Nephrotic Syndrome as a Complication of Intravesical BCG Treatment of Transitional Cell Carcinoma of Urinary Bladder

Abstract

Nephrotic syndrome can be associated with various neoplasms, especially solid tumors and lymphomas. This patient presented with painless hematuria of transitional cell carcinoma of urinary bladder, underwent transurethral resection, but developed recurrence 16 months later. Repeat resection was done and intravesical Bacillus Calmette-Guerin (BCG) injections were started. After six months, the patient developed hypertension and nephrotic syndrome with a biopsy revealing membranous glomerulonephritis, though there was no radiological evidence of tumor. This is the first case of nephrotic syndrome with intravesical BCG instillation in a bladder carcinoma patient.

Keywords:

• nephrotic syndrome
• intravesical BCG
• transitional cell carcinoma
• bladder carcinoma

INTRODUCTION

Paraneoplastic syndromes have polymorphic presentations, but nephrotic syndrome is rare. We describe a case of nephrotic syndrome in transitional cell carcinoma of urinary bladder occurring after intravesical Bacillus Calmette-Guerin (BCG) instillation.

CASE REPORT

A 54-year-old male recently developed painless hematuria and weight loss. Investigations to its cause revealed carcinoma urinary bladder; a transurethral resection of bladder tumor (TURBT) revealed “low grade transitional cell carcinoma” (lamina propria invasion only). After 16 months of TURBT, cystoscopy showed papillary growth in the anterior and lateral wall of bladder and trigone with obscured ureteric orifices. A CT abdomen-confirmed mass was localized to bladder. Histopathology suggested a low-grade transitional cell carcinoma (T2N0M0). TURBT was repeated and post-TURBT cystoscopy revealed similar findings, except that bilateral ureteric orifices were visible. Intravesical BCG injections 120 mg weekly for 6 weeks were administered, followed by same dose monthly.

After the sixth dose of monthly intravesical BCG, the patient reported swelling in the face and feet for the prior two months. No history of polyuria, oliguria, hematuria, dysuria, or nocturia was present, and there were no systemic complaints. Examination revealed BP 180/110 mm Hg and facial and pedal edema; the rest of the examination was non-contributory.

Blood biochemistry revealed total proteins of 40 g/L; albumin, 20 g/L; cholesterol, 8.9 mmol/L; triglycerides, 2 mmol/L; and HDL cholesterol, 1.6 mmol/L. The rest of the hematological profile, kidney, and liver function tests were normal. Rheumatoid factor, VDRL, antistreptolysin O and ANA titre, hepatitis B surface antigen, antibodies to HIV 1 & 2, and hepatitis C virus were negative. Urine examination revealed proteinuria (24 hour urinary output of 1.3 L with proteinuria 3.5 g), with occasional erythrocytes, 7–10 leucocytes/HPF, fine and coarse granular casts, and hyaline casts suggestive of leukocyturia without active sediment. Urine culture was sterile. A contrast CT of abdomen revealed a small capacity bladder with diffusely thick and enhancing walls. No evidence of malignancy was present. Kidney biopsy suggested membranous glomerulonephritis and revealed the diffuse thickening of basement membrane without significant proliferative activity. Tubule, blood vessels, and mesangium were unremarkable. Immunofluorescence showed capillary wall and glomerular deposits of IgM, C3, and IgG, and was negative for IgA.

Prednisolone 80 mg/day was administered, to which the patient responded and went into remission after a month; the patient was normotensive on 10 mg enalapril and 10 mg amlodipine daily, and 24-hour proteinuria was 219 mg. The patient was shifted to alternate day prednisolone and gradually tapered. Patient has been off prednisolone for last six months and is still in remission.

CONCLUSION

Nephrotic syndrome has a recognized association with neoplasms.[1] Various morphological patterns on kidney biopsy have been reported with different neoplasms. The commonest renal lesion associated with solid tumors is membranous glomerulonephritis, with granular deposition of immune complexes.[1] Conversely, 9% of membranous nephropathy patients have associated malignancy.[2] Renal cell carcinoma, gastric adenocarcinoma, and probably a chance association with carcinoid have been seen with membranous glomerulonephritis.[3–5] Although no nephritogenic tumor antigen was demonstrable in association with renal cell carcinoma, there was transient amelioration of nephrotic syndrome after tumor removal.[3] The minimal change lesion is distinctly uncommon with solid tumors and is usually found in association with Hodgkin's disease. Crescentic glomerulonephritis due to tumor-associated immune complex glomerulonephritis has occurred with renal cell carcinoma, and is a rarity.[6] Focal segmental glomerulosclerosis has been reported with hematological malignancies, non-small cell lung cancer,[7] and Hodgkin's disease.[8] Linear IgA bullous disease is also known to occur in association with malignancies.[9]

Nephrotic syndrome associated with transitional cell carcinoma is very rare; only three cases have been reported to date.[2],[9],[10] All three cases had different morphological patterns on kidney biopsy—minimal change in the disease with linear immunoglobulin deposition, membranoproliferative glomerulonephritis with subendothelial immunoglobulin deposition, and linear IgA bullous disease. It is hypothesized that there is antibody formation against a specific component of basement membrane, which is common to both the kidney and the tumor. However, this case was very intriguing because the etiology of nephrotic syndrome was not evident. There were two distinct possibilities: either a paraneoplastic glomerulopathy or BCG-associated glomerulopathy. There was radiological resolution of the tumor in this case when nephrotic syndrome occurred. In other reports with transitional cell carcinoma, proteinuria had disappeared with the resolution of tumor.[2],[10] Besides, nephrotic syndrome occurred after six months of ongoing BCG therapy. To date, nephrotic syndrome associated with BCG instillation has not been reported.

BCG is used as immunostimulant therapy and intravesical instillation is a well-established mode of therapy for bladder tumors. Because BCG is a live-attenuated vaccine, complications of BCG infection (local and systemic) are seen in 10–15% of cases, a contracted bladder being one of them.[11] The present case had a thickened bladder wall post-BCG therapy as a result of intravesical BCG instillation. Dystrophic bladder calcification and granulomatous renal masses may also occur.[12],[13] Another study[14] reported three patients, two with tubulointerstitial nephritis and one with mesangial glomerulonephritis, who had associated granulomatous hepatitis. The postulated mechanisms are hematogenous dissemination via a traumatic instillation or an immune complex mediation.

Hence, this is a case of nephrotic syndrome (membranous glomerulonephritis) following intravesical BCG instillation in a case of transitional cell carcinoma of the urinary bladder. This association of membranous glomerulonephritis has not been reported earlier.