대한내과학회지 : 제 72 권제 5 호 2007 혈액투석중인말기신부전증환자에서관상동맥혈관석회화와혈청 Osteoprotegerin 및 Fetuin-A 농도의상관관계 강원대학교의과대학내과학교실, 영상의학과 2 김상욱 정해혁 한헌 2 =Abstract= Serum osteoprotegerin and fetuin-a level is associated with coronary artery calcification score in the patients with end-stage renal disease Sang-Wook Kim, M.D., Jung Hae Hyuk, M.D. and Heon Han, M.D. 2 Departments of Internal Medicine and Radiology, Kangwon National University College of Medicine, Chuncheon, Korea Background : Coronary artery calcification is frequently seen in hemodialysis patients. The development and progression of coronary artery calcification is similar to osteogenesis, and a naturally occurring serum inhibitor of calcification may be involved. The aim of this study was to evaluate the relationship between coronary artery calcification, bone remodeling related factor, serum osteoprotegerin (OPG), calcification inhibitor and the serum fetuin-a levels in hemodialysis patients. Methods : A total of 51 hemodialysis patient were assessed for their coronary artery calcium (CAC) scores with using multirow spiral computed tomography and measuring the serum OPG level, the serum fetuin-a level, the biochemical markers of inflammation, the lipid profile and the mineral metabolism. Results : The mean serum OPG level was 3,561±1,160 pg/ml and the mean serum fetuin-a level was 28.5± 4.1 mg/dl. The CAC scores were significantly correlated with the duration of dialysis (p=0.0225), hs-crp (p=0.0392), serum phosphate (p=0.0341), Ca x P (p=0.0434), the serum OPG level (p=0.0026) and LDL-cholesterol (p=0.0438), after adjusting for age, gender, BMI, smoking history and the presence of diabetes. Multiple regression analysis showed that the CAC scores were significantly associated with the serum OPG level (p<0.0001) and the serum phosphate level (p=0.0003). The subgroup of the patients with a CAC score greater than 400 (the severe CAC group) had significantly higher OPG levels and lower fetuin-a levels than the groups of the patients with lower CAC scores. Conclusions : Our data suggest that the CAC scores in the patients undergoing hemodialysis were related with higher serum OPG and higher serum phosphate levels. The serum fetuin-a level was significantly lower in the patients with severe coronary artery calcification.