PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org Membranous Nephropathy with Crescents Amanda Walton Basford,* Julia Lewis,* Jamie P. Dwyer,* and Agnes B. Fogo*† Division of Nephrology and Hypertension, Departments of *Medicine and †Pathology, Vanderbilt University Medical Center, Nashville, Tennessee ABSTRACT Membranous nephropathy is a common cause of nephrotic syndrome in adults concentration of 3.4 g/dl, urinalysis with and can be primary or secondary to systemic lupus erythematosus, chronic 2ϩ protein, one red blood cell, and five infection, or drugs. Rapid decline in renal function in patients with membranous white blood cells (WBCs) without casts. nephropathy may be due to renal vein thrombosis, malignant hypertension, or On admission, serum sodium was 136 an additional superimposed destructive process involving the renal paren- mEq/L, potassium was 4.3 mEq/L, chlo- chyma. Crescents are rare in primary membranous nephropathy and thus sug- ride was 107 mEq/L, bicarbonate was 20 gest another underlying disease process, such as combined membranous and focal mmol/L, blood urea nitrogen was 36 mg/ or diffuse lupus nephritis. However, in some patients with membranous nephrop- dl, serum creatinine was 2.84 mg/dl, athy and crescents, the crescentic lesion may be due to a distinct, separate disease magnesium was 2.2 mg/dl, phosphorus process, such as anti-glomerular basement membrane antibodies or anti- was 4.6 mg/dl, total bilirubin was 0.7 mg/ neutrophil cytoplasmic antibodies-related pauci-immune glomerulonephritis. Here dl, amylase was 17 U/L, and lipase was 14 we describe a case with such renal biopsy findings, review previous reported cases, U/L. Urinalysis revealed a specific gravity and discuss possible implications for pathogenesis of the coexistence of these of 1.026; 3ϩ albumin; large blood with lesions. 21 to 50 red blood cells/high-power field; 5 to 10 WBCs/high-power field; no casts, J Am Soc Nephrol 22: 1804–1808, 2011. doi: 10.1681/ASN.2010090923 nitrites, leukocyte esterase, or glucose; and a spot protein-to-creatinine ratio of 2.1 with proteinuria of 5.5 g/24 h. Total Membranous nephropathy is a common He also had nausea, decreased appetite, serum protein was 6.2 g/dl with a mono- cause of nephrotic syndrome in adults mild sore throat, and increased shortness clonal IgM kappa spike in blood and and can be primary or secondary to sys- of breath. He was treated with antibiotics urine. The WBC count was 8.500/␮l temic lupus erythematosus, chronic in- as an outpatient but did not improve, (80.6% polymorphonuclear leukocytes, fection, or drugs.1 Crescents are rare and he presented to the emergency de- 9.8% lymphocytes, 9.3% monocytes), in primary membranous nephropathy, partment when his temperature reached prothrombin time was 17.4 seconds, par- and suggest another underlying disease 103.8°F (39.9°C). The patient had no his- tial thromboplastin time was 35.3 sec- process, such as lupus nephritis. How- tory of rash, cough, sinus symptoms, onds, hemoglobin was 12.8 g/dl, hemat- ever, in some patients with membranous chest pain, gastrointestinal complaints, ocrit was 37%, platelet count was nephropathy and crescents, the crescen- or gross hematuria. He had longstanding 168,000/␮l, iron saturation was 35%, tic lesion may be due to a distinct, sepa- nocturia and frequency but no dysuria. and ferritin was 794 ng/ml. Erythrocyte rate disease process. Here we report a He had taken naproxyn long term twice a sedimentation rate was elevated at 99 case with such findings and discuss pos- day for arthralgias. Hemochromatosis mm/h. Serologies for hepatitis A, B, C, sible implications for pathogenesis. was diagnosed 7 years ago and was HIV, and Ehrlichia and titers for anti-nu- treated with phlebotomy. He also had a clear antibody, anti-neutrophil cytoplas- history of hypothyroidism and cold ag- RESULTS glutinins and was treated for strep throat Published online ahead of print. Publication date 1 year earlier. available at www.jasn.org. Clinical History Examination revealed an obese white Correspondence: Dr. Agnes B. Fogo, MCN C3310, A 59-year-old white male construction man (body mass index of 40) with trace Department of Pathology, Vanderbilt University Med- ical Center, Nashville, TN 37232. Phone: 615-322- worker was admitted with a 2-week his- lower-extremity edema and no other ab- 3070; Fax: 615-343-7023; E-mail: agnes.fogo@ tory of increasing fatigue and weakness, normal findings. Laboratory evaluation vanderbilt.edu low-grade fever, night sweats, and in- 4 months earlier showed normal serum Copyright © 2011 by the American Society of creased serum creatinine (2.84 mg/dl). creatinine (0.9 mg/dl), a serum albumin Nephrology 1804 ISSN : 1046-6673/2210-1804 J Am Soc Nephrol 22: 1804–1808, 2011 www.jasn.org PATHOPHYSIOLOGY of the RENAL BIOPSY mic antibody, anti-myeloperoxidase anti- swelling. Proteinuria improved to 400 also rare, is well recognized.2–26 Correct bodies, cryoglobulin, rheumatoid factor, mg after 3 months. Serum creatinine re- diagnosis relies on a combination of re- and