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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2021  |  Volume : 32  |  Issue : 1  |  Page : 240-244
Splenic Infarcts and Pulmonary Renal Syndrome in a Young Patient with Double-Positive Anti-GBM and ANCA-Associated Vasculitis

1 Department of Medicine, King Abdulaziz Medical City, Ministry of the National Guard- Health Affairs; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
2 King Abdullah International Medical Research Center; Department of Pathology, KAMC, Ministry of the National Guard- Health Affairs, Riyadh, Saudi Arabia
3 Department of Medicine, King Abdulaziz Medical City, Ministry of the National Guard- Health Affairs, Riyadh, Saudi Arabia

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Date of Web Publication16-Jun-2021


Double-positive disease, defined by double-seropositivity for serum anti-glomerular basement membrane (GBM) antibodies and anti-neutrophil cytoplasmic antibodies (ANCA) is a rare cause of pulmonary-renal syndrome. Here, we present an exceptional course of a 20-year-old male with seropositivity for anti-myeloperoxidase anti-neutrophil cytoplasmic antibodies and anti-GBM antibody, who presented first with renal impairment due to focal necrotizing crescentic glomerulonephritis. After receiving treatment, he presented two years later with a relapse manifesting with diffuse alveolar hemorrhage and multiple splenic infarcts. We discuss the clinical presentation patterns and treatment strategies of this entity.

How to cite this article:
Rajah FT, Alhabobi AA, Aloudah NM, Osman AI, Elhassan EA. Splenic Infarcts and Pulmonary Renal Syndrome in a Young Patient with Double-Positive Anti-GBM and ANCA-Associated Vasculitis. Saudi J Kidney Dis Transpl 2021;32:240-4

How to cite this URL:
Rajah FT, Alhabobi AA, Aloudah NM, Osman AI, Elhassan EA. Splenic Infarcts and Pulmonary Renal Syndrome in a Young Patient with Double-Positive Anti-GBM and ANCA-Associated Vasculitis. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2023 Jan 27];32:240-4. Available from: https://www.sjkdt.org/text.asp?2021/32/1/240/318532

   Introduction Top

Double-positive disease (DPD), defined by double-seropositivity for serum anti-glomerular basement membrane (GBM) antibodies and anti-neutrophil cytoplasmic antibodies (ANCA) specific for either myeloperoxidase (anti-MPO) or proteinase 3 (anti-PR3) is a recognized cause of the pulmonary-renal syndrome.[1] DPD has a distinct clinical course when compared to single positive anti-GBM disease or ANCA associated vasculitis (AAV). Patients with DPD are more likely to recover from being dialysis-dependent when compared to anti-GBM disease. Moreover, they have an intermediate long-term renal survival despite more chronic renal damage on kidney biopsy and more advanced age at presentation, when compared to the single-positive diseases.[2] We present an exceptional course of a 20-year-old male with seropositivity for MPO-ANCA and anti-GBM antibody, with focal necrotizing crescentic glomerulonephritis on renal biopsy, who relapsed with diffuse alveolar hemorrhage and multiple splenic infarcts. To our knowledge, this is the first report of double-positive vasculitis presenting with splenic infarcts. The largest published series evaluating this disease consisted of only 37 patients, and our patient underwent a renal biopsy at a much younger age when compared to this cohort.[2] There are also no previously reported cases of double-positive vasculitis in Saudi Arabia.

