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1 J Korean Soc Transplant 2010;24:80-86 DOI: /jkstn Review Article 생체신장이식에서공여기준확대의안정성 가톨릭대학교의과대학내과학교실 황현석ㆍ김석영 Safety for Expanding Living-Donor Criteria in Renal Transplantation Hyeon Seok Hwang, M.D. and Suk Young Kim, M.D. Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea The increasing waiting times for deceased donor kidneys have focused attention on living donors as a useful way to increase the organ supply. However, living donors with potential medical risks for renal transplantation raise medical and ethical questions for donor nephrectomy about conditions such as hypertension, hematuria, obesity, and old age. Data on the long-term risks of conditions are sparse and potential acceptance criteria are under development. Many older donors hope to donate to their offspring, despite the presence of elevated blood pressure. Transplant professionals have internal debates on these situations that require a well-defined scoring system for donating risk. This review summarizes the characteristics and risk of marginal living donors in renal transplantation and discusses strategies for overcoming the current limitation. Key Words: Living donors, Safety, Hypertension, Hematuria, Obesity, Old age, Renal transplantation 중심단어 : 생체장기제공자, 안전성, 고혈압, 혈뇨, 비만, 노년, 신장이식 책임저자 : 김석영, 대전시중구대흥동 가톨릭대학교의과대학내과학교실대전성모병원, Tel: , Fax: alterego54@catholic.ac.kr 제 6 차대한이식학회춘계학술대회에서발표한내용임. 접수일 : 2010 년 6 월 8 일, 게재승인일 : 2010 년 6 월 14 일 J Korean Soc Transplant 80 June 2010 Volume 24 Issue 2

2 행할수있게되었다 (5). 이러한의학적발달은제공자부족현상과맞물려생체신장기증자의기준을다시정립하고공여가능범위를확대하는배경을마련하게되었다. 생체신장기증자의범위를확장하여신장이식을시행하는경우, 제공자의안전성및수혜자의임상경과가관건이라할수있다. 그러나, 이에대한보고는각각의연구결과마다차이가있고정확한의견일치가이루어지지않고있다. 이에본종설에서는확대가능한생체신장이식제공자의안전성및임상경과에대해살펴보고, 이러한신장이식의타당성과한계에대해논의해보고자한다. 확장범위에있는생체신장이식제공자의명명법및정의 확대범위에있는생체신장이식제공자에대한용어는다양한형태로사용되고있다. 예를들면, 하나의내과적질환이동반된생체장기제공자 (living donor with isolated medical disease), 복합생체장기제공자 (complex living donor), 한계생체장기제공자 (marginal living donor), 위험인자를가지고있는생체장기제공자 (living donor at incremental risk), 무증상요검사이상을동반한생체장기제공자 (living donor with asymptomatic urinary abnormality) 등의형태로언급되고있다 (6,7). 그러나확대범위에있는제공자는한가지이상의내과질환을가질수있고요검사이상외에다른내과질환이동반할수있으므로, 한계생체장기제공자나복합생체장기제공자가적합한용어라고생각한다. 한계생체신장이식제공자는편측신적출술을시행하기전, 동반된질환이만성신장병 (chronic kidney disease, CKD) 의위험성을증가시키는지평가를받아야한다 (Table 1). 이러한여러위험인자중생체신장이식제공자기준확장에가장중요한논점이되고있는것은 (1) 혈압이 140/90 mmhg 이상이거나혈압약을복용하는경우 (2) 무증상혈뇨가있는경우 (3) 신체용적지수 (body mass index) 가 30 kg/m 2 이상 (4) 고령의제공자일경우이다. 고혈압이있는제공자고혈압은말기신장병을일으키는주요원인질환이며만성신장병발생위험도를높인다. 대규모역학조사및분석연구를통한보고에따르면, 이식신장공여후 5 10 년이경과하면정상인보다 5 10 mmhg 혈압이증가하며, 중등도의고혈압이라도말기신장병발병위험도를높이는것으로알려져있다 (Fig. 2) (8,9). 그러나, 표적장기손상이없고다른내과질환이없는환자의경우실제말기신장병발병률은그리높지않다. 당뇨가없는고혈압환자의경우말기신장병발병률은 0.01%/ 인-년 (personyears) 내외로보고되며일부에서는 30 40년동안고혈압에노출되더라도말기신장병발병률은 1% 미만이었다 (10,11). 또한가지, 주목할만한것은고혈압에대한정의와기준이지속적으로변화되어왔다는것이다. 과거 년대에는 160/95 mmhg 이상일경우고혈압으로정의하였으나 (12,13), 2007년 Joint National Committee의보고에서는 140/90 mmhg으로기준을낮추었다 (14). 