제88차종합학술대회프로그램및초록 급성신손상 1) 급성신손상의병태생리 119 고려의대신장내과조상경 2) 급성신손상의생체표식자들 122 부산의대백승훈 3) 심장수술후급성신손상 128 연세의대곽영란 4) Acute kidney injury after non-cardiac surgery 133 성균관의대이종환
세부전공학회발표 급성신손상의병태생리 고려대학교의과대학내과학교실 조상경 ㄴ급성신손상은다양한원인에의해급격하게신장기능이저하되어발생하며, 지난수십년간병태생리기전에관한활발한연구에도불구하고조기진단이어렵고, 특이치료가없으며치료예후가불량하다. 전체입원환자의 5 7%, 중환자실입원환자의약 50% 정도에서발생하며, 특히패혈증등에동반된급성신부전의경우 50% 이상의높은사망률을보인다. 수술후발생하는급성신손상역시신장허혈, 신독성약제및동반된심혈관계질환등복합적인기전에의해발생하며환자의 morbidity 및 mortality를증가시키는중요한요인이다. 또한허혈성손상은신장이식후급성거부반응의위험을증가시키고, 장기적으로이식신의생존율을감소시키며, 만성신장병의악화요인으로도작용한다. 임상적으로보면급성신손상은허혈, 신독성물질및패혈증등의다양한원인이복합적으로관여하여발생하는경우가많으며본 review에서는고전적인허혈성급성신손상의병태생리기전에대한최신지견에대해알아보고이외에조영제에의한급성신손상및패혈증성급성신손상에대해간단하게살펴보고자한다. 허혈성급성신손상혈관내피세포손상지속적인세포내 ATP 고갈및재관류후발생되는반응성산소족등에의해혈관내피세포가손상되며급성신손상의초기 (initiation period) 에중요한역할을한다. 형태학적으로는내피세포의 actin-cytoskeleton 및 junctional complex의파괴, 세포부종등이관찰되며기능적으로는 endothelin 등의혈관수축물질의분비또는내피세포 NO (eno) 와같은혈관확장물질의분비저하로인한과도한혈관수축 (intense vasoconstriction) 및혈전형성이관여한다. 또한다양한종류의접착분자 (adhesion molecule) 의발현이증가되어염증반응을유발함으로서신손상에기여하는데, 혈관내피손상에의해시작된염증반응은동반된손상세뇨관상피세포로부터분비되는염증성매개물질분비에의하여더악화되어혈소판및적혈구등과응집되어신장수질부의미세순환을저해함으로서조직허혈을지속시킨다. 신장상피세포손상대사작용이가장활발한신장의근위세뇨관및 loop of Henle가주로위치하는신장의외수질부는정상상태에서도산소분압이 10 20 mmhg정도로감소되어있어허혈에가장민감하다. 지속적인세포허혈시세뇨관상피세포는 actincytoskeleton, junctional complex의파괴및세포극성의소실이초래되고, 기저막으로부터탈락된세포등에의해세뇨관폐색이일어나게된다. 또한 ATP 고갈로인하여세포내칼슘이축적되고, ATP degradation에의한 hypoxanthine의축적은반응성산소족의생성을촉진함으로서세뇨관상피세포의사멸을유도하며, 손상받은세뇨관으로부터분비되는각종염증매개물질은혈관내피세포손상으로부터시작된염증반응을악화시킴으로서신손상에기여한다. 이렇듯다양하고복잡한기전에의한세뇨관상피세포의손상, 사멸및괴사는궁극적으로세뇨관폐색, 사구체여과물질의간질로의역류 (backleakage) 및증가된세뇨관사구체되먹이기기전 (tubuloglomerular feedback) 등을통하여지속적으로사구체여과율의감소를초래하며염증반응을증폭시킴으로서신손상을지속시킨다. 염증반응혈관내피세포손상으로인하여순환백혈구와혈관내피세포접착분자상호작용이증가하여시작된염증반응은곧이어손상된세뇨관상피세포로부터유리되는다양한종류의염증성싸이토카인, 케모카인에의하여더욱악화되어조직손상을촉진시킨다. 중성구가가장빨리신조직에침윤되며여러가지단백분해효소등을유리함으로신손상에기여한다. 단핵구및 T 임파구도 TNF-α, interferon-γ 등의염증매개물질을분비함으로서신손상초기에중요한역할을하는것으로보고되어왔으나인간의급성신부전에서의염증반응의역할은아직확실하지않다. 조영제에의한급성신손상최근진단및치료목적의방사선시술을시행하는빈도 119
가점차증가함에따라방사선조영제에의한급성신부전의빈도도증가하고있으며보고에따르면만성신장병이나당뇨병등의위험인자가있는환자에서 12 26% 정도의비율로발생한다. 이는병원에서발생하는급성신손상의원인중세번째로많은원인을차지하는것으로최근까지조영제에의한급성신손상의병태생리기전에관한연구가활발히진행되고있으나적절한수분공급외에예방법이나치료법은현재로서는없는실정이다. 위험인자환자측위험인자로는만성신장병, 당뇨병, 고혈압, 고령, 급성심근경색증및울혈성심부전등이대표적이고이중만성신장병이가장큰위험인자이며신기능저하의정도는조영제에의한급성신손상의발생과비례하는것으로알려져있다. 당뇨병의경우동반되는신기능의저하가없을경우에는급성신부전의위험이정상군에비해높지않은것으로보고되고있다. 이외에 NSAIDs, ACE inhibitor 등의약물복용도조영제에의한급성신손상의위험을증가시킨다는보고가있으나확실치않다. 조영제의종류나사용하는양도급성신손상의발생과연관이있으며삼투압이높은고장성의조영제 (ionic, high osmolar) 가비교적최근개발된저장성 (nonionic, low osmolar), 혹은등장성 (nonionic, isoosmolar) 의조영제에비하여급성신손상의발생이높은것으로보고되고있다. 혈역학적변화방사선조영제를투여하면일시적으로신혈류가증가하나곧강력한신혈관수축에의해신혈류가다시감소되며수시간이상지속된다. 다양한종류의신혈관수축물질 (vasopressin, endothelin, adenosine, agntiogensin II) 의활성도가증가되며 NO, vasodilatory PG 등의신혈관확장물질의생성이감소되는것이중요한병태생리기전으로생각된다. 여기에조영제가가지고있는점성도 (viscosity) 가신혈관수축에더해져적혈구, 혈소판응집등을증가시킴으로서미세순환장애를유발하고신장조직의허혈을악화시킴으로서신손상을초래하는것으로생각된다. 따라서허혈성신손상과같이허혈성손상에가장민감한신장의외수질부의세뇨관이주로손상받게된다. 직접적세뇨관독성배양된세뇨관상피세포를이용한실험결과조영제는혈역학적변화외에직접적인세뇨관독성을유발한다. 세포내에자연적으로존재하는항산화기전을차단함으로서산화성스트레스에의한세뇨관상피세포의세포사멸을유발하는것으로알려져있으며, 이는현재조영제에의한급 성신손상을줄이기위해많이사용되고있는항산화제의일종인 N-acetyl cysteine 사용의이론적근거이기도하다. 삼투압효과조영제에의한혈역학적변화나세뇨관상피세포에대한직접적세포독성은일반적으로조영제가가지는삼투압과관련되어나타나는것으로알려져있다. 예를들면조영제가아닌고삼투압물질인 mannitol 등도혈관수축을유발하여신혈류및사구체여과율을감소시키고, 또한 osmotic diuresis로인한세뇨관사구체되먹이기기전의활성화로사구체여과율을더욱감소시킨다. 배양세포를이용한실험에서도세뇨관상피세포의세포사멸의정도가조영제의삼투압에비례하는것으로보고된바있어삼투압이조영제에의한신손상에중요한병태생리기전으로생각된다. 그러나최근개발된등장성의 isoosmolar contrast (300 mosm/l) 와기존의low osmolar contrast (600 900 mosm/l) 에의한급성신손상의발생빈도가비슷한것으로보고되고있어, 조영제에의한급성신손상의병태생리기전에는위에서언급한혈역동학적이상, 고삼투압및산화성스트레스등이외에복잡한기전이관여하는것으로생각된다. 패혈증에동반된급성신손상패혈증혹은패혈증쇼크로인한급성신손상은중환자실입원환자에서발생하는급성신손상의 50% 이상을차지하며지지적치료법의발달에도불구하고사망률이 50% 이상으로높게보고되고있다. 또한단기간의사망률뿐아니라환자의장기예후에도악영향을미치는것으로보고되고있으나정확한병인기전은잘알려져있지않은실정이다. 패혈증에동반되는급성신손상의병인기전은흔히말초의혈관확장으로인한전신적저혈압및이로인한교감신경계, rennin-angiontensin-aldosterone 계의활성화로인한지속적인신장내혈관수축으로인한허혈성손상이주된기전으로알려져왔으나최근동물연구및임상연구를통하여실제 hyper dynamic shock에서는신혈류가정상혹은증가되어있음이보고되고있다. 또한극히소수이기는하지만패혈증에동반된급성신손상환자의조직소견상 " 급성세뇨관괴사 " 가거의관찰되지않았다는점은패혈증에동반되는급성신손상이기존의허혈성혹은신독성물질에의한급성신손상과는전혀다른기전에의해발생함을보여준다. 최근의연구동향을보면패혈증에동반되는급성신손상은혈역동학적관점에서 ischemia/vasoconstriction이아닌 hyperemia/vasodilatation과연관되며, 또한세포학적관점에서는상피세포의세포사멸및과도한면역억제반응이패혈증으로인한사망률및급성신부전등의 120
조상경 : 급성신손상의병태생리 발생에중요한역할을하는것으로생각된다. 병인기전뿐아니라패혈증에동반되는급성신손상환자의임상양상및예후에도차이가있다. 일반적으로패혈증에동반되는급성신부전환자의경우신부전의중증도가더심할뿐아니라동반된장기부전의수가더많고, 높은기계호흡의존도, 낮은혈압, 혈관수축약제의빈번한사용등과연관되어있으며신대체요법의필요성이높고, 나아가높은사망률을보이는것이특징이다. 이렇듯일반적인허혈성 / 신독성손상에의한급성신손상과뚜렷이구별되는병인및임상양상을보이는패혈증에동반된급성신손상환자의치료는쉽지않으며중환자실에서혈역동학적변수들 (hemodynamic parameters) 에대한세심한관찰및적극적인치료가매우중요하다. 패혈증의원인이되는감염원의통제및철저한혈당조절, 그리고제한적인수액공급 (restrictive fluid therapy) 을통한지나친용적과다를막고, 적절한시기에혈관수축제를사용함으로써장기관류 (organ perfusion) 을유지하며비교적조기신대체요법치료의적응등을통하여패혈증에동반된급성신손상환자의생존율을증가시킬수있는것으로보고되고있다. 향후지속적인연구를통하여좀더정확한병인기전이밝혀진다면이를바탕으로한여러가지예방, 치료법및조기발견지표 (early biomarker) 등의발견을통하여궁극적으로환자들의예후를개선시킬수있을것으로생각된다. 참고문헌 1. Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio.: Up date on Mechanisms Ischemic Acute Kidney Injury. J Am Soc Nephrol 2006; 17: 1503-20. 2. Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet 2005; 365: 417-30. 