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Chapter 15 / Diet and Urolithiasis 297
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Chapter 16 / Uric Acid Urolithiasis 299
299
From: Current Clinical Urology, Urinary Stone Disease:
A Practical Guide to Medical and Surgical Management
Edited by: M. L. Stoller and M. V. Meng © Humana Press Inc., Totowa, NJ
16
Uric Acid Urolithiasis
Bodo E. Knudsen, MD, Darren T. Beiko, MD,
and John D. Denstedt,
MD
CONTENTS
INTRODUCTION
EPIDEMIOLOGY
URIC ACID: PATHOPHYSIOLOGY
ASSOCIATED CONDITIONS
DIAGNOSIS
TREATMENT
CONCLUSION
REFERENCES
Key Words: Nephrolithiasis; uric acid; pH; dissolution.
INTRODUCTION
Uric acid calculi are responsible for 5–10% of calculi in the North American popu-
lation. These radiolucent stones are of particular interest because of their ability to be
successfully managed with both medical therapy and surgical intervention. The patho-
physiology is unique and important to understand when treatment is being planned.
EPIDEMIOLOGY
The worldwide prevalence of uric acid stones ranges from 5 to 40%. The prevalence
varies geographically with a rate of 5–10% in North America but as high as 40% in Israel
(1–6).
URIC ACID: PATHOPHYSIOLOGY
The final product of purine metabolism is uric acid (2,6,8-trioxypurine). It performs no
known physiologic function in humans. In most mammals uric acid is further converted
300 Knudsen, Beiko, and Denstedt
to allantoin by uricase. However humans lack this enzyme and therefore are unable to
produce the 10–100 times more soluble allantoin.
The volume of urine and the amount of uric acid excreted determine urinary concen-
tration. Nevertheless urine pH remains the single most important determinant of uric
acid solubility. Uric acid has two dissociation constants (pKa): each governs the loss of
a single proton from uric acid, at pH of 5.5 and 10.3 respectively. At the first pKa of 5.5,
the conversion of uric acid to the more soluble anionic urate is controlled. The second
pKa of 10.3 is not clinically significant because mean human urine pH is 5.9 and nor-
mally ranges from 4.8 to 7.4 (7,8). At a urinary pH <5.5 nearly 100% of uric acid is
undissociated and urine becomes supersaturated with uric acid. Conversely, at a pH of
>6.5 the majority of the uric acid exists as anionic urate.
There are both endogenous and exogenous sources of uric acid. Endogenous sources
include de novo synthesis and tissue catabolism. Approximately 300–400 mg/d is pro-
duced under normal circumstances. Certain disease processes are associated with over-
production of uric acid. These include gout, myeloproliferative disorders, and certain
congenital metabolic defects. Patients receiving chemotherapy may also have
elevated uric acid levels secondary to rapid cell turnover.
Exogenous sources of purine are obtained from the diet and can vary greatly from
individual to individual. Purine is broken down in the intestinal tract into free nucleic
acids and then to inosinic acid. The next step is the conversion to hypoxanthine, which
is subsequently converted to xanthine and finally uric acid by xanthine oxidase (Fig. 1).
Foods highest in purine include fish, meats (especially liver, kidney, and heart), sweet-
breads, and yeast (Table 1).
Two-thirds of uric acid elimination is handled by the kidney. The remaining third is
cleared by extra-renal routes, including the skin, nails, hair, saliva, and the gastrointes-
tinal tract (9,10). Bacteria in the bowel convert a portion of the uric acid to carbon dioxide
and ammonia. Carbon dioxide is expelled as gas. The ammonia may be used by bacteria
as an energy source or absorbed and consequently excreted in the urine (11).
Ninety-five percent of serum uric acid exists as monosodium urate, which is freely
filtered at the glomerulus, whereas the remaining 5% is protein bound. A series of steps
involving reabosrption, secretion, and further reabsorption occurs. Ninety-nine percent
of the filtered urate is reabsorbed in the proximal convoluted tubule (PCT). However
50% is then secreted back into the PCT. Postsecretory absorption of 80% of this urate
occurs distally but still within the PCT. Ultimately about 10% of the filtered urate is
excreted in the urine. The fractional excretion of urate does vary with age ranging from
60% in a premature neonate to 12% in a 3 yr old and 7% in the adult (12) population.
