti-GBM antibodies. Asian J Pediatr Nephrol 2020;3:71-4

How to cite this URL:
Kumar M, Sumbul M, Sharma A, Singh R. Takayasu arteritis with ANCA associated vasculitis and anti-GBM antibodies. Asian J Pediatr Nephrol [serial online] 2020 [cited 2021 Jan 26];3:71-4. Available from: https://www.ajpn-online.org/text.asp?2020/3/2/71/305901

  Introduction Top

Vasculitis is currently classified according to the size of the vessels involved and characteristic clinical and histopathologic findings. Chapel Hill Consensus Conference (CHCC) 2012 updated the definitions of vasculitis utilizing the improved understanding of the etiopathogenesis and clinical features of vasculitis subtypes. In CHCC 2012, anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) was defined as necrotizing vasculitis with few or no immune deposits, predominantly affecting small vessels associated with myeloperoxidase (MPO), or 3proteinase (3PR3)-ANCA.[1] Large vessel involvement in ANCA-associated small vessel vasculitis (SVV) has been overlooked in medical literature.[1] Here, we report a case of perinuclear ANCA (p-ANCA)-AAV with concomitant presence of anti-glomerular basement membrane (anti-GBM) antibodies in an adolescent girl who subsequently was found to have co-existing large vessel arteritis consistent with Takayasu arteritis (TA). While serology and light microscopy on histopathology favored a diagnosis of AAV, serology and direct immunofluorescence (DIF) findings supported the presence of anti-GBM antibodies.

  Case Report Top

An 11-year-old girl child was brought to emergency with a history of facial puffiness and dyspnea for 1 week and severe headache and vomiting for 3 days. There was no history of hematuria, oliguria, abnormal urinary stream, dysuria, photosensitivity, or joint pain. On examination, she was sick, irritable, conscious, and oriented (Glasgow coma scale 15). Pulse rate was 88/min, blood pressure 160/100 mm Hg, and saturation was 98%. After initial stabilization, she was shifted to the pediatric intensive care unit. Investigations revealed hemoglobin 5.6 g/dL, total leukocyte count 11,530/mm3 (82% polymorphonuclear cells and 13% lymphocytes), and platelet count of 135,000/mm3. Uncorrected reticulocyte count was 5% with a reticulocyte index of 1.9% (0.5%–2.5%), while lactate dehydrogenase level was 367 U/L. The peripheral blood smear showed normocytic normochromic red cells with mild degree of anisocytosis. Blood urea was 181.3 mg/dL, creatinine 17.4 mg/dL, sodium 134 mmol/L, potassium 5.1 mmol/L, total calcium 6.6 mg/dl (ionized calcium 1.08 mmol/L), phosphorus 6.3 mg/dL, and serum alkaline phosphatase 80 U/L. Urinalysis revealed protein 3+, 80–100 red blood cells per high power field, and occasional granular casts.

Hemodialysis was initiated for uremia, fluid overload, and hypertension. Infection with hepatitis B and C and HIV was ruled out. Ultrasonography revealed normal-sized kidneys with raised echogenicity and partial loss of corticomedullary differentiation. Considering a diagnosis of rapidly progressive glomerulonephritis, therapy with methylprednisolone pulses was initiated empirically. Serum levels of C3 and C4 were 106.8 mg/dL (immunoturbidometry; normal range 90–180 mg/dL) and 24 mg/dL (immunoturbidometry; range 10–40 mg/dL), respectively. Antinuclear antibodies (immunofluorescence antibody) were detected, but anti-double stranded DNA (enzyme-linked immunoassay) antibodies were absent. Anti-MPO antineutrophil cytoplasmic (MPO-ANCA) was strongly reactive by line immunoassay; p-ANCA were present by immunofluorescence assay (IFA, 11.50 IU/L; normal <9.00 IU/L). Anti-PR3 ANCA was negative by line immunoassay and cytoplasmic-ANCA was negative by IFA (1.16 IU/L; normal <3.50 IU/L). Anti-GBM antibodies were strongly reactive by line immunoassay but nonsignificant by IFA (1:10).

