한국임상약학회지제 24 권제 3 호 Korean J Clin Pharm, Vol. 24, No. 3, 2014 Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy Available online at http://www.kccp.or.kr pissn: 1226-6051 만성신부전환자의혈관석회화와사망률에미치는인결합제의영향 신혜연 * 덕성여자대학교약학대학 (2014 년 4 월 6 일접수 2014 년 6 월 30 일수정 2014 년 7 월 3 일승인 ) Effect of Phosphate Binders on Vascular Calcification and Mortality in Korean Patients with Chronic Kidney Disease Hye Yeon Sin* College of Pharmacy, Duksung Women s University, Seoul 132-714, South Korea (Received April 6, 2014 Revised June 30, 2014 Accepted July 3, 2014) Objectives: Current studies are debating on the association of vascular calcification and the benefit of treatment to lower serum phosphorus level in patients with chronic kidney disease. The aim of this study was to evaluate the association of mortality and risk of vascular calcification in patients with CKD who were taking phosphate binders. Methods: This study was conducted through retrospective medical chart review for 420 patients aged 18 years and older who were admitted for chronic kidney disease. Results: Vascular calcification was not statistically significantly associated with increased mortality in patients with CKD [16.7% vs. 19.2%; 95% CI; 0.388 to 1.818 (p=0.656)]. Intervention of calcium-based phosphate binders was not significantly associated with vascular calcification in patients with CKD [9.1% vs. 12.5%; 95% CI; 0.364 to 1.358 (p=0.292)]. Ca x P product 55 mg 2 /dl 2 was not significantly associated with increased 1 year mortality in patients with CKD [25.4% vs. 17.5%; 95% CI; 0.851 to 3.013 (p=0.142)]. Intervention of sevelamer was significantly associated with reduced 1 year mortality in patients with CKD than that of patients who did not take sevelamer [6.3% vs. 25.3%; 95% CI; 0.044 to 0.880 (p=0.020)]. Conclusion: There was not a statistically significant association between vascular calcification and phosphate binder s use. But phosphate binder use was significantly associated with decreased mortality in patients with CKD. Key words - chronic kidney disease, vascular calcification, mortality, phosphate binders 만성신부전 (Chronic Kidney Disease) 은전신적으로칼슘, 인산, ipth (intact parathyroid hormone), 비타민D의대사이상, 뼈의전환속도및뼈의이상, 혈관또는연조직의석회화를야기할수있다. 1) 이와같은무기질대사의이상으로혈장칼슘과인산은정상수치이상으로증가또는감소할수있는데, 이때 ipth, fibroblast growth factor 23 (FGF 23), calcitriol 등은무기질수치를정상으로유지하기위하여혈장에서그수치가증가한다. 2) 그러나신사구체여과율이 30 ml/min 미만으로감소한 4단계또는 5단계만성신부전환자는칼슘과인산의혈장수치를정상으로유지하기위한이보상기전 (compensatory mechanism) 이억제되어혈장의칼슘과인산의수치는정상수치보다높게증가할수있다. 