Pathogenesis of Gout Hyon K' Choi, MD, DrPH David B' Mount, MD and Anthony M' Reginato, MD, PhD adap

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Pathogenesis of GoutHyon K. Choi, MD, DrPH
David B. Mount, MD and Anthony M. Reginato, MD,
PhDadapted from Annals of Internal Medicine
2005143499-516

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Introduction

• Gout is a type of inflammatory arthritis that is
  triggered by the crystallization of uric acid
  within the joints and is often associated with
  hyperuricemia (Figure 1).
• Acute gout is typically intermittent,
  constituting one of the most painful conditions
  experienced by humans.
• Chronic tophaceous gout usually develops after
  years of acute intermittent gout, although tophi
  occasionally can be part of the initial
  presentation.

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Figure 1

• Gout is mediated by the supersaturation and
  crystallization of uric acid within the joints.
• The amount of urate in the body depends on the
  balance between dietary intake, synthesis, and
  excretion.
• Hyperuricemia results from the overproduction of
  urate (10), from underexcretion of urate (90),
  or often a combination of the two.
• Approximately one third of urate elimination in
  humans occurs in the gastrointestinal tract, with
  the remainder excreted in the urine.

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Introduction

• In addition to the morbidity that is attributable
  to gout itself, the disease is associated with
  such conditions as the insulin resistance
  syndrome, hypertension, nephropathy, and
  disorders associated with increased cell
  turnover.
• The overall disease burden of gout remains
  substantial and may be increasing.
• The prevalence of self-reported,
  physician-diagnosed gout in the Third National
  Health and Nutrition Examination Survey was found
  to be greater than 2 in men older than 30 years
  of age and in women older than 50 years of age.
• The prevalence increased with increasing age and
  reached 9 in men and 6 in women older than 80
  years of age.

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Introduction

• Furthermore, the incidence of primary gout (that
  is, patients without diuretic exposure) doubled
  over the past 20 years, according to the
  Rochester Epidemiology Project.
• Dietary and lifestyle trends and the increasing
  prevalence of obesity and the metabolic syndrome
  may explain the increasing incidence of gout.
• Researchers have recently made great advances in
  defining the pathogenesis of gout, including
• elucidating its risk factors
• tracing the molecular mechanisms of renal urate
  transport
• crystal-induced inflammation.

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I.ABSENCE OF URICASE IN HUMANS

• Humans are the only mammals in whom gout is known
  to develop spontaneously, probably because
  hyperuricemia only commonly develops in humans.
• In most fish, amphibians, and nonprimate mammals,
  uric acid that has been generated from purine
  metabolism undergoes oxidative degradation
  through the uricase enzyme, producing the more
  soluble compound allantoin.
• In humans, the uricase gene is crippled by 2
  mutations that introduce premature stop codons.

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ABSENCE OF URICASE IN HUMANS

• The absence of uricase, combined with extensive
  reabsorption of filtered urate, results in urate
  levels in human plasma that are approximately 10
  times those of most other mammals(30 to 59
  µmol/L).
• The evolutionary advantage of these findings is
  unclear, but urate may serve as a primary
  antioxidant in human blood because it can remove
  singlet oxygen and radicals as effectively as
  vitamin C.
• Of note, levels of plasma uric acid (about 300
  µM) are approximately 6 times those of vitamin C
  in humans.
• Other potential advantages of the relative
  hyperuricemia in primate species have been
  speculated.
• However, hyperuricemia can be detrimental in
  humans, as demonstrated by its proven
  pathogenetic roles in gout and nephrolithiasis
  and by its putative roles in hypertension and
  other cardiovascular disorders.

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II.THE ROLE OF URATE LEVELS

• Uric acid is a weak acid (pKa, 5.8) that exists
  largely as urate, the ionized form, at
  physiologic pH.
• Population studies indicate a direct positive
  association between serum urate levels and a
  future risk for gout as shown in Figure 2.
• Conversely, the use of antihyperuricemic
  medication is associated with an 80 reduced risk
  for recurrent gout, confirming the direct causal
  relationship between serum uric acid levels and
  risk for gouty arthritis.

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2005 Annals of Internal Medicine
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Figure 2

• Annual incidence of gout was
  less than 0.1 for men with serum uric acid
  levels less than 416 µmol/L,
  0.4 for men with levels of 416 to 475
  µmol/L, 0.8 for men with levels of 476 to 534
  µmol/L, 4.3 for men with levels of 535 to 594
  µmol/L, and 7.0 for men with levels greater than
  595 mol/L, according to the Normative Aging
  Study.
• The solid line denotes these data points the
  dotted line shows an exponential projection of
  the data points.

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• Urate crystallizes as a monosodium salt in
  oversaturated tissue fluids. Its crystallization
  depends on the concentrations of both urate and
  cation levels.
• Alteration in the extracellular matrix leading to
  an increase in nonaggregated proteoglycans,
  chondroitin sulfate, insoluble collagen fibrils,
  and other molecules in the affected joint may
  serve as nucleating agents.
• Furthermore, monosodium urate (MSU) crystals can
  undergo spontaneous dissolution depending on
  their physiochemical environments.
• Chronic cumulative urate crystal formation in
  tissue fluids leads to MSU crystal deposition
  (tophus) in the synovium and cell surface layer
  of cartilage.
• Synovial tophi are usually walled off, but
  changes in the size and packing of the crystal
  from microtrauma or from changes in uric acid
  levels may loosen them from the organic matrix.
• This activity leads to crystal shedding and
  facilitates crystal interaction with synovial
  cell lining and residential inflammatory cells,
  leading to an acute gouty flare.

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II.THE ROLE OF URATE LEVELS1. Urate Balance

• Furthermore, these factors may explain the
  predilection of gout
• in the first metatarsal phalangeal joint (a
  peripheral joint with a lower temperature) and
• osteoarthritic joints (degenerative joints with
  nucleating debris) and
• the nocturnal onset of pain (because of
  intra-articular dehydration).
• Hyperuricemia results from urate overproduction
  (10), underexcretion (90), or often a
  combination of the two.
• The purine precursors come from exogenous
  (dietary) sources or endogenous metabolism
  (synthesis and cell turnover).

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II.2. The Relationship between Purine Intake
and Urate levels

• The dietary intake of purines contributes
  substantially to the blood uric acid. For
  example, the institution of an entirely
  purine-free diet over a period of days can reduce
  blood uric acid levels of healthy men from an
  average of 297 µmol/L to 178 µmol/L .
• The bioavailable purine content of particular
  foods would depend on their relative cellularity
  and the transcriptional and metabolic activity of
  the cellular content.
• Little is known, however, about the precise
  identity and quantity of individual purines in
  most foods, especially when cooked or processed.

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The Relationship between Purine Intake and
Urate levels

• When a purine precursor is ingested,
• pancreatic nucleases break its nucleic acids into
  nucleotides,
• phosphodiesterases break oligonucleotides into
  simple nucleotides,
• pancreatic and mucosal enzymes remove phosphates
  and sugars from nucleotides.
• The addition of dietary purines to purine free
  dietary protocols has revealed a variable
  increase in blood uric acid levels.
• RNA has a greater effect than DNA,
• ribomononucleotides have a greater effect than
  nucleic acid, and
• adenine has a greater effect than guanine

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The Relationship between Purine Intake and
Urate levels(2)

• A recent large prospective study showed that men
  in the highest quintile of meat intake had a 41
  higher risk for gout compared with the lowest
  quintile, and men in the highest quintile of
  seafood intake had a 51 higher risk compared
  with the lowest quintile.
• In a nationally representative sample of men and
  women in the United States, higher levels of meat
  and seafood consumption were associated with
  higher serum uric acid levels.
• However, consumption of oatmeal and purine-rich
  vegetables (for example, peas, beans, lentils,
  spinach, mushrooms, and cauliflower) was not
  associated with an increased risk for gout.
• The variation in the risk for gout associated
  with different purine-rich foods may be explained
  by varying amounts and type of purine content and
  their bioavailability for metabolizing purine to
  uric acid.

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The Relationship between Purine Intake and
Urate levels

• At the practical level, these data suggest that
  dietary purine restriction in patients with gout
  or hyperuricemia may be applicable to purines of
  animal origin but not to purine-rich vegetables,
  which are excellent sources of protein, fiber,
  vitamins, and minerals.
• Similarly, implications of the recent findings in
  the management of hyperuricemia or gout were
  consistent with the new dietary recommendations
  for the general public, with the exception of the
  guidelines for fish intake (Figure 4).

