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1 대한류마티스학회지 Vol. 18, No. 1, March, 2011 DOI: /jrd 원저 요산저하치료가통풍환자의신기능에미치는영향 조소영 1,2 ㆍ박용범 3 ㆍ이찬희 4 연세대학교대학원의학과 1, 인제대학교의과대학서울백병원내과학교실 2, 연세대학교의과대학내과학교실 3, 국민건강보험공단일산병원류마티스내과 4 The Effect of Hypouricemic Treatment on the Renal Function in Patients with Gout So Young Jo 1,2, Yong-Beom Park 3, Chan Hee Lee 4 Department of Medicine, The Graduate School, Yonsei University 1, Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine 2, Department of Internal Medicine, Yonsei University College of Medicine 3, Seoul, Division of Rheumatology, Department of Internal Medicine, NHIC Ilsan Hospital 4, Goyang, Korea Objective. Hyperuricemia is known as a risk factor that causes and worsens kidney diseases through a variety of mechanisms. Recent animal studies reported that the correction of hyperuricemia improved the renal function, but there have been few human studies. This study examined whether a hypouricemic treatment affects the renal function in Korean patients with gout. Methods. Two hundred sixty-seven gout patients who were prescribed uric acid lowering agents for more than 1 year were enrolled at the Division of Rheumatology in the National Health Insurance Corporation Ilsan Hospital and Yonsei University Severance Hospital from January 2005 to January The following were examined: the levels of serum uric acid and serum creatinine, the amount of 24-hour urine uric acid, glomerular filtration rate (GFR), and abdominal ultrasound findings at baseline and follow-up. Results. Mean age of the study subjects was 54.4±13.9 years. Two hundred forty-seven patients were male and 20 patients were female. The mean treatment duration was 35.0±19.5 months. Among the 267 patients, 219 and 19 patients received monotherapy with allopurinol and benzbromarone respectively, and 29 patients received combination therapy with allopurinol and benzbromarone. After the treatment with uric acid lowering agents, the serum uric acid and creatinine levels decreased significantly (8.05±1.96 mg/dl vs 6.16±1.46 mg/dl, p<0.001, 1.25±0.46 mg/dl vs 1.18±0.42 mg/dl, p=0.001, respectively) and the GFR increased significantly (74.4±27.0 ml/min/1.73 m 3 vs 80.2±31.6 ml/min/1.73 m 3, p<0.001). Conclusion. Treatment with hypouricemic agents reduced the levels of serum uric acid and improved the renal function. These results suggest that a hypouricemic treatment might improve the kidney function in gout patients. Key Words. Gout, Renal function, Hypouricemic treatment < 접수일 :2010 년 10 월 19 일, 수정일 :2010 년 10 월 30 일, 심사통과일 : 2010 년 10 월 30 일 > 통신저자 : 이찬희경기도고양시일산구백석동 1232 번지국민건강보험공단일산병원류마티스내과 chanheell@paran.com 서론통풍은요산의체내과잉합성이나배설장애로인하여고요산혈증이발생되고요산일나트륨결정 (monosodium urate crystal) 이조직에침착되어염증과통증을일으키는질환으로급성통풍성관절염, 만성통풍결절성관절염, 요로계의요석, 통풍성신병증등의다양한임상양상을보인다 (1). 영국의연구자료에따르면 1970년도초기부터 1990년까 26

