원저 Lab Med Online Vol. 1, No. 4: , October 임상화학 콩팥기능이상의신속정확한진단을위하여 Roche 효소법검사와일치시킨 Nova CCX 혈액가스

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1 원저 Lab Med Online Vol. 1, No. 4: , October 2011 임상화학 콩팥기능이상의신속정확한진단을위하여 Roche 효소법검사와일치시킨 Nova CCX 혈액가스분석기를이용한크레아티닌검사평가 Creatinine Determination by Nova CCX Analyzer Harmonized with the Roche Enzymatic Method for Early and Accurate Detection of Renal Dysfunction 김효식 1 박형천 2 정성필 3 김정호 1 Hyo-Sik Kim, M.D. 1, Hyoungchun Park, M.D. 2, Sungpil Chung, M.D. 3, Jeong-Ho Kim, M.D. 1 연세의대강남세브란스병원진단검사의학과 1, 신장내과 2, 응급의학과 3 Departments of Laboratory Medicine 1, Internal Medicine 2, and Emergency Medicine 3, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Background: Early detection of underlying renal dysfunction among emergency patients is important, particularly before imaging studies using contrast media. The estimated glomerular filtration rate (egfr) calculated from creatinine values is useful in situations requiring rapid evaluation and detection of renal impairment. Methods: We evaluated the concordance of egfr determined using the whole blood creatinine test by Nova CCX (Cr-CCX WB; Nova Biomedical, USA) method and the serum creatinine test by Roche Integra 800 (Cr-RE Serum; Roche Diagnostics, Switzerland) enzymatic method, which is known to be traceable to the isotope dilution mass spectrometric (ID-MS) reference method. Results: Compared to Cr-RE Serum (x), Cr-CCX WB (y) showed good correlation but unacceptable total error and negative proportional bias (Deming regression, y=0.92x+0.02; r=0.98; n=61). However, when we adjusted the Cr-CCX WB values with a new slope and offset derived from the Deming regression analysis with Cr-RE Serum, the concordance rate improved from 0.77 to 0.93 (as measured by kappa statistics), and total errors became acceptable except at 1 level. When we used the ID-MS traceable egfr formula, the Nova CCX demonstrated sufficient sensitivity (93.5%) and specificity (100%) for the detection of renal dysfunction (egfr less than 60 ml/min/1.73 m 2 ) in patients. Conclusions: We concluded that if we adjusted the harmonizing factors of Nova CCX according to the ID-MS traceable method, then the Nova CCX might be a relatively accurate point-of-care creatinine analyzer for detecting renal dysfunction among patients undergoing urgent imaging studies with radiological contrast media. Key Words: Creatinine, Estimated glomerular filtration rate, Nova CCX, Enzymatic 서론 만성콩팥병은신부전으로이행되기전에조기에진단되고치료 Corresponding author: Jeong-Ho Kim, M.D. Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eunju-ro, Gangnam-gu, Seoul , Korea Tel: , Fax: , jeongho@yuhs.ac Received: March 29, 2011 Revision received: July 11, 2011 Accepted: July 15, 2011 This article is available from , Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 를받는것이중요하다. 이를위해혈중크레아티닌수치를근거로 Modification of Diet in Renal Disease (MDRD) 공식을이용한사구체여과율추정 (estimation of the glomerular filtration rate, egfr) 계산법이전세계적으로널리이용되고있다 [1]. 특히컴퓨터단층촬영술을해야하는경우에조영제를투여받고검사하는경우가많은데, 조영제의신독성 (contrast-induced nephropathy, CIN) 을일으키는문제가있어이러한콩팥기능감소환자를조기에진단하는것은매우중요하다 [2]. 조영제의신독성은병원에서발생하는신부전증의주요원인으로보고되어있고만성콩팥병환자에서조영제와함께방사선검사시행후조영제의신독성발생위험률이높은것으로알려져있다 [2]. 또한미국과한국의식품의약안정청은 egfr이 30 ml/min/1.73 m 2 이하인환자를대상으로가돌리늄증강자기공명 (gadolinium-enhanced magnetic resonance) 을사용할경우에콩팥성전신섬유증 (nephrogenic systemic sclerosis) eissn

2 김효식외 : Nova CCX 에의한크레아티닌검사평가 의위험을경고한바있다 [3-5]. egfr (less than 60 ml/min/1.73 m 2 ) 의낮은수치는조영제신독성의가장중요한위험인자이며상기와같은이유로 egfr의신속검사가필요하다 [2]. 최근직접전혈 (whole blood) 로크레아티닌을측정하는현장검사법 (point-of-care testing, POCT) 이개발되어조영제를투여받고응급방사선검사를필요로하는환자에게검사소요시간을크게감소시켜그효용성이강조되고있다 [6-9]. 또한동위원소희석질량분석법 (isotope dilution mass spectrometry, ID- MS) 의검사소급성 (traceability) 여부에따른크레아티닌검사법에대한적절한 egfr 계산공식을선택해야한다 [10]. 일반적으로현장검사법장비는재현성이나정확도가떨어지는것으로알려져있고, 특히콩팥기능이약간감소되어있는만성콩팥병질환의진단시크레아티닌농도가높지않을경우에도정확성이유지되는지에대한연구는적은실정이며, 전혈로크레아티닌을측정하는현장검사법장비중에 ID-MS로검사소급성을평가한연구보고는부족한상태이다 [9]. 대상및방법 본연구에서는동일한환자에서혈청과헤파린처리전혈이확보된경우에혈청을사용하여 ID-MS 방법의검사소급성이있다고알려진 Roche Cobas Integra 800 analyzer (Roche Diagnostics, Basel, Switzerland) 로크레아티닌을측정하고, 전혈을사용하여현장검사법장비인 Nova Stat Profile Critical Care Xpress (Nova CCX, Nova Biomedical, Waltham, MA, USA) 로크레아티닌을측정하여비교하였다. 전혈은환자의정맥에서헤파린전혈시험관 (heparinized venous whole-blood, BD vacutainer, Franklin Lakes NJ, USA) 에채혈하여얻었고, 혈청은같은환자에서혈청분리시험관 (serum separator tube, BD vacutainer, Plymouth, UK) 에채혈하여얻었다. 총 61명의환자에서각각의검체를동시에얻었다. 연구기간은 2010년 9월부터 11월까지였으며모든크레아티닌검사는채혈후 4시간내에이루어졌다. 연구기간동안환자검체로크레아티닌검사를시행한날 Nova CCX에서두가지농도의정도관리물질 (quality control, QC) 로일간정밀도 (inter-day imprecision) 평가를진행하였다. Nova CCX와 Roche Integra 800은검사시기본적으로동일한효소 (creatinine amidohydrolase, creatine amidohydrolase 및 sarcosine oxidase) 를사용하지만두장비에서최종산물인과산화수소생성과정에서차이가있는데 Nova CCX는백금전극 (platinum electrode) 을통해전자를발생시켜전류를측정하는방법 (amperometric) 을사용하며, Roche Integra 800은 quinine imine을과산화효소 (peroxidase) 로추가한비색법 (colorimetric) 을사용한다. 