3. Schrier RW, Wang W, Poole B, Mitra A. Acute renal filure: Definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 2004; 114: 5-14. 4. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005; 16: 3365-70. 5. Warnock DG. Towards a definition and classification of acute kidney injury. J A Soc Nephrol 2005; 15: 3149-50. 6. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 2004; 351: 159-69. 7. Ronco C, Bellomo R, Kellum JA, et al. Pathophysiology of Acute Kidney Injury : Roles of Potential Inhibitors of Inflammation. Contrib Nephrol 2007; 156: 39-46. 8. Molitoris BA, Levin A, Warnock DG, Joannidis M, et al. Improving Outcomes from Acute Kidney Injury. J A Soc Nephrol 2007; 18: 1987-94. 9. Sean M. Bagshaw and Rinaldo Bellomo: Fluid resuscitation and the septic kidney: Current Opinion in Critical Care 2006; 12: 527-30. 10. Ronco C, Bellomo R, Kellum JA, et al. Pre-Renal Azotemia: A Flawed Paradigm in Critically III Septic Ptients? Contrib Nephrol 2007; 156: 1-9. 11. Langenberg C, Wan L, Egi M, May CN, Bellomo R. Renal blood flow in experimental septic acute renal failure. Kidney International 2006; 69: 1996-2002. 12. Liping WU, Neriman Gokden, Philip R. Mayeux: Evidence for the Role of Reactive Nitrogen Species in Polymicrobial Sepsis- InducedRenal Peritubular Capillary Dysfunction and Tubular Injury. J A Soc Nephrol 2007; 18: 1807-15. 13. Gupta A, Rhodes GJ, Berg DT, et al. Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2. Am J Physiol Renal Physiol 2007; 293: F245-54. 14. Merten GJ, Patrick Burgess W, Gray LV, Holleman JH. Prevention of Contrast-Induced Nephropathy with Sodiu, Bicarbonate. JAMA 2004; 291: 2328-34. 15. Marenzi G, Marana I, Lauri Gand Assanelli E. The Prevention of Radiocontrast-Agent-Induced Nephropathy by Hemofiltration. N Engl J Med 2003; 349: 1333-40. 16. Ilan Goldenberg, Shlomi Matetzky. Nephropathy induced by contrast media: pathogenesis, risk factors and preventive strategies. CMAJ 2005; 172: 1461-71. 17. Stevens MA, McCullough PA, MPH, Tobin KJ, et al. A Prospective Randomized Trial of Prevention Measures in Patients at High Risk for Contrast Nephropathy. J Am College of Cardiology 1999; 33: 403-11m. 18. Marenzi G, Assanelli E, Marana I, Lauri G, et al. N-Acetylcysteine and Contrast-Induced Nephropathy in Primary Angioplasty. N Engl J Med 2006; 354: 2773-82. 121
세부전공학회발표 급성신손상의생체표식자들 양산부산대학교의학전문대학원마취통증의학교실 백승훈 급성신손상과생체표식자급성신손상 (acute kidney injury) 이란급격하게신장의기능을소실하는질환으로이전에는급성신부전 (acute renal failure) 으로알려졌었다. 일반병동재원환자의 5% 이내, 중환자실에서 30 50% 의유병율을보인다. 중환자실에서급성신손상환자의사망률은그렇지않은경우에비하여 5배이상증가하는것으로알려져있다. 유병율이나사망률이다양한이유는급성신손상의명확한정의가없기때문이다. Acute Dialysis Quality Initiative Working Group에서제안한성인에서의급성신손상에대한분류는 RIFLE (Risk, Injury, Failure, Loss and End-stage) 으로중증도에따른세가지등급 (risk, injury, failure) 과임상결과에따른두가지분류 (loss, end-stage) 를바탕으로하고있다 (Table 1). 생체표식자 (biomarker) 란정상적인생물학적과정과발병과정또는중재적치료에대한약리적인반응을측정하고평가하는지표로알려져있다. 따라서장기의손상이상당히진행되기전에는증상이나타나지않는질병의경우이러한생체표식자가절실히요구된다. 급성신손상의경우 48 시간이내에갑작스런신장기능의저하를초래하기때문에조금이라도빠르게신장의손상정도를파악할수있는생체표식자가필요하다. 혈청 creatinine의경우이전에존재하고있는상당한신손상에대해반응하고이미신장의여과능력이많이소실된상태에서의증가하기때문에급성신손상의조기진단에적합한생체표식자는아니다. 심장수술환자에서혈청 cretinine은수술후 1일째부터상승하기시작 하지만심장수술후급성신손상이시작된대부분의환자들은수술후 2일또는그이후에도혈청 creatinine이신손상의진단기준만큼상승하지않는다. 급성신손상의효과적인치료와예방을위해서는손상발생후수시간이내에효과적인중재가필요하다고동물실험에서보고되었다. 급성신손상의적절한생체표식자는앞서언급된혈청 creatinine보다빠른시기에진단이가능하고비침습적검사방법이어야한다. 급성신손상에높은민감도와특이도를가지고있어야하며신장조직에대한감별력이있고신장조직별손상에대한감별능력이있어야한다. 덧붙여급성신손상에따른사망률과신대체요법에필요성에대한정보를제공할수있는생체표식자가필요하다 (Table 2). 전통적인생체표식자들과한계혈액요소질소 (Blood Urea Nitrogen) 혈액요소질소는암모니아의대사산물로간에서생성된다. 작고극성을뛰지않고단백질과결합하지않기때문에대부분사구체여과를통하여빠르게제거되었다가신세뇨관에서재흡수되기때문에사구체여과율과직접적으로연관성을가지지않는다. 패혈증, 주요외상, 스테로이드치료, 위장관출혈로인한혈액의흡수시에는혈액요소질소의생성이증가하기때문에사구체여과율의감소비율보다훨씬많이증가하고, 반대로심각한영양실조나심각한간질환의경우에는생성이감소되어신손상의여부와상관없이낮게측정된다. 결과적으로혈액요소질소는시간에따른사 Table 1. Risk, Injury, Failure, Loss, and End-stage Kidney (RIFLE) Classification Class Glomerular filtration rate criteria Urine output criteria Risk Injury Failure Loss End-stage Serum creatinine 1.5 Serum creatinine 2 Serum creatinine 3 or Serum creatinine > 4 md/dl with an acute rise > 0.5 mg/dl Persistent acute renal failure = complete loss of End-stage kidney disease > 3 months < 0.5 ml/kg/hour 6 hours < 0.5 ml/kg/hour 12 hours < 0.3 ml/kg/hour 24 hours, or anuria 12 hours Kidney function > 4 weeks 122
