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1 J Korean Soc Transplant 2010;24: DOI: /jkstn Original Article 공여자와수혜자의성별, 연령, 체질량지수조합에따른생체신이식의이식신생존율의장기성적에대한연구 한양대학교의과대학외과학교실 김은진ㆍ권오정 The Graft Outcomes of Living Donor Renal Transplantation according to Gender, Age, and BMI Matching between Donors and Recipients Eun Jin Kim, M.D. and Oh Jung Kwon, M.D. Department of Surgery, Hanyang University College of Medicine, Seoul, Korea Background: Despite significant advances in immunosuppression, supportive therapies, and operative skills, several factors still compromise long-term graft survival of patients who undergo renal transplantation. This study was designed to evaluate the risk factors influencing graft outcomes of living donor renal transplantation. We matched the recipient and donor age, gender, and body mass index (BMI). Methods: A total of 527 living renal transplantations were evaluated. The patients were divided into matching groups by donor and recipient age; group 1 (50 /; 2, 50 /<50; 3, <50/50 ; 4, <50/<50), gender (A, female/female; B, female/male; C, male/female; D, male/male), and BMI ratio (recipient/donor) (I, <0.8; II, 0.8 /<1.3; III, 1.3 ). We compared 1, 3, 5, and 10 year graft survival and analyzed the donor and recipient variables of age, HLA matching, and acute rejection. Results: The risk factors affecting long-term graft survival were recipient gender, acute rejection rate, and HLA-AB matching. In the groups divided according to donor and recipient age, no statistical difference was observed among the groups, but the 3 5 yr graft survival of group 1 (94.1/86.9%) was much higher than group 2 (86.5/75.6%). In the groups divided according to donor and recipient gender, graft survival in group C was higher than that in the other groups. No statistical difference in acute rejection or graft survival were observed in the groups with different BMI ratios. Conclusions: Meticulous preoperative donor and recipient matching for living renal transplantation may improve graft survival and expand the donor and recipient pool. Key Words: Kidney transplantation, Graft survival rate 중심단어 : 신이식, 이식신생존율 서론 신장이식은면역학의발전, 면역억제제의발달, 수술술기및수술후치료의발전으로보편적인치료방법으로받아들여지고있고경제적측면과생활의질향상에큰도움이되어말기신부전환자의가장효과적인치료법으로확립되었다 (1,2). 평균수명의증가등으로만성 책임저자 : 권오정, 서울시성동구행당동산 17 번지한양대학교의과대학외과학교실, Tel: , Fax: ojkwon@hanyang.ac.kr 접수일 : 2010 년 8 월 2 일, 심사일 : 2010 년 9 월 7 일게재승인일 : 2010 년 9 월 13 일 신부전환자는꾸준히증가하고있고이에따라신장이식을기다리는환자는점점증가하고있으나 (3,4) 공여장기의공급은이에훨씬못미치고있다. 우리나라에서도 2000년뇌사의법적인정으로뇌사자로부터의장기이식이꾸준히늘고있어국립장기이식관리센터의보고에의하면, 2008년전체신장이식수혜자는 1,144명, 뇌사자로부터의신장이식은 495예시행되었으나, 신장이식대기자는 7,641명으로공여자의절대적인부족현상은해결되지않았다. 따라서신장이식의성적을더향상시키고공여자부족현상을극복하기위해서이식생존율에영향을미치는여러인자들에대한이해가더욱필요하며특히생체신이식은수술전충분한검사와준비가가능함으로공여자와수혜자의성별, 연령, 체질량지수의조합 J Korean Soc Transplant September 2010 Volume 24 Issue 3

2 에따른장기이식생존율을분석하여더많은공여자확보및이상적인조합을찾고자하였다. 대상및방법 1992년 1월부터 2007년 11월까지한양대학병원외과에서생체공여자로부터신장이식을받고추적관찰이가능하였던 527명을대상으로하였다. 공여자와수혜자의연령에따라 4군, 성별에따라 4군, 체질량지수비에따라 3군으로분류하였다. 공여자와수혜자의연령에따라 1군은 50세이상공여자-50세이상수혜자 (n=18), 2군은 50세이상공여자-50세미만수혜자 (n=104), 3군은 50세미만공여자-50세이상수혜자 (n=66), 4군은 50세미만공여자-50세미만수혜자 (n=339) 로하였다. A군은여자공여자-여자수혜자 (n=79), B군은여자공여자-남자수혜자 (n=149), C군은남자공여자-여자수혜자 (n=99), D군은남자공여자-남자수혜자 (n=200) 로하였다. 수혜자와공여자의체질량지수비에따라제I군은 0.8 미만 (n= 104), 제II군은 0.8이상, 1.3 미만 (n=368), 제III군은 1.3 이상 (n=27) 으로분류하였고각군에따라공여자및수혜자의연령, 성별, human leukocyte antigen (HLA)-AB, HLA-DR 적합도, 급성거부반응여부와 1, 3, 5, 10년이식생존율을비교하였으며공여자및수혜자의연령, 성별, HLA-AB, HLA-DR 적합도, 급성거부반응발생여부에따른 1, 3, 5, 10년이식생존율또한비교분석하였다. 이식후면역억제제는 cyclosporine 혹은 tacrolimus, immuran이나 mycophenolate mefetil, steroid의삼중면역억제제를사용하였다. 급성거부반응은임상적으로의심이되는경우혈관도플러초음파 (doppler duplex scan) 를시행하여신동맥저항지수 (resistive index, RI) 가 0.8 이상인경우급성거부반응으로진단하였으나다른원인에대한감별이필요한경우신생검을시행하여조직학적인확인을하였다. 이식신소실기준은이식신절제나혈액투석을다시시작한때까지로하였고, 환자가사망한경우에는그사망시점을기준으로하였다. 통계분석은 SPSS Window version 17.0 for window (SPSS Inc., Chicago, IL, USA) 를사용하였고각군사이의이식신생존율은 Kaplan Meier 생존분석을통하여산출하였고 log rank test를이용하여군간의생존곡선을비교하여통계학적유의성을평가하였다. 각군의특성은 ANOVA test로비교분석하였고 P 값이 0.05 이하에서통계학적으로의의가있는것으로판정하였다. 결과 1) 장기이식신생존율에영향을주는인자 이식신생존율에영향을주는요소를분석하기위해공여자, 수혜자의성별및연령, HLA-AB 및 DR 일치개수, 급성거부반응발생여부등에따른 1, 3, 5, 10년이식신생존율을비교하였다. 분석결과수혜자의성별, HLA-AB 적합성및급성거부반응의발생여부가이식신의생존율에영향을주었다 (Table 1). 2) 연령에따른공여자와수혜자의조합에따른이식신생존율 HLA-AB 및 HLA-DR 적합성은각각 1군 1.44/0.89, 2 군 1.95/1.16, 3군 1.80/1.08, 4군 1.76/1.07개로각군간의차이는없었으며급성거부반응발생률은 1군 27.8%, 2군 31.6%, 3군 18.2%, 4군 31.9% 로통계학적으로유의한차이는없었다 (Table 2). 각군의 1, 3, 5, 10년이식생존율은각각 1군 100/94.1/86.9/57.6%, 2군 92.3/86.5/ 75.6/55.8%, 3군 97.0/90.9/79.9/64.6%, 4군 95.6/89.7/ Table 1. Factors influencing long-term graft survival 1 yr 3 yr 5 yr 10 yr Donor gender F M Recipient gender F M Donor age < Recipient age < HLA-AB matching HLA-DR matching Acute rejection <0.001 Positive None P J Korean Soc Transplant September 2010 Volume 24 Issue 3