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(Adapted with permission from reference 32
Willett WC,Stampfer MJ. Rebuilding the food
pyramid. Sci Am. 200328864-71.)
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• Data on the relationship between diet and the
  risk for gout are primarily derived from the
  recent Health Professionals Follow-Up Study.
• Implications of these findings in the management
  of hyperuricemia or gout are generally consistent
  with the new Healthy Eating Pyramid, except for
  fish intake.
• The use of plant-derived ?-3 fatty acids or
  supplements of eicosapentaenoic acid and
  docosahexaenoic acid in place of fish consumption
  could be considered to provide patients the
  benefit of these fatty acids without increasing
  the risk for gout. Use of ?-3 fatty acids may
  have anti-inflammatory effect against gouty
  flares.
• Vitamin C intake exerts a uricosuric effect.
• Red arrows denote an increased risk for gout,
  solid green arrows denote a decreased risk, and
  yellow arrows denote no influence on risk. Broken
  green arrows denote potential effect but without
  prospective evidence for the outcome of gout.

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III.PURINE METABOLISM AND GOUT

• The vast majority of patients with endogenous
  overproduction of urate have the condition as a
  result of salvaged purines arising
• from increased cell turnover in proliferative and
  inflammatory disorders (for example, hematologic
  cancer and psoriasis),
• from pharmacologic intervention resulting in
  increased urate production (such as
  chemotherapy), or
• from tissue hypoxia.
• Only a small proportion of those with urate
  overproduction (10) have the well-characterized
  inborn errors of metabolism (for example,
  superactivity of 5-phosphoribosyl-1-pyrophosphate
  synthetase and deficiency of hypoxanthine
  guanine phosphoribosyl transferase).
• These genetic disorders have been extensively
  reviewed in textbooks.

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• PRPP--5-phosphoribosyl-1-pyrophosphate
  synthetase
• HPRT--hypoxanthine guanine phosphoribosyl
  transferase).
• APRT adenine phosphoribosyl transferase PNP
  purine nucleotide phosphorylase

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• The de novo synthesis starts with
  5-phosphoribosyl 1-pyrophosphate (PRPP), which
  is produced by addition of a further phosphate
  group from adenosine triphosphate (ATP) to the
  modified sugar ribose-5-phosphate. This step is
  performed by the family of PRPP synthetase (PRS)
  enzymes.
• In addition, purine bases derived from tissue
  nucleic acids are reutilized through the salvage
  pathway. The enzyme hypoxanthine guanine
  phosphoribosyl transferase (HPRT) salvages
  hypoxanthine to inosine monophosphate (IMP) and
  guanine to guanosine monophosphate (GMP).
• Only a small proportion of patients with urate
  overproduction have the well-characterized inborn
  errors of metabolism, such as superactivity of
  PRS and deficiency of HPRT.
• Furthermore, conditions associated with net ATP
  degradation lead to the accumulation of adenosine
  diphosphate (ADP) and adenosine monophosphate
  (AMP), which can be rapidly degraded to uric
  acid. These conditions are displayed in left
  upper corner.
• Plus sign denotes stimulation, and minus sign
  denotes inhibition..

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PURINE METABOLISM AND GOUT

• Ethanol administration has been shown to increase
  uric acid production by
• net ATP degradation to AMP.
• Decreased urinary excretion as a result of
  dehydration and metabolic acidosis.
• A large-scale prospective study confirmed that
  the effect of ethanol on urate levels can be
  translated into the risk for gout.
• Compared with abstinence, daily alcohol
  consumption of 10 to 14.9 g increased the risk
  for gout by 32 daily consumption of 15 to 29.9
  g, 30 to 49.9 g, and 50 g or greater increased
  the risk by 49, 96, and 153, respectively.
• Furthermore, the study also found that this risk
  varied according to type of alcoholic beverage
• Beer conferred a larger risk than liquor,
• whereas moderate wine drinking did not increase
  risk.

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PURINE METABOLISM AND GOUT

• Correspondingly, a national U.S. survey
  demonstrated parallel associations between these
  alcoholic beverages and serum urate levels.
• These findings suggest that certain nonalcoholic
  components that vary among these alcoholic
  beverages play an important role in urate
  metabolism.
• Ingested purines in beer, such as highly
  absorbable guanosine, may produce an effect on
  blood uric acid levels that is sufficient to
  augment the hyperuricemic effect of alcohol
  itself, thereby producing a greater risk for gout
  than liquoror wine.
• Whether other nonalcoholic offending factors
  exist remains unclear, particularly in regard to
  beer instead, protective factors in wine may be
  mitigating the alcohol effect on the risk for
  gout.

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PURINE METABOLISM AND GOUT

• Fructose is the only carbohydrate that has been
  shown to exert a direct effect on uric acid
  metabolism.
• Fructose phosphorylation in the liver uses ATP,
  and the accompanying phosphate depletion limits
  regeneration of ATP from ADP.
• The subsequent catabolism of AMP serves as a
  substrate for uric acid formation.
• Thus, within minutes after fructose infusion,
  plasma (and later urinary) uric acid
  concentrations are increased.

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PURINE METABOLISM AND GOUT

• In conjunction with purine nucleotide depletion,
  rates of purine synthesis de novo are
  accelerated, thus potentiating uric acid
  production.
• Oral fructose may also increase blood uric acid
  levels, especially in patients with hyperuricemia
  or a history of gout .
• Fructose has also been implicated in the risk for
  the insulin resistance syndrome and obesity,
  which are closely associated with gout.
• Furthermore, hyperuricemia resulting from ATP
  degradation can occur in acute, severe illnesses,
  such as the adult respiratory distress syndrome,
  myocardial infarction, or status epilepticus.

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IV.ADIPOSITY, INSULIN RESISTANCE, AND GOUT

• Increased adiposity and the insulin resistance
  syndrome are both associated with hyperuricemia.
• Body mass index, waist-to-hip ratio, and weight
  gain have all been associated with the risk for
  incident gout in men.
• Conversely, small, open-label interventional
  studies showed that weight reduction was
  associated with a decline in urate levels and
  risk for gout.
• Reduced de novo purine synthesis was observed in
  patients after weight loss, resulting in
  decreased serum urate levels.

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ADIPOSITY, INSULIN RESISTANCE, AND GOUT

• Exogenous insulin can reduce the renal excretion
  of urate in both healthy and hypertensive
  persons.
• Insulin may enhance renal urate reabsorption
  through stimulation of the urateanion exchanger
  uratetransporter-1 (URAT1) (63) or through the
  sodium-dependent anion cotransporter in
  brush-border membranes of the renal proximal
  tubule.
• Because serum levels of leptin and urate tend to
  increase together, some investigators have also
  suggested that leptin may affect renal
  reabsorption.

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ADIPOSITY, INSULIN RESISTANCE, AND GOUT

• In the insulin resistance syndrome, impaired
  oxidative phosphorylation may increase systemic
  adenosine concentrations by increasing the
  intracellular levels of coenzyme A esters of
  long-chain fatty acids.
• Increased adenosine, in turn, can result in renal
  retention of sodium, urate, and water.
• Some researchers have speculated that increased
  extracellular adenosine concentrations over the
  long term may also contribute to hyperuricemia by
  increasing urate production.
• The growing epidemic of obesity and the insulin
  resistance syndrome present a substantial
  challenge in the prevention and management of
  gout.

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V.HYPERTENSION, CARDIOVASCULAR DISORDERS, AND GOUT

• Associations between hypertension and the
  incidence of gout have been observed, but
  researchers were previously unable to determine
  whether hypertension was independently associated
  or if it only served as a marker for associated
  risk factors, such as dietary factors, obesity,
  diuretic use, and renal failure.
• A recent prospective study, however, has
  confirmed that hypertension is associated with an
  increased risk for gout independent of these
  potential confounders.

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HYPERTENSION, CARDIOVASCULAR DISORDERS, AND GOUT

• Renal urate excretion was found to be
  inappropriately low relative to glomerular
  filtration rates in patients with essential
  hypertension.
• Reduced renal blood flow with increased renal and
  systemic vascular resistance may also contribute
  to elevated serum uric acid levels.
• Hyperuricemia in patients with essential
  hypertension may reflect early nephrosclerosis,
  thus implying renal morbidity in these patients.
• Furthermore, studies have suggested that
  hyperuricemia may be associated with incident
  hypertension or cardiovascular disorders.

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VI.RENAL TRANSPORT OF URATE

• Renal urate transport is typically explained by a
  4-component model
• glomerular filtration,
• a near-complete reabsorption of filtered urate,
• subsequent secretion, and
• postsecretory reabsorption in the remaining
  proximal tubule.
• This model evolved from an interpretation of the
  effects of uricosuric and antiuricosuric
  agents drugs and compounds known to affect serum
  urate levels are summarized in the Table.

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Clin exp Nephrol, 2005
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RENAL TRANSPORT OF URATE

• The urate secretion step was incorporated into
  the model to explain the potent antiuricosuric
  effect of pyrazinamide.
• However, direct inhibition of proximal tubular
  urate secretion by pyrazinoate, the relevant
  metabolite, has never been demonstrated.
• Indeed, pyrazinamide has no effect in animal
  species that eliminate urate through net
  secretion, and direct effects of the drug on
  human urate secretion are largely unsubstantiated
  
• Rather, studies utilizing renal brush-border
  membrane vesicles have shown that pyrazinoate
  activates the reabsorption of urate through
  indirect stimulation of apical urate exchange
  (Figure 5).
• Similar mechanisms underlie the clinically
  relevant hyperuricemic effects of lactate,
  ketoacids, and nicotinate

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VI.1.The Renal UrateAnion Exchanger URAT1

• Enomoto and colleagues(63) recently identified
  the molecular target for uricosuric agents, an
  anion exchanger responsible for the reabsorption
  of filtered urate by the renal proximal tubule
  (Table).
• The authors searched the human genome database
  for novel gene sequences within the organic anion
  transporter (OAT) gene family and identified
  URAT1 (SLC22A12), a novel transporter expressed
  at the apical brush border of the proximal
  nephron.

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The Renal UrateAnion Exchanger URAT1

• Urateanion exchange activity similar to that of
  URAT1 was initially described in brushborder
  membrane vesicles from urate-reabsorbing species,
  such as rats and dogs, and was subsequently
  confirmed in human kidneys.
• Frog eggs (Xenopus oocytes) injected with
  URAT1-encoding RNA transport urate and exhibit
  pharmacologic properties consistent with data
  from human brush-border membrane vesicles.

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The Renal UrateAnion Exchanger URAT1

• These and other experiments indicate that
  uricosuric compounds (for example, probenecid,
  benzbromarone, sulfinpyrazone, and losartan)
  directly inhibit URAT1 from the apical side of
  tubular cells (cis-inhibition).
• Conversely, antiuricosuric substances (for
  example, pyrazinoate, nicotinate, and lactate)
  serve as the exchanging anion from inside cells
  (Figure 6), thereby stimulating anion exchange
  and urate reabsorption (trans-stimulation).

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• Urate transporter-1 (URAT1) is located in the
  apical membrane of proximal tubular cells in
  human kidneys and transports urate from lumen to
  proximal tubular cells in exchange for anions in
  order to maintain electrical balance.
• This exchanger is essential for proximal tubular
  reabsorption of urate and is targeted by both
  uricosuric and antiuricosuric agents.
• Sodium-dependent entry of monovalent anions (such
  as pyrazinoate, nicotinate, lactate, pyruvate,
  ß-hydroxybutyrate, and acetoacetate),
  presumptively through the sodiumanion
  cotransporter, fuels the absorption of luminal
  urate via the anion exchanger URAT1.
• Basolateral entry of urate during urate secretion
  by the proximal tubule is stimulated by
  sodium-dependent uptake of the divalent anion
  a-ketoglutarate, leading to urate-a-ketoglutarate
  exchange via organic anion transporter-1 (OAT1)
  or organic anion transporter-3 (OAT3).
• These proteins or similar transporters may
  facilitate the basolateral influx or efflux of
  urate.
• As discussed in the text, although the
  quantitative role of human urate secretion
  remains unclear, several molecular candidates
  have been proposed for the electrogenic urate
  secretion pathway in apical membrane of proximal
  tubules, including URAT1, ATP-driven efflux
  pathway (MRP4), and voltage-driven organic anion
  transporter-1 (OATV1).
• FEu renal clearance of urate/glomerular
  filtration rate.

