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
“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
Dietary
Purines
Endogenous
Purine Synthesis
Tissue
Nucleic acids
Urate
Underescretion
Hyperuricemia
Urate deposition
Gout,
renal calculi
Acute renal failure
(acute tumor lysis)
Damage without
urate deposition
Acceleration of CKD
?
Hypertension, CV disease
Liver sinusoids
cerebellum
brain
Urate
deposition and
inflammation in
Acute Tumor
lung
Lysis
kidney
J Clin Hypertens
2006
Sindrome
Metabolica
Obesità
Mean SUA levels have risen from
1920
Fishberg, Arch Int Med 1920s
1924;
Afro3.40 Americani
Hall, AmJ Med 1967; 1950s
Acido Urico
Insulino
Resistenza
5.00
Diuretici
Nefropatia
Ipertensione
Glynn, Arthritis Rheum 1970s
1983;
6.25
Uric acid mg/dl
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)
Hazard Risk*
(CI)
1.6
1.5
(1.1-1.9)
1.4
1.4
(1.1-1.8)
1.4
(1.1-1.8)
1.2
1.0
p=0.003
p= 0.006
p=0.004
0
Creatinine
HOMA
SUA
207 never treated hypertensive patients *also in model CRP, age, gender, DBP, lipid profile, smoking habits
Modified from Zoccali C, et al. JASN 2006
Relationship of selected variables to the
SUA and endotelial dysfunction in humans
presence of endothelial dysfunction
New onset diabetes on the basis of serum uric acid
levels in primary hypertension
NOD free survival , %
1
,98
,96
,94
AU -, n=609
,92
,9
,88
,86
AU+, n=149
,84
P <0.0001 (log-rank test) HR 20.21
,82
0
2
4
6
8
10
12
14
16
years
Viazzi F et al., Diabetes Care, 2011
SUA as a cardiovascular risk factor:
a stronger association in women -LIFE studyHR for CV end point
per 0.17 mg/dL
0.5
95% CI
1
1.5
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
Iperuricemia
?
Danno vascolare, renale
Cosa sono i radicali liberi?
• Superoxide radical: O2
+ eO2
• Protonation of O2
HO2
• Hydroxyl radical:
H2O2 + Fe2+
OH+OH - + Fe3+
Activated mononuclear cells release
NADPH oxidase
Activated
destruction of
invaders
O2 H2O2
NO, HOCl
Bacteria
NADPH oxidase
2O2 + NADPH
2O2 + NADP+ + H+
Extracellular
Intracellular
(Griendling Circ Res 2000)
Human vascular smooth muscle cells
express a urate transporter
URAT 1
MAP
Kinasi
NFB
AP1
COX2
Uric Acid
TxA2
PDGF
VSMC
Proliferation
Price KL et al, JASN 2006
MCP-1
Macrophage
Infiltration
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)
Hyperuricemia induces arteriolosclerosis
in a BP independent fashion
Normal
rat
Hyperuricem
ic rat
Essential
hypertension
Mazzali et al, AJP Renal Physiol,
2002
Losartan
Urat-1 inhibition
SGLT-2 inhibition (
mg
Dapagliflozin dose
mg/dl decrease
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
Allopurinol
Febuxostat
Losartan
Urat -1 inibitori
SGLT-2
inibitori
Hare J M , Johnson R J Circulation 2003;107:1951-1953
Purine metabolism.
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
Δ SUA f-up
2483 in the allopurinol group (83% gout diagnosis)
7441 in the control group (20% gout diagnosis) adj for basal
levels =0.68
mg/dL
25%
AJ Luk et al. Rheumatology 2009
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
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
Does reducing SUA slows the
progression of renal disease?
Allopurinol group, n=57
Control group, n= 56
24 mos F-up
0,5
allopurinol reduces
CVE (71%) and
hospitalization risk
(60%)
P= 0.0180
P<0.0001
2
0
1
-0,5
0
-1
-1
-1,5
-2
-2
-3
Uric acid change (mg/dl)
-4
eGFR change (ml/min/1.73m2)
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
Impact of allopurinol dose on CV outcome
Li Wei, Br J Clin Pharmac 2011
300 mg vs 100
mg
adj HR 0.75
95% CI 0.59–
0.94
7137 patients aged 60 year
1035 allopurinol users
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
Allopurinolo
inibisce solo la forma ridotta
Ipoxantin
a
Febuxostat
XANTINA
OSSIDASI
Forma ridotta
Xantin
a
XANTINA
OSSIDASI
Forma
ossidata
Acido
Urico
XANTINA
OSSIDASI
Forma ridotta
XANTINA
OSSIDASI
Forma
ossidata
inibisce forma ridotta e ossidata
Febuxosta
t
Febuxosta
t
Febuxostat Compared with Allopurinol in Patients
with Hyperuricemia and Gout: FACT study
% of patients with SUAconcentration of less
than 6.0 mg per deciliter (360 μmol per liter) at
the last three monthly measurements
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
70
60
50
*
53%
*
62%
*p < 0.001 vs allopurinol
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. N Eng J Med 2005
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 –
Proportion of patients (%)
70 –
60 –
50 –
40 –
Patients with Normal Renal Function
Patients with Impaired Renal Functio
175/269 ᵃ ᵇ
170/258
126/262 ᵃ ᵇ ᶜ
122/153
5/11
4/9
• 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.
60/268
30 –
60/258
20 –
10 –
0/10
Febuxostat
120 mg
(n=269)
_
Febuxostat
80 mg
(n=262)
_
_
0–
Allopurinol
300 mg *
(n=268)
Becker MA et al. Arthritis Research & Therapy 2010; 12: R63.
Febuxostat vs Allopurinol:
And the Winner Is...
At the doses tested, safety of
febuxostat and allopurinol was
comparable.
Creatininemia >1.5-<2.0 mg/dl)
100
80
Pazienti (%)
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
(65%), both febuxostat doses were more
efficacious than allopurinol and equally safe.
71,6
%
60
p<0.001
42,3
%
40
20
0
Febuxostat 80 mg
(n=360/503)
Allopurinolo 200 mg
(n=212/501)
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
• 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.
The purine degradation pathway
Allopurinol
Febuxostat
Berry CE et al. J Physiol. 2004; 555(Pt 3):589–606.1
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)
HTN patients with LVH and hyperuricemia have an
increased risk of developing CVD
Probability of
event-free survival (%)
100
Lower LVMI and UA
Lower LVMI and higher UA
90
Higher LVMI and lower UA
Log-rank χ2 13.2;
P<0.004
80
70
Higher LVMI and UA
Adj. incidence of CVD in patients with
0
15
30
was 2.4 fold higher than in
45
60
75
Time to event (months)
N=619 HTN patients free of prior CVD
Iwashima Y et al. Hypertension 2006.
Reducing SUA is associated with beneficial effect
on CV outcomes - LIFE study
400
6.7
P< 0.0001
SUA, mg/dL
6.3
375
5.9
350
5.5
325
5.0
300
4.6
275
0
anni
1
Overall=
9193
Kidney Int, 65:1041-1049; 2004
2
3
Losartan
4
Atenololo
5
6
Reducing SUA is associated with beneficial effect
on cardiac outcomes - RENAAL study
5% risk reduction in CV morbidity and
mortality per 0.5 mg/dL SUA decrement
P<0.017
12% risk reduction in hospitalization
for HF
per 0.5 mg/dL SUA decrement
P<0.001
J Hypertens 2012
Diuretic – related increase in SUA
partially offset the treatment benefit
SHEP study
Treatment group after 1 year
disease
Coronary heart
HR
Placebo, SUA increase < 1 mg/dl (n=1543)
may
95% CI
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
from Franse LV et al, J Hypertens, 2000
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
↓6.1% in nonCKD or stages 1-2
9.4% in CVE
↓60.2% in
stages 3-5