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1 대한류마티스학회지 Vol. 16, No. 3, September, 2009 DOI: /jkra 증례 항인지질항체음성인전신홍반루푸스에동반된콩팥동맥혈전증 1 예 제주대학교의과대학내과학교실 1, 영상의학교실 2 강동구 1 ㆍ김봉수 2 ㆍ장은희 1 ㆍ신상엽 1 ㆍ김진석 1 =Abstract= Renal Artery Thrombosis in a Patient with Systemic Lupus Erythematosus without Antiphospholipid Antibody Syndrome: A Case Study Dong Gu Kang 1, Bong Soo Kim 2, Eun Hee Jang 1, Sang Yop Shin 1, Jinseok Kim 1 Departments of Internal Medicine 1 and Radiology 2, College of Medicine, Jeju National University, Jeju, Korea Systemic lupus erythematosus (SLE) is a multisystemic inflammatory autoimmune disease caused by various autoantibodies and immune complexes. SLE and antiphospholipid antibodies are associated with thrombotic manifestations. However, renal artery thrombosis which causes renal artery occlusion is uncommon even in SLE patients with antiphospholipid antibodies. A 27-year-old woman with SLE suddenly developed left flank pain and generalized edema. From the laboratory workup, the woman was negative for antiphospholipid antibody and nephroticrange proteinuria was detected. Computed tomography revealed renal artery thromboembolism and multiple renal infarctions with parenchymal perfusion defects in the left kidney. Renal biopsy showed WHO classification III and V lupus nephritis. Left flank pain, generalized edema and proteinuria were resolved and the thromboembolism resolved itself after a high dose of steroid and anticoagulation therapy. In SLE patients, sudden onset of unexplained flank pain is considered as a possible symptom of renal vessel thromboembolism even if the antiphospholipid antibody is negative. Key Words: Systemic lupus erythematosus, Antiphospholipid antibodies, Renal infarction < 접수일 :2009 년 5 월 7 일, 수정일 (1 차 :2009 년 7 월 2 일, 2 차 :2009 년 7 월 9 일 ), 심사통과일 :2009 년 7 월 10 일 > 통신저자 : 김진석제주도제주시아라 1 동 제주대학교의과대학내과학교실 Tel:064) , Fax:064) , slera@cheju.ac.kr 248

