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Fibrillary Glomerulonephritis Presenting as Rapidly Progressive Glomerulonephritis
Kidney Biopsy Teaching Case Fibrillary Glomerulonephritis Presenting as Rapidly Progressive Glomerulonephritis Purva Sharma, MD, Michael Kuperman, MD, Lorraine Racusen, MD, and Duvuru Geetha, MD Fibrillary glomerulonephritis (GN) is an uncommon cause of rapidly progressive kidney failure. We report a case of rapidly progressive kidney failure with kidney biopsy showing crescentic GN on light microscopy and immunofluorescence showing linear/globular glomerular basement membrane (GBM) staining for immunoglobulin G and C3, consistent with anti-GBM disease. However, electron microscopy showed fibrillary deposits in the GBM, suggesting a diagnosis of fibrillary GN. As exemplified by this case, it is important to consider fibrillary GN in the differential diagnosis of crescentic GN with linear immunoglobulin G deposits within the GBM. Electron microscopy is crucial to make this diagnosis. Am J Kidney Dis. 60(1):157-159. © 2012 by the National Kidney Foundation, Inc. INDEX WORDS: Fibrillary glomerulonephritis; rapidly progressive glomerulonephritis.
INTRODUCTION Rapidly progressive glomerulonephritis (GN) is defined as any glomerular disease characterized by crescent formation on histology (typically ⬎50%) and rapid loss of kidney function. Anti–glomerular basement membrane (anti-GBM) disease, immune complex GN, and pauci-immune GN are included in the differential diagnosis of crescentic GN. Pauci-immune GN and anti-GBM disease are the most common causes of crescentic GN. Fibrillary GN (FGN) is a glomerular disease characterized by the deposition of irregularly oriented, elongated, nonbranching microfibrils 10- to 30-nm thick in the mesangium and along the capillary walls. It typically presents with subnephrotic- or nephrotic-range proteinuria and often is associated with microscopic hematuria, hypertension, and decreased glomerular filtration rate (GFR). We report an interesting and atypical case of FGN presenting as rapidly progressive kidney failure, with extensive crescent formation and linear immunoglobulin G (IgG) staining in the glomerular capillary walls. CASE REPORT Clinical History and Initial Laboratory Data A 61-year-old Serbian woman with poorly controlled hypertension for 4 years was admitted for rapidly progressive kidney failure because her serum creatinine level increased from 1.2 mg/dL (106.1 mol/L; estimated GFR, 46 mL/min/1.73 m2 [0.8 mL/s/ 1.73 m2] calculated by the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation) to 10 mg/dL (884 mol/L; estimated GFR, 4 mL/min/1.73 m2 [0.1 mL/s/1.73 m2]) in 4 months. She also described leg swelling and generalized fatigue for 2 weeks. Physical examination was unremarkable except for trace leg edema. Urinalysis showed 10-15 red blood cells per high-power field, proteinuria (3⫹), and no casts. A 24-hour urine collection measured proteinuria with protein excretion of 7.7 g. Serologic test results for hepatitis B, hepatitis C, perinuclear antineutrophil cytoplasmic antibody (ANCA), cytoplasmic ANCA, anti-GBM antibody, and HIV (human immunodeficiency virus) Am J Kidney Dis. 2012;60(1):157-159
were negative; C3 and C4 levels were normal. Serum and urine protein electrophoresis with immunofixation showed no monoclonal proteins. We initiated dialysis therapy and performed a kidney biopsy.
