2018- PG Course편집.hwp

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1 PG2 PG Course 2018 Current Management for Advanced Liver Disease Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome Moon Young Kim Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea Portal hypertension (PHT) is associated with hemodynamic changes in intrahepatic, systemic, and portosystemic collateral circulation. Systemic and splanchnic vasodilatation can induce hyperdynamic circulation which is related with ascites development and finally fatal complications such as spontaneous bacterial peritonitis (SBP), hepatolrenal syndrome (HRS), and multi-organ failure. In the management of SBP, antibiotics resistance bacteria have became main issue and appropriate antibiotics application in time and prevention of progression to subsequent acute kidney injury (AKI) and HRS is important. Challenges in precisely evaluating renal function in the patient with cirrhosis remain because of the limitations of serum creatinine (Cr) alone in estimating renal function. Recently new guideline by International Club of Ascites was suggested to early diagnosis and treatment of AKI and HRS and validation about clinical usefulness remained. This review will overview recent diagnosis and management of SBP, AKI, and HRS briefly. Keywords: Cirrhosis, Ascites, Spontaneous bacterial peritonitis, Acute kidney injury, Hepatorenal syndrome Introduction 간경변증의진행과그에따른문맥압항진증및과역동성혈류흐름의발생은하나의연속적인스팩트럼에있으며, 질환의중증도가심해짐에따라정맥류의발생에서점차복수의발생과그에따른이차적감염및신기능의저하로이행되는것이일반적인간경변환자의자연사라고할수있다. 과거에는정맥류의발생과그에따른출혈이비대상성간경변증환자의주요해결과제였으나최근에는그러한정맥류출혈현상과그에따른사망보다는복수및그에따른이차적감염의증가, 신기능의저하및간신증후군의발생이주요합병증으로대두되고있다. 복수생성은내장혈관의확장및그에따른레닌-안지오텐신계의활성화와나트륨과수분의저류가주요기전이다. 복수는원칙적으로는 transudate fluid이지만 opsonic activity가약하고이로인해세균이증식할수있는좋은환경이되고비대상성간경변환자에서흔히동반되는장내세균전위에의해서쉽게감염증또는전신성염증이발생할수있다. 이러한현상은결국자발성복막염이나급성신기능의저하, 간신증후군과같이간경변증의합병증중가장치명적인합병증들로이어지고사망에이르게된다. 따라서이러한질환에대한이해는말기간경변환자의치료와관리에있어서매우중요하며, 이에본글에서는자발성복막염의진단과치료, 급성신손상과간신증후군의최근진단기준과그에따른치료에대해서간략히살펴보고자한다. Spontaneous Bacterial Peritonitis 자발성세균성복막염 (Spontaneous bacterial peritonitis) 은간경변증과복수가있는환자에서뚜렷한복 30 The Liver Week 2018

2 Moon Young Kim 강내감염원인이없이발생하는복수의세균감염으로복강내특정감염이나염증원인에이차감염이배제된상태에서진단하게된다. 자발성복막염은 1907년에 Krencker에의해처음기술되었고 Conn이 1964년에자발적인세균성복막염이라는용어를사용하여명백한감염원인없이간경변에서복막염과균혈증의증후군으로정의하였다. 1 입원한간경변증환자의자발성복막염의발생률은 10-30% 에이르며, 2 예후는불량하여사망률이첫진단이후 1개월, 6개월, 1년에각각 33%, 50%, 58% 로보고되고있다. 3 자발성복막염의주요원인은균주는장내그람음성균으로, 면역이저하된환자에서발생하는장내세균의전위 (bacterial translocation) 와깊은연관이깊다. 진행된간경변환자에서는면역조절장애와더불어장내세균의과증식, 장투과도의증가등의다양한기전에의해병적인세균전위가발생하며, 이때정상장내세균도해로운영향을줄수있다. 90% 이상의경우에한가지의단일박테리아에의해유발되며, 복수의배양을통해 50-60% 에서만원인균이확인된다. 