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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