2 The Effect of Hypouricemic Treatment on Renal Function 27 지 20년동안통풍의유병율은 3배증가하였다고하고 (2) 최근실시한미국의인구조사에서는 (3) 통풍성관절염이류마티스관절염을제치고 40세이상남성에서가장흔한염증성관절염으로보고되었다. 통풍의발생이증가하는요인에는여러가지가있지만, 그중대사증후군이증가하는것이중요하다. 대사증후군은복부비만, 이상지질혈증, 고혈압그리고당불내인성또는당뇨병으로특징지어지는대사이상을말하며 (4), 최근통풍환자에서대사증후군이동반된환자의비율이점차증가하고있다 (5). 한편신장질환이있는환자에서고요산혈증이발생하기도하고고요산혈증으로인해신기능이저하되기도한다 (6). 최근에는고요산혈증이단순히소변으로의요산배설의감소만을반영하는것이아니라다양한기전에의해신장질환의발생및악화를일으킬수있는위험인자라는연구들이보고되고있다 (7-10). 또한동물실험에서는요산저하제를투여하여고요산혈증을조절하였을경우신장질환의진행이억제된다고하였다 (11-14). 따라서본연구에서는통풍환자에서요산저하제를투여하여혈중요산수치를조절하였을때신기능에미치는영향을알아보고자하였다. 적인검사후위환자들을대상으로 allopurinol이나 benzbromarone을단독혹은병용투여하였으며, 약제는사구체여과율이최대 140 ml/min/1.73 m 3 일경우 allopurinol의용량을최대 400 mg/day에서시작하여사구체여과율이 20 ml/min/1.73 m 3 씩감소할때마다 50 mg/day씩용량을감소하였다 (17). 각환자들은주기적 (1 6개월간격 ) 으로요산농도를측정하면서추적관찰하였으며, 요산저하제를 1년이상투여받은후에혈청요산, 혈청크레아티닌, 24시간소변의요산, 사구체여과율을측정하여요산저하제를투여하기전과비교하였다. 통계분석통계학적분석은 SAS (version 9.1.3, SAS Institute Inc감소하였다 Cary, NC, USA) 를이용하였고모든수치는평균 ± 표준편차로표시하였다. 반복측정자료를분석하고혈청요산수치가신기능에미치는효과의유의성을평가하기위해혼합모형 (mixed model) 을이용하였다. 또한혈청요산수치와신기능과의상관관계는피어슨상관계수 (Pearson correlation coefficient) 를이용하여분석하였다. p값이 0.05 보다작을때통계학적으로의미있는것으로해석하였다. 대상및방법대상 2005년 1월부터 2010년 1월까지연세대학교의과대학세브란스병원과국민건강보험공단일산병원류마티스내과에서통풍으로진단받고요산저하제를 1년이상투여받은환자를대상으로하였다. 통풍의진단은활액천자후또는편광현미경검사로음성복굴절을가지는바늘모양의결정체를탐식하고있는백혈구를찾은경우또는미국류마티스학회의진단기준에따라정의하였다 (15). 사구체여과율이 20 ml/min/1.73 m 3 미만의말기신부전환자, 연구시작시점에서이미요산저하제를투여받고있던환자는제외시켰다. 방법통풍으로진단을받은환자는요산저하제를사용하기전에혈청요산, 혈청크레아티닌, 사구체여과율을측정하였다. 사구체여과율은 24시간소변크레아티닌배설률또는 MDRD (Modification of Diet in Renal Disease) 공식에따른혈청크레아티닌으로부터 egfr (estimation of GFR) 을측정하였다 (16). 그외요산저하제선택에영향을미칠수있는 24시간소변의요산배출을측정하였고신장기능악화에영향을미칠수있는구조적문제즉신장의결석여부등을배제하기위해복부초음파를시행하였다. 기본 결과통풍으로진단받고요산저하제를 1년이상투여받은환자는 267명이였으며, 이들의평균연령은 54.4 ± 13.9세, 남자는 247명, 여자는 20명 ( 남녀비 : 12:1) 이었고평균체질량지수는 24.8±3.5 kg/m 2 였다. 267명의환자중고혈압은 115 명, 당뇨는 13명, 고지혈증은 77명에서각각동반하였다. 평균치료기간은 35.0±19.5개월이었고 267명의환자중 allopurinol이나 benzbromarone을단독투여받은환자는각각 219명과 19명이었으며, 평균용량은각각 162.2±83.4 mg/day, 54.4.±22.8 mg/day이었고 29명은 allopurinol과 benzbromarone을병용투여받았으며평균용량은각각 127.6±65.1 mg/day, 54.3±26.3 mg/day였다. 또한치료또는예방목적으로소염진통제를사용한환자는 104명이었다 ( 표 1). 혈청요산요산저하제투여후평균 35.0±19.5개월뒤혈청요산수치는 267명중 223명에서감소하였고, 2명은큰변화가없었으며, 42명에서는오히려증가하였다 ( 표 2). 치료시작전측정한혈청요산수치는 8.05±1.96 mg/dl였으나, 치료후혈청요산수치는 6.16±1.46 mg/dl (p<0.001) 로유의하게감소하였다 ( 표 3).

