Hyperuricemia

Introduction
• Gout (MSU crystal deposition disease) is a clinical syndrome
characterized by extracellular fluid urate saturation, which is
reflected in the blood by hyperuricemia, with serum urate > 6.8
mg/dL (this cut-off level is from approximate limit of urate
solubility).
• The clinical syndrome of gout may include:
1. Recurrent flares of inflammatory arthritis (gout flare)
2. A chronic arthropathy
3. Accumulation of urate crystals in the form of tophaceous deposits
4. Uric acid nephrolithiasis
5. A chronic nephropathy that, in gouty patients, is most often due
to comorbid states
 Introduction (cont’d)
• Hyperuricemia is a predisposition but not sufficient by its own for
the development of urate crystal deposition disease (gout). Higher
level of hyperuricemia do not necessarily mean more severe gout.
• Most hyperuricemic individuals never experience a clinical event
resulting from urate crystal deposition (that is “asymptomatic
hyperuricemia”).
• Uric acid is a weak organic acid and exists in one of two forms in
biological systems, depending upon the prevailing pH : the less
soluble undissociated uric acid form (the most highly represented
form when the pH is less than 5.5, which can occur in the urine),
and the substantially more soluble urate anion form (the most
highly represented form [98 percent] at the physiologic, systemic pH
of 7.4).
 Epidemiology
• Asymptomatic hyperuricemia is very common condition,
which is an established causal factor for gout and is
associated with (but has not been established as a
causal factor for) other chronic disease such as
hypertension, CKD, dyslipidemia, insulin resistance
syndrome, and cardiovascular disease.
• Gout tends to occur earlier in life in male than females
(estrogen hormone have an uricosuric effect, so pre-
menopause women is relatively more protected from
hyperuricemia)
• Some races can also be a risk factor.
 URATE BALANCE
• Urate production
1. Liver is the major site of urate synthesis from degradation of
dietary and endogenously synthesized purine compounds.
• Urate disposal
1. Enzymatic metabolism of urate is very limited in human
(relying on urinary and gastrointestinal excretion for
maintaning urate balance)
2. Urinary excretion — accounts for 2/3 of total urate excretion.
All urate are readily filtered by glomerulus, but in normal
condition, only 7-12% of urate is cleared by the kidney
(means 90% of filtered urate are reabsorbed in tubulus)
 URATE BALANCE (cont’d)
3. Gastrointestinal tract — Urate efflux into the gut lumen is
an active process mediated by urate transporters, rather
than being a concentration-dependent passive process.
• The best studied of these transporters is ABCG2, a high-
capacity urate transporter encoded by the ABCG2 gene on
chromosome 4; it is expressed in intestinal epithelium and
on the luminal surface of renal proximal tubule epithelial
cells
• Intestinal tract bacteria are able to degrade urate, and this
breakdown process (intestinal uricolysis) is responsible for
approximately one-third of total urate disposal,
RENAL REABSORPTIVE URATE TRANSPORT
• Filtered urate is absorbed at the apical membrane by the
urate-anion exchangers URAT1 and OAT10
• Both of these transporters are inhibited by uricosuric agents,
e.g. probenecid
• These transporters have the highest affinity for urate exchange
with aromatic organic anions, such as nicotinate and
pyrazinoate (PZA), followed by lactate, beta-hydroxybutyrate,
and acetoacetate.
• The intracellular concentration of these monovalent anions is
thus a key determinant of the activity of URAT1 and OAT10,
with marked activation of urate transport when their
intracellular concentration is increased
RENAL REABSORPTIVE URATE TRANSPORT

• This activation of urate-anion exchange by

intracellular anionic substrates is referred to as
"trans-activation.“
• The intracellular concentrations of these anions in
proximal tubular cells are largely determined by
apical uptake via the Na+-dependent
monocarboxylate transporters SMCT1 and SMCT2,
such that apical urate absorption by the proximal
tubule has a secondary sodium dependency.
RENAL REABSORPTIVE URATE TRANSPORT

• The particularly potent interactions between

nicotinate and PZA with URAT1 and OAT10 also
have in vivo clinical counterparts. The treatment
of hypercholesterolemia with nicotinic acid (niacin
) is thus frequently complicated by hyperuricemia,
as is the treatment of tuberculosis with
pyrazinamide
• Conversely, losartan and fenofibrate inhibit
URAT1, leading to uricosuria and reduced serum
urate
 RENAL SECRETORY URATE TRANSPORT

• Urate enters the cell from the interstitium across the

basolateral membrane, via the OAT1, OAT2, and OAT3
anion exchangers.
• Unlike OAT10 and URAT1 at the apical membrane, OAT1
and OAT3 exchange urate with divalent anions, primarily
alpha-ketoglutarate.
• Basolateral Na+-dependent uptake of alpha-ketoglutarate
is mediated by the NADC-3 transporter
• At the apical membrane of proximal tubular cells, urate
exits the cell by secretion through 2 ATP-driven efflux
pumps, ABCG2 and ABCC4. In addition, there are 2
electrogenic apical urate antiporters, NPT1 and NPT4,
that also contribute to urate exit during secretion
 REGULATION OF URATE LEVELS
• Volume status and salt balance, in particular, have
potent effects on circulating serum urate
• Experimentally, salt restriction causes significant
hyperuricemia, which is reversed by salt loading.
• Potential neurohumoral mediators include angiotensin-
II and epinephrine, both of which can experimentally
reduce the fractional excretion of urate in humans
• Clinically, volume depletion is associated with
hyperuricemia, which explaining the association
between diuretic use and gout
 REGULATION OF URATE LEVELS (cont’d)
• Modest increase in ECF volume associated with the SIADH is in
turn associated with an increase in fractional excretion of urate 
low urate
• Insulin appears to be anti-uricosuric, due to the enhanced
expression and activation of GLUT9, a high-capacity urate
transporter which is the exclusive basolateral exit pathway for
reabsorbed urate from the renal proximal tubule into the blood 
assoc between hyperinsulinemia in metabolic synd and
hyperuricemia
• Excess PTH also reduce renal urate excretion
• Serum urate is typically depressed during gout flares compared
with baseline levels, which has been postulated to occur due to
cytokine-stimulated uricosuria
 Pathophysiology hyperuricemia
• “Underexcretion” (renal, intestine, or both) is responsible for
most cases of hyperuricemia
• This is not surprising given the complexity of renal uric acid
handling and the sensitivity of the kidney to endogenous
metabolites, alterations in volume status, and drugs.
• Volume depletion due to diuretics, is a common cause of
hyperuricemia
• It is important to note that “underexcretor” have normal rates
of urinary urate excretion, since this is needed for maintain
steady state urate levels. However, it is the reduced efficiency
that obligates a high serum level in order to achieve the
necessary rate of urate excretion
 Pathophysiology hyperuricemia (cont’d)

• Variation in >200 genes has been implicated in serum

urate, most of which encoding urate transporter genes
for reabsorption (e.g.GLUT9) and secretion (ABCG2) in
kidney and intestine.
• Notably, the effects of genetic variation in urate-
determining genes on circulating serum urate may
exceed the effects of diet
• Overexcretion of urinary uric acid may result from either
"extra-renal urate underexcretion“ leading to
compensation increase of renal excretion or from
genuine urate overproduction
 Factors affecting pathophysiology of gout
1. Metabolic, genetic, and other factors that result in hyperuricemia
2. Physiologic, metabolic, and other characteristics responsible for
crystal formation
3. Cellular and soluble inflammatory and innate immune processes
and characteristics of MSU crystals themselves that promote the
acute inflammatory response to MSU crystals
4. Immune mechanisms and other factors that mediate the
resolution of acute inflammation
5. Chronic inflammatory processes and the effects of crystals and
immune cells on osteoclasts, osteoblasts, and chondrocytes that
contribute to the formation of tophi and to bone erosion,
cartilage attrition, and joint injury
 Patophysiology of gout (cont’d)
• Crystal formation depends on concentration of
urate and its solubility (lower temperature
reduce solubility), as well as factors that
influence nucleation and growth of crystals
• Inflammatory responses to crystal deposition and
release, and the phagocytosis of MSU crystals by
neutrophils and a variety of other cells all
contribute to the inflammatory response, which
is highly variable between individuals .
 Risk factors focused on diet
• Only little evidence of causal relationship between diet
and hyperuricemia, but diet may play a role in progression
from hyperuricemia to gout (e.g.triggering gout flares)
• Red meat, innards, and some seafood (sardines, shellfish)
are major source of purine
• Certain vegetables have high purine (e.g. green peas,
spinach, asparagus), but much lower compare to animal
source
• High-fructose corn syrup and sugar (sucrose)-sweetened
beverages. Sucrose = glucose + fructose
• Alcohol : contribute both to hyperuricemia and gout flare.
Risk factors diet, with less evidence-based