Fig. 1. Purine metabolism.
Chapter 16 / Uric Acid Urolithiasis 301
Factors that can affect the renal handling of uric acid include the patient’s volume
status and urine output, serum urate concentration, as well as numerous medications.
Extra-cellular volume expansion is inversely related to serum urate concentration.
Medications such as salicyclates, sulfinpyrazone, and probenecid are uricosuric by way
of impairing urate absorption in the PCT. Thiazides may cause hyperuricosuria by pro-
ducing extra-cellular volume contraction, leading to increased urate secretion in the PCT
(13,14). Pregnancy is associated with hyperuricosuria. This is thought to be the result of
a combination of the increased intravascular volume of pregnancy and fetal urate pro-
duction (11,15).
ASSOCIATED CONDITIONS
Three factors are primarily responsible for uric acid stone formation. These include
(1) low urine pH, (2) low urine output, and (3) high urinary uric acid concentration. The
most important of these factors is low urine pH, but all three interact and influence
subsequent stone formation.
Gastrointestinal Conditions Associated With Uric Acid Lithiasis
Patients with inflammatory bowel disease, ileostomy, or multiple bowel resections,
especially involving the terminal ileum, are at an increased risk of uric acid nephrolithi-
asis. Patients with ulcerative colitis have a 0.5–3.2% incidence of urolithiasis (16–18).
Ileostomy patients have a reported incidence of 50–70% and Crohn’s disease patients
with terminal ileal involvement as high as 80% (19). These patients have a persistently
low urinary pH but otherwise have normal serum and urine uric acid levels. They become
dehydrated as a result of the ongoing water loss from the gastrointestinal tract. This also
results in excessive bicarbonate losses with a resultant metabolic acidosis, hypocitraturia
and low urinary pH. Such patients are at risk for both uric acid and calcium oxalate
lithiasis. Patients with an ileostomy encounter similar difficulties.
Other situations that predispose to chronic dehydration such as working in a hot
environment, heavy physical activity without fluid replacement, or living in an arid
climate can result in increased uric acid stone formation. This may account for the
increased incidence of uric acid stones in the Middle East (20).
Table 1
Foods High in Purine
• Meats • Fish • Vegetables • Mushrooms
B Organ meats B Anchovies B Peas
liver B Herring B Legumes • Yeast
kidneys B Sardines B Spinach
heart B Mackerel B Lentils • Nuts
B Red meat B Fish roe B Beans
B Poultry B Shellfish B Asparagus • Alcohol
wild game B Mussels B Cauliflower B Beer
B Shrimp B Wine
B Scallops
302 Knudsen, Beiko, and Denstedt
Gout and Stones
Primary gout is an inherited disorder characterized by hyperuricemia, persistently
acidic urine and in some patients hyperuricosuria. A recurrent acute or chronic arthritis
of peripheral joints develops that is the result of deposition of monosodium urate
crystals in and about the joints and tendons (21). Sustained hyperuricemia is a function
of decreased renal clearance of urate. This may be caused by a tubular defect that
results in decreased secretion of urate (21). Patients on chronic diuretics or those with
a decreased glomerular filtration rate (GFR) secondary to primary renal disease are
particularly at risk. Longer duration and higher levels of hyperuricemia are associated
with an increased incidence of gouty arthritis. In 10% of cases increased purine syn-
thesis is responsible for the development of gout (11,21).
The incidence of uric acid stones in individuals with primary gout is 10–20% (21–24).
In 40% of these patients stones develop before the onset of articular symptoms (24). The
majority of stone formers are men in the third to fifth decades of life. The patients
universally have acidic urine that promotes the formation of uric acid calculi (25–27).
Hyperuricosuria only occurs in the 10% of patients who have an increase in de novo
synthesis of purines. In fact, patients with gout have a lower rate of hyperuricosuria
compared to normal controls (28).