3 28 조소영외 Table 1. Characteristics of the gout patients N=267 Age at initiation of treatment (yrs) 54.4±13.9 Sex (M, %) 247 (92.5) BMI (kg/m 2 ) 24.8±3.5 Hypertension (%) 115 (43.2) Diabetes mellitus (%) 13 (4.9) Hyperlipidemia (%) 77 (28.8) Duration of treatment (months) 35.0±19.5 Medication (%) Allopurinol 219 (82) Benzbromarone 19 (7.1) Allopurinol plus benzbromarone 29 (10.9) NSAIDs 104 (38.9) M: male, BMI: body mass index, NSAIDs: non-steroidal antiinflammatory drugs. Data is reported as the mean±sd unless specified otherwise. Figure 1. The changes in the serum uric acid levels were correlated with the changes in the serum creatinine levels after the treatment with hypouricemic agents (r=0.18, p=0.003). Table 2. Changes in the serum uric acid, serum creatinine and creatinine clearance in 267 gout patients after treatment with the hypouricemic agents (N, (%)) Serum UA Serum Cr CCr Improved 223 (83.5) 174 (65.2) 164 (61.4) Deteriorated 42 (15.7) 62 (23.2) 88 (33) Not changed 2 (0.7) 31 (11.6) 15 (5.6) UA: uric acid, Cr: creatinine, CCr: creatinine clearance Table 3. Creatinine clearance, serum uric acid, and serum creatinine in 267 gout patients before and after treatment with the hypouricemic agents Before treatment After treatment p-value CCr (ml/min/1.73 m 3 ) 74.41± ±31.55 <0.001 Serum UA (mg/dl) 8.05± ±1.46 <0.001 Serum Cr (mg/dl) 1.25± ± CCr: creatinine clearance, UA: uric acid, Cr: creatinine 신기능 평균 35.0±19.5개월의요산저하치료후혈청크레아티닌수치는 174명에서감소하였고, 31명은큰변화가없었으며, 62명에서는증가하였으며 ( 표 2) 치료시작전혈청크레아티닌수치는 1.25±0.46 mg/dl였고, 치료후에는 1.18± 0.42 mg/dl (p=0.001) 로유의한감소를보였다 ( 표 3). 사구체여과율은 19.8% 에서 24시간소변크레아티닌배설률로측정되었으며사구체여과율의향상은 267명중 164명에서관찰되었고, 88명에서감소하였으며 15명에서는변화가없었다 ( 표 2). 사구체여과율역시치료시작전에는 74.41± ml/min/1.73 m 3 이었으나, 치료후에는 80.18± ml/min/1.73 m 2 (p<0.001) 로의미있게호전되었다 ( 표 3). Figure 2. The changes of serum uric acid levels were correlated with the changes in the creatinine clearance levels after the treatment with hypouricemic agents (r=-0.25, p<0.001). 혈청요산과신기능과의관계 혈청요산수치변화량에따른혈청크레아티닌과사구체여과율의변화량을살펴보면, 혈청요산수치와혈청크레아티닌은유의한양의상관관계 (r=0.18, p=0.003) 를 ( 그림 1), 사구체여과율과는유의한음의상관관계 (r= 0.25, p <0.001) 를보였다 ( 그림 2). 또한혈압, 당뇨, 고지혈증, 진통제사용여부의요인들을보정하기위해혼합모형을이용하여모형에포함시켜혈청요산수치가크레아티닌및사구체여과율에미치는유의성을평가하였으며, 교호작용에대한효과 (covariance estimate) 는각각 0.04 (p<0.001) 와 3.1 (p<0.001) 로유의하게나타났으며혈청요산수치가 1 mg/dl 증가시혈청크레아티닌은 0.04±0.01 mg/dl 증가하였으며사구체여과율은 3.1±0.68 ml/ min/1.73 m 3 감소하였다 ( 표 4).

