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PATHOPHYSIOLOGY of the www.jasn.org

Membranous Nephropathy with Crescents

Amanda Walton Basford,* Julia Lewis,* Jamie P. Dwyer,* and Agnes B. Fogo*†

Division of and , Departments of *Medicine and †Pathology, Vanderbilt University Medical Center, Nashville, Tennessee

ABSTRACT Membranous nephropathy is a common cause of in adults concentration of 3.4 g/dl, urinalysis with and can be primary or secondary to systemic erythematosus, chronic 2ϩ protein, one , and five , or drugs. Rapid decline in renal function in patients with membranous white blood cells (WBCs) without casts. nephropathy may be due to renal vein , 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 . 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 . 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 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 . 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 . 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 . 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 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 , 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 (10 100 mg for 3 months, GBM in membranous nephropathy can mg/dl) and decreased to Ͻ4 mg/dl. and then 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- Biopsy thy. In , 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 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 , 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, 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 “” 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. GBM antibodies. plasma exchange. Serum creatinine was Pauci-immune necrotizing crescentic Membranous nephropathy associated 1.78 mg/dl at discharge. Three weeks glomerulonephritis superimposed on withanti-GBMantibodyglomerulonephritis later, the urinary protein-to-creatinine membranous nephropathy is exception- was first recognized in 1974.2 We have iden- ratio was 2.8. He was treated with angio- ally rare. In contrast, the combination of tified 25 reported cases in addition to the one tensin converting enzyme inhibitor and anti-GBM antibody glomerulonephritis presented here of either membranous ne- then switched to irbesartan because of lip and membranous nephropathy, albeit phropathy followed by anti-GBM glomeru-

J Am Soc Nephrol 22: 1804–1808, 2011 MN and Crescents 1805 PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org lonephritis, mostly in middle-aged or older cently demonstrated to be the phospho- ␣4, and ␣5 collagen protomers.33 The patients (n ϭ 6); anti-GBM glomerulone- lipase A2 receptor in many cases,29,30 and triggering events for such conforma- phritis followed by membranous nephropa- an HLA-DQA1 allele on chromosome tional changes to elicit an autoimmune thy, mostly in younger adults (n ϭ 6); or si- 6p21 is most closely associated with these response remain unknown, although T multaneous findings of membranous antibodies in Caucasians.31 Anti-GBM cell escape from thymic deletion may nephropathy and anti-GBM disease (nϭ13) glomerulonephritis is caused by antibod- play a role.34 Whether membranous ne- (Table 1).2–26 ies to the ␣3IV and ␣5IV noncollagenous phropathy could facilitate such addi- Primary membranous nephropathy is domains of type IV collagen.28,32 Re- tional , or vice versa, are due to antibodies reacting to planted, en- cently, this antibody response has been interesting hypotheses that remain to be dogenous, podocyte-related , re- linked to a conformational change in ␣3, proven. Immune complex deposition

Table 1A. Time course of patients with anti-GBM disease and membranous nephropathy: Membranous nephropathy followed by anti-GBM disease Reference Age/Gender Clinical Presentation Therapy Outcome Klassen2 49/M Edema, chest pain, anuria Steroids Died of seizure Moorthy8 53/M Edema Steroids, azathioprine Hemodialysis Richman9 65/M Edema, renal failure Steroids, CP, PP Died of myocardial infarction Kurki10 54/M Cough, , pleurisy, nephritic Steroids, PP ESRD, transplant Thitiarchakul11 57/? Edema, vomiting, shortness of breath, hemoptysis Steroids, CP, PP Hemodialysis M, male; F, female; CP, cyclophosphamide; PP, plasmapheresis. Adapted from Troxell et al.3 and Patel et al.26