In normal individuals a postprandial increase in urinary pH occurs, referred to as an
alkali tide (29). This results from the secretion of bicarbonate into the serum by parietal
cells of the stomach in response to gastric acid secretion. This produces an increased
urinary pH, which promotes dissolution of uric acid and reduces precipitation and sub-
sequent calculi formation. Patients with gout, and also some idiopathic uric acid stone
formers, may lack this postprandial increase in urinary pH (30,31). The exact mechanism
for this phenomenon remains unclear. One theory is that there is impaired renal ammo-
nium excretion and that this defect may worsen with aging (24,32–35 ). However this
theory has not universally been accepted (36–38) and in fact the etiology may be mul-
tifactorial.
Increased Catabolism
As many as 40% of patients with myelo- or lympho-proliferative disorders develop
uric acid calculi (24). With these disorders there is an increase in the production and
turnover of nucleic acids. In patients receiving chemotherapy an enormous increase in
the endogenous purine pool may occur as a result of tissue necrosis. This can lead to acute
urinary obstruction because of severe crystalluria.
Other benign disorders that are associated with uric acid lithiasis include thalassemia,
hemolytic anemia, polycythemia, and sickle cell disease (39).
Enzymatic Defects Associated With Uric Acid Lithiasis
Hypoxanthine guanine phosphoribosyl transferase (HGPRT) is an enzyme whose
function is to convert hypoxanthine to inosinic acid and guanine to guanylic acid. A
partial or complete HGPRT deficiency may occur as an inborn error of metabolism. The
complete form, known as Lesch–Nyhan syndrome, is X-linked and therefore seen only
in males. It is characterized by self-mutilating behaviors, mental retardation, gout, and
uric acid lithiasis. Infants may present with orange crystal-like deposits in their diapers,
which are a result of uricosuria (40).
Chapter 16 / Uric Acid Urolithiasis 303
Patients with type 1 glycogen storage diseases (GSDs) have either a primary defect
in or impaired function of glucose-6-phosphatase. It is associated with an increased
incidence of uric acid lithiasis. Patients develop hyperuricemia, hyperuricosuria, meta-
bolic acidosis, hypoglycemia, hepatic adenomas, and chronic renal disease (21).
Phosphoribosyl pyrophosphate (PRPP) synthetase overactivity is another X-linked
disorder associated with uric acid lithiasis. PRPP synthetase is responsible for the for-
mation of PRPP from ribose-5-phosphate and adenosine triphosphate. Increased PRPP
synthetase activity results in hyperuricemia and hyperuricosuria (41).
Diet
A diet high in animal protein may result in aciduria and hyperuricosuria with a resultant
increase in uric acid lithiasis (31). Patients generally have normal serum uric acid levels.
Familial
An autosomal dominant inherited form of uric acid lithiasis has been reported in a
group of Israeli Jews. It appears to affect men and women equally, unlike primary gout.
A persistent low urinary pH is manifested and stones may occur at an early age (42).
Idiopathic
Some patients have neither a family history nor any predisposing conditions that can
contribute to uric acid calculi. In one study, a noninherited idiopathic form of uric acid
lithiasis was described in 15% of the population in central Europe. This group of patients
had normouricemia and normouricosuria but did have a persistently low urinary pH (30).
DIAGNOSIS
A detailed history is a key element in the work up of any patient with suspected uric
acid urolithiasis. Items that must be covered include whether the patient has a past history
of uric acid lithiasis, history of bowel disease or previous bowel surgery, risk factors for
dehydration, family history of stones, history of gout, diet specifics, and any other major
medical problems. It is also important to review any medications the patient is taking as
well inquire about the patient’s occupation.
Serum electrolytes, creatinine and urinalysis should be performed in all patients
presenting with renal colic. Urinary pH should be recorded. A pH of <5.5 should alert
the physician to the possibility of uric acid lithiasis in a patient with renal colic. If uric
acid stones are suspected, then a serum uric acid and a complete blood count to screen
for myeloproliferative disorders are recommended.
Initial imaging will vary based on what is available at the presenting institution. A
plain kidney, ureters, and bladder (KUB) radiograph will fail to demonstrate pure uric
acid stones because of their radiolucent nature (Fig. 2A). Stones that are composed of
a combination of uric acid and calcium oxalate may however be visible. An intravenous
pyelogram (IVP) can be performed as a first-line investigation. A radiolucent filling
defect is suggestive of a uric acid stone (Fig. 2B). An IVP may also provide information
regarding the degree of obstruction that a stone is causing. Information regarding stone
size and location can also be obtained.