(korean J Med 72:451-458, 2007) Key Words : Coronary disease, Calcification, Osteoprotegerin, Fetuin-A Received : 2006. 11. 6 Accepted : 2007. 2. 5 Correspondence to : Sang-Wook Kim, M.D., Division of Endocrinology & Metabolism, Department of Internal Medicien, Kangwon National University Hospital, 17-1 Hyoja 3-dong, Chuncheon 200-947, Korea E-mail : exoplanet@kangwon.ac.kr *This study was supported by the Research Grant (2005274) from Kangwon National University. - 451 -
-The Korean Journal of Medicine : Vol. 72, No. 5, 2007 - 서론석회화된관상동맥혈관은죽상경화판 (atherosclerotic plaque) 의중증도, 죽상경화판의불안정성, 심근경색의위험도등과밀접한양의상관관계를가지고있어심혈관질환의독립적인위험인자로인정되고있다 1). 일반인과비교하여투석을받고있는말기신부전환자에서 2 배에서 5배까지더많이발견되는관상동맥혈관석회화는 2) 신부전환자에서심혈관질환이과다발생하는 3) 이유를설명해주는여러비전통적위험인자중하나로인식되고있다. 관상동맥혈관석회화가발생하는기전에대해서는혈관내에발생한병변이말기로진행하면서나타나는수동적이고, 퇴행적인과정의결과물로생각하는경향이있었으나, 최근죽상경화판에서골생성과관련된 BMP (bone morphogenic protein), osteopontin, osteonectin, osteocalcin, MGP (matrix GLA protein) 과같은단백질들이발견되면서 4) 골생성과유사한생리작용이활발하게일어나는능동적인과정으로이해되고있다. Osteoprotegerin (OPG) 은 tumor necrosis factor receptor super-family 에속하는골재형성의핵심이되는단백질이며, RANKL (receptor activator of nuclear factor-κb ligand) 을억제하는 decoy receptor 로알려져있고, 골에서는파골세포의분화와성숙을억제하는작용을한다. 실험동물에서 OPG 유전자를결손시키면혈관석회화가대동맥과신장동맥에형성되고골다공증을유발하는데 5), 반대로 OPG 유전자를과발현시키면이러한석회화가예방된다 6). 말기신부전환자에서는혈청 OPG의증가가관상동맥혈관석회화와독립적인상관관계를가지고있음이보고되어있는데, 실험동물에서는혈관석회화에보호인자로작용하는 OPG가어떻게사람에서는혈관석회화의중증도와밀접한상관관계를보이는지에대해서는아직잘모르고있다 7). Fetuin-A는포유류의세포외액에광범위하게존재하며석회화과정에관련된여러생리물질중유일하게전신적으로작용하는단백질로염기인산칼슘 (Basic calcium phosphate, BCP) 과결합하여, 골외석회화 (extraskeletal calcification) 를억제한다 8). 투석을받고있는말기신부전환자에서 fetuin-a 농도가정상대조군과비교하여저하되어있으며심혈관계사망률과연관이있다는보고는있으나 9) 말기신부전환자에서혈 청 fetuin-a 농도와관상동맥혈관석회화와의상관관계에대한연구는드물다. 본연구는투석을받고있는말기신부전환자에서 multirow spiral CT (MSCT) 를이용하여관상동맥혈관석회화점수 (coronary artery calcification score, CACs) 를정량하고이들환자에서혈관석회화보호인자또는골외석회화억제인자로알려져있는혈청 OPG 농도와혈청 fetuin-a 농도를측정하여이들석회화관련생리물질이 CACs와어떠한상관관계를가지는지횡단면적연구를통해알아보았다. 1. 대상 Table 1. Baseline characteristics of the study subjects N Age (years) Men/Women (N) BMI (kg/m 2 ) Duration of Dialysis (months) * Diabetes (%) Current Smoker (%) Systolic BP (mmhg) Diastolic BP (mmhg) hs CRP (mg/l) * Calcium (mg/dl) Phosphorus (mg/dl) Ca x P (mg 2 /dl 2 ) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) * CAC scores (mm 3 ) * ipth (pg/ml) * 대상및방법 2003년 3월부터 2005년 10월까지강원대학교병원에서유지혈액투석을받고있으면서 20세이상인성인환 51 56.6±12.8 35/16 