급성 신손상: 감별진단 및 New Biomarker

조상경 ( Sang Kyung Jo ),조원용 ( Won Yong Cho ) 대한내과학회 2012 대한내과학회지 Vol.82 No.1

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)

급성 허혈성 신손상 백서에서 α-melanocyte stimulating hormone이 intercellular adhesion molecule-1의 발현 및 신기능에 미치는 영향에 관한 연구

조상경(Sang Kyung Jo),윤종우(Jong Woo Yoon),차대룡(Dae Ryong Cha),조원용(Won Yong Cho),김형규(Hyoung Kyu Kim),원남희(Nam Hee Won),윤수영(Soo Young Yoon),장경현(Kyung Hyun Chang) 대한내과학회 2000 대한내과학회지 Vol.59 No.6

N/A Background : Acute renal failure is a reversible process in majority of cases but mechanisms of renal injury or recovery are poorly understood. Recently neutrophil infiltration is reported to potentiate inflammatory and cytotoxic cascade in ischemic renal injury and α-melanocyte stimulating hormone has been reported to have a potent anti-inflammatory properties in a variety of animal models. We examined the beneficial effects of α-MSH in acute ischemic renal injury in rats and tried to clarify its action mechanism. Methods : After unilateral nephrectomy, renal artery of contralateral kidney was clamped for 40 minutes and reperfused in female Sprague-Dawley rats. α-MSH (50μg) and vehicle was injected intraperitoneally immediately after and 6, 24 hours after reperfusion. Biochemical, histological data, ICAM-1 mRNA, protein expressions and polymorphonuclear cell infiltration were examined. Results : α-MSH significantly attenuated the renal injury, measured by plasma BUN and creatinine level and also the degree of severity of histological injury (BUN 125.2±14.6 mg/dL : 46±19.6 mg/dL (p=0.004), creatinine 3.65±0.81 mg/dL : 1.47±0.5 mg/dL (p=0.005) at 24 hours after reperfusion, BUN 88±12.5 mg/dL : 25.5±15.8mg/dl (p=0.002), creatinine 2.76±0.5 mg/dL : 0.93±0.2 mg/dL (p=0.002) at 72 hours after reperfusion and 5.4±1.94/ 2.6±0.77 (p=0.006) at 24 hours after reperfusion in histilogical grading system). In the α-MSH treated groups, ICAM-1 mRNA expression decreased significantly compared to the vehicle treated ischemic group in 72 hours after reperfusion (0.49±0.01/0.31±0.2, p<0.008). ICAM-1 protein expression also decreased in α-MSH treated group, but it was not statistically significant. Polymorphonuclear cell infiltration showed a significant decrease in the α-MSH treated group at 24 hours after reperfusion (5.05±1.8/1.59±0.4, p=0.009). Conclusion : α-MSH attenuates ischemic renal injury by inhibiting the expression of ICAM-1 and subsequent polymorphonuclear cell infiltration. These results provide a rationale of α-MSH as a potential therapeutic drug in acute renal failure.(Korean J Med 59:641-650, 2000)

심신증후군

조상경 ( Sang Kyung Jo ) 대한내과학회 2016 대한내과학회지 Vol.90 No.5

Although combined cardiac and renal dysfunction is common in hospitalized patients and portends a poor prognosis, lack of understanding of the pathogenesis and classification of the condition has hampered the development of therapeutic strategies. Interactions between the heart and kidney involve multiple hemodynamic and nonhemodynamic factors and are usually bidirectional, as acute or chronic dysfunction of the cardiac or renal systems can negatively affect one another. This review introduces a new definition and classification system of cardiorenal syndrome advocated by a consensus conference of the Acute Dialysis Quality Initiative and summarizes the current understanding of cardiorenal syndrome. (Korean J Med 2016;90:378-383)

지속성 복막투석 환자에서 발생한 투석액의 흉강 누출에 의한 흉수 - 화학적 흉막 유착술로 치료한 4예

성수아 ( Su Ah Sung ),고강지 ( Gang Jee Ko ),김명규 ( Myung Kyu Kim ),김정엽 ( Jeong Yup Kim ),조상경 ( Sang Kyung Jo ),조원용 ( Won Young Cho ),김형규 ( Hyoung Kyu Kim ) 대한신장학회 2005 Kidney Research and Clinical Practice Vol.24 No.1