백승훈 : 급성신손상의생체표식자들 Table 2. Characteristics of an Ideal Biomarker for Acute Kidney Injury Biologic Properties Rapid and reliable Increase in response to injury High sensitive for AKI With a wide dynamic range and cutoff value High specific for AKI Etiologic specificity (given multifactorial etiology of AKI) Level should correlate with injury severity Level should provide prognostic information Applicable across a range of different Populations Physicochemical Properties Stable across a wide range of temperature and ph environment Easily measured in urine or serum Rapid, reliable, and inexpensive measurement using standardized assay platforms Levels unaffected by drugs or other endogenous substances McIlroy DR, Wagener G, Lee HT. Biomarkers of acute kidney injury: an evolving domain. Anesthesiology 2010; 112: 998-1004. Table 3. Proposed Phases of Biomarker Development Goals Study design Phase Selected examples of specific aims Discovery phase Translation phase Validation phase Preclinical exploratory Clinical assay and validation Retrospective longitudinal Prosepective screening Disease control Phase 1 Phase 2 Phase 3 Phase 4 Phase 5 Promising directions identified Clinical assay detects established disease Biomarker detects disease early before it becomes clinically obvious Use biomarker to screen population False referral rates are identified Impact of screening on reducing the burden of disease Pepe MS, Etzioni R, Feng Z, Potter JD, Thompson ML, Thornquist M, Winget M, Yasui Y. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 2001; 93: 1054-61. 구체여과율을정확하게측정하지못하며신손상에따른사구체여과율을반영하는데시간이필요하기때문에급성신손상을진단하는경우에도시간이필요하게된다. 혈청 creatinine 혈청 creatinine은근육에서의 creatinine의생성과신장에서의배설의균형을반영한다. Creatinine의생성이꾸준하고세뇨관에서흡수되지않으며신장에서대사되지않기때문에혈청 creatinine은사구체여과율과반비례하며이는안정적인상태에서는사구체여과율의지표로흔히사용되고있다. 일시적인신장손상 ( 예 : 신장위대동맥교차차단 ) 의경우사구체여과율은일시적으로감소하였다가회복되지만혈청 creatinine은사구체여과율이회복된후상승한다. 이러한시간차이가조기에중재가필요한급성신손상에서혈청 creatinine이적합한생체표식자가될수없는중요한이유이다. 뿐만아니라혈청 creatinin은신장과는관련이없는성별, 근육양, 활동양, 약제, 이화작용의정도에따라서차이가있으며혈청 creatinine측정방법에서도오류가발생할 가능성이있다. 기존의소변내생체표식자들 Fe Na (fractional excretion of sodium) 는 creatinine 의청소율 에대한 Na의청소율을나타내며과혈증과저혈증에서세뇨관의반응을평가하는방법으로신장이전에서초래된질소혈증과급성세뇨관괴사를구별하는방법으로사용된다. 하지만 Fe Na 의경우정상적인세뇨관기능을가진환자에서도이뇨체치료를받거나수술후 sodium 이동이있을때에는증가하게된다. 이러한문제들로인하여급성신손상의조기진단에민감도와특이도를가지지않는다. 새로운생체표식자에대한연구급성신손상에대한연구는현대의학연구분야중혁신기술이나타나면서주목받고있는분야이다. 이전의생체표식자들이급성신손상을조기발견하는데한계를가지고있었고, 새롭게소개된유전체학과단백질체학을이용하여 123
손상된신세뇨관세포의유전자또는단백질을상향또는하향조절하여새로운생체표식자를발견하였다. 이와함께새로운분야로대사산물과그들의변화에대하여생리적, 유전적인연구를진행하는대사체학이주목받고있으며이또한질병이나생리적상태에대한생체표식자를제공하고있다. 새로운생체표식자가소개된경우임상에서사용하기이전에까다로운절차를거치게된다 (Table 3). 혈청, 요생체표식자와급성신손상혈청생체표식자는심각한무뇨증이있거나이뇨제치료나수분공급을하는환자에서유용한진단방법이지만기본적으로요생체표식자가세뇨관의손상여부를평가할수있고조기에신장의병변을발견할수있다. 또한요생체표식자는신손상의급성여부에대해연관성을가지며질환의진행임상경과를예측할수있다. 이러한요생체표식자는크게손상되거나기능저하가생긴신세뇨관세포에서분비되는효소 (alkaline phosphatae, γ-glutamyl transpeptidase, alanine aminopeptidase, glutathione transferase-α, transferase-π, N-acetyl-β- D-glucosaminidase) 근위세뇨관에서재흡수장애로소변으로배설되는저분자량 (<40 kda) 의단백질 (α 1-microglobulin, β 2-microglobulin, retinol-binding protein, cystatin-c), 급성신손상발생시신장에서생성되는특수한단백질 (NGAL, KIM-1, IL-6, IL-8, IL-18, F-actin, Na + /H + exchanger isoform 3) 로구분지을수있다. 새로운생체표식자들 Neutrophil gelatinase-associated lipocalin Neutrophil gelatinase-associated lipocalin (NGAL) 은호중구에 gelatinase에의해공유결합하고있는 25 kda의단백질로단백질분해에저항성을가지고있어서임상적인생체표식자로서적합하다. 정상적인경우신장, 폐, 위, 직장에서매우낮은양이검출된다. NGAL은근위신세뇨관, 원위신세뇨관에서만들어지고분비되며사구체에서자유롭게여과되며근위세뇨관에서수용체결합이나식세포작용을통해빠르게배설된다. 허혈성세뇨관손상후근위신세뇨관에서 mrna가극적으로상향조절되어손상후 2 3시간내에 3 4배상승하면 24시간이내에 10,000배이상상승하게된다. NGAL의구체적인작용에대해서는아직명확하지않으며철의이동에관여하고있을것으로추측하고있다. NGAL이동물모델에서허혈성또는신독성신손상에서가장빠르고활발하게유도된다고보고된후급성신손상의새로운생체표식자의가능성에대한많은연구가이루어졌다. 중환자실에서폐혈증, 허혈, 신독성에의해초래된 신부전환자들의단면연구에서정상적인경우와비교하여혈장 NGAL은 10배, 뇨 NGAL은 100배상승하였다. 혈장과뇨의 NGAL은혈청 creatinine과높은연관관계를보인다. 이전의혈청 creatinine에비하여보다빠르게반응하기때문에조기에신손상을진단할수있다. 소아의심장수술에서는체외순환후 2시간, 4시간의수신자조작특성곡선 (receiver operating characteristic curver) 아래의면적 (AUC ROC) 이 0.99, 1.0으로정확한예측이가능하고뇨와혈장의 NGAL이급성신손상의정도, 사망률, 병원입원기간에대한독립적인예측인자로사용된다. 하지만성인심장수술에서는뇨나혈장의 NGAL의특이도는 70 80%, 민감도는 40 90% 로나타났다. 성인에서민감도와특이도가다양하게나타나는이유는아직명확하지않다. 나이자체가 NGAL의생성에영향을주는지명확하지않고심장질환환자에서존재하는다양한질환이영향을주었을수도있을것이다. 최근의연구에서는다발성외상환자에서급성신손상의조기진단에서뇨 NGAL의민감도와특이도가 90% 이상으로보고되었다 (AUC ROC 0.98). NGAL이급성신손상조기진단에적합하다는근거는많지만진단에사용함에있어서보고된민감도와특이도의다양성의문제가있으므로이를임상진단에적용하기전에숙지하여야한다. Cystatin-C 체내에존재하는유핵세포에서혈중으로일정한비율로분비되는시스테인단백분해억제제로분자량이적고 (13Kd) 생리적 ph에서양극을뛴다. 사구체에서완전하게여과되며근위세뇨관에서거의대부분재흡수되고극히적은양이소변으로배출된다. 혈청 cystatin-c는반감기가 2시간정도이고근육양, 나이, 성별에영향을받지않기때문에만성신질환환자에서혈청 creatinine보다정확하게사구체여과율을나타낼수있다. 요 cystatin-c는급성신손상환자에서신대체요법의필요성을하루전에예측할수있다 (AUC ROC 0.75). 소아의심장수술에서급성신손상이발생한경우혈청 cystatin-c와 NGAL을측정한결과 NGAL은수술후 2시간이내에상승하고 cystatin-c는 12시간이후에상승하였다. Cystatin-C 의측정은수분내에자동으로결과를얻을수있는표준화된상업적검사 (standardized immunonephelometric assay) 가가능한장점이있다. 흡연자, 염증, 면역억제치료중인경우사구체여과율과상관없이 cystatin-c 수치에영향을줄수있고, 세뇨관의손상보다는사구체여과율을반영하기때문에급성신손상의조기진단에적합하지않은면이있으며중환자나성인심장수술후급성신손상의진단에서민감도와특이도에대한연구결과가상이하게보고되고있어서아직진단기준으로 124
