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1 대한내과학회지 : 제 77 권부록 4 호 2009 임상강좌 ANCA- 연관혈관염에동반되는신장질환의이해 경북대학교의학전문대학원내과학교실 박선희 서론 ANCA (Anti-Neutrophil Cytoplasmic Antibody, 항호중구세포질항체 )-연관혈관염이란전신성혈관염중, 세동맥, 모세혈관, 세정맥등을침범하며, 혈중 ANCA가증가되는혈관염을통칭한다. 주로폐, 신장을침범하며, 임상양상, 검사실또는병리소견에따라현미경적다발성동맥염 (microscopic polyangitis, 이하 MPA), Wegener 육아종증 (Wegener s granulomatosis, 이하 WG), 그리고알레르기성육아종성혈관염 (Allergic granulomatous angitis 또는 Churg-Strauss syndrome, 이하 CSS) 등으로구분되며그외전신증세없이신장침범만있는, 신장제한형혈관염 (renal-limited vasculitis) 으로나눌수있다. ANCA-연관혈관염으로통칭되는 MPA, WG, CSS에서신장침범이나타나는빈도는각각 90%, 80%, 45% 에이른다 1). 이에저자는 ANCA-연관혈관염에의한신장침범으로투석을시행한한증례를소개하고, 신장침범시의예후및치료, 그리고 ANCA-연관신장염에의한말기신부전의치료로투석과이식에대해알아보고자한다. 증례심, M/40 주소 : 객혈현병력 : 평소간헐적인노작성호흡곤란이있어오던환자로, 내원 1달전전신쇠약감및소량의객혈이발생하였으나증상이호전되어특별한검사없이지냄. 내원 4일전부터기침이심해지면서객혈이소량씩지속되고전신쇠약감과오심이악화되어내원함. 과거력 : 25년전폐결핵으로치료함. 당뇨및고혈압없음가족력 : 특이소견없음이학적소견 : 혈압 10/70 mmhg 맥박 108/ 분호흡수 20/ 분체온 6.5 만성병색이며결막이창백함. 경부임파절은촉지되지않음심음은정상이나폐음은우측폐야에수포음이관찰됨 복부는특이소견없으며하지부종은없고기타피부병변은관찰되지않음. 검사실소견 : 말초혈액검사상혈색소치 4 g/dl, 헤마토크릿 12%, 백혈구 8,140/µL, 혈소판 290,000/µL, 적혈구침강속도 121 mm/hr였다. 소변검사는요비중이 1.020, 요알부민 (2+), 잠혈반응 (+), 현미경고배율시야에서적혈구 20-0개, 백혈구 0-1개였다. 생화학검사에서 BUN 11. mg/dl, 크레아티닌 1. mg/dl, 혈청총단백질 5.9 g/dl, 알부민 2.8 g/dl, 칼슘 8.7 mg/dl, 인 7.5 mg/dl, 요산 9.1 mg/dl, GOT 8 U/L, GPT 7 U/L, GGT 7 U/L, Na 14 mmol/l, K 6. mmol/l, Cl 105 mmol/l, glucose 97 mg/dl, CRP 11.8 mg/dl, Ferritin 186 ng/dl, Transferrin sat. 2. % 이었다. 24시간요검사상요단백 60 mg/day, 크레아티닌청소율은분당 4.4 ml이었다. 그외혈청검사로시행한 HBsAg (-), HCV(-), VDRL (-), anti-hiv (-), C/C4 97.1/6.9 mg/dl, ASO 159 IU/mL, IgG/IgA/IgM 940/256/26mg/dL, Anti GBM Ab (-) Cryoglobulin (-), Rheumatoid factor 20 IU/L, ANA (-), ANCA: P-ANCA (4+), anti-mpo Ab 74 AAU (0-150) 이었다. 방사선소견 : 흉부 X-선 ( 그림 1A), CT (1B) 및기관지내시경 (1C) 상미만성폐출혈및좌상엽의과거결핵병소가의심됨. 조직소견 : 형광현미경상 IgG, IgM, IgA, C, fibrinogen 모두음성. 광학현미경상 ( 그림 2) 5개의사구체중 28개에서사구체경화가관찰되고, 8개사구체에서반월상 (crescent) 형성됨, 간질의섬유화는심하지않으며간질내염증세포가다수침윤됨치료및경과 : 내원당시요독증상과대사성산증이동반되어경정맥내이중도관삽입후혈액투석을시작함. 현미경적다발성동맥염으로진단되어스테로이드충격요법및혈장교환술시행함. 이후객혈은호전되었으나, 신기능은회복되지않아유지투석요법으로복막투석을시작함. 이후복막투석도관기능부전으로혈액투석전환후현재까지혈액투석을시행하고있음. - S 994 -

- 박선희. ANCA- 연관혈관염에동반되는신장질환의이해 - A C B Figure 1.