이렇게고혈압의진단기준강화를위한이론적배경을살펴보면, 심혈관계질환예방에초점을두었기때문이며실제신장기능부전발생예방에는큰비중을두고있지않다. 따라서, 신장손상의증거가없는중등도의고혈압환자에서신장공여자체가말기신장병의위험을높일지는현재 Table 1. Categories of living-donor risk factors for CKD Type of risk factor Example Direct risk for CKD Current renal disease Reduced nephron mass Genetic risk Cardiovascular risk factor Others Hypertension, obesity Hematuria, proteinuria, nephrolithiasis Old age History of ESRD and diabetes in first degree Smoking, hyperlipidemia Black race, sickle trait Abbreviations: CKD, chronic kidney disease. Adapted from Table 1 of reference [6]. Fig. 2. Prediction of ESRD by initial clinic blood pressure values as a function of time in patients without previous kidney disease. Abbreviations: ESRD, end-stage renal disease. Adapted from reference [10]. J Korean Soc Transplant 81 June 2010 Volume 24 Issue 2

3 까지연구결과만으로는불분명하다. Mayo Clinic은중등도의고혈압을가지고있거나혈압약을복용하고있는 24명의환자를생체신장이식제공자로선정하여이식을진행하였다 (15). 이식신장절제술후 6개월에서 12개월간제공자를전향적으로관찰한결과, 혈압상승, 신장손상등의이상반응은관찰되지않았다. 비록단기간의경과관찰이지만, 이번연구는고혈압환자도적합한생체신장이식제공자가될수있는가능성을제시하였다. 이와함께, 2005년생체신장이식제공자관리를위한 Amsterdam 공청회에서는고혈압환자가다음의조건을만족하는경우신장공여가가능하다는지침을발표하였다. (1) 안정적으로조절되는고혈압 (2) 나이가 50세이상 (3) 사구체여과율이 80 ml/ min이상 (4) 미세알부민배출이하루 30 mg 미만을동시에만족하는경우이다 (16). 그러나 1년이상의경과관찰을시행한연구는아직도미흡한상태이며다른연구들에서도고혈압제공자의장기적인안정성을보장해주지는못한다 (17,18). 그러므로, 고혈압이있는환자가신장이식공여후장기적으로안전한임상적경과를보이는가에대해서는아직더많은연구가필요하다. 무증상현미경적혈뇨가있는제공자 무증상현미경적혈뇨는신장이식제공자검사과정에서흔히발견되는이상소견으로, 적합한소변검체를고배율시야에서관찰했을때 3개이상의적혈구가 2 3번이상검출되면지속성현미경적혈뇨라정의한다 (19). 지속성현미경적혈뇨가이식제공자에서발견되면원인규명을위하여일련의검사를시행한다. 혈뇨는크게사구체성과비사구체성혈뇨로구분하고비사구체성혈뇨는방광경, 방사선학적검사등을통해서원인감별을할수있다 (Table 2). 비사구체성혈뇨를일으킬만한원인 Table 2. Causes of persistent microscopic hematuria Glomerular bleeding (without proteinuria) Thin basement membrane disease IgA nephropathy Aloport's syndrome Urinary stone Non-glomerular bleeding Malignancy (bladder, kidney prostate, ureter) Arteriovenous malformation or fistula Hypercalciuria, hyperuricemia Polycystic kidney disease Hemoglobinopathy Other urinary tract infection 이없다면사구체성혈뇨를의심하는데, 이경우 24시간요화학검사를통하여단백뇨동반여부를확인하여야하고만일 300 mg 이상의단백뇨가검출되면신장공여의금기에해당한다. 단백뇨가없는고립성현미경적혈뇨 (isolated microscopic hematuria) 는원인질환에따라신장제공자로서의적합성여부가결정되므로신장조직검사를반드시시행해야한다 (19). 고립성현미경적혈뇨의경우얇은기저막병 (thin basement membrane disease), IgA 신장병증또는 Alport 증후군이원인일경우가많다. 이중 IgA 신장병증이나 Alport 증후군은신장이식제공자가될수없으며, 얇은기저막병은다른신부전의위험인자가없으면신장이식공여가가능하다. 윤등 (20) 의보고에따르면, 고립성현미경적혈뇨로제공자의신장조직검사를시행할경우얇은기저막병이가장흔하였으며이식신장의경과도양호하였다. 그러나, 단순한조직검사만으로는얇은기저막병과 Alport증후군의초기병변과감별이어려운경우가있다. 따라서, 자세한가족력조사가반드시동반되어야하며, 신장조직검사에서얇은기저막병소견이관찰된다할지라도신장질환의가족력이의심된다면신장이식제공자로가능한지재고하여야한다 (19). 이외에도, 전자현미경및제4형콜라겐 (collagen) 염색, 청력검사, 안과검진및유전자검사를시행하면얇은기저막병, IgA신장병증및 Alport증후군을감별하는데도움을줄수있으므로고립성현미경적혈뇨가있는제공자의추가검사로고려해볼수있다 (Table 3). 과체중또는비만이있는제공자과체중과비만은단백뇨와만성신장질환의중요한위험인자로작용한다 (21). 체질량지수 (body mass index) 가 25 kg/m 2 미만인건강한성인이체질량지수 kg/ m 2 로증가하게되면말기신장병발병률이 3배정도증가하게된다 (22). 이전보고에따르면과체중이나비만이있는환자는정상인보다사구체부피가증가되어있는데, 이는만성신장질환병태생리의근간이되는사구체과여과 (glomerular hyperfiltration) 현상이있다는것을반영한다 (23). 따라서, 단측신장절제술은이러한사구체과여과현상을악화시킬수있으며, 비만환자에게서는공여후예비신장기능 (postdonation renal reserve capacity) 또한감소되어있어과여과현상이악화될위험이높다 (24). Praga 등 (25) 은치료목적으로단측신장절제술을시행한비만환자들의 20 25년간경과를보고하였는데, 수술후 5년이지나면서단백뇨발생률과혈청크레아티닌 (serum J Korean Soc Transplant 82 June 2010 Volume 24 Issue 2