Kidney Biopsy Three cores were obtained and the sample was submitted for light, immunofluorescence, and electron microscopy. There were 8-10 glomeruli per section, 4 of which were globally sclerosed. Three glomeruli had large cellular crescents with a fibrocellular crescent. Glomeruli were of normal size and cellularity, except for one with cellular crescent that was hypertrophied (Fig 1). In several glomeruli, there was segmental thickening of capillary walls and expansion of mesangial areas. No fibrinoid necrosis or intracapillary hypercellularity was noted. Acute tubular injury was evident, but no red blood cell casts were identified. There was mild to moderate mononuclear interstitial infiltrate consisting of lymphocytes and plasma cells. Congo Red stain was faintly positive in glomeruli and vessels without apple green birefringence under polarized light. Immunofluorescence revealed one glomerulus mildly compressed by a cellular crescent. There was linear, nearly global glomerular capillary wall staining for IgG (3⫹; Fig 2), C3 (3⫹), and albumin (1⫹). There was no glomerular staining for IgA, IgM, C1q, or or light chains. Casts stained positive for IgA (3⫹), light chain (1-2⫹), and light chain (1-2⫹). There was interstitial fibrinogen (2⫹). On additional studies, there was diffuse linear/ globular glomerular staining for IgG1 (3-4⫹), IgG2 (trace to 1⫹), and IgG4 (3-4⫹); staining for IgG3 was negative. Electron microscopy showed extensive podocyte foot-process effacement with focal detachment from the capillary tuft. There was variable thickening of glomerular capillary walls, with areas of thickening containing osmophilic material with fibrillar substructure (Fig 3). A few segmental mesangial fibrillary deposits were
From the Johns Hopkins Medical Institutions, Baltimore, MD. Received August 9, 2011. Accepted in revised form December 13, 2011. Originally published online March 9, 2012. Address correspondence to Purva Sharma, MD, 4940 Eastern Avenue, Baltimore, MD 21224. E-mail: [email protected] © 2012 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2011.12.024 157
Sharma et al
Figure 1. Light microscopy shows crescent formation (periodic acid–Schiff stain; original magnification, ⫻200).
noted. Fibrils were nonbranching, randomly oriented, and measured 13.2 ⫾ 2.1 nm in average thickness. There were no subendothelial, subepithelial, or intramembranous electron-dense deposits. The mesangial regions were not expanded, and there were no mesangial electron-dense deposits.
Diagnosis The diagnosis of FGN was made based on immunofluorescence and electron microscopy findings of the kidney biopsy.
Clinical Follow-up The patient was initiated on pulse steroid and intravenous cyclophosphamide therapy after preliminary results of the kidney biopsy showed extensive cellular crescent formation and linear IgG staining within the capillary walls, suggestive of anti-GBM disease. In the following 2 days, she developed shortness of breath. A computed tomography of the chest was performed, revealing bilateral patchy airspace opacities. Considering the kidney biopsy findings on light microscopy and immunofluorescence, we entertained the possibility of Goodpasture syndrome and initiated plasmapheresis. She received a total of 3 sessions. However, after electron microscopy showed fibrillary deposits in the glomerular capillary wall, a diagnosis of FGN was made and plasmapheresis was stopped. She has failed to recover kidney function on oral
Figure 2. Immunofluorescence microscopy shows linear, nearly global glomerular capillary wall staining for immunoglobulin G (original magnification, ⫻200). 158
Figure 3. Electron microscopy shows fibril deposition in the glomerular basement membrane (original magnification, ⫻40,000). Bar in lower right-hand corner denotes 1 m.
cyclophosphamide and prednisone and remains on dialysis therapy 4 weeks later.
