원저 Lab Med Online Vol. 9, No. 1: 12-16, January 임상화학 신기능저하환자에서혈청유리형경쇄 kappa/lambda 비의증가 Increment of Seru

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1 원저 Lab Med Online Vol. 9, No. 1: 12-16, January 2019 임상화학 신기능저하환자에서혈청유리형경쇄 kappa/lambda 비의증가 Increment of Serum Free Light Chain Kappa/Lambda Ratio in Patients with Renal Dysfunction 정재원 1 정명아 2 김현주 1 김세환 1 오애진 1 이진경 1 홍영준 1 장윤환 1 Jae Won Jung, M.D. 1, Myeong A Cheong, M.D. 2, Hyun Ju Kim, M.T. 1, Sae Hwan Kim, M.T. 1, Ae-chin Oh, M.D. 1, Jin Kyung Lee, M.D. 1, Young Jun Hong, M.D. 1, Yoon Hwan Chang, M.D. 1 한국원자력의학원원자력병원진단검사의학과 1, 신장내과 2 Departments of Laboratory Medicine 1 and Internal Medicine 2, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea Background: Since free light chain (FLC) is metabolized in the kidney, serum FLC concentration and kappa/lambda ratio are increased in patients with decreased renal function, even in the absence of monoclonal protein. In this study, we measured serum FLC levels to investigate the change in kappa/lambda ratios in relation to the severity of renal dysfunction. Methods: Serum FLC concentrations were measured in 92 archived serum samples from patients diagnosed with chronic kidney disease using the Freelite assay (The Binding Site Group Ltd., UK), and kappa/lambda ratios were calculated. Serum creatinine levels were assayed to calculate estimated glomerular filtration rate (egfr), and patients were divided into subgroups according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines. We analyzed the difference in serum FLC levels and kappa/lambda ratios between subgroups. Results: Serum FLC levels and kappa/lambda ratios increased depending on the severity of renal dysfunction. When patients were classified by setting cut-off value of egfr as 60 ml/min/1.73 m 2 (group A: egfr 60 ml/min/1.73 m 2, group B: <60 ml/min/1.73 m 2 ), the kappa/lambda ratio of group B was significantly higher than that of group A (group B: 1.60±0.46 vs. group A: 1.35±0.27, P =0.018). Serum FLC kappa/lambda ratios were within the previously determined renal reference interval ( ). Conclusions: When interpreting results of serum FLC kappa/lambda ratio, renal function status should be considered in addition to hematological findings. If renal function deteriorates, a wider renal reference interval is preferred instead of the usual reference interval. Key Words: Serum free light chain, Kappa/lambda ratio, Chronic kidney disease 서론 체액성면역을담당하는항체, 즉면역글로불린은각각 2 개의 중쇄 (heavy chain) 와 2 개의경쇄 (light chain) 로이루어져있다. 유 Corresponding author: Yoon Hwan Chang Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea Tel: , Fax: , cyhlabo@kirams.re.kr Received: May 18, 2018 Revision received: September 7, 2018 Accepted: September 20, 2018 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. 