고요산 혈증 , 통풍
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고요산 혈증 , 통풍. 내과 세미나 이대목동병원 강덕희 교수 직접 설명. Clinical Implication of Hyperuricemia in Chronic Kidney Disease. Duk-Hee Kang Division of Nephrology, Ewha University School of Medicine, Seoul, Korea. Prevalence of Hyperuricemia in Different Groups of Population. 2~35% in general population - PowerPoint PPT PresentationTRANSCRIPT
고요산 혈증 , 통풍
내과 세미나이대목동병원 강덕희 교수 직접 설명
Duk-Hee KangDivision of Nephrology, Ewha University School
of Medicine, Seoul, Korea
Clinical Implication of Hyperuricemia in Chronic Kidney Disease
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
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
Pathways for Uric Acid Transport
URAT1 GLUT9(URATv1)
Anzai N et al, Clin Exp Nephrol, 16:89, 2012
AfricanAmerican
Obesity
DyslipidemiaInsulinresistance
Renaldisease
Hypertension
Male gender
Postmenopausal
womenAgeDiuretics
Alcohol Uric Acid
Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia in CKD
고요산혈증의 임상적 의의
Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia
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
Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia
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
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.
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
Obermayr RP et al, J Am Soc Nephrol 19:2407–2413, 2008
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
Haririan A et al, Transplantation 89:573, 2010Haririan A et al, Am J Transplant 11:1943, 2011
Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia
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
Allopurinol Control
SBP (mmHg)
Allopurinol Control
Cr (mg/dl)
Am J Kidney Dis 47:51, 2006
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
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
Lessons from Experimental Study Lessons from Epidemiologic Study &
Clinical Trials Lessons from Interventional Studies Treatment of Hyperuricemia in CKD
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
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
Guideline for Allopurinol Dose according to Renal Function
Hande KR et al, Am J Med. 1984;76:47-56
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
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
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
Recombinant uricase : RasburicaseR
non-purine selective XO inhibitor : FebuxostatR
Other Drugs for Treatment of Hyperuricemia
Blood, 15:2998, 2001
NEJM, 353:2450, 2005
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
Effect of Drugs to manage CV Risk Factors on Serum Uric Acid Level
Borghi C, Hot Topics in Cardiology 14:15, 2008
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.
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.
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.
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
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 .