3 Table 2. Characteristics of study population group according to donor and recipient age Group 1 (n=18) 50 /50 ) Group 2 (n=104) 50 /<50) Group 3 (n=66) <50/50 ) Group 4 (n=339) <50/<50) P Donor age (mean±sd) 53.2± ± ± ±7.8 Recipient age (mean±sd) 54.3± ± ± ±8.3 HLA-AB matching 1.44± ± ± ± HLA-DR matching 0.89± ± ± ± Acute rejection Graft survival (1 yr/3 yr/5 yr/10 yr) 100/94.1/86.9/ /86.5/75.6/ /90.9/79.9/ /89.7/81.0/ Table 3. Characteristics of study population group according to donor and recipient gender Group A (n=79) Female/Female) Group B (n=149) Female/Male Group C (n=99) Male/Female Group D (n=200) Male/Male) P Donor age (mean±sd) 40.3± ± ± ±11.2 <0.001 Recipient age (mean±sd) 35.8± ± ± ± HLA-AB matching 2.0± ± ± ± HLA-DR matching 1.10± ± ± ± Acute rejection Graft survival (1 yr/3 yr/5 yr/10 yr) 96.3/91.3/84.9/ /89.2/75.7/ /94.9/87.7/ /85.0/75.7/ ) 성별에따른공여자와수혜자의조합에따른이식신생존율 Fig. 1. Graft survival according to age matching (donor/recipient). Group 1, 50 /50 ; Group 2, 50 /<50; Group 3, <50/50 ; Group 4, <50/<50. In the groups according to donor and recipient age, there was no statistical difference among the groups (P=0.230) 81.0/65.9% 로통계학적으로유의한차이는보이지않았다 (Fig. 1, P=0.230). 각군의공여자와수혜자의연령의평균은 A군 40.3/ 35.8세, B군 42.6/37.5세, C군 37.4/40.2세, D군 38.0/ 38.6세로수혜자의연령에따른차이는없었으나여자가공여자인군 (A, B군 ) 이남자가공여자인군 (C, D군 ) 보다평균연령이더많았다 (P<0.001). HLA-AB 및 HLA-DR 항원적합성은 A군 2.0/1.10개, B군 1.67/1.09개, C군 1.75/ 1.04개, D군 1.82/1.09개로각군간의차이는없었다. 급성거부반응은 A군 20.2%, B군 38.1%, C군은 26.1%, D군은 38.2% 로 B군과 D군의발생빈도가더높았다 (Table 3, P=0.012). 각군의 1, 3, 5, 10년이식생존율은 A군은 96.3/91.3/84.9/64.6%, B군은 95.3/89.2/75.7/ 58.9%, C 군은 99.0/94.9/87.7/83.7%, D군은 93.5/85.0/75.7/57.9% 로 1, 3년이식생존율의차이는없었으나 A, C 군의 5년이식생존율이 B, D보다더높았으며 C군의 10년이식생존율이다른군보다더높았다 (Fig. 2). J Korean Soc Transplant September 2010 Volume 24 Issue 3

4 Fig. 2. Graft survival according to matching gender (donor/recipient). Group A, female/female; Group B, female/male; Group C, male/female; Group D, male/male. Graft survival in group C was higher than that in the other groups (Group A, P=0.006; Group B, P<0.001; Group D, P<0.001). Fig. 3. Graft survival according to body mass index (BMI) ratio (recipient/donor). Group I, <0.8; Group II, 0.8 /<1.3; Group III, 1.3. No statistical difference in graft survival was observed in the groups with different BMI ratios. Abbreviation: BMI, body mass index. Table 4. Characteristics of study population group according to body mass