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Year : 2021  |  Volume : 17  |  Issue : 2  |  Page : 609-612

Bacillus Calmette–Guérin-induced perinuclear antineutrophil cytoplasmic antibodies associated vasculitis in bladder cancer

Department of Nephrology, University of Health Sciences Bakırkoy Dr. Sadi Konuk Research and Educational Hospital, Istanbul, Turkey

Date of Submission30-Jun-2020
Date of Decision29-Aug-2020
Date of Acceptance30-Sep-2020
Date of Web Publication11-Jun-2021

Correspondence Address:
Sibel Yucel Kocak
Department of Nephrology, University of Health Sciences Bakırkoy Dr. Sadi Konuk Research and Educational Hospital, Istanbul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_890_20

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 > Abstract 

Intravesical instillation of Bacillus Calmette–Guérin (BCG) immunotherapy remains the most effective adjuvant treatment for noninvasive bladder cancer. Systemic BCG-related complications are rare and usually related to infective agent or an immune-mediated reaction. We discussed a case with perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) vasculitis, developing after instillation of BCG for non-invasive bladder cancer. A 68-year-old man presented with nephritic syndrome a few months after BCG instillations which was performed for his non–muscle-invasive bladder cancer adjuvant therapy. The renal function had declined slowly after the first instillation and urinary sediment reveals the new onset of nephritic proteinuria and hematuria. High titer of p-ANCA was present. His renal biopsy was consistent with acute renal vasculitis. The patient's creatinine level regressed with immunosuppressive therapy and he was clinically followed up without hemodialysis. Here, we presented a patient that diagnosed as p-ANCA related vasculitis occurred after BCG instillation.

Keywords: Bacillus Calmette–Guérin, bladder cancer, vasculitis

How to cite this article:
Kocak SY, Kudu A, Apaydın S. Bacillus Calmette–Guérin-induced perinuclear antineutrophil cytoplasmic antibodies associated vasculitis in bladder cancer. J Can Res Ther 2021;17:609-12

How to cite this URL:
Kocak SY, Kudu A, Apaydın S. Bacillus Calmette–Guérin-induced perinuclear antineutrophil cytoplasmic antibodies associated vasculitis in bladder cancer. J Can Res Ther [serial online] 2021 [cited 2021 Sep 23];17:609-12. Available from: https://www.cancerjournal.net/text.asp?2021/17/2/609/318117

 > Introduction Top

Intravesical instillation of Bacillus Calmette–Guérin (BCG), an attenuated live strain of Mycobacterium bovis, immunotherapy remains the most effective adjuvant treatment for nonmuscle-invasive bladder cancer and generally well tolerated. Following instillation, both local and systemic BCG-related complications may occur.[1],[2] Systemic complications of BCG instillation are rare and related to the infective agent or an immune-mediated reaction. Here, we discussed a patient with recurrent noninvasive bladder cancer, treated with transurethral resection and intravesical instillation of BCG, developing perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) vasculitis after instillation of BCG.

 > Case Report Top

A 68-year-old man was diagnosed as a low grade of noninvasive urothelial carcinoma. Endoscopic resection was performed for the treatment of noninvasive bladder carcinoma and the patient was followed by cystoscopy. Bladder cancer recurred and biopsy revealed high grade noninvasive urothelial carcinoma in the follow-up. Intravesical BCG was administered. After the first instillation of BCG, creatinine levels increased slowly, and 3 months after the first intravesical administration of BCG, the patient was admitted to a nephrology outpatient clinic with a creatinine level of 4.16 mg/dL. The patient had a history of hypertension and was using a calcium antagonist for treatment. Basal creatinine level was 1.82 mg/dL. Urinary ultrasonography revealed a normal kidney size but increased parenchymal echogenicity. Urinalysis revealed proteinuria of 2.5 g/day. Urinary sediment showed 15–20 red blood cells. C3 and C4 levels were in a normal range. p-ANCA titer was highly elevated at 173 u/mL (positive) which was measured by the enzyme-linked immunosorbent assay method (normal range 12–18 u/mL). Serum ANA and anti-dsDNA levels were negative. The patient was hospitalized and underwent renal biopsy with a diagnosis of rapidly progressive glomerulonephritis (acute on chronic renal failure) and nephritic syndrome. Renal biopsy was examined by light and immunofluorescence microscopy. Light microscopy revealed global sclerosis in 21 glomeruli and 1 glomerulus with fibrocellular crescent formation [Figure 1] and another glomerulus showing segmental fibrinoid necrosis and early crescent formation [Figure 2]. Furthermore, moderate tubulointerstitial infiltration and scarring were seen in renal biopsy [Figure 3]. Immunofluorescence staining for IgG, IgA, IgM, C3, C1q, fibrinogen, kappa, and lambda were negative. The histomorphological findings in renal biopsy were consistent with renal vasculitis which could be observed in microscopic polyangiitis and accepted that it was induced by instillation of BCG used for the treatment of bladder cancer. Although there were chronic changes in renal biopsy, crescent formation and segmental fibrinoid necrosis were detected, too. The patient's diagnosis was accepted as rapidly progressive glomerulonephritis and treated with three times pulse steroid (500 mg methylprednisolone/day) and oral mycophenolate mofetil. Decreasing 24 h proteinuria, hematuria, and serum creatinine levels were observed and accepted as responding immunosuppressive treatment. Laboratory results including creatinine levels and proteinuria before and after the treatment are shown in [Figure 4].
Figure 1: Fibrocellular crescent formation in Bowman space (PAS, ×40)

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Figure 2: Glomerulus with segmental fibrinoid necrosis and early crescent formation(x40), Jonesæ methenamine silver

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Figure 3: On the background, there were many globally sclerotic glomeruli along with tubular atrophy and interstitial fibrosis and inflammation (PAS, ×10)

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Figure 4: Proteinuria and creatinine levels for 1 year follow-up

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 > Discussion Top

The intravesical administration of BCG, an attenuated live strain of Mycobacterium bovis, has become a mainstay of adjuvant therapy for recurrent superficial bladder cancer or in situ carcinoma. BCG effectively eradicates existing carcinoma in situ, decreases recurrence of carcinoma, and disease progression after transurethral resection.[3] The pathogenesis of tumor destruction due to BCG has not been understood very well yet. One potential mechanism involves adhesion of BCG to the bladder urothelium and triggers an inflammatory cascade, inducing neutrophil, and Th1 chemotaxis. Th1-induced production of interleukin 2, tumor necrosis factor, and interferon γ is thought to mediate tumor destruction.[4]

Although the administration of BCG intravesically is generally well tolerated and usually a safe therapy, BCG-related complications may occur following instillation as it is an attenuated vaccine. Most of the BCG-related complications are relatively minor. They include urinary frequency, cystitis, fever, and hematuria. Data about complications of BCG instillation have come from case reports up to date. As the variability of clinical features of complications and the onset of the complications can be delayed months to years after the last instillation, diagnosis and treatment of these complications may be very difficult for clinicians. The pathogenesis of complications has not been fully understood as they can be seen as local or systemic. Systemic complications may be related to a disseminated infection including BCG sepsis or an immune response occurred after instillation of BCG. Immune response of systemic complications is due to cross-reactivity between tissue self-antigens and mycobacterial antigens. Immunologic side effects are relatively rare comparing with local and systemic disseminated infection.[2],[5] BCG-related immunologic complications can effect almost any organs, as an example, granulomatous hepatitis was reported after BCG administration and had incomplete remission after adding steroid and intravenous immunoglobulin.[6] Reactive arthritis and hypersensitivity reactions can also occur as immunologic side effects of BCG instillation.

Renal immunologic complications after BCG instillation were rarely reported and diagnosed by performing a renal biopsy. Nephritic or nephrotic syndrome can be observed in affected patient. Acute azotemia, proteinuria, eosinophilia can be seen with interstitial nephritis without ARB-positive culture.[7] It was reported that granulomatous nephritis as complication in which cases given intrarenal BCG and nephroureterectomy had been performed after.[8] In 2018, Selmi et al. reported a case of p-ANCA positive renal granulomatosis with polyangiitis following intravesical BCG therapy. In that case, the patient had to be started chronic hemodialysis. In our case, the patient had been diagnosed as microscopic polyangiitis and had not necessary any hemodialysis session.[9] Glomerulonephritis with immune deposits and vasculitis with renal involvement were also reported in some series of cases. Nan et al. reported the first case of Henoch–Schönlein purpura following intravesical administration of BCG.[10] Furthermore, an 80-year-old man was reported with cryoglobulinemic vasculitis following intravesical instillations of BCG.[11] Asín et al. analyzed 282 cases and found that kidney parenchymal involvement in 10 cases (3.5%), nephritis in 5 cases (only one of them was tubulointerstitial nephritis and the others were granulomatous inflammation), and no vasculitis were detected.[12] In our case, we reported a focal necrotizing and crescentic glomerulonephritis with p-ANCA positivity, diagnosed after instillation of BCG used for noninvasive bladder cancer adjuvant therapy. The patient previously had hypertension and decreased renal function, accepted as chronic renal failure, and admitted to outpatient nephrology clinic 3 months after the first instillation. His urinary sediment revealed hematuria and nephrotic-range proteinuria. High titers of p-ANCA and normal complement levels were detected. Renal biopsy was performed with an indication of acute on chronic renal failure. Renal biopsy with p-ANCA positivity revealed renal vasculitic involvement and the patient was treated with immunosupressives, first pulse steroid then with oral mycophenolate mofetil. After management with immunosuppressives, creatinine level was decreased to nearly basal value and did not change during in follow-up.

 > Conclusion Top

Renal immunologic side effects of intravesical BCG instillation are rare. Cases of cryoglobulinemic vasculitis, Henoch–Schönlein purpura, glomerulonephritis with immune deposits following intravesical administration of BCG were reported. Here, we present a patient with p-ANCA-associated focal necrotizing and crescentic glomerulonephritis after BCG instillation. This is a case of p-ANCA-associated necrotizan glomerulonephritis that was successfully managed with immunosuppressive therapy.

Declaration of patient consent

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

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Conflicts of interest

There are no conflicts of interest.

 > References Top

Lamm DL. Comparison of BCG with other intravesical agents. Urology 1991;37:30-2.  Back to cited text no. 1
Koya MP, Simon MA, Soloway MS. Complications of intravesical therapy for urothelial cancer of the bladder. J Urol 2006;175:2004-10.  Back to cited text no. 2
Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette - Guérin in the treatment of superficial bladder tumors. J Urol 1976;116:180-3.  Back to cited text no. 3
Rosevear HM, Lightfoot AJ, O'Donnell MA, Griffith TS. The role of neutrophils and TNF-related apoptosis-inducing ligand (TRAIL) in bacillusCalmette-Guérin (BCG) immuno-therapy for urothelial carcinoma of the bladder. Cancer Metastasis Rev 2009;28:345-53.  Back to cited text no. 4
Lamm DL, van der Meijden PM, Morales A, Brosman SA, Catalona WJ, Herr HW, et al. Incidence and treatment of complications of bacillus Calmette - Guérin intravesical therapy in superficial bladder cancer. J Urol 1992;147:596-600.  Back to cited text no. 5
Salvador R, Vilana R, Bargalló X, Araque X, Nicolau C. Tuberculous epididymo-orchitis after intravesical BCG therapy for superficial bladder carcinoma: Sonographic findings. J Ultrasound Med 2007;26:671-4.  Back to cited text no. 6
Fry A, Saleemi A, Griffiths M, Farrington K. Acute renal failure following intravesical bacille Calmette Guérin chemotherapy for superficial carcinoma of the bladder. Nephrol Dial Transplant 2005;20:849-50.  Back to cited text no. 7
Soda T, Hori D, Onishi H, Miyakawa M. Granulomatous nephritis as a complication of intrarenal bacille Calmette - Guérin therapy. Urology 1999;53:1228.  Back to cited text no. 8
Selmi Y, Kheder-Elfekih R, Jebali H, Fatma LB, Smaoui W, Krid M, et al. A case of renal granulomatosis with polyangiitis following intravesical bacillus Calmette - Guérin therapy. Saudi J Kidney Dis Transpl 2018;29:185-8.  Back to cited text no. 9
[PUBMED]  [Full text]  
Nan DN, Fernández-Ayala M, García-Ibarbia C, Gutiérrez-Santiago M, Hernández JL. Henoch-Schönlein purpura after intravesical administration of bacillus Calmette-Guérin. Scand J Infect Dis 2005;37:613-5.  Back to cited text no. 10
Granel B, Serratrice J, Moranger PE, Disdier P, Weiller PJ. Cryoglobulinemia vasculitis following intravesical instillations of bacillus Calmette - Guérin. Clin Exp Rheumatol 2004;22:481-2.  Back to cited text no. 11
Asín MA, Fernández-Ruiz M, López-Medrano F, Lumbreras C, Tejido A, San Juan R, et al. Bacillus Calmette - Guérin (BCG) Infection following ıntravesical BCG administration as adjunctive therapy for bladder cancer: Incidence, risk factors, and outcome in a single-ınstitution series and review of the literature. Medicine 2014;938179:236-54.  Back to cited text no. 12


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


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