Understanding Uric Acid

F: Bruder Stapleton
Key Points

1.serum uric acid concentrations vary as a function of age

2.certain medications may effect uric acid excretion

3. it is important to assess extracellular volume status in the evaluation of children with

hyperuricemia

Key words : hyperuricosuria : uric acid metabolism :hyperuricemia :urate :serum uric
acid :urinary uric acid excretion:acute uric acid nephropathy:tumor lysis syndrome :uricolysis

Physicians caring for children seldom consider measuring serum uric acid or urinary uric
acid levels, most likely because gout or hyperuricemia is most often encountered in adults.
Because uric acid disorders are uncommon in children,pediatricians frequently are unfamiliar
with uric acid metabolism and renal handling of uric acid. At times,altered serum or urinary uric
acid values can be valuable in clarifying renal and / or fluid and electrolyte disorders .

CASE SCENARIO 1 : HYPERURICOSURIA WITH A NORMAL SERUM URIC ACID

CONCENTRATION
Patient 1 is a 4-year-old boy with cystic fibrosis and documented pancreatic insufficiency. At
3 years and 9 months of age, he was switched from pancrelipase capsules to equivalent doses of
pancrelipase powder.during the next 3 months,his mother gradually increased the daily intake of
pancrelipase powder from the recommended seven packets to 15-20 packets because of
persistent stool abnormalities.shortly thereafter, the child had intermittent episodes of
dysuria,with deposition of orange crystals on the penis and in the urine.physical examination
showed a well –nourished child who weighed 16 kg (25 th percentile) and was 95 cm tall (<3rd
percentile). Orange crystals covered the penis and inner thighs.freshly voided urine was filled
with uric acid crystals ,occasional uric acid casts and had a Ph of 5 , with a specific gravity of
1.016 (fig .1 ).laboratory evaluation designed to identify known renal and systemic causes of
hyperuricosuria gave normal results. Creatinine clearance was normal. Serum electrolytes were
normal and the serum bicarbonate was 23 mEq/L.the serum uric acid concentration ranged
between 3 and 5.6 mg/Dl, and 24-h urinary uric acid excretion ranged to 621 mg (39
mg/kg).fractional excretion of uric acid was 40 % (normal values –table 1). Assays for red-cell
hypoxanthine guanine phosphoribosyltransferase activity were comparable to those of three
controls. What can explain the high urinary uric acid load with a normal serum uric acid ? to
answer this questions, one must first consider some aspects of uric acid metabolism.
1. URIC ACID METABOLISM AND RENAL ELIMINATION

Metabolism urine : uric acid is created in the body as the final oxidation product
of purine catabolism. Uric acid is a weak organic acid with a pKa of 5.75. at physiologic
Ph, uric acid is present almost entirely as monosodium urate. The solubility of
monosodium urate is nearly 15 times that of uric acid in aqueous solution.in human
plasma,saturation occurs at a monosodium urate concentration of approximately
7mg/dL.the proton concentration of a solution containing uric acid determines not only
the relative amount of monosodium urate ,but also the solubility of urate. thus,in
maximally acidified urine,uric acid predominates with minimalsolubility (1).
Elimination : the renal elimination of uric acid involves four components: glomerular
filtration,tubular reabsorption,tubular secretion,and reabsorption beyond
secretorysites.uric acid is nearly completely filtered by the glomerular membrane ;tubular
reabsorption,secretion,and further reabsorption occurs along the proximal renal tubule
(2).excessive excretion of uric acid may be the result of increased uric acid production or
either decreased renal tubular reabsorption or increased secretion (3).

1.1 Tubular Secretion and Postsecretory Reabsorption of Uric Acid

Tubular secretion of uric acid presumably occurs in the late convoluted or early
proximal straight tubule(4). Active cellular uptake occurs at the basolateral
membrane,thereby generating a high intracellular uric acid concentration, which
promotes passive diffusion across the luminal cell membrane into the tubular fluid. An
active apical transporter , URAT 1, has been identified in the proximal tubule (5).

The fourth component of renal uric acid transport, “postsecretory” reabsorption , was
proposed from clearance studies that demonstrated an inhibition of the uricosuric effect
of probenecid by pyrazinamide(6). This conclusion appears justified because the
simultaneous administration of these two pharmacologic agents does not affect the renal
clearance of either drug . based on calculated secretory rates , substantial reabsorption of
secreted urate occurs.

Daily Uric Acid Excretion :Mean Daily urinary uric acid excretion for adult
meningesting a purine –free diet is less than 600 mg/day . in adults, normal fractional
excretion of uric acid is less than 10%. Daily excretion rates in women are less than men.
Urinary urate excretion of greater than 800 mg /day in men eating an unrestricted diet is
considered excessive (5).
 Clearance studies have shown that the renal handling of uric acid during early de opment
and during childhood is significantly different from that of adults (8). Uric acid excretion is
extremely high in the ne onatal period with values exceeding 20 mg/kg/day in term infants. The
fractional excretion of uric acid in premature and term infants is also an values as high as 60 at
dramatically elevated compared with adult values with m 29-31 weeks' gestational age and 38%
at term (Table 1). An inverse relationship exists between the fractional excretion of uric acid
measured during the first day of life and gestational age. Fractional excretion of uric acid
declines during early postnatal development.

Although the serum uric acid co uric acid c centration and may in tion of dilute and often
alkaline urine by the newborn infant helps to decrease the likeli- unts of uric acid without hood
of uric acid precipitation and allows excretion of large a harmful effects (9). Uric acid clearance
in infants is related to sodium excretion and uri- nary flow rate. The decline in the fractional ex
presumed to reflect changes in renal tubular transport be actually increases during this period of
development. retion of uric acid during early life is se the filtered uric acid load actually
increases during this period of development.

The mean urate excretion is 13.5 mg/kg/day in children 3 years of age and declines
during childhood (/0). The high fractional excretion of uric acid in young children also
progressively declines. This fall in the fractional excretion of urate with increas sing age may be
due to a relative increase in urate re n rather than a etion (Table l).

Uric acid excretion in children has been a ed by comparing ur uric acid entration. This
urinary uric acid to creatinine ratio is higher to urinary creatinine c in young children than in
adults and declines to adult levels during early child Because n atinine ratio, for total urate
excretion, excretion per unit body weight, and fractional excretion uric acid all vary with age, a
mal values for urinary uric acid to cr reference table with age-related no mals is required for
interpretation of data.

A more of uric acid excretion (above age 2 years) e (UUA x m and 24-h urine samples
were arable (0.53/dL e in children aged 3 A more reliable andc is possible by measuring acid
excretion per deciliter of creatinine cleara SCr/UCr) (11). Values of rand and (0.53/dL and
0.56/dL, respectively) and do not vary significantly with age in children aged 3 months to 14
years. A normal value of less han 0.56 mg uric acid per deciliter gl lar filtrate may be used after 2
years of age (Table 1). An increased value of (UUA x SCr)/UCr in a patient withn sive
production of uric acid. This rationale suggests that the patie in Case 1 had an increased
production of uric acid. This rationale seggests that the patien in case i had an increased
production of uric acid. The high urinary uric acid excretion was due to the high-dose pancreatic
extract with ingestion of large amounts or uric acid precursors. (12).
CASE SCENARIO 2: HYPERURICEMIA WITH LOW URINARY URIC ACID
EXCRETION

Patient 2 was a 17-year-old white male in whom an elevated serum concentration of uric acid of
11.5 mg/dL was discovered at a routine pre-school physical examination. He was entirely
asymptomatic and was taking no medications. He was an above-average student and grade-
appropriate. There was no family history of gout or renal disease. He e physical exa at the age of
14 years. Evaluation at that time demonstrated a normal creatinine clearance, normal excretory
urogram, and orthostatic proteinuria. He had subsequently been, examined at yearly intervals; his
creatinine cleara tein excretion weren height was 182 cm, weight was 83.2 kg, and blood
pressure was 124/82 mmHg. There were no tophi and examination of the musculoskeletal and
neurological system was normal.

Laboratory data included hemoglobin 14.8 g/dL, white blood cell count 8600 mm3.
platelet count 300,000/mm3, reticulocyte count 1%, sodium 143, potassit rea nitrogen 16, and
creatinine 1.1 mg/dL.

During the evaluation of this patient, hype d in the father and four brothers. All of the
members of the family with hyperuricemia were asymptomatic. A complete clearance were
normal in all family members. Carefulevlution of renal function in this patien indicated tht
thepatien had a selective defect in renal tubular secrection (13).

2. PHYSIOLOGICAL FACTORS AFFECTING RENAL EXCRETION OF

URATE IN HUMANS

2.1. Extracellular Volume and Urine Flow Rate

The volume of the extracellular fluid compartmen has an important influence on the renal
handling of urate. In particular, the "effective arterial circulatory volume is most significant in
influencing renl uric acid excretion. Extracellular volume expansion with ither isotonic or
hypertonic (3%) saline increases uric acid excretion and promotes hypouricemia, presumably by
inhibiting tubular urate reabsorption or by increasing peritubular backleak of uric acid (14). In
contrast, extra cellular volume depletion by diuretics diminishes uric acid excretion 47-67% (15).
Volume contraction during diarrheal dehydration in young children has been with shown to
increase serum uric acid concentrations, particularrly in association with hypernatremia (16).

The effect of urinary flow rate on uric acid excretion can be difficult to separate from the
effect of extracellular fluid volume. During antidiuresis owing to extracellular fluid volume
contraction, the urinary urate concentration increases and may result in a small amount of urate
back-diffusion in the distal terminal nephron tubules (17). Conversely, during diuresis, the
diminished urinary urate concentration may reduce diffusion of urate.
 The syndrome of inappropriate antidiuretic hormone secrection(SIADH) illustrates the
important influence of extracellular fluid volume on urate clearence (18.19) In SIADH,
antidiuresis results in expansion of the extracellular fluid compartment, which then leads to
increased excretion of uric acid. Serum uric acid concentrations and fractional excreation of urate
were studied in two group of hyponatremic neonates, one with SIADH and the other with
hyponatremic dehydration (20) The neonates with.

SIADH had a mean serum urate concentration of 2.46 0.54 mg/dL and an elevated fractional
excretion of urate of 78 t 0.18%, whereas volume-depleted hyponatremic infants had a serum
urate concentration of 8.49 2.45 mg/dL. Water restriction and subsequent correction of serum
osmolality in the patients with SIADH resulted in an increase in the mean serum urate
concentration to 4.95 t0.86 mg/dL and a significant decrease in the fractional urate excretion to
51 0.08%. The site of reduced uric acid reabsorption in patients with SIADH is believed to be in
the postsecretory component of urate reabsorption in the nephron.

2.2. Clinical Relevance Extracellular volume contractic particularly with hypernatremia, is

associated with hyperuricemia. The syndrome of inappropriate ADH secretion on the other hand,
i associated with hypouricemia.

