Download - 고요산 혈증 , 통풍
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고요산 혈증 , 통풍
내과 세미나이대목동병원 강덕희 교수 직접 설명
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Duk-Hee KangDivision of Nephrology, Ewha University School
of Medicine, Seoul, Korea
Clinical Implication of Hyperuricemia in Chronic Kidney Disease
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Prevalence of Hyperuricemiain Different Groups of Population
2~35% in general population 25~40% of untreated hypertension 50% of hypertension on diuretics 70~100% of malignant hypertension ~ 50% in CKD at the onset of renal
replacement therapy
approximately doubled between 1990 and 2010
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Urate in blood3-10 mg/dl
(180-600 μM)
xo
xo in other organs: lung, brain, etc.
IntestineDietary purines, fructose, alcohol
Liver
De-novo purine synthesisPurine catabolism
Cellular degradation: leukemia, lymphomas,
chemotherapy
Muscle (strenuous exercise)
Purines
xo Urate
Uric Acid
Filtration
Reabsorption
Secretion
Post-secretoryreabsorption
Kidney
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Pathways for Uric Acid Transport
URAT1 GLUT9(URATv1)
Anzai N et al, Clin Exp Nephrol, 16:89, 2012
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AfricanAmerican
Obesity
DyslipidemiaInsulinresistance
Renaldisease
Hypertension
Male gender
Postmenopausal
womenAgeDiuretics
Alcohol Uric Acid
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Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia in CKD
고요산혈증의 임상적 의의
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Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia
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Phenotype of Hyperuricemic Animal
Hypertension Microvascular remodeling Induction of oxidative stress Decrease in NO production:
endothelial dysfunction Vascular & renal inflammation Activation of renin-angiotensin
system Renal disease: glomerular
hypertrophy & interstitial fibrosis
Insulin resistance
All could be ameliorated by uric acid-lowering therapy
Based on the results from 106 uric acid-related Manuscripts published since 2000
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Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia
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Sturm G et al, Exp Gerontol 43:347–352, 2008.
Uric acid as a risk factor for progression of non-diabetic chronic kidney disease?
: The Mild to Moderate Kidney Disease (MMKD) Study
Disease proression/1 mg/dl increment of UA
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Domrongkitchaiporn S et al, J Am Soc Nephrol 16:791, 2005
• In 6,400 subject with normal kidney function, a serum uric acid>8 mg/dL was associated with a 10-fold increased risk for the development of renal insufficiency within 1 year in women and a 2.9-fold increased risk in men.
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Obermayr RP et al, J Am Soc Nephrol 19:2407–2413, 2008
Uric acid≥9 mg/dL
7≤Uric acid<9.0 mg/dL
2.5
1.5
3.12
1.74
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Obermayr RP et al, J Am Soc Nephrol 19:2407–2413, 2008
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Hyperuricemia & Progression of Renal Disease
: IgA Nephropathy
• Uric acid at the time of diagnosis in IgA nephropathy is an independent risk factor for poor outcome.
Syrjanen J et al, NDT, 15:34, 2001
• Hyperuricemia in IgA nephropathy is associated with both glomerular and tubulointerstitial damage, and correlated with hypertension. HU is a risk factor for renal prognosis in IgA nephropathy.
Ohno I et al, Nephron, 87 : 333, 2001
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Haririan A et al, Transplantation 89:573, 2010Haririan A et al, Am J Transplant 11:1943, 2011
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Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia
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Feig DI et al, JAMA 300:924, 2008
• N=30 (11-17 yrs)• Newly diagnosed never-
treated stage 1 essential HT
• Uric acid ≥ 6 mg/dL• Allopurinol, 200 mg bid for
4 weeks• Cross-over with 2-week
washout
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Allopurinol Control
SBP (mmHg)
Allopurinol Control
Cr (mg/dl)
Am J Kidney Dis 47:51, 2006
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Goicoechea M et al, CJASN, 2010
• 113 CKD patients with eGFR<60 ml/min• Allopurinol 100 mg/day vs. placebo• Follow-up for 24 months
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Talaat KM et al, Am J Nephrol 27:435, 2007
• 20 CKD patients on allopurinol
• Stop allopurinol & f-up for 12 months
ACEi ARB Others
ACEi ARB Others
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Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia in CKD
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Life style modification with treat hyperlipidemia Avoid drugs raise uric acid level
Xanthine oxidase inhibitor
Uricosuric agent
Conventional Treatment of Hyperuricemia
Urate overproduction/renal insufficiency/nephrolithiasis/prevention of uric acid nephropathy/tophaceous gout/failure of uricosuric agent
Diuretics/CsA/low-dose salicylate/EMB/PZA/nicotinic acid
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Non-selective xanthine oxidase inhibitorUsual starting dose 300 mg/dayStarting from <100 mg/day in patients with GFR less than 50
ml/minCommon side effects : indigestion, headache, diarrhea, skin
rash, urticaria, fever, interstitial nephritis, eosinophilia, ARF, BM suppression, granulomatous hepatitis, vasculitis, toxic epidermal necrolysis, hypersensitivity syndrome (rash, fever, hypotension, pulmonary edema)
Allopurinol
Drug discontinuation in up to 5%; severe AE in 2% (allopurinol hypersensitivity syndrome) 20% mortality
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Guideline for Allopurinol Dose according to Renal Function
Hande KR et al, Am J Med. 1984;76:47-56
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Ampicillin or amoxicillin increase the risk of skin rash.
