uric acid in health and disease

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)- 6mg/dl
Purines
Xanthine
hypoxanthine
Uric acid
Diet Synthesized
de novo
Xanthine
oxidase
Xanthine
oxidase

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

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

5. 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

6. 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

7.  Gouty nephropathies are very uncommon nowadays as 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

8. Uric acid and CKD
 Uric acid is independent risk factor for development of incident CKD
through several mechanisms:
 Direct endothelial toxicity to kidneys
 Exacerbation of other risk factors, specifically hypertension, diabetes or
metabolic syndrome.
 Epidemiologic studies suggest this association by Weiner et al,
Obermeyer et al.

9. Uric acid and CKD
 Hyperuricemia in the progression of CKD: Decrease renal
perfusion by afferent arteriolar smooth muscle proliferation
 Conflicting data:
 weak association by Chonchol et al
 significant association by Bellomo et al, Bartakovav et al and chang et al.
 no association by Madero et al

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

11. 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 ●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%.

12. Gout
Results from increased body pool of 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)

13. 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.

14. Risk factors: Medications
↑ risk following organ transplant: accelerated clinical course,
40% with tophi and polyarticular presentation
Cyclosporin
↑ incidence of goutPyrazinamide,
Ethambutol,
Niacin
Nearly 6% ↑ in mean serum urate and 23% ↓ in uric acid
clearance
Incresae incidence of gout
Low dose aspirin
pyrazinamide
↑ uric acid reabsorptionDiuretics
ResultMedication
Choi HK et al, NEJM, 2004;350: 1093-1103, Choi HK et al, Lancet, 2004;363:1257-
1281

15. Gout and hyperuricemia
• Elevated serum urate with local factors leads to crystal deposition in
joints
• Monosodium urate (MSU) crystals 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

16. Acute attack
• 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.

17. Acute attack
Courtesy of American College of Rheumatology slide

18. 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

19. Advanced gout
Courtesy of American college of Rheumatology slide

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

21. 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

22. Treatment goals
• Treat acute arthritic attack promptly
• Prevent recurrence of acute gouty arthritis
• Lower urate levels
• Prevent or reverse complications of the disease resulting from deposition
of MSU crystal in joints
• Prevent or reverse co-morbid conditions like obesity, Hypertension and
triglyceridemia and renal complications and less commonly
myeloproliferative states, Lesch-Nyhan syndrome and drugs.

23. Management of hyperuricemia
• Initiated in patients with frequent gout attacks, tophi or urate
nephropathy.
• Reduction of serum urate levels to <6 mg/dl generally reduces the
recurrence of gouty arthritis, but levels <5 mg/dl necessary for resorption
of tophi.
• Two choices of therapy
• Xanthine oxidase inhibitors
– Allopurinol, febuxostat
Do not initiate during acute attacks but after the pt is stable and low dose
colchicin has been initiated to prevent risk of any flares. ( reason unknown)
• Uricosuric agents;
– probenecid, sulphinpyrazone ,Benzbromarone

24. XO inhibitor - Allopurinol
More effective the uricosuric drugs BUT…
 Relatively weak XO inhibitor
 Short half life
 Converted to oxypurinol; responsible of pharmacological activity
 Cautious use needed in patients with renal impairment, nephrolithiasis
 Hypersensitivity; even after months or years of treatment
 Symptoms of allopurinol toxicity include fever, rash, vasculitis,
eosinophilia, and worsening of renal function

25. Novel Xanthine oxidase inhibitor - Febuxostat

26. Febuxostat
• Non-purine, selective xanthine oxidase/xanthine dehydrogenase inhibitor

27. Mechanism of action
Okamoto K et al J Biol Chem. 2003;278:1848–1855
Purines
Xanthine
hypoxanthine
Uric acid
Diet Synthesized
de novo
Xanthine
oxidase
Febuxostat

28. Mechanism of action
• Completely inhibits activity of XO enzyme by obstructing substrate
binding
• Activities of other enzymes in purine metabolism affected by < 4%
• Inhibits both oxidized and reduced forms of XO
• Febuxostat >> more potent than allopurinol in inhibiting XO
Okamoto K et al J Biol Chem. 2003;278:1848–1855

29. Dosage and administration
• Recommended dosage in hyperuricemia and gout: 40 mg or 80 mg OD.
• Starting dose: 40 mg OD
• If sUA < 6 mg/dL, not achieved after 2 weeks with 40 mg, Febuxostat 80
mg is recommended.
• It can be taken without regard to food or antacid use.

30. Special population
• Renal or hepatic impairment: No dose adjustment necessary
• Gout Flares: concurrent flare prophylaxis with a NSAID or colchicine is
recommended.
• Elderly: No dose adjustment is necessary
• Pediatric use: Safety and effectiveness in pediatric patients under 18
years of age have not been established.
• Pregnancy and lactation: Pregnancy Category C: cautious use

31. Summary: Clinical efficacy
• Significant ↓ in UA< 6mg/dl as early as 7 days in 50% of patients
• ↓ in incidence of gout flare comparable to placebo, when concurrent
prophylactic treatment is given
• ↓ UA < 4 mg/dl in nearly 50% patients
• Significantly ↑ number of patients achieve UA< 6mg/dl with Febuxostat
compared to allopurinol.
• Uric acid ↓ effect is sustained (52 weeks)
• Significantly ↑ number of patients with baseline UA ≥ 10, achieve UA<
6mg/dl with Febuxostat compared to allopurinol
• Significant ↓ in UA< 6mg/dl with Febuxostat in patients with mild to
moderate renal impairment where allopurinol has no effect.

32. Thank you