4 그람양성구균 (Gram positive cocci) 은전체자발성복막염원인의약 25% 를차지하는것으로알려져있으며, 간경변증환자에서그람양성구균에의한감염은치료적시술, 장기간의항생제사용등과관련되어자발성복막염뿐아니라기타폐렴이나요로감염에서도최근에급증하고있다. 5 이외에도 extended spectrum β lactamase producing (ESBL) 그람음성균, methicillin resistant Staphylococcus aureus (MRSA), flouroquinolone resistant (QR) 그람음성균, vancomycin resistant Enterococcus 등의항생제내성균주들의증가가 SBP의치료에있어서많은변화를가져오고있다. 특히 ESBL 그람음성균 (E. coli 와 Klebsiella) 은가장흔한다약제내성균주로서 (73%), 장기간의예방적 norfloxacin 투약을받은환자에서호발하고있다. 6 1) 진단자발성복막염은임상적으로진단할수없으며복수검사를꼭필요로한다. 복수를동반한간경변증환자에서복막염의징후 ( 복통, 구토, 장마비등 ), 감염의증상, 원인이불분명한합병증 ( 간기능악화, 신기능악화, 간성뇌증 ) 이발생한경우에는자발성세균성복막염을의심하고복수천자를시행해야한다. 7 원칙적으로는복수배양에의한균동정이필요하나, 배양을통해서균이확인되지않는경우가많기에다형핵호중구 (polymorphonuclear leukocyte, PMN) 이 250/mm 3 이상일때진단할수있으며, 복수에적혈구가섞여있을경우적혈구 250/mm 3 당 PMN을 1/mm 3 씩빼서계산한다. 7 복수에서 PMN 250/mm 3 이상소견을보이는환자의약 40% 는적절한배양검사에서도균이동정되지않으나 (culture negative neutrocytic ascites), 8 비슷한임상경과를보이므로경험적항생제치료를한다. 9 일부환자에서는복수내세균의상재화 (colonization) 에의해복수천자결과 PMN이 250/mm 3 미만이지만복수배양에서단일균주가배양되는경우도있다 (monomicrobial non-neutrocytic bacterascites). 이런경우에도열, 복통등과같은감염의증상이있거나, 원인이불분명한합병증 ( 신기능악화혹은간성뇌증등 ) 이동반되었을때는경험적항생제치료가필요하다. 2) 치료복수의감염이의심되는환자에서는복수의균배양및항생제감수성결과가나오기전에 3세대 cephalosporin 계통의항생제를이용한경험적항생제치료를시작한다. Cefotaxime은가장많이연구된약제로자발성복막염환자에서 cefotaxime 정주치료는복수내약물농도가매우높아, 69-98% 의높은감염소실효과를보인다. 10 Ceftriaxone 정주치료는 % 의감염소실율을보이며, cefotaxime 정주치료와 31

3 Postgraduate Course 2018 치료효과가비슷하다. Quinolone 계통약제의경우에도 cefotaxime 치료와비슷한감염소실률과생존률을보였으나, 지역사회획득자발성복막염의원인균에서 quinolone 계통약제에대한내성이점차증가하고있어주의가필요하다. 복수배양결과가보고된이후에는항생제감수성결과및증상등에따라항생제교체및치료기간의조정을고려해야한다. 7 병원에입원하고 48-72시간이상경과후에발생한경우병원내감염자발성복막염으로정의하며, 지역사회획득자발성복막염의 1차경험적치료인 3세대 cephalosporin 치료에실패할위험이높으며, 따라서지역사회감염 SBP에비해높은사망률을보인다. 최근국내에서도 ESBL 생성균주의증가와 enterococcus나 MRSA와같은다약제내성그람양성균에의한자발성복막염의증가가문제가되고있다. 7 경험적항생제의선택에서는감염의중증도, 다약제내성균감염의위험인자, 지역별역학을고려하여선택해야한다. 특히, 경험적항생제를 2일간투여하고복수내 PMN이치료전에비해 25% 이상줄지않으면치료실패로판정하고 ESBL 생성균주나 MRSA, enterococcus, pseudomonas 등 cephalosporin으로치료가되지않는균을표적으로하여항생제를교체한다. 중증의감염상태이거나다약제내성균의위험인자를가진환자에서는 carbapenem ± glycopeptide 치료를고려하며, 내성발생을줄이기위해서는 48-72시간후재평가를통해하향조정을하는것이필요하다. 7 알부민은항생제와함께자발성복막염치료의근간을이룬다. 알부민 (1.5 g/kg within 6 h of diagnosis, followed by 1 g/kg on day 3) 과 cefotaxim 병합치료는 cefotaxim 단독치료에비해서비가역적신장애발생을감소시키고입원기간중및 3개월사망률을유의하게낮추는효과가보고되었다. 11 특히, 혈청빌리루빈 4 mg/dl 이상혹은혈청 creatinine(scr) 1.0 mg/dl 이상인경우에는 SBP에동반되어신기능장애발생위험이높고이러한환자에서는알부민치료가더욱고려되어야한다. 12 3) 예방정맥류출혈에의해서도이차적으로자발성복막염이발생할수있으며, 복수유무에관계없이위장관출혈이발생한간경변환자에서는항생제를투여해야한다. 13 양성자펌프억제제 (proton pump inhibitors, PPI) 은위내산도를증가시켜위장관을통해들어온세균에대한방어를억제하고장내세균총의변화를유발할수있다. 메타분석에서 PPI의투여는대조군에비해 SBP의위험을 3배증가시키는것으로나타났다. 14 베타차단제 (nonselective beta blocker) 의투여는 Child-Pugh A와 B에서는자발성복막염의발생을억제한다는보고가많으나, 15 불응성복수를동반한말기간경변에서는생존률을낮출수있어주의가필요하다. 16 자발성복막염이발생한적이없는간경변환자가복수내단백이낮은경우 (< 1 g/dl) 에는장기간의예방적항생제투여가생존률향상과자발성복막염예방에도움이된다. 17 또한자발성복막염에서회복된환자들도재발률은 6개월에 43% 에서 2년내 74% 까지보고되고있으며, 18 지속적인예방적항생제투여의고려가필요하다. Norfloxacin은다양한임상상황에서가장많이연구된약제로자발성복막염의일차및이차예방의첫번째선택약제로추천된다. 17 Rifaximin의예방적치료효과는최근에국내외적으로여러보고가있으나그결과가상이하여추가적인연구가필요하다. 19,20 Acute Kidney Injury and Hepatorenal Syndrome 간신증후군 (hepatorenal syndrome) 으로대표되는급성신손상은간경화및문맥압항진증에의해발생 32 The Liver Week 2018

4 Moon Young Kim 하는신장혈류의감소와그에따른사구체여과율 (glomerular filtration rate, GFR) 의감소에의한신장기능장애이다. 간신증후구의예후는매우불량하여 1형의경우중간생존기간이 1개월, 2형의경우 6.7개월정도로보고되고있다. 21 그유병률도진단기준에따라차이가있으나, 한보고에따르면입원환자의약 19% 에서급성신손상이발생하며이중약 17% 에서간신증후군이발생한다. 22 최근에권고된 IAC 기준에 23 따르면간경변입원환자의반수이상에서급성신손상이발생한다는보고도있다. 24 1) 병태생리진행된간경변증에서는심한전신및내장동맥혈관확장으로인한유효혈류량감소가악화되고이에따른교감신경계와레닌-안지오텐신계등의항진이점차심해지면서신동맥혈류량이감소하고강력한신장혈관의수축으로인하여유효혈류량의보충에도불구하고회복이되지않는간신증후군이발생하게된다. 제 1형간신증후군에서는신장피질동맥의심한혈관수축을동반한다. 25 복수가없거나이뇨제에반응하는복수를가진간경변환자는피질신혈관의혈류가보존되어있지만이뇨제내성복수및간신증후군환자는신장피질동맥의혈류흐름이상당히감소된다. 26 기저에만성신기능저하 (chronic kidney disease) 가없는대상성의간경변환자는신혈류량 (renal blood flow) 이오랜기간동안완만하게감소하면서정상적인 GFR을보일수있다. 이는경도및중등도로감소된신혈류량을여과율 (filtration fraction) 을원심성신장동맥에대한안지오텐신 II의혈관수축작용과구심성신동맥에대한프로스타글란딘의혈관확장효과에의해서증가시켜보상하기때문이다. 39,59 그러나진행된간경변에서는신혈류량이더욱감소하여이와같은보상작용으로는여과율을유지하지못하고 GFR이더욱감소하게된다. 27 이러한상태에서 angiotensin-converting enzyme inhibitors, angiotensin II-receptor blockers, nonsteroidal anti-inflammatory drugs 등의약제의사용등에의해이러한보상작용을약화시키고결국급성신손상을유발하게된다. 이러한상황은감염증에의해서유발이되며, 적절한감염치료후에도감염관련간신증후군환자의약 70% 에서는간신증후군이회복되지못한다는보고가있다. 28 또한간신증후군은전신성염증반응증후군과도연관이있어, 다기관전향적연구에따르면약 59% 의간신증후군환자에서전신성염증반응증후군과관련이있었고, 이중 50% 는감염증을동반하였다. 29 2) 진단 (1) 급성신손상간경변증환자에서는근육양의감소로인해근육에서의 creatine으로부터 creatinine의생산이감소하고, 신세뇨관에서의 creatinine 분비가증가하며, 혈청빌리루빈수치가높은경우에서는혈청 creatinine (serum creatinine, scr) 수치의측정이실제보다낮게되어, scr 값을근거로신기능을평가하는경우실제신기능보다더기능이좋은것처럼보일수있다. 30 따라서간경변증환자에서는 scr을이용하여신기능을평가하는데문제가있을수있으며, 또한수일또는수주동안의 scr의변화를고려하지않고 1.5 mg/dl이라는하나의기준치로평가하면신손상이급성인지만성인지를구분할수없다는점도문제점으로지적되어왔다. 23 최근 International Club of Ascites (ICA) 에서는급성신손상의새로운진단기준을제시하였는데, 간경변환자에서정확히평가가어려운요량의변화는급성신손상의진단기준에포함되지않으며, scr이 48시간이내에 0.3 mg/dl 이상증가하거나 1주일이내에기저치에비해 50% 이상증가하는경우를급성신손 33

5 Postgraduate Course 2018 Table 1. The diagnostic criteria of acute kidney injury in cirrhosis 49 Parameter Baseline SCr Definition of AKI Staging Definition Stable SCr 3 months If not available, a stable SCr closest to the current one If no previous SCr at all, use admission SCr in SCr 26.5μmoL/L (0.3 mg/dl) 48 hours, or 50% from baseline Stage 1 : SCr 26.4 μmol/l (0.3 mg/dl) or SCr x from baseline Stage 2 : SCr> x from baseline Stage 3 : SCr>3.0 x from baseline, or SCr 352 μmol/l (4.0 mg/dl) with an acute of 26.4 μmol/l (0.3 mg/dl), or Initiation of renal replacement therapy Table 2. The treatment response according to 2015 International Club of Ascites guideline 7 급성신손상악화급성신손상호전치료반응정의 scr, serum creatinine 급성신손상단계가증가하거나신대체술이필요한경우급성신손상단계가하강한경우무반응급성신손상단계하강소견없음부분반응급성신손상단계가하강. scr은기저치에비해 0.3 mg/dl 이상상승된상태완전반응급성신손상단계가하강. scr은기저치에비해 < 0.3 mg/dl 이하로회복한경우 상으로정의하였고, scr의상승정도에따라 3단계로분류하였다. 