Ground-glass opacity and consolidative density with peribroncheal distribution is noted in right lower lobe.

Bronchoscopic examination shows fresh blood at carina. ANCA- 연관혈관염의신장침범시의예후 Figure 2.

interstitial inflammatory cells. ANCA연관혈관염의 5년환자생존율은 WG, MPA, CSS 에서각각 69~91%, 45~76% 60~97% 에이른다 2).

2 - 박선희. ANCA- 연관혈관염에동반되는신장질환의이해 - A C B Figure 1. Chest X-ray (A), Chest CT (B) and bronchoscopic findings (C) at initial presentation showing diffuse alveolar hemorrhage. Chest CT shows air bronchogram and consolidative density in right upper lobe with sparing subpleural space. Ground-glass opacity and consolidative density with peribroncheal distribution is noted in right lower lobe. Cavitary lesions in left upper lobe, probably is associated with old tuberculosis. Bronchoscopic examination shows fresh blood at carina. ANCA- 연관혈관염의신장침범시의예후 Figure 2. Periodic Acid Schiff staining, 200 Light microscopy of kidney showing crescents with infiltration of interstitial inflammatory cells. ANCA연관혈관염의 5년환자생존율은 WG, MPA, CSS 에서각각 69~91%, 45~76% 60~97% 에이른다 2). 생존에영향을미치는인자로진단당시의투석의존도, 혈관염에의한조직손상정도 (Vasculitis damage index, VDI), 진단시신기능순서로높은사망위험도를나타내었다 ( 표 1). ANCA-연관혈관염에서신장침범은흔한소견이며이는말기신부전의중요한원인이다. 영국의보고에의하면 ANCA-연관혈관염은말기신부전에이르는원인의 4% 를차지한다. ANCA-연관혈관염이신장을침범할경우, 흔히급속진행성사구체신염으로발병하며조직학적으로는형광현미경에서음성을보이는반월상사구체신염 (pauci-immune crescentic glomerulonephritis) 이특징적이다. 그러나병리학적소견은경한국소성분절성사구체외세포증식에서부터사구체전반에걸친괴사성사구체신염등으로다양하게나타 - S 995 -

