Iperuricemia con o senza depositi di

1. HEARTLINE IRCCS San Martino Genoa Cardiology Meeting 15/16 Novembre 2013 Iperuricemia con o senza depositi di urato: inquadramento clinico e nuove strategie terapeutiche”, Giacomo Garibotto Università degli Studi di Genova IRCCS-AOU San Martino - IST

2. “The viscera in time are so much injured, from the stagnation of the morbific matter therein, that the organs of secretion no longer perform their functions, whence the blood, overcharged with vitiated humours, stagnates, and the gouty matter ceases to be thrown upon the extremities as formerly, so that at length death frees him from his misery.” Thomas Sydenham, 1683 A Treatise of the Gout and the Dropsy

3. TALBOTT JH, RERPLAN KL: The kidney in gout. Medicine39:405—407, 1960 • ..there is an abundance of clinical and pathological data to implicate the kidney heavily in the pathogenesis of the most importantcomplication. . . . Deposition of urate crystals may be followed by fibrosis as a sequel. • Laboratory evidence of renal involvement is a frequent finding in patients with gout. The development of renal insufficiency was critical in 18 per cent of the larger series and 25 per cent in the smaller series of postmortemprotocols .

4. Grantham JJ, Cuosno AM: The Kidney (3rd ed),BRENNER BM, RECTOR Ft. I'hiladelphia, Saunders. 1986, pp 688—689 …gouty nephropathy is a chronic form of interstitial nephritis resulting from the prolonged deposition of sodium urate crystals in the renal parenchyma. The distinctive histologic features of gouty nephropathy are the presence of urate crystals in the medulla and the surrounding giant cell reaction…

5. Cotran, Rubin, and Tolkoff-Rubin,Tubulointerstitialdiseases, in The Kidney (3rd ed), BRENNER BM, RECTOR FC, Philadelphia, Saunders, 1986 -The very existence of chronic gouty nephropathy, i.e. a chronic nephropathy specifically caused by deposition of urate crystals in the kidney is controversial. -In summary, many factors may contribute to chronic nephropathy in a patient with gout…..

6. Kidney International, Vol. 30 (1986), pp. 280—287 NEPHROLOGY FORUM Requiem for gouty nephropathy Principal discussant: LAURENCE H. BECK …there is merely an association of SUA with other risk factors, including hypertension, renal disease, elevated lipoprotein levels, and use of diuretic agents..

7. ANNI 80-90 • Grandi progressi nella terapia della nefropatia acuta da acido urico (acute tumorlysis) • Diverso approccio all’iperuricemia isolata: Scuola statunitense: trattare uricemia solo se sintomatica o > 12 mg/dl Scuola europea: Trattare uricemia se > 6.8 mg/dl • pKa 5,75 nel sangue e 5,25 nelle urine

10. Paulev Human Physiology Hyperuricemia= volume depletion + reduced secretion of uric acid. (also) genetically influenced

11. The Hyperuricemia Cascade Endogenous Purine Synthesis Dietary Purines Tissue Nucleicacids Urate Underescretion Hyperuricemia Urate deposition Damage without urate deposition Gout, renal calculi Acute renal failure (acute tumor lysis) Acceleration of CKD ? Hypertension, CV disease

12. Liver sinusoids cerebellum brain Urate deposition and inflammation in Acute Tumor Lysis lung kidney

15. J Clin Hypertens 2006 Sindrome Metabolica Obesità Afro-Americani Acido Urico Insulino Resistenza Mean SUA levels have risen from 1920 Diuretici Nefropatia Ipertensione Fishberg, Arch Int Med 1924; Hall, AmJ Med 1967; Glynn, Arthritis Rheum 1983;

18. Metanalisi:l’aumento di 1 mg/dl di uricemia è associato ad aumento del: • 13% del rischio di ipertensione (Grayson 2011) • 16% di malattia coronarica (Kim 2011) • 13% di stroke (Kim 2012) • 17 % di sviluppo di diabete (Kodama 2012)

19. SUA and endotelial dysfunction in humans Relationship of selected variables to the presence of endothelial dysfunction 1.5 (1.1-1.9) 1.6 1.4 1.2 1.0 0 1.4 (1.1-1.8) 1.4 (1.1-1.8) Hazard Risk* (CI) Modified from Zoccali C, et al. JASN 2006 p=0.003 p= 0.006 p=0.004 Creatinine HOMA SUA 207 never treated hypertensive patients *also in model CRP, age, gender, DBP, lipid profile, smoking habits

20. 1 ,98 ,96 ,94 ,92 ,9 ,88 ,86 ,84 ,82 0 2 4 6 8 10 12 14 16 New onset diabetes on the basis of serum uric acid levels in primary hypertension AU -, n=609 NOD free survival , % AU+, n=149 P <0.0001 (log-rank test) HR 20.21 years Viazzi F et al., Diabetes Care, 2011

21. SUA as a cardiovascular risk factor:a stronger association inwomen-LIFE study- HR for CV end point per 0.17 mg/dL 95% CI 1 1.5 0.5 All, SUA P<0.0001 All, adj SUA P= 0.09 women, SUA P<0.0001 women, adj SUA P= 0.03 men, SUA P 0.065 men, adj SUA P=0.41 Kidney Int, 65:1041-1049; 2004

22. Iperuricemia ? Danno vascolare, renale

23. Superoxide radical: O2 + e-O2 Protonation of O2 Hydroxyl radical: H2O2 + Fe2+OH+OH - + Fe3+ Cosa sono i radicali liberi? HO2

24. Activated mononuclear cells release NADPH oxidase Activated destruction of invaders O2 H2O2 NO, HOCl Bacteria NADPH oxidase 2O2 + NADPH 2O2 + NADP+ + H+

25. Extracellular Intracellular (Griendling Circ Res 2000)

27. Human vascular smooth muscle cells express a urate transporter NFB AP1 URAT 1 MAP Kinasi COX2 Uric Acid TxA2 MCP-1 PDGF Macrophage Infiltration VSMC Proliferation Price KL et al, JASN 2006

28. A Model of Mild Hyperuricemia Uricase inhibitor Oxonic acid (OA) Normal Rat SUA (0.5-1.4 mg/dl) Hyperuricemic Rat SUA (1.7-3.0 mg/dl)

29. Hyperuricemia induces arteriolosclerosis in a BP independent fashion Normal rat Hyperuricemic rat Essential hypertension Mazzali et al, AJP Renal Physiol, 2002

30. Losartan Urat-1 inhibition SGLT-2 inhibition (

32. Dapagliflozin dose mg mg/dl decrease

33. Reducing SUA is associated with beneficial effect on cardiac and renal outcomes - RENAAL study 5% risk reduction in CV morbidity and mortality per 0.5 mg/dL SUA decrement P<0.017 6% risk reduction per 0.5 mg/dL SUA decrement corrected for baseline and change in other risk markers 9.5 12.3 14.3 J Hypertens 2012

34. Allopurinol Febuxostat Losartan Urat -1 inibitori SGLT-2 inibitori

35. Purine metabolism. Hare J M , Johnson R J Circulation 2003;107:1951-1953 Acido Urico

36. Δ SUA f-up adj for basal levels =0.68 mg/dL Allopurinol and mortality in hyperuricaemic patients 9924 veterans with SUA> 7.0 mg/dl, 98% males, 88% white, mean age 62.7 years, 23903 person-years of f-up 2483 in the allopurinol group (83% gout diagnosis) 7441 in the control group (20% gout diagnosis) 25% AJ Luk et al. Rheumatology 2009

37. Effect of allopurinol on mortality and hospitalisations in CHF: a retrospective cohort study All cause mortality Struthers AD et al. Heart 2002;87:229–234

38. Allopurinol Slows the Progression of Renal Disease Through Its Ability to Lower SUA Level SUA levels significantly decreased in subjects treated with allopurinol, from 9.75±1.18 mg/dL to 5.88±1.01 mg/dL (P < 0.001). Siu YP et al. Am J Kidney Dis 47:51-59

39. Does reducing SUA slows the progression of renal disease? Allopurinol group, n=57 allopurinol reduces CVE (71%) and hospitalization risk (60%) Control group, n= 56 24 mos F-up P<0.0001 P= 0.0180 Control group HR 1.88 accelerated progression adj for age, gender, diabetes, UA, hs-CRP, albuminuria, CKD etiology, RAS blockers Goicoechea M et al; CJASN 2010

40. Impact of allopurinol dose on CV outcome Li Wei, Br J ClinPharmac 2011 300 mg vs 100 mg adj HR 0.75 95% CI 0.59–0.94 7137 patients aged 60 years 1035 allopurinol users

41. Effects of Urate-Lowering Therapy in Hyperuricemia on Slowing the Progression of Renal Function: A Meta-Analysis Wang H, et al, J Ren Nutr. 2012

43. Ipoxantina Xantina Acido Urico XANTINA OSSIDASI Forma ossidata XANTINA OSSIDASI Forma ossidata XANTINA OSSIDASI Forma ridotta XANTINA OSSIDASI Forma ridotta Febuxostat Febuxostat Allopurinolo inibisce solo la forma ridotta Febuxostat inibisce forma ridotta e ossidata

44. Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout: FACT study 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter at the last three monthly measurements 80 * 62% 70 *p < 0.001 vs allopurinol * 53% 60 50 % of patients with SUAconcentration of less than 6.0 mg per deciliter (360 μmol per liter) at the last three monthly measurements 40 30 21% 20 10 0 Febuxostat 80 mg(n=255) Febuxostat 120 mg(n=250) Allopurinol 300 mg(n=251) Becker MA, et al. NEngJMed 2005

45. Allopurinol- and Placebo-Controlled, Efficacy Study of Febuxostat: APEX study Subjects (n =1.072) with serum urate level >8.0 mg/dL and gout and normal or impaired RF (creat. >1.5 to <2.0 mg/dl) 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 – Patients with Normal Renal Function Patients with Impaired Renal Function 175/269 ᵃ ᵇ 170/258 • Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function. • a = p < 0.05 versus allopurinol in patients with impaired renal function; b = p < 0.001 versus allopurinol in all patients; c = p < 0.001 versus febuxostat 120 mg in all patients. 126/262 ᵃ ᵇ ᶜ Proportion of patients (%) 122/153 5/11 4/9 60/268 60/258 0/10 _ _ _ Febuxostat 80 mg (n=262) Allopurinol 300 mg * (n=268) Febuxostat 120 mg (n=269) Becker MA et al. Arthritis Research & Therapy 2010; 12: R63.

46. Creatininemia >1.5-<2.0 mg/dl) Febuxostat vs Allopurinol: And the Winner Is... In subjects with mild/moderate renal impairment (65%), both febuxostat doses were more efficacious than allopurinol and equally safe. 71,6% 100 2,269 subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial Urate-lowering efficacy of febuxostat80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. p<0.001 80 60 42,3% Pazienti (%) 40 20 0 Allopurinolo 200 mg(n=212/501) Febuxostat 80 mg(n=360/503) At the doses tested, safety of febuxostat and allopurinol was comparable.

47. Effect of febuxostat on renal function and CV damage in cardiac surgery patients NU-FLASH Trial Cardiac surgery patients with hyperuricemia (n=141) were randomized to or allopurinol Sezai A, Circ J; in press 2013

48. Che cosa ha detto? • Molti studi indicano che livelli aumentati di acido urico costituiscono un fattore predittivo di ipertensione, eventi cardiovascolari e renali • L’acido urico sembra essere implicato nelle fasi precoci del danno cardiorenale • Dati su casistiche meno estese indicano che la riduzione dell’uricemia conferisce protezione renale e cardiovascolare • Il nuovo inibitore delle xantine ossidasi febuxostat è più potente e tollerabile rispetto all’allopurinolo.

50. The purine degradation pathway Febuxostat Allopurinol Berry CE et al. J Physiol. 2004; 555(Pt 3):589–606.1