22.5±3.3 25 (1-111) 43.1% 13.7% 142±12 80±9 0.15 (0.02-1.86) 9.4±0.7 5.0±0.9 47.1±11.1 153±31 86±20 42±10 113 (42-500) 199 (0-2745) 46.5 (4.3-385.8) Osteoprotegerin (pg/ml) Fetuin-A (mg/dl) 3,561±1,160 28.5±4.1 * Median and range (minimum-maximum). BMI, body mass index; hs-crp, highly sensitive C-reactive protein; Ca x P, Calcium phosphorus product; CAC, Coronary artery calcification; LDL, low-density lipoprotein; HDL, high density lipoprotein; ipth, intact parathyroid hormone - 452 -
- Sang-Wook Kim, et al : Serum osteoprotegerin and fetuin-a level in coronary artery calcification - Table 2. Partial Pearson correlation analysis between the coronary artery calcium score * and the clinical and biochemical variables after adjusting for age, gender, body mass index, smoking history and diabetes mellitus Variable Correlation Coefficient p value Log Duration of Dialysis Systolic BP Diastolic BP Log hs-crp Calcium Phosphorus Ca x P Osteoprotegerin Fetuin-A Total cholesterol LDL cholesterol HDL cholesterol Log Triglycerides 0.34 0.07 0.17 0.31 0.18 0.32 0.31 0.44-0.14 0.26 0.31 0.06 0.00 0.0225 0.6541 0.2758 0.0392 0.2402 0.0341 0.0434 0.0026 0.3662 0.0897 0.0438 0.7186 0.9894 * Log (CACs+1). hs CRP, highly sensitive C-reactive protein; Ca x P, Calcium phosphorus product; LDL, low-density lipoprotein; HDL, high density lipoprotein 자를대상으로하였다. 본연구는강원대학교병원임상연구위원회의승인을받았으며 51명의환자가본연구에동의하였고, 이들로부터문서화된동의서를받았다. 환자들의평균나이는 56.6±12.8 세이었으며남자가 35명, 여자가 16명이었다. 투석기간의중간값 (median) 은 31.5개월 ( 범위 : 1~111개월 ) 이었다 ( 표 1). 말기신부전의원인으로당뇨병성신증 22명, 사구체신염 15명, 고혈압 4명, 다발성다낭성신질환 1명, 원인을알수없었던경우는 9명이었다. 과거병력에서만성심부전, 심근경색, 협심증, 뇌경색등심혈관질환이있었던환자는 15명이었다. 환자들은투석액으로중탄산염완충액을사용하였고합성막인 Polyflux 6 L (Gambro Dialysatoren GmbH & Co. KG, Hechingen, Germany), 또는 F6 HPS (Fresenius Medical Care AG, Bad Homburg, Germany) 를사용하여 Gambro의 PhoenixTM 또는 Toray의 TR-321로회당 4시간동안주 3회혈액투석을시행하였으며환자의상황에따라 2회또는 4회의투석을시행하였다. 2. 방법모든환자에서문진및신체검사를시행하였고의무기록지를조사하여심혈관질환유무, 당뇨병, 흡연력, 투석기간을조사하였고, 신장과체중을측정하여체질 량지수를구하였다. 환자의혈압은 1개월마다투석전후로안정상태에서 2회측정하였으며관상동맥혈관석회화점수를측정하기위한 CT 촬영을전후하여최소한 5 개월동안측정한혈압측정치를평균하였다. 관상동맥혈관석회화점수 (Coronary artery calcium score, CACs) 는 MSCT (LightSpeed Plus, GE Medical Systems, Milwaukee, USA) 를이용하여면적과부피모두를측정하였으며이중부피로측정한값을통계처리에이용하였다. CT 촬영시정보수집조건 (data acquisition parameter) 은이전의논문에서보고된바와같다 10). CT 촬영은 2003년 4월, 2003년 10월, 2004년 4월, 2004 년 10월, 2005년 4월에각각시행하였으며 2회이상측정한경우 CACs의단순평균을구하였다. 환자들은 Rumberger 등 11) 의제안에따라 CACs에따라분류하였는데 CACs가 0-99인경우 ( 최소또는경미 ), 100-399 ( 중등도 ), 400 이상 ( 중증 ) 으로묶어분석하였다. 최소또는경미한경우폐쇄성관상동맥질환이있을가능성이낮고, 중등도인경우는관상동맥질환의동반가능성이비교적높으며, 중증인경우는심하고광범위한관상동맥질환이있음을의미한다. 혈액채취는 8시간이상공복후혈액투석전에시행하였다. 일반화학검사는 CT 촬영을전후하여 1개월간격으로총 5회실시하였고, 혈청지질검사와 ipth, CRP - 453 -