2 강동구외 : 항인지질항체음성전신홍반루푸스의콩팥동맥혈전증 서론전신홍반루푸스는다양한자가항체와면역복합체에의해전신적인증상이발생하는자가면역질환이다. 전신홍반루푸스환자에서는죽상경화증및심혈관계질환의빈도가높은것으로알려져있다. 문헌에따르면인종에따라차이는있지만전신홍반루푸스환자에서전반적인동맥과정맥혈전증의빈도는 16/1,000인년 (patient-years), 13/1,000인년으로보고되고있다 (1). 전신홍반루푸스환자에서항인지질항체증후군이동반된경우에는동맥및정맥혈전증, 유산, 신경질환, 혈소판감소증의빈도가더높은것으로알려져있으며 (2), 전신홍반루푸스환자의약 30 50% 에서항인지질항체를가지고있고그중에서약 1/3이항인지질항체증후군으로진행한다 (3). 그러나항인지질항체가양성인경우라도콩팥동맥의협착을유발하는콩팥동맥혈전증이보고된경우는흔하지않다 (4). 국내에서항인지질항체가음성인전신홍반루푸스환자에서혈전증에의한콩팥동맥협착은보고된바가없으며외국의보고도드물어소아환자에서는 Tusugawa 등의보고가유일하며 (4) 성인환자에서는 Suwabe 등의보고가있다 (5). 본저자들은항인지질항체가음성인전신홍반루푸스환자에서발생한콩팥동맥혈전증 1예를경험하였기에보고하는바이다. 증례 27세여자환자가내원 3주전부터발생한전신부종과 1주전부터발생한왼쪽옆구리통증을주소로본원내과외래로내원하였다. 환자는본원내원전인근병원에내원하여급성신우신염과신증후군의증으로입원치료일주일후증상호전되어퇴원하였다. 그러나퇴원이틀뒤인본원내원 2일전다시왼쪽옆구리통증이악화되고전신부종이발생하여정밀검사위해본원내과로전원되었다. 환자는 4년전반복적인안면홍조, 간헐적인구강궤양과레이노현상으로전신홍반루푸스를진단받았으며경구프레드니솔론과항말라리아제를복용하다가치료를임의로중단하고지내왔고그이후 특이약물복용병력은없었다. 입원당시혈압은 120/90 mmhg, 심장박동수는 80 회 / 분, 체온은 36.4 o C, 체중은 42 kg였으며좌측늑골척추각타진시통증을호소하였고양하지에중등도의함몰부종이있었다. 흉부청진에서호흡음및심음은정상이었고복부의이학적검사도정상이었다. 내원당시의혈액검사소견은백혈구 6,600/uL ( 림프구 10.2%), 혈색소 9.3 g/dl, 혈소판 169,000/uL, PT 1.77 INR ( 정상 : INR), aptt 43 sec ( 정상 : sec), 혈청알부민 1.8 g/dl, AST 124 IU/L, ALT 57 IU/L, ALP 646 IU/L, 혈액뇨소질소 24.1 mg/dl, 혈중크레아티닌 1.2 mg/dl, C 반응단백 (hs-crp) 4.85 mg/dl, FDP test ug/ml ( 정상 : <5 ug/ml), D-dimer<0.5 ug/ml ( 정상 : <0.5 ug/ml), anti-dsdna antibody IU/mL ( 정상 : IU/mL), anti-ss-a/ro antibody는양성이었고 anti-sm antibody, anti-rnp antibody, anti-ss-b/la antibody는음성이었으며, C3 62 mg/dl ( 정상 : mg/dl), C46 mg/dl ( 정상 : mg/dl), VDRL 정성검사음성이었다. 루푸스항응고인자확진검사는음성이었고, IgG/IgM 항카디오리핀항체, IgG/IgM Anti-beta2 glycoprotein-i antibody 모두음성으로항인지질항체증후군의증거는없었다. 소변검사에서요단백 +++, 혈뇨 +++, 무작위요단백 627 mg/dl, 무작위요중크레아티닌 mg/dl으로무작위요단백과요중크레아티닌분획 (random urine proteincreatinine ratio) 으로계산해보았을때단백뇨는약 5.1 g/day였다. 흉부단순촬영에서좌측늑막삼출액이보였고, 복부컴퓨터단층촬영에서왼쪽콩팥실질의관류장애및콩팥동맥의혈전증을시사하는다발성콩팥동맥충만결손이관찰되었다 ( 그림 1A). 환자의 SLEDAI (SLE disease activity index) 는단백뇨 4점, 혈뇨 4점, 늑막삼출액 2점, 보체감소 2점, anti-dsdna 증가 2점, 탈모 2점으로총 16점이었다. 입원후저분자량헤파린으로항응고요법을시행하면서환자의왼쪽옆구리통증은호전되었고하지부종과단백뇨를조절하기위해 ramipril, furosemide 복용및간헐적인알부민보충을시행하였다. 입원 1주후추적관찰을위해시행한콩팥동맥컴퓨터단층혈관조영술에서왼쪽콩팥실질의다발성관류장애는호전을보였으며콩팥동맥혈전증은사라진 249

대한류마티스학회지 제 16 권 제 3 호 2009 Fig. 1. 27-year-old woman with multiple left renal infarctions.

Multiple filling defects (arrows) in left main and segmental renal arteries suggest the thromboembolism.

as well as a decreased extent of parenchymal loss. Fig. 2. 27-year-old woman with lupus nephritis WHO class III+V.

Capillary loops are focally thickened with subendothelial deposition (H&E stain, 400).

3 대한류마티스학회지 제 16 권 제 3 호 2009 Fig year-old woman with multiple left renal infarctions. (A) Contrast-enhanced computed tomography image during corticomedullary phase shows multiple parenchymal perfusion defects in the left kidney compatible with renal infarctions. Multiple filling defects (arrows) in left main and segmental renal arteries suggest the thromboembolism. (B) Follow-up contrast-enhanced maximal intensity projection image obtained one week later shows the thromboembolism is no longer present in the left main and segmental renal arteries as well as a decreased extent of parenchymal loss. Fig year-old woman with lupus nephritis WHO class III+V. (A) Light microscopy shows moderate hypercellular mesangial tissue and focal endocapillary proliferation. Capillary loops are focally thickened with subendothelial deposition (H&E stain, 400). (B) Electron microscopy shows diffuse effacement of epithelial foot processes and wide spread subepithelial electron-dense deposition ( 5,000). 소견을 보였다(그림 1B). 그러나 환자의 체중은 입 는 광학 현미경 사진에서 사구체의 일부 분절에서 원 당시 42 kg에서 48 kg으로 증가하였고, 단백뇨도 국소적인 모세혈관 내 증식 및 내피 밑 침착을 보이 진행하는 양상을 보였으며 무작위 요단백과 요중 크 고 전자 현미경 사진에서 미만성 발 세포의 소실 및 레아티닌 분획은 20.8이었다. 저자들은 입원 1주 후 광범위한 상피밑 전자밀도침착 소견을 보여 WHO 부터 고용량의 프레드니솔론(1 mg/kg)을 경구 투여 classification III와 V, ISN (international society of neph- 하기 시작하였고 입원 2주 후 초음파 유도 하 우측 rology)/rps (renal pathology society) classification III 콩팥 조직검사를 시행하였다. 콩팥 조직검사의 결과 A/C와 V가 동반된 루푸스 신염 소견을 보였다(그림 2). 250

