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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2018  |  Volume : 29  |  Issue : 6  |  Page : 1488-1493
Cerebral venous sinus thrombosis as a warning signal for double positive crescentic glomerulonephritis in a young male with complete renal recovery

1 Department of Nephrology, INHS Kalyani, Vishakhapatnam, Andhra Pradesh, India
2 Department of Medicine, INHS Kalyani, Vishakhapatnam, Andhra Pradesh, India
3 Department of Cardiology, INHS Kalyani, Vishakhapatnam, Andhra Pradesh, India
4 Department of Neurology, INHS Kalyani, Vishakhapatnam, Andhra Pradesh, India
5 Department of Renal Pathology, Lal Path Lab, New Delhi, India

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Date of Submission02-Jan-2018
Date of Decision12-Feb-2018
Date of Acceptance14-Feb-2018
Date of Web Publication27-Dec-2018


Double positive crescentic glomerulonephritis is relatively rare in young population and has variable outcomes. Although increased incidence of deep venous thrombosis in antineutrophil cytoplasmic antibody-associated vasculitis has been reported, cerebral venous sinus thrombosis (CVT) is very rare. We present a young male who presented with CVT followed by rapidly progressive crescentic glomerulonephritis and with appropriate therapeutic modalities he had complete renal and partial neurological recovery.

How to cite this article:
Jha VK, Padmaprakash K V, Pandey R, Sharda V, Sharma A. Cerebral venous sinus thrombosis as a warning signal for double positive crescentic glomerulonephritis in a young male with complete renal recovery. Saudi J Kidney Dis Transpl 2018;29:1488-93

How to cite this URL:
Jha VK, Padmaprakash K V, Pandey R, Sharda V, Sharma A. Cerebral venous sinus thrombosis as a warning signal for double positive crescentic glomerulonephritis in a young male with complete renal recovery. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2022 May 16];29:1488-93. Available from: https://www.sjkdt.org/text.asp?2018/29/6/1488/248291

   Introduction Top

Copresentation with both antineutrophil cyto-plasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) antibodies is found to be relatively rare. Current studies of such “double-positive” cases report small numbers and have variable outcomes. Usually, in these cases, both antibodies are found at the time of clinical presentation with rapidly progressive crescentic glomerulonephritis (RPGN), and it is unclear which is the primary contributor to renal damage. In recent years, the relationship between inflammation and thrombosis has also been deeply investigated and it is now suggested that immune and coagulation systems are functionally interconnected.[1] Although increased incidence of deep venous thrombosis in ANCA-associated vasculitis has been reported;[1],[2],[3] however, cerebral venous sinus thrombosis (CVT) has rarely been reported. CVT followed by double positive crescentic glomerulonephritis has never been reported. We present a young male who initially presented with cerebral venous thrombosis with left hemiparesis and subsequently had double positive crescentic glomerulo-nephritis requiring dialysis support. Later with adequate immunosuppression and plasma exchange, he had complete renal recovery and marked improvement in his neurological status.

