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1 대한내과학회지 : 제 82 권제 1 호 특집 (Special Review) - 급성신손상, 그변화의시기에서 급성신손상 : 감별진단및 New Biomarker 고려대학교의과대학내과학교실 조상경 조원용 Acute Kidney Injury: Differential Diagnosis and New Biomarker Sang Kyung Jo and Won Yong Cho Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Incidence of acute kidney injury (AKI) is increasing and despite advances in supportive care, mortality from AKI in critically ill patients still exceeds 50%. Major causes of AKI can be classified into prerenal, renal and postrenal AKI and many of prerenal or ischemic acute tubular necrosis (ATN) are caused by decreased renal blood flow. In addition, exposure to nephrotoxicant or diverse drugs can lead to AKI and diseases that affect larger renal vessels, glomeruli, or renal microvasculature are also other causes of AKI. Because type of renal injury or initiation of proper therapy in setting of AKI is important in determining patient prognosis, differential diagnosis utilizing patients history, physical examination, and laboratory data including urinalysis, urine diagnostic indices, radiologic examination is important. Lack of sensitive biomarkers for early detection of AKI, which resembles troponin in acute myocardial infarction is one critical factor that has hampered the successful translation of various therapeutic strategies that were effective in animal research. However, over the last decade, efforts to identify and validate novel urine or plasma biomarkers in AKI led to identification of several promising biomarkers including neutrophil gelatinase associated lipocalin (NGAL), interleukin-18 (IL-18), cystatin-c and liver type fatty acid binding protein (L-FABP). Although far from replacing serum creatinine in clinical practice yet, data from large clinical studies are promising and here I briefly reviewed the characteristics of them and possible clinical utility in AKI. (Korean J Med 2012;82:5-10) Keywords: Differential diagnosis of AKI; Biomarker of AKI 급성신손상의감별진단급성신손상은허혈성손상, 신독성약제외에도신혈관질환, 급성사구체신염, 결체조직질환에서의신장침범등의다양한원인에의해발생할수있으며원인질환에따른 치료법및예후가다양하고조기에치료를시작하는것이신장의비가역적손상을막고신기능을보존하는데있어매우중요하므로원인질환에대한감별진단이매우중요하다. 급성신손상의감별진단에서가장기본이되는것은환자의병력청취및신체검사소견, 요검사를포함하는검사실검 Correspondence to Sang Kyung Jo, M.D., Ph.D. Department of Internal Medicine, Korea Univesity Anam Hospital, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul , Korea Tel: , Fax: , sang-kyung@korea.ac.kr - 5 -