3 - 대한내과학회지 : 제 77 권부록 4 호 Table 1. Factors affecting survival in ANCA-associated systemic vasculitis Risk Factors Risk of death (95% CI) Level of evidence Dialysis dependence at diagnosis VDI 1 at diagnosis Impaired renal function at diagnosis Serum albumin level.0g/l at diagnosis Age >52 HR 8.2 ( ), p=0.00 HR 5.54 ( ), p=0.022 HR 5.10 ( ) HR 4.5 (1.-16) HR.4 ( ), p=0.04 Modified from Mukhtyar et al (2); VDI, vasculitis damage index 날수있다. 그러나 ANCA-연관혈관염의각아형에서신장침범의차이나그에따른예후의차이등을보고한논문은드물다. 유럽혈관연구회 (European Vasculitis Study Group, 이하 EUVAS) 에서시행한 CYCAZAREM과 MEPEX 연구로부터얻은 17예의신조직소견을분석한보고에의하면 ) MPA에의한경우가, WG에의한경우보다병리학적으로만성손상이더심하였다. ANCA-연관신장염의예후에대해보고한연구들은많으나 4-7), 이연구들은대상환자, 조직학적손상의분류방법, 치료방법, 일차변수등이달라서로비교하기가어렵다. Weidner 등은신조직검사에서 ANCA-연관신장염이진단된 80명환자를후향적으로분석하여 WG에서사망률이더높고, Proteinase- (PR)-양성 ANCA를보인군이 Myeloperoxidase (MPO)- 양성 ANCA를보인환자군에비해사망률이높다고보고하였다 8). Booth등은 246명의 ANCA-연관신장염환자를대상으로한 5년간의후향적분석에서 ANCA- 연관신장염의 1년, 5년환자생존율은각각 82%, 76% 이었고사망률은나이, 말기신부전으로의진행, 내원시혈청크레아티닌, 폐혈증과관련됨을보고하였다 9). 또한전체환자의 28% 가말기신부전으로진행하였다 9). 그러나이연구들은후향적분석이라는한계가있으며표준화된전향적연구에서나온결과를살펴보겠다. EUVAS에서치료를표준화하고, 신장손상의정도를같은기준으로점수화하여시행한전향적연구중의하나인 CYCAZAREM연구에서 96례의신조직검사를분석하여임상적, 조직학적예후인자를조사하였다 10). 18개월째의사구체여과율은기저사구체여과율, 신조직검사상섬유소성괴사및분절성반월상비율에따라결정되었다. 그러나조직학적소견은재발이나사망을예측하지는못하였다. 또한 MEPEX 연구의심한신장침범을보인 100례의환자에서 12개월째의사구체여과율을예측하는예후인자는나이, 정상사구체비율, 세관위축, 상피세포내세포침윤및기저사구체여과율등이었다 11). 섬유성반 월상은진단시투석시작과관계되었으며정상사구체비율, 치료군등은 12개월째의투석과관계가있었다. 따라서 ANCA-연관신장염의예후는신기능및환자의나이와밀접하게관계되므로, 신장침범을조기에발견하여일찍치료를시작하는것이중요하다고하겠다. ANCA- 연관혈관염의신장침범시의치료 ANCA-연관혈관염의초기사망원인은치료와관련된부작용에의한경우가많으므로 12), 활동성혈관염을조절하면서동시에치료에따른부작용을최소화할수있는적절한치료가중요하다고하겠다. 특히신장침범으로사구체여과율이저하되고환자가고령인경우, 부작용위험이더욱증가할수있으므로약물의용량조절및세심한추적관찰이중요할것으로생각된다. 치료는크게진단및평가단계로시작하여, 관해유도요법, 관해유지요법그리고추적관찰기등으로나눌수있다. ANCA-연관혈관염의치료지침으로는유럽의 EULAR (The European League Against Rheumatism) 1), 영국의 BSR and BHPR (British Society of Rheumatology and British Health Professionals in Rheumatology) 14), 호주의 CARI (Caring for Australasians with Renal Impairment) 15) 지침그리고일본후생성의혈관염연구그룹 16) 등이제안한지침등이있다. 혈관염의침범정도에따라국소성 (localized), 초기전신성 (early systemic), 전신성 (generalized), 심한 (severe), 또는불응성 (refractory) 혈관염으로구분할수있다. 심한혈관염 은신장또는다른주요장기의기능장애가있을때를의미하며, 보통혈청크레아티닌 500 μmol/l (5.6 mg/dl) 이상인경우가이에해당한다. 이지침들을근거로치료방법을요약하면아래와같다. 1. 관해유도요법 1) Cyclophosphamide (CYC) - S 996 -