3. SYSTEMIC ACID-BASE EFFECTS AND ENDOGENOUS METABOLITES

Impaired urinary excretion of uric acid and hyperuricemia frequently accompany metaboli
acidosis. Tubular secretion of uric acid is directly inhibited by both lactic acid and B-
hydroxybutyrate (21). Reduced urate excretion also has been reported in severe respiratory
acidosis and in diabetic ketoacidosis. During exentration, an increasein serum lactase
concentrtion reduces urate excretion. Hyperlactic acidemia may also represent the common
mechanism by which ethanol abuse, branched-chain ketoaciduria (maple syrup urine disease)
type I glycogen storage disease, heat stress, and hereditary ce affect urate excretion (I). In type I
glycogen storage disease and fructose intolerance, uric acid production is increased as a result of
intracellular depletion of high energy phosphates (22). Intracellular ATP depletion results in the
diffusion of adenosine from the cell. Adenosine is then metabolized to uric acid and i of both the
serum uric acid and increases both the serum uric acid concentration and total uric acid
excretion. (23). The development of gluco- suria and osmotic diuresis is associated with
decreased urate reabsorption in the proximal tubule. Recent studies have demostrated thatt the
reduced renal tubular re occurs distal to secretory (24).

CASE SCENARIO 3: HIGH SERUM URIC ACID WITH ELEVATED URINARY URIC
ACID EXCRETION

Patient 3, a 14-year-old boy, presented to his pediatrician with fatigue. He was an honor
student and was taking no medications His physical examination was nor- mal. Laboratory tests
showed a hemoglobin 12 gm/dL, white blood cells 7000/mm, BUN 35 mg/dL, creatinine 8
mg/dL, sodium 137 mEq/L, potassium 5 mEą/L, chloride 107 mEq/L, bicarbonate 20 mEa/L,
serum uric acid 35 mEa/L. Serum LDH concentration was normal. Urinary uric acid excretion
was 1100 mg/dL (normal 600 mg/dL) and the uric acid excretion per dL GER was 1.2 mg/dL
(normal0.57 mg/dL).What caused this patient's hyperuricemia? The patient had an increased
urinary excretion of uric acid secondary to increased production of uric acid. A bone aspirate
revealed acute T-cell leukemia (25). His renal failure was due to acute urate nephropathy. This
complication occurs most frequently as tumor lysis syndrome during initial chemotherapy for
lymphoid malignancie

4. HYPERURICEMIA

The serum uric acid concentration is an important physiologic regulator of uric acid cretion.
Tubular secretion of urate into the urine seems to account for the major mech-anisms by which
urinary urate excretion increases with hyperuricemia. The capacity to increase tubular secretion
in response to acute uric loads is greater in children and also explains why Patient 1 had a
normal serum uric acid despite a high dietary load of purine precursors (13). An approach to the
patient with hyperuricemia is shown in fig.2

5. RENAL CONSEQUENCES OF HYPERURICEMIA

Acute uric acid nephropathy is an important etiology of oliguric acute renal failure
among selected groups of patients in whom a massive uricosuria develop. The most common
clinical setting for acute urate nephropathy occurs with rapid turnover of nucleoproteins in
patients with leukemia, lymphoma, or other neoplasms, especially during cytotoxic therapy

Called tumor lysis syndrome, acute renal failure with hypemia during therapy for
leukemia or lymphomas is associated with hyperkalemia, acidosic, hypocalemia, and
hyperphosphatemia (26, 27). These metabolic complications develop rapidly and may be life-
threatening. Rarely, spontaneous acute urate nepropathy may precede cytotoxic therapy in
patients with leukimia or lymphoma (25).

Additional c es of renal failure from increased serum uric acid aciduria include inherited
disorders of purine metabolism (i.e.. Lesch-Nyhan syndroma hypoxanthine-guanine
phosphoribosyl transferase deficiency), hemolysis, rhabdomy-olysis, perinatal asphyxia,
extremen exercise and prolonged muscle contraction from status epilepticus. Important risk
factors for acute renaal failure from hyperuricemia are dehydration and/or acidemia.

Many pharmacologic agents increase uric acid excreation. Some, such as the diuretic
ticrynafen, have produced acute renal failure. Radiographic contrast agents also a markedly
increase uric acid excretion and exrection and should be avoided, or used with caution, during
hyperuricemia.
Urinary flow drops dramatically in patients with acute uric acid nephropathy. Oliguria results
from renal tubular obstruction by the the precipitation of uric acid in collecting tubules (28). As a
result of intraluminal obstruction of the distall nephron, dilatation of proximal tubules occurs. As
discussed previously, uric acid is least soluble in highly concentrated urine of low pH and,
predictably, uric acid precipitation occurs in the renal medulla and papilla in acute uric acid
nephropathy (Fig. 3). Uric acid precipitation may also occur in the vasa recti supplying the distal
nephron.Histological studies of kidneys during acute urate nephropathy show minimal interstitial
cellular infiltration, and the pathologic changes of acute urate nephropathy are reversible.

Renal function in acute uric acid n excretion of urate, rather than the serum urate level.
Precipitation of uric acid in the distal renal tubules and distal renal mic and distal tubule
pressure, and a marked increase in peritubular capillary vascutance. In patients with hyperuric of
GFR, and para-amino hippurate (PAH) cleara athy ed proximal tubule culature results in in and
leukemia, inulin clear e (CIN) a meas ae, a measure of renal plasma flow, ed (29). The filtration
fraction (CI/CPAR) is also decreased. Studies of acute hyperuricemia in laboratory animal
models have shown similar alterations in CIN and renal blood flow. Urinary flow is almost
always markedly diminished

6. PHARMACOLOGIC AGENTS AFFECTING URIC ACID METABOLISM

A wide variety of pharmacologic agents are known to affect uric acid metabolism (30).
Hyperuricemia may result from either inhibition of tubular secretion or from enhanced tubular
reabsorption (Table 2). Conversely, hypouricemia may develop when tubular reabsorption is
inhibited or tubular secretion is increased

7. PATHOPHYSIOLOGY OF HYPOURICEMIA WITH HYPERURICOSURIA

Idiopathic hyperuricosuria may result from altered renal tubular urate transport. With
renal urate wasting, serum uric acid concentrations are decreased (<2 mg/dL). Decreased tubular
reabsorption of urate is the most frequent transport defect in patients with renal hyperuricosuria
(31-33). Uric acid is reabsorbed in both the early and late segments of the proximal tubule. It
appears that most defects in urate reabsorption occur in the early or"presecretory" s egments.
Less commonly, some children have increased tubular secretion of uric acid (32). Idiopathic
renal hyperuricosuria may affect multiple

Family members and is frequently asymptomatic. Other etiologies of renal urate wasting
include the Fanconi syndrome, cystinosis, Wilson's disease, and parenteral hyperalimen- tation
(34). A substantial number of pharmacological agents increase urinary uric acid excretion (Table
3). Obviously, any cause of increased uric acid production with hype- ruricemia may result in
hyperuricosuria. An approach to the patient with hypouricemia is shown in Fig. 4.
8. THERAPY FOR ACUTE SEVERE HYPERURICEMIA WITH NEPHROPATHY

Although the mortality in acute urate nephropathy was once nearly 45 %, current dialysis
therapies have dramatically improved survival.mortality is now related almost exclusively to the
underlying disease process.medical therapy for patients at risk for urate nephropathy is directed
toward reducing intrarenal precipitation of uric acid by maintaining a high urine flow rate with as
much hydration as the level of renal function allows (35).

To prevent acute uric acid nephropathy in patients undergoing induction antineoplastic

therapy, intravenous fluid administration is begun at 3000 Ml/m2 body surpace area per day in
both children and adults , when extracellular fluid volume allows . in patients with extracellular
fluid volume depletion, replacement of fluid deficits must precede high volume maintenance. An
alkaline urine is maintained with intravenous sodium bicarbonate infusions. When the urine pH
cannot be maintained above a pH of 7.0, acetazolamide may also be given orally (provided
systemic acidosis is not present ). The relative protective roles of urinary flow rate, urine
osmolality , and urine pH in the prevention of acute urate nephropathy have been examined in
laboratory settings (36). These studies suggest that a high tubular fluid flow rate, regardless of
urine pH or osmolality , offers the maximal protection against urate nephropathy. As
aforementioned, use of uricosuric drugs, especially radiographic contrast agents, should be
avoided in patients with hyperuricemia (fig.3).

During cytotoxic therapy or in patients with a sustained source of urate overproduction ,

the filtered urate load is reduced by administering either intravenous or oral
allupurinol.allupurinol is an inhibitor of xanthine oxidase and is effective in reducing the
concentration of uric acid in the serum.urinary oxypurine excretion is markedly increased during
allupurinol therapy and renal failure secondary to xanthine precipitation has been observed rarely
during allopurinol therapy (37).

Dialysis or hemofiltration is effective in reducing the serum uric acid concentration and
in treating the metabolic consequences of acute renal failure (38). The clearance of uric acid by
hemodialysis is 10 times greater than with peritoneal dialysis ;therefore,hemodialysis is the
dialysis treatment of choice for acute renal failure from uric acid nephropathy. Hemodialysis
should be the initial treatment if oliguria or life-threatening hyperkalemia are present when renal
failure is discovered.occasionally , acute renal failure resolves after one or two dialysis
treatments (26). Due to the tremendous production of uric acid with initial cytotoxic therapy,
frequent hemodialysis therapies maybe required. When time and the initial metabolic
derangements allow, continuous arteri ovenous or venovenous hemofiltration or
hemodiafiltration has been shown to be advantageous as renal replacement therapy for patients
with acute tumor lysis syndrome. Continuous hemodiafiltration allows for the provision of
intravenous nutrition and more flexibility in management.allupurinol is removed by
hemodialysis, and a dose should be given at the conclusion of dialysis treatment.

Uricolysis therapy with the intravenous administration of the enzyme, uricase (uric acid
oxidase), is an exciting advance in the treatment and prevention of urate nephropathy during
cytotoxic therapies (34). Uric acid is degraded to allantoin in the presence of uricase. Allantoin
is extremely soluble, is filtered by the glomerular membrane, and has no known nephrotoxicity.
Intravenous administration of uricase in doses of 0,15 -0,2 mg/kg,diluted in saline , is
administered over 1-2 h during the first 5-7 days of chemotherapy. This regimen is superior to
allopurinol in reducing serum uric acid concentrations and preventing oliguric acute renal failure
in children with leukemia. Some patients (<5%) receiving the nonrecombinant uricase develop
bronchospasm, hives, and other hypersensitivity reactions. Uricase should not be administered to
patients with G6PD deficiency. Enzymatic uricolysis therapy may replace the initial use of
allupurinol and dramatically reduce the need for dialysis therapies in patients with tumor lysis
syndrome.

8.1. Hyperuricemia in the Pathogenesis of Hypertension and Progression of Chronic Kidney

Disease

Individuals with hypertension and chronic kidney disease frequently have increased serum
concentrations of uric acid. Traditional thinking has considered hyperuricemia in these settings
as a secondary phenomenon and has not considered a primary pathogenetic mechanism related to
uric acid (7). Recent studies have hypothesized that uric acid is toxic to vascular endothelial cells
and may result in the development of essential hypertension and progressive loss of renal
function (39,40). This interesting hypothesis is currently the focus of rigorous study and
potentially offers new therapeutic options in these condition.

8.2 SUMMARY

1. serum uric acid and urinary uric acid values vary during childhood and differ from adult
values

2. serum uric acid concentrations are altered by changes in extracellular fluid volumes

3. unexplained extreme hyperuricemia in an otherwise normally developing child should raise

the possibility of leukemia or lymphoma , regardless of the peripheral white blood cell count

4. hyperuricemia is an important cause of acute renal failure in children undergoing acute tumor
lysis

5. chronic hyperuricemia may contribute to the development of hypertension and progression of

chronic kidney disease.
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