• Foods that may increase risk of gout flare or worsen

symptom – Fatty meals have been implicated in
precipitating flares, which may be related to long-chain
fatty acids priming the "first signal" and "second signal"
required for NLRP3 inflammasome activation
• Foods that may decrease risk of incident gout and/or
gout flares – low fat dairy products, cherries, vit C
supplementation, coffee, fish and omega-3 fatty acids.
• NOTE that these dietary effect of foods on urate level is
modest, based on small or low-quality study, and
DOSE-DEPENDENT
 RISK FACTORS focused on drugs
• Thiazide and loop diuretics are independent risk factors
for hyperuricemia, incident gout, and gout flares, while
potassium-sparing diuretics are not.
• Beta blockers have been reported to increase serum urate
and the risk of incident gout
• Aspirin — paradoxal effect. Higher doses (> 3 g/day) can ↓
serum urate, whereas low to moderate doses (up to 3
g/day) can ↑ serum urate and the risk of flare for patients
with gout. Aspirin can be used safely with urate lowering
pharmacotherapy if those who need aspirin.
• Calcineurin inhibitors
 Risk factors for gout flare
• Dietary factors
• Alcohol consumption
• Intermittent diuretic use
• Trauma or surgery
• Initiation of urate-lowering therapy
 Management
• Evaluation and therapy of asymptomatic
hyperuricemia is indicated for persistent urate
level >8 mg/dL. (repeat measurement at least
one week).
• If urate level 7-8, repeat measurement, and if
<7 : we do not pursue evaluation and therapy
 Non pharmacologic Tx : diet
• Purine-restricted diets only modestly reduce serum urate levels
(mean serum urate ↓ only ± 1 mg/dL), but still recommended.
• Diets that severely restrict purines may be unpalatable and
impractical to implement and are therefore usually reserved for
patients who do not tolerate medicines).
• Counsel patients about ways to ensure they obtain adequate
daily protein when they reduce purine intake, since some
common high-purine foods are also rich in proteins (eg, red
meat, seafood)  plant protein, low fat dairy products
• Patient with uric acid level controlled (<6 mg/dL) and on stable
urate-lowering therapy, purine rich foods may not trigger flares
or promote disease progression.
 Uric Acid Kidney Disease
• acute uric acid nephropathy
• chronic urate nephropathy, and
• uric acid nephrolithiasis
 ACUTE URIC ACID NEPHROPATHY (UAN)

• Characterized by acute oliguric or anuric kidney failure

due at least in part to uric acid precipitation within the
distal tubules and collecting ducts.
• However, in UAN caused by tumor lysis, other
independent mechanisms may contribute, such as the
release of substances from malignant cells that injure the
endothelium or hyperphosphatemia.
• Clinical setting when UAN occur : patients with rapid
malignant cell turnover such as in lymphoma, leukemia, or
a myeloproliferative disease, especially following
chemotherapy or radiotherapy.
 ACUTE URIC ACID NEPHROPATHY (UAN)

• The diagnosis should be suspected when AKI

develops in clinical setting above in
association with marked hyperuricemia
(serum urate generally > 15 mg/dL).
• This is in contrast to most other forms of AKI
in which the serum urate usually <12 mg/dL,
except for prerenal disease in which there is
an increase in proximal sodium and urate
reabsorption
 ACUTE URIC ACID NEPHROPATHY (UAN)

• The urinalysis in UAN may show many uric

acid crystals, but can be unremarkable due to
no output from the obstructed nephrons.
• Overexcretion of uric acid can be documented
in many patients by a uric acid-to-creatinine
ratio (mg/mg) > 1 on a random urine
specimen; in comparison, the value is below
0.60-0.75 in most other forms of AKI
 Prevention of acute UAN

• Intensive intravenous volume expansion

• Use of a recombinant urate oxidase (
rasburicase) to convert urate to the much
more water-soluble end product, allantoin
• Xanthine oxidase inhibitor (allopurinol or
febuxostat) to reduce uric acid production.
 Treatment of acute UAN
• Therapy after the onset of AKI consists of allopurinol, febuxostat,
or rasburicase and an attempt to "wash out" the uric acid crystals
by increasing urine output with IV fluids and a loop diuretic
• Sodium bicarbonate should not be given at this time, particularly
if the patient does not have a metabolic acidosis, since it has not
been proven effective and may increase the risk of calcium
phosphate precipitation.
• HD can remove excess circulating urate in patients with
persistent oliguria or anuria, and is useful in managing the
volume status and other complications of acute kidney injury.
• The prognosis for complete recovery is excellent if treatment is
initiated rapidly.
 Chronic urate nephropathy
• A form of CKD induced by the deposition of sodium
urate crystals in the medullary interstitium
• The crystals induce a chronic inflammatory response,
similar to that seen with tophus formation elsewhere in
the body, potentially leading to interstitial fibrosis and
CKD
• The clinical features of this disorder are nonspecific:
kidney function impairment, bland urinary sediment,
mild proteinuria, and serum urate concentrations often
higher than expected (“out for proportion”) for the
degree of impaired kidney function.
 Chronic urate nephropathy
• However, there is no universally accepted definition
for "out of proportion“, some suggest following
definition :
1. > 9 mg/dL if the SCr ≤1.5 mg/dL.
2. > 10 mg/dL if the SCr between 1.5-2 mg/dL
3. > 12 mg/dL with more advanced renal failure
• Thus, chronic urate nephropathy is difficult to
separate from the multiple other causes of kidney
function impairment in people with gout, such as HT
and DM