index (BMI) ratio (recipient/donor) Group I (n=104) (<0.8) Group II (n=368) (0.8 /<1.3) Group III (n=27) (1.3 ) P Donor age (mean±sd) 41.8± ± ± Recipient age (mean±sd) 35.1± ± ±7.8 <0.001 HLA-AB matching 1.73± ± ± HLA-DR matching 1.09± ± ± Acute rejection Graft survival (1yr/3yr/5yr/10yr) 90.4/84.6/80.6/ /89.7/80.2/ /92.6/88.9/ ) 체질량지수비에따른수혜자와공여자의조합에따른이식신생존율각군의공여자와수혜자의연령의평균은 I군 41.8/ 35.1세, II군 39.1/38.8세, III군 36.5/43.1세이었고 HLA- AB 및 HLA-DR 적합성은각각 I군 1.73/1.09, II군 1.79/ 1.09, III군 1.74/1.09로각군간의차이는없었다. 급성거부반응발생률은 I군 26.9%, II군 31.89%, III군 25.92% 로발생률에차이를보이지않았다 (Table 4). 각군의 1, 3, 5, 10년이식생존율은 I군 90.4/84.6/80.6/63.7%, II 군 96.5/89.7/80.2/64.2%, III군 96.3/92.6/88.9/67.1% 로각군간의차이를찾을수없었다 (Fig. 3). 고찰 1956년 Harrison 등 (5) 에의해 monozygotic twin에서 최초로성공적인신장이식이이루어진이후면역학적발전및면역억제제의발달등으로신장이식은현재말기신부전환자의치료중가장좋은치료법으로확립되었다 (1,2). 평균수명의연장으로인한고령인구의증가로신장질환역시증가하고있으며 (3,4) 해마다신장이식을기다리는말기신부전환자의수는꾸준히증가하고있으나공여자의부족으로시행되는신장이식수는한정되어있어신장이식대기자는점점증가하고있다 (3,6). 이러한공여자의부족을해결하기위하여고령의공여자, marginal 공여자, ABO incompatible 공여자, 교환공여자등의여러방법들이시도되고있으며 (6-8) 이러한프로그램을통한성공적인신장이식을위해서는장기이식신생존율에영향을주는인자에대한정확한분석이중요하다. 이식신의예후에영향을미치는인자들은꾸준히연구되어왔으며여러인자들이단독으로또는서로연관되 J Korean Soc Transplant September 2010 Volume 24 Issue 3

5 어이식신의예후에영향을미치는것으로알려져왔다. 공여자유형, 공여자의연령및성별, HLA 적합도, 이식전투석기간등이이식신의장기생존율에영향을주는인자임은여러문헌에서보고되고있다 (1,8-14). 공여자의연령과이식신의생존율의연관성에대하여서는논란이있다. 많은문헌에서공여자의연령이많을수록이식신생존율이좋지않음을주장하고있으며이는연령이많아질수록신장에신장경화 (nephrosclerosis), 동맥경화발생가능성이높으며사구체여과율의점진적인저하로인한결과로설명하고있다 (11,15,16). Busson 과 Benoit (17) 도고령공여자의경우수술중냉허혈시간을연장시키는경향이있어급성세뇨관괴사의발생률이높아져이식신의예후에나쁜영향을미친다고하였다. 그러나최근공여자부족해결을위해시도되고있는고령공여자-고령수혜자조합의신장이식에대한연구들에서좋은결과가발표되고있다 (8,18,19). Cohen 등 (18) 은냉허혈시간의연장, 재신이식등의위험인자들을피한다면고령공여자-고령수혜자의신장이식도성공적일수있음을주장하였고 Fritsche 등 (19) 은급성거부반응의위험성때문에 HLA-matching이고령공여자- 고령수혜자간의신장이식의성공여부에중요한인자라하였다. 본연구에서는공여자의연령에따른장기이식생존율은유의한차이를보이지않았다 (Table 1). 고령의공여자군 (1,2군) 에서는통계학적으로유의한차이를보이지는않았으나 (P=0.448) 1군의 3/5년이식생존율 94.1/ 86.9%, 2군의 3/5년이식생존율 86.5/75.6% 로고령의수혜자로의신장이식이결과가더좋음을알수있었다. 고령의수혜자의경우고령의공여자로부터의이식신생존율이젊은공여자로부터의이식신생존율과차이가없었다 (P=0.895). 따라서공여자부족을해결하기위해서는고령의공여자로부터의신장이식도적극적으로시도하여야하며특히고령의수혜자와 matching함으로써공여자의확대를기대할수있겠다. 신장이식초창기에는환자가고령일수록 1차적인신장질환의유병기간이길고, 혈관및심장, 순환계등에속발하는다른전신적합병증이많이동반되며, 면역억제제투여에대한탄력성이약화되어이식신의생존율및환자사망률이높다고생각하여, 수혜자의연령에대한제한을두고 50세이상의환자에서는신장이식을기피해왔다 (20). 그러나본연구에서는수혜자의연령에따른이식생존율에차이가보이지않았고공여자와수혜자의연령의조합에따른장기이식생존율분석에서도통계학적으로유의한차이가없어 50세이상의고령의말기신부전환자에서도신장이식이가장효과적인치료법이라 고생각한다. 