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1 대한내과학회지 : 제 90 권제 5 호 특집 (Special Review) - Kidney: Connection to other organ injuries 신장과폐의양방향소통 순천향대학교천안병원신장내과 길효욱 Bidirectional Crosstalk between Kidney and Lung Hyo-Wook Gil Division of Nephrology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea Data reported recently suggest that acute kidney injury (AKI) is a systemic disease that adversely affects the function of other organs including the heart, lung, liver, brain and immune system which is related to the high mortality rate of affected patients. Kidney and lung function are closely related in both health and disease. Data support deleterious bidirectional crosstalk between the lung and kidney. AKI is a common complication in patients with acute respiratory distress syndrome, and has been reported to exert adverse effects on the lungs. Mortality rates for AKI combined with acute lung injury (ALI) can be up to 80% in critically ill patients. Although AKI-associated ALI presents clinically as increased pulmonary edema, the mechanism of AKI-associated ALI extends beyond simple volume overload. Data from animal studies suggest that AKI-induced pulmonary edema is related to both cardiogenic edema (due to elevated hydrostatic pressure) and non-cardiogenic edema (due to pulmonary endothelial and epithelial cell injury caused by inflammation, oxidative stress, and apoptosis). ALI with mechanical ventilation causes a decline in renal hemodynamic function and apoptosis. Elucidation of the mechanisms of kidney lung crosstalk would facilitate development of effective therapies and reduce the mortality rate of AKI combined with respiratory failure. (Korean J Med 2016;90: ) Keywords: Acute kidney injury; Respiratory distress syndrome, Adult; Acute lung injury 서론신부전은신장자체의기능상실뿐만아니라타장기의기능에영향을미친다. 또한간, 심장, 폐의기능저하에따라이차적으로신부전이오는경우는임상적으로흔하게관찰되어왔다 [1,2]. 최근임상적, 실험실적연구를통해신장과심장, 간, 폐, 뇌, 혈액등이서로밀접하게 crosstalk을하고 있다고제시되고있다. 이중신장과폐는생리적으로도밀접한연관이있는데산염기조절, 혈압과체액항상성유지, renin angiotensin system 등으로연결되어있으나질병상태에서서로에게어떠한영향을미치는지는잘알려져있지않다. 하지만과거 1950년대부터급성신부전발생시흉부 X선사진에서폐의투과도증가가관찰된다고보고하였고, 만성신부전환자에게서도심장의비대없이도폐부종이관찰되 Correspondence to Hyo-Wook Gil, M.D. Division of Nephrology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, 31 Soonchunhyang 6gil, Dongnam-gu, Cheonan 31151, Korea Tel: , Fax: , hwgil@schmc.ac.kr Copyright c 2016 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 90, No. 5, 어 uremic lung이라고명명하기도하였으나투석의발전으로이러한용어는더이상사용하지는않았다 [3]. 