- 대한내과학회지 : 제 72 권제 5 호통권제 561 호 2007 - Figure 1. Comparison of the serum OPG levels and serum fetuin-a levels between the groups of CAC scores. The subgroup of the patients with a CAC score greater than 400 (the severe CAC group, group 3) had significantly higher OPG levels ( * p=0.0027) than both group 1 and group 2, and they had lower fetuin-a levels ( p=0.0039) than the group of patients with lower CAC scores (group 1). OPG, osteoprotegerin; CACs, coronary artery calcification score. 검사는 3개월간격으로 3회실시하였다. CRP는최하 0.01 mg/dl까지검출할수있는 Latex agglutination 법 (Denka, Tokyo, Japan) 으로측정하였는데환자가급성염증성질환에이환된경우 1개월이내의검사치는분석에서제외하였다. OPG는상업화된 ELISA 키트 (Oscotech, Seoul, Korea) 를이용하여측정하였고, 시험내 (intraassay) 변이계수 (Coefficient of variance, CV) 는 4.8~ 8%, 시험간 (inter-assay) 변이계수는 4.3~5.6% 이었다. fetuin-a 는 ELISA 키트 (BioVendor GmbH, Heidelberg, Germany) 를이용하여측정하였으며측정한계는 0.35 ng/ml, 시험내 (intra-assay) CV는 3.3~4.8%, 시험간 (inter-assay) CV는 2.5~7.4% 이었다. 3. 통계분석모든측정치는평균 ± 표준편차또는중앙값과범위로표시하였다. CRP는기하평균을구하였고, 관상동맥혈관석회화점수 (CACs), 투석기간, Triglycerides, hs-crp, ipth는비정규분포를보이므로로그변환하여분석하였다. 이과정에서 CACs가 0인경우로그변환을시행하면결측치로처리되어분석에서누락되므로, CACs에 1을더한값을로그변환하여통계분석에이용하였다. CACs와혈압, 혈청알부민, 칼슘, 인, Ca x P, 지질, OPG, fetuin-a 등여러변수들간의상관관계는연령, 성별, 체질량지수, 흡연력, 당뇨병유무를보정한 Pearson 편상관분석 (partial correlations) 을이용하여알아보았다. 다변량회귀분석은 CACs를종속변수로 OPG, 혈청인, Ca x P, LDL 콜레스테롤, 투석기간, CRP를독립변수로하여분석하였으며단계별선택방법 (stepwise selection) 을사용하였다. CACs의중증도에따라분류한 3군사이의임상적, 생화화적인자들의비교는일원배치분산분석 (one-way ANOVA) 을이용하여검증하였으며사후검정은 Tukey'sb 검정방법을사용하였다. 통계처리는 SPSS 12.0 소프트웨어를사용하였고, 모든통계치는양측검정으로 p-value 가 0.05 미만일때유의한것으로판정하였다. 결과연구대상환자들의임상적, 생화화적인자들은표 1 에서제시된바와같다. 대상환자전체에서혈청 OPG 농도의평균값은 3,561±1,160 pg/ml, fetuin-a 농도의평균값은 28.5±4.11 mg/dl 이었다. CACs의중간값은 199 mm 3 ( 범위, 0-2745) 이었으며 5명의환자에서 CAC - 454 -