백승훈 : 급성신손상의생체표식자들 사용하기에는미흡한점이있다. Liver type-fatty Acid Binding Protein Liver type-fatty Acid Binding Protein (L-FABP) 는간과신장을포함한다양한장기에서발현되는 14 kda의단백질이다. L-FABP의주요기능은지방산 (fatty acid) 의세포내흡수및대사에관여하는것이다. 유리지방산은쉽게산화되어산화스트레스를초래하며이는세포손상을야기하게된다. 지방산의대사과정에관여하는 L-FABP는세포내지방산의축적을억제하여유리지방산의산화를예방할수있다. L-FABP는사구체에서여과되며입자가작아근위세뇨관에서대부분흡수되므로요에서증가하는경우근위세뇨관손상을의심할수있다. 근위세뇨관손상을유발할수있는환경에서신장의 L-FABP 발현이증가되고소변내 L-FABP 가증가하게된다. 그러므로이러한요 L-FABP의증가는세뇨관의구조적손상이전에발생하므로급성신손상의조기발견에유용한생체표식자로사용될수있다. 임상시험에서도소아의심장수술후에혈장 L-FABP, 요 L-FABP가증가하는경우급성신손상을예견할수있었고특히요 L-FABP는조영제에의해유도된급성신손상을혈청 creatinine이변화없는시기에증가하여조기진단이가능함을보여주었다. 하지만요 L-FABP의상승은소아의심장수술에서요 NGAL이 (L-FABP: 4시간후, NGAL: 2시간후 ) 보다빠르게상승한다고보고되었기때문에급성신손상의조기진단의생체표식자로서는다양한임상군에서의연구결과가필요할것으로생각된다. Interleukin-18 Interleukin-18 (IL-18) 은전구염증사이토카인으로 caspase-1 에의해분해되어 18-kDa의활동성형태로되며신세뇨관의상피세포에서급성신손상에서생성된다. 동물실험에서허혈성급성신손상에서요 IL-18의증가가관찰되었으며 IL-18을중화하는항혈청이급성신손상을예방함을보여주었다. 소아의심장수술에서는수술후 4 6시간내에요 IL-18이상승하여 12시간에최고에도달하여 48시간유지되지만성인심장수술에서는급성신손상에대한예측능력이좋지않았다. 또한소아중환자에서역시급성신손상의조기예측인자로서는좋지않은결과를보여주었고소아패혈증환자에서보다증가된 IL-18수치를보여주었다. IL-18이급성신손상의조기진단의생체표식자로사용되기위해서는전신염증반응과는독립적인예측인자라는임상결과가필요하다. Kidney Injury Molecule-1 Kidney Injury Molecule-1 (KIM-1) 은정상적인신장에서는 발현되지않고허혈성혹은신독성신손상에서근위세뇨관에서발현되는막관통당단백질 (transmembrane glycoprotein) 이다. 1상임상시험에서급성신손상에서요 KIM-1이증가하였고만성신질환, 신전성질소혈과감별이가능하다고보고되었다. 하지만조영제에의해서유발된급성신손상에서는요 KIM-1이증가하지않았다. 최근의전향적연구에서성인심장수술의경우요 KIM-1, NGAL, N-Acetyl-β- D- Glucosaminidase (NAG) 를측정한결과수술후 KIM-1이 AUC ROC 0.68로급성신손상을예측할수있었고이는낮은수치이지만상대적으로 NGAL, NAG보다는높은결과였다. 세가지생체표식자를함께측정할경우수술후급성신손상의조기진단의민감도를높일수있으며 AUC ROC 0.75 0.78로증가하였다. NGAL의경우초기에가장민감한생체표식자이고 KIM-1은허혈성또는신독성신손상에서 NGAL보다는조금늦지만의미있는특이도를증가시켜준다. N-Acetyl-β- D-Glucosaminidase N-Acetyl-β- D-Glucosaminidase (NAG) 는근위세뇨관의상피세포에존재하는가장활동적인리소조옴효소이다. 130 kda 이상의분자량을가지고있어사구체의기저막을통과하지못하기때문에요를통한배설은일정하다. 세뇨관상피세포손상을가진신손상에서는요 NAG 수치가증가하지만어떠한경우에는세뇨관상피세포의손상없이리소조옴효소의활성도만증가하는경우가있다. 임상적으로는신이식후거부반응을조기에발견하거나만성신질환의과정을추적하는데사용되고있다. Glutathione transferase Glutathione transferase (GST)-α는근위세뇨관, GST-π는윈위세뇨관의상피세포에서형성된다. 소변에서 GST의증가는병변의위치를정확하게파악할수있다. 중환자의연구결과에서높은민감도와특이도를보여주었고신대체요법의필요성에대한예측인자로적합하다. 하지만두개의 isoenzyme을분리해서측정하여야한고효소들이빠르게비활성화되기때문에소변채집과정에서특별한주의가요구된다. 그외의생체표식자급성신손상에대한연구가증가되면서많은생체표식자들이확인되고있다. 앞서언급한소변내생체표식자외에도혈청내의 IL-6, 8, 10, proatrial natriuretic peptide, neutrophil CD11b등에관한연구가보고되고있지만제한된연구결과와명확한역할들이밝혀지지않아서급성신손상의진단에사용하기에는제한을가지고있다. 125
급성신손상의진단이러한급성신손상의생체표식자들을연구하는데있어서가장큰장애물은임상에적용하는것이다. 이러한임상적용에는비용효과와결과를만족해야하는문제점들이있다. 앞서살펴본생체표식자들에서알수있듯이하나의생체표식자가모든환자에서급성신손상을조기진단하는데적합하지는않았다. 게다가각각의생체표식자가급성신손상의병태생리과정에서다른시간에상승하는것을살펴볼수있었다. 따라서우리에게주어진목표는지금껏알려진생체표식자를어떻게조합하여급성신손상의조기진단이가능하고예후를개선시킬수있는방법을찾는것이다. 이제까지알려진생체표식자들의조합은다음과같다 (Fig. 1). ㆍ급성신손상의조기진단및감별진단 혈청 cystatin C의상승, 소변 cystatin C, KIM-1, IL-18 의상승 혈청 cystatin C의상승, 소변 IL-18, NGAL, GST-π의상승ㆍ급성신손상의과정예측 소변 actin, IL-6, IL-8의상승 소변 actin, IL-6, IL-8, γ-glutamyl transpeptidase의상승ㆍ급성신손상의중증도평가 소변 NAG, KIM-1의증가ㆍ급성신손상의사망률예측 소변 NAG, KIM-1, IL-18의증가앞서언급하였듯이급성신손상은높은유병율과사망률 Fig. 1. Potential use of a kidney marker panel as a diagnostic tool in assessing kidney failure. Ho E, Fard A, Maisel A.Evolving use of biomarkers for kidneyinjury in acute care settings. Curr Opin Crit Care. 2010 16: 399-407. 126
백승훈 : 급성신손상의생체표식자들 로인하여빠른진단과중재가필요한질환이다. 이전의많은연구에도불구하고이상적인단일생체표식자는아직발견되지않았다. 아직까지대부분의임상의들은기본적으로혈청 creatinine을기준으로진단을하고있지만이는만족할만한결과를이끌어내지못하고있다. 현재에도많은연구결과들이등장하고있지만이를적용하기에는많은시간이필요할것으로생각된다. 참고문헌 1. Miller RD Miller s Anesthsia, 7th Ed. Churchill Livingstone. 2. McIlroy DR, Wagener G, Lee HT. Biomarkers of acute kidney injury: an evolving domain. Anesthesiology. 2010; 112: 998-1004. 3. Moore E, Bellomo R, Nichol A. Biomarkers of acute kidney injury in anesthesia, intensive care and major surgery: from the bench to clinical research to clinical practice. Minerva Anestesiol. 2010; 76: 425-40. 4. Lisowska-Myjak B. Serum and urinary biomarkers of acute kidney injury. Blood Purif. 2010; 29: 357-65. 5. Al-Ismaili Z, Palijan A, Zappitelli M. Biomarkers of acute kidney injury in children: discovery, evaluation, and clinical application. Pediatr Nephrol. 2011; 26: 29-40. 6. Ho E, Fard A, Maisel A. Evolving use of biomarkers for kidney injury in acute care settings. Curr Opin Crit Care. 2010; 16: 399-407. 127
세부전공학회발표 심장수술후급성신손상 연세대학교의과대학마취통증의학교실 곽영란 심장수술후발생하는급성신손상 (acute kidney injury, AKI) 은 20 30% 의환자에서발생하는드물지않은합병증으로수술후예후및사망률과밀접한관련이있다. 특히수술후혈장내 creatinine 농도가조금만상승해도예후가악화될수있다는보고들이많아지면서 AKI의예방및적정한치료는심장수술을시행받는환자관리에서매우중요한부분이다. AKI의정의및진단 AKI에대한정의는매우다양하나최근혈장 creatinine의작은증가도수술후예후를악화시킬수있다는여러연구결과들을반영하여수술후 48시간이내에혈장 creatinine 농도가 0.3 mg/dl 이상또는기저치의 50% 이상증가했을때를 AKI로진단하는 Acute Kidney Injury Network (AKIN) 또는 RIFLE (Risk Injury Failure Loss ESRD) classification이 가장흔하게사용되고있다 (Fig. 1). 현재까지는혈장 creatinine의변화를이용하여 AKI를진단하는것이가장널리통용되는진단방법이나실제 creatinine 농도변화는신손상을민감하게반영하지못한다. AKI의진단시기와예후는직접적인상관관계를갖기때문에 AKI 발생초기에이를정확하게진단하는것이매우중요하다. 따라서보다민감한신손상표지자에대한연구들이활발하게진행되어왔으며, 최근에많이연구되고사용되는것들로는 neutrophil gelatinase-associated lipocalin, interlukin- 18, kidney injury molecule-1, liver-type fatty acid binding proteins, cystatin C 등이있으나아직까지 creatinine을대체할만한표준신손상표지자는없다. AKI의위험인자심장수술후발생하는 AKI의위험인자는매우잘알려 Fig. 1. RIFLE and AKIN classifications for AKI. Cr: serum creatinine, GFR: glomerular filtration rate, ARF: acute renal failure. 128