이후신장과폐와의연관성에대한연구는점차줄었으나최근급성폐부전또는급성신부전에서서로밀접한연관성이있다고제기되고있다. 급성신부전의조기진단을위해많은바이오마커가개발되어왔으나아직까지도급성신부전환자의사망률은과거에비해큰차이를보이지않고있으며특히급성신부전과폐손상이동반시매우높은사망률을보인다. 투석의발달에불구하고사망률이감소하지않은것은신부전이타장기에영향을미치기때문으로생각되며이에대한치료및예방이필요하다는데공감을얻고있다. 본고에서는최근에밝혀지고있는폐와신장의연결고리에대해폐손상이신장에미치는영향과신장손상이폐에미치는영향을임상자료와실험실적근거를살펴보고자한다. 폐손상이신장에미치는영향폐손상은산소및이산화탄소분압변화, 염증성사이토카인분비, 심폐상호작용을통한심박출량의변화로신장에영향을미칠수있다. 신장은산소농도에매우민감한장기이다. 산소농도변화에따른자기조절작용 (autoregulation) 의보상기전으로항상성을유지하지만급성폐손상시이런방어기전이충분치않아신장의혈류량이줄수있다. 부종이관찰되는 25명의안정적인만성폐쇄성폐질환환자를대상으로한연구에서심장기능에이상은없으나증가된이산화탄소분압이신장혈관수축을일으켜혈류량이줄어결국사구체여과율감소와체액저류가온다고보고하였고또한이러한영향을주는데에는저산소보다이산화탄소의분압이중요하다고보고하였다 [4]. 만성폐쇄성폐질환환자의부종의기전중하나로증가된이산화탄소가신장세뇨관의 Na + /H + 역방향수송체자극과신장내교감신경자극으로인해소디움저류가기전으로제시된다. 급성폐손상 (acute lung injury) 이나더심한형태인급성호흡곤란증후군 (acute respiratory distress syndrome) 에서비심인성폐부종이관찰되며, 다장기부전으로진행하기도한다 [5]. 또한이런경우대부분기계환기를하기때문에급성폐손상자체와기계환기에따른영향으로신장기능에이상이올수있다 [6,7]. 폐부전에따른신장기능의이상의원인으로혈역학적변화, 혈중산소및이산화탄소분압의변화, 사이토카인증가와관련있는 biotrauma가그기전으로 제시된다. 특히호기종말양압 (positive endexpiratory pressure, PEEP) 기계환기의경우심박출량의감소와같은혈역학적변화와, 교감신경의항진, renin angiotensin축의증가, 항이뇨호르몬분비및 atrial naturetic peptides 분비등의신경호르몬에관한변화로인해사구체여과율감소와체액의저류가올수있다 [8]. 동물실험에서 PEEP을주었을때의미있게소변양저하, 소변소디움배설감소, 사구체여과율감소가관찰되었다 [9]. 이는위에말한다양한기전이같이작용했기때문일것이다. 임상연구인 Acute Respiratory Distress Syndrome Network (ARDSNet) 연구에서급성폐손상시 low tidal volume으로기계환기를하는경우급성신부전의기간이줄어든다고보고하였다 [10]. 하지만이연구에서는급성신부전을 creatinine 2.0 mg/dl 이상으로정의하였기에해석상주의를요한다. 이후 ARDSNet [10-12] 에포함된 876명의대상으로급성신부전을 creatinine이기저보다 50% 이상상승을하였을때정의했을때, 24% 에서급성신부전이발생하였고, 신부전이있는그룹의사망률은 58% 로없는환자 28% 에비해유의하게높았다 [6]. 급성폐손상시에혈중산소분압감소와이산화탄소분압증가는만성폐쇄성폐질환환자와비슷하게신장에영향을미칠것이다. 기계환기시에염증성 (proinflammatory) 매개물질들이증가해서전신에영향을미치는데, 기계환기환자의기관지폐포세척액과혈중에서높은 TNF-α, IL-1β, IL-6, IL-8이관찰되는것은염증성사이토카인이타장기에도영향을줄수있음을시사한다 [13]. 급성폐손상환자에서기계환기를하는경우더높은신부전발생을보였다 [7]. 동물실험에서도기계환기시신장에세포자멸이관찰되는데이런결과를종합해보면급성폐손상과기계환기에의한염증성물질의증가로인해신장손상이발생할수있음을시사한다. 여러동물실험등에서급성폐손상에의한신부전기전등이밝혀지고있으나아직까지치료에대한연구들은미흡한편이다. 현재까지의임상적연구들을살펴보면기계환기시폐보호기계환기치료가염증반응을줄여주어폐를보호하는효과이외에도급성신부전을의미있게줄였다 [7,13]. 급성신부전과급성폐부전이있는환자에서체액과다시사망률이증가한다는것은잘알려져있지만, 치료적으로저체액을유지시에폐기능의호전과급성신부전등의빈도의증가는없었으나, 결과적으로사망률은줄이지못하였다 [14]. 하지만이연구에서도급성신부전의정의를 creatinine 2.0 mg/dl 이상으로하였기때문에급성신부전의발생에차이