Many institutions are now performing noncontrast enhanced computerized tomogra-
phy (CT) as a first line radiographic investigation for renal colic. Uric acid calculi are
readily apparent on CT images (Fig. 2C). Hounsfield units (HU) between 300 and 600
304 Knudsen, Beiko, and Denstedt
are typical of pure uric acid calculi. HUs are generally somewhat lower for uric acid
compared to calcium oxalate calculi (43–45). A radiolucent filling defect on IVP has a
broad differential diagnosis including blood clot, fungal ball, papillary necrosis, and
transitional cell carcinoma. A CT scan can aid in differentiating these possibilities based
both on the appearance of the lesions and their HU, which are between 20 and 55 HU for
soft tissues (46).
Renal ultrasound is a reasonable imaging option especially when used to follow
patients with a history of uric acid lithiasis or in pregnancy. It offers the advantage of no
radiation exposure but is less sensitive when compared to CT or IVP for detecting
ureteric calculi and misses 20–30% of acute obstructions caused by a ureteric stone (47).
With respect to metabolic evaluation, hyperuricosuria is a known risk factor for uric
acid lithiasis. Pak defines hyperuricosuria as a mean 24-h urinary excretion of greater
than 600 mg/d on two of three collected samples (48).
TREATMENT
General Measures
Therapeutic goals include first achieving a stone free state and secondarily preventing
new stone formation. In order to achieve these goals uric acid concentration must be
reduced below the supersaturation point in the urine. Treatments are aimed at increasing
the daily urinary volume, increasing the urinary pH, and reducing the amount of uric acid
excreted.
General measures include encouraging patients to maintain a daily urine output of
greater than 2 L and dietary counseling to reduce intake of purine rich food.
Fig. 2. Radiographic imaging of uric acid stone. (A) KUB demonstrating lack of radiopaque
stone. (B) IVP showing filling defect in left renal pelvis. (C) CT scan with corresponding stone
demonstrated.
Chapter 16 / Uric Acid Urolithiasis 305
Chemolysis of Uric Acid Lithiasis
Uric acid stones are one of the few stone types that are amenable to dissolution therapy
either in the form of oral or intravenous (IV) therapy, or via direct instillation of irrigating
agents. Dissolution is an attractive treatment option especially for patients who have
little or no symptoms, no associated infection, and do not have high-grade obstruction.
Surgical drainage of the kidney is required first in the form of a stent or nephrostomy if
one or more of the above are present. Dissolution therapy however remains an option
after the kidney is appropriately drained and any infection treated.
As previously stated, uric acid has two dissociation constants, one at a pKa of 5.5
where the conversion of uric acid to the more soluble anionic urate is controlled and a
second, clinically insignificant one at a pKa of 10.3. The goal is therefore to raise the
urinary pH to a level where the stones can be dissolved. At a pH of 5.0, the solubility of
uric acid is 6–8 mg/100 mL. At a pH of 7.0 this increases to 158 mg/100 mL. Therefore
the goal is to increase the pH to approx 6.5 (49). Raising the pH higher than this, especially
with oral therapy, increases the risk of calcium phosphate stone formation (50).
Oral Dissolution
In a patient with good renal function in the affected kidney and a stone size of 1 cm
or less, oral dissolution therapy is an excellent option with success rates in excess of 80%.
It may however take several months for the stones to dissolve (51,52).
Oral alkalinization of urine can be achieved with either sodium bicarbonate or potas-
sium citrate. The dose of sodium bicarbonate is 650–1000 mg three to four times per day.
The sodium load may prove problematic in patients with congestive heart failure or in
the elderly. Potassium citrate is a better option and is administered at a dose of 15–30 meq
three to four times per day. Caution is advised in patients with renal insufficiency
because of the potassium load. Patients should be given either nitrazine paper or pH
strips in order to optimize therapy to a urinary pH of 6.5. Care should be taken not to over
correct the pH as calcium phosphate stone formation can occur at a pH greater than 7.0
(49). Potassium citrate administration may also act as a stone inhibitor and prevent new
stones from developing (25). Stone dissolution rates can be expected to be approx 1 cm
of stone radius per month. Patients should be imaged regularly during treatment to ensure
active dissolution.
In addition to alkalinizing the urine with sodium bicarbonate or potassium citrate,
allopurinol may be added to the treatment protocol. Some favor adding allopurinol only
in patients with hyperuricosuria and hyperuricosemia (49). It is not unreasonable how-
ever to add it in all patients with uric acid stones undergoing dissolution therapy pro-
vided that there is no contraindication. Allopurinol is an inhibitor of the enzymes
xanthine oxidase and hypoxanthine oxidase, which convert hypoxanthine to xanthine
and xanthine to uric acid, respectively. Hypoxanthine and xanthine are both much more
soluble than uric acid and are excreted by the kidney. De novo purine synthesis is also
decreased with the administration of allopurinol. The recommended dose is 300 mg
once per day. The dose should be adjusted in patients with renal insufficiency. The
medication is well tolerated but approx 20% of patients may develop a fever, rash, or
gastrointestinal upset. Liver enzymes should be periodically monitored as they may
become elevated and hepatitis can develop. The most severe complication is Stevens–
Johnson syndrome, which may lead to a fatal vasculitis. Pruritus usually is the initial
complaint and precedes the hemorrhagic skin lesions and vasculitis. The onset of pru-
306 Knudsen, Beiko, and Denstedt
ritus in a patient taking allopurinol should prompt the physician to immediately stop it
(11,49,53,54).
Intravenous Dissolution
Intravenous alkalinization can be performed but is usually reserved for hospitalized
patients with acute urinary obstruction. Intravenous therapy raises urinary pH faster and
to a greater degree than oral dissolution therapy. One-sixth molar lactate solution, which
is metabolized to bicarbonate, has been used to dissolve uric acid calculi (49,55).
Direct Dissolution
Direct dissolution of uric acid calculi, via an antegrade nephrostomy or retrograde
catheters, can be performed. Its primary use it to treat residual stones following a surgical
procedure or after shockwave lithotripsy. Tromethamine (THAM, pH 8.6), 0.3 M
tromethamine E (THAM-E pH 10.5), and sodium bicarbonate (pH 7.0–9.0) may all be
used. Patients however must be hospitalized to receive the treatment, which contributes
significantly to costs. Furthermore, recent advances in endourology have increased
surgical stone-free rates and therefore direct dissolution is becoming a historical option
(11,49,56).
Surgical Treatment of Uric Acid Calculi
Uric acid calculi are amenable to extracorporeal shockwave lithotripsy. However
targeting these radiolucent stones with fluoroscopy may not be possible unless they are
mixed stones with a significant calcium component. Retrograde instillation or intrave-
nous infusion of contrast via a ureteric catheter can facilitate visualization. Alterna-
tively, ultrasound can be used to target uric acid calculi (57).
Ureteroscopy with intracorporeal lithotripsy and percutaneous nephrolithotripsy are
both effective modalities for treating uric acid calculi. Electrohydraulic, ultrasonic,
pneumatic, or Holmium:YAG laser lithotripsy are all effective fragmentation devices.
Holmium:YAG laser lithotripsy results in the production of cyanide. No clinical toxicity
or side effects have been demonstrated by its production (58).
CONCLUSION
Uric acid calculi are a relatively common problem but may be amenable to appropriate
medical dissolution therapy. Effective medical treatment options include dissolution
therapy using oral sodium bicarbonate or potassium citrate, intravenous one-sixth molar
lactate solution or direct instillation of THAM, THAM-E, or sodium bicarbonate. When
medical therapy fails or an indication for surgical intervention is present, uric acid calculi
may be successfully treated by any of the available endourologic treatment options,
including extracorporeal shockwave lithotripsy, ureteroscopic lithotripsy, or percutane-
ous nephrolithotripsy. Knowledge of the size and location of the stone, along with an
understanding of the pathophysiology of uric acid urolithiasis and the associated condi-
tions is paramount in determining the best treatment option.
REFERENCES
1. Gutman AB, Yu TF. Uric acid nephrolithiasis. Am J Med 1968; 45: 756.
2. Hesse A, Schneider HJ, Berg W, Hienzsch E. Uric acid dihydrate as urinary calculus component.
Invest Urol 1975; 12: 405.