이식신의신장조직의양은이식신의생존율을결정하는중요한요소이다 (21,22). Nicholson 등 (21) 은여성공여자-남성수혜자의경우남성공여자-여성수혜자의경우에비해서이식신생존율이더나쁘며이는신장의콩팥단위 (nephron) 개수는신장의무게와밀접한관계가있는데여성의콩팥은남성의콩팥보다더작고콩팥단위의개수는 17% 더적기때문이라고설명하고있다. 본연구에서도남성공여자-여성수혜자의이식신생존율이여성공여자-남성수혜자보다더좋았으나 (P<0.001) 두군간에급성거부반응여부에차이가있어이에따른통계학적치우침 (bias) 이발생하였을가능성이있어급성거부반응여부에차이가보이지않는여성공여자-여성수혜자군과남성공여자-남성수혜자군의이식신생존율을비교하였고역시남성공여자-여성수혜자군의이식신생존율이더좋음을알수있었다 (P=0.006). 또한남성공여자-남성수혜자군과의비교에서도남성공여자-여성수혜자군의이식신생존율이더좋아 (P<0.001) 단순히공여자의성별또는이식신의무게보다는공여자와수혜자의적절한조합이중요함을알수있었고보편적으로남성이여성보다몸무게및체질량지수가더큼을생각해보았을때공여자의체질량지수가수혜자보다더클때좋은이식신생존율을얻을수있다는가설을세워볼수있다. Kasiske 등 (23) 은체질량지수가작은공여자로부터체질량지수가큰수혜자로의신장이식에서이식실패율이현저히높음을보고하였다. 이는여러연구들에서주장되어왔던과부하가설을뒷받침하는것으로콩팥단위개수가부적절한경우이를보상하기위해사구체에서과투과가이루어지게되고이는신장에지속적인손상을입히게된다. 본연구에서의체질량지수비에따른공여자와수혜자의이식신생존율에서는유의한차이를보이지않았다. 이는우리나라가서양에비해비만인구가적어 III군이다른군에비해그수가현저히적은한계점으로생각한다. 결론 1992년 1월부터 2007년 11월까지한양대학병원외과에서생체공여자로부터신장이식을받고추적관찰이가능하였던 527명을대상으로공여자와수혜자의성별, 연령, HLA-AB, HLA-DR 적합도, 급성거부반응여부에따른이식신장기생존율을비교분석한결과수혜자의성별, HLA-AB 적합도, 급성거부반응발생여부가이식신의생존율에영향을주었다. 고령공여자-고령수혜자와 J Korean Soc Transplant September 2010 Volume 24 Issue 3

6 젊은공여자-고령수혜자의이식신생존율에차이가없어고령공여자-고령수혜자의신장이식도성공적일수있음을알수있었으며남성공여자-여성수혜자의이식신생존율이다른군에비해월등히좋았으나다른군들의이식신생존율은큰차이가없었다. 따라서젊은공여자, 남성공여자만을선호하기보다는공여자와수혜자의적절한조합이더좋은신장이식결과및공여장기의확보에중요하다. REFERENCES 1) Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to N Engl J Med 2000;342: ) Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LYC, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341: ) Calne R. Clinical transplantation: current problems, possible solutions. Philos Trans R Soc Lond B Biol Sci 2005;360: ) Sims RJ, Cassidy MJ, Masud T. The increasing number of older patients with renal disease. BMJ 2003;327: ) Harrison JH, Merrill JP, Murray JE. Renal homotransplantation in identical twins. Surg Forum 1956;6: ) Hayes JM, Novick AC, Streem SB, Hodge EE, Bretan PN, Graneto D, et al. The use of single pediatric cadaver kidneys for transplantation. Transplantation 1988;45: ) Alexander JW, Vaughn WK. The use of marginal donors for organ transplantation. The influence of donor age on outcome. Transplantation 1991;51: ) Remuzzi G, Cravedi P, Perna A, Dimitrov BD, Turturro M, Locatelli G, et al.; Dual Kidney Transplant Group. Long-term outcome of renal transplantation from older donors. N Engl J Med 2006;354: ) Gjertson DW, Cecka JM. Living unrelated donor kidney transplantation. Kidney Int 2000;58: ) Koo DD, Welsh KI, McLaren AJ, Roake JA, Morris PJ, Fuggle SV. Cadaver versus living