Andrea Ungar, MD, PhD, FESC

Syncope Unit, Hypertension Centre

Geriatric Intensive Care Medicine

University of Florence, Italy

Iperuricemia e insufficienza

renale nell’anziano

Iperuricemia e insufficienza

renale nell’anziano

L’epidemiologia

N= 177570

Adj for: BMI, creatinine, proteinuria, race, HT, diabetes, age, gender, family history of renal disease,

glicosuria, Hb, education

Arch Int Med 2009

41632 subjects mean age 45.4 years 4 years mean follow-up3186 (7.6%) subjects developed kidney dysfunction

Relationship between SUA Levels and CKD in a Japanese Cohort with Normal or Mildly Reduced Kidney Function Tojama T, 2015

Mortality

In conclusion, the present meta-analysis found that

elevated serum uric acid levels predicted mortality

risk in patients with CKD. These results indicated urgent

need for randomized trials to evaluate whether

interventions targeting serum uric acid can reduce

mortality in patients with CKD

Iperuricemia e insufficienza

renale nell’anziano

I meccanismi patogenetici

Proposed Mechanism

for Uric Acid–Mediated

Hypertension

Feig DI et al. N Engl J Med. 2008;359(17):1811-21

Uric acid and Renal Blood Flow (RBF) in

humans

Perlstein TS et al, Kidney Int 2004

90

94

98

102

106

110P=0.001

RE

NA

L V

OLU

ME

m

l*m

2/k

g

164

168

172

176

180

184

188

RE

NA

LV

OLU

ME

/R

.I.

ml*

m2/k

g

P<0.001

0,55

0,57

0,59

0,61

RE

NA

L R

ES

IS

TIV

E I

ND

EX

P<0.05

6

8

10

12

14

16

18

20

22

AC

R m

g/g

P<0.01

n= 418, Mean ± SD Viazzi F, Pontremoli R et al. Am J Hypertens 2007

High SUALow SUA

Mild Hyperuricemia and signs of renal damage in

Primary Hypertension

Systemic vascular changes seem partially to mediate

the association between SUA and renal function in

hypertensive patients, regardless of kidney function.

Normal Rat Hyperuricemic Rat Essential

Hypertension

Blood Pressure Arteriolar Thickness (μm)

weeks Mazzali et al, AJP Renal Physiol, 2002

BP independent pro-ATHEROSCLEROTIC

effect of hyper-Uricemia

Sanchez-Lozada LG, NDT 2008

Febuxostat attenuates arteriolosclerosis and

systemic as well as glomerular BP

Hyperuricemic Rat

+ febuxostat

Arteriola

afferente efferente

Angiotensina II + ++

Endotelina-1 + ++

Noradrenalina + ++

Nitrossido ++ +

PGE2 ++ -

PGI2 ++ ++

Fattori paracrini e resistenze arteriolari

nel glomerulo renale

VasocostrittoriVS.

Vasodilatanti

Effetti sistemici e renali

dello Stress Mentale in

giovani sani

PR

P

(ml/

min

/1,7

3m

2)

100

200

300

400

500

600

*

FG

(ml/

min

/1,7

3 m

2)

20

60

100

140

180

FF

(%)

*

15

25

35

45

*

RR

(Dyn

e/se

c/cm

-5/1

,73 m

2)

- 30 9060300 minuti

BL Stress I Rec II Rec

3000

9000

15000

21000

27000

33000

**

* = p< 0,05 vs. BL

** = p< 0,001 vs. BL

Castellani S, Ungar A et al,

J Lab Clin Med, 129:462-9, 1997

80

100

120

140

70

80

90

-30 0 30 60 90 min

60

PA

(m

m H

g)

FC

(b

pm

)

stress mentale

minuti

****P

R P

(ml/

min

/1,7

3m

2)

100

200

300

400

500

600*

*F

G

(ml/

min

/1,7

3 m

2)

20

60

100

140

180

*

F F

(%)

15

25

35

45

*

*

**

R R

(Dyne/

sec/

cm-5

/1,7

3 m

2)

3000

9000

15000

21000

27000

33000

- 30

**** ***

***9060300

BL Stress I Rec II Rec

* = p< 0,05 vs. BL

** = p< 0,01 vs. BL

*** = p< 0,001 vs. BL

Giovani (n=8)

Anziani (n=8)

Castellani S, Ungar A et al,

J Lab Clin Med, 132:186-94, 1998

Come reagisce agli aumenti

pressori il rene del paziente

iperuricemico ??????

Mechanism by which uric acid contributes to the development of renal and non-renal diseases.

Johnson R, Nephrol Dial Transplant 2013

Iperuricemia e insufficienza

renale nell’anziano

E’ il momento di agire?

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

J Hypertens 2012

9.5

12.314.3

6% RR per 0.5 mg/dL SUA decrementP <0.015% RR per 0.5 mg/dL SUA decrement P<0.01

Renal morbidity and mortality

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

The purine degradation pathway

FebuxostatAllopurinol

Malik Uk et al, Free Radical Biology & Medicine 2011

Febuxostat is more potent than allopurinol at inhibiting XO free in solution.

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%

42,3

%

0

20

40

60

80

100

Febuxostat 80 mg

(n=360/503)

Allopurinolo 200 mg

(n=212/501)

Pa

zie

nti

(

%)

p<0.001

Creatininemia >1.5-<2.0 mg/dl)

At the doses tested, safety of

febuxostat and allopurinol was

comparable.

Iperuricemia e insufficienza renale

nell’anziano

• I livelli di acido urico sono un fattore di rischio indipendente di

insufficienza renale

• L’acido urico potrebbe essere implicato nelle prime fasi del danno

cardio-vasculo-renale in considerazione di molti meccanismi

patogenetici comuni

• Il Febuxostat ha una maggiore efficacia ed una migliore tollarabilità

dell’allopurinolo nel paziente con insufficienza renale

• Il trattamento con inibitori della xantino-ossididasi sembrano in

grado di ridurre la progressione del danno renale, anche se

saranno necessari ampi trial randomizzati per confermare questa

possibilità

Sezai A, Circ J 2013

Effect of febuxostat on renal function and CV damage in cardiac surgerypatientsNU-FLASH Trial

Febuxostat (80 mg)= 69 pz

Allopurinol (300 mg)= 70 pz