곽영란 : 심장수술후급성신손상 져있는데연구및보고자들에따라약간의차이는있으나, 여성, 좌심실기능저하, 심부전, 당뇨, 말초혈관질환, 만성폐기종, 응급수술및수술전혈장 creatinine의상승등이다 Table 1. Cleveland Clinic Foundation Acute Renal Failure Scoring System Risk Factor Female gender Congestive heart failure Left ventricular EF < 35% Preoperative use of IABP COPD Insulin-requiring diabetes Previous cardiac surgery Emergency surgery Valve surgery only (reference to CABG) CABG + valve (reference to CABG) Other cardiac surgeries Preoperative creatinine 1.2 to < 2.1 mg/dl (reference to 1.2) Preoperative creatinine > 2.1 (reference to 1.2) Min score, 0; max score, 17 Points EF: ejection fraction, IABP: intra-aortic balloon pump, COPD: chronic obstructive pulmonary disease, CABG: coronary artery bypass grafting. Clin J Am Soc Nephol 2006; I; 19-32. 1 2 1 2 1 1 1 2 1 2 2 2 5 (Table 1). 이중에서도혈장 creatinine의상승은가장중요한위험인자로투석이필요한 AKI 환자의 10 20% 가수술정혈장 creatinine 농도가 2.0 4.0 mg/dl 이었으며, 수술전 creatinine 농도가 4.0 mg/dl 이상인환자의경우수술후투석을받을확률이 25 28% 가까이된다. 수술과관련하여서는보고자에따라차이는있으나체외순환없는관상동맥우회술이체외순환을이용한수술에비해 AKI의발생빈도가낮다고하며, 대동맥판막수술, 체외순환시간및대동맥겸자시간, 수혈, 체외순환중의혈액희석 (24% 미만 ), 체외순환중의저혈압및수술후혈관수축제의사용정도가 AKI의발생과밀접한관련이있다. AKI의병태생리 AKI의발생원인으로흔히거론되는것이주술기혈역학불안정및이에따른신혈류의감소, 허혈-재관류에의한손상, 체외순환에의한전신염증반응의활성화및활성산소산물 (reactive oxygen species, ROS) 의생성등이다 (Table 2). 다른드문원인으로는 atheroembolism이신혈관내로들어가발생하는손상, 항생제및비스테로이드성소염제및마취제등에의한손상등이있다. 체외순환을이용한심장수술을시행받는환자에서발생한 AKI는무엇보다도허혈- 재관류에의한손상및 ROS와염증관련인자의생성에의한손상과밀접한관련이있다. Table 2. Pathophysiological Factors in Acute Kidney Injury Preoperative Intraoperative Postoperative Chronic kidney disease Renovascular disease Prerenal azotemia Recent diuresis NPO status Impaired LV function ACEI/ ARB Nephrotoxins IV contrast Other medications Endotoxemia Inflammation Decreased renal perfusion Hypotension Lack of pulsatile flow Vasoactive agents Anesthetic effects Embolic events CPB-induced inflammation Nephrotoxins Free hemoglobin Free radicals, oxidative stress Hemodilution Systemic inflammation Reduced LV function Vasoactive agents Hemodynamic instability Nephrotoxins Volume depletion Sepsis/infection LV: left ventricular, ACEI: angiotensin-converting enzyme inhibitor, ARB: angiotensin receptor blocker, IV: intravenous, CPB: cardiopulmonary bypass, NPO: nothing by mouth. Table 3. Protective Strategies for Acute Kidney Injury Minimizing exposure to radiocontrast dyes/nephrotoxic agents Allowing adequate recovery from AKI before surgery Optimizing cardiovascular function and oxygen delivery Goal-directed therapy/perioperative hemodynamic optimization Urinary alkalinization Considering less extensive surgery Avoiding CPB Minimally invasive cardiothoracic surgery Endovascular aortic aneurysm repair Appropriate glucose homeostasis Early continuous renal replacement therapy (CRRT) Statins Fenoldapam N-acetylcysteine Supportine evidence Most Least 129
AKI의예방과치료 (Table 3) 환경요법 (Optimizing Milieu Therpy) AKI의발생을줄이기위해서는무엇보다도수술전또는수술중환자의신기능이정상으로유지되도록힘쓰는것이중요하다. 수술전의신기능이정상으로회복되기를기다린후심장수술을시행하는것이수술후 AKI의발생을줄이는데중요하다. 특히수술전조영제를이용한검사를받은환자들은조영제의양에따라차이는있지만조영제를사용한후 5일이내에까지는신기능이감소되어있으므로이시기에심장수술을시행할경우수술후 AKI 발생이증가한다. 수술중수혈, 심한혈액희석과용혈또한 AKI 발생을증가시킨다. 수혈이 AKI와밀접한관련이있기는하나체외순환중혈색소치의급격한감소또한 AKI의발생과밀접한관련이있는데혈색소치가기저값의 50% 미만으로감소하면 AKI의발생빈도는급격하게증가한다. 용혈은수혈및체외순환시간과관련이있다. 비만과당뇨또한 AKI의발생과연관이있으며, 수술전 HbA1C 값이높은환자에서 AKI가생길위험이높다. 수술중혈당을 80 110 mg/dl 사이로유지하는것이수술후신대체요법 (renal replacement therapy) 을필요로하는 AKI 발생을줄이는데도움이된다. 연구에따라서는혈당이 180 mg/dl 이하로만유지되어도 AKI 발생빈도에는영향을미치지않는다는보고도있다. 체외순환중및주술기에수액및수혈관리와심근수축촉진제등을사용한 Goal directed therapy 를통해혈역학을안정적으로유지하는것 (hemodynamic optimization) 이신장으로의산소공급을원활하게함으로써 AKI 발생을감소시킬수있다는보고도있다. 화학요법 AKI의예방및치료에사용되는약제들은주로신혈류를증가시키는약제, 나트륨뇨배설촉진제 (natriuresis), 항염증작용을갖는약제들이다. 신혈류를증가시키는것으로알려진약제들중도파민은 AKI 발생을예방하는데효과가없는것으로증명되었다. 선택적인도파민-1 작용제인 fenoldopam이심장수술중신기능을보호하는데도움이된다는보고들이있고주요수술을시행받는환자들에서 fenoldopam이사망률과 AKI 발생을감소시켰다는보고도있으나심장수술에서 fenoldopam 의효과에대해서는아직까지는이견이있다. 특히 fenoldopam 주입에따른저혈압의발생은이약제에의한신혈관확장효과를상쇄시킬수있으므로주의가요구된다. 나트륨뇨배설촉진을유발하는약제들로는 furosemide, mannitol 및 nesiritide 등이있다. Furosemide는이론적으로는 Henle씨루프의 Na-K-2Cl cotransporter 작용을억제하여산소소모량을감소시키고, debris에의한 tubule의폐쇄를방지하여 AKI의정도를감소시킬수있을것으로생각되었으나, 현재까지의연구결과들을종합해보면 furosemide 사용은 AKI 발생을줄이거나예방하는데도움이되지않는다. Mannitol은 osmotic diuresis를통해 tubule의폐쇄를막고, 자유기 (free radical) 를제거하는등의다양한효과를갖고있어체외순환회로의충진액에주입하여많이사용한다. 신기능보호효과가보고된바도있으나이와는달리 tubule의손상을증가시킨다는보고도있어좀더연구가필요하다. 수술후빈뇨또는무뇨증상이있는환자에서 mannitol-frosemide-dopamine의 cocktail을초기부터지속정주하는것이신기능손상으로부터의회복을촉진한다는보고도있다. Nesiritide는 natriuretic peptide로 medullary collecting tubule 에서의 sodium의흡수를저해할뿐만아니라사구체여과율을증가시켜나트륨뇨배설을촉진한다. 최근 nesiritide가좌심실기능이감소된환자에서신기능을유지하는데도움이되며만성신부전이있는환자들에서도신기능을유지하는데도움이된다는보고들이있으나좀더대규모의연구다필요하다. 항염증반응및항산화작용을갖는약제들중가장활발하게연구되고잇는것이 N-acetylcysteine (NAC) 이다. NAC 은조영제에의한신손상을예방하는효과가보고되면서심장수술을시행받는환자에서도 AKI를예방하는데도움이될것으로생각되어많은연구가진행되었다. 그러나여러대규모연구에서 AKI의발생및신기능손상정도를줄이는데도움이되지않는다는보고들이많으며, 수술전신기능이감소된환자에서수술후신기능감소정도를완화시키는경향만이관찰되었을뿐다른예후에는차이가없었다는보고등이잇따르면서현재심장수술을시행받는환자에서 NAC을 AKI 예방목적으로사용하는것은권장되지않는다. 그외에최근연구가진행되고있는약제들은아래와같다. 수액을공급하면서 sodium bicarbonate를함께주입하여소변을알칼리화시키는것은혈색소가 methemoglobin으로전화되는것을막아서 tubule 내의 cast 형성을억제하고, endocytotic hemoglobin uptake를억제하여 proximal tubular cell necrosis를방지하고, ph-dependent Haber-Weiss radical production의억제를통해산화에의한신손상을줄일뿐만아니라 iron-mediated radical injury를억제하는등의기전을통해신손상을줄일수있다는이론적장점을갖고있고적은비용으로손쉽게시행할수있다는장점이있다. 최근의연구에따르면심장수술중 sodium bicarbonate를지속정주한는것이생리식염수만을이용하여수액치료를하는것에비해 AKI의발생을감소시킨다는보고가있었다. 130