또한 Nova CCX와 Roche Integra 800의정확도를평가하기위해 CLSI 지침서에따라 6가지농도로제조한신선냉동혈청을일본검사의학표준물질기구 (Reference material institute for clinical chemistry standards, ReCCS) 에의뢰하여 ID-MS 법으로기준값을얻은 6가지농도의검체를해동한후에냉장보관한후에매일중복 (duplicate) 측정하며 3일간크레아티닌농도를측정하여평가하였다 [11,12]. 통계분석은엑셀 (Excel, Microsoft, Redmond, WA, USA) 과 Analyse-It version 2.21 (Analyse-It Software Ltd, Leeds, UK) 을사용하였다. 결과 대상군총 61명의연령은 58.6±16.4 ( 평균 ± 표준편차 ) 세였으며남성이 33명, 여성이 28명이었다. 이중 egfr이 30 ml/min/1.73 m 2 미만인환자가 16명, ml/min/1.73 m 2 인환자가 14명, 60 ml/ min/1.73 m 2 이상인환자가 31명이었다. 연구기간동안 Nova CCX 에서시행한 2가지농도의정도관리물질 (0.89 mg/dl, 5.86 mg/dl) 의검사차례내 (within-run) 변이계수, 일간 (between-day) 변이계수및총변이계수는크레아티닌농도 0.89 mg/dl (SD, 0.03) 에서각각 2.1%, 2.0% 및 2.9% 였고, 크레아티닌농도 5.86 mg/dl (SD, 0.16) 에서각각 1.5%, 2.2% 및 2.7% 였다. 정확도평가를위해시행한 ReCCS 검사결과와의비교분석에서전반적으로 Nova CCX 결과는비교적큰음성오차 (negative bias) 를보였고총오차 (total error) 기준으로최소한의허용기준인 11.4% 이내의농도는 0.81 mg/dl 의한가지농도밖에없었다 [13] (Table 1). 환자의검체를대상으로한 Nova CCX의크레아티닌검사결과 (y) 에서도 Roche Integra 800의검사결과 (x) 보다전체적으로비슷하지만 -8% 의음성오차를보이는것을알수있었다 (y = 0.92x+ 0.02, r = 0.98; Deming 회귀방정식 ). 또한전혈대신에 Roche Integra 800 검사시에사용한혈청으로 Nova CCX로검사한결과 (x) 와비교했을경우에도 Nova CCX 전혈검사결과 (y) 는유사하지만약간다른음성오차를보였다 (y = 0.90x+ 0.0, r = 0. 99; Deming 회귀방정식 ). 따라서 Roche Integra 800 결과를기준으로 Nova CCX 결과에기기일치도인자 (instrument harmonizing factors) 적용한후각각의장비로계산한크레아티닌비교평가결과는 y=1.00x (r = 0.97; Roche, x; Nova CCX, y; Fig. 1) 로일치도가개선되었으며총오차의허용범위를벗어나는경우는 0.81 mg/dl에서양의오차를보이며벗어난것외에다른농도는모두허용범위내에들었다 (Table 1). 한편, egfr의일치도는 Table 2와같이 kappa값으로 0.77에서 0.93 으로개선되었다. egfr 검사의의학적결정치인 60 ml/min/1.73 m 2 보다높고 90 ml/min/1.73 m 2 미만인환자들까지포함하여 43명을대상으로, 180

3 김효식외 : Creatinine Determination by Nova CCX Table 1. Evaluation of bias and total error of Nova CCX creatinine determination CFS creatinine Level CFS creatinine target value* Creatinine Average Nova CCX method before adjustment Total CVa (%) Bias (%) TE (%) Remark* Creatinine Average Nova CCX method after adjustment Total CVa (%) Bias (%) TE (%) Remark* Level Acceptable Unaccpetable Level Unaccpetable Desirable Level Unaccpetable Desirable Level Unaccpetable Desirable Level Unaccpetable Acceptable Level Unaccpetable ) 9.43 Acceptable *Remark, unacceptable, acceptable, and desirable were based on TE (%) described in the reference #9, i.e., desirable TE, 7.6%; acceptable TE, %; unacceptable, TE>11.4%. Abbreviations: CFS, commutable frozen serum; ReCCS, Reference material institute for clinical chemistry standards; CVa, analytical coefficient of variation, total precision of creatinine