리형경쇄 (free light chain, FLC) 는형질세포에서면역글로불린이생산되는과정에서중쇄와결합하지못한경쇄로, 정상적으로소량이만들어지고생성후수시간내에신장에서제거되어혈중에축적되지않는다 [1, 2]. 그러나, 형질세포골수종 (plasma cell myeloma) 과같은단클론성형질세포질환의일부에서는 FLC의생산이매우증가하게되어혈중 FLC 농도가높아지게되고, 원주신장병증 (cast nephropathy) 이발생하여신조직에손상을유발하게된다 [3, 4]. 단세포군감마글로불린병증 (monoclonal gammopathy) 의진단은혈청 FLC 검사와함께단백전기영동검사 (protein electrophoresis, PEP), 면역고정전기영동검사 (immunofixation electrophoresis, IFE) 등전통적검사방법과기타검사소견및임상소견, 영상소견등을종합하여이루어지게되며, 단세포군감마글로불린병증의선별검사로서혈청 FLC 검사, 혈청및소변 PEP 및 IFE 검사를모두함께시행할때진단민감도를 98.6% 까지상승시킬수있다 [5]. 또 12 eissn

2 한, 경쇄침착질환 (light chain deposition disease) 에대한민감도는혈청및 FLC 소변 PEP 및 IFE 검사를모두시행할때는 83.3%, 혈청 FLC 검사만단독시행할때는 77.8% 로, PEP 또는 IFE 검사단독시행 ( 각각 55.6%) 시보다민감도가높다 [5]. 현재 PEP 및 IFE와함께혈청 FLC 측정은다발골수종등의형질세포질환의진단과추적검사에필수적인검사이며, International Myeloma Working Group (IMWG) 에서발표한다발골수종진단기준및치료반응기준에도 FLC 검사항목이포함되어있다 [6, 7]. 혈중 FLC는신장에서사구체여과에의해걸러지며, 신세뇨관에서재흡수및분해된다. 따라서, 사구체여과율이감소되어있는만성신질환환자에서는단클론단백이없는상태에서도제거율이떨어져다클론성 (polyclonal) FLC의혈중농도가상승하고 kappa/ lambda 비도증가하는것으로알려져있다 [8, 9]. FLC의검사방법중가장흔히사용되는방법은면역비탁법또는면역혼탁법으로측정하는 Freelite 검사 (The Binding Site Group Ltd., Birmingham, UK) 이다. 이검사법에서제조사가제시하는정상신기능을가진대상군에대한혈중 FLC kappa/lambda 비의참고범위는 이며 [10], 이범위를벗어나는결과는단세포군감마글로불린병증을의심하여야한다. 그러나, 신기능이저하된환자에서는신기능이정상인환자에비해혈중 FLC kappa/lambda 비가증가되는경향이있어단세포군감마글로불린병증과의감별에혼선을줄수있기때문에, 신기능저하군에대한참고범위를따로설정할필요가있음을여러논문에서제기하였다 [11-14]. 본연구에서는신기능저하환자를대상으로혈중 kappa FLC 및 lambda FLC의분포를측정하고, 신기능감소정도에따른 kappa/lambda 비의연관성에대해분석하고자하였다. 재료및방법 본연구는한국원자력의학원기관윤리심의위원회 (institutional review board) 의승인 (K ) 을받은후, 한국원자력의학원국가방사선혈액자원은행에보관된만성신질환환자 92명의혈청잔여검체를대상으로시행하였다. Roche cobas c501 (Roche Diagnostics, Mannheim, Germany) 장비를이용하여혈청크레아티닌정량검사 (Jaffe법), kappa FLC 및 lambda FLC 정량검사 (Freelite, The Binding Site Group Ltd.) 를시행하였다. 측정된 FLC 값을이용하여 kappa/lambda 비 (kappa FLC/lambda FLC) 를계산하였다. 단클론단백의존재를확인하기위해 HYDRAGEL PROTEIN E (Sebia, Issy-Ies-Moulineaux, France) 를이용한 PEP 검사를함께시행하였고, 뚜렷한띠가관찰된경우 HYDRAGEL IF (Sebia) 를이용하여 IFE 검사를추가로실시하였다. 측정된혈청크레아티닌결과치와환자의나이, 성별및인종정보를바탕으로 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 공식을이용하여 egfr 을계산하였고 [15], 미국 National Kidney Foundation 의 Kidney Disease Improving Global Outcomes (KDIGO) 지침의분류 에따라대상환자들의 egfr 을기준으로신기능경도감소군 (G2, egfr ml/min/1.73 m 2 ), 중등도감소군 (G3, egfr ml/min/1.73 m 2 ), 중증감소군 (G4, egfr ml/min/1.73 m 2 ), 신부전군 (G5, egfr <15 ml/min/1.73 m 2 ) 으로분류하였다 [16]. 각 군에서의 kappa FLC, lambda FLC 및 kappa/lambda 비의분포를 관찰하여신기능감소정도에따라 kappa/lambda 비의차이가있 는지알아보기위해 SPSS 통계프로그램 (version 23.0, SPSS Inc., Chicago, USA) 을이용하여 Kruskal-Wallis test 및 Mann-Whitney U test 를시행하였으며, P <0.05 일경우통계학적으로유의한차이 가있는것으로간주하였다. 정규성검정을위해 Kolmogorov-Smirnov test 를시행하였다. 결과 대상환자군의특성을 Table 1 에제시하였고, KDIGO 지침에따 라환자군을 4 개군으로분류하였을때각군의혈중 FLC 및 kappa/ lambda 비의분포는 Table 2 와같다. 총 92 명의대상자중남성은 Table 1. Demographic and laboratory characteristics of study population of patients with renal dysfunction (N=92) Characteristics Age (yr) Sex Number Median 66 Range Male 52 (56.5%) Female 40 (43.5%) Kappa FLC (mg/l) <3.3 0 (0%) (5.4%) > (94.6%) Lambda FLC (mg/l) <5.7 0 (0%) (38.0%) > (62.0%) Kappa/lambda ratio < (0%) (65.2%) > (34.8%) egfr (ml/min/1.73 m 2 ) (27.2%) (47.8%) (15.2%) <15 9 (9.8%) Abbreviation: FLC, free light chain. 13

3 Table 2. Distribution of serum FLC and kappa/lambda ratio in patients with renal dysfunction Groups Kappa FLC (mg/l) Lambda FLC (mg/l) Kappa/lambda ratio Total (N=92) 42.2 ( )* 30.8 ( )* 1.41 ( )* G2 (mild kidney dysfunction) (N=25) 24.0 ( )* 18.0 ( )* 1.32 ( )* G3 (moderate kidney dysfunction) (N=44) 42.4 ( )* 30.2 ( )* 1.40 ( )* G4 (severe kidney dysfunction) (N=14) 84.7 ( )* 51.3 ( )* 1.77 ( )* G5 (kidney failure) (N=9) ( )* 58.5 ( )* 1.86 ( )* Reference interval (Katzmann et al. [10]) ( )* Renal reference interval (Hutchison et al. [9]) 43.8 ( )* 38.0 ( )* 1.1 ( )* *Data are medians (min-max); Data are central 95% intervals. Abbreviation: FLC, free light chain P=0.128 P=0.002 P=0.045 P= P=0.018 K/L ratio K/L ratio P=0.284 P= Group A A Group B B Fig. 1. Comparison of kappa/lambda ratio among patient groups according to severity of renal dysfunction. (A) Comparison between 4 groups divided by KDIGO guideline (group 2, mildly decreased; group 3, moderately decreased; group 4, severely decreased; group 5, kidney failure). (B) Comparison between two groups, group A (egfr 60 ml/min/1.73 m 2 ) vs. group B (egfr <60 ml/min/1.73 m 2 ). KDIGO represents Kidney Disease Improving Global Outcomes. 52명, 여성은 40명이었으며전체평균연령은 63.2±10.7세 ( 중앙값 66세, 범위 34 86세 ) 였다 (Table 1). egfr에따라분류시신기능경도감소군 (G2) 25명, 중등도감소군 (G3) 44명, 중증감소군 (G4) 14명, 신부전군 (G5) 9명이었다. 혈중 kappa FLC 중앙값은 42.2 mg/ L ( 참고범위 : mg/l), lambda FLC 중앙값은 30.8 mg/l ( 참고범위 mg/l), kappa/lambda 비의중앙값은 1.41 ( 참고범위 ) 이었다 (Table 2). Katzmann 등 [10] 이제시한 FLC 정상참고범위를기준으로하였을때, kappa FLC가증가된환자는전체의 94.6% (87/92) 였고, Lambda FLC가증가된환자는전체의 62.0% (57/92), kappa/lambda 비가증가된환자는전체의 34.8% (32/92) 이었다 (Table 1). Kolmogorov-Smirnov test 를시행하여혈중 FLC 및 kappa/lambda 비의정규성에대해검정한결과모두비정규분포를이루고있었다 (P <0.001). 신기능에따른 4개군분류에서그룹간차이를 Kruskal-Wallis test로분석하였을때각군의혈중 kappa FLC, lambda FLC 및 kappa/lambda 비값은신부전군, 중증감소군, 중등도감소군, 경도감소군순으로높았으며, 일부그룹간 ( 신부전군과중등도감소군간, 중증감소군과경도감소군간, 그리고신부전군과경도감소군간 ) 에서통계적으로유의한차이를보였다 ( 각각 P = 0.031, 0.045, 0.002) (Fig. 1A). egfr 60 ml/min/1.73 m 2 를기준으로 ( 그룹 A: egfr 60 ml/min/1.73 m 2, 그룹 B: <60 ml/min/ 1.73 m 2 ) 재분류하여 Mann-Whitney U test를통해분석하였을때, kappa/lambda 비는그룹 B가그룹 A에비해높았으며통계적으로유의한차이를보였다 ( 그룹 B: 1.60±0.46 vs 그룹 A: 1.35±0.27, P = 0.018) (Fig. 1B). 고찰 신기능이정상인경우혈청 FLC는신장에서의제거기전을통해빠르게제거된다. 혈청 FLC의생산량은 kappa FLC가 lambda 14