이때 scr의기저치는 3개월이내의측정값이있는경우가장최근의수치를기저치로사용하며, 이전측정값이없는경우에는입원당시의수치를기저치로사용하도록하고있다 (Table 1). 23 (2) 간신증후군간신증후군은기능적신손상으로분류되기는하나사구체 (glomerulus), 혈관및세뇨관 (renal tubule) 에다양한형태의손상이복합적으로존재할수있고, 만성손상이함께관찰되기도한다 년에개정된간신증후군진단기준은 2주이내 scr이두배이상증가하여 2.5 mg/dl 이상으로되는경우를간신증후군의진단기준으로하고있어, 간신증후군에서신기능의회복을기대할수있는 terlipressin 등혈관수축제와알부민치료의시작시기가너무늦어지는문제가있었고이러한경우치료반응도떨어져수정이필요하게되었다. 32 이에따라 2015년 ICA에서새롭게제시한간신증후군의진단기준에서는 scr의기준치를없애고 ICA의급성신손상진단기준에따른급성신손상이있는간경변성복수환자에서 2일간의이뇨제중단및혈장증량 ( 체중 1 kg당 1 g의알부민투약, 최대 100 g) 에도반응하지않는경우를간신증후군의진단기준으로정의하고 scr 절대값에무관하게조기에혈관수축제및알부민치료를시작하도록하고있다 (Table 2, 3, Figure 1). 23 고전적진단기준의간신증후군에서는질환진행의급성여부및 scr에따라 1형과 2형을나누었으나, 2015년 ICA의개정된간신증후군진단에서는진단에필요한 scr 절대값 (1.5 mg/dl) 이없어지고, 급성신손상이반드시선행되어야하는진단지침의변화에따라아형에따라분류하지않고모두간신증후군으로통일하였다. 23 그러나, 실제임상적으로는급성신손상과간신증후군 (1형) 외에도다양한양상의아급성및만성적신기능저하가진행된간경변환자에게흔히동반되며, 이들에대한정의와분류및임상 34 The Liver Week 2018

6 Moon Young Kim Table 3. The diagnostic criteria of hepatorenal syndrome according to 2015 International Club of Ascites guideline 7 1) 복수가동반된간경변증 2) ICA-AKI 진단기준에따른급성신손상의진단 3) 2 일간의이뇨제중단및알부민 (1 g/kg body weight/day, 하루최대 100 g 까지 ) 을사용하여혈장량을늘려도급성신손상의호전이없을때. 4) 전신적인쇼크가없어야함. 5) 동시또는최근에신독성이있는약제 (NSAIDs, aminoglycosides, iodinated 조영제등 ) 사용력이없어야함. 6) 구조적신손상의증거가없음 - 단백뇨하루 500 mg/day 이하 - 혈뇨 50 RBC/high power field 이하 - 신초음파에서정상소견. 적유의성에대한자료는매우부족한상태이다. 3) Treatment of Acute Kidney Injury and Hepatorenal Syndrome (1) 급성신손상의일반적치료간경변증에동반되는급성신손상의치료는신손상의원인, 유발요인의유무, 다른장기의기능저하및동반질환의유무를확인해야하며 (Figure 1), 치료초기에급성신손상을일으킬수있는가역적인유발인자를우선교정하는것이중요하다. 구조적손상을감별하기위해단백뇨와혈뇨에대한확인이필요하고, 신독성약제나방사선조영제등에의한신손상의가능성을확인및중단되어야한다. 또한 NSAIDs, 혈관확장제의투여여부도확인하여중단하는것이필요하고, 이뇨제의경우용량을줄이거나중단해야한다. 급성신손상 1단계에서혈장량이부족한경우 crystalloid 수액, 알부민, 혈액제제등을투여하여적극적으로혈장량을늘려주어야하며, 필요시세균감염에대한치료도병행되어야한다. 이러한일차적치료에반응하여 scr이기저치대비 0.3 mg/dl 증가이내의범위로회복이되면입원기간중에는 2-4일, 퇴원후에는 2-4주의간격으로 6개월간 scr을중점적으로추적검사하는것이필요하다. 33 일차적치료에도불구하고신손상이급성신손상 2, 3단계로악화되는경우, 또는급성신손상 2, 3단계로내원한경우에는이뇨제는중단되어야하며, 이후 2일간연속적으로혈장량증가를위한치료와함께 1 g/kg/day ( 최대 100 g/day) 의알부민을정주하고, 263,307 치료반응이없고간신증후군에합당하다면알부민과함께 terlipressin과같은혈관수축제투여를고려해야한다. 23 (2) 약물치료현재간신증후군의기본치료는혈관수축제와알부민의병합치료이다. 알부민은음전하를띠고있어나트륨을끌어당기고이를통해서수분을끌어당기는교질삼투압 (oncotic pressure) 효과와, 34 전염증성싸이토카인, 세균의부산물 (bacterial products), 활성산소등을흡수, 제거하는기능을가지고있는것으로알려져있다. 35 알부민투여는간경변증의급성비대상성악화에동반된급성신손상환자들에서신혈류를향상시키며이는이차적으로항진된교감신경계를완화시키는효과를갖는다. 36 알부민단독으로는간신증후군의호전을기대하기어렵지만, 37 알부민은앞서언급한항염, 항산화효과와면역반응을조절하고내피세포의안정화효과로인해서혈관수축제의작용을돕는효과를한다. ICA에서는알부민을체중 1 kg 당 1 g ( 최대하루 100 g) 을 2일간투여하여, 간신증후군발생여부를판단하는중요한지표로활용하고있다. 23 혈관수축제는간신증후군치료의중심을이루고있으나, 간신증후군발생이전의급성신손상에서 35

7 Postgraduate Course 2018 Figure 1. The treatment algorithm of acute kidney injury 7 의투약의효용성에대해서는아직자료가부족하다. Vasopressin의유도체인 terlipressin은혈관벽의평활근세포에존재하는 V1 vasopressin 수용체에작용하여혈관수축을유발한다. Terlipressin은간경변증환자에서증가된내장혈관의혈액을내장혈관의수축을통해서다른주요장기로의순환으로이동시킴으로써보상성으로항진된교감신경계를안정시키고신장으로의혈류와관류를호전시킨다. terlipressin 투여 36 The Liver Week 2018

8 Moon Young Kim 는 mg을 4-6시간마다정맥주사하며약물투여 3일이경과해도 scr이 25% 감소하지않으면 4시간간격으로최대 2 mg/ 회까지증량하며, 간신증후군이회복될때까지혹은 15일까지유지요법을시행할수있다. 최근에허혈성부작용을줄이기위해 terlipressin의한번에 (bolus does) 투여와지속주입 (continuous infusion) 을비교한연구에서, 부작용발생은 62.1% 와 35.3% 로지속주입한경우유의하게적었으며, 투여되는 terlipressin의총량도지속주입의경우더적었던반면, 치료반응은 64.9% 와 76.5% 로양군간에차이가없는것으로나타나, 향후본약제투여방법에대한추가연구및고려가필요하다. 38 여러연구들을통해서 terlipressin과알부민의병합요법은약 27%-44% 에서간신증후군의회복을보여간신증후군치료의주요약물치료로인정받고있으나, 39,40 생존율의향상은보여주지못하였으며, 이는 terlipressin과알부민의병합요법에도불구하고간신증후군으로부터회복되지못하는경우가과반이상이기때문으로생각된다. 본약제의부작용은많게는 30% 정도까지보고되고있으며, 복통, 설사와함께비교적드물게나타나지만손발끝의허혈성부작용이나저나트륨혈증, 서맥등의부정맥이나타날수있다. 한편, terlipressin 치료반응의예측은임상적으로중요한데, terlipressin 치료후평균혈압의상승은좋은예후인자이며, 치료전고빌리루빈혈증 (10 mg/dl 초과 ) 이심한경우, scr 5 mg/dl 이상이었던경우에는나쁜예후인자로알려져있다. 41 Terlipressin이간신증후군의치료에있어서가장좋은근거중심의치료제이지만아직미국을포함한세계여러나라에서사용이허가되지않고있으며, 이들지역에서는 norepinephrin을기반으로하는알부민병합치료가시행되고있다. 간신증후군에대한 norepinephrine과 terlipressin의무작위비교연구에서 norepinephrine은 terlipressin과유사한효과와부작용을보여주었다. 42 그러나이들연구들은작은규모의비눈가림연구들이라는제한점이있다. Norepinephrine은시간당 mg로지속주입하며, 중환자실에서평균동맥압 10 mmhg상승을목표로용량을조절한다. (3) 비약물적치료약물치료에도불구하고간경변증환자가요독증상, 체액과다, 불응성고칼륨혈증및대사성산증등을보이게되면신대체요법 (renal, replacement therapy, RRT) 의고려가필요하며, 진행된간경변환자들은유효혈장량의부족과혈역학적불안정, 출혈위험등으로효과적인혈액투석이어려운경우가많아, 지속적신대체요법 (continuous renal replacement therapy) 이많이이용된다. 그러나신대체요법자체가간신증후군회복을시키는것은아니기때문에, 간이식을전제로하지않는신대체요법은생존률향상에도움이되지않는다. 43,44 경경정맥간내문맥전신단락술은과거에는간신증후군에효과가있다는보고들이일부있었으나제한된조건의환자들에대한결과들이었고혈관수축제와알부민병합치료와비교한무작위대조군연구결과가없다. 특히, 간성뇌증의위험증가, 전신동맥의이완을통한전신혈압저하의위험, 신장관류압저하에의한신기능을더욱악화시킬가능성등으로인해실제임상에서의적용에는주의가필요하다. 기타인공간이라불리는간보조장치로는 molecular adsorbent recirculating system (MARS), extracorporeal liver assist device, bio-artificial liver, bio-artificial liver support system, modular extracorporeal liver support 등은간신증후군에서아직까지효과가입증되지못하였다. (4) 간이식간이식은간신증후군의치료에있어유일하게장기생존율을증가시킬수있는치료이며, 이식전신기 37

9 Postgraduate Course 2018 능의저하는이식후의생존율과합병증의발생에영향을줄수있다. 45,46 간이식후신기능은약 50%-75% 에서회복되는것으로알려져있으며, 47,48 간이식전신기능저하의기간은이식후신기능회복을예측함에있어서중요한인자이다. 이식전에 14일이상신대체요법을받은경우에는장기간의허혈에따른신장의구조적변화로인해신기능이회복되지못할가능성이높으며, 최근에는간이식전 4주이상신대체요법치료를받은경우에는간과신장을동시에이식할것을권고하고있다. 43 간이식후간신증후군으로부터회복된환자의예후는좋으며, 6개월에서 1년사이의생존율이 90% 이상인것으로보고되고있으나, 48 이식후에도신기능이회복되지못한경우에는 1년생존율이 60% 까지감소하므로, 48 간신증후군환자가약물치료에반응하지않을때는가능한조기에간이식을해야한다. 결론 간경변증과문맥압항진증의진행에따라대상성에서비대상성간경변증으로이행함에있어서복수의발생은대표적인현상으로이후에여러합병증을수반하게된다. 자발성복막염과급성신손상의발생및간신증후군은그중에서도진행된말기간경변에서주로나타나는현상으로불량한예후를시사한다. 자발성복막염은그진단에있어서오랫동안큰변화는없으며, 치료에있어서도기존 3세대세팔로스포린계항생제가주로이용되나최근다양한내성균주의출현으로일차항생제치료에반응하지않은경우가증가하고있다. 특히균배양검사양성률이상대적으로낮고보고시기가늦기때문에치료시작 2-3일경과후에치료반응을평가하고적절하게항생제를교체투약하는것이중요하다. 급성신손상과간신증후군은최근에치료적접근에있어서큰변화는없고여전히난치성질환으로인식되고있으며, 좀더적극적이고체계적인치료를위해새로이제시된진단가이드라인에대한실제임상현장에서의유용성에대한평가가필요하다. 특히, 만성신질환의성격을동반하는경우가증가함에따라이러한현상에대한좀더정확한진단기준과치료지침에대한지속적연구가필요하다. References 1. Conn HO. Spontaneous Peritonitis and Bacteremia in Laennec's Cirrhosis Caused by Enteric Organisms. A Relatively Common but Rarely Recognized Syndrome. Ann Intern Med 1964;60: Hurwich DB, Lindor KD, Hay JE, Gross JB, Jr., Kaese D, Rakela J. Prevalence of peritonitis and the ascitic fluid protein concentration among chronic liver disease patients. Am J Gastroenterol 1993;88: Khan J, Pikkarainen P, Karvonen AL, Makela T, Peraaho M, Pehkonen E, et al. Ascites: aetiology, mortality and the prevalence of spontaneous bacterial peritonitis. Scand J Gastroenterol 2009;44: Park YH, Lee HC, Song HG, Jung S, Ryu SH, Shin JW, et al. Recent increase in antibiotic-resistant microorganisms in patients with spontaneous bacterial peritonitis adversely affects the clinical outcome in Korea. J Gastroenterol Hepatol 2003;18: Such J, Runyon BA. Spontaneous bacterial peritonitis. Clin Infect Dis 1998;27: ; quiz Fernandez J, Acevedo J, Castro M, Garcia O, de Lope CR, Roca D, et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 2012;55: 대한간학회. 간경변증진료가이드라인 - 복수및관련합병증 Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000;32: The Liver Week 2018

10 Moon Young Kim 9. Kim SU, Kim DY, Lee CK, Park JY, Kim SH, Kim HM, et al. Ascitic fluid infection in patients with hepatitis B virus-related liver cirrhosis: culture-negative neutrocytic ascites versus spontaneous bacterial peritonitis. J Gastroenterol Hepatol 2010;25: Runyon BA, Akriviadis EA, Sattler FR, Cohen J. Ascitic fluid and serum cefotaxime and desacetyl cefotaxime levels in patients treated for bacterial peritonitis. Dig Dis Sci 1991;36: Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341: Sigal SH, Stanca CM, Fernandez J, Arroyo V, Navasa M. Restricted use of albumin for spontaneous bacterial peritonitis. Gut 2007;56: Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver D, Practice Parameters Committee of the American College of G. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46: Deshpande A, Pasupuleti V, Thota P, Pant C, Mapara S, Hassan S, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol 2013;28: Senzolo M, Cholongitas E, Burra P, Leandro G, Thalheimer U, Patch D, et al. beta-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int 2009;29: Mandorfer M, Bota S, Schwabl P, Bucsics T, Pfisterer N, Kruzik M, et al. Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 2014;146: e Fernandez J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133: Tito L, Rimola A, Gines P, Llach J, Arroyo V, Rodes J. Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors. Hepatology 1988;8: Hanouneh MA, Hanouneh IA, Hashash JG, Law R, Esfeh JM, Lopez R, et al. The role of rifaximin in the primary prophylaxis of spontaneous bacterial peritonitis in patients with liver cirrhosis. J Clin Gastroenterol 2012;46: Lutz P, Parcina M, Bekeredjian-Ding I, Nischalke HD, Nattermann J, Sauerbruch T, et al. Impact of rifaximin on the frequency and characteristics of spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites. PLoS One 2014;9:e Alessandria C, Ozdogan O, Guevara M, Restuccia T, Jimenez W, Arroyo V, et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology 2005;41: Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008;48: Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol 2015;62: Huelin P, Piano S, Sola E, Stanco M, Sole C, Moreira R, et al. Validation of a Staging System for Acute Kidney Injury in Patients With Cirrhosis and Association With Acute-on-Chronic Liver Failure. Clin Gastroenterol Hepatol 2017;15: e Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012;367: Rivolta R, Maggi A, Cazzaniga M, Castagnone D, Panzeri A, Solenghi D, et al. Reduction of renal cortical blood flow assessed by Doppler in cirrhotic patients with refractory ascites. Hepatology 1998;28: Mindikoglu AL, Dowling TC, Wong-You-Cheong JJ, Christenson RH, Magder LS, Hutson WR, et al. A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements. Am J Nephrol 2014;39: Barreto R, Fagundes C, Guevara M, Sola E, Pereira G, Rodriguez E, et al. Type-1 hepatorenal syndrome associated with infections in cirrhosis: natural history, outcome of kidney function, and survival. Hepatology 2014;59: Thabut D, Massard J, Gangloff A, Carbonell N, Francoz C, Nguyen-Khac E, et al. Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute func- 39

11 Postgraduate Course 2018 tional renal failure. Hepatology 2007;46: Kim DJ, Kang HS, Choi HS, Cho HJ, Kim ES, Keum B, et al. Serum cystatin C level is a useful marker for the evaluation of renal function in patients with cirrhotic ascites and normal serum creatinine levels. Korean J Hepatol 2011;17: Trawale JM, Paradis V, Rautou PE, Francoz C, Escolano S, Sallee M, et al. The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study. Liver Int 2010;30: Rodriguez E, Elia C, Sola E, Barreto R, Graupera I, Andrealli A, et al. Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis. J Hepatol 2014;60: Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated cirrhosis. Gut 2013;62: Wong F. Drug insight: the role of albumin in the management of chronic liver disease. Nat Clin Pract Gastroenterol Hepatol 2007;4: Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology 2013;58: Garcia-Martinez R, Noiret L, Sen S, Mookerjee R, Jalan R. Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury. Liver Int 2015;35: Martin-Llahi M, Pepin MN, Guevara M, Diaz F, Torre A, Monescillo A, et al. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008;134: Cavallin M, Piano S, Romano A, Fasolato S, Frigo AC, Benetti G, et al. Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study. Hepatology 2016;63: Sanyal AJ, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L, Appenrodt B, et al. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008;134: Sanyal AJ, Boyer TD, Frederick RT, Wong F, Rossaro L, Araya V, et al. Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies. Aliment Pharmacol Ther Nazar A, Pereira GH, Guevara M, Martin-Llahi M, Pepin MN, Marinelli M, et al. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 2010;51: Singh V, Ghosh S, Singh B, Kumar P, Sharma N, Bhalla A, et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study. J Hepatol 2012;56: Nadim MK, Kellum JA, Davenport A, Wong F, Davis C, Pannu N, et al. Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2012;16:R Zhang Z, Maddukuri G, Jaipaul N, Cai CX. Role of renal replacement therapy in patients with type 1 hepatorenal syndrome receiving combination treatment of vasoconstrictor plus albumin. J Crit Care 2015;30: Gonwa TA, Klintmalm GB, Levy M, Jennings LS, Goldstein RM, Husberg BS. Impact of pretransplant renal function on survival after liver transplantation. Transplantation 1995;59: Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002;35: Marik PE, Wood K, Starzl TE. The course of type 1 hepato-renal syndrome post liver transplantation. Nephrol Dial Transplant 2006;21: Wong F, Leung W, Al Beshir M, Marquez M, Renner EL. Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation. Liver Transpl 2015;21: Wong F. Acute kidney injury in liver cirrhosis: new definition and application. Clin Mol Hepatol 2016;22: The Liver Week 2018

추계 Single Topic Symposium-편집.hwp

추계 Single Topic Symposium-편집.hwp Nosocomial spontaneous bacterial peritonitis: broader-spectrum antibiotics 송도선가톨릭대학교의과대학성빈센트병원소화기내과 Do Seon Song Department of Internal Medicine, St. Vincent s Hospital, College of Medicine, The Catholic