DISCUSSION FGN is a rare glomerular disease, usually idiopathic, but which may be associated with malignancy, dysproteinemia, or autoimmune disease.1 FGN is found in 0.8%-1.5% of native kidney biopsies.2-4 The light microscopic features are varied and include mesangial expansion/hypercellularity with or without “double contours” on special stains.1,4 Histologic patterns of FGN can include diffuse proliferative GN, membranoproliferative GN, mesangial proliferative/sclerosing GN, membranous GN, and diffuse sclerosing GN. In comparison with patients with mesangial proliferative/sclerosing and membranous GN, patients with more proliferative (membranoproliferative GN and diffuse proliferative GN) and sclerosing (diffuse sclerosing) forms have elevated serum creatinine levels and increased proteinuria upon presentation.4 Less commonly, the biopsy may show crescentic GN.5 Independent predictors of end-stage renal disease include older age, elevated creatinine level, and proteinuria at kidney biopsy and a greater percentage of global glomerulosclerosis.1 There is IgG immunostaining in almost all cases, usually accompanied by C3, and the staining is mesangial and parietal. IgG4 is the predominant IgG subtype in most cases, whereas some cases have both IgG1 and IgG4. Similar staining for IgG subclasses can be found in anti-GBM disease.6,7 IgA, IgM, and C1q deposition are rarely found. Glomerular deposits are Congo Red negative, which helps distinguish FGN from amyloid. There has been one other case report of FGN in which light microscopy showed crescent formation and fibrinoid necrosis, with immunofluorescence showing linear and pseudo-linear staining of the capillary walls for IgG with a lack of significant mesangial staining.8 In the study by Fogo et al,9 some patients had linear Am J Kidney Dis. 2012;60(1):157-159
Fibrillary Glomerulonephritis Presenting as Rapidly Progressive Glomerulonephritis
staining on immunofluorescence and crescents. Positive staining for IgG with negative staining for and light chains is present in 5% of patients with FGN in the series reported by Nasr et al.1 The typical presentation of fibrillary GN is proteinuria, often nephrotic range; decreased GFR; hematuria; and hypertension.1 FGN is considered to be a purely kidney disease. However, there has been one case report of pulmonary hemorrhage in which there were similar immunoglobulin and fibrillary deposits in both renal glomeruli and pulmonary alveolar capillary interstitium on postmortem examination. This suggests that a circulating factor may be the cause for the disease rather than local production of immunoglobulins, as is currently thought.10 Despite the administration of steroids and cytotoxic agents, the prognosis remains poor. Half the patients develop end-stage renal disease and about 40% have permanent renal dysfunction.1,4 On the basis of light and immunofluorescence microscopy, this case first appeared to reflect crescentic GN due to anti-GBM antibody. However, electron microscopy showed characteristic fibrillary deposits of about 13-14 nm, establishing the diagnosis of FGN. Anti-GBM antibody was tested twice in this patient and results were negative. The unusual and important aspects of this case of FGN are (1) the presence of near-global IgG staining, largely limited to capillary walls; (2) active cellular crescents; and (3) presentation as rapidly progressive kidney failure. It is crucial to keep the diagnosis of FGN in mind when considering the differential diagnosis of crescentic GN with extensive IgG staining in glomerular capillary walls on kidney biopsy, especially when there is nephrotic-range proteinuria. FGN and anti-
Am J Kidney Dis. 2012;60(1):157-159
GBM diseases have different treatments and prognosis, and it is imperative to make an accurate diagnosis.
ACKNOWLEDGEMENTS We thank Paul Segal, DO, from Johns Hopkins Medical Institutions for assistance in editing this manuscript. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Nasr SH, Valeri AM, Cornell LD, et al. Fibrillary glomerulonephritis: a report of 66 cases from a single institution. Clin J Am Soc Nephrol. 2011;6(4):775-784. 2. Iskandar SS, Falk RJ, Jennette JC. Clinical and pathologic features of fibrillary glomerulonephritis. Kidney Int. 1992;42(6): 1401-1407. 3. Duffy JL, Khurana E, Susin M, Gomez-Leon G, Churg J. Fibrillary renal deposits and nephritis. Am J Pathol. 1983;113(3): 279-290. 4. Rosenstock JL, Markowitz GS, Valeri AM, Sacchi G, Appel GB, D’Agati VD. Fibrillary and immunotactoid glomerulonephritis: distinct entities with different clinical and pathologic features. Kidney Int. 2003;63(4):1450-1461. 5. Guerra G, Narayan G, Rennke HG, Jaber BL. Crescentic fibrillary glomerulonephritis associated with hepatitis C viral infection. Clin Nephrol. 2003;60(5):364-368. 6. Segelmark M, Butkowski R, Wieslander J. Antigen restriction and IgG subclasses among anti-GBM autoantibodies. Nephrol Dial Transplant. 1990;5(12):991-996. 7. Yan Y, Cui Z, Zhao MH. [The distribution and clinical significance of IgG subclasses of anti-glomerular basement membrane antibodies.] Beijing Da Xue Xue Bao. 2004;36(5):501-504. 8. Sethi S, Adeyi OA, Rennke HG. A case of fibrillary glomerulonephritis with linear immunoglobulin G staining of the glomerular capillary walls. Arch Pathol Lab Med. 2001;125(4):534-536. 9. Fogo A, Qureshi N, Horn RG. Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis. 1993;22(3):367-377. 10. Masson RG, Rennke HG, Gottlieb MN. Pulmonary hemorrhage in a patient with fibrillary glomerulonephritis. N Engl J Med. 1992;326(1):36-39.