- 김상욱외 2 인 : 관상동맥혈관석회화와혈청 Osteoprotegerin 및 fetuin-a - Table 3. Multiple linear regression analysis (stepwise method) of the variables influencing the CAC score Unstandardized Coefficients Standardized Coefficients p value B Standard Error Beta p value Osteoprotegerin Phosphorus 0.0005 0.4351 0.0001 0.1395 0.5887 0.3710 <0.0001 0.0031 Dependent variable: Log (CAC+1), independent variable: Osteoprotegerin, phosphorus, LDL cholesterol, Ca x P, Log Duration of dialysis, Log hs-crp Table 4. The groups of coronary artery calcium scores and the clinical and biochemical variables N Age BMI Duration of Dialysis Systolic BP Diastolic BP hs CRP Calcium Phosphorus Ca x P Osteoprotegerin T * Fetuin-A T * 0-99 100-399 > 400 p value 20 55.3±14.9 22.0±2.9 6 (1-99) 139±18 77±13 0.10 (0.02-1.41) 9.1±0.6 4.8±1.0 44.4±11.2 3,147±1,226 a 29.9±5.7 a 10 52.6±11.5 21.7±3.1 23 (1-111) 145±9 83±4 0.22 (0.03-0.47) 9.5±0.6 5.1±1.0 48.6±11.2 3,321±1,122 a 30.2±2.7 a, b 21 61.5±9.6 23.6±3.4 30 (2-99) 142±8 80±7 0.29 (0.04-1.86) 9.4±0.7 5.2±0.9 49.4±11.7 4,239±766 b 26.5±2.6 b - 0.0826 0.2519 0.0621 0.6450 0.2756 0.0739 0.5171 0.4457 0.4492 0.0027 Total Cholesterol LDL Cholesterol HDL Cholesterol Triglycerides 145±29 81±18 42±11 111 (42-452) 168±35 91±25 45±9 140 (60-500) 154±28 88±19 41±10 110 (50-496) 0.1510 0.4106 0.6264 0.6718 * The same letters indicate non significant difference between groups based on Tukey's-B multiple comparison tests. BMI, body mass index; hs-crp, highly sensitive C-reactive protein; Ca x P, Calcium phosphorus product; LDL, low-density lipoprotein; HDL, high density lipoprotein 0.0039 의증거가관찰되지않았다. CACs에따라분류하였을때, 0-99 mm 3 ; 20명, 100-399 mm 3 ; 10명, 400 mm 3 이상인경우는 21명이었다. 대상군의연령, 성별, 체질량지수 (BMI), 흡연력, 당뇨병유무를보정하여 CACs와임상적, 생화학적인자들과의편상관관계를분석하였는데 ( 표 2), 투석기간 (p= 0.0225), Log hs-crp (p=0.0392), 혈청인 (p=0.0341), Ca x P (p=0.0434), 혈청 OPG 농도 (p=0.0026), LDL 콜레스테롤 (p=0.0438) 이유의한양의상관관계를나타내었다. 이상의결과에서유의하게나타난변수인투석기간, hs-crp, 혈청인, Ca x P, 혈청 OPG 농도, LDL 콜레스 테롤을독립변수로, CACs를종속변수로한다변량회귀분석에서는혈청 OPG 농도 (p<0.0001) 와혈청인농도 (p=0.0003) 가유의한독립변수로나타났다 ( 표 3). CACs에따라 3군으로분류하여임상적, 생화학적인자들을비교한결과는표 4에나타내었다. 혈청 OPG 농도는 CACs가 400 이상인중증인군에서최소또는경미한군또는중등도의군과비교하여유의하게높게나타났으며혈청 fetuin-a 농도는 CACs가 400 이상인군에서최소또는경미한군과비교하여유의하게낮게나타났다. 그림 1은 CACs 분류에따라혈청 OPG 농도와 fetuin-a 농도만을따로도식화한것이다. 환자의연령, - 455 -
-The Korean Journal of Medicine : Vol. 72, No. 5, 2007 - 투석기간, hs-crp 농도, 혈청인농도, Ca x P, LDL 콜레스테롤등은 CACs 각군사이에유의한차이를나타내지않았다. 고찰말기신부전으로투석을받고있는환자의주요사망원인은심혈관계질환으로사망원인의 50% 이상을차지하고있으며, 그빈도는일반인과비교하여현저히높은것으로알려져있다 12). 죽상동맥경화증은일반인과마찬가지로말기신부전증환자에서중요한심혈관계사망원인이지만고혈압, 고지혈증, 내당능장애와같은죽상동맥경화증의고전적위험인자만으로이들환자에서나타나는심혈관질환의과다발생을충분히설명하지는못한다. 이에따라호모시스틴이나, CRP의증가, 투석과관련된산화스트레스의증가와같은비전통적위험인자들이신부전증환자의심혈관질환사망률증가에기여하는것으로보고되고있으며, 최근에는무기질대사의이상에따른관상동맥혈관석회화가말기신부전증환자의심혈관질환사망률과밀접한상관관계가있음이알려지고있다 13). 본연구의결과유지투석을받고있는말기신부전증환자에서관상동맥혈관석회화점수 (CACs) 는연령, 성별, 체질량지수 (BMI), 흡연력, 당뇨병유무를보정하였을때, 혈청 OPG 농도, 혈청인, Ca x P, hs-crp, LDL 콜레스테롤농도, 투석기간과유의한상관관계를가짐을알수있었다. 이중혈청 OPG 농도와혈청인농도는다변량회귀분석에서관상동맥혈관석회화점수에독립적인영향을미치는유의한변수였다. 한편, 석회화정도에따라환자를분류하였을때, 관상동맥혈관석회화점수가중증으로높은경우혈청 OPG 농도가높게나타났으며 fetuin-a는유의하게낮음을알수있었다. Osteoprotegerin은생쥐형질전환모델에서혈관석회화를억제하는인자로밝혀졌지만, 사람을대상으로한여러역학연구에서는관상동맥혈관의중증도와연관되어있음이보고되어 14), 심혈관질환발생의독립적인위험인자로인식되고있다. 본연구의결과에서는관상동맥혈관석회화가심할수록혈청 OPG 농도가증가되어있었으며석회화에독립적인영향을미치는인자로나타났는데, 혈관보호인자로추정되는 OPG가혈관석회화가진행된경우에특히더높게나타나는이러한현상에대해아직만족할만한설명은없다. 연구자에따라 혈청 OPG가혈관손상에대해반응성또는길항조절인자로서과잉분비되었기때문일가능성을제시하거나, 한편으로는죽상경화성혈관병변의진행에따라나타나는, 질환의중증도를반영하는단순한지표일가능성도있는것으로보고있다 15). 한편혈청인이 CACs와유의한독립적상관관계를나타내었는데저자등은이전의논문에서관상동맥혈관석회화의진행에혈청인이중요한독립적위험인자임을밝힌바있고 10), 이는만성신부전환자에서무기질대사의이상, 특히혈청인의증가가석회화와밀접한연관이있다고한여러연구결과와일치되는결과로생각된다. Jono 등 16) 은사람의혈관평활근세포 (Human smooth muscle cell, HSMC) 를무기인이높은배지에서배양하면 HSMC에서평활근세포의지표가사라지고골세포로의분화지표인 cbfa-1과오스테오칼신이발현되며, 석회화가나타난다고하였다. 이는무기인대사의장애를특징으로하는만성신부전증환자에서혈관석회화가빈발하는현상을설명할수있는실험결과로생각된다. 저자등은이전연구에서 10) 관상동맥혈관석회화의진행에영향을미치는혈액인자로는 hs-crp가독립적인유의성을보인다고보고하였으며, 이번연구에서도 CACs와유의한상관관계가있음을확인할수있었다. LDL 콜레스테롤도유의한상관관계를보여주었는데이는말기신부전증환자에서죽상동맥경화증의발생에따라죽상반에칼슘의침착이이루어진다는병태생리적설명 17) 과부합하는결과로생각된다. Fetuin-A는단순상관분석에서 CACs와유의한상관관계를보였지만보정한결과유의한상관성을확인할수없었다. 하지만중증의 CACs를보이는경우그농도가저하되어있음을알수있었는데이는투석환자에서만성염증이존재할경우음성급성반응기물질 (acute phase reactant) 인 fetuin-a 농도의저하가나타나고, 혈관병변의칼슘침착을억제하는능력이감소됨에따라 fetuin-a 농도가높거나정상으로유지되었던군과비교하여더심한칼슘침착이일어났던것으로저자들은추론하였다. 본연구의제한점으로는첫째, 본연구는횡단면적연구로서관상동맥혈관석회화에영향을미칠것으로추정되는여러위험인자들과의상관관계는확인할수있었지만원인인자가무엇인지는규명할수없는한계점 - 456 -
- Sang-Wook Kim, et al : Serum osteoprotegerin and fetuin-a level in coronary artery calcification - 이있다. 앞으로잘디자인된전향적연구가필요할것으로생각된다. 둘째, 특정지역의환자를모집단으로하여일개기관의제한된환자만을대상으로하였으므로본연구의결과를확장하여일반화하기에는무리가있을것으로생각된다. 셋째, 연구대상환자의수가적어대상환자를여러군으로분류하여상호비교하는데제한점이있었으며, 여러변수들간의상관관계를분석하는데있어서도통계적파워가약한단점이있다고하겠다. 이상으로본연구에서는유지혈액투석을받고있는말기신부전증환자에서관상동맥혈관석회화는무기인대사의장애, 혈청 OPG 농도의증가및혈청 fetuin-a 농도의저하와밀접한상관관계가있음을알수있었다. 요약목적 : 투석을받고있는말기신부전증환자에서관상동맥혈관석회화점수 (coronary artery calcification score, CACs) 와혈청 OPG 농도및혈청 fetuin-a 농도의상관관계를알아보았다. 방법 : 51명의말기신부전증환자를대상으로 MSCT를촬영하여 CACs를구하였으며, 혈청 OPG 농도와 fetuin-a 농도를측정하였다. 모든환자에서체중, 신장, 혈압을측정하였으며심혈관질환병력과투석기간을조사하였다. 환자의혈액을채취하여 hs-crp, 혈청인, 혈청 CaxP, 혈청지질농도를측정하였다. 결과 : 대상환자에서혈청 OPG 농도의평균값은 3,561±1,160 pg/ml, fetuin-a 농도의평균값은 28.5± 4.1 mg/dl 이었다. 대상군의연령, 성별, 체질량지수 (BMI), 흡연력, 당뇨병유무를보정하였을때, 투석기간 (p=0.0225), hs-crp (p=0.0392), 혈청인 (p=0.0341), Ca x P(p=0.0434), 혈청 OPG 농도 p=0.0026), LDL 콜레스테롤 (p=0.0438) 이관상동맥혈관석회화점수와유의한양의상관관계를나타내었다. 다변량회귀분석에서는혈청 OPG 농도 (p<0.0001) 와혈청인농도 (p=0.0003) 가 CACs에유의한독립변수로나타났다. CACs에따라 3 군으로분류하여비교한결과, 혈청 OPG 농도는 CACs 가 400 이상인중증인군에서최소또는경미한군또는중등도의군과비교하여유의하게높게나타났으며혈청 fetuin-a 농도는 CACs가 400 이상인군에서최소또는경미한군과비교하여유의하게낮게나타났다. 결론 : 유지혈액투석을받고있는말기신부전증환 자에서관상동맥혈관석회화는무기인대사의장애, 혈청 OPG 농도의증가와밀접한상관관계가있었으며혈청 fetuin-a 농도는특히관상동맥혈관석회화가심한경우저하되어있음을알수있었다. 중심단어 : 관상동맥질환, 혈관석회화, 만성신부전증 REFERENCES 1) Shaw LJ, Raggi P, Schisterman E, Berman DS, Callister TQ. Prognostic value of cardiac risk factors and coronary artery calcium screening for all-cause mortality. Radiology 228:826-833, 2003 2) Raggi P, Boulay A, Chasan-Taber S, Amin N, Dillon M, Burke SK, Chertow GM. Cardiac calcification in adult hemodialysis patients: a link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 39:695-701, 2002 3) Cheung AK, Sarnak MJ, Yan G, Dwyer JT, Heyka RJ, Rocco MV, Teehan BP, Levey AS. Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int 58:353-362, 2000 4) Moe SM, Chen NX. Pathophysiology of vascular calcification in chronic kidney disease. Circ Res 95:560-567, 2004 5) Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260-1268, 1998 6) Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik PJ, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blockinga process resembling osteoclastogenesis. J Exp Med 192:463-474, 2000 7) Barreto DV, Barreto FC, Carvalho AB, Cuppari L, Cendoroglo M, Draibe SA, Moyses RM, Neves KR, Jorgetti V, Blair A, Guiberteau R, Fernandes Canziani ME. Coronary calcification in hemodialysis patients: the contribution of traditional and uremia-related risk factors. Kidney Int 67:1576-1582, 2005 8) Heiss A, DuChesne A, Denecke B, Grotzinger J, Yamamoto K, Renne T, Jahnen-Dechent W. Structural basis of calcification inhibition by alpha 2-hs glycoprotein/fetuin-a: formation of colloidal calciprotein particles. J Biol Chem 278:13333-13341, 2003 9) Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, - 457 -
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