anti-phospholipid antibodies were mained stable between 1.7 and 1.9 mg/dl. nal biopsy findings and serologic testing. negative. Blood and urine cultures and Repeat anti-GBM antibody was negative. Of note, not all patients with anti-GBM rapid strep test were negative. Comple- Because of financial constraints, the pa- antibodies have circulating anti-GBM ment 3 (C3) was normal (148 mg/dl) and tient remained on daily oral cyclophos- detected by standard assays.27 then decreased to 57 mg/dl 3 days later. phamide 150 mg for 5 months, then daily Recognition of linear staining of the Complement 4 was low at admission (10 cyclophosphamide 100 mg for 3 months, GBM in membranous nephropathy can mg/dl) and decreased to Ͻ4 mg/dl. and then azathioprine 100 mg daily with be technically difficult because of the in- The chest x-ray was normal. Kidneys tapering prednisone. At 7 months after tense granular staining of the immune were normal size by ultrasound with diagnosis, creatinine clearance was 74 complex deposits. Linear immunofluo- mild increased parenchymal echogenic- ml/min and proteinuria was 330 mg/24 h rescence staining of the GBM can be seen ity. A renal biopsy was performed. without hematuria. in settings other than anti-GBM glomer- ulonephritis, such as diabetic nephropa- Kidney Biopsy thy. In diabetic nephropathy, the linear The biopsy showed characteristic fea- DISCUSSION accentuation of the GBM with anti-IgG tures of membranous nephropathy is typically not accompanied by linear C3 with occasional capillary wall subepi- Initially the patient’s acute rise in serum staining, although nonspecific C3 stain- thelial spikes and frequent holes on creatinine was thought to be due to de- ing may be seen. Tubular and Bowman’s Jones silver stain (Figure 1A). In addi- creased renal perfusion in the setting of capsule basement membranes may also tion, 13 of 26 glomeruli showed cellu- fever, decreased oral intake, and expo- show linear accentuation for anti-IgG in lar crescents with segmental necrosis sure to nonsteroidal anti-inflammatory diabetic nephropathy, although usually but with no associated mesangial or en- drugs. However, because of the systemic weaker than the GBM. In anti-GBM an- docapillary proliferation or glomerular signs and symptoms, lack of response to tibody glomerulonephritis, variable basement membrane (GBM) splitting. fluids, and active urine sediment, a renal granular or linear C3 staining is present, Immunofluorescence showed granular biopsy was done. The renal biopsy and the latter can be continuous or dis- capillary loop 3ϩ intensity for IgG, 1ϩ showed the unusual combination of continuous. If linear C3 is present, this for C3, 0 to trace for C1q, and 2ϩ for membranous nephropathy and cres- may be helpful to support a diagnosis of kappa and lambda (0 to 3ϩ scale) (Fig- cents. When extensive crescents are su- anti-GBM-related disease. ure 1B). IgA and IgM were negative. An perimposed on membranous nephropa- In 1958, Drs. Stanton and Tange de- underlying 1ϩ linear staining of the thy, the possibility of a mixed International scribed nine patients with acute renal fail- GBMs could be discerned for IgG, Society of Nephrology/Renal Pathology ure and pulmonary hemorrhage linked to kappa and lambda. Electron micros- Society class V membranous lupus nephri- antibody formation to the GBM and copy showed numerous subepithelial tis with superimposed focal or diffuse class coined the term “Goodpasture syndrome” and occasional intramembranous de- III or class IV lupus nephritis with severe in recognition of Dr. Ernest Goodpas- posits and complete overlying foot activity should be considered. Typically ture’s description of a young man who process effacement (Figure 1C). Occa- such a combined lupus nephritis lesion died with pulmonary hemorrhage and sional mesangial deposits were present. would also have associated endocapillary renal failure in the 1918 influenza pan- No subendothelial deposits or reticular proliferation and concomitant subendo- demic.28 Although the patient de- aggregates were present. The final diag- thelial deposits, reticular aggregates, and scribed by Goodpasture most likely did nosis was membranous nephropathy full house staining by immunofluores- not have anti-GBM disease in that he with superimposed anti-GBM-anti- cence. Some cases of lupus nephritis may had lesions in organs other than lung body-mediated glomerulonephritis. have active necrotizing lesions with mini- and kidney, the Goodpasture eponym mal subendothelial deposits and prolifera- became associated with the syndrome Clinical Follow-Up tion. However, in the patient presented of alveolar hemorrhage and rapidly An anti-GBM titer was obtained and was here there were no reticular aggregates, progressive glomerulonephritis and positive at 38 AU/ml. The patient was staining of immunoglobulins in deposits Goodpasture disease when this syn- treated with oral cyclophosphamide 150 was limited to IgG, and the patient did drome was specifically due to anti- mg daily and prednisone 50 mg with not clinically have lupus.