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INTRODUCTION Rapidly progressive glomerulonephritis (GN) is defined as any glomerular disease characterized by crescent formation on histology (typically ⬎50%) and rapid loss of kidney function. Anti–glomerular basement membrane (anti-GBM) disease, immune complex GN, and pauci-immune GN are included in the differential diagnosis of crescentic GN. Pauci-immune GN and anti-GBM disease are the most common causes of crescentic GN. Fibrillary GN (FGN) is a glomerular disease characterized by the deposition of irregularly oriented, elongated, nonbranching microfibrils 10- to 30-nm thick in the mesangium and along the capillary walls. It typically presents with subnephrotic- or nephrotic-range proteinuria and often is associated with microscopic hematuria, hypertension, and decreased glomerular filtration rate (GFR). We report an interesting and atypical case of FGN presenting as rapidly progressive kidney failure, with extensive crescent formation and linear immunoglobulin G (IgG) staining in the glomerular capillary walls. CASE REPORT Clinical History and Initial Laboratory Data A 61-year-old Serbian woman with poorly controlled hypertension for 4 years was admitted for rapidly progressive kidney failure because her serum creatinine level increased from 1.2 mg/dL (106.1 mol/L; estimated GFR, 46 mL/min/1.73 m2 [0.8 mL/s/ 1.73 m2] calculated by the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation) to 10 mg/dL (884 mol/L; estimated GFR, 4 mL/min/1.73 m2 [0.1 mL/s/1.73 m2]) in 4 months. She also described leg swelling and generalized fatigue for 2 weeks. Physical examination was unremarkable except for trace leg edema. Urinalysis showed 10-15 red blood cells per high-power field, proteinuria (3⫹), and no casts. A 24-hour urine collection measured proteinuria with protein excretion of 7.7 g. Serologic test results for hepatitis B, hepatitis C, perinuclear antineutrophil cytoplasmic antibody (ANCA), cytoplasmic ANCA, anti-GBM antibody, and HIV (human immunodeficiency virus) Am J Kidney Dis. 2012;60(1):157-159
were negative; C3 and C4 levels were normal. Serum and urine protein electrophoresis with immunofixation showed no monoclonal proteins. We initiated dialysis therapy and performed a kidney biopsy.
Kidney Biopsy Three cores were obtained and the sample was submitted for light, immunofluorescence, and electron microscopy. There were 8-10 glomeruli per section, 4 of which were globally sclerosed. Three glomeruli had large cellular crescents with a fibrocellular crescent. Glomeruli were of normal size and cellularity, except for one with cellular crescent that was hypertrophied (Fig 1). In several glomeruli, there was segmental thickening of capillary walls and expansion of mesangial areas. No fibrinoid necrosis or intracapillary hypercellularity was noted. Acute tubular injury was evident, but no red blood cell casts were identified. There was mild to moderate mononuclear interstitial infiltrate consisting of lymphocytes and plasma cells. Congo Red stain was faintly positive in glomeruli and vessels without apple green birefringence under polarized light. Immunofluorescence revealed one glomerulus mildly compressed by a cellular crescent. There was linear, nearly global glomerular capillary wall staining for IgG (3⫹; Fig 2), C3 (3⫹), and albumin (1⫹). There was no glomerular staining for IgA, IgM, C1q, or or light chains. Casts stained positive for IgA (3⫹), light chain (1-2⫹), and light chain (1-2⫹). There was interstitial fibrinogen (2⫹). On additional studies, there was diffuse linear/ globular glomerular staining for IgG1 (3-4⫹), IgG2 (trace to 1⫹), and IgG4 (3-4⫹); staining for IgG3 was negative. Electron microscopy showed extensive podocyte foot-process effacement with focal detachment from the capillary tuft. There was variable thickening of glomerular capillary walls, with areas of thickening containing osmophilic material with fibrillar substructure (Fig 3). A few segmental mesangial fibrillary deposits were
From the Johns Hopkins Medical Institutions, Baltimore, MD. Received August 9, 2011. Accepted in revised form December 13, 2011. Originally published online March 9, 2012. Address correspondence to Purva Sharma, MD, 4940 Eastern Avenue, Baltimore, MD 21224. E-mail: [email protected] © 2012 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2011.12.024 157
Sharma et al
Figure 1. Light microscopy shows crescent formation (periodic acid–Schiff stain; original magnification, ⫻200).