Thiazide diuretics increase the blood level of allopurinol.
Allopurinol increases the blood levels of certain drugs.
Azathioprine Mercaptopurine Anti-cancer drug Cyclosporine ChlorpropamideWarfarinTheophylline
Allopurinol : Drug Interaction
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Inhibit the reabsorption of uric acid in proximal tubuleNo effect in high producer of uric acid (>800 mg/day),
>moderate renal failure, patients with renal stone & on aspirin
Side effects : GI trouble, hypersensitivity, hepatic failure, uric acid stone, seizure, renal failure
250 mg bid for 1 week 500 mg bid for weeks dose adjustment
Drink at least 10 or more full glasses of water a day Complicated drug interaction :
AspirinHeparin/Indomethacin/ketoprofen/MTX
ProbalanR/BenemidR/ProbenateR
Probenecid
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Inhibit the reabsorption of uric acid in proximal tubule, anti-thrombotic & anti-platelet action
Can use in patients with renal impairmentSide effects : GI trouble, hepatotoxicity (1st 6 months), hypersensitivity, renal failure, chest pain, headache, conjunctivitis
25~50 mg/day dose adjustment (up to 50 mg tid)Drink at least 10 or more full glasses of water a dayNarcaricinR, UrinonR
Benzbromarone
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Recombinant uricase : RasburicaseR
non-purine selective XO inhibitor : FebuxostatR
Other Drugs for Treatment of Hyperuricemia
Blood, 15:2998, 2001
NEJM, 353:2450, 2005
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Review of 88 published papers40 mg of febuxostat vs. 300 mg of allopurinolMild-to-moderate AE: liver enzyme elevation (4.6~6.6%)
No need to dose-adjustment in subject of eGFR 30-89 ml/min
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Effect of Drugs to manage CV Risk Factors on Serum Uric Acid Level
Borghi C, Hot Topics in Cardiology 14:15, 2008
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We commonly hesitate to prescribe uric acid-lowering medicine.
Common Mistakes in Prescribing Uric Acid-lowering Medicine in CKD
Patients
We sometimes prescribe too high dose of medicine and underestimate the risk of SAE.
We prescribe these medicines in acute stage of gout. Uric acid-lowering medicine sometimes aggravate gout attack in CKD patients due to abrupt changes in serum uric acid level: Start low, go slow to avoid flare.
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First, we have to decide to treat hyperuricemia or not according to the patients’ characteristics.
General Guideline in Prescribing UA-lowering Medicine in CKD Patients
(I)
1. Try to find the aggravating factors of hyperuricemia & correct them, if possible.
2. Life style modification with diet.3. Consider several drugs with uric acid-lowering
effects such as losartan, statin, sevelamer or AST120.
If FEUA is normal or high, prescribe XO inhibitor, but with adequate dose, careful monitoring & consideration of drug reaction.
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If patient is not tolerable to XO inhibitor, uricosuric agents can be tried according to patients’ residual renal function, co-morbidity & concurrent medication.
General Guideline in Prescribing UA-lowering Medicine in CKD Patients
(II)
Bezbromarone is more effective in patients with >stage III CKD than other uricosuric agents.
Careful monitoring of side effect is necessary. High-flux dialysis is helpful for controlling hyperuricemia in
HD patients.
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Persistent Asymptomatic Hyperuricemia
Hx, PE & Lab to find potentially treatable cause
of HU
Tx or correct underlying conditions24hr urine UA, FEUA
Under-excretion FEUA<6%
Over-production FEUA>6%
800 mg/D or 12 mg/kg/D
Repeat in 5 days of low purine diet
Decrease dietary purine consumption
normalizeUUA>670 mg/D
Inherited cause of
over-production
Inherited or acquired causes
of under-excretion
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Take-Home Message 다양한 임상 및 기초 연구 결과들은 요산이 고혈압 및 심혈관계 질환 발생의
원인 인자일 가능성을 강하게 제시하고 있다 . 최근 연구 결과들은 요산 농도와 신장기능 사이의 연관을 제시하고 있으며 ,
요산이 신장병의 발생 및 악화에도 관여할 가능성을 시사하고 있다 . 만성 신장병 환자에서 xanthine oxidase 억제제 투여는 신장기능의
저하 속도를 지연시킨다는 보고들이 있다 . 하지만 , 요산 농도의 감소로 신장병 발생이 줄어들고 생존율이 호전되는 지에 관해서는 아직 대규모 인구를 대상으로 장기에 걸쳐 진행된 임상연구는 없는 상태이다 .
요산은 단순히 통풍을 유발하는 물질이 아니며 혈관 , 심장 , 신장 , 간 및 지방세포 등에 직접적으로 영향을 미칠 수 있다 . 따라서 고요산혈증의 임상적 의의는 다시 검증되는 것이 필요하다 .