Transcript Gout-related nephropathy

Gout and comorbidities
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Background
• Gout is an inflammatory disease caused by the
deposition of monosodium urate (MSU) crystals
in joints and other tissues
• Hyperuricaemia (serum uric acid >7.0 mg/dl or
420 μmol/l) is a crucial prerequisite for gout
• Gout is not a minor disease since it may induce
disability, severe nephropathy and increases
cardiovascular risk
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Ru L-B. Imm Cell Biol 2010;88:20-23.
Lukas E, et al. Eur J Heart Fail 2002;4:403-410.
Richette P, et al. Lancet 2010;375:318-328.
Gout and comorbidities
• Kidney disease
• Cardiovascular disease
• Metabolic syndrome
– Hypertension
– Obesity
– Dyslipidaemia
– Type 2 diabetes
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Weaver Al, et al. Cleve Clin J Med 2008;75(suppl5):S9-S12.
Kidney disease
Gout-related nephropathy
• Uric acid nephrolithiasis
• Acute uric acid nephropathy
• Chronic urate nephropathy
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Uric acid nephrolithiasis
• It is the most frequent type of gout-related nephropathy,
arising in about 10-40% of patients
• In Europe and the US uric acid stones account for 5-10%
of stones
• 80% of kidney stones in patients with gout are entirely
composed of uric acid
• Men with gout have a two-fold higher risk of kidney stones
than do patients without gout
• Calcium oxalate stones are 10- to 30-fold more prevalent
in patients with gout than in persons without gout
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Liebman SE, et al. Curr Rheumatol Rep 2007;9:251-257.
Maalouf NM, et al. Curr Opin Nephrol Hypertens 2004;13:181-189.
Uric acid nephrolithiasis:
risk factors and pathogenesis
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Relatively high serum uric acid levels
Low urinary pH
Low fractional excretion of urate
Treatment with uricosuric agents
Uric acid kidney stones precede arthritis
in 40% of patients
Moe OW. Lancet 2006;367:333-344.
Avram Z, Krishnan E.Rheumatology (Oxford) 2008;47:960-964.
Uric acid nephrolithiasis:
treatment
• Increase urinary output
• Alkalinisation of urine
• Xanthine oxidase inhibitors
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Moe OW. Lancet 2006;367:333-344.
Kidney disease
Gout-related nephropathy
• Uric acid nephrolithiasis
• Acute uric acid nephropathy
• Chronic urate nephropathy
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Pathogenesis of uric acid nephropathy
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Shimada, et al. Nephrol Dial Transplant 2009;24:2960-2964.
Clinical appearance
of uric acid nephropathy
• Acute renal failure
• Rarely flank pain
• Uric acid levels >15 mg/dl
(900 μmol/l)
• Urinalysis sometimes shows
uric acid cristals
• Uric-acid/creatinine ratio >1
By kind permission of L. Punzi,
Rheumatology Unit, University of Padua
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Conger JD. Med Clin North Am 19990;74(4):859-871.
Kidney disease
Gout-related nephropathy
• Uric acid nephrolithiasis
• Acute uric acid nephropathy
• Chronic urate nephropathy (gouty nephropathy)
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Chronic urate nephropathy
(gouty nephropathy) (I)
• Rare entity
• Kidney lesions in patients with gout are characterised by
advanced arteriolosclerosis, glomerulosclerosis, and
interstitial fibrosis, often with the presence of urate crystals in
the outer medulla
• However, the responsibility of crystals is doubtful, since crystal
deposition is focal and the lesions are diffuse and crystals
could also be found in normal kidneys in the absence of
inflammation
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Feig DI, et al. N Engl J Med 2008;359(17):1811-1821.
Chronic urate nephropathy
(gouty nephropathy) (II)
• The most characteristic findings, such as advanced
arteriolosclerosis and glomerulosclerosis, are indistinguishable from
those observed with long-standing hypertension or age-related
glomerulosclerosis and may simply reflect the fact that most patients
with gout have hypertension and are older
• Both experimental and clinical studies suggest that an elevated level
of uric acid itself can lead to kidney disease without the deposition
of uric acid crystals. Experimental studies in rats have shown that
raising uric acid levels can cause de novo kidney disease as well as
accelerate existing kidney disease
• The principal lesions from increased uric acid in the rat are
glomerulosclerosis, interstitial fibrosis, and arteriolar disease,
conditions similar to those observed in “gouty” nephropathy, except
for the absence of intrarenal urate crystals
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Feig DI, et al. N Engl J Med 2008;359(17):1811-1821.
Uric acid increases the risk
of kidney disease
n=13,338, ARIC and Framingham, follow-up 8.5 years
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Weiner DE, et al. J Am Soc Nephrol 2008;19:1204-1211.
Effect of allopurinol on progression
of chronic kidney disease
Prospective, randomised open label study of allopurinol 100 mg vs placebo,
mean follow up 23.4 months
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Goicoechea M, et al. Clin J Am Soc Nephrol 2010;5:1388-1389.
Effect of allopurinol on progression of
chronic kidney disease and
urinary albumin excretion
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Goicoechea M, et al. Clin J Am Soc Nephrol 2010;5:1388-1389.
Gout and comorbidities
• Kidney diseases
• Metabolic syndrome
• Cardiovascular disease risk
– Hyperuricaemia?
– Gout?
– Both?
By kind permission of L. Punzi, Rheumatology Unit, University of Padua
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Feig DI, et al. N Engl J Med 2008;359(17):1811-1821.
Hyperuricaemia is associated with groups
at increased cardiovascular risk
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Post-menopausal women
Blacks
Hypertension
Metabolic syndrome
Renal disease
Feig DI, et al. N Engl J Med 2008;359(17):1811-1821.
Gout and cardiovascular risk factors
Prevalence of cardiovascular risk factors in rheumatic patients and
a sample of the general population
80
72%
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General population
68%
62%
Patients (%)
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Rheumatic outpatients
57%
50
40
30%
30
26%
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17%
21%
10
0
Hypertension
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Overweight
Obesity
Cigarette
smoking
Adapted from: Meek IL, et al. Rheumatology 2012 Jul 30. [Epub ahead of print]
Hyperuricaemia and hypertension
• The prevalence of hyperuricaemia in hypertensive patients is
between 20 and 40%
• The prevalence of hypertension among gouty patients is
between 25 and 50%
• Recent large epidemiological studies have found that serum
urate levels predict the later development of hypertension
• The Normative Aging Study showed that the serum urate level
independently predicted the development of hypertension
• The MRFIT study showed that normotensive men with
hyperuricaemia at baseline had an 80% excess risk of
developing hypertension compared to those who did not have
hyperuricaemia
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Edwards NL. Curr Opin Rheumatol 2009;21:132-137.
Perlstein TS, et al. Hypertension 2006;48:1031-1036.
Krishnan E, et al. Hypertension 2007;49:298-303.
Uric acid mediated hypertension
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Feig DI, et al. N Engl J Med 2008;359:1811-1821.
Survival from total cardiovascular
disease mortality, by sUA levels
Males (n=41,879)
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Females (n=48,514)
Chen JH, et al. Arthritis Rheum 2009;61(2):225-232.
Hazard ratios of hyperuricaemia on
cardiovascular mortality(1) and
all-cause mortality(2)
(1)
(2)
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Chen JH, et al. Arthritis Rheum 2009;61(2):225-232.
Cardiovascular disease mortality with
increasing serum uric acid levels
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Chen JH, et al. Arthritis Rheum 2009;61(2):225-232.
Gout is an independent risk factor for
all-cause and cardiovascular mortality
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Kuo CF, et al. Rheumatology (Oxford) 2010;49:141-146.
Risk of myocardial infarction among
patients with gout
Incidence of MI
1000 patient-years
2,5
2.5
2,2
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p<0.001
(Log rank test)
1,5
1.5
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0,6
0,5
0.5
00
Patients without gout
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Patients with gout
Kuo CF, et al, Rheumatology 2012 Jul 10. [Epub ahead of print]
Gout and metabolic syndrome
• Up to 76% of patients with gout have the metabolic syndrome
• Hyperuricaemia associated with the metabolic syndrome has
been attributed to insulin resistance and hyperinsulinaemia
• However, recent studies have shown that hyperuricaemia
precedes the development of obesity, diabetes and even
hyperinsulinaemia
• In a study of non-obese patients who developed metabolic
syndrome, those with hyperuricaemia had a 10-fold increased
risk compared to those with normal uricaemia
• There is also some evidence suggesting that lowering serum
urate levels can reverse features of the metabolic syndrome
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Edwards NL. Curr Opin Rheumatol 2009;21:132-137.
Choi HK, Ford ES. Am J Med 2007;120:442-447.
Prevalence of metabolic syndrome
according to the presence of gout
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Choi HK, et al. Arthritis Care Res 2007;57:109-115.
Prevalence of individual components
of the metabolic syndrome
according to the presence of gout
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Choi HK, et al. Arthritis Care Res 2007;57:109-115.
Comorbid conditions in two European
populations of patients with gout
UK population
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German population
Annemans, et al. Ann Rheum Dis 2008;67:960-966.
Gout and obesity
• Increased body mass index is directly correlated
with hyperuricaemia, and leptin may be a
contributory factor
• Greater adiposity and weight gain are strong risk
factors for gout, whereas weight loss is
protective
• Increased adiposity and the insulin resistance
syndrome are both associated with
hyperuricaemia
• Body mass index, waist-to-hip ratio, and weight
gain have all been associated with the risk of
incident gout in men
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Choi HK, et al. Arch Int Med 2005;165:742-748.
Gout and insulin resistance
• Metabolic syndrome increases the risk for type 2
diabetes up to five times
• Insulin resistance contributes to the hyperuricaemia,
but it is unclear whether insulin resistance inhibits the
urinary excretion of uric acid or increases the
production of uric acid
• Only some patients with hyperuricaemia develop
attacks of gout and a direct association between gout
and insulin resistance has not been proven
• Insulin senitivity in patients with gout is lower than that
of healthy people, suggesting that insulin resistance
and metabolic syndrome may be considered as an
important pathogenic mechanism in gout and could
have therapeutic implications1
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1. Yoo HG, et al. Rheumatol Int 2009.
Gout and diabetes
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There is a known association of gout with diabetes
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The mechanisms involved are still unclear
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Can diabetes and other co-morbidities influence the efficacy
and/or safety of urate-lowering therapy in patients with gout?
Becker MA, et al. Diabetes Obes Metab 2013;15:1049-55.
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The first evaluation of urate-lowering therapy
in gout patients with and without diabetes
(post-hoc analysis)
CONFIRMS TRIAL
n=2,269 patients with serum uric acid ≥ 8 mg/dl
Patients with
diabetes
N=312
Patients without
diabetes
N=1,1957
Febuxostat
40 mg* (n=89)
Febuxostat
40 mg (n=668)
Febuxostat
80 mg (n=113)
Febuxostat
80 mg (n=643)
Allopurinol
300/200 mg
(n=110)
Allopurinol
300/200 mg
(n=646)
* Febuxostat 40 mg is not registered in EU
Becker MA, et al. Diabetes Obes Metab 2013;15:1049-55.
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Achievement of sUA target levels
in gout patients with and without diabetes
Adapted from Fig. 2a in: Becker MA, et al. Diabetes Obes Metab 2013;15:1049-55.
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Efficacy of urate-lowering therapy in diabetics
and non-diabetics with moderate renal impairment
Adapted from Fig. 2c in: Becker MA, et al. Diabetes Obes Metab 2013;15:1049-55.
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Adverse events of urate-lowering therapy
in diabetic and non-diabetic patients
Graphic processing of the text in: Becker MA, et al. Diabetes Obes Metab 2013;15:1049-55.
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Gout: management of comorbidities
Hypertension, obesity, diabetes, dyslipidaemia
must be recognized and treated
(some treatments lower serum uric acid levels)
• Hypertension
– Stop diuretics
• Hyperlipidaemia
– Diet
• Stop smoking
• Diabetes
– Improve insulin sensitivity
– Weight reduction
– Exercise
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Zangh W, et al. Ann Rheum Dis 2006;65:1312-1324.