NEW USES OF HYPOURICEMIC DRUGS

1. NEW USES OF HYPOURICEMIC DRUGS
Gianni Bellomo
Department of Nephrology-Ospedale di Assisi, Assisi(Pg),
Italy

2. • Uric Acid is the oxidation end-product of purine metabolism in
man and greater apes(uricase gene non-functional)
• Endogenous production(liver, muscle, intestine), accounts for
about 2/3 of total body amount, the remaining 1/3 exogenous
• Elimination is 70% urinary(250-750 mg/day), 30% GI
• UA is a weak acid; at physiological pH, tends
at a concentration >6.8 mg/dl
to precipitate

3. Serum Uric Acid Concentration in Individuals with Normal
Renal Function
Serum Concentration (mg/dL)
Age
Males
Females
<5 years
3.6±0.9
5-10 years
4.1±1.0
12 years
4.4±1.1
4.5±0.9
15 years
5.6±1.1
4.5±0.9
>18 years
6.2±0.8
4.0±0.7
Harkness RA et al.. Plasma uric acid levels in children. Arch Dis Child. 1969;44:773–8

4. CLASSES OF HYPOURICEMIC DRUGS
•Xanthine oxido-reductase
inhibitors
•Uricases
•Uricosuric drugs

5. XANTHINE OXIDO-REDUCTASE INHIBITORS
ROS
Allopurinol
Febuxostat
Oxypurinol

6. URICASES
Uric acid
Rasburicase
Allantoin

7. URICOSURIC AGENTS
estrogens

8. USES OF URATE-LOWERING DRUGS
APPROVED INDICATIONS
GOUT
TUMOR LYSIS SYNDROME
RECURRENT CALCIUM OXALATE CALCULI
EMERGING INDICATIONS
HYPERTENSION
CHRONIC KIDNEY DISEASE(CKD)
ANGINA
REPERFUSION INJURY
CONGESTIVE HEART FAILURE

9. EMERGING INDICATIONS
HYPERTENSION
CHRONIC KIDNEY DISEASE(CKD)
ANGINA
REPERFUSION INJURY
CONGESTIVE HEART FAIL

11. For a 1 mg/dl increase in uric acid level, the
pooled RR for incident hypertension after
adjusting for potential confounding was
1.13 (95% CI 1.06–1.20). These effects
were significantly larger in younger study
populations (P 0.02) and tended to be
larger in women

12. Randomized, double-blind, placebo-controlled, crossover trial
involving 30 adolescents (aged 11-17 years) who had newly
diagnosed, never-treated stage 1 essential hypertension and
serum uric acid levels > 6 mg/dL.
Allopurinol 200 mg bid for 4 weeks vs placebo

13. Intervention study of allopurinol in adolescent
hypertension:Results

14. Double-blind RCT, comparing for 8 weeks in pre-hypertensive,
obese adolescents(11-17 yrs), serum UA >=5.0 mg/dl
allopurinol(100 mg bid week 1, 200 mg bid weeks 28,
probenecid(250 bid week 1, 500 mg weeks 28, and
placebo

17. Blood Press. 2011 Apr;20(2):104-10.
Effect of allopurinol on blood pressure and aortic compliance in
hypertensive patients.
Kostka-Jeziorny K, Uruski P, Tykarski A.
Sixty-six patients aged 25-70 with mild and moderate arterial
hypertension randomized to antihypertensive therapy on
either perindopril (n = 35) or hydrochlorothiazide (n = 31).
After 8 weeks of antihypertensive therapy, 150 mg of
allopurinol daily was added for the next 8 weeks.
Allopurinol does not produce additional antihypertensive
effects in patients with treated arterial hypertension.
Allopurinol increases aortic compliance
independently of ACE-I or thiazide-based,
antihypertensive therapy. However, this effect is
significantly dependent on the initial PWV in the aorta and
on SBP changes during allopurinol therapy

18. Subjects with asymptomatic hyperuricemia and no history of gout and 30
normouricemic control subjects were enrolled in this 4-month
randomized prospective study. Thirty hyperuricemic patients received 300
mg/d allopurinol and were compared with 37 hyperuricemic patients and
30 normouricemic subjects in matched control groups
Allopurinol treatment resulted in a decrease in serum uric acid, a
decrease in systolic BP, an increase in FMD, and an increase in eGFR
compared with baseline. No significant change vs baseline was
observed in the control hyperuricemic and normouricemic groups.

19. Randomized, controlled trial of 54 hyperuricemic patients with chronic
kidney disease. Patients were randomly assigned to treatment with
allopurinol, 100 to 300 mg/d, or to continue the usual therapy for 12
months
There were no significant differences in systolic or
diastolic blood pressure at the end of the study
comparing the 2 groups. There was a trend toward a lower
serum creatinine level in the treatment group compared with controls
after 12 months of therapy. Overall, 4 of 25 patients (16%) in the
allopurinol group reached the combined end points of significant
deterioration in renal function and dialysis dependence compared with
12 of 26 patients (46.1%) in the control group (P 0.015).

21. Prospective, randomized trial of 113 patients with estimated GFR
(eGFR) <60 ml/min. Patients were randomly assigned to treatment
with allopurinol 100 mg/d (n 57) or to continue the usual therapy (n
56) for 24 months.
BP control was similar in both groups, and no
significant differences were observed in the
follow-up period in SBP and DBP
Allopurinol treatment slowed down renal disease
progression independently of age, gender,
diabetes, C-reactive protein, albuminuria, and
renin-angiotensin system blockers use. heart
disease, and C-reactive protein

22. CONCLUSIONS-HYPERTENSION
• Data
from intervention studies are
insufficient to allow for widespread use of
allopurinol in hypertension
• A possible exception may be represented by
hyperuricemic adolescents with essential
hypertension, with serum UA>5.0 mg/dl,where
a trial of allopurinol therapy may be justified

23. EMERGING INDICATIONS
HYPERTENSION
CHRONIC KIDNEY DISEASE(CKD)
ANGINA
REPERFUSION INJURY
CONGESTIVE HEART FAILURE

24. LONGITUDINAL STUDIES
INVESTIGATING THE
ASSOCIATION BETWEEN SERUM
URIC ACID AND DECLINE OF
RENAL FUNCTION IN THE
GENERAL POPULATION

25. Author and
source
N
(age,country)
Major findings
Followup
(years)
Threshold
(mg/dl)
Hsu et al. Arch Intern
177750
(40.8,USA)
Higher uric acid quartile conferred 2.14fold increased risk of ESRD over 25
years
25
>7.0 pooled
Domrongkitchaiporn
et al. JASN 2005;16: 791-
3499
(42.5,Thailan
d)
Hyperuricemia(>6.29 mg/dl) associated
with increased odds(1.68)of reduced
renal function
12
>6.3 pooled
Obermayr et al. JASN
21475
(44.2,Austria)
Uric acid >7 mg/dl increased risk of
CKD 1.74-fold in men and 3.12-fold in
women
7
>7.0 pooled
Weiner et al.
13338
(57.6,USA)
Each 1 mg/dl increase in uric acid
increased risk of CKD 7–11%
8,5
>6.2 pooled
48177
(48.4,Japan)
Uric acid >8 mg/dl increased CKD risk
three-fold in men and 10-fold in women
Med 2009;169: 342-50
99
2008;19:2407-13
JASN
2008; 19:1204–1211
Iseki et al. AJKD
2004;44:642-50
2
>7.0 in men
>6.0 in women

26. Author and
source
N
(age,country)
Major findings
Followup
(years)
Threshold
(mg/dl)
5
>6.3 in men
>4.9 in women
24-28
>6.5 in men
>5.3 in women
Bellomo et al. AJKD
900
(41.4, Italy)
Each 1 mg increase in uric acid
associated with 1.28 odds ratio of
reduced e-GFR at 5 years
Ben Dov et al. NDT
2449 (48,
Israel)
Uric acid >6.5 mg/dl in men and > 5.3
mg/dl in women,associated with hazard
ratios of 1.36 for all-cause mortality
and 2.14 for incident CKD
Mok Y et al. NDT 2011
20148
(43.7,Korea)
Uric Acid in highest quartile conferred
adjusted HR 2.3 in men and 1.4 in
women for incident CKD
10
>6.3 in men
>4.6 in women
Kuo CF et al. Scand
J
Rheumatol 2011;40:116-21
63785(50.0,
Taiwan)
Hyperuricemia associated with HR 1.28
for accelerated GFR decline(>3 ml/min
*1.73 m2)
12
>7.7 men
>6.6 women
Xiang L et al. NDT 2011
1410
(59.1,China)
Uric acid in highest quartile conferred
adjusted OR 2.14 for incident CKD
4
>6.3 in men,
>5.1 in women
Chonchol et al. AJKD
5808 (73,
USA)
Uric acid strongly associated with
prevalent but weakly with incident
CKD(age >65 yrs)
2010; 56:264-72
2011;26:2558-66
epub
epub
2007;50:239-47
8.5
>5.9 pooled

27. LONGITUDINAL STUDIES
INVESTIGATING THE
ASSOCIATION BETWEEN
SERUM URIC ACID AND
DECLINE OF RENAL FUNCTION
IN ESTABLISHED CKD

28. Author and
source
N (age)
Major findings
Follow
-up
(years)
Threshold
(mg/dl)
2.4
NA
Hunsicker LG et al.
840(50)
Sturm G et al. Exp
Pts with wide range of renal function
(22746,18- (CKD stages 1-5); uric acid associated
65)
to renal function decline only in those
not taking urate lowering drugs(HR
1.27 per mg/dl increase)
7
>7.0 pooled
Madero M et al.
840(52.2)
MDRD cohort; mean baseline GFR
33.0 ml/min;uric acid associated to all
cause and CV mortality(HR 1.57 and
1.47 respectively), but not to CKD
progression (borderline significant
when adjusting for allopurinol use)
10
>8.4 pooled
Liu WC et al. CJASN
3303(63.5)
pts with
stage 3-5
CKD
Significantly increased HR for all
cause(1.39) and CV mortality(1.40) in
third and fourth(1.85,1.42)UA quartiles.
Need for RRT not related to UA
quartiles, renal progression borderline
significant
2.8
>8.3 pooled
Chang HY et al. Am
31331
(>40)
Uric acid associated with CKD
progression in patients with stage 3,
but not 4-5 disease
4
>7.0 pooled
Kidney Int 1997;
51:1908-19
Gerontol 2008; 43:
347-52
AJKD 2009; 53:796803
2012 epub
J Med Sci 2010;
339:509-15
MDRD cohort, GFR<70 ml/min; Uric
acid not associated with GFR decline
over time

29. Intervention studies

30. Author,
source
Study population
Neal et al.
Transplantation
2001;72:1689-91
18 liver transplant
recipients with gout (n
= 8) and
hyperuricemia (n = 10,
UA>6.1 mg/dl) women,
>7.6 men)
Allopurinol
(dose not
stated)
Mean serum creatinine
decreased from 2.0 to 1.8
mg/dl over a median
period of 3 months
Retrospective
study;
indication bias;
small sample
size
Fairbanks et al.
QJM
2002;95:597-607
27 patients with FJHN
Allopurinol
(dose not
stated)
Early treatment associated
with slower decline of
renal function
Case
series,single
center, partially
inadequate
controls
Whelton A et al. J
Clin Rheumatol
2011;17;7-13
Post-hoc analysis of
the FOCUS study: 116
pts with gout, baseline
UA 9.7 mg/dl. Average
end of study UA 4.8
mg/dl
Febuxostat,
40-120 mg for
5 years
Mathematical modelling
predicted 1ml/min GFR
improvement for each 1
mg/dl UA decrease
Open label,
single center,
post-hoc
analysis
Siu et al. AJKD
2006;47:51-59
54 CKD patients with
proteinuria >0.5 g per
day, serum creatinine
>1.4 mg/dl and serum
uric acid >7.6 mg/dl.
Average end of study
UA 5.8 mg/dl
Allopurinol
100–200 mg
daily or their
usual therapy
for 12 months)
Lower serum creatinine in
the allopurinol arm than
the control arm (2.0 ± 0.9
vs 2.9 ± 0.9 mg/dl; P =
0.08) and no differences in
effect on proteinuria (2.53
± 4.85 g per day vs 2.16 ±
1.93 g per day; P = NS)
Small sample
size, open-label
design, short
duration of
follow-up
Goicoechea et al.
CJASN
2010;5:1388-93
113 CKD patients with
eGFR <60 ml/min/1.73
m2 . (mean UA 7.6
mg/dl) Average end of
study UA 6.0 mg/dl
Allopurinol 100
mg daily or no
study
medication for
24 months
Allopurinol slowed the
decline in eGFR (1.3 ± 1.3
ml/min/1.73 m2 vs –3.3 ±
1.2 ml/ min/1.73 m2);
reduced CV events and
CRP;no effect on BP
Small sample
size; open label
and singlecenter study
Intervention
Study findings
Limitations

31. Author, source
Study population
Intervention
Study findings
Limitations
Kao et al.
53 stage 3 CKD
patients with LVH.
Average end of
study UA 4.6 mg/dl
Allopurinol 300
mg daily or
placebo for 9
months
Allopurinol reduced
LVMI (–1.42 ± 4.67
g/m2 vs 1.28 ± 4.45
g/m2) and improved
brachial artery FMD
(1.26 ± 3.06% vs –1.05
± 2.84%); improved
augmentation index
(p=0.015)
Surrogate endpoints only
Small sample
size
Open label
Momeni et
al. Iran J Kidney
40 patients with
type 2 diabetes and
overt nephropathy
(proteinuria >500
mg/24 h, and serum
creatinine <3.0
mg/dl) Average end
of study UA 5.3
mg/dl
Allopurinol 100
mg or placebo
(mean UA 6.3
mg/dl)
Treated patients had
lower serum UA and 24
h proteinur1a after 4
months of follow-up
Small sample
size, singlecenter, short
follow-up,
blinding unclear
Kanbay et
al. CJASN
2011;
72 hyperuricemic
subjects (>7.0
mg/dl),32 on
allopurinol,40 no
treatment, and 30
normouricemic
controlsAverage
end of study UA 5.8
mg/dl
4-month
treatment with
allopurinol, 300
mg vs no study
medication
Allopurinol treated
patients had increased
e-GFR with respect to
baseline, decreased
systolic BP
Small sample
size, short
duration,
blinding unclear
Ejaz AA et
al. Int J Urol
26 pts undergoing
cardiac surgery.
UA>6.5 mg/dl
Rasburicase vs
placebo
Treated pts had lower
urine NGAL vs
controls
Small sample,
unblinded
JASN
2011;22:1382-89
Dis 2010;4:128-32
Nephrol 2012

32. CONCLUSIONS-CKD
The evidences accumulated so far, only suggest
a causal role for uric acid in the genesis and/or
progression of CKD, and thus…
An adequately powered, double-blind, placebocontrolled RCT evaluating the effects of urate-lowering
therapy on renal and cardiovascular outcomes is
needed, to establish causality and inform clinical
practice and public health policy-makers about the
benefits and risks associated with treating asymptomatic
hyperuricemia in patients with CKD.

33. HOWEVER…………..
GIVEN THE EVIDENCE AVAILABLE:
• All
patients with gout must be treated
• It is reasonable(but not mandatory)to
treat patients with CKD stage 2-3A and
marked hyperuricemia(>8.0 mg/dl)
• At present, the data supporting
allopurinol treatment in CKD stage 3B-5
and ESRD, is insufficient to allow for
widespread use

34. EMERGING INDICATIONS
HYPERTENSION
CHRONIC KIDNEY DISEASE(CKD)
ANGINA
REPERFUSION INJURY
CONGESTIVE HEART FAILURE

36. This systematic review and meta-analysis of
prospective cohort studies shows a significant,
modest association between hyperuricemia
and CHD events, independent of traditional
CHD risk factors. The overall risk of CHD
death increased 12% for each increase of
1mg/dl of uric acid

37. The significant relationship between uric acid and maximal vasodilatory
response to acetylcholine (ACh), creatinine, and C-reactive protein (CRP).
Zoccali C et al, J Am Soc Nephrol 17: 1466–1471, 2006.

38. Allopurinol 300 mg/day
For three months

39. Allopurinol 300 mg, 7 days
Doehner W, Schoene N, Rauchhaus M, et al Circulation. 2002;105:2619 –2624.

40. A randomized, double-blind, placebo-controlled, crossover
study was conducted in 80 patients with CAD, comparing
allopurinol (600 mg/day)for 4 weeks with placebo. Endothelial
function was assessed by forearm venous occlusion
plethysmography, flow-mediated dilation, and pulse wave
analysis..

43. Methods—65 patients (aged 18–85 years) with angiographically
documented coronary artery disease, a positive exercise
tolerance test, and stable chronic angina pectoris (for at least 2
months) were recruited into a double-blind, randomised, placebocontrolled, crossover study of allopurinol (600 mg per day) or
placebo for 6 weeks. Primary endpoint was the time
to ST
depression, and the secondary endpoints were total exercise
time and time to chest pain

44. 28%
20%
12%

45. CONCLUSIONS - ANGINA
•Recent evidence suggests xanthine-oxidase
inhibition may contribute additional benefit in
patients with stable angina
•The required dosage of allopurinol is
probably higher(600-900 mg/day) than that
commonly used to lower urate levels in gout