donor kidneys: impact of donor factors on antigen induction before transplantation. Kidney Int 1999;56: ) Halloran PF, Melk A, Barth C. Rethinking chronic allograft nephropathy: the concept of accelerated senescence. J Am Soc Nephrol 1999;10: ) Opelz G, Wujciak T, Döhler B, Scherer S, Mytilineos J. HLA compatibility and organ transplant survival. Collaborative Transplant Study. Rev Immunogenet 1999;1: ) Mange KC, Joffe MM, Feldman HI. Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors. N Engl J Med 2001;344: ) Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis. Transplantation 2002;74: ) Basar H, Soran A, Shapiro R, Vivas C, Scantlebury VP, Jordan ML, et al. Renal transplantation in recipients over the age of 60: the impact of donor age. Transplantation 1999;67: ) Bilgin N, Karakayali H, Moray G, Demirağ A, Arslan G, Akkoç H, et al. Outcome of renal transplantation from elderly donors. Transplant Proc 1998;30: ) Busson M, Benoit G. Is matching for sex and age beneficial to kidney graft survival? Clin Transplant 1997;11: ) Cohen B, Smits JM, Haase B, Persijn G, Vanrenterghem Y, Frei U. Expanding the donor pool to increase renal transplantation. Nephrol Dial Transplant 2005;20: ) Fritsche L, Hörstrup J, Budde K, Reinke P, Giessing M, Tullius, et al. Old-for-old kidney allocation allows successful expansion of the donor and recipient pool. Am J Transplant 2003;3: ) Park K, Suh JS, Kim YS, Kim SI. Living-donor renal transplantation, univariate analysis of risk factors influencing renal allograft outcome from 500 cases. J Korean Surg Soc 1991;41: ( 박기일, 서재석, 김유선, 김순일. 생체신이식 500 예를대상으로분석한이식성적에영향을미치는인자에관한연구. 대한외과학회지 1991;41: ) 21) Nicholson ML, Windmill DC, Horsburgh T, Harris KP. Influence of allograft size to recipient body-weight ratio on the long-term outcome of renal transplantation. Br J Surg 2000;87: ) Brenner BM, Cohen RA, Milford EL. In renal transplantation, one size may not fit all. J Am Soc Nephrol 1992;3: ) Kasiske BL, Snyder JJ, Gilbertson D. Inadequate donor size in cadaver kidney transplantation. J Am Soc Nephrol 2002;13: J Korean Soc Transplant September 2010 Volume 24 Issue 3

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untitled J Korean Soc Transplant 2009;23:154-160 DOI: 10.4285/jkstn.2009.23.2.154 Original Article 단일기관에서교환이식프로그램을이용한배우자간신장이식및부부간신장이식의결과 한양대학교의과대학외과학교실 임진규ㆍ김민수ㆍ권오정 The Results of Spousal Donor Kidney Transplantation