4 The Effect of Hypouricemic Treatment on Renal Function 29 Table 4. Significance of the random effects in mixed model analysis* Variance-covariance estimates (SE) of random effects Serum Cr p CCr p Serum UA 0.04 (0.01) < (0.68) <0.001 *The analysis was performed adjusting for confounding variables (hypertension, diabetes mellitus, hyperlipidemia, treatment with NSAIDs), SE: standard error, UA: uric acid, Cr: creatinine, CCr: creatinine clearance 고 통풍은고요산혈증에의해 2차적으로발생하는요산결정체가조직에침착되어발생하는질환으로, 침범된조직에따라다양한임상상을나타낸다. 최근통풍의증가요인으로대사증후군이대두되고있으며통풍과대사증후군의상호연관성에관한연구가활발히진행되고있다. 미국성인통풍환자에서대사증후군의유병률은 63% 이며 (18) 국내에서조사된한국인통풍환자에서대사증후군의유병률은 44% 로보고되고있다 (5). 이러한대사증후군은심혈관질환과제 2형당뇨병의위험률을증가시키며, 더나아가신기능저하에도영향을미친다 (19). 신기능저하는통풍의가장빈번한합병증으로통풍환자의 20 60% 에서경도에서중등도의신기능저하가보고된다 (20). 또한요산저하제가임상에적용되기이전, 통풍환자의 10 25% 에서말기신부전으로의진행이보고되었다 (21). 최근미국에서 13,338명의일반인구를대상으로시행한광범위한임상역학연구는증가된혈청요산수치가신질환발생의독립적인위험요소임을보여주고있다 (22). 통풍과관련되어나타나는신장질환은크게요산배설량증가에의한요로결석, 갑자기많은요산이생성되어다량의요산이세뇨관, 집합관, 요관등에침착되면서요로를막아발생하는급성신부전, 요산결정체가신간질에침착되어만성염증반응을유발하여발생하는요산염신장병으로결국만성신부전으로진행할수있다. 지금까지보고된요산이신기능에미치는다양한작용과기전에대해서알아보면, 요산은혈관평활근세포의염증반응을유도하여 p38 미토겐활성화단백질키나아제 (p38 mitogen-activated protein kinases), B 핵인자 (nuclear factor-b), 활성단백질 1 (activator protein-1) 을활성화시키고사이클로옥게나지 2 (cyclooxygenase-2), 단핵구화학유인물질단백질 1 (monocyte chemoattractant protein-1), 인터루킨 1 (interleukin 1), 인터루킨 6 (interleukin 6), 종양괴사인자 (tumor necrosis factor) 의발현을증가시켜혈관병변과죽상경화증의발생에영향을미친다 (11,23-25). 또한산틴산 찰 화효소 (xanthine oxidase) 는자유라디칼 (free radical) 을생성하여죽상경화증을일으키고이는산틴산화효소억제제 (xanthine oxidase inhibitor) 인 allopurinol에의해억제된다 (26). 레닌-안지오텐신계의활성화와산화질소합성효소 1 (nitric oxide synthase-1) 발현의억제는혈압과사구체압을증가시키는혈역학적효과와 (27,28) 직접적으로혈관평활근세포의증식을통해신장의수입세동맥병변을일으켜신기능악화의중요기전으로작용한다 (29). 또한 Saito 등의연구에의하면혈청요산농도가혈장레닌활성도와연관이있음이보고된바있다 (30). 마지막으로요산은직접적으로신장세뇨관세포에작용하여신장상피세포의표현형변이, 특히상피-중간엽세포변이를유발하는데, 이는신장조직의변화가발생하기이전에발생하는조기기전으로서최근관심이높아지고있다. 역으로고요산혈증을적극적으로교정하였을경우신장질환의진행속도가완화되는데고요산혈증동물모델에서 allopurinol을투약하여혈중요산농도를정상으로유지시켰을때레닌과사이클로옥게나지 2의발현이감소하고결과적으로신장질환의진행과조직학적변화가억제되었다 (11,12,14). 또한신장질환동물모델에서고요산혈증을교정하는경우뚜렷한혈압조절의향상, 단백뇨감소, 사구체경화 (glomerulosclerosis), 세뇨관섬유화 (tubulointerstitial fibrosis), 혈관병증 (vasculopathy) 의정도가감소되는것을보여주고있다 (13). 외국에서보고된임상연구를살펴보면 Perez-Ruiz 등은신기능저하가있는만성통풍환자에서요산저하제사용으로고요산혈증을조절하였을경우 87명중 30명의환자에서사구체여과율이향상되었다고보고한바있으며 (31), Siu 등은만성신장질환을동반한고요산혈증환자에서 1년간 allopurinol을투약한경우대조군에비해수축기혈압이감소되었으며신장질환의악화속도가완화되었다고보고하였다 (32). 그러나현재까지보고된임상연구는소수에그치며, 국내보고된임상연구도아직까지없다. 이에본저자들은한국인통풍환자에서요산저하제투약으로고요산혈증을조절하였을경우신기능에미치는영향을분석하고자하였다. 본연구에서는통풍환자에서혈청요산농도를치료목표인 6 mg/dl 이하로조절하기위하여요산저하제로서 allopurinol이나 benzbromarone을사용하였다. Allopurinol은산틴산화효소의활성화를억제시켜요산생성을억제하는제 1차요산저하치료제로서혈청요산수치가치료농도에도달하거나또는최대용량에도달할때까지지속적으로증량해야하며 (33), 신기능장애가있을경우 allopurinol의독성위험이증가하므로최대허용량은감소된다 (17). Benzbromarone은강력한요산배설제로서요산배설이

5 30 조소영외 활발히이루어지지않는환자에서치료약제로선택할수있으며 (33) 신기능장애가있을경우에는사용에제한이있다 (34). 본연구에서는요산저하치료를통해고요산혈증을조절하였을경우, 신기능이향상되는것을보여주었다. 즉, 요산과신기능사이에서로상관관계가있음을알수있었다. Perez-Ruiz 등의연구에서는요산저하치료후신기능의향상을입증하였으나, 참여한환자의수가적었으며소염진통제를사용하던통풍환자에서소염진통제가신기능에미치는영향에대해명확히밝히지못하였다 (31). Siu 등의연구에서는혈청요산수치호전에따른혈청크레아티닌수치의향상을입증하였으나사구체여과율향상에대해서는통계학적유의성을입증하지못하였다 (32). 본연구는신기능에영향을미칠수있는고혈압, 당뇨, 고지혈증, 소염진통제사용등의변수를보정하였을때, 요산저하치료가신기능을유의하게향상시킨다는것을보여주고있다. 본연구의제한점으로는요산저하치료후통풍의치료목표인 6 mg/dl 이하로유지하지못하거나혈청요산수치가악화된환자에서환자의생활습관이나약물에대한순응도여부등을확인해봐야하며환자가복용하고있는약물중고요산혈증을일으킬만한약물은없는지, 체내요산생산이증가되는상황은없는지등을확인해보는것이필요하다. 두번째로요산저하치료를받은환자들만을대상으로하였다는점에서치료받지않는환자군과의비교연구가필요할것으로생각되며, 세번째로본연구는후향적인연구로시간에따른혈청요산수치와신기능과의관계를보여주지못하였다. 따라서본연구를토대로대규모의전향적인연구를진행한다면요산저하치료가통풍환자의신기능에미치는영향을평가하는데큰도움이될것으로생각된다. 결 본연구에서요산저하치료는통풍환자의혈중요산수치와혈중크레아티닌수치를떨어뜨리고신기능을향상시켰다. 이는요산저하치료가통풍환자의신장기능을향상시킬수있음을시사하는소견이라생각된다. 론 참고문헌 1. Marc CH, Alan JS, Josef SS, Michal EW, Michael HW. Rheumatology. 4th ed. p , London, Mosby, Harris CM, Lloyd DC, Lewis J. The prevalence and prophylaxis of gout in England. J Clin Epidemiol 1995;48: Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58: Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112: Rho YH, Choi SJ, Lee YH, Ji JD, Choi KM, Baik SH, et al. The prevalence of metabolic syndrome in patients with gout: a multicenter study. J Korean Med Sci 2005;20: Vaziri ND, Freel RW, Hatch M. Effect of chronic experimental renal insufficiency on urate metabolism. J Am Soc Nephrol. 1995;6: Syrjänen J, Mustonen J, Pasternack A. Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy. Nephrol Dial Transplant 2000;15: Ohno I, Hosoya T, Gomi H, Ichida K, Okabe H, Hikita M. Serum uric acid and renal prognosis in patients with IgA nephropathy. Nephron 2001;87: Bo S, Cavallo-Perin P, Gentile L, Repetti E, Pagano G. Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes. Eur J Clin Invest 2001;31: Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res 2001;24: Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002;13: Sánchez-Lozada LG, Tapia E, Santamaría J, Avila- Casado C, Soto V, Nepomuceno T, et al. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int 2005;67: Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41: Nakagawa T, Mazzali M, Kang DH, Kanellis J, Watanabe S, Sanchez-Lozada LG, et al. Hyperuricemia causes glomerular hypertrophy in the rat. Am J Nephrol 2003;23: Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yü TF. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 1977; 20: Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al; National Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139: Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in pa-

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract