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

Iperuricemia con o senza depositi diurato: inquadramento clinico e nuove strategie terapeutiche”, Iperuricemia con o senza depositi diurato: inquadramento clinico e nuove strategie terapeutiche”,

Università degli Studi di Genova IRCCS-AOU San Martino - IST

HEARTLINEIRCCS San MartinoGenoaCardiologyMeeting15/16 Novembre 2013

Giacomo Garibotto

“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

TALBOTT JH, RERPLAN KL: The kidney in gout. Medicine

39:405—407, 1960

• ..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 .

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…

Cotran, Rubin, and Tolkoff-Rubin,Tubulointerstitial diseases, 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…..

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..

ANNI 80-90• 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

Paulev Human Physiology

Hyperuricemia=

volume depletion+reduced secretion of uric acid. (also) genetically influenced

The Hyperuricemia Cascade

DietaryPurines

TissueNucleic acids

EndogenousPurine 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

?

Liver sinusoids

cerebellum

brain

lung

kidney

Urate deposition and inflammation in Acute Tumor Lysis

Mean SUA levels have risen from 1920

6.25

5.00

3.40

1970s

1950s

1920s

Uric acid mg/dl

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

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)

Relationship of selected variables to the Relationship of selected variables to the presence of presence of endothelial dysfunctionendothelial dysfunction

Mod

ified

fro

m Z

occali

C, et

al.

JA

SN

2006

1.6

1.4

1.2

1.0

0 Creatinine HOMA Creatinine HOMA SUASUA

p=0.003 p= 0.006 p=0.004

Haza

rd R

isk*

(CI)

1.4(1.1-1.8)

1.5

(1.1-1.9)

1.4 (1.1-1.8)

207 never treated hypertensive patients *also in model CRP, age, gender, DBP, lipid profile, smoking habits

SUA and endotelial dysfunction in humans

NO

D f

ree s

urv

ival ,

%

years

AU -, n=609

AU+, n=149P <0.0001 (log-rank test) HR 20.21

New onset diabetes on the basis of serum uric acid New onset diabetes on the basis of serum uric acid levels in primary hypertensionlevels in primary hypertension

Viazzi F et al., Diabetes Care, 2011

,82

,84

,86

,88

,9

,92

,94

,96

,98

1

0 2 4 6 8 10 12 14 16

All, SUA P<0.0001All, SUA P<0.0001

All, adj SUA P= 0.09

women, SUA P<0.0001women, SUA P<0.0001

women, adj SUA P= 0.03women, adj SUA P= 0.03

men, SUA P 0.065

men, adj SUA P=0.41

SUA as a cardiovascular risk factor:a stronger association in women -LIFE study-

0.5 1 1.5

HR for CV end point per 0.17 mg/dL

95% CI

Kidney Int, 65:1041-1049; 2004

Danno vascolare, renale

Iperuricemia

?

• Superoxide radical: O2 + e- O2

• Protonation of O2

• Hydroxyl radical:

H2O2 + Fe2+ OH+OH - + Fe3+

Cosa sono i radicali liberi?

HO2

Activated

NADPH oxidase

2O2 + NADPH 2O2 + NADP+ + H+

Bacteria

Activated mononuclear cells release NADPH oxidase

O2 H2O2

NO, HOCl

destruction of invaders

(Griendling Circ Res 2000)

Extracellular

Intracellular

Human vascular smooth muscle cells express a urate transporter

Uric Acid

VSMC Proliferatio

n

MAP Kinasi

TxA2

PDGF

COX2

Macrophage

Infiltration

MCP-1

NFB AP1

Price KL et al, JASN 2006

URAT 1

A Model of Mild Hyperuricemia

Normal Rat SUA (0.5-1.4 mg/dl)

Hyperuricemic Rat SUA (1.7-3.0 mg/dl)

Uricase inhibitor

Oxonic acid (OA)

Mazzali et al, AJP Renal Physiol, 2002

Hyperuricemia induces Hyperuricemia induces arteriolosclerosisarteriolosclerosisin a BP independent fashionin a BP independent fashion

Essential hypertensi

on

Hyperuricemic rat

Normal rat

Losartan Urat-1 inhibition SGLT-2 inhibition (

mg/dl decrease

Dapagliflozin dosemg

Reducing SUA is associated with beneficial effect on cardiac and renal outcomes -

RENAAL study

J Hypertens 2012

9.5

12.3 14.3

6% 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

LosartanUrat -1 inibitoriSGLT-2 inibitori

AllopurinolFebuxostat

Purine metabolism.

Hare

J M

, J

oh

nson

R J

Cir

cu

lati

on

20

03

;10

7:1

95

1-1

95

3

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, 23903 person-years of f-up2483 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

Δ SUA f-up adj for basal levels =0.68

mg/dL

25%

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

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).

Does reducing SUA Does reducing SUA slowsslows the the progression of renal disease? progression of renal disease?

Goicoechea M et al; CJASN 2010

Allopurinol group, n=57Control group, n= 56

-2

-1,5

-1

-0,5

0

0,5

Uric acid change (mg/dl)

P<0.0001

24 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

-4

-3

-2

-1

0

1

2

eGFR change (ml/min/1.73m2)

P= 0.0180

Li Wei, Br J Clin Pharmac 2011Li Wei, Br J Clin Pharmac 2011

Impact of allopurinol dose on CV outcomeImpact of allopurinol dose on CV outcome

300 mg vs 100 mg adj HR 0.7595% CI 0.59–0.94

300 mg vs 100 mg adj HR 0.7595% CI 0.59–0.94

7137 patients aged 60 years1035 allopurinol users

Effects of Urate-Lowering Therapy in Hyperuricemia on Slowing the Progression of Renal Function: A Meta-AnalysisEffects of Urate-Lowering Therapy in Hyperuricemia on Slowing the Progression of Renal Function: A Meta-Analysis

Wang H, et al, J Ren Nutr. 2012

Febuxostat

XANTINA OSSIDASI

Forma ridotta

XANTINA OSSIDASI

Forma ossidata

XANTINA OSSIDASI

Forma ridotta

XANTINA OSSIDASI

Forma ossidata

Ipoxantina

Acido Urico

Xantina

Febuxostat

Allopurinolo

inibisce solo la forma ridotta

Allopurinolo

inibisce solo la forma ridotta

Febuxostat

inibisce forma ridotta e ossidata

Febuxostat

inibisce forma ridotta e ossidata

Becker MA, et al. N Eng J Med 2005

*p < 0.001 vs allopurinol

Febuxostat 80 mg(n=255)

% o

f pati

ents

wit

h S

UA

conce

ntr

ati

on o

f le

ss t

han 6

.0 m

g p

er

deci

liter

(36

0 μ

mol

per

liter)

at

the last

thre

e m

onth

ly

measu

rem

ents

* 53%

* 62%

21%

0

10

20

30

40

50

60

70

80

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

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 –Febuxostat

80 mg(n=262)

Febuxostat120 mg(n=269)

Allopurinol300 mg *(n=268)

_ _

Patients with Normal Renal FunctionPatients with Impaired Renal Function

_

4/9122/153

170/258

5/11

60/258

0/10

126/262 ᵃ ᵇ ᶜ

175/269 ᵃ ᵇ

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 < 0.001 versus allopurinol in all patients; c = p < 0.001 versus febuxostat 120 mg in all patients.

Prop

ortio

n of

pat

ient

s (%

)

Becker MA et al. Arthritis Research & Therapy 2010; 12: R63.

Allopurinol- and Placebo-Controlled, Efficacy Study of Febuxostat: APEX studySubjects (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)

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.

In subjects with mild/moderate renal impairment mild/moderate renal impairment (65%), both febuxostat doses were more

efficacious than allopurinol and equally safe.

71,6%

42,3%

0

20

40

60

80

100

Febuxostat 80 mg(n=360/503)

Allopurinolo 200 mg(n=212/501)

Paz

ien

ti

(%

)

p<0.001

Creatininemia >1.5-<2.0 mg/dl) Creatininemia >1.5-<2.0 mg/dl)

At the doses tested, safety of At the doses tested, safety of febuxostat and allopurinol was febuxostat and allopurinol was

comparable.comparable.

Sezai A, Circ J; in press 2013Sezai 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

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.

Berry CE et al. J Physiol. 2004; 555(Pt 3):589–606.1

The purine degradation pathway

FebuxostatAllopurinol

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)

Pro

bab

ilit

y o

f even

t-fr

ee s

urv

ival (%

)

Time to event (months)

70

80

100

90

0 15 30 45 60 75

Lower LVMI and Lower LVMI and UAUA

Iwashima Y et al. Hypertension 2006.

HTN patients with LVHLVH and hyperuricemiahyperuricemia have an increased risk of developing CVDdeveloping CVD

N=619 HTN patients free of prior CVD

Lower LVMI and higher Lower LVMI and higher UAUA

Higher LVMI and lower Higher LVMI and lower UAUA

Higher LVMI and Higher LVMI and UAUA

Log-rank Log-rank χχ2 2 13.2; 13.2; P<0.004P<0.004

Adj. incidence of CVD in patients with was 2.4 fold higher than in

275

300

325

350

375

400

Losartan AtenololoOverall= 9193

0 1 2 3 4 5 6 anni

SU

A, m

g/d

L

P< 0.00016.7

6.3

5.9

5.5

5.0

4.6

Reducing SUA is associated with beneficial effect on CV outcomes - LIFE study

Kidney Int, 65:1041-1049; 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, 1157-1162

Reducing SUA is associated with beneficial effect on cardiac outcomes - RENAAL

study

J Hypertens 2012

5% risk reduction in CV morbidity and mortality per 0.5 mg/dL SUA decrement P<0.017

12% risk reduction in hospitalization for HFper 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

Diuretic – related increase in SUA may partially offset the treatment benefit

SHEP study

from Franse LV et al, J Hypertens, from Franse LV et al, J Hypertens, 20002000

Treatment group after 1 year Coronary heart disease

HR 95% CI

Placebo, SUA increase < 1 mg/dl (n=1543)

1

Placebo, SUA increase ≥ 1 mg/dl (n=296)

1.08 0.63-1.83

Chlorthalidone, SUA increase < 1 mg/dl (n=985)

0.56 0.37-0.85*

Chlorthalidone, SUA increase ≥ 1 mg/dl (n=942)

0.96 0.67-1.39

148.217 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