2 - The Korean Journal of Medicine: Vol. 82, No. 1, 사소견과복부초음파검사등의방사선학적소견이다. 병력및신체검사소견 최근고혈압, 당뇨등만성신장병의원인이될수있는질환의유병률이증가함에따라급성신손상을만성신장병과감별하는것또한매우중요하며, 자세한병력청취를통해급만성신손상및급성신손상의원인질환에대한결정적인도움을얻게되는경우가많이있다. 자세한병력을청취해보면급성신손상은원인이될만한사건 (event), 예를들어구토, 설사, 금식등으로인한탈수로신장혈류가감소될수있을만한병력이있는경우가있으면서전신탈수상태를반영하는신체상변화가있는경우가많다. 또한관절염혹은관절통이있는사람에서연관된결체조직질환 ( 전신성홍반성낭창 ) 이급성신부전의원인인경우가있으며, 혹은관절통을완화시킬목적으로복용한비스테로이드성소염진통제 (nonsteroidal anti-inflammatory drug, NSAID) 가급성간질성신염을일으키거나기존의만성신장병을악화시키는 (acute on chronic) 경우도있다. 그외에도심한간경변증의과거력이나심한복수, 황달이있는환자에서는비가역적인간신증후군이급성신손상의원인일수있으며, 동맥경화증이심한환자에서혈관조영술후급성신손상이발생하였다면조영제에의한급성신손상혹은 cholesterol 색전증에의한급성신손상의가능성모두를생각해볼수있다. 또한급성신손상환자에서철저한신체검사가중요하며, 특히체내의용적상태 (volume status) 를평가할수있는검사, 예를들어경정맥상태, 기립성저혈압의유무, 액와부발한여부등은쉽게시행할수있는신체검사이다 (Table 1). 검사실검사소견 요검사소견외래나응급실에서손쉽게할수있는요검사소견은급 Table 1. Physical examination in differential diagnosis of AKI - Postural hypotension, dehydrated tongue, skin turgor - Dilatation of central vein, S3 gallop, bilateral crackles in lung field - Ascites, peripheral pitting edema, jaundice - Enlarged prostate, palpable mass in pubis - Exudate, hemorrhage, papilledema, Roth s spot - Livedo reticularis - Purpura, petechia 성신손상의감별진단에도움을주는경우가많다. 특히신장질환은요검사를통해쉽게진단에접근할수있어서초기의감별진단에용이하지만, 환자에게수액치료나이뇨제치료등을시행하는경우에는원래질병에서나타났던양상과틀리므로주의한다. 표 2에서여러가지요검사소견을통해서원인질환을감별하는방법을알수있다. 그러나최근에는만성신장병이기존에있는상태에서급성신손상을받는경우가많아해석에혼란을주기도한다. 요화학검사지표 급성신손상이있는환자의요를채취하여시행하는요화학검사는감별진단에아주유용한정보를제공한다. 요중소디움농도, 요비중, 요삼투압등의검사는환자의세뇨관이제대로기능하고있는지를알아보는검사이다. 세뇨관기능이정상적으로작동하는신전성급성신손상의경우에는요의농축과함께세뇨관에서소디움의재흡수가활발히일어나는것이요검사상반영된다. 이와같은검사에서유용한정보를얻기위해서는환자가도착한즉시어떤처치도하지않은상태에서검사를시행해야한다. 특히수액투 Table 2. Urinalysis in AKI Casuse of AKI Urinalysis Prerenal AKI Specific gravity > 1.015, ph: < 6 Protein: trace-1+ Hyaline cast Postrenal AKI Protein : trace-1+ Occult blood + Leukocyturia, hematuria Glomerular diseases Specific gravity > 1.020, ph: < 6 Protein : 1-4+ Hematuria, RBC cast, leukocyturia Vascular diseases Specific gravity > 1.020, ph: < 6 Protein: trace-2+ Hematuria, RBC cast Interstitial diseases Specific gravity 1.010, ph: 6-7 Protein : trace-1+ Leukocyturia, leukocyte cast, eosinophiluria, hematuria, tubular epithelial cast Acute tubular necrosis Muddy brown colored urine Specific gravity : 1.010, ph: 6-7 Protein: trace-1+ Occult blood, hemautira, leukocyturia, gracular cast, tubular epithelial cast - 6 -