noted. Fibrils were nonbranching, randomly oriented, and measured 13.2 ⫾ 2.1 nm in average thickness. There were no subendothelial, subepithelial, or intramembranous electron-dense deposits. The mesangial regions were not expanded, and there were no mesangial electron-dense deposits.
Diagnosis The diagnosis of FGN was made based on immunofluorescence and electron microscopy findings of the kidney biopsy.
Clinical Follow-up The patient was initiated on pulse steroid and intravenous cyclophosphamide therapy after preliminary results of the kidney biopsy showed extensive cellular crescent formation and linear IgG staining within the capillary walls, suggestive of anti-GBM disease. In the following 2 days, she developed shortness of breath. A computed tomography of the chest was performed, revealing bilateral patchy airspace opacities. Considering the kidney biopsy findings on light microscopy and immunofluorescence, we entertained the possibility of Goodpasture syndrome and initiated plasmapheresis. She received a total of 3 sessions. However, after electron microscopy showed fibrillary deposits in the glomerular capillary wall, a diagnosis of FGN was made and plasmapheresis was stopped. She has failed to recover kidney function on oral
Figure 2. Immunofluorescence microscopy shows linear, nearly global glomerular capillary wall staining for immunoglobulin G (original magnification, ⫻200). 158
Figure 3. Electron microscopy shows fibril deposition in the glomerular basement membrane (original magnification, ⫻40,000). Bar in lower right-hand corner denotes 1 m.
cyclophosphamide and prednisone and remains on dialysis therapy 4 weeks later.
DISCUSSION FGN is a rare glomerular disease, usually idiopathic, but which may be associated with malignancy, dysproteinemia, or autoimmune disease.1 FGN is found in 0.8%-1.5% of native kidney biopsies.2-4 The light microscopic features are varied and include mesangial expansion/hypercellularity with or without “double contours” on special stains.1,4 Histologic patterns of FGN can include diffuse proliferative GN, membranoproliferative GN, mesangial proliferative/sclerosing GN, membranous GN, and diffuse sclerosing GN. In comparison with patients with mesangial proliferative/sclerosing and membranous GN, patients with more proliferative (membranoproliferative GN and diffuse proliferative GN) and sclerosing (diffuse sclerosing) forms have elevated serum creatinine levels and increased proteinuria upon presentation.4 Less commonly, the biopsy may show crescentic GN.5 Independent predictors of end-stage renal disease include older age, elevated creatinine level, and proteinuria at kidney biopsy and a greater percentage of global glomerulosclerosis.1 There is IgG immunostaining in almost all cases, usually accompanied by C3, and the staining is mesangial and parietal. IgG4 is the predominant IgG subtype in most cases, whereas some cases have both IgG1 and IgG4. Similar staining for IgG subclasses can be found in anti-GBM disease.6,7 IgA, IgM, and C1q deposition are rarely found. Glomerular deposits are Congo Red negative, which helps distinguish FGN from amyloid. There has been one other case report of FGN in which light microscopy showed crescent formation and fibrinoid necrosis, with immunofluorescence showing linear and pseudo-linear staining of the capillary walls for IgG with a lack of significant mesangial staining.8 In the study by Fogo et al,9 some patients had linear Am J Kidney Dis. 2012;60(1):157-159
Fibrillary Glomerulonephritis Presenting as Rapidly Progressive Glomerulonephritis
staining on immunofluorescence and crescents. Positive staining for IgG with negative staining for and light chains is present in 5% of patients with FGN in the series reported by Nasr et al.1 The typical presentation of fibrillary GN is proteinuria, often nephrotic range; decreased GFR; hematuria; and hypertension.1 FGN is considered to be a purely kidney disease. However, there has been one case report of pulmonary hemorrhage in which there were similar immunoglobulin and fibrillary deposits in both renal glomeruli and pulmonary alveolar capillary interstitium on postmortem examination. This suggests that a circulating factor may be the cause for the disease rather than local production of immunoglobulins, as is currently thought.10 Despite the administration of steroids and cytotoxic agents, the prognosis remains poor. Half the patients develop end-stage renal disease and about 40% have permanent renal dysfunction.1,4 On the basis of light and immunofluorescence microscopy, this case first appeared to reflect crescentic GN due to anti-GBM antibody. However, electron microscopy showed characteristic fibrillary deposits of about 13-14 nm, establishing the diagnosis of FGN. Anti-GBM antibody was tested twice in this patient and results were negative. The unusual and important aspects of this case of FGN are (1) the presence of near-global IgG staining, largely limited to capillary walls; (2) active cellular crescents; and (3) presentation as rapidly progressive kidney failure. It is crucial to keep the diagnosis of FGN in mind when considering the differential diagnosis of crescentic GN with extensive IgG staining in glomerular capillary walls on kidney biopsy, especially when there is nephrotic-range proteinuria. FGN and anti-
Am J Kidney Dis. 2012;60(1):157-159
GBM diseases have different treatments and prognosis, and it is imperative to make an accurate diagnosis.
ACKNOWLEDGEMENTS We thank Paul Segal, DO, from Johns Hopkins Medical Institutions for assistance in editing this manuscript. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Nasr SH, Valeri AM, Cornell LD, et al. Fibrillary glomerulonephritis: a report of 66 cases from a single institution. Clin J Am Soc Nephrol. 2011;6(4):775-784. 2. Iskandar SS, Falk RJ, Jennette JC. Clinical and pathologic features of fibrillary glomerulonephritis. Kidney Int. 1992;42(6): 1401-1407. 3. Duffy JL, Khurana E, Susin M, Gomez-Leon G, Churg J. Fibrillary renal deposits and nephritis. Am J Pathol. 1983;113(3): 279-290. 4. Rosenstock JL, Markowitz GS, Valeri AM, Sacchi G, Appel GB, D’Agati VD. Fibrillary and immunotactoid glomerulonephritis: distinct entities with different clinical and pathologic features. Kidney Int. 2003;63(4):1450-1461. 5. Guerra G, Narayan G, Rennke HG, Jaber BL. Crescentic fibrillary glomerulonephritis associated with hepatitis C viral infection. Clin Nephrol. 2003;60(5):364-368. 6. Segelmark M, Butkowski R, Wieslander J. Antigen restriction and IgG subclasses among anti-GBM autoantibodies. Nephrol Dial Transplant. 1990;5(12):991-996. 7. Yan Y, Cui Z, Zhao MH. [The distribution and clinical significance of IgG subclasses of anti-glomerular basement membrane antibodies.] Beijing Da Xue Xue Bao. 2004;36(5):501-504. 8. Sethi S, Adeyi OA, Rennke HG. A case of fibrillary glomerulonephritis with linear immunoglobulin G staining of the glomerular capillary walls. Arch Pathol Lab Med. 2001;125(4):534-536. 9. Fogo A, Qureshi N, Horn RG. Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis. 1993;22(3):367-377. 10. Masson RG, Rennke HG, Gottlieb MN. Pulmonary hemorrhage in a patient with fibrillary glomerulonephritis. N Engl J Med. 1992;326(1):36-39.
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