4 - 박선희. ANCA- 연관혈관염에동반되는신장질환의이해 - Table 2. Dose modification of pulsed cyclophosphamide for renal function and age (as used in randomized controlled trial) Age, years < >70 Adapted from Mukhtyar et al 1) < mg/kg/pulse 12.5 mg/kg/pulse 10 mg/kg/pulse Creatinine (μmol/l) mg/kg/pulse 10 mg/kg/pulse 7.5 mg/kg/pulse 신장침범을포함한전신성혈관염의경우, 경구 (2 mg/ kg/day, 하루최대용량 200 mg) 또는정맥내 CYC와스테로이드병합치료를시행한다. EUVAS의경우, CYC 15mg/kg 매 2주마다 번정맥내투여하고, 매 주마다 ~6 번투여하였다. 부작용을줄이기위해환자의나이나신기능의저하에따라감량을하는것이중요하며용량감소는 < 표 2> 과같다. 또투석을시행중인환자의경우는투석을통한약물제거를고려하여야한다 17). 또한 CYC 대사체에의한독성을방지하기위해충분한수분공급과 2-mercaptoethanesulfonate sodium (Mesna) 등의투여가필요하며, CYC 투여이후백혈구감소등의부작용에대한감시가필수적이다. 폐포자충감염에의한폐렴을예방하기위한예방적 Trimethoprim/Sulfamethoxazole (800/160mg 격일복용또는 400/80 mg 매일복용 ) 의투여가필요하다. 2) Methotrexate (MTX) 치명적이지않은혈관염의경우나신장침범이없는경우는, 부작용이적은 MTX (20-25 mg/week 경구또는비경구 ) 와 Glucocorticoid 병합치료를시행할수있다. 그러나관해유도를위해서 CYC보다오랜기간복용하여야한다. ) 스테로이드스테로이드는다른면역억제제와함께쓰이며 prednisolone 1 mg/kg/day로시작하여한달간사용후첫 개월에 15 mg이하로감량한다. 관해가오면유지기동안 10 mg이하로유지한다. 골다공증의예방을위해칼슘, 비타민 D치료를함께시행한다. 적효과가확실하지않다. 2. 관해유지요법관해가유도되면재발을방지하기위해저용량의스테로이드와 Azathiopurine (AZA, 2 mg/kg/day) 또는 MTX (20-25 mg/kg/week), leflunomide (20-0 mg/day) 를병합할수있다. 최근 Mycophenolate mofetil 도관해유도또는유지요법으로사용되고있으나전향적연구결과가부족하다. 그외 Etanercept는관해유도와유지에서표준치료와비교시효과가없는것으로보고되었다 19). 관해유지요법을지속하는기간에관한정설은없으나, 적어도 18개월 ( 특히 WG의경우 ) 까지유지해야재발을줄일수있다. 관해유지요법에 Trimethoprim/Sulfamethoxazole을추가하는것이 WG의재발방지에도움이된다 20). ANCA의정량적검사가재발을예측할수있는지는불분명하며이에관한상충되는임상결과가보고되므로추적시 ANCA 농도와함께임상적재발의징후를함께추적하는것이중요하다 21-2). 재발또는불응성혈관염에사용할수있는기타면역조절제로는면역글로불린 (2 g/kg for 5 days) 24), 15-Deoxyspergualin (0.5 mg/kg/day for six cycles) 25), Anti-thymocyte globulin (2.5 mg/kg/day for 10 days) 26), Infliximab (~5 mg/kg/infusion every 1-2 month) 27), Mycophenolate mofetil (2 g/day) 28), Rituximab (75 mg/m 2 BSA weekly for 4 weeks) 29) 등이있다. 투석과이식 1. 투석 4) 혈장교환술혈장교환술은심한신장침범 ( 혈청크레아티닌 500 μmol/l 또는 5.65 mg/dl) 시, 경구 CYC 및스테로이드와함께시행될경우신생존율을향상시킨다 18). 그러나환자생존율을향상시키는지또는신장이외다른기관침범시는그치료 ANCA-연관신장염의치료에도불구하고약 20% 의환자에서말기신부전으로진행하여신대체요법이필요하게된다 0). ANCA-연관신장염에의해투석을시작한환자의사망률은비당뇨성신질환에의한투석환자의사망율과큰차이가없다 1). 또한투석중인환자는일반적으로혈관염의 - S 997 -