배양된 인 근위세뇨관 상피세포에서 고농도의 단백질이 TGF-β와 Fas 유전자 발현에 미치는 영향

서지아 ( Ji A Seo ),조상경 ( Sang Kyung Jo ),한금현 ( Kum Hyun Han ),성수아 ( Su Ah Sung ),이지은 ( Ji Eun Lee ),이소영 ( So Young Lee ),김상욱 ( Sang Wook Kim ),차대룡 ( Dae Ryong Cha ),조원용 ( Won Yong Cho ),김형규 ( Hyun Kyu K 대한신장학회 2002 Kidney Research and Clinical Practice Vol.21 No.6

배 경 : 사구체신염은 다량의 단백뇨와 세뇨관간질의 규조적인 변화를 특징으로 하며 이는 말기신부전으로의 진행을 예측하는데 있어서 사구체의 변화보다 중요한 인자로 알려져 있다. 이러한 세뇨고나간질의 구조변형은 세뇨관 내에 포함된 다량의 단백이 세뇨관 상피세포에 흡수되어 대사되는 과정에서 상피세포로부터 Transforming Growth Factor-β 등의 fibrosing cytokine과 Monocyte Chemeatactant Peptide-1 등의 염증성 chemokine의 발현이 증가하고 그에 따른 각종 염증성 변화가 일어나는 것에 기인하는 것으로 알려져 있다. 이러한 염증성 변화이의에도 다량의 단백뇨에 의한 세뇨관 간질세포의 소설이 일어나는 기전으로 아포프토시스가 관여하리라는 가정 하에 고농도의 단백 및 당뇨병성 신증으로 인한 신증후군 환자의 단백뇨에 노출된 근위세뇨관 상피세포에서 아포프토시스와 연관된 Fas 유전자의 발현과 TGF-β의 발현을 관찰하였다. 방 법 : 인 근위세뇨관 상피세포를 배양한 뒤 bovine serum albumin (1, 10 ㎎/mL)과 당뇨병성 신증으로 인한 신증후군 환자의 단백뇨 (1, 10 ㎎/mL)에 노출시켰고 대조군은 약물처리를 하지 않고 배양하였다. 24시간 토출시킨 뒤 RNA를 추출하여 RT-PCR 방법으로 Fas 유전자와 TGF-β 발현을 정량하였다. 결 과 : 약물처리를 하지 않은 대조군의 TGF-β 발현은 human ribosamal protein L-19에 대한 상대값이 0.45±0.02였고 BSA 10 ㎎/mL 군에서는 0.78±0.12 (p=0.016), 단뇨병성 신증으로 인한 신중후군 환자의 단백뇨 10 ㎎/mL에 노출된 군서는 0.7±0.08 (p=0.012)로 증가하여 두 군 모두에서 통계적으로 유의한 증가를 보였다. 대조군의 Fas 유전자 발현은 human ribosomal protein L-19에 대한 상대값이 0.7±0.09였고 이에 비해 BSA 10㎎/mL 군에서는 0.97±0.09로 유의하게 (p=0.021) 증가하였으며 당뇨병성 신증으로 인한 신증후군 환자의 단백뇨 10 ㎎/mL에 노출된 군에서는 0.94±0.14(p=0.067)로 증가하였으나 통계적인 유의성은 없었다. 또한 10 ㎎/mL의 BSA좌 TGF-β에 대한 항체에 함께 노출된 군에서의 Fas 유전자 발현은 0.78±0.19로 TCF-β에 대한 항체에 노출되지 않은 군에서 보여졌던 Fas 유전자 발현의 증가가 관찰되지 않았다. 결 론 : 정상적으로는 노출되지 않는 고농도의 단백에 노출시 세뇨관 상피세포는 TGF-β 및 Fas 유전자의 발현증가로 매게되는 아포프토시스를 통한 세포사멸의 과정을 통해 세뇨관간질의 위측에 관여하는 것으로 생각된다. Background : Glomerular diseases of diverse origins are characterized by heavy proteinuria and tubulointerstitial changes in pathology. Numerous studies have recently demonstrated that interstitial fibros and tubular atrophy are better predictors of renal disease progression compared with glomerular pathology. One of the important mechanisms of these tubuloimerstitial injury is tubulointerstitial damage due to increased protein trafficking across the proximal tubular epithelial cells. We tested the hypothesis that tubular cells exposed to high concentration of protein express TGF-β, which can be related to tubulointerstitial fibrosis, and Fas antigen, which can be associated with tubular cell apoptosis. Methods : Cultured human proximal tubular cells were incubated with varying concentrations of BSA (1, 10 ㎎/mL) and nephrotic range proteinuria, due to diabetic nephropathy (1, 10 ㎎/mL), with or without inactivation of complement. After 24 hr-incubation period, the expressions of TGF-β and Fas mRNA were examined by RT-PCR. Results : The amount of expression of TGF-β was increased in BSA 10 ㎎/mL group (0.78±0.12, p=0.016) and in diabetic proteinuria 10 ㎎/mL group (0.78±0.08, p=0.012) compared to control group which was incubated in medium alone (0,48±0.02), and the amount of expression of Fas was increased in BSA 10 ㎎/mL group (0.97±0.09, p=0.021) and showed increased tendency in diabetic proteinuria 10 ㎎/mL group (0.94±0,14, p=0.067) also. Furthermore, the anti TGF-β antibody ameliorated the increased albumin-induced expression of Fas. Conclusion : Collectively, our results showed that protein overload increased the expression of TGF-β & Fas, which can play an important role in tubulointerstitial atrophy by inducing apoptosis of renal tubular cells.