4 FLC보다약 2배가량많지만, 신장에서의제거율은단량체 (monomer) 형태의분자크기가작은 kappa FLC가이합체 (dimer) 형태의 lambda FLC보다 3배정도빠르기때문에, 혈청에서측정되는 kappa/ lambda 비도중앙값 0.58 ( 참고범위 ) 로낮은값을보인다 [1, 2]. 하지만신장기능이떨어져사구체여과율이감소할경우혈청 FLC의제거기전은신장에서의제거보다는망상내피계에서의세포흡수작용 (pinocytosis) 에의한제거가큰비중을차지하게되며, 망상내피계의제거기전은분자의크기와관계없이 FLC를제거한다. 따라서사구체여과율의감소가심할수록점차적으로혈중 FLC의생산량에영향을받게되어 kappa FLC의혈중농도가상대적으로상승하여 kappa/lambda 비율이증가하게되며 [9, 17]. 신기능이저하된환자에대한혈중 FLC의 kappa/lambda 비참고범위도정상인구집단을대상으로하는참고범위보다높게산정해야한다고보고되어있다 [3, 9, 11-14]. Hutchison 등의만성신질환환자대상연구에서는신기능저하환자군에대한혈청 FLC kappa/lambda 비의참고범위 (renal reference interval) 를 로제시하였다 [9]. 본연구에서는신기능저하환자 92명을대상으로 Freelite 검사 (The Binding Site Group Ltd.) 를이용하여혈청 FLC와 kappa/lambda 비를측정하였는데, 환자수가 120명이되지않아신기능저하환자에서의참고범위를자체적으로설정하지는않았으며, 기존에발표된참고범위의검증과정으로서측정된 kappa/lambda 비를제시된 renal reference interval에적용하였을때모두범위내의결과를보였다. 신기능을반영하는 egfr의감소정도에따라그룹을나누어그룹간 kappa/ lambda 비를분석하였을때, 신기능감소가심할수록 kappa/lambda 비는증가하였으며유의한차이를보였다. 임상에서혈청 FLC kappa/lambda 비가일반적인참고범위 ( ) 에서는벗어났지만 renal reference interval ( ) 안에들어있는결과를보일경우, 즉 kappa/lambda 비가 정도의값을보일경우에는해석에주의를요하게된다. 한연구에따르면, 만약신기능이정상이라면이범위 ( ) 의 kappa/lambda 비결과는단클론성질환과연관이있음을시사하며추가적인검사시행및임상소견검토가필요하고, 신기능이비정상이라면대체로신기능저하로인한결과일가능성이높지만, 일부환자에서는아밀로이드경쇄아밀로이드증 (Amyloid light-chain amyloidosis) 등의특정질환이동반되었는지에대한추가적인검사가필요하다는주장이제기되었다 [11]. 또한, 만성염증이나감염, 자가면역질환등의질환이동반되었을때에도혈중 FLC가다클론성증가를보일수있으며 [8, 18], 환자의혈중에단클론단백이존재함에도불구하고 polyclonal background 에가려져서 kappa/lambda 비값이참고범위내에있을수있기때문에, 혈중 FLC 및 kappa/lambda 비결과는다른검사소견및임상소견을종합하여해석하여야할필 요가있다. 본연구의제한점은다음과같다. 첫째, 본연구는단일기관의 92명의신기능저하환자검체만을대상으로하였으며, 신기능저하환자군전체를대표하지못할수있다는점이다. 둘째, 신기능저하만을변수로하여산출된결과로감염, 염증등기타만성질환의동반여부는반영되지않았다는점이다. 결론적으로, Freelite 검사를이용하여신기능저하군을대상으로분석한혈중 FLC 및 kappa/lambda 비의분포는기존연구결과와유사한결과를보였다. 신기능저하정도에따라 5개의그룹으로나누어그룹간 kappa/lambda 비를비교한결과신기능저하가심한그룹일수록 kappa/lambda 비의값이높았으며, 통계적으로유의한차이를보였다. 혈중 FLC kappa/lambda 비의값이 의값을보이는경우에는환자의신기능을확인하여결과의해석을단클론성이상에의한것인지, 또는신기능저하로인한다클론성이상인지주의하여해석하여야한다. 요약 배경 : 혈청유리형경쇄 (free light chain, FLC) 는신장에서대사되므로, 신기능이저하된환자에서는단클론단백이존재하지않는상태에서도혈청 FLC 농도가상승하고 kappa/lambda 비도증가하는것으로알려져있다. 본연구에서는신기능저하환자에대해혈중 FLC 및 kappa/lambda 비를측정하고, 신기능저하의정도에따른 kappa/lambda 비의연관성에대해분석하고자하였다. 방법 : 한국인만성신질환환자 92명의보관된혈청검체를대상으로 Freelite 검사 (The Binding Site Group Ltd., UK) 를사용하여 kappa FLC, lambda FLC를정량하였고, kappa/lambda 비를구하였다. 혈청크레아티닌측정값을이용하여사구체여과율추정값 (estimated glomerular filtration rate, egfr) 을계산하였고, 미국 National Kidney Foundation의 Kidney Disease Improving Global Outcomes (KDIGO) 지침의분류에따라신기능경도감소군, 중등도감소군, 중증감소군, 신부전군으로분류하였고, 그룹간 kappa FLC, lambda FLC 및 kappa/lambda 비의차이가있는지분석하였다. 결과 : 신기능감소의정도가심할수록혈중 FLC 및 kappa/lambda 비가높았으며, egfr 60 ml/min/1.73 m 2 를기준으로환자를분류하였을때 ( 그룹 A: egfr 60 ml/min/1.73 m 2, 그룹 B: <60 ml/ min/1.73 m 2 ) 그룹 B의 kappa/lambda 비가그룹 A에비해유의하게높았다 ( 그룹 B: 1.60±0.46 vs 그룹 A: 1.35±0.27, P = 0.018). 신기능저하환자에서의혈청 FLC kappa/lambda 비참고범위검증결과모든환자에서기존참고범위 ( ) 내의값을보였다. 결론 : 혈청 FLC kappa/lambda 비결과를해석할때에는혈액학적소견외에도환자의신기능을반드시참조하여야하며, 신기능이 15