3 - Sang Kyung Jo, et al. AKI-Differential diagnosis and new biomarker - Table 3. Urine diagnostic indices in differentiation of prerenal vs. intrinsic renal AKI Prerenal ATN Specific gravity > < Urine osmolality (mosmol/kgh 2O) > 500 < 350 Uosm/Posm > 1.3 < 1.1 Urine sodime (meq/l) < 20 > 40 U/P urea nitrogen > 8 < 3 U/P creatinine > 40 < 20 Renal failure index (RFI) < 1 > 1 Fractional excretion of sodium FENa (%) a < 1 > 1 Fractional excretion of urea FEurea (%) b < 35 > 35 U, uirne; P, plasma; RFI, renal failure index = U Na (U/P Cr). a FE Na (fractional excretion of sodium) (%) = (U/PNa U/PCr) 100. b FE urea might be more effective in case of diuretic use or presence of bicarbonaturia. 여, 이뇨제등이사용되지않은상태이어야하며, glucose, contrast agent, carbenicilline 등항생제가요중에존재하는경우에도결과가틀리게나올수있다는것을알고있어야한다. 또한기존의기저질환, 특히만성신장병이있는경우에는해석이틀려질수있다. 아래표에서열거한지표중 renal failure index 및 FE Na 가가장유용한지표이다. 그러나 bicarbonaturia, 염분소실이있는만성신장병, 부신기능저하가있을경우신전성급성신손상에서도 FE Na 가 1% 이상일경우가많으며반대로신후성급성신부전, 급성사구체신염및혈관염에서는신전성신손상이아님에도불구하고 FE Na 가 1% 미만으로나오는경우도있음을알고있어야한다. 방사선학적검사 신장초음파검사신장의크기를측정함으로서많은경우에양측성으로신장의크기가감소되어있는만성신장병과의감별에도움을받을수있다. 대부분의급성신손상에서는크기가정상이거나혹은약간커져있다. 특히신후성급성신손상에서관찰되는양측신장의수신증은진단에결정적인도움이되며, 최근에실시되고있는 doppler를이용하면신혈류상태도 평가할수있다. DTPA 신스캔 DTPA 를이용한신스캔을통해서신혈류를파악할수있고, 신혈관상태를평가할수있다. 급성신손상에서통상적으로 3주가지난뒤에도이뇨가일어나지않고신기능이회복되지않는경우에신스캔을시행하여예후를결정하기도한다. 급성신손상의초기에시행한신스캔상신장내관류가좋은경우에는대부분예후가양호하여신기능이회복되는경우가많다. 갈륨스캔 (gallium 67 scan) Gallium 스캔검사로급성뇨세관괴사와간질성신염을감별할수있다. 세뇨관괴사의경우에는음성이나급성간질성신염에서는양성으로나타난다. 그외신우신염, crescenetic GN에서도양성으로나타날수있다. 신혈관촬영신동맥또는신정맥촬영이유용한정보를주는경우가있으나조영제로인한손상이올수있어주의를요한다. 신좌상 (renal trauma), 신혈관폐색, 다발성동맥염 (polyarteritis nodosa), 신정맥혈전증등의진단에유용하다. 그외검사역행성신우촬영 (retrograde pyelography) 과경피신루설치술 (percutaneous nephrostomy), 하행성신우촬영술 (antegrade pyelogrophy) 등은요로폐색을진단하는데유용한방법으로조영제로인한신손상을피할수있다. 특히신후성급성신손상의경우경피적신루설치술을시행함으로서급성신손상의진행을막고신장기능의회복을기대할수있다. 급성신손상과새로운 Biomarker 최근급성신손상은주로중환자실에입원하는환자에서패혈증등으로야기된다장기부전 (multiple organ dysfunction syndrome) 의형태로나타나며이들환자의사망률은동물모델을이용한급성신손상의병태생리기전에대한이해, 지속적신대체요법등지지적치료법의기술적발달에도불구하고 50% 이상으로매우높은실정이다 [1,2]. 아직까지임상 - 7 -

- 대한내과학회지 : 제 82 권제 1 호통권제 617 호 2012 - Plasma cystatin C Urinary cystatin C KIM-1, NGAL NAG, L-FABP, α GST, π GST IL-18 Figure 1. Pathophysiology of urinary proteins [3].

4 - 대한내과학회지 : 제 82 권제 1 호통권제 617 호 Plasma cystatin C Urinary cystatin C KIM-1, NGAL NAG, L-FABP, α GST, π GST IL-18 Figure 1. Pathophysiology of urinary proteins [3]. 적으로급성신손상을진단하는데있어혈청요소질소나크레아티닌의상승에의존하고있으나, 크레아티닌은잘알려져있다시피손상의종류 (type), 시기 (onset), 진행 (propagation) 혹은회복 (recovery) 등의급성신손상의핵심적요소를예측하고평가하는데전혀도움을주지못한다. 이렇듯급성신손상에서적절한 biomarker의부재는다양한실험적치료법의임상으로의성공적 translation을방해하고있는가장큰요소가되고있다. 그러나지난십여년간급성신손상에서유용한새로운 biomarker를찾아내고, 나아가이들의임상적유용성을입증하기위한수많은연구가진행되어왔고그중일부는임상에서실제로이용되고있기도한실정이다. 비교적잘알려져있는급성신손상의몇가지새로운 biomarker에대해간단히 review 하고자한다. 멀지않은미래에급성신손상의조기진단및예후예측에크레아티닌을대신하여새로운 biomarker가쓰일수있으리라생각된다. Neutrophil gelatinase associated lipocalin (NGAL) 중성구에서발견되는 25 kda의단백질로서허혈성손상후에신장의근위, 원위세뇨관에서발현이증가되며혈장 및소변에서발견된다 [4]. 소아및성인심장수술후발생하는급성신손상에서크레아티닌보다더일찍상승하여급성신손상을조기에진단하는데유용한것으로잘알려져있으며 [5,6], 또한신장이식수술후이식신지연기능 (delayed graft function) 의조기진단에도유용하다 [7,8]. 조영제사용후발생하는급성신손상의조기진단및간이식수술후발생하는수술후급성신손상의조기발견에도유용함이보고된바있다 [9,10]. 최근연구에의하면급성신손상의조기진단외에도급성신손상의회복및장기예후의예측에도유용할수있을것으로생각된다 [11]. 혈장 NAGL의경우 Alere사의 Triage NGAL Test 는국내일부병원의응급실에서측정가능하다. Interleukin-18 IL-1 superfamily에속한염증성싸이토카인으로신장손상후근위세뇨관외에대식세포, 수지상세포등의염증세포에서발현이증가하며혈장및소변에서검출된다. 다른종류의신손상에비해확립된세뇨관괴사 (established ATN) 환자의소변에서 IL-18치가증가되며, 2005년에발표되었던중환자실에입원한급성호흡부전환자 (acute respiratory distress - 8 -

5 - 조상경외 1 인. 급성신손상 - 감별진단, biomarker - syndrome network trial) 를대상으로한연구에서소변중 IL-18 이이들환자에서급성신손상의조기진단외에사망을예측할수있는독립적인인자로서유용함이알려져있다 [7,8,12]. Liver type fatty acid binding protein (L-FABP) 주로는간세포에서생성되나신장손상후근위세뇨관에서발현이증가되며소변중에발견된다. 현재까지급성신손상에서의임상연구결과는 NGAL이나 IL-18의경우보다는미약하나최근연구결과에따르면소변중의 L-FABP 가증가한것이급성신손상을동반한패혈증환자에서사망을예측할수있는독립적인인자임이밝혀졌고 [13] 또한중환자실에입원하여치료받은환자에서소변중의 NGAL 과함께급성신손상의진단및사망률예측에유용한 biomarker 임이보고된바있다 [14]. 진연구결과에대해간략히살펴보았으나아직급성신손상의진단및예후예측에기존의크레아티닌을대신하여임상적으로널리쓰이고있는 biomarker는없다. 새로개발되어지는 biomarker가임상적유용성을획득하기까지는이러한 biomarker가단지우수한정확도와신뢰도를가지고질환의조기진단및예후예측에유용하다는것으로충분하지않으며궁극적으로이들 biomarker를통해얻는정보가환자의임상적예후를개선시키는데결정적역할을할수있는가가중요할것이다. 예를들면어떤종류의 biomarker가증가되어있는것이신대체요법이필요하게될고위험환자를가려내는데유용한지혹은치료적 intervention에대한반응정도를평가하는데, 혹은환자의장기예후를예측하는데도움을줄수있어야한다는것이다. 다양한특징을가진보다더많은수의환자를대상으로하는지속적인임상연구가필요한실정이다. Cystatin C 모든유핵세포에서생성되는 13 kda의 cystein protease inhibitor로서사구체를통해여과된다. 크레아티닌과는달리세뇨관세포에서의 modification이없으며근육, 성별, 나이등에의해영향을받지않는다는장점이있으나갑상선기능이상이나 glucocorticoid에의해영향을받을수있다는것이단점이다. 심장수술후, 중환자실입원환자및조영제에의한급성신손상의조기진단에있어서모두크레아티닌보다우월한것으로보고된바있다 [15-18]. Kidney injury molecule-1 (KIM-1) Kidney injury molecule-1 (KIM-1) 은 immunoglobulin 과 mucin domain 을가지는 type 1 transmembrane glycoprotein으로정상신장및소변에서검출되지않으나허혈혹은신독성물질에의한급성신손상에서탈분화된근위세뇨관 (dedifferentiated proximal tubule) 에서발현이증가된다 [19]. 혈청 creatinine 보다조기에급성신손상을진단할수있으며또한급성신손상환자에서신대체요법및사망등의예후를예측하는데도유용한것으로보고된바있다 [20]. 결론이상에서몇몇새로운 biomarker의특성및현재까지알려 중심단어 : 급성신손상 ; 감별진단 ; 생물학적지표 REFERENCES 1. Xue JL, Daniels F, Star RA, et al. Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to J Am Soc Nephrol 2006;17: Han WK, Waikar SS, Johnson A, et al. Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 2008;73: Briggs JP. The hunt for the perfect biomarker for acute kidney injury: back to gamma-trace?. Kidney Int 2008;74: Mishra J, Ma Q, Prada A, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003;14: Mishra J, Dent C, Tarabishi R, et al. Neutrophil gelatinaseassociated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365: Devarajan P, Krawczeski CD, Nguyen MT, Kathman T, Wang Z, Parikh CR. Proteomic identification of early biomarkers of acute kidney injury after cardiac surgery in children. Am J Kidney Dis 2010;56: Parikh CR, Jani A, Mishra J, et al. Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant 2006;6: Hall IE, Yarlagadda SG, Coca SG, et al. IL-18 and urinary - 9 -

6 - 대한내과학회지 : 제 82 권제 1 호통권제 617 호 NGAL predict dialysis and graft recovery after kidney transplantation. J Am Soc Nephrol 2010;21: Bagshaw SM, Bennett M, Haase M, et al. Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness. Intensive Care Med 2010;36: Han WK, Wagener G, Zhu Y, Wang S, Lee HT. Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery. Clin J Am Soc Nephrol 2009;4: Yang HN, Boo CS, Kim MG, Jo SK, Cho WY, Kim HK. Urine neutrophil gelatinase-associated lipocalin: an independent predictor of adverse outcomes in acute kidney injury. Am J Nephrol 2010;6: Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 2005;16: Doi K, Noiri E, Maeda-Mamiya R, et al. Urinary L-type fatty acid-binding protein as a new biomarker of sepsis complicated with acute kidney injury. Crit Care Med 2010; 38: Doi K, Negishi K, Ishizu T, et al. Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit. Crit Care Med 2011;39: Herget-Rosenthal S, Marggraf G, Hüsing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004;66: Ahlström A, Tallgren M, Peltonen S, Pettilä V. Evolution and predictive power of serum cystatin C in acute renal failure. Clin Nephrol 2004;62: Ristikankare A, PöyhiäR, Kuitunen A, et al. Serum cystatin C in elderly cardiac surgery patients. Ann Thorac Surg 2010;89: Nejat M, Pickering JW, Walker RJ, et al. Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and predicts mortality in the intensive care unit. Crit Care 2010;14:R Han WK, Bailly V, Abichandani R, Thandani R, Bonventre JV. Kidney Injury Molecule-1 (KIM-1) : a novel biomarker for human proximal tubule injury. Kidney Int 2002;62: Liangos O, Perianayagam MC, Vaida VS, et al. Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol 2007;18:

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract