Presentation is loading. Please wait.

Presentation is loading. Please wait.

Iperuricemia con o senza depositi di urato: inquadramento clinico e nuove strategie terapeutiche”, Università degli Studi di Genova IRCCS-AOU San Martino.

Similar presentations


Presentation on theme: "Iperuricemia con o senza depositi di urato: inquadramento clinico e nuove strategie terapeutiche”, Università degli Studi di Genova IRCCS-AOU San Martino."— Presentation transcript:

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

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. Medicine 39:405—407, there is an abundance of clinical and pathological data to implicate the kidney heavily in the pathogenesis of the most important complication.... 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 postmortem protocols.

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, Tubulointerstitial diseases, in The Kidney (3rd ed), BRENNER BM, RECTOR FC, Philadelphia, Saunders, 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 Grandi progressi nella terapia della nefropatia acuta da acido urico (acute tumor lysis) 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

8

9

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

11 The Hyperuricemia Cascade Dietary Purines Tissue Nucleic acids Endogenous Purine Synthesis 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 lung kidney Urate deposition and inflammation in Acute Tumor Lysis

13

14

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

16

17

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

20 NOD free survival, % years AU -, n=609 AU+, n=149 P < (log-rank test) HR New onset diabetes on the basis of serum uric acid levels in primary hypertension Viazzi F et al., Diabetes Care, 2011

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

22 Danno vascolare, renale Iperuricemia ?

23 Superoxide radical: O 2 + e - O 2 Protonation of O 2 Hydroxyl radical: H 2 O 2 + Fe 2+ OH+OH - + Fe 3+ Cosa sono i radicali liberi? HO 2

24 Activated NADPH oxidase 2O 2 + NADPH2O 2 + NADP + + H + Bacteria Activated mononuclear cells release NADPH oxidase O 2 H 2 O 2 NO, HOCl destruction of invaders

25 (Griendling Circ Res 2000) Extracellular Intracellular

26

27 Human vascular smooth muscle cells express a urate transporter Uric Acid VSMC Proliferation MAP Kinasi TxA 2  PDGF  COX2 Macrophage Infiltration  MCP-1 NF  B AP1 Price KL et al, JASN 2006 URAT 1

28 A Model of Mild Hyperuricemia Normal Rat SUA ( mg/dl) Hyperuricemic Rat SUA ( mg/dl) Uricase inhibitor Oxonic acid (OA)

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

30 Uric acid stimulates VSMC proliferation and oxidative stress Corry DB et al, J Hypertens 2008 Uric acid stimulates VSMC proliferation and oxidative stress via the tissutal RAS

31 Sanchez-Lozada LG, NDT 2008 Febuxostat attenua arteriolosclerosi e ipertensione sistemica e glomerulare Ratto iperuricemic o Ratto trattato con febuxostat

32 Serum Uric acid Pro-oxidant compounds

33 Losartan Urat-1 inhibition SGLT-2 inhibition (

34

35 mg/dl decrease Dapagliflozin dose mg

36 Losartan but not irbesartan significantly lowers SUA in patients with type 2 diabetes and nephropathy- a post- hoc analysis of the RENAAL and IDNT trials J Hypertens 2012

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

38 Losartan Urat -1 inibitori SGLT-2 inibitori Allopurinol Febuxostat

39 Purine metabolism. Hare J M, Johnson R J Circulation 2003;107:

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

41 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

42 Allopurinol Slows the Progression of Renal Disease Through Its Ability to Lower SUA Level Siu YP et al. Am J Kidney Dis 47:51-59 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).

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

44 Li Wei, Br J Clin Pharmac 2011 Impact of allopurinol dose on CV outcome 300 mg vs 100 mg adj HR % CI 0.59– patients aged 60 years 1035 allopurinol users

45 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

46

47 Febuxosta t XANTINA OSSIDASI Forma ridotta XANTINA OSSIDASI Forma ossidata XANTINA OSSIDASI Forma ridotta XANTINA OSSIDASI Forma ossidata Ipoxantin a Acido Urico Xantin a Febuxosta t Allopurinolo inibisce solo la forma ridotta Febuxostat inibisce forma ridotta e ossidata

48 Becker MA, et al. N Eng J Med 2005 *p < vs allopurinol Febuxostat 80 mg (n=255) % of patients with SUAconcentration of less than 6.0 mg per deciliter (360 μmol per liter) at the last three monthly measurements * 53% * 62% 21% Febuxostat 120 mg (n=250) Allopurinol 300 mg (n=251) 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 Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout: FACT study

49 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0 – Febuxostat 80 mg (n=262) Febuxostat 120 mg (n=269) Allopurinol 300 mg * (n=268) _ _ Patients with Normal Renal Function Patients with Impaired Renal Function _ 4/9 122/ /258 5/11 60/258 0/10 126/ /269 60/268 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 < versus allopurinol in all patients; c = p < versus febuxostat 120 mg in all patients. P roportion of patients (%) Becker MA et al. Arthritis Research & Therapy 2010; 12: R63. 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)

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

51 Sezai A, Circ J; in press 2013 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

52 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.

53

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

55 Iperuricemia > 6.0 mg/dl Iperproduzione Dieta alcool Elevato turnover cellulare e chemioterapia Disturbi genetici (rari) Iposecrezione Genetica CKD Insulino resistenza Ipertensione Diuretici tiazidici o d’ansa Ciclosporina Aspirina (piccole dosi)

56 Probability of event-free survival (%) Time to event (months) Lower LVMI and UA Iwashima Y et al. Hypertension LVHhyperuricemia developing CVD HTN patients with LVH and hyperuricemia have an increased risk of developing CVD N=619 HTN patients free of prior CVD Lower LVMI and higher UA Higher LVMI and lower UA Higher LVMI and UA Log-rank χ ; P<0.004 Adj. incidence of CVD in patients with was 2.4 fold higher than in

57 Overall= anni SUA, mg/dL P< Reducing SUA is associated with beneficial effect on CV outcomes - LIFE study Kidney Int, 65: ; 2004 Reducing SUA is associated with beneficial effect on CV outcomes - LIFE study Attenuating the increase in SUA explain 29% of the treatment effect on the composite end-point Uricosuric action of losartan via the inhibition of URAT 1 in hypertensive patients AmJHypertens 2008;21,

58 Reducing SUA is associated with beneficial effect on cardiac and renal outcomes - RENAAL study J Hypertens 2012 Renal events rate per 100 pz-years % risk reduction per 0.5 mg/dL SUA decrement corrected for baseline and change in other risk markers 5% risk reduction in CV morbidity and mortality per 0.5 mg/dL SUA decrement P<0.017 Attenuating the increase in SUA explain % of the treatment effect on the CV and renal end-point

59 Reducing SUA is associated with beneficial effect on cardiac outcomes - RENAAL study J Hypertens % risk reduction in CV morbidity and mortality per 0.5 mg/dL SUA decrement P< % risk reduction in hospitalization for HF per 0.5 mg/dL SUA decrement P<0.001 Attenuating the increase in SUA explain 20% of the treatment effect on the CV end- point

60

61

62

63 Rilevanza dell’iperuricemia cronica con e senza deposito di urato nelle malattie cardiovascolari L’iperuricemia cronica si comporta in modo non dissimile da fattori di rischio cardiovascolare tradizionali con i quali spesso si associa in una relazione talmente stretta da lasciare supporre l’esistenza di un nesso patogenetico

64

65 Diuretic – related increase in SUA may partially offset the treatment benefit SHEP study from Franse LV et al, J Hypertens, 2000 Treatment group after 1 year Coronary heart disease HR95% CI Placebo, SUA increase < 1 mg/dl (n=1543)1 Placebo, SUA increase ≥ 1 mg/dl (n=296) Chlorthalidone, SUA increase < 1 mg/dl (n=985) * Chlorthalidone, SUA increase ≥ 1 mg/dl (n=942)

66 patients, mean eGFR 84 ml/min/1.73m2, CKD stages III-IV 6%, UA>7 mg/dl 15.6% Mean follow-up 1.26 ±0.95 yrs CV morbidity: MI, subacute CHD, HF, cerebrovascular disease or peripheral arterial disease 33% in UA in pts with UA >5.7 mg/dl 9.4% in CVE ↓6.1% in non- CKD or stages 1-2 ↓60.2% in stages 3-5


Download ppt "Iperuricemia con o senza depositi di urato: inquadramento clinico e nuove strategie terapeutiche”, Università degli Studi di Genova IRCCS-AOU San Martino."

Similar presentations


Ads by Google