gout uric acid cardiovascular effects renal disorde

1. Uric acid in health and disease
Dr Lalit Agarwal
Woodlands Hospital
Kolkata

2. Normal Uric acid metabolism
• Food
– Organ meat (liver, kidneys), Beer,
other alcoholic beverages, Yeast,
Legumes (dried beans, peas),
Mushrooms, spinach, cauliflower
• Normal level of serum uric acid
(sUA)- 6.8mg/dl (M) 6mg/dl (F)
Purines
Xanthine
hypoxanthine
Uric acid
Diet Synthesized
de novo
Xanthine
oxidase
Xanthine
oxidase
5C-sugar,P,N base
Purine A,G or
pyrimdine C,T & U
APRT & HGPRT

3. Abnormal Uric acid metabolism:
Cardiovascular
events and mortality
Dietary purinesTissue nucleic
acids
Endogenous purine
synthesis
URATE
Overproduction Underexcretion
HYPERURICEMIA
Silent tissue
deposition(tophi)
GOUT Renal
manifestations
Prevalence 15.9%
About 2/3 rd of such individuals remain asymptomatic
90%

4. Asymptomatic Hyperuricemia:
Pharmacologic Intervention?
• Nearly 67% (2/3rd of patient) are asymptomatic
and hence untreated
• Not recommended, unless:
– Uric acid is persistently >13 mg/dL in men and
>10 mg/dL in women
– Patient to receive chemotherapy or radiation
therapy with potential for tumor lysis syndrome
– Daily urinary uric acid >1100 mg (due to 50%
risk of uric acid calculi)

5. • Old belief : UA is unlikely to be a risk factor
for vascular and renal disease.
• Does Hyperuricemia cause or increase the
risk of cardiovascular disease, hypertension
and CKD- this complex interaction was
incompletely understood ?

6. • The paradigm of the causative association
of hyperuricemia with cardiovascular and
renal diseases seems to have progressed
from skepticism to increasing evidence of
a true relationship.
• Recent preclinical and clinical evidence
suggests that chronic hyperuricemia is an
independent risk factor for hypertension ,
metabolic syndrome and CVdisease

7.  Acute uric acid nephropathy
 Chronic urate nephropathy
 Uric acid nephrolithiasis
3 renal diseases by Uric acid
pH
Urate

8. Accelerated tissue breakdown
Overproduction/ overexcretion of uric acid
Renal tubular obstruction by urate and uric acid crystals
Acute oligoanuric renal failure
Acute uric acid nephropathy
Malignancy (leukemia, lymphoma): cell lysis due to chemotherapy or
radiation therapy

9. Acute Uric Acid Nephropathy
• Common/rare causes
• C/F: AKI in appropriate clinical setting and
marked hyperuricemia, uric acid crystals in
urine, release of other intracellular
constituents
• Prevention and treatment: Hydration,
Rasburicase, XO inhibitor, Avoid
Sodabicarbonate, Hemodialysis

10. Uric acid and new onset CKD
(cause of CKD)
 Uric acid is independent risk factor for development
of incident CKD through several mechanisms:
 Direct endothelial toxicity to kidneys (uricotoxicity)
 Hyperuricemia is risk factor for hypertension,
diabetes or metabolic syndrome. These chronic
diseases lead to CKD over time.
 Epidemiologic studies suggest this association by
Weiner et al, Obermeyer et al.

11. Uric acid and new onset CKD
• Uric acid levels between 7 to 9 mg/dl
doubles the risk for incident kidney disease
• Uric acid levels more than 9 mg/dl triples
the risk of incident kidney Disease

12. Uric acid and new onset CKD
• Hyperuricemia is an independent risk factor
for renal dysfunction and cardiovascular
events, with 18.4% women and 25.8% men
with Hyperuricemia also suffering from
chronic renal failure
• A meta-analysis of 13 studies containing
190,718 participants showed a positive
association between Hyperuricemia and
CKD.

13.  Gouty nephropathies are very uncommon nowadays as
hyperuricemia well managed.
 Severe tophaceous gout and hereditary disorder of purine
metabolism.
 Deposition of sodium urate crystals in medullary
interstitium, chronic inflammatory response,interstitial
fibrosis and CKD.
 C/F of Chronic urate nephropathy is non specific..
 Hyperuricemia out of proportion to degree of renal failure
c/w modest hyperuricemia of kidney diseases.
Chronic urate nephropathy

14. Uric acid and progression of CKD
 A 14% increase in the risk of kidney disease
progression was demonstrated for each 1 mg/dL
increase in uric acid levels in the Cardiovascular
Health Study.
? Slow progression by Urate lowering therapy:
• Goicoechea et al Allopurinol slows down
progresison of CKD.
• Sircar et al Febuxostat slowed the progression
of CKD stages ¾.

15. Uric acid as a marker of kidney function.
(Effect of ckd)
• 90% cases of hyperuricemia is due to renal
under-excretion(genetic or acquired) of uric
acid.
• Waste product accumulating in renal
dysfunction like other nitrogenous waste
products.
• At what level causes toxicity (renal &extra
renal (CVS),so when to give treatment is
unknown in CKD

16. Uric acid and CKD
Still these data are insufficient to provide any
recommendations to treat asymptomatic
hyperuricemia in CKD

17. Uric acid nephrolithiasis
• 5 to 10 percent of all renal calculi. however, UA stones seen in
40 % or more in areas with hot, arid climates.
• a high urine uric acid concentration and an acid urine pH
promote pptn.
• Gout, UA overproduction, Chronic diarrhea, Diabetes and
metabolic syndrome
• Diagnosis. asymtomatic or symptomatic
• ●Alkalinization of the urine (ph 6-7)●Increased fluid intake
●Reduction of uric acid production with reduced purine intake
and xanthine oxidase inhibitors.
• XO inhibitors can reduce urine uric acid excretion by 40-50%.

18. Gout
Results from increased body pool /loadof urate with hyperuricemia
Occurring predominantly in men
Characterized by (episodic acute arthritis) painful inflammation of joints; big
toe (most common), feet, hands etc
Chronic arthritis: results in deformity
Caricature ‘The gout’ by James Gillray (1799)

19. Risk factors:
• Age and gender
Comorbidities
• Hypertension
• Cardiovascular disease
• Chronic renal failure
• Diabetes mellitus
• Dyslipidemia
• Metabolic syndrome
Number of metabolic syndrome components
Juan García Puig; Curr Opin Rheumatol. 2008;20(2):187-191.

20. Trigger factors for Gout
• Genetic and acquired renal acid under excretion (90%)
• Genetic overproduction (10%)
• Alcohol (↑production, ↓excretion)
• Obesity (↑production, ↓excretion)
• Insulin resistance
• Medication
• High purine diet
Wood AJJ et al. N Engl J Med.
1996;334:445-451.
– Thiazide diuretics
– Loop diuretics
– Cyclosporine
– Low-dose ASA
– Niacin
– Ethambutol
– Pyrazinamide
–Tacrolimus

21. Gouty Arthritis: pathology
• Elevated serum urate with local factors leads to crystal deposition in
joints
• At > 6.8mg/dl concentrations (MSU) crystals precipitates & released into
the joint space initiate an acute inflammatory response
– Self limiting, but crystals and low level inflammation persists
• Chronic crystal presence leads to low grade inflammation and damage
joints
• Lowering serum urate to 4-6mg/dl can reduce crystals and tophi, resulting
eventually in fewer attacks and less joint damage.
• Uric acid level may not correlate with the severity of articular disease

22. Acute attack/flare
• Abrupt onset, severe inflammation,
often single joint (mono or polyarticular)
• Untreated attack subside: 3-10days
• Most common- big toe (90%)
• Other common sites: ankle, feet, knees
• Least common sites: elbow, wrist,
fingers
• Extraarticular manifestations
• 50% of patients with acute gout will
have normal serum uric acid levels.
• Pptating factors – dietary excess,trauma
surgery, excessive ethanol, hypouricemic
therapy, medical illness.

23. Acute attack
Courtesy of American College of Rheumatology slide

24. Advanced gout
• Chronic low grade inflammation due to MSU crystals
• Clinically detectable tophaceous deposits
• Chronic inflammation: erosion and joint damage (visible on X-ray,
MRI)
Chronic
inflammation
Tophus
Courtesy of American college of Rheumatology slide

25. Advanced gout
Courtesy of American college of Rheumatology slide

26. Gout- tophus at other sites
Solid urate deposits in tissues: Irregular destructive nodularity produced
Courtesy of American college of Rheumatology slide

27. Diagnosing gout
• Inflamed joint fluid aspirate or in
tophus
• Needle shaped crystals
• Yellow or blue in color
Uric acid crystals as seen under
polarizing microscope
Courtesy of American college of Rheumatology slide

28. Treatment goals
• Treat acute arthritic attack promptly by colchicin, steroid,
NSAIDs (ULT has no role in acute attack)
• Prevent recurrence of acute gouty arthritis give ULT +
prophylaxis (3-6 months)
• Lower urate levels by ULT(don’t change, start, stop during
attack)
• All hyperuricemic pts with 3 gouty attacks, tophi,
nephrolitiasis should receive ULT. Lifelong treatment
• Prevent or reverse co-morbid conditions like obesity,
Hypertension and triglyceridemia and renal complications
and less commonly myeloproliferative states, Lesch-
Nyhan syndrome and drugs.

29. Comorbidities Associated
with Hyperuricemia
• Renal
manifestations1
• Obesity2
• Metabolic syndrome3
• Diabetes mellitus4
• Heart failure5
• Hyperlipidemia2
• Hypertension6
• Cardiovascular
disease7
1. Vazquez-Mellado et al. Best Pract Res Clin
Rheumatol. 2004;18:111-124
2. Nakakanishi et al. Int J Epidemiol. 1999;28:888-893
3. Ford et al. JAMA. 2002;287:356-359.
4. Boyko et al. Diabetes Care. 2000;23:1242-1248.
5. Anker et al. Circulation. 2003;107:1991-1997.
6. Gavin et al. Am J Cardiovasc Drugs. 2003;3:309-314.
7. Niskanen et al. Arch Intern Med. 2004;164:1546-1551.

30. Hyperuricemia and
Diabetes Mellitus
• Diabetics have a significantly higher uric acid
level compared to non-diabetic subjects.
• Considering that the prevalence of obesity and
thus metabolic syndrome/ insulin resistance is
rising across the globe, it is very likely that the
number of type 2 diabetic patients with
Hyperuricemia will also increase.

31. Studies demonstrating some associations with
Hyperuricemia and Cardiovascular outcomes
Alderman M, Aiyer KJ. Uric acid: role in cardiovascular disease and effects of losartan. Curr Med Res Opin. 2004 Mar;20(3):369-79.

32. Management of
Hyperuricemia

33. In some of the countries like Japan,
treatment of asymptomatic
hyperuricemia is recommended to
prevent non- gout diseases like
hypertension, CAD, and CKD .

34. Japanese Guidelines
• Hyperuricemia- Serum Uric Acid > 7.0 mg (Male or
Female)
• Life style modification- Serum Uric Acid 7-8 mg.
• Drug Therapy – Serum Uric Acid 8-9 mg.
> 9 mg. definitely requires drug therapy
• In gout –Serum Uric Acid should be lower 6.0 mg %

35. • Patients with asymptomatic
Hyperuricemia with an SU level 9
mg/dL or greater should be treated with
urate lowering drugs.
• Drug therapy should be considered in
those with a level between 8 and 9
mg/dl only if they have Hyperuricemia-
associated comorbidities like obesity,
diabetes mellitus, hypertension,
ischemic heart disease, or dyslipidemia.
• Patients over 50 years of age with an SU
level >7 mg/dl and comorbidities
should be treated
Key recommendations of the ISN
position paper on Hyperuricemia

36. Key recommendations of the ISN
position paper on Hyperuricemia
• Serum urate measurement should be
included in the list of investigations for
the evaluation of CVD.
• Patients with chronic renal failure
should be screened for Hyperuricemia,
which, if detected, must be treated.
• The use of Febuxostat is
recommended instead of allopurinol,
as the latter is more toxic and the risk
of life-threatening Steven-Johnson
Syndrome in CKD patients is higher.

37. Take Home Message
• Hyperuricemia increases the risk for HTN,
CKD, risk of CVD, morbidity and mortality.
• There are lots of studies concerning uric acid
and possible links to hypertension, renal disease
and cardiovascular disease.
• Despite such evidence, there is no global
consensus for treatment of asymptomatic
hyperuricemia to reduce cardiovascular & renal
risk.
• CKD markedly increases the risk for
hyperuricemia and gout due to under excretion
of uric acid.

38. Conclusion
• Need to gather Indian data --- To develop
Indian specific guidelines for the management
of Hyperuricemia.
• In the absence of any recommendation at
present– we may follow Japanese guideline.
• Need to arrive at common consensus, weather
or not to treat cases of Asymptomatic
Hyperuricemia before the Development of
complication like Gout, diabetes, CVD, CKD,
Nephrolithiasis

39. THANK
YOU