5 - 대한내과학회지 : 제 77 권부록 4 호 활동성이낮아진다고보고되나종종재발을경험하기도한다. 그러나투석중인환자의경우, 재발에의한증상이투석중생기는합병증과의감별이어려운경우가있어 ( 예, 소화기혈관염증상과복막투석환자의복막염, 폐출혈과혈액투석중인환자의폐부종등 ) 진단이늦어져치명적인경우가있다. Lionaki 등은 ANCA-연관신장염에의해투석을시작한환자를대상으로말기신부전으로진행한환자와신기능이회복되어투석을중단한환자, 투석전단계의만성신부전으로진행한환자를비교해보았다 2). 전체말기신부전환자의원인중 ANCA연관신염이처음발생한경우가 51%, 재발한경우가 6%, 활동성혈관염의소견없이신질환이서서히진행한경우가 4% 에이르렀다. 또한투석중인환자는 ANCA-연관신장염의재발은적으나감염의위험은 2배이상높았다. 또다른연구에서는이전의 ANCA-연관신장염의원인이나투석막의종류등은재발에영향을미치지않았다 ). 투석중인환자에서 ANCA연관혈관염이재발한경우의치료는처음치료와크게다르지않으나감염의위험이높으므로, 치료로인한부작용과혈관염의활동성을모두고려하여치료방침을결정하여야한다. 투석중인환자를대상으로한전향적인연구는거의없으므로관해유도치료이후언제까지유지요법을시행해야할지구체적인지침을찾기는어렵다. 그러나소규모후향적연구에서스테로이드를장기간투여하는투석환자는영양상태가더나쁘다고보고되므로유지요법중이러한부작용에대한감시가요구된다. 2. 이식 ANCA-연관신장염에서도다른원인질환에서와마찬가지로신이식을하는것이투석에비해환자생존율이높다. 그러나성공적인신이식을위해서는관해후언제이식을할지, 또한이식이후의재발위험이나이식후의면역억제제가혈관염에미치는영향등을충분히고려하여야한다. 신이식후지속적인면역억제제의복용에도불구하고환자당년간 (per patient per year) 0.02~0.1의재발이보고된다. 주로급성신부전또는급성진행성사구체신염으로발병한다. Nachman등의보고에의하면, 신이식후재발한 60% 의환자는사구체신염으로재발하였으나, 40% 는신장외증상으로만재발하였다 4). 신이식이후재발에영향을미칠수있는인자로는이식전투석기간, 이식당시 ANCA유무, 이식후면역억제제의종류등이있다. 먼저 ANCA연관신장염에의한말기신부전시이식을위 해어느정도기다려야하는지에관한정확한답은없다. 그러나이식전투석기간이길었던경우와짧았던경우재발에큰차이가없었던것으로보아 4), 일단관해가왔다면이식을위해오래기다리는것이재발방지에도움이되지는않는다. 두번째이식전 ANCA양성이면이식을할수없는가? 항기저막항체질환에의한이식과달리, ANCA가양성이라도임상적으로관해에도달했다면신이식을시행할수있다. 셋째, 면역억제제는어떤것을선택하는것이재발방지에도움이되는가? 초기보고에따르면 cyclosporine을포함한면역억제제가 azathiopurine을포함한약제보다재발률을낮다고하였으나 5), 최근연구에서는별차이가없다고보고된다. 또한 Mycophenolate mofetil (MMF) 은관해유지에도사용되나, 이식후 MMF를사용한다고재발을막을수있는것은아니다. 이식후재발이생긴경우역시 CYC와스테로이드로치료할수있다. 그러나이식환자에서재발한경우, 세포독성이적은치료제의사용으로치료에따른합병증발생을최소화할수있는임상연구가필요할것으로생각된다. 요 ANCA- 연관혈관염에의한신장침범은환자의사망률을높이는주된원인이며, 급속진행성사구체신염으로발병하여조기에치료하지않으면말기신부전으로진행한다. 환자의나이와진단시신기능이예후에중요하므로조기에진단하여빨리치료를시작하는것이중요하다. 그러나신장침범으로사구체여과율이감소된경우, 치료약제의감량이필요하다. 말기신부전으로진행시투석또는이식을시행할수있으며, 재발위험은투석전환자군에비해낮으나감염의위험이증가되므로치료방침결정에세심한주의가요구된다. 약 REFERENCES 1) Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 7:1512-2, ) Mukhtyar C, Flossmann O, Hellmich B, Bacon P, Cid M, Cohen-Tervaert JW, Gross WL, Guillevin L, Jayne D, Mahr A, Merkel PA, Raspe H, Scott D, Witter J, Yazici H, Luqmani RA; European Vasculitis Study Group (EUVAS). Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis 67: , 2008 ) Hauer HA, Bajema IM, van Houwelingen HC, Ferrario F, Noël LH, Waldherr R, Jayne DR, Rasmussen N, Bruijn JA, - S 998 -

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( )Kjbt014.hwp 대한수혈학회지 : 제 18 권제 3 호, 2007 항호중구세포질항체양성혈관염환자에서시행한혈장교환술 1 예 이윤수 1 ㆍ박정란 1 ㆍ송규섭 1 ㆍ김용림 2 ㆍ서장수 1 = Abstract = 경북대학교병원진단검사의학과 1, 내과 2 Plasma Exchange in a Patient with Antineutrophil Cytoplasmic Antibody-associated