4 Table 3. Differential diagnosis of persistent microscopic hematuria TBMN X-linked Alport's syndrome IgAN Family history of hematuria Common Common Only in isolated cases Family history of renal failure Uncommon Common Usually absent Family history of deafness Uncommon Common Absent Deafness at adult Rare <10% incidence Absent Retinopathy and lenticonus Absent Rare Absent GBM by EM Thinned Thinned with lamellation Normal Type IV collagen in GBM α3-α5 chains all presnet Normal α3-α5 chain distribution Normal or patch loss IgA staining Negative Negative Positive with C3 and IgG in mesangium Genes affected COL4A3/COL4A4 COL45 6q22-23 Abbreviations: TBMN, thin basement membrane nephropathy Ig, immunoglobulin; IgAN, IgA nephropathy; GBM, glomerular basement membrane EM, electron microscopy. Adapted from Table 4 of reference [19]. J Korean Soc Transplant 83 June 2010 Volume 24 Issue 2

5 고령의제공자 를효과적으로이식할수있는한방법이다. 고령제공자에서신장공여후의경과를관찰한보고를살펴보면수년간혈청크레아티닌이안정적으로유지되었으며젊은제공자들과비교하여사구체여과율감소가더빠르지않았다 (17,30,31). 그러므로, 고령자체가신장공여의금기사항이되기는어렵다. 하지만신장기능은 30세를전후하여감소되기때문에고령제공자의경우공여전신장기능이감소되어있고, 고혈압, 동맥경화, 심장부전등신장기능악화를유발할수있는동반이환질환이많다. 따라서고령의제공자는이식전신장기능평가를비롯하여동반질환유무를살피는것이중요하고이식후에도안정적인신장기능유지가가능한지평가해야한다. 뇌사제공자 (deceased donor) 의경우, 50세이상의제공자는이식후에지연이식신장기능 (delayed graft function), 급성및만성거부반응의발생빈도가높아이식신장기능부전이빠른시간내에발생하는것으로보고된다 (31,32). 하지만생체신장이식에서는고령제공자에대한정확한기준이없으며제공자의나이가이식신장에악영향을주는지에대해서도일관된결과를보여주고있지않다. de La Vega 등 (33) 은신장제공자를 50세이상과이하로구분하고이들로부터신장이식을시행받은수혜자를분류하여비교분석하였는데, 두환자군에서이식신장과환자생존율에차이가없었다. 또한, 55세이상의제공자와 45세이하의제공자로부터이식을시행받은환자를후향적으로비교한보고에서도같은결과를보여주었다 (34). 이와반대로, 60세이상의제공자를대상으로한경우는제공자나이가이식신장생존율에가장큰영향을주는독립인자였으며 (35), 55세이상을고령의제공자로정의한다른두보고에서도제공자의나이가이식신장생존율에부정적인영향을주었다 (36,37). 이와같이, 생체이식에서제공자의나이가이식신장에어떤영향을미칠지명확하지않으나최근수년간말기신장환자의연령변화를살펴보면고령제공자에서도양호한이식신장생존율을기대할수있다. 2000년도에접어들면서투석환자들의고령화가진행되어 2008년도에는 60 69세의투석환자가가장많은비중을차지하였다 (2). 그러므로, 상대적으로적은신장단위가필요한고령환자가고령제공자로부터신장이식을받을경우양호한이식신장생존율을기대할수있다. 실제로, 고령제공자로부터받은이식신장이양호한경과를보였던보고를살펴보면고령의제공자는고령의수혜자에게이식이시행되었다 (33, 34). 따라서, 고령제공자를나이짝짓기 (age matching) 를통하여이식을시행하는것은고령의제공자 한계생체장기제공자이식의윤리적측면 한계생체장기제공자를이식을위해서는 3가지윤리적평가원칙이있어야한다 (6). 첫째는말기신장병환자에게최선의치료를하고자하는제공자의선행의지가있어야하고 (beneficence), 둘째는이식이제공자에게해를주어서는안되며 (nonmaleficence), 셋째는제공자의자율성이보장되어야한다 (autonomy). 이중첫번째와두번째항목이한계생체장기제공자이식에서서로부딪치기쉬운데, 부모자식간이식이대표적인경우라할수있다. 고혈압으로한계생체장기제공자에해당하는부모가말기신장병환자인자식에게신장공여를갈망할경우, 선행의지의원칙과해악금지의원칙이서로줄다리기를하는상황이발생한다. 이러한경우, 의료진은신장공여로인한만성신장병위험성에대해충분한설명을해야하고제공자는물질적, 재정적이익발생과무관해야하며의사결정이진행되는모든단계에서제공자의자율성이보장되어야한다. 또한, 자율성보장을위해엄격한사전동의 (informed consent) 과정이필요하며, 2명의서로다른신장내과의사가제공자와수혜자를관리하는것도한자율성보장을위한한방법이될수있다. 요약및결론 한계생체장기제공자는제공자부족현상을해결할수있는대안중의하나이며많은환자들에게신장이식기회를증대시킬것이다. 한계생체장기제공자로부터이식을시행하기위해서는철저한의학적평가가선행되어야하고이는윤리적평가와조화되어하나의체계를형성해야할것이다. 하지만한계생체장기제공자의안정성에대한장기고찰자료가부족한상태이며이식기관마다한계생체장기제공자의기준및위험도평가에대한의견일치가이루어지지않았다. 그러므로, 향후다기관연구를통해한계생체장기제공자의위험인자평가프로그램을개발하고이식후에는한계생체장기제공자를관리하는프로그램도마련되어야하겠다. REFERENCES 1) Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients J Korean Soc Transplant 84 June 2010 Volume 24 Issue 2

6 Hyeon Seok Hwang and Suk Young Kim: Safety for Expanding Living Kidney Donor 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341: ESRD registry committee, Korean Society of Nephrology. Current renal replacement therapy in Korea [Internet]. Seoul: Korean Society of Nephrology; 2009 [cited 2010 Jan 2]. Available from: index.html. Park CG, Kim JS, Shin JS, Kim YH, Kim SJ. Current status and future perspectives of xenotransplantation. J Korean Soc Transplant 2009;23: (박정규, 김정식, 신준섭, 김용희, 김상준. 이종장기이식의 현황과 전망. 대한 이식학회지 2009;23: ) Ibrahim HN, Foley R, Tan L, Rogers T, Bailey RF, Guo H, et al. Long-term consequences of kidney donation. N Engl J Med 2009;360: Kaneku HK, Terasaki PI. Thirty year trend in kidney transplants; UCLA and UNOS Renal Transplant Registry. Clin Transpl 2006;1-27. Reese PP, Caplan AL, Kesselheim AS, Bloom RD. Creating a medical, ethical, and legal framework for complex living kidney donors. Clin J Am Soc Nephrol 2006; 1: Steiner R. How should we ethically select living kidney donors when they all are at risk? Am J Transplant 2005;5: Boudville N, Prasad GV, Knoll G, Muirhead N, ThiessenPhilbrook H, Yang RC, et al ; Donor Nephrectomy Outcomes Research (DONOR) Network. Meta-analysis: risk for hypertension in living kidney donors. Ann Intern Med 2006;145: Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334:13-8. Textor S, Taler S. Expanding criteria for living kidney donors: what are the limits? Transplant Rev 2008; 22: Brancati FL, Whelton PK, Randall BL, Neaton JD, Stamler J, Klag MJ. Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT. Multiple Risk Factor Intervention Trial. JAMA 1997;278: Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med 2005;165: Torres VE, Offord KP, Anderson CF, Velosa JA, Frohnert PP, Donadio JV Jr, et al. Blood pressure determinants in living-related renal allograft donors and their recipients. Kidney Int 1987;31: Roberts J, Maurer K. Blood pressure levels of persons 6-74 years. United States, Vital Health Stat ;i-v, Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al ; National High Blood Pressure Education Program Coordinating Committee. Seventh re- J Korean Soc Transplant 16) 17) 18) 19) 20) 21) 22) 23) 85 port of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42: Textor SC, Taler SJ, Driscoll N, Larson TS, Gloor J, Griffin M, et al. Blood pressure and renal function after kidney donation from hypertensive living donors. Transplantation 2004;78: Delmonico F ; Council of the Transplantation Society. A report of the Amsterdam forum on the care of the live kidney donor: data and medical guidelines. Transplantation 2005;79(6 Suppl):S Tsinalis D, Binet I, Steiger J, Gasser TH, Thiel G. Can borderline living kidney donors (BLKD) be used safely for