인산 Correspondence to : Hye Yeon Sin College of Pharmacy, Duksung Women s University, Samyang-ro 144 gil 33, Dobong-gu, Seoul 132-714, South Korea Tel: +82-2-901-8739, Fax: +82-2-901-8386 E-mail: hyshin@duksung.ac.kr 의수치가증가하면심혈관계이상, 속발성골이영양증 (secondary hyperparathyroidism), 골외성석회화 (extraskeletal calcification) 가발생하는것과관계가있으며, 3) 만성신부전환자의사망률과이환율이증가하는것과도관계가있다. 또한만성신부전이없는경우라도고인산혈증은심혈관계질환의위험을증가하는것과관계가있다. 4-5) 현재까지혈장인산의수치를목표수치로조절하기위하여사용한약물치료가유익한효과가있는지에관하여확인된무작위대조시험 (RCT) 은없었으며, 6-8) 인결합제 (calcium-based phosphate binders, sevelamer) 를사용할때만성신부전환자의사망률을감소하는유익한효과가있는지도명확하지않다. 최근연구에의하면뼈의전환속도가낮은만성신부전환자는 9) 혈관의석회화위험이매우높은것으로나타났으며, 10-11) 만성신부전환자의혈관의석회화는높은사망률과관련이있다. 11) 그러나혈관의석회화와사망을개선하기위하여사용하는인결합제약물치료가유익한효과가있는지는아직알려져있지않다. 12) 일부연구에의하면칼슘함유인결합제사용과인산수치의증가는혈관석회화의위험요인으로여겨지고있다. 4,5,11,13) 199
200 Kor. J. Clin. Pharm., Vol. 24, No. 3, 2014 그이유는혈관의석회화의원인중에서혈장의칼슘과인산은세포간질속에서서로합하여 hydroxyapatite형태의무기질을형성하여석회화를야기하기때문이다. 1,13) 따라서본연구는만성신부전환자에게인결합제를사용할때혈관의석회화와사망에미치는영향및혈관석회화가사망에미치는영향을분석하려고한다. 그리고혈장인산과칼슘, 그리고칼슘과인의곱이 (Ca P) 혈관석회화에미치는영향도함께분석하려고한다. 서의의사의진단기록과전자의무기록중복부방사선, 심혈관조영술, 전산화단층촬영검사자료에서혈관석회화진단기록이있을때로정의하였다. 실험실적검사자료로혈장칼슘, 인산, serum creatinine, blood urea nitrogen, 혈장알부민수치를수집하였다. 혈장칼슘의수치는환자의혈장알부민수치에따라보정하였다 (corrected calcium). 약물치료를받은환자와약물치료를받지않은환자군으로나누어각검사자료의변화수치와질병의발생유무를관찰하였다. 연구방법 연구대상본연구는만성신부전 (egfr < 30 ml/min/1.73 m 2 ) 을갖고있는 18세이상의한국인남 녀 420명을대상으로관찰한연구이다. 강원도강릉시에소재한병원의신장내과에서 2010년 8월에서 2012년 3월까지입원치료환자중에서의무기록실직원이무작위로선택한환자를대상으로 3년동안후향적으로검토하였다. 본연구계획은강릉아산병원임상시험심사위원회 (institution review board, IRB) 로부터승인을받았으며, 환자는인결합제를사용한환자와사용하지않은환자로분류하여관찰하였다. 환자의신체검사기록, 과거병력, 현재병력, 각검사자료를환자의무기록과전자의무기록 (electronic medical record) 에서수집하여사용하였다. 사례대조연구로사망을분석하기위하여 2개의약물사용군과 2개의대조군으로나누어분석하였다 ; 전체 420명중에서칼슘함유인결합제사용군은칼슘함유인결합제사용자 266명중에서중도절단자를제외한 201명이며, sevelamer사용군은 sevelamer사용자 38명중에서중도절단자를제외한 32명이다. 칼슘함유인결합제사용군과 sevelamer사용군의대조군은인결합제를사용한적이없는환자 152명중에서중도절단자를제외한 111명이다. 그리고음식에존재하는인산과결합하여위장관내에서인산의흡수를제한하기위하여환자는인결합제를음식과함께복용하였다. 질병의정의및자료수집각질환의정의는명기된의사의진단이있거나기록된의무기록자료가있을때로정의하였다. 만성신부전환자의건강상태를평가하기위한과거병력으로당뇨, 고혈압, 심장질환 (atrial fibrillation, congestive heart disease, atherosclerotic heart disease cardiomyopathy, cardiac arrhythmia 등 ), 동맥경화 (atherosclerosis), 말초혈관질환 (peripheral vascular disease), 급성관상동맥질환 [MI, coronary heart disease, acute coronary syndrome, coronary revascularization (PCI, CABG)], 뇌혈관질환 (Cerebrovascular disease, TIA포함 ), 속발성골이영양증 (secondary hyperparathyroidism), 골다공증 (osteoporosis), 뼈이상 (osteopathy), 혈관석회화 (Coronary artery calcification, vascular calcification) 를포함하였다. 