46. EMERGING INDICATIONS
HYPERTENSION
CHRONIC KIDNEY DISEASE(CKD)
ANGINA
REPERFUSION INJURY
CONGESTIVE HEART FAILURE

47. Model
Disease or trigger
Mode of XO
inhibition
Effect of XO inhibition
Reference
Human (169 patients)
Coronary bypass
surgery
Allopurinol
Decreased hospital mortality rate, increased cardiac
index
Johnson, 1991
Human (90 patients)
Coronary bypass
surgery
Allopurinol
Reduced arrhythmias, need for inotropes and
perioperative myocardial infarction in patients
Rashid, 1991
Human (140 patients)
Myocardial infarction
Allopurinol
Increased incidence of infarct extensions in the
treatment group
Parmley, 1992
Human (80 patients)
Ischemic heart
disease
Allopurinol
erinit
Decreases in serum and daily urinary levels of uric
acid and lipid peroxidation,I mprovement of central
hemodynamics
Kaliakin, 1993
Human (50 patients)
Coronary bypass
surgery
Allopurinol
Improves postoperative recovery and reduces lipid
peroxidation in patients
undergoing coronary artery bypass grafting
Coghlan, 1994
Human (20 patients)
Coronary bypass
surgery
Allopurinol
Cardio- allopurinol : Failed to demonstrate a
in protective effect of patients with good left
ventricular function undergoing elective coronary
artery surgery
Taggart, 1994
Human (20 patients)
Coronary bypass
surgery
Allopurinol
Allopurinol reduced uric acid ,however, allopurinol
had no efficacy for the level of lactate, pyruvate, CK,
and CK-MB
Yamazaki,
1995
Human (33 patients)
Coronary bypass
surgery
Allopurinol
Better recovery of cardiac output and left ventricular
stroke work after bypass surgery and reduction of
plasma XO activity and concentrations of uric acid
Castelli, 1995
Human (52 patients)
Coronary bypass
surgery
Allopurinol
Allopurinol failed to improve left ventricular stroke
work after cardiopulmonary bypass surgery
Coetzee, 1996
Human (38 patients)
Percutaneous
transluminal coronary
angioplasty in atients
with acute myocardial
infarction
Allopurinol
Allopurinol pretreatment was effective in inhibiting
generation of oxygen-derived radical during
reperfusion and in the recovery of left ventricular
function
Guan, 2003

49. Allopurinol
400 mg

50. Allopurinolo, 400 mg

51. Allopurinol 400 mg loading
dose,+ 100 mg qd for 1
month

52. CONCLUSIONS – REPERFUSION INJURY
• Most, but not all the studies, tend to favour a role
for xanthine-oxidase inhibition, in preventing, or
attenuating reperfusion injury after CABG or
PTCA
• Adequately powered RCTs are not available

53. EMERGING INDICATIONS
HYPERTENSION
CHRONIC KIDNEY DISEASE(CKD)
ANGINA
REPERFUSION INJURY
CONGESTIVE HEART FAILURE

54. Serum UA and survival in patients with CHF
<6,7
6.7-10.0
10.1-13.4
>13.4

55. Change in cardiac oxygen consumption and contractile function after
intracoronary allopurinol in pts with dilated cardiomyopathy
Cappola, T. P. et al. Circulation 2001;104:2407-2411
Copyright ©2001 American Heart Association

56. Cappola, T. P. et al. Circulation 2001;104:2407-2411

59. Allopurinol 300 mg iv

61. Effect of allopurinol treatment on endothelium dependent
vasodilation in normouricemic and hyperuricemic CHF patients
W Doehner, S D Anker
Heart 2005;91:707–709.

62. Time-matched, nested case-control analysis of a retrospective cohort of
patients with HF who were 66 years or older using health
care databases in Quebec, Canada. The primary outcome
measure was a composite measure of HF readmission
and all-cause mortality. The secondary outcome measure was
all-cause mortality.

65. Patients (n 405) with CHF were randomized to
oxypurinol (600 mg/day) or placebo. Efficacy
at 24 weeks was assessed using a composite
end point comprising heart failure morbidity,
mortality, and quality of life.

66. All patients, no
oxypuinol
benefit with

67. >9.5 mg/dl
<9.5 mg/dl

68. CONCLUSIONS - CHF
 Available data do not support
widespread use of xanthine oxidase
inhibitors in CHF
No benefit is apparent in treated
normouricemic patients
 Xanthine oxidase inhibition should
be reserved for patients with gout and
severe hyperuricemia

69. POST SCRIPTUM
Why should we treat
ASYMPTOMATIC
HYPERURICEMIA?

71. Thank you for your attention