   Case Report Top

A previously healthy 20-year-old Saudi male developed flu-like symptoms associated with hemoptysis. The symptoms resolved after a few days and did not prompt him to seek medical help. He then developed transient gross hematuria for one day for which he visited a local hospital and was diagnosed with renal stones and renal impairment. He was given oral antibiotics for his symptoms and advised to follow-up with a specialist for the renal impairment. One month later, he presented to our hospital with a one-month history of subjective fever, persistent nausea and vomiting, and intermittent, right flank pain. There was no associated hematuria or hemoptysis at this time. On physical examination, he was pale with height (cm): 170.5, weight (kg): 107, and body mass index: 36.81. Abdominal exam revealed a distended abdomen with bulging flanks and mild peri-umbilical tenderness. The rest of the examination was unremarkable. Urine testing revealed microscopic hematuria and sub-nephrotic range proteinuria (2.5 mg/24 h). Initial laboratory investigations revealed normocytic anemia [91 g/L (normal: 120–160)] and thrombocytosis [519×109/L (150–400)]. He had elevated blood urea nitrogen [18.2 mmol/L (3.2–7.4)] and creatinine [632 μmol/L (64–110)]. Renal ultrasound was unremarkable. He was electively started on hemodialysis due to uremic symptoms. The presence of renal impairment with the history of pulmonary manifestations prompted serologic testing. Erythrocyte sedimentation rate was 149 mm/h (0–15) and C-reactive protein was 199 mg/L (<3.5). Enzyme-linked immuno-assay showed strongly positive MPO-ANCA at 64.9 units (<20) and anti-GBM antibodies at 172.49 units (<20), however, PR3-ANCA was negative at 1.99 units (<20). Antinuclear antibodies, anti-double-stranded DNA antibodies, anti-streptolysin O titers, and C3 and C4 complement components were all normal. Percutaneous renal biopsy was performed, and tissue samples were analyzed by light microscopy and immunofluorescence. Light microscopy showed global glomerulosclerosis in seven out of 42 glomeruli, cellular crescents in 35 out of 42 glomeruli, and fibrinoid necrosis and karyorrhexis in few glomeruli [Figure 1]a and [Figure 1]b, with heavy neutrophilic interstitial infiltration. Moderate interstitial fibrosis and tubular atrophy, as well as moderate arterial and hyaline arteriolo-sclerosis were seen. Immunofluorescence showed diffuse global linear staining of the GBM for IgG [Figure 1]c accompanied by staining for kappa and lambda light chains. Diagnosis of glomerulonephritis caused by anti-GBM disease and coexistent AAV was made. Treatment was started with daily plasmapheresis sessions for 10 days, as well as IV methylprednisolone pulses (500 mg/day) for three days followed by oral prednisone (60 mg/day). Hemodialysis was electively started due to uremic symptoms and was discontinued after 8 sessions as the creatinine plateaued at 300 μmol/L and the symptoms resolved. Oral cyclophosphamide (75 mg/day) was also started but was discontinued after four months as anti-GBM level was trending down. Oral prednisone was tapered down to 5 mg and discontinued after one year. Eight months from the first presentation, he was readmitted for refractory hyperkalemia and was started on chronic peritoneal dialysis (PD). Anti-GBM level became normal after six months, and MPO-ANCA level was steadily declining.
Figure 1: (a) Low power view shows diffuse cellular crescent formation with few glomeruli showing fibrous and fibrocellular crescents with evidence of marked interstitial lymphocytic infiltrate and no granuloma seen (PAS stain, ×10). (b) Glomerulus with cellular crescent and residual capillary lobule with no apparent proliferation or GBM thickening (PAS and trichrome stains, ×40). (c) Immunofluorescence showing strong positive linear staining for IgG (+3). Furthermore, there was similar staining for kappa and lambda light chains (2+) and albumin (1+), but the rest of the antibodies (IgA, IgM, C3, C1q, and C4) were all negative.

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Two years later, he presented with a one-month history of intermittent hemoptysis, skin rash over the left shin, and abdominal pain. The patient was not in respiratory distress but had inspiratory crackles were over his lower lung fields. There was a tender, palpable, non-blanchable, 10 cm by 8 cm purpura over his left shin. The rest of the physical examination was unremarkable. Complete blood count showed normocytic anemia (67 g/L). Serology showed MPO-ANCA of 56.44 units, still positive but declining, however, anti-GBM antibody was negative (1.42 units). Chest X-ray showed right-sided patchy pulmonary infiltrate, thus pulmonary hemorrhage was suspected [Figure 2]. Chest computed tomography (CT) scan showed ground-glass opacities mostly representing resolving pulmonary hemorrhage and abdominal CT showed multiple splenic infarcts [Figure 3]a and [Figure 3]b. Skin biopsy was consistent with leukocytoclastic vasculitis. Diagnosis of recurrent systemic AAV was made. Treatment was started with I.V. methylprednisolone pulses (250 mg/day) for three days, then oral prednisone, 60 mg/day, with subsequent taper off gradually. Additionally, he was treated with rituximab 700 mg IV first, followed by 500 mg after a week and at six months. The rash resolved after pulse therapy, and symptoms gradually improved. During the subsequent 10-month follow-up visits, he remained well. PD was continued with regular care at our center.
Figure 2: Chest X-ray shows right sided patchy pulmonary infiltrate and thus pulmonary hemorrhage was suspected.

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Figure 3: (a) An axial image of the chest showing bilateral alveolar hemorrhage that are more prominent in the right lung. (b) An axial image of the upper abdomen from a contrast-enhanced computed tomography scan showing multiple diffuse non-enhancing regions within the spleen representing infarctions (red arrows).

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The authors obtained all appropriate consent forms from the patient for the publication of the case report.

   Discussion Top

True DPD is considered to be a rare entity, however, the true incidence is not known.[2] Several studies have found that about 30% to 50% of patients with anti-GBM disease have detectable ANCA, especially anti-MPO, and up to 10% of patients with ANCA also have circulating anti-GBM antibodies.[3],[4],[5] The current evidence suggests that the presence of both ANCA and anti-GBM antibodies in individual patients represent a new disease entity and the concurrence cannot be due to chance alone.[1]

McAdoo et al reported the largest published series to compare the outcomes of patients with both ANCA and anti-GBM autoantibodies to those with single-positive AAV and anti-GBM disease.[2] Consistent with their findings, the biopsy of our patient matches anti-GBM disease and ANCA disease. The diffuse severe crescent formation was seen, as well as various stages of cellular crescents with chronic interstitial scarring and inflammation. Strikingly, our patient underwent a biopsy at a much younger age compared to patients with DPD described in the series, whose ages at biopsy ranged from 46 to 76 years. Vasculitis, including granulomatosis with polyangiitis, is a known cause of splenic infarction.[6] However, there are no reported cases in PubMed of splenic infarcts associated with double positive vasculitis, or P-ANCA vasculitis. This may be because splenic infarcts can frequently have a silent clinical presentation and are thus underdiagnosed.[6]

When compared to anti-GBM disease, patients with DPD have a higher tendency to be off dialysis when treated, but the relapse rate is higher.[2] In view of the current literature there are no optimal strategies in treating DPD. Our case was treated initially as typically done for anti-GBM disease with a short course of cyclophosphamide and prednisone. He gradually developed end-stage renal disease requiring dialysis and presented with a relapse two years later, manifesting with hemoptysis and atypical features such as abdominal pain found to result from splenic infarcts. This underscores the closer prognostic resemblance of DPD to AAV rather than anti-GBM disease and emphasizes the importance of long-term immune suppressive therapy similar to AAV.

In conclusion, the current literature on true DPD is limited. Further studies are needed to establish the optimal management strategy, including duration and choice of immune-suppression therapy.

Conflict of interest: None declared

   References Top

McAdoo SP, Pusey CD. Anti-glomerular basement membrane disease. Clin J Am Soc Nephrol 2017;12:1162-72.  Back to cited text no. 1
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. 2
Levy JB, Hammad T, Coulthart A, Dougan T, Pusey CD. Clinical features and outcome of patients with both ANCA and anti-GBM anti bodies. Kidney Int 2004;66:1535-40.  Back to cited text no. 3
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. 4
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. 6. Vanhoenacker FM, Op de Beeck B, De Schepper AM, Salgado R, Snoeckx A, Parizel PM. Vascular disease of the spleen. Semin Ultrasound CT MR 2007;28:35-51.  Back to cited text no. 5

Correspondence Address:
Elwaleed A Elhassan
Nephrology and Renal Transplantation Division, Department of Medicine, KAMC-RD, P. O. Box: 22490, Mail Code 1443, Riyadh 11426
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.318532

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