transplantation? Kidney Blood Press Res 1999;22: Gracida C, Espinoza R, Cedillo U, Cancino J. Kidney transplantation with living donors: nine years of follow-up of 628 living donors. Transplant Proc 2003;35: Vadivel N, Stankovic A, Rennke HG, Singh AK. Accepting prospective kidney donors with asymptomatic urinary abnormalities: are we shooting in the dark? Kidney Int 2007;71: Yoon HE, Kim SH, Kim YK, Roh ES, Chun YJ, Lee HY, et al. Renal biopsy findings of prospective kidney donors and clinical course of renal allografts. J Korean Soc Transplant 2007;21: (윤혜은, 김수현, 김용균, 노은 숙, 전연주, 이희연, 등. 신장 공여 예정자에서 시행한 신장 조직 검사 소견과 이식신의 경과. 대한이식학회지 2007;21: ) Tozawa M, Iseki K, Iseki C, Oshiro S, Ikemiya Y, Takishita S. Influence of smoking and obesity on the development of proteinuria. Kidney Int 2002;62: Ng I n o d 2 e i c 7-3 V r s, ( o ) 6. 7 ( S ) H June 2010 Volume 24 Issue 2

7 ( 최소연, 이정은, 도연실, 장은희, 김용균, 허우성, 등. 당뇨병과고혈압이없는성인에서대사증후군과만성신질환의상관관계. 대한신장학회지 2007;26:420-6.) 29) Heimbach JK, Taler SJ, Prieto M, Cosio FG, Textor SC, Kudva YC, et al. Obesity in living kidney donors: clinical characteristics and outcomes in the era of laparoscopic donor nephrectomy. Am J Transplant 2005;5: ) Tavakol MM, Vincenti FG, Assadi H, Frederick MJ, Tomlanovich SJ, Roberts JP, et al. Long-term renal function and cardiovascular disease risk in obese kidney donors. Clin J Am Soc Nephrol 2009;4: ) Nyberg SL, Manivel JC, Cook ME, Gillingham KJ, Matas AJ, Najarian JS. Grandparent donors in a living related renal transplant program. Clin Transplant 1997;11: ) Young A, Storsley L, Garg AX, Treleaven D, Nguan CY, Cuerden MS, et al. Health outcomes for living kidney donors with isolated medical abnormalities: a systematic review. Am J Transplant 2008;8: ) Woo YM, Gill JS, Johnson N, Pereira BJ, Hariharan S. The advanced age deceased kidney donor: current outcomes and future opportunities. Kidney Int 2005;67: ) de La Vega LS, Torres A, Bohorquez HE, Heimbach JK, Gloor JM, Schwab TR, et al. Patient and graft outcomes from older living kidney donors are similar to those from younger donors despite lower GFR. Kidney Int 2004;66: ) Kumar A, Verma BS, Srivastava A, Bhandari M, Gupta A, Sharma RK. Long-term followup of elderly donors in a live related renal transplant program. J Urol 2000;163: ) Toma H, Tanabe K, Tokumoto T, Shimizu T, Shimmura H. Time-dependent risk factors influencing the long-term outcome in living renal allografts: donor age is a crucial risk factor for long-term graft survival more than 5 years after transplantation. Transplantation 2001;72: ) Matas AJ, Payne WD, Sutherland DE, Humar A, Gruessner RW, Kandaswamy R, et al. 2,500 living donor kidney transplants: a single-center experience. Ann Surg 2001;234: ) Kerr SR, Gillingham KJ, Johnson EM, Matas AJ. Living donors >55 years: to use or not to use? Transplantation 1999;67: J Korean Soc Transplant 86 June 2010 Volume 24 Issue 2

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R