Table 1B. Time course of patients with anti-GBM disease and membranous nephropathy: Anti-GBM disease followed by membranous nephropathy Reference Age/Gender Clinical Presentation Therapy Outcome Agodoa12 22/F Cough, weakness, syncope, hematuria None Recovery Savige13 20/M Hematuria “Cytotoxic drugs,” PP Recovery Savige13 18/F Hematuria PP, steroids, CP Elder14 20/M Hemoptysis, dyspnea, fever, hematuria Steroids, CP Recovery, proteinuria Keilstein15 17/M Hemoptysis, hematuria Antibiotics Recovery M, male; F, female; CP, cyclophosphamide; PP, plasmapheresis. Adapted from Troxell et al.3 and Patel et al.26

Table 1C. Time course of patients with anti-GBM disease and membranous nephropathy: Simultaneous finding of anti- GBM disease and membranous nephropathy Reference Age/Sex Clinical Presentation Therapy Outcome Moorthy8 44/M Ankle edema Steroids Dialysis Pasternak16 19/F Hemoptysis, hematuria Steroids, azathioprine Nephrectomy, dialysis Sharon17 25/M Hemoptysis, hematuria, edema Steroids, CP, PP Died (pulmonary hemorrhage) Jennette18 17/M Sore throat, fever, minimal hemoptysis Steroids, CP Recovery Tomaszewski19 22/F Hemoptysis, hematuria Pettersson20 20/M Sore throat, fever, lumbar pain, Steroids, PP Recovery hematuria Savige,13 patient 1 16/F Hemoptysis, hematuria, edema Steroids, CP, PP Recovery Savige,13 patient 2 47/M History of hematuria, anuria Dialysis, transplant Savige,13 patient 3 21/M Hematuria, hemoptysis Steroids, CP, PP Recovery Savige,13 patient 4 20/F Hematuria, anemia Steroids, CP, PP Recovery Meisels21 50/M Edema for 4 months, then hematuria Steroids, CP, PP Recovery Sano22 54/F Hematuria, proteinuria, acute renal failure Steroids, PP Dialysis Nasr23 53/M Cough, sore throat, fatigue, dyspnea, Steroids, CP, PP Dialysis hematuria Singh24 48/F Anuria Steroids, CP, PP Dialysis Hoshino25 71/F Fatigue, nausea, pitting edema, Steroids Renal insufficiency pulmonary edema Troxell3 49/M Fatigue, hematuria, flank pain Steroids, CP, PP Dialysis Patel26 59/M Nausea, vomiting, renal insufficiency Steroids, CP, PP Dialysis Patient presented 59/M Fatigue, hematuria, acute renal failure Steroids, CP, PP Recovery here M, male; F, female; CP, cyclophosphamide; PP, plasmapheresis. Adapted from Troxell et al.3 and Patel et al.26