Percutaneous kidney biopsy, performed on day 4 of admission under ultrasound guidance, was inadequate for opinion, and showed focal necrotizing glomerulonephritis, with fibrocellular and fibrous crescents in 4 or 5 glomeruli [Figure 1]a. There was severe acute tubular injury, multifocal chronic interstitial inflammation, and significant interstitial edema. Focal arteriolar and arterial necrosis were present [Figure 1]b. DIF study also revealed linear staining of immunoglobulin (Ig) G along glomerular capillaries [Figure 1c]. The impression was that of focal necrotizing crescentic glomerulonephritis, likely AAV.
Figure 1: (a and b) Light microscopy renal biopsy image showing focal necrotizing glomerulonephritis featuring fibrocellular/fibrous crescents, acute tubular injury and focal arteriolar/arterial necrosis (c) direct immunofluorescence renal biopsy image showing linear staining of immunoglobulin G along glomerular capillaries

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On day 7 of admission, the right radial and brachial pulses were not palpable. Carotid Doppler revealed moderately echogenic circumferential thickening of the right common carotid artery at the origin in a 1.25 cm long segment, with reduction of the luminal area by 70%. Axial computed tomography angiography images [Figure 2]a] depicted concentric wall thickening of brachiocephalic artery involving the origins of right subclavian and common carotid arteries. Maximum intensity projection [Figure 2]b and volume-rendered image [Figure 2c] revealed wall thickening of the right and left common carotid arteries with luminal narrowing. No other large vessels nor other regions of the aorta indicated any abnormality or features of polyarteritis nodosa. Criteria for the diagnosis of TA were met, based on the European League against Rheumatism (EULAR) classification criteria[2], and the Indian Takayasu clinical activity score 2010 (ITAS2010) was 13, indicating active disease.[3]
Figure 2: (a) Axial maximum intensity projection computed tomography angio image depicting concentric wall thickening of innominate artery (arrows) with the involvement of origins of right subclavian and right common carotid arteries (b) maximum intensity projection and (c) volume-rendered computed tomography angio image reveal wall thickening of right and left common carotid arteries (arrows) with luminal narrowing

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Despite the administration of three intravenous pulses of methylprednisolone, one pulse of cyclophosphamide, and seven sessions of therapeutic apheresis on alternate days, the patient continued to have oliguria, dialysis-dependence, and severe hypertension requiring three drugs; she also developed gross hematuria. On day 20 of admission, she had pulmonary hemorrhage following, which she was ventilated mechanically for severe respiratory distress. The girl succumbed to massive pulmonary hemorrhage and multiorgan dysfunction on day 22 of hospital stay. [Figure 3] indicates the timeline of significant events.
Figure 3: Timeline of significant events

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  Discussion Top

The vasculitides are a heterogeneous group of uncommon systemic disorders characterized by inflammation of blood vessels leading to end-organ injury. The incidence of childhood vasculitis is estimated at 50 cases/100,000 children annually.[4] They are conventionally classified as small, medium, and large vessel vasculitides based on the size of the vessels involved and associated clinical and histopathological characteristics. The index patients were difficult to categorize due to concomitant involvement of both small (glomerular capillaries) and large (aorta) vessels. Based on the presence or absence of deposits of Igs or complement components, SVV is categorized as AAV and immune complex SVV.[1] AAV, characterized by inflammation and fibrinoid necrosis of small vessel walls without such deposits,[5] is further classified based on the type of ANCA on IFA and ELISA. Typically, granulomatosis with polyangiitis has a cytoplasmic staining pattern of ANCA by IFA and specificity against PR3 on ELISA. In contrast, microscopic polyangiitis and renal limited AAV are typically associated with p-ANCA (IFA) and MPO-ANCA (ELISA).[6] Our patient appeared to have renal limited microscopic polyangiitis/AAV based on clinical presentation, presence of anti-MPO or p-ANCA, and biopsy findings of focal necrotizing glomerulonephritis with crescents and vascular necrosis. The diagnosis of anti-GBM disease was also considered, based on positive anti-GBM antibody assay by line immunoassay and immunofluorescence study on biopsy revealing linear staining of IgG along glomerular capillaries. However, anti-GBM antibodies are described in 10% of patients with AAV, particularly in patients with p-ANCA or anti-MPO AAV,[7],[8] and are also known to cause characteristic linear staining for along the GBM.[7],[8],[9]

The diagnosis of TA in our patient was based on the demonstration of stenotic lesions in the major branches of the aorta in presence of characteristic clinical presentation. While pediatric vasculitis activity score and pediatric vasculitis damage index have not been validated adequately in childhood TA. Our patient satisfied the classification criteria of EULAR and had a high score on ITAS2010 scoring.[10] While acute phase reactants (erythrocyte sedimentation rate and C-reactive protein) are valuable nonimaging investigations to monitor disease course, their correlation with disease activity is weak. Serum autoantibodies such as anti-endothelial cell antibodies and elevated serum levels of vascular endothelial growth factor, matrix metalloproteinase-9, and interleukins-6 and -18 are inconsistent biomarkers for disease activity. Levels of pentraxin-3 and ratios of platelets and neutrophils to lymphocytes might reflect the inflammatory phase.[10] However, these levels were not examined in the current patient due to lack of availability, stormy disease course, and financial constraints. However, the focal necrotizing glomerulonephritis and the presence of ANCA are not explained by a predominant diagnosis of TA. The most common glomerular lesions in TA are nonspecific ischemic changes, such as collapsed and/or hyalinized tuft that follow arterial narrowing or long-standing renovascular hypertension.[2] While ANCA positivity is not a feature of most vasculitides known to cause large vessel involvement, ANCA may occasionally be associated with large vessel involvement. In contrast to the predominantly stenotic complications of TA, luminal occlusion, prominent perivasculitis, and dissection are important complications of ANCA-associated large vessel disease. Hence, large vessel may rarely be affected even with predominantly SVV.[11] However, while ANCA-associated large vessel involvement is reported,[12],[13] TA has never been described in association with AAV. Given the rarity of the association, the plan for immunosuppression in the present patient was empiric and was combined with plasma exchanges in order to remove autoantibodies completely.

Overall, the report indicates that different forms of systemic vasculitis may overlap such that all sizes of vessels can be affected in a single patient at the same point of time. More information is required on the mechanisms of disease in such patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the parents have given his consent for images and other clinical information to be reported in the journal. The parents understand that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65:1-1.  Back to cited text no. 1
Gulati A, Bagga A. Large vessel vasculitis. Pediatr Nephrol 2010;25:1037-48.  Back to cited text no. 2
Misra R, Danda D, Rajappa SM, Ghosh A, Gupta R, Mahendranath KM, et al. Development and initial validation of the Indian Takayasu Clinical Activity Score (ITAS2010). Rheumatology (Oxford) 2013;52:1795-801.  Back to cited text no. 3
Batu ED, Ozen S. Vasculitis: Do we know more to classify better? Pediatr Nephrol 2015;30:1425-32.  Back to cited text no. 4
Siomou E, Tramma D, Bowen C, Milford DV. ANCA-associated glomerulonephritis/systemic vasculitis in childhood: Clinical features-outcome. Pediatr Nephrol 2012;27:1911-20.  Back to cited text no. 5
Brogan P, Eleftheriou D, Dillon M. Small vessel vasculitis. Pediatr Nephrol 2010;25:1025-35.  Back to cited text no. 6
McAdoo SP, Tanna A, Hrušková Z, Holm L, Weiner M, Arulkumaran N, et al. Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients. Kidney Int 2017;92:693-702.  Back to cited text no. 7
Javed T, Vohra P. Crescentic glomerulonephritis with anti-GBM and p-ANCA antibodies. Case Rep Nephrol 2012;132085. doi:10.1155/2012/132085..  Back to cited text no. 8
Kluth DC, Rees AJ. Anti-glomerular basement membrane disease. J Am Soc Nephrol 1999;10:2446-53.  Back to cited text no. 9
Russo RA, Katsicas MM. Takayasu Arteritis. Front Pediatr 2018;6:265.  Back to cited text no. 10
Chirinos JA, Tamariz LJ, Lopes G, Del Carpio F, Zhang X, Milikowski C, et al. Large vessel involvement in ANCA-associated vasculitides: Report of a case and review of the literature. Clin Rheumatol 2004;23:152-9.  Back to cited text no. 11
Carels T, Verbeken E, Blockmans D. p-ANCA-associated periaortitis with histological proof of Wegener's granulomatosis: Case report. Clin Rheumatol 2005;24:83-6.  Back to cited text no. 12
Vega J, Guarda FJ. Large vessel involvement in ANCA-associated vasculitis: Report of one case. Rev Med Chil 2015;143:1206-9.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3]


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