levels; TE, total error=bias+1.96 Cva. Table 2. Comparison of renal dysfunction according to the estimated glomerular filtration rate (egfr) calculated using Nova CCX with Roche enzymatic method Nova CCX (whole blood) Unadjusted (slope, 1.0; offset, 0) Adjusted (slope, 1.087; offset, ) <60 ml/min/1.73 m 2 60 ml/min/1.73 m 2 *<60 ml/min/1.73 m 2 * 60 ml/min/1.73 m 2 Roche (serum) <60 ml/min/1.73 m ml/min/1.73 m Kappa statistics improved from 0.77 to 0.93 (95% confidence interval, ; P <0.0001). *After adjustment of harmonizing factors according to the Roche enzymatic method. Creatinine level by Nova CCX method using whole blood with factors Scatter plot with deming fit Identity Deming fit ( x) 95% CI bands Creatinine level by Roche enzymatic method using serum Fig. 1. Deming fit of 61 creatinine values determined using Nova CCX and Roche enzymatic method after adjustment of harmonizing factors. 기기일치도인자 (slope =1.087; offset =-0.022) 적용후 egfr 비교 평가의결과는 y = 0.97x+3.44 (r = 0.98; Roche, x; Nova CCX, y; Fig. 2) 이었다. Roche 효소법과비교하여 Nova CCX 에서 egfr 이 60 ml/ egfr (ml/min/1.73 m 2 ) by Nova CCX adjusted factors using whole blood Scatter plot with deming fit Identity Deming fit ( x) 95% CI bands egfr (ml/min/1.73 m 2 ) by Roche enzymatic method using serum Fig. 2. Deming fit of egfr values lower than 90 ml/min/1.73 m 2 (n=43) determined Nova CCX and Roche enzymatic method after adjustment of harmonizing factors; correlation coefficient, r=0.98. min/1.73 m 2 미만의신기능감소환자를발견해낼수있는민감도 (sensitivity) 와특이도 (specificity) 는각각 93.5%, 100% 였다

4 김효식외 : Nova CCX 에의한크레아티닌검사평가 고찰 혈청크레아티닌의정확도평가는종전의외부정도관리를통해서알기어렵고, 신선동결혈청을사용하여평가할필요가있다 [14]. 본연구에서는 61명의무작위환자를대상으로동시에채혈된전혈과혈청으로각각 Nova CCX 장비와 Roche Integra 800 장비로크레아티닌검사결과를실제환경에서비교하였다. Nova CCX 전혈검사결과는 Roche Integra 800 혈청검사결과보다크레아티닌검사결과가전반적으로다소낮게측정이되었다. 이는 Nova CCX의크레아티닌측정방법과동일한방법을사용하는 Nova StatSensor POCT 전혈검사의비교연구와유사하였다 [9]. 일반적으로현장검사기기는검사결과를신속하게얻을수있는반면에재현성이나정확도가떨어지는것으로알려져있고, NOVA StatSensor 역시보정이필요하다는연구결과를보였다 [10]. 그러나저자들이 Nova CCX를 ID-MS에검사소급성이있는 Roche Cobas Integra 효소법과비교하고기기일치도인자를입력하여보정한후에다시측정한경우오차를많이줄일수있었고, 가장낮은 0.81 mg/dl의농도외에는모두총오차가허용범위내에들었다 [12] (Table 1). 가장낮은농도인 0.81 mg/dl는 egfr상정상범위내에들어가는농도이고더구나양성오차를보이므로콩팥기능의이상을찾는데민감도가감소될가능성은적다고판단된다. 유사장비인 Nova StatSensor는손끝피부천자를통해모세혈관혈액으로검사할수있는편리성이있는데, 기기일치도인자를조절한후에민감도는 96% 로높아졌지만, 특이도는 79% 로낮아져서진단의효율에문제가있었다 [9]. 하지만본연구에서의 Nova CCX는기기일치도인자를조절한후에민감도와특이도가각각 93.5% 및 100% 로 Nova CCX가더우수한진단효율을보인것은피부천자혈액이아닌헤파린처리혈액을사용하였기때문이라볼수있다. 즉, StatSensor 는피부천자혈액으로단지 1.2 μl의혈액이필요하지만, Nova CCX는적어도 150 μl의전혈이필요하다. 조영제를사용하여컴퓨터단층촬영이나심장혈관조영술을하는환자는대개혈액검사를하게되므로혈액검사시에함께크레아티닌용헤파린처리전혈을채혈하여검사를하면비교적검사결과를신속하게얻을수있다. 이에비해중앙검사실에서검사를하려면, 검체의수송및원심분리등의시간이소요되어시간이더많이소요된다. 그러나요즘응급실이나수술방등에는현장검사용혈액가스분석기를보유하고있는경우가많으므로이분석기에크레아티닌을함께검사함이효율적이라할수있다. 더욱이본연구와같이 Roche Integra 800과일치도평가를진행한후계산한기기일치도인자를적용하였을경우콩팥기능장애를찾는데우수한민감도와특이도와정확성을보였다. 특히조영제를투여하고방사선검사를응급으로시행할필요가있는경우에도움이된다. 만성콩팥병환자에서발생할 수있는조영제의신독성은반드시예방해야할중요한문제이다. 그러나 Nova CCX 장비는크레아티닌전극막교환주기가 1주일정도로짧으므로철저한정도관리와 Roche Cobas Integra 효소법과같은참고방법과의주기적인비교평가를통해그정확도를유지해야할것이다. 이를위해본연구자들의기관에서는매주 1회씩진단검사의학과의임상병리사 1명이두가지농도의검체로응급진료센터에비치된 Nova CCX 장비로측정하고바로진단검사의학과의기준표준화장비인 Cobas Integra에서측정을하여검사결과를비교하고분석함으로써실제환자검체에서의일치도를평가하고있다. 결론적으로 Nova CCX 전혈크레아티닌측정방법은참고방법과의주기적인비교및철저한정도관리를한다면신속한결과를가져올수있는현장검사방법일뿐만아니라, 만성콩팥병의진단에민감도와특이도가우수한유용한검사법이라고생각된다. 요약 배경 : 조영제를사용하여영상의학검사를시행해야되는응급환자에게콩팥기능의신속한판단은중요하다. 크레아티닌수치로 egfr의측정은콩팥기능의신속한평가에큰도움을준다. 방법 : 전혈과혈청이동시에확보된 61명의환자검체를대상으로전혈을사용한 Nova CCX 크레아티닌검사결과와혈청을사용한동위원소희석질량분석법에검사소급성이확인된 Roche Integra 800 크레아티닌효소법검사결과의일치도를평가하였다. 결과 : Nova CCX 전혈크레아티닌검사결과는 Roche Integra 800 혈청검사결과와비교하여좋은상관관계를보였지만허용범위를벗어나는음성오차를보였다. 계산된기기일치도인자를적용한후정확도평가결과총오차가한가지농도를제외하고모두허용기준범위내에있었으며, 일치율비교에서 kappa값이 0.77에서 0.93 으로개선되었다. 또한 Nova CCX 크레아티닌결과를 egfr 공식을적용한후콩팥기능이감소되어있는환자 (egfr< 60 ml/ min/1.73 m 2 ) 를찾아낼수있는민감도와특이도는각각 93.5%, 100% 로높아졌다. 결론 : Nova CCX 전혈크레아티닌검사는 ID-MS에검사소급성이있는참고방법과맞추고주기적정도관리를하면, 조영제를투여하여방사선검사를진행해야하는환자중에콩팥기능이감소되어있는환자를신속하고정확하게찾아내는데중요한역할을할수있다고판단된다. 감사의글 신선동결혈청을제조하고또한일본표준검사실 ReCCS 에의뢰 182

5 김효식외 : Creatinine Determination by Nova CCX 하여참값을측정하고그일부검체를공여해준분당서울대병원송정한교수님께감사를드리며, 크레아티닌전극을공급해준동방 POC 회사에감사합니다. 참고문헌 1. Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, et al. Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem 2007;53: Barrett BJ and Parfrey PS. Clinical practice. Preventing nephropathy induced by contrast medium. N Engl J Med 2006;354: U.S. Food and Drug Administration. Information for healthcare professionals: gadolinium-based contrast agents for magnetic resonance imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance). SafetyInformationforPatientsandProviders/ucm htm (Updated in Dec 2010). 4. Kim KH, Fonda JR, Lawler EV, Gagnon D, Kaufman JS. Change in use of gadolinium-enhanced magnetic resonance studies in kidney disease patients after US Food and Drug Administration warnings: a cross-sectional study of Veterans Affairs Health Care System data from Am J Kidney Dis 2010;56: Korea Food and Drug Administration. Information for safety letter for gadolinium based-contrast agents. mid=394&pageno=2&seq=8824&cmd=v (Updated in Sep 2010). 6. Flegar-Mestrić Z and Perkov S. Comparability of point-of-care wholeblood electrolyte and substrate testing using a Stat Profile Critical Care Xpress analyzer and standard laboratory methods. Clin Chem Lab Med 2006;44: Korpi-Steiner NL, Williamson EE, Karon BS. Comparison of three whole blood creatinine methods for estimation of glomerular filtration rate before radiographic contrast administration. Am J Clin Pathol 2009; 132: Schnabl KL, Bagherpoor S, Diker P, Cursio C, Dubois J, Yip PM. Evaluation of the analytical performance of the Nova StatSensor creatinine meter and reagent strip technology for whole blood testing. Clin Biochem 2010;43: Shephard M, Peake M, Corso O, Shephard A, Mazzachi B, Spaeth B, et al. Assessment of the Nova StatSensor whole blood point-of-care creatinine analyzer for the measurement of kidney function in screening for chronic kidney disease. Clin Chem Lab Med 2010;48: Vickery S, Stevens PE, Dalton RN, van Lente F, Lamb EJ. Does the ID- MS traceable MDRD equation work and is it suitable for use with compensated Jaffe and enzymatic creatinine assays? Nephrol Dial Transplant 2006;21: Clinical and Laboratory Standards Institute. Preparation and validation of commutable frozen human serum pools as secondary reference materials for cholesterol measurement procedures; approved guideline. CLSI document C37-A. Wayne, PA: Clinical and Laboratory Standards Institute Reference material institute for clinical chemistry standards (ReCCS). (Updated in Mar 2005). 13. Myers GL, Miller WG, Coresh J, Fleming J, Greenberg N, Greene T, et al. Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clin Chem 2006;52: Miller WG, Myers GL, Ashwood ER, Killeen AA, Wang E, Thienpont LM, et al. Creatinine measurement: state of the art in accuracy and interlaboratory harmonization. Arch Pathol Lab Med 2005;129:

Na +, K +, Cl, tco 2, BUN, Creatinine, Glucose, ica에대하여 Clinical and Laboratory Standards Institute (CLSI) 의기준에따라정밀도, 직선성, 상관성등의성능평가를시행하였다. 재료및방법 후, 원

Na +, K +, Cl, tco 2, BUN, Creatinine, Glucose, ica에대하여 Clinical and Laboratory Standards Institute (CLSI) 의기준에따라정밀도, 직선성, 상관성등의성능평가를시행하였다. 재료및방법 후, 원 원저 Lab Med Online Vol. 5, No. 2: 57-62, April 2015 임상화학 현장검사화학분석기기인 Abbott i-stat CHEM8+ 의성능평가 Evaluation of i-stat CHEM8+ Point-of-Care Chemistry Analyzer 김도균 신화춘 김병광 정순호 임종백 Do-kyun Kim, M.D., Hwachoon