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The Renal UrateAnion Exchanger URAT1

• In addition to urate, URAT1 has particular
  affinity for aromatic organic anions, such as
  nicotinate and pyrazinoate, followed by lactate,
  ß-hydroxybutyrate, acetoacetate, and inorganic
  anions, such as chloride and nitrate.
• Enomoto and colleagues (63) provided unequivocal
  genetic proof that URAT1 is crucial for urate
  homeostasis
• --A handful of patients with familial
  renal hypouricemia were shown to carry loss
  of-function mutations in the human SLC22A12 gene
  encoding URAT1, indicating that this exchanger is
  essential for proximal tubular reabsorption.
• Furthermore, pyrazinamide, benzbromarone, and
  probenecid failed to affect urate clearance in
  patients with homozygous loss-of-function
  mutations in SLC22A12, indicating that URAT1
  isessential for the effect of both uricosuric and
  antiuricosuric agents.

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VI.2.Secondary Sodium Dependency of Urate
Reabsorption

• Antiuricosuric agents exert their effect by
  stimulating renal reabsorption rather than
  inhibiting tubular secretion.
• The mechanism appears to involve a priming of
  renal urate reabsorption through the
  sodium-dependent loading of proximal tubular
  epithelial cells with anions capable of a
  trans-stimulation of urate reabsorption .
• Studies from several laboratories have indicated
  that a transporter in the proximal tubule brush
  border mediates sodium-dependent reabsorption of
  pyrazinoate, nicotinate, lactate, pyruvate,
  ß-hydroxybutyrate, and acetoacetate, monovalent
  anions that are also substrates for URAT1 (63).

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Secondary Sodium Dependency of Urate Reabsorption

• Increased plasma concentrations of these
  antiuricosuric anions result in their increased
  glomerular filtration and greater reabsorption by
  the proximal tubule.
• The augmented intraepithelial concentrations in
  turn induce the reabsorption of urate by
  promoting the URAT1-dependent anion exchange of
  filtered urate (trans-stimulation) (Figure 6).

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Secondary Sodium Dependency of Urate Reabsorption

• Urate reabsorption by the proximal tubule thus
  exhibits a form of secondary sodium dependency,
  in that sodium dependent loading of proximal
  tubular cells stimulates brush-border urate
  exchange urate itself is not a substrate for the
  sodiumanion transporter.
• The molecular identity of the relevant
  sodium-dependent anion cotransporter or
  cotransporters remains unclear however, a
  leading candidate gene is SLC5A8, which encodes a
  sodium-dependent lactate and butyrate
  cotransporter.

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Secondary Sodium Dependency of Urate Reabsorption

• Preliminary data indicate that the SLC5A8 protein
  can also transport both pyrazinoate and
  nicotinate, potentiating urate transport in
  Xenopus oocytes that co-express URAT1.
• The antiuricosuric mechanism explains the
  long-standing clinical observation that
  hyperuricemia is induced by increased
  b-hydroxybutyrate and acetoacetate levels in
  diabetic ketoacidosis (95), increased lactic acid
  levels in alcohol intoxication (45), or increased
  nicotinate and pyrazinoate levels in niacin and
  pyrazinamide therapy, respectively (96).

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Secondary Sodium Dependency of Urate Reabsorption

• Urate retention is also known to be provoked by a
  reduction in extracellular fluid volume and by
  excesses of angiotensin II, insulin, and
  parathyroid hormone URAT1 and the
  sodium-dependent anion cotransporter or
  cotransporters may be targets for these stimuli.

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VI.3.Dose-Dependent Dual Response in Urate
Excretion

• A conundrum(??) in the pathophysiology of gout
  has been how certain anions can exhibit either
  uricosuric or antiuricosuric properties,
  depending on the dose administered.
• Monovalent anions that interact with URAT1 have
  the dual potential to increase or decrease renal
  urate excretion because they can both
  trans-stimulate and cis-inhibit apical urate
  exchange in the proximal tubule.
• For example, a low concentration of pyrazinoate
  stimulates urate reabsorption as a consequence of
  trans-stimulation, whereas a higher concentration
  reduces urate reabsorption through extracellular
  cis-inhibition of URAT1(Figure 7).

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• The anti-uricosuric agent pyrazinoate (PZA), a
  metabolite of pyrazinamide, has dual effects on
  urate transport by the proximal tubule.
• Urate uptake by brush-border membrane vesicles
  isolated from canine kidney cortex is shown, in
  the presence of 100 mM sodium (Na) with 0.1 mM
  PZA, 0 PZA, or 5 mM PZA.
• The concentration results in Na-dependent uptake
  of PZA and a potentiation of urate uptake via
  urate transporter-1 (URAT1) in contrast, the
  higher concentration cis-inhibits URAT1, thus
  reducing urate uptake by the membrane vesicles.
• Paradoxical effects of pyrazinoate and nicotinate
  on urate transport in dog renal microvillus
  membranes.
• J Clin Invest. 198576543-7.

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Dose-Dependent Dual Response in Urate Excretion

• Dissenting(??) opinions notwithstanding, these
  observations remain consistent with the basic
  scheme of apical urate transport shown in Figure
  6.
• Biphasic effects on urate excretion (that is,
  antiuricosuria at low doses and uricosuria at
  high doses) are particularly well described for
  salicylate.
• Salicylate cis-inhibits URAT1, explaining the
  high-dose uricosuric effect low anti-uricosuria
  reflects a trans-stimulation of URAT1 by
  intracellular salicylate, which is evidently a
  substrate for the sodiumpyrazinoate transporter.
• Minimal doses of salicylate75, 150, and 325 mg
  dailywere shown to increase serum uric acid
  levels by 16, 12, and 2 mol/L, respectively.
• However, the effect on the risk for gout of this
  salicylate-induced increase in the serum uric
  acid level has not been determined.

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VI.4.Other Renal Urate Transporters

• At the basolateral membrane of proximal tubular
  cells, the entry of urate from the surrounding
  interstitium appears to be driven by
  sodium-dependent uptake of divalent anions, such
  as a-ketoglutarate, rather than monovalent
  carboxylates, such as pyrazinoate and lactate
  (Figure 6).
• Candidate proteins for this basolateral urate
  exchange activity include both OAT1 and OAT3,
  each of which function as anion1-
  -dicarboxylate2- exchangers at the basolateral
  membrane of the proximal tubule.

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X.SUMMARY

• The disease burden of gout remains substantial
  and may be increasing.
• As more scientific data on modifiable risk
  factors and comorbidities of gout become
  available, integration of these data into gout
  care strategy may become essential, similar to
  the current care strategies for hypertension and
  type 2 diabetes.
• Recommendations for lifestyle modification to
  treat or to prevent gout are generally in line
  with those for the prevention or treatment of
  other major chronic disorders
• Weight control, limits on red meat consumption,
  and daily exercise are important foundations of
  lifestyle modification recommendations
• Plant-derived ?-3 fatty acids or supplements of
  eicosapentaenoic acid and docosahexanoic acid
  instead of consuming fish for cardiovascular
  benefits.

54
SUMMARY

• Further riskbenefit assessments in each specific
  clinical context would be helpful.
• Daily consumption of nuts and legumes as
  ecommended by the Harvard Healthy Eating Pyramid
  (32) may also provide important health benefits
  without increasing the risk for gout.
• Similarly, a daily glass of wine may benefit
  health without imposing an elevated risk for
  gout, especially in contrast to beer or liquor
  consumption.
• These lifestyle modifications are inexpensive and
  safe and, when combined with drug therapy, may
  result in better control of gout.

55
SUMMARY

• Effective management of gout risk factors (for
  example, hypertension) and the antihypertensive
  agents with uricosuric properties (for example,
  losartan or amlodipine could have a better risk
  benefit ratio than diuretics for hypertension in
  hypertensive patients with gout.
• Similarly, the uricosuric property of fenofibrate
  may be associated with a favorable risk benefit
  ratio among patients with gout and the metabolic
  syndrome.

56
SUMMARY

• The recently elucidated molecular mechanism of
  renal urate transport has several important
  implications in conditions that are associated
  with high urate levels.
• In particular, the molecular characterization of
  the URAT1 anion exchanger has provided a specific
  target of action for well known substances
  affecting urate levels.
• Genetic variation in these renal transporters or
  upstream regulatory factors may explain the
  genetic tendency to develop conditions associated
  with high urate levels and a patients particular
  response to medications.
• Furthermore, the transporters themselves may
  serve as targets for future drug development.

57
Thank you for your attention