혈관석회화는의무기록 신부전의기준및전해질의기준환자의신장기능및만성신장의단계는 The Modification of Diet in Renal Disease (MDRD) equation을사용하여계산한신사구체여과율 [(estimated glomerular filtration rate) = 186.3 (serum creatinine) -1.154 age -0.203 (0.742 for women)] 에따라분류하였다. 14) 만성신부전은신사구체여과율이 30 ml/min/1.73 m 2 미만이며만성신부전으로명기된의사의진단이있을때로정의하였다. 혈장칼슘의정상수치는 8.5-10.2 mg/dl이며고칼슘혈증 (hypercalcemia) 은혈장칼슘수치가 10.2 mg/dl를초과할때로정의하였다. 혈장칼슘수치는환자의혈장알부민수치에따라다음의수식을사용하여보정하였다 : calcium corrected = measured serum calcium + 0.8 (4.0 measured serum calcium) 혈장인의정상수치는 2.5-4.5 mg/dl ( 만성신부전 4단계 ), 2.5-5.5 mg/dl ( 만성신부전 5단계 ) 이며, 고인산혈증은혈장인의수치가 5.5 mg/dl를초과할때로정의하였다. KDIGO Guideline에따라칼슘과인의곱 (Ca PO4) 의정상수치는 55 mg 2 /dl 2 미만으로정의하였다. 분석방법본관찰연구는만성신부전으로입원치료한환자를대상으로진행한연구로써치료시작후중도에중단하였어도통계량을극대화하기위하여모두분석에포함하였다. 환자의기본적특성중연속변수는 t-test로검정하였고, 명목변수는누적빈도로나타냈다. 약물치료후발생한사망과혈관석회화는 chi-squared 검정법, Fisher s exact test와 linear regression model 중에서군집관찰값을보정하는데매우유익한일반화추정방정식 (GEE, Generalized Estimating Equation) 을사용하였다. 약물사용과시간경과에따른사망률의변화와석회화에따른사망발생과의관계는일반화추정방정식 (GEE) 을사용하였다 ( 다만환자의초기병원입원력이다르고환자를직접면담할수없는관찰연구의제한점이있어생존분석을시행하지못함 ). 칼슘수치 (>10.2), 혈장인산수치 (>5.5) 에따른집단별석회화발생비교는 chi-squared 검정법을사용하였다. 검사자료는유의수준 0.05에서기술적통계량을분석하여평균, 표준편차또는백분율로표시하였다. 검사자료는 SAS (Ver. 9.3) 로분석하였다.
만성신부전환자의혈관석회화와사망률에미치는인결합제의영향 201 연구결과 환자의기본특성만성신부전 (egfr < 30 ml/min/1.73 m 2 ) 을보유한 18세이상의우리나라남녀를대상으로관찰한본연구는 463명을검토하였고이중에서 43명은만성신부전환자가아닌경우 (8명), 신장내과에입원하지않은경우 (23명), 초기환자의기록이없는경우 (12명) 로서연구에서제외하였다. 420명의기 Table 1. Basic characteristics (n= 420). Characteristics Mean±SD Patients (number) Male Female 228±54.3 192±45.7 Age (year) Male Female 59.5±13.4 59.1±12.9 Hospital stay(day) 20.9±22.6 ESRD (year) 4.3±4.3 DM (year) 16.5±8.2 HD (year) 4.3±4.2 CAPD (year) 3.9±3.4 Weight (kg) 63.4±49.5 Height (cm) 164.5±73.3 Blood pressure on admission SBP (mmhg) DBP (mmhg) 143.8±30.9 81.8±17.0 Heart rate (beats/min) 83.4±17.4 Respiratory rate (breaths/min) 22.3±12.5 Estimated Glomerular Filtration Rate (egfr) 8.1±5.6 Laboratory data Serum albumin (g/dl) Blood glucose (mg/dl) Blood Urea Nitrogen, BUN (mg/dl) Calcium corrected (mg/dl) Phosphorus (mg/dl) Past medical history (PMH) Diabetes mellitus (DM) Acute coronary syndrome (ACS) Vascular calcification Atherosclerosis Heart failure (HF) Osteoporosis Osteopathy Cerebrovascular disease (CVD) Hypertension (HTN) 3.4±0.6 157.0±87.6 70.0±50.4 8.6±1.3 5.1±3.4 217±51.7 40±9.5 17±4.1 12±2.9 43±10.3 14±3.3 44±10.5 60±14.3 357±85.0 Data are expressed by mean (standard deviation). Patients and Past medical history are expressed by number (%). ESRD is an abbreviation for End Stage Renal Disease, DM for Diabetes Mellitus, HD for Hemo Dialysis, CAPD for Continuous Ambulatory Peritoneal Dialysis 본특성은 Table 1에서와같이환자의평균나이는 59세이며모두만성신부전을갖고있다 [egfr: 8.1 ml/min/1.73 m 2 (SD ±5.7)]. 칼슘함유인결합제를사용한환자는모두 266명이며, sevelamer를사용한환자는 38명이다. 관찰연구전환자가복용한약물들은 statins (66.9%), antidiabetic agents (50.1%), angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers/calcium channel blockers (76.2%), darbepoetin (82.9%) 등이있다. 환자중에서치료결과가없는환자, 경제적사유로치료를중단한환자, 그리고제 3의병원으로전원한환자의경우는치료결과와사망여부를알수없으므로사망결과는중도절단하였다. 연구기간 1년동안중도절단된환자는모두 76 명이다 ( 중도절단자가연구결과에미치는영향의분석결과유의한차이는없었다 ) 인결합제사용과사망률인결합제를사용한환자 268명중에서중도절단자를제외한 234명과인결합제를사용하지않은환자 111명을비교할때인결합제를사용한환자는 1년내 37명이사망하였다 [15.8% vs. 25.2%; 95% CI: 0.32-0.969 (p=0.037)](fig. 1). 칼슘함유인결합제를사용한환자 266명중에서중도절단자를제외한 201명과칼슘함유인결합제를사용하지않은환자 111명을비교할때칼슘함유인결합제를사용한환자는 1년내 35명이사망하였고 [17.4% vs. 25.2%: 95% CI: 0.356-1.097 (0.099)], 2년내 54명이사망하였다 [32.3% vs 47.7%, 95% CI: 0.308-0.889 (p=0.016)](table 2). 칼슘함유인결합제를사용한환자의시간경과에따른사망률이유의성있게더낮은것과관련있었다 (p<0.0001). sevelamer 를사용한환자 38명중에서중도절단자를제외한 32명과 sevelamer를사용하지않은 111명을비교할때 sevelamer를사용자는 1년내 2명이사망하였고 [6.3% vs. 25.2% 95% CI: 0.044-0.880 (p= 0.020)], 2년내 4명이사망하였다 [17.4% vs. 47.7% 95% CI: 0.073-0.733 (p= 0.009)]. Sevelamer 을사용한환자의시간경과에따른사망률이유의성있게더낮은것과관련있다 (p<0.0001). 중도절단자를제외한만성신부전환자 344명 Fig. 1. Intervention of phosphate binders was associated with decreased mortality rate in patients with CKD.
202 Kor. J. Clin. Pharm., Vol. 24, No. 3, 2014 Table 2. Mortality according to intervention of phosphate binders in patients with CKD. Phosphate binders (234 vs. 111) Drugs *(number of patients) Calcium-based phosphate binders (201 vs. 111) Sevelamer HCl (32 vs. 111) Number of events (mortality rate, %) p-value 95% Confidence Interval 1-year mortality 37 (15.8) 0.037 0.320-0.969 2-year mortality 58 (30.4) 0.005 0.284-0.803 3-year mortality 62 (32.5) 0.002 0.267-0.753 1-year mortality 35 (17.4) 0.099 0.356-1.097 2-year mortality 54 (32.3) 0.016 0.308-0.889 3-year mortality 58 (34.7) 0.009 0.293-0.842 1-year mortality 2 (6.3) 0.020 0.044-0.880 2-year mortality 4 (17.4) 0.009 0.073-0.733 3-year mortality 4 (17.4) 0.003 0.062-0.625 Intervention of Phosphate binders (Calcium-based phosphate binders and sevelamer) was associated with lower mortality rate in patients with CKD than that of patients who did not take. *Number of patients: indicates the number taking each phosphate binders vs number not taking it. The number of patients censored for which no death was recorded is 76 중에서칼슘과인의곱이 (Ca PO 4 55 mg 2 /dl 2 ) 정상수치이상인환자 (67명) 는 1년내 17명이사망하였고 [25.4% vs. 17.5%: 95% CI: 0.851-3.013(p=0.142)], 2년내 27명이사망하였고 [47.4% vs. 33.5%: 95% CI: 0.990-3.229(p=0.053)], 3년내 27명 [(47.3% (p=0.150)) 이사망하였다. 그리고시간경과에따른사망률변화는유의성있게관계가있었다 (p <0.001). 만성신부전환자의사망률은 420명중에서 1년내 65명 (15.5%) 사망하였고, 2년내 100명 (23.8%) 이사망하였다. 급성관상동맥질환병력이나심장병력을가진만성신부전환자의 1년사망률과인결합제사용은유의한관계가없다 (p=0.153). 만성신부전환자의사망원인중에서가장큰것은말기신부전으로서 36명 (55.4%) 이며그다음원인은패혈증및쇼크로 9명 (13.8%), 그리고심혈관계질환 5명 (7.7%) 순이다. 인결합제사용과혈관의석회화인결합제를사용한환자 268명과인결합제를사용하지않은 152명을비교할때인결합제를사용한환자의혈관석회화는 10.1%[95% CI: 0.784-1.464 (p=0.444)] 이다. 칼슘함유인결합제사용환자 230명과칼슘함유인결합제를사용않은환자 152명을비교할때칼슘함유인결합제사용한환자의 혈관석회화는 9.1%[95% CI: 0.364-1.358 (p=0.292)] 이며, sevelamer을사용한환자 36명과 sevelamer을사용하지않은환자 152명을비교할때 sevelamer 을사용한환자의혈관석회화는 16.7%[95% CI: 0.515-3.804 (p= 0.508) 이었다 (Table 3). 혈관에석회화가존재하는만성신부전환자 54명과석회화가없는환자 291명을비교할때석회화가있는환자 9명은 1년내사망하였고 [16.7% vs. 19.2%: 95% CI: 0.388-1.818 (p=0.656)], 13명은 2년내에사망하였다 [29.6% vs 37.2%: 95% CI: 0.352-1.427 (p=0.333)]. 혈관석회화와시간경과에따른사망률변화는유의한관계가없었다 (p=0.674) (Fig. 2). 보정칼슘수치 (calcium corrected) 가 10.2 mg/dl를초과할때인수치가 5.5 mg/dl를초과할때 [15.2% vs. 16.7%: 95% CI: 0.391-3.201 (p=0.833)] 석회화발생률이증가하는것과유의한관련이없었다. 고찰 18세이상의우리나라만성신부전환자를대상으로혈관석회화와사망위험을관찰한본연구의결과는다음과같다. 투석을받는만성신부전환자중에서동맥석회화는고칼슘 Table 3. Vascular Calcification according to intervention of phosphate binders. Drugs *(number of patients) Number of events (Calcification, %) p-value 95% Confidence Interval Phosphate binders (268 vs. 152) 27 (10.1) 0.444 0.420-1.464 Calcium-based phosphate binders (230 vs. 152) 21 (9.1) 0.292 0.364-1.358 Sevelamer HCl (36 vs. 152) 6 (16.7) 0.508 0.515-3.804 Intervention of Phosphate binders (Calcium-based phosphate binders and sevelamer) was not associated with reduced calcification in patients with CKD than that of patients who did not take. *Number of patients: indicates the number taking each phosphate binders vs number not taking it.
만성신부전환자의혈관석회화와사망률에미치는인결합제의영향 203 Fig. 2. Calcification was not associated with increased mortality rate in patients with CKD (p=0.612). 혈증, 고인산혈증또는비정상적인뼈의재형성 (bone remodeling) 으로인하여혈관의평활근세포들이 chondrocyte, osteoblast 와같은세포로전환하는과정처럼보이지만현재까지정확한기전은알려져있지않다. 1,6,10) 본연구에서인결합제사용유무에따른환자의석회화는유의한관계가없었는데, 최근연구에의하면투석중인만성신부전환자의혈관석회화는 50-70% 이고 1) 관상동맥석회화 (coronary artery calcification) 는 50% 인것으로나타났으며, 만성신부전은 (egfr < 30 ml/min/1.73 m 2 ) 관상동맥에석회화가증가하는것과관계가있었다. 15,16) 본연구에서혈관에석회화가존재하는환자의사망률은석회화가없는환자와비교할때유의한관계가없었고, 혈관석회화가있는환자의시간경과에따른사망률도통계적으로유의한관계가없었다. 따라서만성신부전환자에게혈관의석회화는사망률을증가시키는것과관련없는것으로볼수있다. 다음으로인결합제의사용이사망률에미치는영향에관한본연구의결과 sevelamer나칼슘함유인결합제의사용은사망률을유의성있게감소하는것과관련있으며, 시간경과에따른사망률도감소하는것과관련있으나이와대하여해외연구결과에따르면, 인결합제사용은사망률을감소시키지못하는것으로나타났다. 17,18) 이와같은연구결과의차이에영향을미치는요인으로는연구에참여한환자의만성신부전의심각한정도, 투석의방법 ( 우리나라는혈액투석과복막투석사용빈도가외국에비하여높음 ), 섭취음식중인산함량의차이, 약물순응도, 심혈관질환의심각한정도및심혈관질환을연구에포함하는지여부등으로보인다. 따라서고인산혈증을조절하기위하여사용하는인결합제의사망률감소에관한영향은현재까지일치하지않고있다. 만성신부전환자의무기질대사이상인고칼슘혈증, 고인산혈증, 그리고속발성골이영양증은동맥혈관의석회화를촉진할수있는인자로서 KDIGO clinical guideline, 2009 에의하여밝혀졌으나, 4,5,11,19) 혈관석회화와사망률증가에관한해외연구결과는서로일치하지않는다. 본연구에서심부전병력을가진만성신부전환자의 1년사망률과인결합 제사용은사망률감소와는관계가없었는데, 이것은혈중칼슘과인의수치를목표치로조절하여도만성신부전환자의심혈관계사망률을감소하지못함을보인 2011년에발표된논문의결과와일치한다. 20) 그러나심혈관계질환력을가진만성신부전환자의사망률은심혈관계병력이없는환자에비하여높다고주장하는의견도있다 (15% vs. 7%). 21-23) Reynolds의연구에의하면, 인산이존재할때혈관평활근세포에서분비되는뼈단백질들 (osteonectin, osteopontin, bone sialoprotein, type I collagen, alkaline phosphatase) 은세포배양시무기질화된혹을형성할수있으며이뼈와혈관의석회화과정에서칼슘과인은중요인자로작용할수있다고하였지만, 24-28) 고칼슘과인의곱이혈관석회화와직접적인관련이없다고주장하는의견도있다. 26) 이와관련하여본연구의결과는칼슘보정수치가 10.2 mg/dl를초과하는환자의혈관석회화는인산수치가 5.5 mg/dl이상인환자의혈관석회화와비교할때유의한관계가없었다. 또한칼슘과인의곱이 55 mg 2 /dl 2 이상인환자의사망률은칼슘과인의곱이 55 mg 2 /dl 2 미만인환자의사망률과비교할때사망률에유의한차이가없었으나, 시간경과에따른사망률에는유의한차이를보여주고있다. 이것은만성신부전을갖고있는환자의사망률과칼슘과인의곱수치와의관련성을제시하고있는것으로환자의사망률에미치는장기적인임상연구가필요하다고사료된다. 고인산혈증은속발성골이영양증과연조직석회화를야기할수있으며혈중 calcitriol 수치를낮출수있는데이와같은고인산혈증을조절하여목표수치를유지할때만성신부전환자의사망률을감소시키는여부는확실치않으므로 KDOQI guideline 2010 4) 에의하면투석중인 3~5단계만성신부전환자의경우칼슘함유인결합제또는 calcitriol/vitamin D ( 사망률은 vitamin D사용시개선되지않음 29) ) 의사용량을제한하고동맥에석회화가있는경우에칼슘함유인결합제의사용을제한하고있다. 그리고고인산혈증을치료하기위하여인결합제를사용하거나, 인산을포함한식사를제한하거나투석을사용할수있지만, 18) 높은심혈관계사망과관련있는만성신부전환자의고인산혈증을 30-31) 치료할때현재의투석과인산을제한하는식이요법효과에관하여아직논란의여지가있다. 12,.32) 현재인산의목표수치를유지하기위하여사용하는약물로는주로칼슘함유인결합제와관상동맥과동맥에칼슘축적이적은 sevelamer가있다. 3) 국내건강보험심사평가원에의하면만성신부전환자에게칼슘함유인결합제를사용할수있는보험기준은칼슘과인의곱수치가 55 mg 2 /dl 2 이하이며칼슘수치는 10.2 mg/dl이상일때이다. Sevelamer를사용할수있는보험기준은말기신부전으로인산수치가 5.5 mg/dl이상이거나칼슘과인의곱수치가 55 mg 2 /dl 2 이상일때이며 Cinacalcet은칼슘의수치가 10.2 mg/dl이상인사람으로투석이필요한만성신부전환자이거나 3개월이상 vitamin D치료에반응이없는환자로칼슘수치가 9.0-10.2 mg/dl (ipth level > 300 pg/ml) 인환자
204 Kor. J. Clin. Pharm., Vol. 24, No. 3, 2014 에게사용할수있다. 따라서 KDOQI guideline에의한목표수치보다고인산혈증을나타내는다수의만성신부전환자에게인결합제를사용하여고인산혈증을치료할때보험기준으로인한어려움이있다. 30) 또한칼슘과인의곱수치가 55 mg 2 /dl 2 이상인환자와사망간관계에대하여장기적인무작위대조시험이필요하며이에따른인결합제사용을위한보험기준도재고할필요가있을것으로본다. 본연구는단일의료기관을대상으로진행된것이므로모든대상자에게본연구결과를적용하지못할수있다. 또한연구에참여한우리나라만성신부전환자는혈액투석과복막투석을사용하는빈도가외국인에비하여높으며섭취하는음식의인함량에도차이가있고, 입원환자의과거인결합제의사용약력이현재약물사용에미치는영향을분석하기어려운점도있다. 왜냐하면인결합제는질병발생시일시적또는간헐적으로사용하는특징이있기때문이다. 또한이러한단점을보완하기위하여인결합제를처음사용하는만성신부전환자만을대상으로평가한다면, 모집단규모가현저히감소하여통계적분석이곤란할수도있다. 그리고환자마다초기입원병원이다르고환자의의무기록만으로는그기간의정확성을평가하기어려우며관찰연구로서환자에게직접적으로약력을질의할수없는제한점이있다. 따라서일정한연구기간을설정하여발생한신체질병, 검사수치변화와연구기간전발생한결과 ( 과거병력, 검사수치, 질병진행 ) 를비교함으로써약물사용에따른석회화와사망에미치는영향을추정하였다. 또한검사자료를기초로한임상관찰연구이므로혈관석회화를나타내는전산화단층촬영영상을제공할수없고약 3년간의기간동안관찰한연구이므로장기적인결과를나타내지못하는제한점이있다. 결 혈관석회화의존재는만성신부전환자의사망률의증가와는연관이없었다. 인결합제는혈관의석회화를감소하지못하는것과관계가있으나만성신부전환자의사망률은감소하는것과관계가있다. 그러나인결합제를사용할때환자의사망과혈관석회화에미치는유익한효과에관하여임상연구결과가일치하지않으므로만성신부전환자의사망률과석회화를감소하기위해사용하는인결합제의장기적효과에관한지속적연구가필요하다. 또한고인산혈증으로야기되는혈관의석회화와사망률을개선할수있는새로운인결합제의개발도필요하다고사료된다. 론 감사의말씀 본연구는덕성여자대학교 2014년도교내연구비지원에의해수행되었음. 참고문헌 1. Moorthi RN, Moe SM. CKD-Mineral and bone disorder: Core Curriculum 2011. Am J Kidney Dis 2011;58:1022-36. 2. Rodriguez-Ortiz ME, Lopez I, Muñoz-Castañeda JR, et al. Calcium deficiency reduces circulating levels of FGH23. J Am Soc Nephrol 2012;23:1190-97. 3. Bellinghieri G, Santoro D, Savica V. Emerging drugs for hyperphosphatemia. Expert Opin. Emerging Drugs 2007;12: 355-65. 4. Uhlig K, Berns JS, Kestenbaum B, et al. KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD Mineral and Bone Disorder (CKD-MBD). Am J Kid Dis 2010;55:773-99. 5. Seaghdhaa CM, Hwang SJ, Muntner P, et al. Serum phosphorus predicts incident chronic kidney disease and end-stage renal disease. Nephrol Dial Transplant 2011;26:2885-90. 6. Barreto DV, Barreto Fde C, de Carvalho AB, et al. Phosphate binder impact on bone remodeling and coronary calcification--results from the BRiC study. Nephron Clin Pract 2008;110:c273-83. 7. Block G A, Raggi P, Bellasi A, et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 2007;71:438-41. 8. Qunibi W, Moustafa M, Muenz LR, et al. CARE-2 Investigators. A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) study. Am J Kidney Dis 2008;51:952-65. 9. Coen G, Manni M, Mantella D, et al. Are PTH serum levels predictive of coronary calcifications in haemodialysis patients. Nephrol Dial Transplant 2007;22:3262-67. 10. Barreto FC, Barreto DV, Liabeuf S, et al. Effects of uremic toxins on vascular and bone remodeling. Semin Dial 2009;22:433-37. 11. Moe SM, Chen NX. Mechanism of vascular calcification in CKD. J Am Soc Nephrol 2008;19:213-16. 12. McCullough PA, Chinnaiyan KM. Annual progression of coronary calcification in trials of preventive therapies. Arch Intern Med 2009;169:2064-70. 13. Lau WL, Pai A, Moe SM, et al. Direct effects of phosphate on vascular cell function. Adv Chronic Kidney Dis 2011;18:105-12.
만성신부전환자의혈관석회화와사망률에미치는인결합제의영향 205 14. Levey AS, Josef CJ, Bolton K, et al. National kidney foundation KDOQI clinical practice guideline for chronic kidney disease; evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-S266. 15. Budoff MJ, Rader DJ, Reilly MP. Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) study. Am J Kidney Dis 2011;58:519-26. 16. Chen NX, Moe SM. Vascular calcification: Pathophysiology and risk factors. Curr Hypertens Rep 2012;14:228-37. 17. Suki WN, Zabaneh R, Cangiano JL, et al. Effect of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney International 2007;72:1130-37. 18. Navaneethan SD, Palmer SC, Craig JC, et al. Benefits and Harms of Phosphate Binders in CKD: A Systematic Review of Randomized Controlled Trials. Am J Kid Dis 2009;54:619-37. 19. Moe SM, Drueke TB, Block GA, et al. KDIGO clinical guideline for the management of CKD-MBD. Kidney Int 2009;76:S1-S130. 20. Suetonia C, Palmer AH, Peter M, et al. Serum levels of phosphorous, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease (a systemic review and metaanalysis). JAMA 2011;305:1119-27. 21. Stevens LA, Li S, Wang C, et al. Prevalence of CKD and Comorbid Illness in Elderly Patients in the United States: Results From the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 2010;55:S1-S28. 22. Snyder JJ, Collins AJ. Association of preventive health care with atherosclerotic heart disease and mortality in CKD. J Am Soc Nephrol 2009;20:1614-22. 23. United States Renal Data System (USRDS) annual data report. 1 2013;74:81-82. 24. Reynolds JL, Joannides AJ, Skepper JN, et al. Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to change in extracellular calcium and phosphate concentration: A potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 2004;15:2857-67. 25. Cecilia MG. The emerging role of phosphate in vascular calcification. Kidney Int 2009;75:890-97. 26. O Neill WC. The fallacy of the calcium-phosphorus product. Kid Intern 2007;72:776-92. 27. Terai K, Nara H, Takakura K, et al. Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels. British J Pharm 2009;156:1267-1278. 28. Linefsky JP, O Brien KD, DPhil RK, et al. Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels. J Am Coll Cardiol 2011;58:291-297. 29. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Intern 2007;72:1004-1013. 30. Foley RN, Collins AJ, Kalra PA. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults. The atherosclerosis risk in communities (ARIC) study. Am Heart J 2008;156:556-63. 31. Foley RN, Collins AJ, Chales A, et al. Serum phosphate and left ventricular hypertrophy in young adults: The coronary artery risk development in young adults study. Kidney Blood Press Res 2009;32:37-44. 32. Hutchison A J. Oral phosphate binders. Kid Intern 2009;75:906-914.