Crescentic Glomerulonephritis With Ribbon-like Immunofluorescence Pattern

Crescentic Glomerulonephritis With Ribbon-like Immunofluorescence Pattern Venumadhav Chirunomula, MBBS,1 Venu Kondle, MD,2 Bhavani Vaddey, MBBS,1 Robert B. Colvin, MD,3 and Neeraja Kambham, MD1 INDEX WORDS: Fibrillary glomerulonephritis; crescents; immune complexes.

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rescentic glomerulonephritis (GN) is characterized by extensive glomerular crescents (⬎50% glomeruli) and rapid loss of kidney function, often described as rapidly progressive GN. Crescentic GN can be categorized as pauci-immune type, anti–glomerular basement membrane (anti-GBM) nephritis, and immune complex– mediated process, primarily based on immunofluorescence microscopy (IF) and electron microscopy (EM). Although both pauci-immune and anti-GBM nephritis lack electron-dense deposits, the latter is characterized by linear IF staining with immunoglobulin G (IgG). The immune complex–mediated category, with evidence of deposits by using both IF and EM, includes several entities, such as systemic lupus erythematosus, IgA nephropathy, Henoch-Schönlein purpura GN, postinfectious GN, and membranoproliferative GN.1 The case described here represents an unusual cause of crescentic GN with a ribbon-like pattern of staining on IF.

CASE REPORT Clinical History A 51-year-old white woman was seen by her primary care physician for a 4- to 6-week history of abdominal pain. She had a brief episode of diarrhea and vomiting at the onset of the illness. Her medical history was significant for bipolar disorder, hypertension, and Hodgkin disease. She underwent splenectomy for Hodgkin disease and has been in remission for the last 25 years. There was no history of fevers, prior kidney disease, exposure to toxins, nephrotoxic drug intake, diabetes mellitus, smoking, alcohol, or illicit drug use. Medications included olanzapine, escitalopram, topiramate, and carbamazepine. No significant family history was noted. Physical examination showed a mildly obese patient. Blood pressure was 160/88 mm Hg, pulse rate was 90 beats/min, respiratory rate was 18 breaths/min, and temperature was 36.7°C. The remainder of physical examination findings were normal. Urinalysis showed 3⫹ protein and 2⫹ blood. Laboratory abnormalities included the following values: serum creatinine, 8.7 mg/dL (663 ␮mol/L); estimated glomerular filtration rate, 5 mL/min/1.73 m2 (0.08 mL/s/ 1.73 m2); serum potassium, 5.5 mEq/L (5.5 mmol/L); serum sodium, 125 mEq/L (125 mmol/L); serum albumin, 2.5 g/dL (25 g/L); and alkaline phosphatase, 166 U/L. Hemoglobin level was 11 g/dL (110 g/L), hematocrit was 33%, and white blood cell count was 13.6 ⫻ 103/␮L (13.6 ⫻ 109/L). Baseline serum creatinine level was unknown, and it was unclear

whether the kidney failure was acute or chronic. The patient did not have clinical manifestations of systemic lupus erythematosus, human immunodeficiency virus (HIV) infection, or other systemic disorders. Hepatitis C antibody test result was negative, and serum and urine protein electrophoresis did not show evidence of a monoclonal spike. Antineutrophil cytoplasmic antibody serological test was not performed. A kidney biopsy was performed.

Kidney Biopsy On light microscopic examination, 40 glomeruli were seen, of which 30 were globally or near globally sclerosed. Several globally sclerosed glomeruli had features of fibrous crescents with disrupted Bowman capsules. The remaining 10 glomeruli had circumferential cellular crescents with fibrin extravasation (Fig 1A). A few open capillary loops in 1 glomerulus had mild segmental mesangial proliferation. GBMs were of normal thickness and contours. Extensive tubular atrophy and interstitial fibrosis were seen, involving more than 70% of the cortex sampled. Diffuse interstitial inflammation was observed with lymphocytes and fewer neutrophils and eosinophils. Features of acute tubular injury, such as luminal ectasia, loss of brush borders, and simplified epithelium, were seen. Blood vessels were normal. By means of IF, there was 3⫹ ribbon-like staining along all GBMs with antisera to IgG, C3, ␬, and ␭ (Fig 1B). Focal 2⫹ granular staining also was seen in mesangium. Focal tubular basement membranes also had linear staining with IgG. No glomerular staining was observed with IgA, IgM, albumin, and C1q. All 7 open glomeruli had cellular crescents, highlighted by fibrinogen stain (2⫹). On EM, GBMs were irregularly thickened with electron-dense material along the lamina densa, subepithelial, and subendothelial locations. A few electron-dense deposits also were observed in mesangial areas. On higher magnification, electron-dense areas were composed of randomly oriented fibrils 17 to 21

From the 1Department of Pathology, Stanford University Medical Center, Stanford; 2Nephrology Division, Sutter North Medical Group, Yuba City, CA; and 3Department of Pathology, Massachusetts General Hospital, Boston, MA. Received September 1, 2008. Accepted in revised form October 29, 2008. Originally published online as doi:10.1053/ j.ajkd.2008.11.011 on January 5, 2009. Address correspondence to Neeraja Kambham, MD, Assistant Professor, Department of Pathology, Rm H2110, 300 Pasteur Dr, Stanford, CA 94305-5324. E-mail: nkambham@ stanford.edu © 2009 by the National Kidney Foundation, Inc. 0272-6386/09/5402-0023$36.00/0 doi:10.1053/j.ajkd.2008.11.011

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Figure 1. Kidney biopsy findings. (A) Circumferential cellular crescent with compressed capillary tuft (periodic acid– Schiff; original magnification ⫻400). (B) Immunofluorescence microscopy with antisera to immunoglobulin G shows a pseudolinear pattern along the capillary walls. (C) Electron microscopy with randomly oriented fibrils along the glomerular basement membrane (fibril thickness, 17 to 21 nm).

nm thick (Fig 1C). Occasional capillary loops had reduplicated basement membranes. Tubuloreticular inclusions were not identified. Podocytes showed diffuse foot-process effacement. We attempted IgG subtyping by using an IF method; however, unfortunately, no intact glomeruli were identified in the remainder of the frozen tissue. We subsequently performed IgG4 staining by means of immunohistochemistry using a monoclonal antibody to IgG4 (Zymed, Carlsbad, CA; dilution, 1:200) on an automated immunostainer (Ventana Medical Systems, Tucson, AZ). No staining was observed in the biopsy tissue.

Diagnosis Kidney biopsy findings were that of fibrillary GN (FGN) with extensive crescents involving open and sclerosed glomeruli. Although the ribbon-like pattern of staining on IF raised the possibility of anti-GBM crescentic GN, the ultrastructural features of fibrillar electron-dense material (thickness 17 to 21 nm) along capillary walls and mesangial areas were diagnostic of FGN. Although a component of acute tubular injury was seen, based on the severity of glomerulosclerosis and chronic tubulointerstitial damage, kidney failure seemed largely irreversible.

Clinical Follow-up Although the presentation was not typical of rapidly progressive GN, given the lack of known prior kidney disease, the patient was started on intravenous steroid and cyclophosphamide therapy before the biopsy results. Based on the preliminary biopsy findings suggestive of crescentic GN, plasmapheresis was initiated, but subsequently discontinued when the final diagnosis of FGN was confirmed. After a 3-day course of methylprednisone, high-dose steroid therapy was started. Serum anti-GBM antibody test results also were negative. Unfortunately, the patient did not regain kidney function and was started on hemodialysis therapy with steroid tapering. There was no recovery of kidney function.

DISCUSSION Crescentic GN with a linear pattern of glomerular capillary wall staining for IgG is most worri-

some for anti-GBM disease. Although our patient did not have a fine linear IF pattern in the presence of extensive crescents and consequent collapse of the capillary tuft, the ribbon-like pattern as in our patient with FGN may be mistaken for anti-GBM nephritis. The ribbonlike pattern can be defined best as broad linearity that has been alternately described in the FGN literature as “pseudolinear,” “continuous,” or “confluent.”2-5 In retrospect, the pseudolinear pattern in our patient is focally interrupted with associated mesangial staining, which argues against antiGBM nephritis. Other diagnostic entities that should be considered in the setting of crescents and pseudolinear IF pattern include rare cases of monoclonal immunoglobulin deposition disease (MIDD) with crescents, early membranous nephropathy with finely granular capillary wall deposits on IF, and nonspecific linear IgG staining in pauci-immune crescentic GN. Nodular sclerosing glomerulopathy is the most common glomerular pattern in MIDD, but occasional cases of light and heavy chain deposition diseases have extensive crescents.6-9 Light or heavy chain restriction usually is evident on IF in MIDD. Early membranous nephropathy can appear as a linear pattern on IF, but the fine granularity often is apparent on higher magnification. Both membranous nephropathy and MIDD can be diagnosed easily by using EM. Occasional cases of pauci-immune crescentic GN can have nonspecific linear IgG staining along the GBM and tubular basement membrane, as in patients with diabetes mellitus.10 This nonimmunologic trapping of the immunoreactants can be distinguished from antiGBM disease only with careful clinical and serological correlations.11 FGN is an uncommon cause of crescentic GN, and IF usually shows characteristic

Crescentic GN With Ribbon-like IF Pattern

smudgy staining with IgG and C3 in the mesangium and often band-like staining along the capillary walls. An isolated capillary wall staining pattern, as in our patient, is uncommon in patients with FGN.5,12 Given these differential diagnostic considerations, ultrastructural examination is critical in rendering an accurate diagnosis. FGN was described first by Rosenmann and Eliakim13 in 1977. Subsequently, Alpers et al14 coined the term. FGN is an uncommon disease contributing to approximately 1% of the primary GN in the white population.12,15 It is seen more commonly in women, with peak incidence between the fifth and sixth decades. FGN is characterized by widespread glomerular deposition of extracellular, random, nonbranching, elongated microfibrils. These microfibrils are Congo red negative and derived from immunoglobulin without evidence of such systemic disease as cryoglobulinemia, systemic lupus erythematosus, or other disorders with organized deposits. Associated conditions reported in a few patients with FGN include hepatitis C infection and HIV infection.2,16,17 The clinical presentation of FGN includes asymptomatic proteinuria, nephrotic syndrome, hematuria, hypertension, and decreased glomerular filtration rate.18,19 Light microscopy findings are heterogeneous and can show membranoproliferative, mesangial proliferative, diffuse proliferative, membranous, or diffuse sclerosing patterns,3,19 although the first 2 predominate. The characteristic ultrastructural features include randomly oriented fibrils in the mesangium and capillary walls that measure on average 20 nm in diameter, but range from 10 to 30 nm. The immunoglobulin deposits in FGN are polyclonal. However, data in the literature suggest that IgG is either monotypic (composed exclusively of IgG1 or IgG4 subtype) or more frequently oligotypic with both IgG1 and IgG4.15,19 IgG2 and IgG3 typically are absent. These accumulations of homogenous immunoglobulins seem to precipitate in the formation of organized deposits of FGN.15 IgG4 activates only the alternate pathway15 with associated C3 deposition in glomeruli and, in some cases, hypocomplementemia.20 Several studies have shown that the incidence of lymphoproliferative and myeloproliferative disorders is extremely low in patients with FGN.15,18,19,21 Conversely, the related entity, im-

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munotactoid glomerulopathy, has monoclonal IgG deposits with light chain restriction, and these patients often have associated paraproteinemia and B-cell neoplasms. Immunotactoid glomerulopathy has organized deposits in the form of microtubules with apparent lucent cores measuring more than 30 nm thick.22 Although some investigators prefer to consider FGN and immunotactoid glomerulopathy as a single group of disorders,4 the variable frequency of lymphoplasmacytic disorders and monoclonal deposits seems to justify their separation into distinct categories. Nearly half the patients with FGN develop end-stage renal disease in 2 to 4 years,3 and extensive glomerulosclerosis and diffuse proliferative GN are associated with adverse outcome.19 Immunosuppressive therapy consists of steroids,23 although it often is ineffective and does not seem to correlate with clinical outcome.12,15,19 Unfortunately, FGN can recur in kidney transplants24,25 and also can result in graft loss. Occasional crescents can be seen in up to 20% of patients with FGN, but crescentic GN with greater than 50% crescents, as in our patient, is unusual.15,26 As expected, the presentation of rapidly progressive GN often is seen in the setting of extensive glomerular proliferation or crescents. Data regarding treatment and outcome of patients with crescentic FGN are limited, although a recent article showed a beneficial role of cyclophosphamide in 2 patients with crescentic FGN.27 In conclusion, this case represents an unusual presentation of FGN with extensive crescents and ribbon-like IgG staining on IF, which can be misdiagnosed as anti-GBM nephritis. EM is critical in rendering an accurate diagnosis of FGN.

ACKNOWLEDGEMENTS The authors acknowledge the expert technical assistance of Anita Briley (Stanford Pathology Electron Microscopy Lab). Support: None. Financial Disclosure: None.

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