임상 연구 : 사구체 여과율의 지표로서 혈청 Cystatin C의 유용성

성수아 ( Su Ah Sung ),김정엽 ( Jeong Yup Kim ),조상경 ( Sang Kyung Jo ),조원용 ( Won Yong Cho ),김형규 ( Hyoung Kyu Kim ) 대한신장학회 2006 Kidney Research and Clinical Practice Vol.25 No.4

한국의 당뇨병성 신증 및 대혈관 합병증의 발생에서 Angiotensin Converting Enzyme Gene 과 Plasminogen Activator Inhibitor-1 Gene Polymorphism 에 관한 연구

윤종우(Jong Woo Yoon),조상경(Sang Kyung Jo),한상엽(Sang Yup Han),차대룡(Dae Ryong Cha),조원용(Won Yong Cho),김형규(Hyung Kyu Kim) 대한신장학회 2001 Kidney Research and Clinical Practice Vol.20 No.4

Background: Although development of DM nephropathy in NIDDM patients is associated with poorly controlled blood sugar level and hypertension, relationship of genetic factor is also emphasized. Recent studies showed that an insertion or deletion (I/D) polymorphism in the ACE gene and a 4/5- guanine tract polymorphism in the promotor region of the PAI-1 gene are associated with the myocardial infarction. The aim of this study were to determine the relationships of these polymorphism and substance activities to DM nephropathy and macroangiopathy. Methods 72 NIDDM patients who suffered from DM more than 6 years and 62 non-diabetic healthy control were evaluated. After extraction of DNA from peripheral blood, ACE and PAI-1 gene polymorphisrns were determined by polymerase chain reaction, SSCP electrophoresis and silver stain. Serum PAI-1 level was dctected by Immulyse PAI-1 ELISA kit(Bipool Sweden). Results: Total 134 samples were evaluated and ACE genotype were DD 27(20%), ID 88(66%), and II 19(14%). PAI-1 genotype were 4G4G 26(19%), 4G5G 73(55%), and 4G5G 35(26%). The distribution of ACE and PAI-1 polymorphism according to presence or absence of nephropathy were DD 10, ID 32, II 8, 4G4G 9, 4G5G 31, and 5G5G 10 in DM nephropathy group and DD 3, ID 17, II 2, 4G4G 5, 4G5G 12, and 5G5G 5 in non-nephropathy group. There were no significant differences in the distribution of ACE and PAI-1 gene between the two groups. The distribution of ACE and PAI-1 polymorphism according to macroangiopathy were DD 6, ID 16, II 3, 4G4G 5, 4G5G 15, and 5G5G 5 in macroangiopathy group and DD 7, ID 33, II 7, 4G4G 9, 4G5G 28, and 5(;5(i 10 in non-macroangiopathy group. There were no significant differences in the distribution of ACE and PAI- 1 gene between macroangiopathy and non-macroangiopathy groups. Serum PAI-1 level according to PAI-1 gene and ACE gene polymorphism were 4G4G 47.9919.73, 4G5G 40.1918.49, 5G5G 40.37±20.99ng/mL, DD 37.99±16.64, ID 44.80 20.:35, and II:31.92 12.% and had a tendency that is higher in 4G4G genotype. Conclusion: From the above results, we cannot define the relationships of ACE and PAI-1 gene polymorphism and PAI-1 activities to DM nephropathy and macrovascular complications of NIDDh1 patients, but prospective studies including more patients population will be required.