4 강동구외 : 항인지질항체음성전신홍반루푸스의콩팥동맥혈전증 콩팥조직검사시행후경구프레드니솔론은지속적으로사용하였고저분자량헤파린은경구와파린으로변경하였다. 입원 1달뒤전신부종이호전되어퇴원하였으며현재외래에서추적관찰하면서프레드니솔론용량감량중이다. 고찰전신홍반루푸스는원인이알려지지않은전신질환으로기본적인병태생리는면역복합체의침착, 보체의활성화, 염증반응의결과로생각되며 (6) 일반적으로심혈관계질환의발생의빈도가높은것으로알려져있다. Mok 등은 625명의전신홍반루푸스환자를대상으로관찰하여인종에따라 60개월뒤의동맥질환의이환율은 5.1% 에서 8.5%, 정맥질환의이환율은 3.7% 에서 10.3% 로보고하였으며, 동맥질환은뇌경색및일과성허혈발작이대부분 (65%) 이었고정맥질환은심부정맥혈전증또는폐동맥혈전증이대부분 (80%) 이었다 (1). 전신홍반루푸스환자에서관상동맥질환을일으키는위험인자로는진단당시고령, 긴유병기간, 긴프레드니솔론사용기간, 고혈압의병력, 폐경, 고지혈증등이있다 (7). 전신홍반루푸스환자에서항인지질항체가양성인경우에는혈전증의발병률이높다는것은잘알려진사실로, 문헌에의하면콩팥혈전증이있는전신홍반루푸스환자는일반적으로항인지질항체가양성인소견을보인다 (8, 9). Laskin 등의보고에의하면전 신홍반루푸스환자에서루푸스항응고인자가양성인경우에는혈전증의빈도가 40% 였으나루푸스항응고인자가음성인경우에는혈전증의빈도가 12% 였고, 항카디오리핀항체가양성인경우에는혈전증의빈도가 40% 였으며항카디오리핀항체가음성인경우에는혈전증의빈도는 18% 였다 (10). 그리고 Annexin V라는 anti-thrombotic plasmaprotein이혈관내피세포에결합하는것을항인지질항체가저해함으로인해전신홍반루푸스환자에서심혈관질환이높아진다고알려져있다 (3). 따라서전신홍반루푸스에서항인지질항체의존재는그렇지않은경우에비해혈전증의빈도를높인다고추정할수있다. 전신홍반루푸스환자에서콩팥혈전증이동반된경우에일반적으로동맥혈전증보다정맥혈전증이많이발생하며 (11) 콩팥동맥침범이있는경우에도주로소동맥에서혈전증이관찰되었다. 콩팥동맥혈전증이콩팥정맥혈전증보다드문이유는혈관간세포에의한다량의산화질소와프로스타글란딘 I2의합성이혈소판활성화를억제하여사구체모세혈관의혈전증발생을예방하기때문이라고보고된바있다 (12). 전신홍반루푸스환자에서항인지질항체외에심혈관계질환을유발하는다른요소로는염증반응, 스테로이드치료에의한과다응고, 고혈압, 이상지질혈증, 지질의산화등을생각해볼수있다. 최근에는 C 반응단백및염증반응이죽상경화증의위험인자로생각되고있고, 죽상경화증부위에활성화된대식세포와 T 세포가많다는점에서죽상경화증이 Table 1. Comparison of previous renal infarction cases of SLE patients negative for antiphospholipid antibodies to the current case A* B C Sex Male Female Female Race Asian Asian Asian Age 13-year old 42-year-old 27-year-old SLE duration 11-month 8-year 4-year Symptom Hypertension, fever, Right abdominal pain Left flank pain, generalized edema seizure, abdominal pain Drug history Prednisolone, mizoribine, Prednisolone, azathioprine Prednisolone, hydroxychloroquine dilazep dihydrochloride Other complication CNS lupus, lupus nephritis Lupus nephritis Lupus nephritis *Tsugawa K, Tanaka H, Kudo M, Nakahata T. Renal artery thrombosis in a pediatric case of systemic lupus erythematosus without antiphospholipid antibodies. Pediatr Nephrol 2005; 20(11): , Suwabe H, Moriuchi J, Hoshina Y. Renal and cerebral infarctions in a patient with systemic lupus erythematosus without antiphospholipid antibodies. Ryumachi 1993;33(4): , Current case 251

5 대한류마티스학회지제 16 권제 3 호 2009 염증성질환으로이해되고있다 (13). 또한 ESR, α1 antitrypsin, C반응단백, TNF-α 등의급성기반응물질들이전신홍반루푸스환자의심혈관질환과관련이있는것으로알려져있고, 전신홍반루푸스환자에서볼수있는특징적인이상지질혈증인고밀도지질단백의감소와중성지방의상승, 정상또는약간상승한저밀도지질단백은 TNF-α에의한간의지질합성촉진및 lipoprotein lipase의억제에의한것으로설명된다 (3). 본증례의환자는전신홍반루푸스로진단후에일시적으로프레드니솔론및항말라리아제를복용하다가추적소실되었으며이로인해질병의활성도가높아져있었던상태로생각된다. 이전에보고되었던항인지질항체가음성인전신홍반루푸스환자에서발생한콩팥경색증례와비교해보면모두루푸스신염이동반되었으며복부또는옆구리의통증이있었고 Tusugawa 등의보고 (4) 에서는소아환자에서발생한콩팥경색이었으며중추신경계합병증도동반되어있었다 ( 표 1). 결론적으로본증례는항인지질항체음성인전신홍반루푸스환자에서도콩팥동맥혈전증이발생할수있음을보여주며, 상기고찰에서언급한내용을종합해볼때본증례의환자에서는높은질병의활성도로인한전신적인염증반응이혈전증의발생에기여를했을것으로추정된다. 이에전신홍반루푸스의지속적인치료로질병의활성도를떨어뜨리는것이혈전성합병증의발생을예방하는데도움이될것이라고생각되며, 전신홍반루푸스환자에서갑작스러운원인불명의옆구리통증이있을때는콩팥혈전증과콩팥경색의가능성에대한임상적인주의가필요하다. 요약저자들은갑작스러운옆구리통증을주소로내원한전신홍반루푸스환자에서컴퓨터단층촬영검사소견을바탕으로콩팥동맥혈전에의한콩팥경색을진단하였으나혈액검사소견에서항인지질항체증후군의증거는없었던증례를경험하였기에문헌고찰과함께보고하는바이다. 참고문헌 1) Mok CC, Tang SS, To CH, Petri M. Incidence and risk factors of thromboembolism in systemic lupus erythematosus: a comparison of three ethnic groups. Arthritis Rheum 2005;52: ) Appel GB, Pirani CL, D'Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol 1994;4: ) Frostegard J. SLE, atherosclerosis and cardiovascular disease. J Intern Med 2005;257: ) Tsugawa K, Tanaka H, Kudo M, Nakahata T. Renal artery thrombosis in a pediatric case of systemic lupus erythematosus without antiphospholipid antibodies. Pediatr Nephrol 2005;20: ) Suwabe H, Moriuchi J, Hoshina Y. Renal and cerebral infarctions in a patient with systemic lupus erythematosus without antiphospholipid antibodies. Ryumachi 1993;33: ) Hall S, Buettner H, Luthra HS. Occlusive retinal vascular disease in systemic lupus erythematosus. J Rheumatol 1984;11: ) Nikpour M, Urowitz MB, Gladman DD. Premature atherosclerosis in systemic lupus erythematosus. Rheum Dis Clin North Am 2005;31: ) Asherson RA, Derksen RH, Harris EN, Bouma BN, Gharavi AE, Kater L, et al. Chorea in systemic lupus erythematosus and "lupus-like" disease: association with antiphospholipid antibodies. Semin Arthritis Rheum 1987;16: ) Hernandez D, Dominquez ML, Diaz F, Fernandez ML, Lorenzo V, Rodriquez A, et al. Renal infarction in a severely hypertensive patient with lupus erythematosus and antiphospholipid antibodies. Nephron 1996;72: ) Laskin CA, Clark CA, Spitzer KA. Antiphospholipid syndrome in systemic lupus erythematosus: is the whole greater than the sum of its parts? Rheum Dis Clin North Am 2005;31: ) Soltesz P, Veres K, Lakos G, Kiss E, Muszbek L, Szeqedi G. Evaluation of clinical and laboratory features of antiphospholipid syndrome: a retrospective study of 637 patients. Lupus 2003;12: ) Raij L, Shultz PJ. Endothelium-derived relaxing factor, nitric oxide: effects on and production by mesangial cells and the glomerulus. J Am Soc Nephrol 1993;3: ) Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999;340:

Jksvs019(8-15).hwp

Jksvs019(8-15).hwp Grade I Grade II Grade III 12 대한혈관외과학회지 : 제 20 권 제 1 호 2004 Control Group A Group B Fig. 4. Microscopic findings of vein wall in control, group A and group B on the day of 7 after venous occlusion. The