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 .