Monoclonal gammopathy-associated pauci-immune extracapillary-proliferative glomerulonephritis successfully treated with bortezomib
A 60-year-old male was referred to our department in April 2011 by his nephrologist due to an increase in his serum creatinine to 140.8 µmol/L (1.6 mg/dL), haematuria of 290 erythrocytes/µL and spot urine protein–creatinine ratio (UPCR) of 1.9 g/g. He had also developed hypertension during the previous months. His medical history was uneventful, and physical examination did not show any pathologies. He subsequently underwent renal biopsy showing pauci-immune extracapillary-proliferative glomerulonephritis (4 of 14 crescents) with mild tubular atrophy and interstitial fibrosis (20%), as well as lymphohistiocytic infiltration (A). Polymorphonuclear leukocytes were present in the glomerulus and in the interstitium. Immunofluorescence revealed minimal mesangial deposits of C3 and complement complex C5b-9 as well as IgM. Immunofluorescence for IgA, IgG and fibrinogen was negative. No amyloid deposits or myeloma casts were identified. Serum C3 and C4 complement levels were normal. Serum ANCAs and cryoglobulines showed negative results. No anti-glomerular basement membrane antibodies were present. The patient received four monthly cycles of cyclophosphamide i.v. along with steroids. Informed consent was obtained from the patient prior to submission of this manuscript. During therapy, serum creatinine stabilized to 132.0 µmol/L (1.5 mg/dL), proteinuria (UPCR) decreased to 0.5 g/g and haematuria improved to 32 erythrocytes/µL, respectively. Maintenance treatment with azathioprine was started and the patient returned to the care of his nephrologist.\nAfter 10 months, the patient was referred to our service again with newly diagnosed macrohaematuria, increased UCPR of 5 g/g and elevated serum creatinine of 169.8 µmol/L (1.93 mg/dL). A thorough investigation revealed an increased serum β2-microglobulin of 3.5 mg/L and a pathological serum IgG kappa/lambda free light-chain ratio of 5.2 (normal value: 0.26–1.65) due to elevated serum IgG kappa light chains of 74.0 mg/L (normal range: 3.3–19.4 mg/L). A bone marrow biopsy showed an increase of monoclonal kappa-positive plasma cells to 10%. Re-evaluating the initial renal biopsy, no evidence of light-chain deposition disease, fibrillary glomerulonephritis or amyloidosis was present.\nA new renal biopsy was performed, again showing pauci-immune extracapillary-proliferating glomerulonephritis (4 of 10 crescents) with mild interstitial fibrosis. In this biopsy, there was also no evidence of classical myeloma-associated kidney disease. Due to the relapse of rapidly progressive glomerulonephritis after cyclophosphamide therapy and leucopenia during azathioprine treatment, we decided to administer two doses of 1 g of rituximab i.v. within 4 weeks and maintained the patient on a reduced dose of azathioprine in combination with cyclosporine A [, ]. Unfortunately, the patient showed rapid deterioration of his renal function within the following 8 weeks to a serum creatinine level of 303.6 µmol/L (3.45 mg/dL), an increase of proteinuria to 9 g/g and an increase of haematuria. The serum kappa/lambda free light-chain ratio also increased to 9.1. Because of the underlying plasma cell dyscrasia and rapidly worsening kidney function, we decided to start the patient on the proteasome inhibitor bortezomib (1.3 mg/m2 body surface i.v. on Days 1, 8, 15, 22) in combination with dexamethasone based on the treatment recommendations for multiple myeloma. After the first cycle of bortezomib/dexamethasone, serum creatinine decreased to 140.8 µmol/L (1.6 mg/dL), and urinalysis showed reduced proteinuria of 2 g/g. A control biopsy was performed revealing residual sclerosed crescents, completely sclerosed glomeruli, mild interstitial fibrosis and tubular atrophy (B). No signs of active extracapillary proliferations were detected. After the second cycle of bortezomib/dexamethasone, the patient showed clinical remission with serum creatinine levels of 103.8 µmol/L (1.18 mg/dL), minimal proteinuria of 0.48 g/g, no haematuria and well-controlled hypertension. Maintenance therapy of monthly bortezomib was initiated, and the patient showed stable serum creatinine values as well as stable proteinuria with 8 months of follow-up.