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along the GBM may cause release of Ed., edited by Feehally J, Floege J, Johnson damaged GBM antigens into the circula- R, Philadelphia, Elsevier Limited, 2007, pp 231–241 tion or unmask cryptic epitopes, which 2. Klassen J, Elwood C, Grossbery AL, Milgrom leads to the formation of nephritogenic F, Montes M, Sepulveda M, Andres GA: anti-GBM antibodies. Alternatively, a Evolution of membranous nephropathy into patient with an initial anti-GBM anti- anti-glomerular basement membrane glo- body-mediated renal lesion could have merulonephritis. N Engl J Med 290: 1340– 1344, 1974 release of GBM antigens into the circula- 3. Troxell ML, Saxena AB, Kambham N: Con- tion that then complex with the circulat- current anti-glomerular basement mem- ing anti-GBM antibody, leading to glo- brane disease and membranous glomerulo- merular deposition of immune complexes. nephritis: A case report and literature Anti-GBM antibodies could also form in review. Clin Nephrol 66: 120–127, 2006 4. Hecht N, Omoloja A, Witte D, Canessa L: situ complexes with freed GBM antigens Evolution of antiglomerular basement mem- within capillary walls. brane glomerulonephritis into membranous Given the patient’s history of 2ϩ al- glomerulonephritis. Pediatr Nephrol 23: buminuria on urinalysis and low serum 477–480, 2008 albumin 4 months before admission, it is 5. Cui Z, Zhao MH, Wang SX, Liu G, Zou WZ, Wang HY: Concurrent antiglomerular base- possible he then had undiagnosed mem- ment membrane disease and immune com- branous nephropathy that was possibly plex glomerulonephritis. Ren Fail 28: 7–14, due to excessive use of nonsteroidal anti- 2006 inflammatory drugs. Rapid decline of re- 6. Hayano K, Miura H, Fukui H, Otsuka Y, Hat- nal function in membranous nephropa- tori S: [A case of anti-GBM nephritis (cres- centic glomerulonephritis) associated with thy could be due to several causes, membranous nephropathy]. Nippon Jinzo including malignant hypertension; renal Gakkai Shi 34: 821–826, 1992 vein thrombosis; tubulointerstitial ne- 7. Nayak SG, Satish R: Crescentic transforma- phritis; crescentic glomerulonephritis; tion in primary membranous glomerulopa- and rarely, as in our patient, anti-GBM- thy: Association with anti-GBM antibody. Saudi J Kidney Dis Transplant 18: 599–602, mediated disease. Progression to end- 2007 stage renal disease in such patients has 8. Moorthy AV, Zimmerman SW, Burkholder usually been rapid; however, the diagno- PM, Harrington AR: Association of crescen- sis has rarely been made early enough to tic glomerulonephritis with membranous expect aggressive treatment to be suc- glomerulonephropathy: A report of three 28 cases. Clin Nephrol 6: 19–325, 1976 cessful. Fortunately, the prompt diag- 9. Richman AV, Rifkin SI, McAllister CJ: Rapidly nosis by renal biopsy in our patient al- progressive glomerulonephritis combined lowed early initiation of aggressive antiglomerular basement membrane anti- Figure 1. (A) Prominent GBM with capil- therapy. Interestingly, our patient has re- body and immune complex pathogenesis. Hum Pathol 12: 597–604, 1981 lary wall subepithelial spikes is characteris- mained in remission with minimal pro- 10. Kurki P, Helve T, von Bonsdorff M, Tornroth tic of membranous nephropathy. Segmen- teinuria, stable serum creatinine, and T, Pettersson E, Riska H, Miettinen A: Trans- tal necrosis and cellular crescents are with minimal side effects from therapy 2 formation of membranous glomerulonephri- ϫ shown (Jones silver stain, 400). (B) Char- years after presentation. The remission tis into crescentic glomerulonephritis with acteristic granular capillary wall staining of proteinuria with bland urine sediment glomerular basement membrane antibod- pattern of subepithelial deposits appear in and stable creatinine further suggest the ies. Nephron 38: 134–137, 1984 11. Thitiarchakul S, Lal SM, Luger A, Ross G: membranous nephropathy with underlying possibility that membranous nephropa- linear GBM pattern (insert) corresponding Goodpasture’s syndrome superimposed on thy and anti-GBM disease could be to anti-GBM antibody (anti-IgG immuno- membranous nephropathy. A case report. fluorescence ϫ400, insert ϫ2000). (C) Nu- pathogenically linked in this patient. Int J Artif Organs 18: 763–765, 1995 12. Agodoa LCY, Striker GE, George CRP, Glas- merous subepithelial and scattered in- sock R, Quadracci LJ: The appearance of tramembranous deposits with surrounding nonlinear deposits of immunoglobulins in matrix reaction and overlying effacement DISCLOSURES Goodpasture’s syndrome. Am J Med 61: of foot processes are diagnostic of mem- None. 407–413, 1976 branous . Anti-GBM anti- 13. Savige J, Dowling J, Kincaid-Smith P: Su- body binding is not visualized by electron perimposed glomerular immune com- microscopy, which is thought to reflect the plexes in anti-glomerular basement mem- REFERENCES diffuse distribution of the , ␣3 (IV) brane disease. Am J Kidney Dis 14: 145– collagen, within the GBM (transmission 153, 1989 electron microscopy, ϫ3000). 1. Couser WG: Membranous nephropathy. In: 14. Elder G, Perl S, Yong J, Fletcher J, Mackie J: Comprehensive Clinical Nephrology, 3rd Progression from Goodpasture’s disease to

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