고요산 혈증 , 통풍

1. 고요산 혈증, 통풍 내과 세미나 이대목동병원 강덕희 교수 직접 설명

2. Clinical Implication of Hyperuricemia in Chronic Kidney Disease Duk-Hee Kang Division of Nephrology, Ewha University School of Medicine, Seoul, Korea

3. Prevalence of Hyperuricemia in 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

4. xo xo xo Intestine Dietary purines, fructose, alcohol Kidney Urate Filtration Liver De-novo purine synthesis Purine catabolism Reabsorption Urate in blood 3-10 mg/dl (180-600 μM) Secretion Cellular degradation: leukemia, lymphomas, chemotherapy Purines Post-secretory reabsorption Uric Acid Muscle (strenuous exercise) in other organs: lung, brain, etc.

5. Pathways for Uric Acid Transport GLUT9 (URATv1) URAT1 Anzai N et al, Clin Exp Nephrol, 16:89, 2012

6. Male gender Post menopausal women Diuretics Age Alcohol African American Uric Acid Hypertension Obesity Renal disease Dyslipidemia Insulin resistance

7. 고요산혈증의 임상적 의의 • Lessons from Experimental Study • Lessons from Epidemiologic Study & Clinical Trials • Lessons from Interventional Studies • Treatment of Hyperuricemia in CKD

8. Lessons from Experimental Study • Lessons from Epidemiologic Study & Clinical Trials • Lessons from Interventional Studies • Treatment of Hyperuricemia

9. All could be ameliorated by uric acid-lowering therapy 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 Based on the results from 106 uric acid-related Manuscripts published since 2000

10. Lessons from Experimental Study • Lessons from Epidemiologic Study & Clinical Trials • Lessons from Interventional Studies • Treatment of Hyperuricemia

11. 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 Sturm G et al, Exp Gerontol 43:347–352, 2008.

12. 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. Domrongkitchaiporn S et al, J Am Soc Nephrol 16:791, 2005

13. 2.5 3.12 1.5 1.74 Uric acid≥9 mg/dL 7≤Uric acid<9.0 mg/dL Obermayr RP et al, J Am Soc Nephrol 19:2407–2413, 2008

14. Obermayr RP et al, J Am Soc Nephrol 19:2407–2413, 2008

15. 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

17. Haririan A et al, Transplantation 89:573, 2010 Haririan A et al, Am J Transplant 11:1943, 2011

18. Lessons from Experimental Study • Lessons from Epidemiologic Study & Clinical Trials • Lessons from Interventional Studies • Treatment of Hyperuricemia

19. 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 Feig DI et al, JAMA 300:924, 2008

20. SBP (mmHg) Cr (mg/dl) Allopurinol Control Allopurinol Control Am J Kidney Dis 47:51, 2006

21. 113 CKD patients with eGFR<60 ml/min • Allopurinol 100 mg/day vs. placebo • Follow-up for 24 months Goicoechea M et al, CJASN, 2010

22. 20 CKD patients on allopurinol • Stop allopurinol & f-up for 12 months ACEi ARB Others ACEi ARB Others Talaat KM et al, Am J Nephrol 27:435, 2007

23. Lessons from Experimental Study • Lessons from Epidemiologic Study & Clinical Trials • Lessons from Interventional Studies • Treatment of Hyperuricemia in CKD

24. Conventional Treatment of Hyperuricemia  Life style modification with treat hyperlipidemia  Avoid drugs raise uric acid level  Xanthine oxidase inhibitor  Uricosuric agent Diuretics/CsA/low-dose salicylate/EMB/PZA/nicotinic acid Urate overproduction/renal insufficiency/nephrolithiasis/prevention of uric acid nephropathy/tophaceous gout/failure of uricosuric agent

25. Allopurinol • Non-selective xanthine oxidase inhibitor • Usual starting dose 300 mg/day • Starting from <100 mg/day in patients with GFR less than 50 ml/min • Common 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) • Drug discontinuation in up to 5%; severe AE in 2% (allopurinol hypersensitivity syndrome) 20% mortality

26. Guideline for Allopurinol Dose according to Renal Function Hande KR et al, Am J Med. 1984;76:47-56

27. Allopurinol : Drug Interaction • 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 • Chlorpropamide • Warfarin • Theophylline

28. Probenecid • Inhibit the reabsorption of uric acid in proximal tubule • No 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 : • Aspirin • Heparin/Indomethacin/ketoprofen/MTX • ProbalanR/BenemidR/ProbenateR

29. Benzbromarone • Inhibit the reabsorption of uric acid in proximal tubule, anti-thrombotic & anti-platelet action • Can use in patients with renal impairment • Side 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 day • NarcaricinR, UrinonR

30. Blood, 15:2998, 2001 NEJM, 353:2450, 2005 Other Drugs for Treatment of Hyperuricemia  Recombinant uricase : RasburicaseR  non-purine selective XO inhibitor : FebuxostatR

31. Review of 88 published papers • 40 mg of febuxostat vs. 300 mg of allopurinol • Mild-to-moderate AE: liver enzyme elevation (4.6~6.6%) • No need to dose-adjustment in subject of eGFR 30-89 ml/min

34. Effect of Drugs to manage CV Risk Factors on Serum Uric Acid Level Borghi C, Hot Topics in Cardiology 14:15, 2008

35. Common Mistakes in Prescribing Uric Acid-lowering Medicine in CKD Patients • We commonly hesitate to prescribe uric acid-lowering medicine. • 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.

37. General Guideline in Prescribing UA-lowering Medicine in CKD Patients (I) • First, we have to decide to treat hyperuricemia or not according to the patients’ characteristics. 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.

38. General Guideline in Prescribing UA-lowering Medicine in CKD Patients (II) • If patient is not tolerable to XO inhibitor, uricosuric agents can be tried according to patients’ residual renal function, co-morbidity & concurrent medication. • 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.

39. Persistent Asymptomatic Hyperuricemia Hx, PE & Lab to find potentially treatable cause of HU 24hr urine UA, FEUA Tx or correct underlying conditions Over-productionFEUA>6%800 mg/D or 12 mg/kg/D Under-excretion FEUA<6% Repeat in 5 days of low purine diet UUA>670 mg/D normalize Inherited or acquired causes of under-excretion Inherited cause of over-production Decrease dietary purine consumption

40. 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.