   Case Report Top

A 29-year-old male RB, a sailor, was admitted as a case of fever with thrombocytopenia. He was managed conservatively initially but on 6th day of admission, he developed left-sided hemiparesis. Magnetic resonance imaging (MRI) brain and magnetic resonance venogram done at that time revealed CVT involving right frontotemporoparietal region. He was put on heparin; however, the course was complicated after two doses of heparin by upper gastrointestinal bleed and was not treated thereafter. Fever work up was negative. Cerebrospinal fluid analysis was also done to rule out infectious/parainfectious causes which was normal. Antinuclear antibody profile was normal. He was treated symptomatically with osmotic diuretics, opioid analgesics, and other supportive measures. He got discharged after symptomatic improvement and was under follow-up of neurophysician and physiotherapist. His renal function tests were normal at the time of discharge. Within few days of discharge from hospital, he got readmitted with a history of generalized weakness, anorexia and unquan-tified weight loss. Initial evaluation revealed advanced azotemia (urea -180 mg/dL, serum creatinine -9.8 mg/dL), anemia (Hb -7.2 g/dL), microscopic hematuria [albumin 2+, 60–80 red blood cell (RBC)/HPF], and normal-sized kidneys. In view of features suggestive of RPGN, he underwent renal biopsy after two sessions of hemodialysis (HD) with blood transfusion on May 11, 2017. Further evaluations revealed: serum bilirubin -0.8 mg/dL, aspartate aminotransferase/alanine aminotrans-ferase -43/47 IU/L, serum albumin -3.1 g/dL, thyroid profile -normal, repeat urine RE/ME-protein 2+, large number of RBC. HIV, HBsAg, antiHCV -negative, HCV RNA qualitative -negative, serum cryoglobulins -negative, ANA profile -negative, C3 -181 mg/dL (80–156 mg/dL), c-ANCA-Negative, p-ANCA-strongly positive (1:320), anti GBM-621 (<7 IU/mL), antiphospholipid antibody workup (APLA) work up (LAC, ACL, Anti beta2 glycoprotein) -negative, prothrombotic work up (protein C/S deficiency, factor V Leiden, antithrombin III deficiency, serum homocysteine) -normal, plasma cell disorder work up (serum immunofixation, serum free light chain assay) -normal, chest X-ray posteroanterior (PA) view - normal, high-resolution computed tomography chest -normal study, electrocardiogram -normal, and renal biopsy No. 180813/17.05.17 ([Figure 1], [Figure 2], [Figure 3]) - 17 glomeruli – one glomeruli sclerosed, 13/17 glomeruli reveal overlying partial/circumferential fibrocellular and cellular crescents. At least, 10/17 glomeruli reveal segmental to global fibrinoid tuft necrosis. Underlying tufts are variably compressed and show focal intra-glomerular neutrophil infiltration. Viable areas reveal non proliferative morphology. Interstitial fibrosis and tubular atrophy – 10%–20%, severe acute tubular injury, focal chronic interstitial inflammation, interstitial edema, focal arteriolar necrosis. Direct immunofluo-rescence -IgG 3+ pattern less/linear along the glomerular capillaries.
Figure 1: The images show necrotizing glomerular lesions with overlying crescents (H and E stains, ×450).

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Figure 2: Masson’s trichrome stain which shows reddish areas of fibrinoid necrosis (×450).

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Figure 3: Silver methenamine stained section which shows silver negative areas of necrosis and fibrin deposition (×450).

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Course in Hospital

He was put on methyl prednisolone pulse (500 mg IV x 5 days) just after renal biopsy followed by oral steroid 35 mg/day (weight = 38 kg). He required four sessions of HD postbiopsy in view of azotemia/oligoanuria. He was put on plasmapheresis -10 sessions starting from May 18, 2017 and was also administered i.v. cyclophosphamide 500 mg and total four such doses were given within three months. His renal parameters gradually started improving and he became dialysis-independent after total six sessions of HD. He achieved serum creatinine-1.0 mg/dL within three months and was put on tapering dose of steroid with plan to stop within six months and azathioprine (2 mg/kg/ day). His repeat p-ANCA and anti-GBM antibody are negative. He gained 4 kg weight and his general condition improved. His repeat MRI brain was suggestive of partial resolution of cerebral venous thrombosis and subacute infarct in the right fronto temporo parietal region with ex vacuo dilatation of right lateral ventricle [Figure 4].
Figure 4: Magnetic resonance imaging brain showing partial resolution of cerebral venous thrombosis and subacute infarct in right frontotemporal parietal region with ex vacuo dilatation of the right lateral ventricle.

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   Discussion Top

The phenomenon of double positivity (ANCA and anti-GBM positivity) was first reported within few years of the first description of ANCA in the 1980s and has been observed in several series from around the world over the subsequent 30 years.[4] It is clear that the two antibody populations associated with these diseases are antigenically distinct[5] and that this phenomenon is not due to cross-reactivity, although the mechanisms of the association are not fully understood. Several studies have reported the outcomes of these patients who are double positive, although with conflicting findings. In the largest series till now, McAdoo et al[6] retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients from four European centers with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis and also features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. Patient, in our case is young, had severe renal disease and no lung hemorrhage at presentation. In another UK study by Levy et al,[7] 5% of all ANCA-positive serum samples were also positive for anti-GBM antibodies, and 32% of all anti-GBM positive samples had detectable ANCA. Of 27 patients with both antibodies, 82% had anti-myeloperoxidase specific p-ANCA. Pulmonary hemorrhage occurred in 44%. Renal biopsy showed extensive glomerular cellular crescents in most patients. Patient and renal survival rates were 52% and 26%, respectively, at one year. Sixty-eight percent of patients were dialysis dependent at presentation, and none of these recovered renal function, despite immunosuppression with or without plasma exchange. Contrary to this study even the patient in the index case was dialysis dependent at presentation and his renal function recovered with immunosuppression and plasma exchange.

Rutgers et al[8] reviewed the Limburg renal biopsy register (1978 to 2003; n = 1,373) for cases of chronic glomerulonephritis. They identified 46 MPO-ANCA positive, 10 doublepositive, and 13 anti-GBM positive patients. Renal survival analysis showed significant differences among the three groups (P = 0.04, with 65%, 10%, and 15% off dialysis therapy at 1 year, respectively). They concluded that in patients with both anti-GBM antibodies and MPO ANCAs, histological findings differ from those of patients with anti-GBM anti-bodies only. However, renal survival in these patients is not better than that in anti-GBM positive patients and is worse compared with patients with MPO-ANCAs only.

In recent years, evidence supporting an increased frequency of venous thrombotic events in AAV has arisen. The prevalence of venous thrombosis in AAV ranges between 5.8% and 30%.[9] The increased incidence of venous thromboembolism (VTE) in granulo-matosis with polyangiitis (GPA) has been well recognized. Analysis of 167 patients demonstrated an incidence of seven VTE per 100 person-years of follow-up in those patients with no prior history of VTE.[2] The risk in GPA was similar to that seen in those in the general population with recurrent DVT. Similarly, retrospective data from a French cohort support a similar risk in patients with microscopic polyangiitis and Churg–Strauss as in GPA.[3] Currently, there are no significant data on the use of antiplatelet and/or anti-coagulant therapy in AAV. Although there is increased risk of deep venous thrombosis, incidence of CVT has been rarely reported in AAV. In a case report, Saito et al describes a 72-year-old woman presenting MPO-ANCA-associated hypertrophic pachymeningitis and venous thrombosis.[10]

There is no available literature mentioning thrombosis risk in patients with anti-GBM disease or double positive crescentic glome-rulonephritis. The present case has special features in the form of CVT preceding the onset of crescentic glomerulonephritis, patient being young and having double antibody positive (both anti-GBM and p-ANCA positive), dialysis dependent at the onset, no lung involvement and complete renal recovery along with serological remission just before three months. CVT in the setting of double antibody positive crescentic glomeruloneph-ritis has never been reported. This case stresses the importance of small vessel vasculitis as an etiological factor for CVT and its treatment with adequate immunosuppression to prevent further complications involving other organs. Timely intervention with immunosuppression and plasma exchange may prevent the long-term complication.

   Conclusion Top

Double positive crescentic glomeruloneph-ritis though very rare in young population should be considered in appropriate clinical setting. In a young patient with CVT, small-vessel vasculitis activity should be considered to prevent other organ involvement. Patient should be aggressively treated with plasma exchange and immunosuppression to prevent long-term complication.

Conflict of interest: None declared.

   References Top

Emmi G, Silvestri E, Squatrito D, et al. Thrombosis in vasculitis: From pathogenesis to treatment. Thromb J 2015;13:15.  Back to cited text no. 1
Merkel PA, Lo GH, Holbrook JT, et al. Brief communication: High incidence of venous thrombotic events among patients with Wegener granulomatosis: The Wegener’s clinical occurrence of thrombosis (WeCLOT) study. Ann Intern Med 2005;142:620-6. '  Back to cited text no. 2
Allenbach Y, Seror R, Pagnoux C, et al. High frequency of venous thromboembolic events in Churg-Strauss syndrome, Wegener’s granulo-matosis and microscopic polyangiitis but not polyarteritis nodosa: A systematic retrospective study on 1130 patients. Ann Rheum Dis 2009; 68:564-7.  Back to cited text no. 3
Jayne DR, Marshall PD, Jones SJ, Lockwood CM. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulo-nephritis. Kidney Int 1990;37:965-70.  Back to cited text no. 4
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. 5
McAdoo SP, Tanna A, Hrušková Z, 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. 6
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. 7
Rutgers A, Slot M, van Paassen P, van Breda Vriesman P, Heeringa P, Tervaert JW. Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis. Am J Kidney Dis 2005;46:253-62.  Back to cited text no. 8
Ames PR, Margaglione M, Mackie S, Alves JD. Eosinophilia and thrombophilia in Churg Strauss syndrome: A clinical and pathogenetic overview. Clin Appl Thromb Hemost 2010;16: 628-36.  Back to cited text no. 9
Saito T, Fujimori J, Yoshida S, Kaneko K, Kodera T. Case of cerebral venous thrombosis caused by MPO-ANCA associated hyper-trophic pachymeningitis. Rinsho Shinkeigaku 2014;54:827-30.  Back to cited text no. 10

Correspondence Address:
Dr. Vijoy Kumar Jha
Department of Nephrology, INHS Kalyani, Vishakhapatnam -530 005, Andhra Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.248291

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

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