3 - Hyo-Wook Gil. Kidney lung crosstalk - 를보이지않았을수있고, 또한저체액그룹에서오히려더높은 creatinine 수치를보여향후연구에서는좀더타당한급성신부전의정의를사용하고중심정맥압을이용한체액의상태를파악하는것보다더효과적인방법이무엇인지연구가필요한실정이다. 요약하자면, 폐손상시다른장기들, 특히신장과 crosstalk할수있다. 또한기계환기를하는급성폐손상환자에서는가스교환장애, 사이토카인의증가, 심박출량의감소, 교감신경의항진, 항이뇨호르몬분비장애등이관여하여신장손상이올수있다. 신부전이동반된폐손상환자에서사망률이높기때문에향후연구는폐기능의보전뿐만아니라신장기능악화를방지할수있는치료적방법에대한접근이필요하다. 신장손상이폐에미치는영향급성신부전환자는기계환기가필요한호흡부전이발생할확률이두배증가하며, 투석을필요로할정도의심한급성신부전환자역시기계환기가필요로할확률이더욱높아진다 [15,16]. 또한기계환기가필요한급성신부전환자의경우사망률이 81% 으로급성신부전과폐손상이동반되는경우매우높은사망률을보인다. 급성신부전환자가폐이외의다른장기부전을동반한경우보다폐부전이있을때사망률이더증가한다. 신장과폐와의상호관계를알아내고이에대한적절한치료를개발하는것은급성신부전치료에있어중요할수있다. 임상적으로급성신부전에의한호흡기적합병증은심장성또는비심장성폐부종, 폐의체액제거능력감소, 기계환기가필요로한호흡부전으로나눌수있다 [2]. 이에대한기전연구는주로실험실적으로증명되고있으나기전에대한이해는향후치료의방향을설정하는데중요하기때문에좀더자세히알아보겠다. 급성신부전에서심장성폐부종 (cardiogenic pulmonary edema) 일반적으로급성신부전환자에서체액과잉은흔하게관찰되며발생시사망률이높아진다고알려져있다. 한연구에서는체액과잉이있는환자의사망률이 2.07배상승한다고보고하였다 [17]. 급성신부전에의한심장성폐부종의경우심장기능이정상인경우에도발생할수있으며중심정맥압의상승이동반된상태에서흉부방사선상양측폐의침윤이있는경우의심을할수있다. 신기능장애로인해정수압이 상승하여폐간질에부종이발생하게된다. 정수압상승을줄이기위해이뇨제투여및투석을통해체액을제거하면호전될수있다. 급성신부전에서비심장성폐부종 (non-cardiogenic pulmonary edema) 임상적근거폐의내피세포손상시모세혈관안의체액이직접간질로빠져나갈수있어비심장성폐부종이온다. 폐의내피세포와상피세포가동시에손상시에는폐포성부종 (alveolar pulmonary edema) 까지발생하며부종액에단백질이포함되어있다. 이런경우심기능, 중심정맥압, 폐동맥설입압 (pulmonary capillary wedge pressure) 은정상으로관찰된다 [5]. 흉부방사선촬영만으로심장성과감별이되지는않는다. 급성신부전환자를대상으로한소규모임상연구에서정상또는낮은폐동맥설입압에서도폐부종이관찰되었는데이는비심인성폐부종이급성신부전과연관있음을시사하는소견이다 [18,19]. 급성신부전환자의부검에서폐부종과관련된폐의백혈구침착이관찰된다 [20]. 또한급성신부전이없는환자에비해급성신부전이있는환자에서폐부종액에서단백질이많이검출되는데이는급성신부전이비심장성폐부종의발생과관련이있는것을시사한다. 이에대한관련기전으로급성신부전시발생하는염증성물질과산화스트레스등이관련있을것으로추정된다. 급성신부전환자의자료를보아도혈중 IL-6, IL-8, TNF 가증가해있으며 IL-6 농도는사망률과밀접한연관이있다 [21]. 이러한결과들은급성신부전에의한폐손상에있어염증성매개물질들이직접적인내피세포손상을초래해폐부종이발생한다는걸시사한다. 실험실적근거임상연구에비해동물실험에서는더많은근거들이제시되고있다. 양쪽신장의허혈재관류손상후폐에중성구침착이관찰되며, 단백질, 염증성유전자의증가가관찰된다 [22]. 폐의염증은신장의허혈성손상후에 1-2시간후에관찰되며, 4-8시간후에최고를보이고 24-36시간후에정상수준으로떨어진다 [22-24]. 중성구의침착은내피세포를따라침착이일어나기때문에환자에서발생하는폐부종의원인으로설명될수있다. 폐손상에관여하는 TNF, TNFR1, ICAM-1 등여러염증성매개물질이관여할것으로제시되고있다. IL-6 시그널링이염증성반응과관련있고, IL-10 이 IL-6의작용을억제하여폐손상을줄여줄수있어치료로서

4 - 대한내과학회지 : 제 90 권제 5 호통권제 669 호 가능성이제시되었다 [23,25]. 폐부종발생의중요한기전중하나는폐상피세포의체액에대한제거능력이다. 폐의상피세포에서소디움채널, Na-K ATPase, aquaporin-5 와 -1의발현이알려져있고이채널들은체액제거에관여하는데급성신부전동물모델에서이러한채널의기능이떨어지는것이관찰된다 [26,27]. 즉급성신부전에의해폐의내피세포, 상피세포모두가손상이올수있으며이로인해폐부종이발생하는것으로생각되어진다. 급성신부전에서폐의세포자멸 (apoptosis) 과산화스트레스 (oxidative stress) 산화스트레스는급성신부전과연관된폐손상에중요역할을할수있다. 횡문근융해증쥐모델에서급성신부전과폐에염증세포증가및투과도증가가관찰되며폐에서산화스트레스의증가및항산화물질의감소가관찰된다 [28]. 세포자멸은손상된세포를제거하는데매우중요한기전이지만과도하게발생시질병상태가될수있는데급성폐손상에세포자멸반응이관여하는것은잘알려져있다. 급성신부전동물모델에서폐에서세포자멸을증가시키는유전자발현이증가함이관찰되고 caspase 의존성세포자멸도관찰된다 [22]. 급성신부전에의한폐의산화스트레스증가및세포자멸유도가폐손상의하나의기전으로작용할수있을것이다. 급성신부전환자에서폐기능보전을위한치료급성신부전의조기진단에대한연구는많은진전이있었으나아직특별한치료는없다. 위에서언급했듯급성신부전과기계환기를동반한폐손상이있는경우폐를보호하기위한 low tidal volume이신장손상을줄여주나, 그외다른어떠한치료가두장기를보호하는데도움이되는지모른다. 다만기전적으로급성신부전에의한폐손상에염증매개성물질이관여하므로이를제거하는지속적정정맥혈액투석여과법이도움이될것같지만현재까지는일반적인혈액투석보다사망률을줄여주지는못한다고보고되어향후개별염증매개물질제거에따른효과를알아보아야할것이다. 최근소규모연구에서 57명의패혈증성급성신부전환자에서 pulse indicator continuous cardiac output (PICA) 을이용하여 24시간지속적신대체요법 (continuous renal replacement therapy, CRRT) 을하는경우폐부종을나타내는여러지표가 호전되고중환자실입원기간이줄었다고보고하였다 [29]. 이는 PICA 라는특별한모니터링장치를이용하는방법이지만향후급성신부전시 CRRT의용량을정하거나체액량을조절하는데도움을줄수있을것으로생각된다. 체외막산소공급 (extracorporeal membrane oxygenation, ECMO) 은급성호흡성곤란증후군환자에게서사용되어지고있다. 급성호흡부전과급성신부전이동반된환자에게서 CRRT와 ECMO 를동시에시행하는것의효과는아직논란의여지는있으나안전하고효과적으로혈액을정화시킬수있다는보고들이있어희망적이라고생각된다 [30]. 국내에서는여러외인적인요인으로 ECMO 사용이제한적이긴하나향후 CRRT를동반해서사용시폐와신장의보호효과를나타내는지세심한관찰이필요할것이다. 결 급성신부전과급성폐손상이동반시매우높은사망률을보인다. 또한폐기능이떨어지는경우신장의기능에장애가오고반대로급성신부전에의해폐손상이올수있음이여러연구를통해제시되고있다. 폐와신장간의 crosstalk 에대한기전을연구하는것은급성신부전환자의치료를향상시킬수있고사망률을줄이는데도움을줄수있다. 중심단어 : 급성신부전 ; 급성호흡곤란증후군 ; 급성폐손상 론 REFERENCES 1. Shiao CC, Wu PC, Huang TM, et al. Long-term remote organ consequences following acute kidney injury. Crit Care 2015;19: Faubel S, Edelstein CL. Mechanisms and mediators of lung injury after acute kidney injury. Nat Rev Nephrol 2016;12: Bass HE, Singer E. Pulmonary changes in uremia. J Am Med Assoc 1950;144: Hemlin M, Ljungman S, Carlson J, et al. The effects of hypoxia and hypercapnia on renal and heart function, haemodynamics and plasma hormone levels in stable COPD patients. Clin Respir J 2007;1: Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012;122: Liu KD, Matthay MA. Advances in critical care for the nephrologist: acute lung injury/ards. Clin J Am Soc Nephrol

5 - 길효욱. 신장과폐의소통 ;3: Ranieri VM, Giunta F, Suter PM, Slutsky AS. Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome. JAMA 2000;284: Koyner JL, Murray PT. Mechanical ventilation and the kidney. Blood Purif 2010;29: Hall SV, Johnson EE, Hedley-Whyte J. Renal hemodynamics and function with continuous positive-pressure ventilation in dogs. Anesthesiology 1974;41: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342: Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network. JAMA 2000;283: Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med 2002;30: Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999;282: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006;354: Waikar SS, Liu KD, Chertow GM. The incidence and prognostic significance of acute kidney injury. Curr Opin Nephrol Hypertens 2007;16: Metnitz PG, Krenn CG, Steltzer H, et al. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002;30: Bouchard J, Soroko SB, Chertow GM, et al. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney Int 2009;76: Rackow EC, Fein IA, Sprung C, Grodman RS. Uremic pulmonary edema. Am J Med 1978;64: Gibson DG. Haemodynamic factors in the development of acute pulmonary oedema in renal failure. Lancet 1966;2: Hopps HC, Wissler RW. Uremic pneumonitis. Am J Pathol 1955;31: Simmons EM, Himmelfarb J, Sezer MT, et al. Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int 2004;65: Deng J, Hu X, Yuen PS, Star RA. Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/ reperfusion. Am J Respir Crit Care Med 2004;169: Klein CL, Hoke TS, Fang WF, Altmann CJ, Douglas IS, Faubel S. Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy. Kidney Int 2008;74: Gu J, Chen J, Xia P, Tao G, Zhao H, Ma D. Dexmedetomidine attenuates remote lung injury induced by renal ischemia-reperfusion in mice. Acta Anaesthesiol Scand 2011;55: Andrés-Hernando A, Altmann C, Ahuja N, et al. Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice. Am J Physiol Renal Physiol 2011;301:F907-F Ma T, Liu Z. Functions of aquaporin 1 and alpha-epithelial Na+ channel in rat acute lung injury induced by acute ischemic kidney injury. Int Urol Nephrol 2013;45: Rabb H, Wang Z, Nemoto T, Hotchkiss J, Yokota N, Soleimani M. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int 2003;63: Rodrigo R, Trujillo S, Bosco C. Biochemical and ultrastructural lung damage induced by rhabdomyolysis in the rat. Exp Biol Med (Maywood) 2006;231: Liu H, Liu Y, Sun JK, et al. Extravascular lung water monitoring of renal replacement therapy in lung water scavenging for septic acute kidney injury. Int J Clin Exp Med 2015; 8: Allardet-Servent J, Castanier M, Signouret T, Soundaravelou R, Lepidi A, Seghboyan JM. Safety and efficacy of combined extracorporeal CO2 removal and renal replacement therapy in patients with acute respiratory distress syndrome and acute kidney injury: the pulmonary and renal support in acute respiratory distress syndrome study. Crit Care Med 2015;43:

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