곽영란 : 심장수술후급성신손상 수술전에 HMG-CoA reductase inhibitor인 statin계열의약물을복용하는것이심장수술후 AKI 의위험을감소킬수있는가에대한연구도최근활발하게이루어지고있는것중의하나이다. Statins은 AKI 발생의가장중요한기전인염증반응및산화스트레스를감소시키는작용을한다. 그러나최근의 meta analysis 결과에따르면수술전 statins 의복용이사망률과심방세동및뇌졸증의위험은감소시키나심근경색및 AKI 발생에는별다은영향을미치지않는다고한다. 수술후 statins치료를조기에시작하는것이 statins 복용을중단하는것에비해 AKI의발생을억제하는데도움이된다는보고는있다. Human recombinant erythropoietin (EPO) 은조혈작용외에도세포자멸 (apoptosis) 및염증반응을억제하는효과를갖고있으며, 신세포의수선및회복기 (repair-recovery phase) kidney-homing circulating stem cell을조절하는능력을갖고있어신기능을보호하는데도움이될것을예측할수있으며, 최근 EPO가 AKI에미치는영향에대한연구결과들이자주보고되고있다. 조영제를사용하는시술, 신장이식및심장수술등에서 EPO가신기능을유지하는데도움이된다는예비결과보고들이있으며, 관상동맥우회술을시행받는환자에서 EPO 정주가 AKI 발생빈도를감소시켰다는결과가보고된바있다. 그외에도 diltiazem 및 enalapril 등을이용한연구들도있으나연구에따라결과에차이가있어심장수술에서일상적으로사용하기에는부적절하며좀더연구가필요하다. 지속적인신대체요법의조기사용 (Early continuous renal replacement therapy) 지속적인정맥-정맥혈액투석 (veno-venous hemodialysis) 와같은지속적인신대체요법 (Continuous renal replacement therapy, CRRT) 은간헐적인신대체요법에비해혈역학을보다안정적으로유지할수있다. AKI와주술기 CRRT에대한연구에따르면심장수술후 AKI가발생하였을때 CRRT를조기에시행하는것이예후를좋게하고사망률을줄일수있다고한다. 결론적으로심장수술에서 AKI는매우중요하고도치명적인합병증으로예후및사망률에직접적인영향을미친다. 이의예방과치료에대한지침들은아직까지확실하게정립되어있지는않으나예정된수술은신기능이회복된후에시행하며, 수술전환자의위험정도를정확하게판단하고, AKI의발생위험이높은환자에서는가능한덜침습적인시술을선택하는것이필요하다. 또한수술중및수술후 goal directed therapy를통해혈역학적안정을유지하여야하며, 체외순환시간및대동맥겸자시간을가능한줄이고용혈과조영제에의한손상및심한혈액희석에의한손상 또한줄이도록노력하여야한다. Statins 복용및소변의알칼리화, EPO 등몇가지화학적치료방법들이희망적인결과를보여주고는있으나이들의일상적인사용을위해서는좀더많은연구들이진행되어야하며, 이와함께 AKI 의조기진단을위한신손상표지자의발굴에도노력을기울여야한다. 마지막으로심한 AKI가발생한경우에는 CRRT를조기에시행하는것이신손상으로부터의회복을앞당기는데도움이된다. 참고문헌 1. Harel Z, Chen CT. Predicting and preventing cute kidney injury after cardiac surgery. Curr Opin Nephrol Hypertens 2008; 17: 624-8. 2. Garwood S. Cardiac surgery-associated acute renal injury: new paradigms and innovative therapies. J Cardiothorac Vasc Anesth 2010; 24: 990-1001. 3. Rosner MH, Portilla D, Okusa MD. Cardiac surgery as a cause of acute kidney injury: pathogenesis and potential therapies. J Intensive Care Med 2008; 23: 3-18. 4. Shaw A, Swaminathan M, Stafford-Smith M. Cardiac surgeryassociated acute kidney injury: putting together the pieces of the puzzle. Nephron Physiol 2008; 109: 55-60. 5. Coleman MD, Shaefi S, Sladen RN. Preventing acute kidney injury after cardiac injury. Curr Opin Anesthesiol 2011; 24: 70-6. 6. Haase M, Fielitz Ah, Bagshaw SM, Ronco C, Bellomo R. Cardiopulmonary bypass-associated acute injury: A pigment nephropathy? 7. Park M, Coca SG, Nigwekar SU, Garg AX, Garwood S, Parikh CR. Prevention and treatment of acute kidney injury in patients undergoing cardiac surgery: a systematic review. Am J Nephrol 2010; 31: 408-18. 8. Brienza N, Teresa M, Marucci M, Fiore T. Does perioperative hemodynamic optimization protect renal function in surgical patients? A meta analytic study. Crit Care Med 2009; 37: 2079-90. 9. Nigwekar SU, Kandula P, Hix J, Thakar CV. Off-pump coronary bypass surgery and acute kidney injury: A meta analysis of randomized and observational studies. Am J Kidney Dis 2009; 54: 413-23. 10. Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med 2007; 33: 409-13. 11. Mehta R, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Critical care 2007; 11: R31. 12. Miceli A, Bruno VD, Capoun R, Romeo F, Angelini GD, Caputo M. Occult renal dysfunction: a mortality and morbidity risk factor in caoroanry artery bypass grafting surgery. J Thorac Cardiovasc Surg 2011; 141: 771-6. 13. Hudson C, Hidson J, Swaminathan M, Shaw A, Stafford-Smith M, 131
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세부전공학회발표 Acute kidney injury after non-cardiac surgery 성균관대학교의과대학마취통증의학교실 이종환 Introduction 수술후급성신손상 (acute kidney injury) 은전체병원내에서발생하는급성신손상중 18 47% 를차지하는심각한합병증이다 [1]. 이의발생은위장관출혈, 호흡기계감염, 그리고폐혈증등의수술후심각한합병증의발생과연관되어있고 [2,3], 환자의입원비용을증가시키고 [4], 사망률의증가와도관련이있다 [5,6]. 또한수술후신부전발생자체가다른인자들과는독립적으로환자의예후에악영향을미친다는보고들도있다 [7,8]. 하지만이전의연구들은심장수술후급성신손상에대한내용이대부분이었으며, 수술후급성신손상에대한정의또한각각의연구들에따라서다양하였다. 이에본강의에서는최근에통용되는급성신손상의정의, 비심장수술후급성신손상의빈도와위험인자, 그리고현재까지발표된급성신손상의예방법들에대하여개략적으로살펴보고자한다. Injury Network) classification (Table 1) 이있다 [12,13]. 또한심장수술을받은환자들을대상으로한연구에서는정상범위내에서도 creatinine 절대값의작은증가 (0.3 mg/dl) 가환자의수술후사망률과밀접한관계가있으며 creatinine의상대적인변화보다환자의예후를더잘반영한다는보고도있다 [5]. Definition of acute kidney injury 임상적으로 acute renal involvement의범위는일시적인 oliguria부터 renal replacement therapy (RRT) 가필요한상태까지다양하게나타나며, 이러한다양한증상이똑같은임상적중요성을갖는것은아니다 [9]. 또한 1994년에출판된수술후급성신부전 (acute renal failure) 에대한 review에서는대상이된 28개논문모두에서서로다른 criteria로급성신부전을정의했음을밝힌바있다 [10]. 이에 2004년 American Society of Nephrology Renal Research Group에서는이러한급성신부전의다양한정의와임상적증상을포괄하는개념으로급성신손상을사용할것을권고하였다 [11]. 이보고에의하면급성신손상은 serum creatinine의 minimal한상승부터 anuric renal failure까지이질환의임상증상전범위를포괄하는개념이다 [11]. 현재급성신손상의정의와분류에통용되는기준으로는 RIFLE (risk, injury, failure, loss, and end-stage renal disease) classification (Fig. 1) 과이를수정한 AKIN (Acute Kidney Fig. 1. RIFLE classification [12]. The classification system includes separate criteria for creatinine and urine output (UO). A patient can fulfill the criteria through changes in serum creatinine (SCreat) or changes in UO, or both. The criteria that lead to the worst possible classification should be used. Note that the F component of RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage kidney disease) is present even if the increase inscreat is under threefold as long as the new SCreat is greater than 4.0 mg/dl (350 μmol/l) in the setting of an acute increase of at least 0.5 mg/dl (44 μmol/l). The shape of the figure denotes the fact that more patients (high sensitivity) will be included in the mild category, including some without actually having renal failure (less specificity). In contrast, at the bottom of the figure the criteria are strict and therefore specific, but some patients will be missed. *GFR: Glomerular Filtration Rate, **ARF: Acute Renal Failure. 133
Table 1. AKIN Classification for Acute Kidney Injury [13] Stage Serum creatinine criteria Urine output criteria 1 2 3* Increase in serum creatinine of more than or equal to 0.3 mg/dl ( 26.4 μmol/l) or increase to more than or equal to 150% to 200% (1.5- to 2-fold) from baseline Increase in serum creatinine to more than 200% to 300% (>2- to 3-fold) from baseline Increase in serum creatinine to more than 300% (>3-fold) from baseline (or serum creatinine of more than or equal to 4.0 mg/dl [ 354 μmol/l] with an acute increase of at least 0.5 mg/dl [44 μmol/l] Less than 0.5 ml/kg/h for more than 6 hours Less than 0.5 ml/kg/h for more than 12 hours Less than 0.3 ml/kg/h for 24 hours or anuria for 12 hours The staging system proposed is a highly sensitive interim staging system is based on recent data indicating that a small change in serum creatinine influences outcome. Only one criterion (creatinine or urine output) has to be fulfilled to qualify for a stage. *Given wide variation in indications and timing of initiation of renal replacement therapy (RRT), individual who receive RRT are considered to have met the criteria for stage 3 irrespective of the stage they are in at the time of RRT. 하지만, creatinine의상승은기본적으로급성신손상이후에따라오는변화이다. 또한최근의연구들에서 AKIN classification의경우환자의예후의예측에있어서어떠한향상된결과도보이지못했다는보고가있고 [14], RIFLE criteria 상동일한임상지표를가지고있는 oliguric renal failure 환자가 non-oliguric renal failure 환자에비해훨씬더높은 30 일그리고 long-term 사망률을보인다는결과도보고되고있다 [15]. 따라서최근에는급성신손상의조기진단을위해다양한생체지표 (biomarker) 들이연구되고있다. 이중대표적인것으로는 neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), retinol-binding protein, N-acetyl-β-D-glucosaminidase (NAG), 그리고 kidney injury molecule-1 (KIM-1) 등이있다 [16]. 이러한새로운생체지표들은최근심장수술후급성신손상을예측하는인자로서활발히연구되고있으며 [17-21], 최근에는 urinary biomarker들의조합을통하여심장수술후에급성신손상을 serum creatinine의상승이전에알아낼수있다는것또한보고되고있다 [22]. 하지만비심장수술후급성신손상을예측하는인자로서이러한생체지표의사용에대해서는아직까지충분한연구결과가나오지않았다. 물론간이식을받은환자들에게서 urinary NGAL이수술후급성신손상의믿을만한지표이고 [23] 신장이식후에 IL-8과 NGAL이 delayed graft function을예측할수있는생체지표라는보고들이있지만 [24], 최근 non-cardiac major surgery를받은환자들을대상으로한연구에서는 serum 또는 urine에서의 NGAL이수술후급성신손상과관련이없다는보고도있다 [25]. 따라서아직까지비심장수술후급성신손상의예측인자로서이러한 biomarker 의임상적적용에는더많은연구가필요할것으로보인다. Incidence of acute kidney injury after non-cardiac surgery 전통적으로급성신손상은심장수술에서광범위하게연구되어왔으며그빈도는 1 30% 로보고되고있다 [9]. 본질적으로급성신손상은심혈관수술에만국한되는부작용이아님에도불구하고단지그발생빈도가낮을것이라는예상에서비심장수술에서급성신손상의발생은간과되어온것이사실이다. 하지만최근의연구결과를살펴보면그발생빈도가그다지낮지않음을알수있다. 우선 2007년수술전정상신기능을가진비심장수술을받은 15,102명을대상으로한연구에서수술후급성신손상은 0.8% 의환자에서발생하였고 0.1% 의환자에서는 RRT가필요하였음을보고하였다 [6]. 또한최근 75,952명의일반수술을받은, 신기능장애가없는입원환자들을대상으로한연구에서는약 1% 의환자에서수술후신기능손상이발생하였으며, 이의발생은다른기저동반질환여부에무관하게사망률을 8배증가시켰음또한보고하였다 [26]. 이와같은결과로볼때비심장수술에서수술후급성신손상의발생빈도는절대적으로높다고할수는없으나, 여타다른주술기부작용들 (cardiac adverse events 또는 venous thromboembolism) 의발생빈도와다르지않음을알수있다 [26]. 또한비심장수술을받고중환자실에들어온환자들의경우에는급성신손상의발생빈도가 7.5% 로보고되고있으며, 사망률의독립적인위험인자로밝히고있다 [27]. 한가지흥미로운점은 10,518명을대상으로한연구를살펴보면수술후급성신손상의발생그자체가이후의회복여부와관련없이환자의 outcome에영향을주는것으로보인다는사실이다 [28]. 이연구에서수술후급성신손상이발생한후완전한신기능의회복을보인환자들의경우에도 134
이종환 :Acute kidney injury after non-cardiac surgery Table 2. Preoperative and Intraoperative Risk Factors for Acute Kidney Injury after Cardiac Surgery [29] Preoperative Intraoperative (a) Female sex (b) Severe cardiac disease, for example congestive heart failure, left ventricular ejection fraction less than 35% (c) Previous cardiac surgery (d) Preoperative cardiac angiography (e) Preoperative insertion of intra-aortic balloon pump (f) Severe comorbidity, for example insulin-dependent diabetes, chronic obstructive pulmonary disease (g) Chronic kidney disease, for example elevated serum creatinine or decreased baseline GFR (h) Use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockade or diuretic therapy (i) The complexity of the planned surgical procedure (j) Emergency surgical procedure (k) Perioperative red blood cell transfusion (a) Duration of CPB (b) The number of red blood cell units administered (c) Low mean arterial pressure during CPB (d) Perioperative hemodilution, for example Hct less than 25% (e) Postoperative use of norepinephrine Table 3. General Surgery Acute Kidney Injury Risk Index [28] Risk factor Age 56 yr Male sex Active congestive heart failure Ascites Hypertension Emergency surgery Intraperitoneal surgery Renal insufficiency-mild or moderate* Diabetes mellitus-oral or insulin therapy Five General Surgery Acute Kidney Injury Risk Index classes are based on the number of risk factors the patient possesses: class I (zero, one, or two risk factors), class II (three risk factors), class III (four risk factors), class IV (five risk factors), and class V (six or more risk factors). *Preoperative serum creatinine value > 1.2 mg/dl. 급성신손상이발생하지않은환자들에비해사망률이 20% 증가하는것을보였다 [28]. Risk factors for acute kidney injury after non-cardiac surgery 급성신손상을받기쉬운환자들을선별하고급성신손상이발생되는정확한시점을아는것은수술후급성신손상을예방하는데중요한역할을할것이다. 하지만심장수술후급성신손상의경우많은연구들을통해수술전그리고수술중위험인자들 (Table 2) 이제시되고있는데반해비심 장수술에서위험인자들은많은연구가이루어지지않았던것이사실이다. 하지만최근의연구에서비심장수술후급성신손상의위험지표들이제시되었는데그구체적인내용은 Table 3와같다 [28]. 이연구에의하면 0 2개의위험인자를가진환자들에비해 3개, 4개, 5개, 그리고 6개이상의위험인자를가질경우급성신손상의 hazard ratio는각각 3.1, 8.5, 15.4, 그리고 46.3으로증가한다 [28]. Intervention to prevent acute kidney injury after non-cardiac surgery 수술후급성신부전의예방을위해여러가지방법들이소개되어왔으나가장큰문제는그근거가빈약하다는것이다. 뿐만아니라이전의 53개의연구들을검토한최근의보고에서는신기능보호를위해전통적으로사용되어왔던 dopamine과그유사물질, diuretics, calcium channel blocker, ACE inhibitor, 그리고 hydration fluids 모두주술기신기능을보호한다는어떠한근거도찾을수없다고밝히고있다 [30]. 또한한때 tight한 glucose control (blood glucose 80-110 mg/dl) 이심장수술후신기능장애를줄일수있는것으로보고되었으나 [31], 최근발표된 NICE-SUGAR trial [32] 에서 tight한 glucose control을받은환자들에서통상적인 glucose control을받은환자들에비해높은사망률을보여그효용성에대한의문이제기되었다. 최근의 NICE-SUGAR trial 을포함한다른 meta-analysis결과를토대로한다면아마도외과계중환자실에있는환자들에게는 tight한 glucose control 방법이사망률을낮추는데역할을할수도있을것으 135
로생각된다 [33]. 하지만이방법의비심장수술후급성신손상의예방효과에대해서는언급할수없는것이사실이다. 이제까지소개된많은신기능보호방법중유일하게근거에기반을둔방법은 goal-directed therapy에의한 hemodynamic optimization이다. Goal-directed therapy는적절한감시장치, 수액, 그리고 inotropic drugs들을사용하여적절한심박출량을유지하고이를통해조직에산소공급을증가시켜 organ failure를방지하고자하는개념이다 [34]. 신장의기준으로보았을경우저혈압또는저혈량증이발생하였을경우 renal hypoperfusion에의한신기능손상의위험에처하게되고 [9] 과량의수액공급이이루어질경우역시 third space loss를증가시키고 intra-abdominal hypertension을유발하여 [35-37] 결국신기능의장애를야기할수있다 [35,38-40]. 따라서타당한감시장치를이용하여각환자에따른적정량의수액과약물을사용한심박출량의유지와조직으로산소공급의증가를그목표로하는 goal-directed therapy는수술후신손상을예방할수있는합리적인방법이라할수있을것이다. 또한최근의 meta-analysis에서는 goal-directed therapy가수술후신기능저하의위험성을감소시키는것으로보고하고있다 [41]. 하지만지나친수액과 inotropics의사용으로심박출량을지나치게높게유지하는것또한 myocardial ischemia등의합병증을고려할때피하는것이합당할것으로생각된다. 이외에도최근몇가지약물들이수술후급성신손상의예방에효과가있다는연구들이있다. 우선신장피질과수질의혈류를증가시키고신장의산소요구량을줄이는것으로알려져있는 [42] 선택적 DA-1 agonist인 fenoldopam이 renal replacement therapy의사용을줄이고병원내사망률을감소시킨다는보고가있으며 [43,44], 최근의연구에서는 Statin 의사용이 major 수술후신장합병증을예방할수있을것이라고보고하였다 [45]. 또한 preglomerular artery를확장시키고 rennin-agiotensin axis를억제하는물질인 atrial natriuretic peptide [46] 역시최근의 Cochrane review [47] 에서 major 수술후 low dose를사용하였을경우 prevention study들에서 renal replacement therapy사용의빈도를줄이는것을보고하였으나, 사망률에서는대조군과차이를보이지않았고 high dose의사용은단지부정맥이나저혈압등의부작용발생과연관되어있는것또한보고되었다. 하지만필자의개인적인소견으로는아직까지이러한약물들의비심장수술후급성신손상의예방효과의규명에는더많은연구들이필요할것으로보인다. Conclusion 비심장수술후급성신손상은다양하고심각한수술후 합병증과연관성이있으며, 다른요인들과무관하게환자의예후에악영향을미치는심각한합병증이다. 하지만심장수술후급성신손상과는달리비심장수술후급성신손상의경우상대적으로그위험성이저평가되어온것이사실이며, 그결과너무나많은분야들이아직까지모호한상태이다. 또한이러한비심장수술후급성신손상을예방하는방법으로는 goal-directed therapy에의한 hemodynamic optimization이유일하다고할수있다. 따라서향후위험군의선별및신기능보호법등에관한많은연구들이필요할것으로생각된다. References 1. Carmichael P, Carmichael AR. Acute renal failure in the surgical setting. ANZ J Surg 2003; 73: 144-53. 2. Aronson S, Blumenthal R. Perioperative renal dysfunction and cardiovascular anesthesia: concerns and controversies. J Cardiothorac Vasc Anesth 1998; 12: 567-86. 3. Thakar CV, Yared JP, Worley S, Cotman K, Paganini EP. Renal dysfunction and serious infections after open-heart surgery. Kidney Int 2003; 64: 239-46. 4. Dimick JB, Pronovost PJ, Cowan JA, Lipsett PA. Complications and costs after high-risk surgery: where should we focus quality improvement initiatives? J Am Coll Surg 2003; 196: 671-8. 5. Lassnigg A, Schmid ER, Hiesmayr M, Falk C, Druml W, Bauer P, Schmidlin D. Impact of minimal increases in serum creatinine on outcome in patients after cardiothoracic surgery: do we have to revise current definitions of acute renal failure? Crit Care Med 2008; 36: 1129-37. 6. Kheterpal S, Tremper KK, Englesbe MJ, O Reilly M, Shanks AM, Fetterman DM, Rosenberg AL, Swartz RD. Predictors of postoperative acute renal failure after non cardiac surgery in patients with previously normal renal function. Anesthesiology 2007; 107: 892-902. 7. Druml W. Long-term prognosis of patients with acute renal failure: is intensive care worth it? Intensive Care Med 2005; 31: 1145-7. 8. Bagshaw SM. The long-term outcome after acute renal failure. Curr Opin Crit Care 2006; 12: 561-6. 9. Brienza N, Giglio MT, Marucci M. Previnting acute kidney injury after noncardiac surgery. Curr Opin Crit Care 2010; 16: 353-8. 10. Novis BK, Roizen MF, Aronson S, Thisted RA. Associtation of preoperative risk factors with postoperative acute renal failure. Anesth Analg 1994; 78: 143-9. 11. American Society of Nephrology. American Society of Nephrology Renal Research Report. J Am Soc Nephrol 2005; 16: 1886-1903. 12. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative workgroup. Acute renal failuredefinition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204-12. 136
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