유지 혈액투석 중인 말기 신부전 환자에서 치료적 위내시경 후에 발생한 십이지장 근육내 혈종 및 췌장염 1 예

이소영(So Young Lee),조상경(Sang Kyung Jo),박선민(Sun Min Park),서지아(Ji A Seo),성수아(Su Ah Sung),한금현(Kum Hyun Han),조원용(Won Yong Cho),김형규(Hyoung Kyu Kim),정석인(Suk In Jung) 대한신장학회 2002 Kidney Research and Clinical Practice Vol.21 No.4

Intramural duodenal hematoma is a rare finding in the adult, especially when related to iatrogenic complications of ulcer treatment, it can lead to biliary obstruction and pancreatitis, which can be fatal in severe case. We report one case of intramural duodenal hematoma complicated with pancreatitis after endoscopic hemostasis in a chronic renal failure patient with maintenance hemodialysis. He had a duodenal ulcer bleeding treated with endoscopic epinephrine injection and electro-coagulation therapy, but on the second day, he complained of persistent abdominal pain, nausea and vomiting. Abdominal ultrasound showed acute, edematous pancreatitis and a mass with low echodensity in the wall of the 2nd portion of the duodenum. Symptom and laboratory findings were persistent under conservative therapy, 7 days later, gastric resection, hematoma evacuation was carried out, subsequently the patient recovered from the pancreatitis but the patient died of septic shock and multiple organ dysfunction.

혈전성 혈소판 감소성 자반증의 임상상을 보인 항사구체 기저막 항체질환 1 예

천정현(Jeong Hyun Chun),서상렬(Sang Yeol Suh),조상경(Sang Kyung Jo),김형규(Hyoung Kyu Kim),조원용(Won Yonpg Cho) 대한신장학회 2001 Kidney Research and Clinical Practice Vol.20 No.2

Thrombotic thrombocytopenic purpura(TTP) was first described in 1925, however, the definite cause of TTP remained unknown. Further study revealed that the pathogenesis of thrombotic thrombocytopenia was related to autoimmune disease. Autoantibodies generated by vessel injury and other causes result in excessive platelet aggregation and consumption. Recently, many autoimmune diseases and conditions associated with vascular injury have been reported to be accompanied by TTP-like feature, such as microangiopathic hemolytic anemia and thrombocytopenia. Anti-glomerular basement membrane(GBM) mediated glomerulonephritis is also related to autoantibody against collagen IV fiber in GBM, and cha- racterizded by diffuse glomerular capillary injury. Although the relationship of these two diseases is not clearly defined, here we report a case of anti- GBM antibody disease accompanied by TTP-like feature in a 40-year old man admitted for dyspnea. The patient had hemolytic anemia, thrombocytopenia, and acute renal failure. Anti-GBM antibody was positive and crescent formation and linear deposition of IgG along glomerular basement membrane was seen in renal biopsy. Disease progressed with no clinical response despite of prompt treatment by steroid and cyclophosphamide pulse therapy and plasmapheresis.

허혈성 손상을 유발한 인근위 상피 세포에서 α-MSH가 Tumor Necrosis Factor α 및 NF Κ B의 활성화에 미치는 영향에 대한 연구

이소영 ( So Young Lee ),김상욱 ( Sang Wook Kim ),조상경 ( Sang Kyung Jo ),권영주 ( Young ),차대룡 ( Dae Ryong Cha ),조원용 ( Won Yong Cho ),김형규 ( Hyung Kyu Kim ) 대한신장학회 2003 Kidney Research and Clinical Practice Vol.22 No.1

배경 : 급성 신부전을 유발하는 허혈, 재관류 손상시의 병태 생리적 기전은 아직 명백이 규명 되지는 않았으나 국소 염증 반응이 중요한 역할을 하며 이러한 염증 반응을 매개하는 대표적인 염증성 화학물질인 Tumor necrosis factor α (TNG α)가 허혈, 재관류 손상시 발현이 증가되고 이것이 신조직의 염증성 손상 및 apoptosis에 관여한다고 보고되고 있다. 저자는 허혈성 신손상 초기에 세뇨관 상피 세포에서 생성이 증가되는 TNF α가 신손상의 주된 요소로 작용할 것이라는 가정하에 사람 근위 세뇨관 상피 세포를 배양하여 화학적 저산소증을 유발한 후 TNF α의 발현을 살펴보고, 또한 이 과정에서 TNG α 유전자의 생성을 증가시키는 것으로 알려진 NFkB의 발현을 관찰하였다. 또한 강력한 항염증 작용을 가지며, 허혈, 재관류 손상시 신손상 경감 효과를 가지는 것으로 보고된 바 있는 α-MSH의 TNF α, NFkB 및 신상피세포의 아포프토시스에 미치는 영향을 연구하였다. 방법 : 계대 배양 7-15회된 사람 근위 상피 세포를 이용하여 2 ??M의 antimycin A와 농도를 달리한 deoxy-D-glucose를 이용하여 화학적 저 산소증을 유발하였다. 실험군을 저산소증을 유발하기 24 시간 전에 50 ??M의 α-MSH을 추가하여 대조군과 RT-PCR 방법으로 TNF α의 발현을 비교하였고, gel shift assay로 NFkB의 발현 양상을 비교하였다. 또한 각 군에서 TUNEL 및 DNA laddering을 관찰하여 각 군 세포의 아포프토시스 발생 정도를 비교하였다. 결과 : Antimycin A와 deoxyglucose의 농도를 각각 달리하여 apoptosis를 가장 많이 유발하는 조건을 정하였는데, 2 ??M의 antimycin A와 2mM의 deocyglucose그리고 1 mM의 glucose를 투여하여 ATP level을 정상의 25% 정도로 감소시킨 군 (group A)과 여기에 glucose를 10 mM을 투여하여 ATP level을 정상의 50% 정도로 감소시킨 군 (goroup B)에서 apoptosis를 보인 세포가 가장 많았다. Group A, B와 이에 α-MSH를 투여한 군에서 TNFα 에 대한 RT-PCR을 하였는데, densitometry로 측정한 L19에 대한 TNF α의 비율이 105.15±16.5 (group B)와 18.75±0.85 (group B + α-MSH)로 유의하게 감소하였다 (p<0.05). 세포의 아포프토시스를 보기 위하여 시행한 TUNEL 및 DNA laddering에서도 group A와 B의 대조군에서보다 α-MSH 투여군에서 유의하게 아포프토시스가 감소하는 소견을 보였다. 결론 : α-MSH는 배양한 신상피 세포에서 화학적 저산소증에 의한 세포의 아포프토시스를 감소시키며 이러한 α-MSH의 신손상 경감 효과는 부분적으로 TNF α 및 그와 관련된 신호전달물질인 NFkB의 활성과 관련이 있을 것으로 생각할 수 있겠다. mBackground : Tumor necrosis factor a (TNF), potent proinflammatory cytokine, may be related with ischemia/reperfusion injury induced tubular cell inflammation and apoptosis. We examined TNF and its major nuclear transcriptional factor, NFkB activation in cultured human tubular cells in hypoxic condition and the effect of α-MSH, potent antiinflammatory agent, which have been reported to reduce renal I/R injury in rats. Methods : Hypoxic culture condition was produced by oxidative pathway inhibitor (Antimycin 2mM) and glycolytic pathway inhibitor (deoxy-D-glucose 2 mM and 10 mM) for 1 hour and re-oxygenation was performed by placing the cells in normal medium. The expression of TNF mRNA was studied by RT-PCR and NFkB DNA binding activity was analysed by Electomobility shift assays (EMSA) and cellular apoptosis was assessed by the terminal deoxynucleotidy1 transferase-mediated dUTP biotin nick-end labelling (TUNEL) method and DNA laddering. These data were compared between the α-MSH and the vehicle-treated groups. Results : Measured ATP level was 49% of control by luciferase-based assay kit. I/R injury caused an increase in TNF mRNA and NFkB activation and was accompanied by morphologicl evidence of apoptosis α-MSH significantly reduced the degree of apoptosis, as well as TNF mRNA and NFkB activity (TNF/L19 mRNA ratio, vehicle/α-MSH : 105.15±16.5/18.75±0.85, p<0.05) (NFkB activity, vehicle/α-MSH : 5624/4803 densitometric index (DI), p<0.05). Conclusion : These findings suggest that α-MSH can decresae cellular apoptosis in hypocic tubular cells and this protective effect of α-MSH may be related, in partially, with supression of TNF and NFkB activity.