5 저하되어있는경우에는기존의참고범위에비해넓게설정된 kappa/ lambda 비참고범위를적용하는것이바람직할것으로생각된다. 이해관계 저자들은본연구와관련하여어떠한이해관계도없음을밝힙니다. 감사의글 검체를제공해주신한국원자력의학원국가방사선혈액자원은행에감사의뜻을표합니다. REFERENCES 1. Bradwell AR, Carr-Smith HD, Mead GP, Harvey TC, Drayson MT. Serum test for assessment of patients with Bence Jones myeloma. Lancet 2003;361: Bradwell AR. Serum free light chain measurements move to center stage. Clin Chem 2005;51: Heher EC, Rennke HG, Laubach JP, Richardson PG. Kidney disease and multiple myeloma. Clin J Am Soc Nephrol 2013;8: Finkel KW, Cohen EP, Shirali A, Abudayyeh A; American Society of Nephrology Onco-Nephrology Forum. Paraprotein related kidney disease: evaluation and treatment of myeloma cast nephropathy. Clin J Am Soc Nephrol 2016;11: Katzmann JA, Kyle RA, Benson J, Larson DR, Snyder MR, Lust JA, Rajkumar SV, Dispenzieri A. Screening panels for detection of monoclonal gammopathies. Clin Chem 2009;55: Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016;17:e Nowrousian MR, Brandhorst D, Sammet C, Kellert M, Daniels R, Schuett P, et al. Serum free light chain analysis and urine immunofixation electrophoresis in patients with multiple myeloma. Clin Cancer Res 2005; 11: Hutchison CA, Harding S, Hewins P, Mead GP, Townsend J, Bradwell AR, et al. Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease. Clin J Am Soc Nephrol 2008;3: Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell AR, et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem 2002;48: Hutchison CA, Plant T, Drayson M, Cockwell P, Kountouri M, Basnayake K, et al. Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure. BMC Nephrol 2008;9: Abadie JM, van Hoeven KH, Wells JM. Are renal reference intervals required when screening for plasma cell disorders with serum free light chains and serum protein electrophoresis? Am J Clin Pathol 2009;131: Diamantidis MD, Ioannidou-Papagiannaki E, Ntaios G. Novel extended reference range for serum kappa/lambda free light chain ratio in diagnosing monoclonal gammopathies in renal insufficient patients. Clin Biochem 2009;42: Park JW, Kim YK, Bae EH, Ma SK, Kim SW. Combined analysis using extended renal reference range of serum free light chain ratio and serum protein electrophoresis improves the diagnostic accuracy of multiple myeloma in renal insufficiency. Clin Biochem 2012;45: Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150: Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3: Leung N, Barnidge DR, Hutchison CA. Laboratory testing in monoclonal gammopathy of renal significance (MGRS). Clin Chem Lab Med 2016;54: Hutchison CA and Landgren O. Polyclonal immunoglobulin free light chains as a potential biomarker of immune stimulation and inflammation. Clin Chem 2011;57:

012임수진

012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar