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[Frontiers in Bioscience 8, s1339-1355, September 1, 2003]
1339
URIC ACID STONE DISEASE
Michael E. Moran
Peter’s Kidney Stone Center, Albany, NY
TABLE OF CONTENTS
1. Abstract
2. Introduction
3. History
4. Physiology
4.1. Purine Metabolism
4.2. Crystalline Composition and Solubility
4.3. Supersaturation and Precipitation
5. Clinical Characteristics
5.1. Laboratory
5.2. Radiographic
5.3. Urolithiasis and Gout
5.4. Gout and Urolithiasis
5.5. Bowel Disease and Uric Acid Stones
5.6. Catabolic States
6. Rare Disorders of Purine Metabolism
6.1. Xanthine Stone Disease
6.2. 2,8- dihydroxyadenine Urolithiasis
6.3. Lesch-Nyhan Syndrome
6.4. Oxypurinol Urolithiasis
6.5. Ammonium Urate Stones
6.6. Endemic
6.7. Laxative Abuse
7 Therapy
7.1. Chemodissolution
7.2. Prevention
7.3. Surgical
8. Conclusions
9. References
1. ABSTRACT
The trend in uric acid stone formation appears to
be on the rise again throughout much of the world. This is
thought secondary to diet, body habitus, and social reasons.
Uric acid stone disease has a rich and fascinating medical
history and probably is the oldest known stone disease.
Uric acid stone disease is strongly linked to the purine
metabolic pathway, and its treatment is primarily medical.
Uric acid stone disease can be prevented and these are one
of the few urinary tract stones that can be dissolved
successfully. Surgical intervention with uric acid stone
disease represents a failure of medical therapy and a whole
host of modern, minimally invasive methods are available
for treating patients with this disease. Finally, uric acid
nephrolithiasis is associated with a variety of inborn errors
of metabolism based on mutations of key enzymes in the
purine metabolic pathways. This review of uric acid stone
formation will start with historical consideration, review
basic biochemistry, and physiology and then focus upon
specific clinical scenarios. The discussions will be heavily
referenced for those interested in greater details.
2. INTRODUCTION
Stone disease has afflicted humans since before
recorded time. The first known stone, a bladder calculus, is
well described in a 5
th
Century BC Egyptian youth of about
7 years of age. The stone was a mixture of uric acid and
struvite. Uric acid was of primary interest to the founding
fathers of chemistry.1). Urinary stones were quite common
at the close of the 19
th
Century when the founders of
chemistry were investigating basic chemical composition,
so it is quite natural that they turned their attention to stone
disease. Uric acid was the first urinary stone constituent
that had been successfully identified.
Uric acid is the end product of human purine
nucleotide metabolism. As such, uric acid is far from an
ideal end product because it is poorly soluble. In excess,
uric acid can precipitate as sodium hydrogen urate
(common in joints and tissues) or as uric acid, sodium
urate, or ammonium urate in the urinary tract. Man is
continually on the precipice of crystallization and
precipitation as the urine is relatively supersaturated with
Uric Acid Stone Disease
1340
uric acid with an average of 600 mg/day. Human uric acid
handling has become a complex physiologic issue.
Humans lack the enzyme, uricase that nearly all other
species have to oxidize uric acid into the more soluble
allantoin.
Uric acid is a weak acid with the hydrogen atom
at position 9 of the imidazole ring easily dissociated in the
physiologic range (pKa
1
= 5.75).
3. History of Uric Acid Chemistry
Uric acid stone formation represents one of the
more fascinating enigmas of chronicled human diseases.
Hippocrates (460- 370 B.C.) noted the clinical features of
gout, its hereditary nature and male predominance. Gouty
tophi and uric acid bladder and kidney stones had been
identified. Galenus (131- 201 A.D.) proposed relationships
between gout and urolithiasis. Paracelsus (1493- 1541)
believed stones were caused by dietary excesses.(2)
Thomas Sydenham (1624-1689) suffered from kidney
stones and gout. He hypothesized that specific increase in
excretion of a kidney stone producing substance resulted in
precipitates of stones. Sydenham’s insight is shown as
follows: …”the gout breeds the stone in the kidney of many
subjects either (1) because the patient is obliged to lie long
on his back, or (2) because the secretory organs have
ceased performing their proper functions; else (3) because
the stone is formed from a part of the same morbific
matter.” Sir William Osler (1849- 1919) followed in the
lineage of great medical minds that suffered from
urolithiasis. In his first edition of The Principles and
Practice of Medicine, his magnum opus, Osler specifically
refers to chemical varieties of calculi; “Uric acid, by far the
most important, which may form the renal sand, the small
solitary, or the large dendritic stones.” (3)
The chemical composition of calculi parallels the
infancy of clinical chemistry. One requisite of early
chemists was the requirement of an abundant substrate.
Calculus disease during the late 18
th
and early 19
th
Century
was endemic and concurrent with the Industrial Revolution.
Thus stones, particularly bladder calculi were readily
available. In 1776, Karl Wilhelm Scheele (1742-1786) in
seminal studies on bladder stones noted that though barely
soluble in water, they turned litmus paper red and thus were
acidic. Upon heating, the stones produced an odor of
prussic acid. He gave the name lithic acid to the substance
and thought that all urinary stones were of similar
chemistry. Another chemist, T.B. Bergman (1734-1794)
made similar observations. In 1795 George Pearson (1751-
1828) presented an investigation of 300 stones from the
collection of Mr. Heaviside. With exquisite attention to
detail, he concluded that lithic acid is not present in the
stone but was an oxide. Pearson suggested in his paper to
change the name to uric acid. Pearson further points out
that most stones do contain uric acid (194/200) but in
varying concentrations. Antoine F. Fourcroy (1755-1809)
also experimented upon a large number of uroliths and
tended to agree with the misconceptions of Scheele.
Fourcroy is considered the father of clinical chemistry. His
insightful investigations included questioning whether uric
acid was confined to humans, if uric acid existed outside of
the urine, how it was formed, if there was any left in the
urine after stone precipitated, etc. He proposed and
probably performed the first multi-center investigation of
environmental and geographic regions to see if different
stone types were seen in different areas. Fourcroy and his
colleague, Nicolas Louis Vauquelin, not only expanded the
chemical properties of uric acid, they identified the sodium
and ammonium salts. Fourcroy also pursued the
therapeutic possibility of dissolving such stones and
commented that only pure uric acid stones should be
capable of being dissolved.(4)
The rigorous method of experimental pursuit by
these early investigators included experiments and
dissection of various animal species. They noted that man
was the only mammal to form uric acid stones. Pearson
and Vauquelin could not find uric acid stones in large
carnivores (lions and tigers). Fourcroy followed-up these
observations by confirming a lack of uric acid stones in the
horse, cow, rabbit, dog, cat, pig and rat.
William Hyde Wollaston (1766-1826) was
another contemporary of these other investigators who also
was interested in stone chemistry. Wollaston further
refined chemical techniques to investigate the properties of
uric acid, and also became an expert in crystallography.
Wollaston was the first to identify cystine from the bladder
of a 5 year old boy. He differentiated this stone from uric
acid and correctly identified the first amino acid. He
published the most significant work on urolithiasis up to
this time in 1797; On Gouty and Urinary Concretions.(5)
A contemporary of Wollaston was Alexander Marcet. He
too was a physician and chemist, working in London and
obtained calculi from Norwich Hospital. He was the first
to discover xanthine stones. His book An Essay on the
Chemical History and Medical Treatment of Calculous
Disorders in 1817 was encyclopedic of the knowledge of
stones at the time.(6) These were the pioneering fathers of
calculous disease and serve a fitting introduction to the
discussion of uric acid stone disease which first garnered
attention of emerging science.
4.0. URIC ACID PHYSIOLOGY
4.1. Purine Metabolism
A huge literature is available regarding the
physiology of purines and pyrimadines. These nucleic acid
precursors form the foundations of understanding the
physiology of this disease. In fact, if not for the lack of a
single enzyme, uricase, human diseases such as gout and
uric acid stone formation would not exist. As noted by our
forefathers, among mammalian species, only humans and
the great apes excrete uric acid as the end product of purine
metabolism.(7) The net production of uric acid comes from
two primary sources, dietary ingestion and the endogenous
production via nucleotide synthesis (Figure 1). This
process appears to be most active in liver cells but occurs in
all living cells. The synthesis of purines is a sequence of
10 enzymatic steps by which small precursor molecules are
placed into a purine ring synthesized on ribose phosphate.
These small molecular species include glutamine, glycine,
and formate to form 5-phosphoribosyl pyrophosphate (5-
Uric Acid Stone Disease
1341
Figure 1. Urinary uric crystals seen under regular
microscopy.
RPP), the backbone of the molecule. This high-energy
molecule is then involved in purine synthesis in two ways:
it combines with L-glutamine and proceeds through de
novo synthesis; or it participates in the salvage of purine
bases, which can be reconverted to ribonucleotides. The
enzymatic process of combining 5-PRPP and glutamine
uses the enzyme 5-PRPP amidotransferase that is the major
step in the pathway and subject of feedback control.
Phosphoribosyl-n-amine is the highly labile amino sugar
product of this reaction and it is converted to inosinic acid
(IMP) in a series of 8 steps using glycine. There is little
evidence that the intermediates along this pathway
accumulate during synthesis. IMP can then be converted to
adenylic acid (AMP) and/or guanylic acid (GMP), both of
which are essential to DNA and RNA synthesis. Both
AMP and GMP can feedback on the control of 5-PRPP
amidotransferase limiting production. IMP can also be
catabolized to inosine by a specific 5’-
phosphomonoesterase and nonspecific acid and alkaline
phosphates. This is a costly pathway in terms of energy
utilized, requiring 6 moles of adenosine triphosphate (ATP)
for generating one mole of inosinic acid, the first precursor.
Purine interconverstion is a built-in method of conserving
energy and complexly allowing this pathway to reuse
preformed purines. The hydrolysis of nucleoproteins and
free purines from the diet can be reutilized in the formation
of mononucleotides. This obviously is the result of the
reversal of the reactions. The enzyme hypoxanthine-
guanine phosphoribosyl-transferase (HPRTase) catalyzes
the transfer of ribose-5-phosphate from 5-PRPP to
hypoxanthine and guanine to form IMP and GMP
respectively. HPRTase activity is also subject to negative
feedback inhibition by IMP or GMP and APRTase activity
is inhibited by AMP excess. There are hereditary
syndromes of enzyme deficiency that can disrupt this
reutilization pathway. Lesch-Nyhan syndrome is an
HPRTase deficiency associated with very high incidence of
uric acid stones, interstitial nephritis, and neurological
syndrome of choreoathetosis, mental retardation, spasticity,
and self-mutliation. Enzyme deficiencies have been
described for APRTase activity and the association of 2,8-
dihydroxyadenine stone formations.
The last step in the production of uric acid
involves xanthine oxidase degradation of hypoxanthine and
xanthine to uric acid. This enzyme is rather indiscriminate
and acts upon a host of substrates. Liver and the small
bowel have the highest concentrations of this enzyme but
the kidney, spleen, skeletal muscle, and heart have activity.
Hereditary deficiency in xanthine oxidase has also been
discovered. These patients excrete xanthine and
hypoxanthine as the end products of purine metabolism.
Xanthine is less soluble in urine than is uric acid and these
patients suffer from recurrent xanthine stone formation.
4.2. Crystalline Composition and Solubility
The primary determinant of uric acid solubility is
the pH of the urine. At a pH of 5, uric acid solubility is 8
mg/dl; at a pH of 7.0 it is 158 mg/dl. The first pKa of uric
acid is variously quoted from 5.35 to 5.75.(8) In a graph
of the dissociation curve for uric acid, the urine pH on the
abscissa, the percent of total uric acid as free undissociated
uric acid on the ordinate, and a pKa of 5.57. At this point
50% of the total uric acid is free. The second dissociable
proton has a pKa about 10.3 and is not normally clinically
significant. The solubility of uric acid in urine is different
than in water, being modulated by other ions. At a pH of
5.35, only 200 mg/L of urine can be present without
exceeding supersaturation. When the urine pH is raised to
6.5, greater than 1,200 mg/L remains soluble.(9) Sodium
concentration has a significant impact upon the solubility of
uric acid. As sodium concentrations rise from 6 to 140
mEq/L this results in a 20-fold reduction in the solubility of
sodium urate. Ammonium urate is also sparingly soluble
with only 5.4 mg/dl at a pH of 7.4.
4.3. Supersaturation and Precipitation
The average adult consumes approximately 2mg
of purine per kilogram of body weight, which results in
200-300 mg of urine uric acid daily. Endogenous
production is also about 300 mg/day. Endogenous
production comes from de novo synthesis and tissue
catabolism and purine reclamation. In studies by Coe, uric
acid excretion was estimated to be 5.6 mg/kg/day.(10)
Dietary RNA purines contributed 50% and DNA 25% of
the urinary uric acid.(11) Total uric acid excretion is about
600 mg/day for an average person. Excretion of xanthine
and hypoxanthine is normally in the range of 5-10 mg/day.
Urinary excretion of uric acid and quantification
of the amount varies upon the methods used to collect the
specimens, upon the size and gender of the patient, the
baseline renal function and dietary ingestion.(12) Urine
collected and stored refrigerated, for example will have uric
acid crystallize and precipitate at the bottom of the
container, skewing measurements.(13) Dietary
consumption of purine varies from day-to-day and from
person-to-person. These fluctuations in dietary
consumption translate to wide variations in urinary
excretion of uric acid.(14) Looking more closely at 24
hour urine determinations, Pak in a series of 225
urolithiasis patients on random diets found by comparing
two 24-hour urines, a high degree of correlation from one
to the other.(15) Of these 225 patients, 27 were uric acid
stone formers. Uric acid excretion was 609+/- 214 in the
first sample and 597 +/- 203 in the second with a %
concordance of 84.2, an r of 0.68 (p< 0.0001).(15) They
Uric Acid Stone Disease
1342
did not break-out the 27 uric acid stone formers for separate
analysis, however daily variation was substantial with the
95% confidence intervals (2 standard deviations) ranging
from 101 to 1097 mg/day. Finally, other factors can affect
urinary uric acid levels. This includes the ingestion of
alcohol, long associated with gout and uric acid
urolithiasis.(16) Fructose ingestion is another potential
variable.(17) Obesity has long been linked to disorders of
purine metabolism, both gout and uric acid stone
formation.(18) A last consideration should be the ability
of the intestinal microenvironment to process and
catabolize purines. The gut microorganisms are capable of
metabolizing purines and possess the enzyme uricase.(19)
5. CLINICAL CHARACTERISTICS
5.1. Clinical Presentation
As pointed out earlier, uric acid stone disease has
been on the decline. Associated diseases of purine metabolism
have been on the rise and at least one contemporary article
suggests that uric acid stone disease may be back on the rise.
In a review of 5477 stone patients in Japan, the incidence of
uric acid stones was noted to rise to 7.2% between 1975 and
1993. This was an increase by 3.5 fold compared to the
number of uric acid stones in 1975. These authors further
noted that males were most commonly affected and
hypothesized that gout, hyperuricemia and alcohol ingestion
could account for these observations.(20) In another
investigation of 652 stone patients, 36 had predominately uric
acid stones (5.5%). The male to female ratio was 11:1 and the
average age of the male uric acid patient was 49 +/-11 years.
Serum uric acid levels were higher in males with pure uric acid
stones. Those with pure uric acid stones and mixed stones
were noted to have lower urinary calcium levels.(21) The
prevalence of uric acid stone disease varies by location from a
low of 2% in Texas to a high of 37.7% in Iran. It is well
known that this variability by region is probably multifactorial
with climatic, dietary, and ethnical influences all having some
degree of influence.(22) One study that firmly places
occupation and the hot environment as significant factors for
uric acid stone prevalence comes from Borghi and colleagues.
In a study of machinists at a glass plant, a high incidence of
uric acid stones were noted in workers exposed to heat stress
(38.8%). They next randomized 21 workers to heat exposure
and 21 controls and found that uric acid concentration (722 +/-
195 vs. 482 +/- 184 mg./L, p<0.001), specific gravity (1,026
+/- 4 vs. 1,021 +/- 6,p<0.005) and pH (5.31 +/- 0.28 vs. 5.64
+/- 0.54, p<0.02) respectively were all adversely affected.(23)
Another epidemiologic study looked at 264 patients with pure
uric acid stones and compared them to those patients
presenting with other types of calculi. The patients with the
uric acid stones were older men. They had comparatively
lower incomes and spent less money on food but consumed
more alcohol. The urinary pH was lower in this group but
serum and urinary uric acid levels were not significantly
different than the other stone formers. These authors
concluded that alcohol again plays a significant role in uric
acid stone disease and that these stones were more prevalent
than suspected.(24)
5.2. Laboratory
Patients with uric acid stone disease represent the
culmination of relatively intricate pathophysiology
involving purine metabolism. Radiolucent purine-derived
stones include uric acid, uric acid dihydrate, ammonium
acid urate, sodium urate monohydrate, xanthine, 2,8-
dihydroxyadenine and oxypurinol. Chemical analysis and
crystallographic evaluation of these stones is not adequate.
False positives for uric acid are possible for the rarer types,
particularly xanthine and 2,8-dihydroxyadenine stones.
Infrared spectroscopy and/or x-ray diffraction techniques
are far superior. Because of the clinical and genetic
ramifications of purine metabolism deficiencies, children
who present with a radiolucent stone should have
mandatory stone analysis.
Serum chemistries and complete blood counts
should be performed in all patients with a uric acid stone.
Sodium, potassium and chloride can be altered by
metabolic acidosis. Specifically, sodium and potassium
serum levels can be decreased in patients with laxative
abuse or chronic diarrheal syndromes. Serum CO
2
concentrations could be diminished in these patients with
chronic metabolic acidosis. Serum phosphorus levels have
had some utility in predicting tumor lysis syndrome and
subsequent acute uric acid nephropathy. Higher serum
phosphorus levels indicate a heightened risk of this
preventable complication. Serum creatinine is important to
estimate the baseline renal function and the BUN is helpful
assessing the patient’s fluid status. A complete blood count
may identify hematologic disorders unknown to the patient
presenting initially with a uric acid stone.
Serum uric acid levels should be quantified. It
has been widely reported that serum uric acid
concentrations are virtually nonexistent in patients with
xanthinuria (below 2 mg./dL or < 119 µmol). The most
common potential association is with hyperuricemia and
gout. Once these are excluded, idiopathic and inherited uric
acid stone formers are sought. In addition, if a particular
group of patients have gout, these patients will have higher
serum uric acid levels. It has been estimated that only 1/3
of patients with uric acid stones have hyperuricemia.(25)
Other series vary with ranges from 21 to 33%. One of the
problems with serum determinations is that typically diet is
not controlled nor is the 24-hour urine excretion known.
Typically patients with either idiopathic uric stone disease
or gout do tend to have higher serum uric acid levels. In
gout patients with and without uric acid stone formation
both tend to have higher serum levels than normals. Also,
it can be noted that maximal serum uric acid values for
gouty patients with stones are slightly higher than in those
without stones.
Urine determinations are an essential aspect in
the evaluation of gout and uric acid stone formation.
Urinary values such as pH, specific gravity, and a complete
urinalysis with appropriate cultures to identify urease-
producing infections are essential. Twenty-four hour urine
chemistry for uric acid levels is vital. Urine should not be
preserved refrigerated, but rather with added acids to
prevent bacterial overgrowth so as not to induce uric acid
crystallization and spuriously low urinary levels. The
ability of spot urine samples in predicting stone risk is
uncertain.(26) The need to evaluate more than a single 24
Uric Acid Stone Disease
1343
hour specimen is also controversial.(27) Over excretion is
regularly sought in the expectation of finding those patients
with hereditary underlying enzyme defects. The partial
defects such as hypoxanthine guanine phophoribosyl
transferase (HPRT) might be discovered. The absence of
HPRT leads to classic Lesch-Nyhan syndrome in children
and over excretion of uric acid is typically severe. The
partial impairments of this enzyme in Kelley-Seegmiller
syndromes can be encountered as well. Other levels of
purine metabolites such as xanthine, hypoxanthine, and 2,8-
dihydroxyadenine can be measured with high definition
liquid chromatography.
Low urine pH and a fixed acidification defect
have long been known to affect uric acid stone formers. A
very low 24-hour urine pH can be used to support the
diagnosis of uric acid stones or crystalluria even without
the actual stone analysis. Urine creatinine is required to
insure that an adequate urine collection has been obtained.
In patients with mixed stone disease a more extensive
urinary chemistry panel is warranted. Also in patients with
cystinuria, commonly uric acid levels will be significantly
higher than normals and should be sought.
Low urinary volume is a consistent finding in
some uric acid stone formers, especially patients with
laxative abuse, chronic diarrheal syndromes, small bowel
surgery, Crohn’s disease, and some drug-related disorders.
Low urine volumes can be secondary to poor oral intake,
excessive gastrointestinal losses or both. Insensible losses
also need to be considered for patients in a hot climate or
performing heavy manual labor.
Hyperuricosuria can occur as a consequence to
excess dietary ingestion, purine glutton. In gouty patients
there is almost a linear increase in stone formation based
upon the degree of hyperuricosuria. At levels above 1,000
mg/day about 50% of these patients will develop a uric acid
stone. It is also known that 75% to 90% of gout patients
have renal under excretion as a cause of their
hyperuricemia. These patients have a reduced renal
clearance of uric acid.(28) Stone disease activity thus
correlates between the degree of hyperuricosuria and the
degree of hyperuricemia (47% of gout patients with a
serum uric acid level above 11 mg/dL).(29)
The final measurable variable in purine-related
stone disease is those rare patients with enzyme
abnormalities resulting in either overactive or deficient key
enzyme activities. Both glucose-6-phosphate deficiency in
type I glycogen storage disease and a superactive variant of
glutathione reductase are rare conditions found in gouty
patients and associated with overproduction of uric
acid.(30,31) Phosphoribosylpyrophosphate synthetase
mutations can occur with subsequent gout and uric acid
stone production.(32) The enzyme amidotransferase exists
in two forms, a smaller active and a larger inactive form.
Mutations of this enzyme are known and the possibility of
uric acid hyperescretion is possible.(33) Deficiencies,
either complete or incomplete with the enzyme
hypoxanthine guanine phosphoribosyl transferase (HPRT)
lead to overproduction of uric acid by shutting down the
salvage pathways of purine metabolism. Likewise,
deficiencies in the adenine phosphoribosyl transferase
(APRT) enzyme can be complete or incomplete and leading
to 2,8-dihydroxyadenine stone formation. Xanthine
oxidase can be absent as in congenital xanthinuria or
iatrogenically from allopurinol administration. A final
method of increased renal urate clearance is a rare tubular
defect called the “Dalmatian Dog Mutation” by Seegmiller.
Stone formation is common.(34) These specific disorders
will be discussed later, however some caveats are relevant.
First, the pathophysiology of these disorders is still
incompletely understood and many enzyme abnormalities
have numerous genetic determinants. Second, red blood
cell assays of these enzymes do not appear to be as reliable
as fresh tissue assays using fibroblasts or small intestinal
mucosa.
5.2. Radiographic Appearance
All purine-derived metabolic calculi are
classically nonopaque, rendering them difficult to locate on
conventional kidney-ureter-bladder (KUB) films. In
perhaps the initial report on x-rays for the diagnosis of
stone disease, the authors suggest that some stones might
not be visible.(35) This feature, radio-lucency makes
follow-up and secondary interventions difficult to monitor
success or failure of therapy. Faintly opaque uric acid and
2-8 dihydroxyadenine calculi have been described, and the
astute practitioner should be aware of this. In fact, larger
uric acid stones have higher densities and are more likely to
be faintly opaque. Tomograms are typically performed in
following stone patients. These are of little practical aid in
the follow-up or management of these patients.
Intravenous urography (IVU) provides both functional
information regarding the urinary tract as well as
anatomical details regarding the stone and its effects within
the collecting system. These calculi will be radiolucent and
are not diagnostic for the stone type, but merely suggestive.
The IVU is widely available and does provide functional
information that aids in the management of these patients.
Ultrasonography can usually identify uric acid stones and
hydronephrosis when the stones are in the kidney. The
limitation of this modality is when multiple stones are
present and the presence or absence of ureteral stones.
Ultrasonography is much more subjective in the presence
of ureteral calculi. The computerized tomogram (CT Scan)
is the gold standard for both diagnosis and follow-up of
purine-derived metabolic calculi.
Dretler and Prien noted in 45 patients with 100%
uric acid stones that on retrospective review almost ½ were
apparent. They also appreciated that those larger than 2
cm. were more clearly identified.(36) Computerized
tomography scans have become the gold standard for
investigating radiolucent filling defects because it is non-
invasive nature.(37) Some investigators strenuously
support the ability of CT to provide density values
(Hounsfield units) to correctly predict a stones
composition, particularly uric acid. Mitcheson and
investigators evaluated 80 urinary calculi with 3 specific
parameters: absolute computerized tomography value, the
difference between CT values measured at 2 different x-ray
energies, and CT value-frequency histograms (pixel
Uric Acid Stone Disease
1344
patterns). Uric acid stones were differentiated from all
other stones at a significance level of p<0.001. They
established a minimal stone size for analysis of 5 mm.(38)
CT scans might distinguish a density difference as small as
0.5% while plain x-rays require approximately 5%
difference. The reported attenuation values for uric acid
stones are from 346 to 400 HUs.(39) Another study of 102
chemically pure stones was scanned on a General Electric
HiSpeed Advantage scanner (50 uric acid stones).
Absolute CT values for uric acid stones were 409+/- 118
and using dual kilovolt CT values were 0 +/- 41 HUs.(40)
In a study of stone size and scan collimation, Saw and
coworkers from Indianapolis noted that at 1-mm
collimation, stone groups could be differentiated by
attenuation. At wider collimation, attenuation became
lower and discrimination was lost. By 10-mm collimation
only some uric acid stones of about 6 mm could be
predicted.(41) The primary problem with these studies,
though well performed and comparative to other stones of
known composition is that they were all done in vitro and
any putative advantage to this technique would occur while
the stones are still in vivo.
Moving to in vivo studies of uric acid stones, the
CT method of identification is more tenuous. Motley and
colleagues from San Antonio evaluated 100 patients on a
GE High-Speed Advantage CT scanner prior to surgical
intervention. There were 4 uric acid stones in their group
and in vivo CT densities had a mean of 50 +/- 24 (far less
than previous studies reported in vitro). In addition,
comparing calcium (87), uric acid (7), struvite (4) and
cystine (2) the overlap of ranges precluded accurate
identification.(42)
In conclusion, all methods of imaging play a role
in the diagnosis and management of patients with uric acid
stones. A regular radiograph may reveal no calculus or a
faint trace of a stone. Ultrasound utilizes no ionizing
radiation and can be helpful, but it is not a physiologic
study and false negatives and positives are possible.
Intravenous urography is more time consuming than CT
scans but do provide function as well as anatomical details.
Retrograde pyelography is even more invasive, however
the urologist at times of intervention uses this routinely.
CT scanning, as pointed out early by Resnick and
colleagues clearly delineates radiolucent stones and is a
non-invasive method to identify purine-based stones.(43)
The primary problem with all imaging modalities is
monitoring the outcomes of uric acid stone patients once a
primary surgical intervention has been initiated. In this
scenario, the urologist has placed hardware into the urinary
collecting system and stone-free status cannot be readily
confirmed. Even CT scans become less reliable with
indwelling nephrostomy tubes or ureteral stints overlying
potentially significant residual stones.(44)
5.3. Stone Disease and Gout
Stone disease and its relationship to gout have a
long historical record as previously described. In the long-
term studies by Dr. Ts’ai- Fan Yu, she noted that 22% of
2118 gouty patients gave a history of renal stones. She also
observed that stone prevalence rose with the levels of
increasing uric acid excretion. The highest incidence was
in patients excreting greater than 1,000 mg of uric acid
daily on a purine restricted diet, 49%.(45) Most stone
forming gout patients are men and the age of onset is about
36 years. Stones tend to occur before any systemic
symptoms of gouty arthritis are evident (40%). In studies
by Asplin and coworkers, about 75% to 90% of gout
patients have renal under excretion as a cause of their
hyperuricemia.(46)
5.4. Gout and Stone Disease
While arthritis is the most significant problem in
patients with gout, renal disease remains the most frequent
extra articular complication of this disease process.
Significant impairment in renal function was historically
reported in 40% of gouty patients prior to the introduction
of allopurinol. Gouty nephropathy was seen clinically in
the setting of prolonged hyperuricemia and correlated with
the duration and magnitude of the disease. The kidneys in
patients with gouty nephropathy were literally crystallized.
Urate crystals were noted in the medulla or pyramids with
significant giant cell inflammatory response.
5.5. Bowel Disease and Uric Acid Stone Formation
The incidence of uric acid stones is significantly
higher than the normal population (5 to 10%), occurring in
20 to 30% of these patients. Surgery alters the relative
distribution; the presence of an ileostomy adversely affects
the stone prevalence as well as the number of patients that
form uric acid stones (as high as 50%). The urine of these
patients is low volume secondary to the gastrointestinal
loss. Add an ileostomy and volume loss is even more
pronounced. The average loss from pooled investigations
of patients with an ileostomy is between 500 to 700 cc per
day.(47,48) These same studies indicate that urine output
is typically below 1 liter per day. More than 90% of
ileostomy fluid loss is water. Compared to the normal
adult loss in feces of less than 150 cc per day, this loss is
significant.(48)
In more detailed investigations, Clarke and
colleagues noted total body water was depleted by 11% in
patients with an ileostomy.(48) Additionally, sodium is
lost accounting for a 7% decrease as well as significantly
lowered urinary sodium concentrations.(49) Despite
evidence for sodium conservation in these patients, plasma
aldosterone concentrations have been controversial in most
series.(50,51) Kennedy and coworkers in a group of 39
ileostomists with proctocolectomy and less than 10 cm of
terminal ileum resected plus an ileostomy showed a
significant raised mean plasma aldosterone. Also, the
plasma renin activity was increased, but not markedly so.
They speculated that ileum adaptation might explain
differences between studies.(47)
The second contributing factor increasing the risk
of uric acid stone formation in patients with IBD is acidic
urine. Since uric acid is a weak acid with it’s first
dissociable hydrogen ion with a pKa of 5.75, the urine’s pH
plays a significant role in stone risk. At a urine pH of 5,
only approximately 100 mg/L of uric acid can be held in
solution. Hydrogen ion excretion is known to be increased
Uric Acid Stone Disease
1345
in IBD patients and markedly so in those with an
ileostomy.(52) Unlike most uric acid stone formers
without IBD, these patients have increased ammonium
excretion in addition to titratable acid. This is thought to be
secondary to intestinal loss of bicarbonate. This is again
intensified in patients with active ileal disease and with
ileostomies because the pH of ileal fluid is 7.0.(47)
There has been extensive investigation indicating
that purine metabolism is not generally affected by IBD.
The net excretion of uric acid is therefore not markedly
higher than in normal patients. The water loss with
subsequent lower urinary volume in addition to the lower
pH drives the solubility product of uric acid into the high-
risk range. Ileostomy patients excrete significantly more
supersaturated urine for uric acid than controls and even
more that most patients with uric acid stone formation
without IBD.(52) A footnote at the conclusion of the
discussion of inflammatory bowel disease and purine
metabolism is necessary. A patient with ulcerative colitis
and gout taking allopurinol at 600 mg/day was noted to
have multiple recurrent radiolucent renal calculi. These
were found to be the oxypurine metabolite of allopurinol,
oxypurinol.
5.6. Catabolic States and Uric Acid Stone Disease
Hyperuricemic acute renal failure was first
described by Bedrna and Polcak in 1929.(53) Even prior
to this, Rudolph Virchow, in 1851 noted hyperuricemia and
uricosuria complicating the course of leukemia.(54)
Hyperuricemia can occur spontaneously secondarily to the
rapid turnover of nucleic acids in patients with lymphomas
and leukemias. It can also occur with the administration of
chemotherapy leading to rapid cell destruction. There are
two known mechanisms which increased urinary
concentrations of uric acid can induce renal impairment.
First is secondary to mechanical obstruction by large
volumes of crystals or actual stones and the second is by
the deposition of crystals in the intrarenal tubules. In the
scenario of acute hyperuricemic nephropathy, the tubules,
collecting ducts, pelvis and ureters can literally become
blocked from deposition of uric acid crystals. Dunn and
Polson in 1926 noted a severe selective damage to the
ascending limb of Henle of rabbits given massive doses of
lithium monourate.(55) In microdissections, it has been
observed that a critical factor is the sudden precipitation of
crystals in the collecting tubules.(56) The clinical
manifestation is initial oliguria, progressing to anuria and
rapidly rising serum creatinine. Although hyperuricemia is
seen most commonly in association with acute and chronic
leukemias, lymphomas, myeloma, and the
myeloproliferative syndromes, there has been an
association with nonhematologic malignancy such as
breast, sarcoma and testicular cancers.(57)
Stones are noted with increased frequency
inpatients with myeloproliferative disorders, up to 40%.
Other blood dyscrasias have been also noted to predispose
to uric acid stone formation includes plasma cell
dyscrasias, thalassemias, polycythemia, hemolytic anemia,
and sickle cell anemia. Hyperuricemia and hyperuricosuria
have been noted in patients with hyperthyroidism due to
Grave’s disease.(58) Treatment of the catabolic turnover
of purines in patients with these problems has been
hydration, alkalinization and allopurinol. Doses beginning
at 100 mg/day upwards to 1,000 mg/day have been reported
to obviate the tumor lysis syndrome and prevent acute uric
acid nephropathy. Uricosuric therapy using
benzbromarone has also been effective. In an open-
controlled, randomized trial over 24 weeks, serum uric acid
lowering effects of daily allopurinol 100 mg with 20 mg of
benzbromarone was compared to 300 mg of allopurinol.
Both preparations led to decreases in serum uric acid levels
to normal but the combination therapy was more
pronounced.(59) Another comparative investigation
confirms the efficacy of the uricosuric agent,
benzbromarone over allopurinol in a crossover trial. The
serum uric acid level was reduced from 9.89 +/- 1.43 mg/dl
to 5.52 +/- 0.83 mg/dl and from 9.53+/-1.48 to 4.05 +/- 0.87
mg/dl by allopurinol and benzbromarone respectively
(p<0.005).(60) In another long term investigation of
allopurinol used intravenously in 1,172 patients treated in the
United States as an adjunct to chemotherapy, 87% of adult
patients normalized or improved elevated serum uric acid
levels.(61) Another new uricosuric drug is CGS-12970, a
thromboxane synthase inhibitor. 1-methyl-2(3-pyridyl)-1-
indoleoctanoic acid is a reversible thromboxane synthase
inhibitor that was tried in 20 healthy males receiving two doses
12 hours apart. Serum uric acid levels declined between 34%
and 47% and urine uric acid levels fell between 28% and
134% within 12 hours of the first dose.(62) Finally, the ability
of urate oxidase to catalyze the conversion of uric acid to the
more soluble product allantoin has been therapeutically utilized
to prevent tumor lysis syndrome. Rasburicase is a new
recombinant form of urate oxidase available for clinical
evaluation. A multi-institutional trial of rasburicase has been
performed at 6 sites including 52 patients. The rasburicase
versus allopurinol group experienced a 2.6-fold (95% CI: 2.0 –
3.4) less exposure to uric acid. Four hours after the first dose,
patients randomized to rasburicase compared to allopurinol
achieved an 86% vs. a 12% reduction in serum uric acid levels
(p<0.0001).(63)
6. RARE DISORDERS OF PURINE METABOLISM
6.1. Xanthine Stone Disease (Xanthinuria)
Auscher and colleagues described a large kindred
family with urolithiasis and gout.(64) These patients were
noted to have an autosomal recessive pattern of xanthine
oxidase deficiency. Serum and urinary uric acid levels
were low and purine end- products, xanthine and
hypoxanthine were elevated. These patients had little
symptoms except for the formation of xanthine stones.
There exist two inherited forms of xanthinuria. One is a
deficiency in the enzyme xanthine dehydrogenase where
the less soluble end product of guanylic acid breakdown,
xanthine accumulates. Xanthine oxidase is a flavoprotein
containing molybdenum. The other form of heritable
xanthinuria is molybdenum cofactor deficiency presenting
in infancy with microcephaly and severe CNS
manifestations.(65)
The reported solubility of xanthine at pH of 5 is
known to be 50 mg/L (compared to 150 mg/L for uric
Uric Acid Stone Disease
1346
Table 1. Guidance for consumption of purine containing food
High levels of purines
Best To Avoid
Moderate levels of purines
Eat Occasionally
Low levels of purines
No Restriction
Liver Asparagus Carbonated drinks
Kidney Beef Coffee
Anchovies Bouillon Fruits
Sardines Chicken Breads
Herrings Crab Grains
Mussels Duck Macaroni
Bacon Ham Cheese
Scallops Kidney beans Eggs
Cod Lentils Milk products
Trout Lima beans Sugar
Haddock Mushrooms Tomatoes
Veal Lobster Green vegetables
Venison Oysters
Turkey Pork
Alcohol esp beer Shrimp
Spinach
acid).(66) In one study, only 30 to 40% of patients with
xanthinuria formed radiolucent stones.(67) Screening
laboratory studies indicate that the most common finding is
a serum uric acid below 2 mg/dL or < 119 µmol/L. In the
United States, the incidence of xanthinuria is not known but
from 1 in 6,000 to 1 in 69,000 has been suggested. Both
types have been reported with similar distribution.(68)
More common, but still rare is the iatrogenic
induction of xanthinuria by allopurinol administration. In
particular, patients with uric acid overproduction such as
those with Lesch-Nyhan syndrome or those with partial
HGPRT deficiency can lead to overproduction of the
oxypurines, xanthine and hypoxanthine.(69) Normally
during allopurinol administration, the plasma levels of
oxypurines remains between 0.5 and 2.0 mg/dL, well below
the solubility limits. Patients with overproduction as noted
earlier, and in some patients with myeloproliferative
disorders can result in levels of xanthine above this
limit.(70).
Since alkalinization has little affect upon the
solubility of xanthine it adds little to the therapeutic
regimen. High fluid intake is the key to therapy.
Dehydration is to be avoided whenever possible. Low
purine diet is effective (Table 1). There currently is no
drug available that will reduce the risk of xanthine stone
formation in these rare patients. In patients with iatrogenic
allopurinol-induced xanthinuria, withdrawal of allopurinol
is necessary.
6.2. 2-8 Dihydroxyadenine Stone Disease (APRT
Deficiency)
The deficiency of adenine phosphoribosyl
transferase (APRT) prevents the conversion of the adenine
nucleotide to adenylic acid via the scavenger pathway. The
result is increased production of the precursors 8-
hydroxyadenine and 2,8-dihyrdroxyadenine (8-DHA and
2,8-DHA). This is a genetic disorder of metabolism
localized to the long arm of chromosome 16. There
currently is no evidence to suggest that heterozygotes get
calculi or significantly excrete adenine, 8-DHA or 2,8-
DHA. There are reported patients with these calculi that
have only partial APRT deficiency.(71,72)
The disease has been described in virtually all
parts of the world now, but appears to be less frequent in
the United States currently.(73,74) The disease was first
described by Kelley and colleagues in 1968.(75) Stones
are seen in these patients only because of the poor
solubility of 2,8-DHA. Calculus formation and crystal
nephropathy are primarily seen in children with this disease
but adults can develop stones.(76-78) 2,8-
dihydroxyadenine stone give a false-positive reaction to the
colorimetric analysis for uric acid stones. Thus, infrared
spectroscopy or x-ray diffraction analysis of these stones is
mandatory. These stones are typically radiolucent making
the differential diagnosis any of the purine-containing
stones possible, but as with uric acid stones there are
exceptions.(79) These patients tend to be well clinically,
they do present with recurrent urolithiasis and occasionally
crystal-induced nephropathy with no systemic symptoms of
gout. This nephropathy can be very significant as
demonstrated by a case of recurrent stones following a
successful kidney transplant 23 years later.(80) Despite
the absent or decreased APRT activity adenine can be
catabolized to 8-DHA and 2,8-DHA making it a far
different clinical problem than its counterpart salvage
enzyme deficiency (HPRT) inducing the Lesch-Nyhan
syndrome.
The clinical diagnosis of this rare syndrome
includes a high degree of suspicion. Stone analysis with
the appropriate methods (IR or XRD) is crucial. These
stones tend to be grayish in color, not the golden-yellowish-
brown of uric acid stones. The stones themselves crush
easily and do not react with uricase. Once suspect, absence
of erythrocyte APRT activity is confirmatory. Reports on
the diagnosis by analysis of the urinary sediment, noting a
significance of 2,8-dihydroxyadenine crystals has appeared.
The crystals were brownish spheres noted in two family
members of a symptomatic subject.(81,82) Therapy
includes a high fluid intake. Diets low in purine are also
utilized. Alkalinization drug therapy has no therapeutic
Uric Acid Stone Disease
1347
benefit since 2,8-DHA solubility is not pH dependent in the
physiologic range. Allopurinol does reduce the production
of 2,8-DHA. At doses of 10 mg/kg/day, the elimination of
2,8-DHA has been noted.(83) Allopurinol dosing should
be reduced in patients with renal impairment. In patients
with high levels of excretion or with higher doses of
allopurinol, oxypurinol stones can be induced. Shock wave
lithotripsy has been used successfully in patients presenting
with these stones.(84,85)
6.3. Lesch Nehyan Syndrome (HPRT Deficiency)
In 1959 Catel and Schmidt first described an 18
month infant with hyperuricemia, hyperuricosuria and
enchephalopathy.(86) In 1964 Michael Lesch and William
Nyhan described two brothers with a clinical syndrome of
hyperuricemia, hyperuricaciduria, and severe neurologic
dysfunction including choreoathetosis, mental retardation,
and autodestructive behavior.(87) In 1966, the sex-linked
inheritance of the syndrome became widely recognized.
Seegmiller and colleagues demonstrated the following year
that complete deficiency of hypoxanthine guanine
phosphoribosyl transferase (HPRT) was the cause of the
syndrome described by Lesch and Nyhan.(88) The
prevalence of this disorder is from 1/100,000 to 1/380,000
live births. It affects all races. Much has been learned
about this rare disorder characterized initially by excess
uric acid in the urinary tract. Infants are often first noted to
have orange crystals in the diapers, with subsequent stone
formation and hematuria. The psychomotor elements of
the syndrome become manifest within the first 3 to 6
months of life. A high serum uric acid level is typically
what prompts more detailed testing, but some infants have
borderline levels secondary to high renal clearances. In
1969, Kelley and colleagues described a partial deficiency
of the HPRT enzyme in patients with gouty symptoms and
uric acid stone disease without the neurologic stigmata of
Lesch-Nyhan syndrome.(89)
A great deal of recent emphasis by researchers in
this field are focusing upon the primary genetic etiology of
this disorder.(90) The HPRT gene is located at the long
arm of chromosome Xq26-27 and consists of 57 base pairs.
Over 2,000 mutations are now known throughout this gene
coding region from exon 1-9.(91) In addition, unexpected
affected females have now been described.(92) There is
evidence that a specific set of Alu repetitive units in DNA
elements may the basis of Lesch-Nyhan syndrome that can
be traced phylogenetically through chimpanzee, gorillas
and to humans.(93) Detailed gene analysis of Lesch-
Nyhan variants have also been reported depending upon the
severity of the neurologic presentation in four groups:
group 1- normal development but HPRT deficiency,
group2- mild neurologic symptoms, group 3- severe
neurologic deficiencies, and group 4- full blown Lesch-
Nyhan syndrome.(94) In a review of genetic inherited
mutations correlating to the severity of the disease, Jinnah
and colleagues noted several points. The mutations are
throughout the long arm of the Xq26 region, but some sites
are “hot spots.” Next genotype-phenotype correlations
provide no indication of the specific mutation’s location.
Cases that are less severe (groups 1 and2 from Puig)
typically have mutations permitting some enzyme function.
Finally, knowledge of the mutations provides a rough guide
of the phenotype.(95) As genetic knowledge advances; the
hope for specific genetic interventions for this devastating
disease may be possible. Adenovirus vector expressing the
human HPRT cDNA has been used to transfect cells in
culture, restoring purine metabolism.(96) In another
attempt at somatic gene therapy, Palella and coworkers
used a recombinant herpes simplex virus type I vector to
transfect rat neuronal cells with human HPRT mRNA
transcripts.(97)
There currently exists no great therapy for the
neurologic manifestations of this disease; however,
allopurinol can prevent the formation of uric acid
crystalluria, nephrolithiasis and gouty arthritis associated
with this syndrome. Starting doses are 10 mg/kg/day and
adjusted to maintain high-normal serum uric acid levels.
There have been reports of allopurinol therapy inducing
xanthine and oxypurinol stones in these patients so
response to the dose and monitoring are necessary. A high
urinary output decreases both of these potential
consequences of allopurinol therapy in patients with Lesch-
Nyhan syndrome.
6.4. Oxypurinol Stone Disease
Allopurinol is an analog of hypoxanthine and it
and its primary metabolite, oxypurinol inhibit the enzyme
xanthine oxidase. Allopurinol blocks the conversion of
hypoxanthine and xanthine to uric acid.(98) Associated
with this blockage, the serum urate levels decline and
urinary uric acid levels fall. Allopurinol has a short half-
life of one to three hours but its active metabolite;
oxypurinol persists much longer, 15 to 20 hours. Utilizing
high-performance liquid chromatography, Safranow has
demonstrated that oxypurinol could be found in 9
predominant uric acid stones in patients taking
allopurinol.(99) Patients receiving allopurinol in higher
doses can form oxypurinol stones. One patient with
regional enteritis and recurrent uric acid stone disease
treated with 600 mg of allopurinol daily began to develop
small, soft, yellow stones shown to be oxypurinol.(100)
Oxypurinol is not so soluble and it may precipitate in larger
allopurinol dosages and if used over a long period of
time.(101)
6.5. Ammonium Urate Stones
Four stone types of uric acid and urate are
known: anhydrous uric acid (most common form), uric acid
dihydrate (very unstable), ammonium acid urate, and
sodium acid urate monohydrate. These latter two stone
types are most commonly found in bladder calculi. The
necessary condition to form ammonium acid urate calculi is
a high concentration of ammonium. This can occur due to
an intriguing number of mechanisms such as urinary
infections, secondary to dehydration, starvation, acidosis,
and excess of acid-forming foods.
6.6. Endemic Ammonium Urate Stones
Endemic bladder stone disease is reported
primarily in children and has steadily declined in most
Western countries. Its decline has been associated with a
rise in living standards, particularly in urban centers. This
Uric Acid Stone Disease
1348
is paralleled by a rise in general nutrition. He types of
endemic bladder stones depend upon the composition of the
urine, which in turn, reflects the dietary consumption.
Diets that are low in animal protein, calcium, phosphate,
but high in cereal are acidogenic. This subsequently leads
to urine with relatively high concentrations of ammonium
and urate ions. This is the scenario where ammonium acid
urate precipitation occurs.(102) In one recent
investigation of children from Pakistan, peak age of stone
formation in 1,440 children was 6 to 10 years for renal
calculi and 1 to 5 years for bladder calculi (43% of renal
and 38% of bladder stones). Bladder stones were more
common prior to the mid 1980s in 60% of these children.
The number of endemic bladder stones declined to 15% by
the mid 1990s. Ammonium acid urate occurred in 210
children (27%). Diet, dehydration and poor nutrition were
the main identified risk factors in these children.(103) In
studies from Niger, India, South Africa, Australia’s
aboriginal children and Navajo Indian children reveal that
40% of endemic stones are nearly pure and almost 50% of
the remaining had ammonium urate constituents.(104-108)
6.7. Other causes of ammonium urate calculi
Herring reported the incidence of these stones in
the United States at 0.2%.(109) In a contemporary series
from North America similar rates were reported from
Canada and Cleveland, Ohio. 3.1% of stones contained
some and 0.2% were predominantly ammonium acid
urate.(110,111) The primary conditions associated with
nonendemic ammonium acid urate stone are inflammatory
bowel disease, laxative abuse, obesity and urease-
producing urinary tract infections.(111) In a review of
patients with AAU calculi, obesity and/or urinary tract
infections accounted for the etiology of most of these
stones. Patients with inflammatory bowel disease and
laxative abuse had stones with the greatest proportion of
ammonium urate.
Urease-producing urinary tract infections are a
prime importance in ammonium urate stone disease. These
infections commonly result in stones of mixed composition
with ammonium urate and magnesium ammonium
phosphate hexahydrate (struvite).(112) The ureolytic
infections can produce large amounts of ammonium
resulting in alkaline urine. Of the 16 patients (36.4%) with
documented urease-producing infections, Soble noted that
only 19.9% of the stones volume was ammonium urate
with the majority being struvite.(111)
Laxative abuse is another known risk factor
producing AAU stones and it has been reported in patients
with anorexia nervosa.(113) In a multi-institutional review
of patients with laxative abuse and ammonium urate
calculi, Dick and associates hypothesized that
gastrointestinal loss of water and electrolytes causes
volume depletion. Intracellular acidosis occurs with serum
potassium and bicarbonate levels becoming slightly
decreased.(114) Also noted was low serum magnesium
levels secondary to gastrointestinal losses. The urine
chemistries of this unique group of stone formers were
obtained on laxatives. Urinary values for volume, citrate,
sodium, potassium, magnesium, phosphorus and uric acid
were all reduced. Supersaturation for major crystal systems
was calculated using EQUIL 2. It was noted that the
negative affects of laxatives persisted for a few weeks after
discontinuing these drugs. Studies by Teotia found that
ammonium urate formed over a pH range from 6.0 to 7.5.
Ammonium urate solubilizes nearly completely from the
urine at a pH of less than 5.7.(115)
Clinically, most patients with laxative abuse are
women although occasional males have been noted.(116)
Sodium loss is the hallmark feature in these patients with
urinary sodium typically below 10 to 15 mEq. per day.
Phenolphthalein screens upon the urine of patients suspected
with this syndrome can be performed. Other agents can cause
this syndrome including bisacodyl, bisoxatin, danthron,
oxyphenisatin and senna all capable of being identified in the
urine of these patients.(117) These calculi are generally
radiolucent. Rapid stone formation and encrustation of urinary
stints has been reported.(118) Stones have been documented
to regress if the offending laxative is removed and urinary
chemistry returns to normal.(111,119) One final comment is
necessary on ammonium urate stones in human deficiency
virus infected individuals. In a review from a single center, 24
patients with acquired immunodeficiency disease (AIDS), all
receiving protease inhibitors were noted to have urolithiasis.
There were 2 ammonium acid urate stones in this group (8.3%)
and these two unusual stones were 50% of those with indinavir
calculi making these stones always a consideration in a patient
presenting with HIV and a radiolucent stone.(120).
7. Therapy
The therapy of purine metabolic stone disease
essentially mirrors that of uric acid, but some vital
exceptions will be noted. The rare stone types xanthine and
2,8-dihydroxyadenine should both be considered if the right
clinical circumstances are present. Stone analysis is the
key to successful identification and knowledge of the serum
uric acid level is crucial. Two methods of chemical analysis
for purine-derived metabolic stones, the phosphomolybate
colorimetric test and the muroxide test cannot discriminate
uric acid from its precursors 2,8-dihydroxyadenine.
Infrared spectroscopy and X-ray diffraction analysis are far
more reliable methods of stone identification. With all
purine-derived calculous patients some overall parameters
should be utilized therapeutically. Hydration is the
cornerstone of therapy. As the urinary volume increases,
the supersaturation decreases. It is inexpensive and usually
well tolerated. Dietary purine restriction is essential. The
table lists foods high in purines, which should be avoided.
Alcohol has usually been listed as a risk factor and should
be avoided. All of the urologic methods that will be
discussed are equally applicable to the rare purine stones:
xanthine, 2,8-dihroxyadenine, monosodium urate, and
ammonium urate calculi. Shock wave lithotripsy can
fragment these stones if they can be targeted at the F2 of
the lithotriptors. All can be destroyed with ultrasonotrodes
or the holmium:YAG laser.
7.1. Chemodissolution
There is little doubt that the primary
method for treating patients with known uric acid stones is
medical dissolution. The first pKa of this purine metabolite
Uric Acid Stone Disease
1349
is 5.75 making manipulation of the urinary pH an easily
accomplished therapeutic maneuver.(8) Increasing the
urinary volume further enhances the therapeutic efficacy of
alkaline medications. In addition, decreasing the oral
purine load from dietary sources can effectively help
manage patients, since 40-60% of excretable uric acid is
derived from exogenous sources.(116) Sodium should be
restricted as well during active therapy because the sodium
salts of uric acid are less soluble than uric acid itself.(121)
The modern foundations for oral alkalinization
therapy follow the principles outlined by Pak and
colleagues for metaphyllaxis of calcium stones.(122) Oral
potassium citrate is the logical oral drug of choice since it
does not involve the addition of sodium in the presence of a
patient obviously supersaturating with uric acid.(123)
Potassium citrate at doses from 30 to 80 mEq per 24 hours
increased the urine pH from 5.3 to 6.19 and reduced new
stone formation rate from 1.2 to 0.01 stones per year in
patients with known uric acid lithiasis.(123) Unfortunately,
potassium citrate is associated with a large number of side
effects, predominately gastrointestinal upset.(124) To
maintain the urine’s pH from 6.0 to 6.5 often requires daily
consumption of 30 to 60 mEq three to four times a
day.(125) Preparations of potassium citrate very from
slow release wax matrix tablets (UroCit K
TM
, Mission
Pharmaceuticals), to crystalline powder (Polycitra K
Crystals
TM
, Baker Norton Pharmaceuticals), to liquid
(Polycitra K
TM
, Baker Norton Pharmaceuticals), to a simple
pill (SlowK). If one variety fails another may be more
tolerable to a given patient. In addition, the sodium or
mixed sodium/potassium preparations may be a fall back
alternative as is sodium bicarbonate.(126) Truly
recalcitrant patients who cannot tolerate any of the
aforementioned urinary alkalinizing medications can be
placed on acetazolamide (Diamox
TM
, 250 mg. at
bedtime).(127) The role of the citrus fruit juices, orange
and lemon, have been definitively documented enough to
warrant their routine utilization. 1.2 liters of reconstituted
orange juice increases urine pH from 5.7 to 6.5, and
increases urinary citrate from 571 to 952 mg/d (equivalent
to ingesting 60 mEq of potassium citrate).(128) Orange
juice has no hypocalciuric effect and increases urinary
oxalate excretion. Lemon juice on the other hand does not
have these drawbacks but maintains the increased citrate
load noted by Pak and collegues.(129) The xanthine
oxidase inhibiting drug, allopurinol, has no role in the acute
management for dissolution.(123) It’s use for decreasing
supersaturation is widely recognized but it will not help
dissolve a concretion that is already formed.
7.2. Prevention
Since most of the risk factors for uric acid
precipitation are known, it would be prudent to devise
methods that could be used to prevent these stones from
recurring. This is particularly important because the
natural history of uric acid stone formation generally is a
more aggressive course than for idiopathic calcium stone
formers. (Coe).
Potassium-containing oral alkalizing agents have
therefore assumed a greater role in the armamentarium for
prophylaxis. Compliance in the general stone population
is known to be poor in long-term follow-up investigations.
In one such study, Tiselius from Sweden noted that 62% of
patients responding to a questionnaire reported compliance
with citrate therapy.(130) In an intermediate follow-up
study, Lee reviewed 493 patients with a 34.2% stone
recurrence rate and only 49.3% remained on medical
prophylaxis longer than 12 months.(131) An additional
study on patients with surgically-active uric acid stones, all
patients were either partially or totally non-compliant with
oral alkaline therapy for a variety of reasons including lack
physician-related information, concerns regarding possible
side effects and medical neglect.(44) Drop out rates might
also be contributed by the inconvenience of multiple,
timed, daily dosings necessary with potassium citrate.(132)
For all of these reasons, it has become desirable to
develop methods of decreasing the risk of new stone
formation and minimizing the inconvenience to the patient.
Therefore alkaline therapy strategies have evolved into
dosing patients who are presently stone free with low doses
of potassium citrate at bedtime. The rationale has been that
the urine will become the most supersaturated with the
decreased urinary volumes of the evening. In addition,
acidity probably reaches its lowest point during sleep. The
alkaline dose would therefore provide risk reduction at
these key times. Some investigators have sought even
lowering this dose to every other night suppression.
7.3. Surgical Therapy
Uric acid stone disease is predominately a
medical condition, capable of being managed by
chemodissolution and prevention. There are patients
however that do present for surgical intervention. Classic
indications for open stone surgery are evolving steadily
with minimally invasive surgical procedures making these
operations a thing of the past. In fact, every open operation
now has its minimally invasive counterpart that can be
done by those skilled in these techniques. The history of
stone surgery is linked closely with the specialty of
urology. Desnos describes in detail how itinerant
lithotomists of centuries ago would treat predominately uric
acid bladder stones.(133) In the past 20 years, the field of
subspecialization, endourology might well relegate open
stone surgery to the same historical status practiced by
those vagabond surgeons.(134) Hippocrates’ axiom for
physicians to …”not cut on patients laboring from the
stone…” might finally be achieved.
Looking closely at the indications for open stone
surgery articles published just 2 years ago have to be
seriously reconsidered. As new, less invasive techniques
come to the forefront of therapy the old standards are
always questioned. Paik and Resnick assess the trend to
less aggressive surgical interventions in 2000. They
suggest that there are diminishing indications for open
stone surgery and list these as follows: complex stone
burden, minimally invasive treatment failures, associated
anatomic abnormalities, morbid obesity, comorbid medical
diseases, concomitant open surgery and non-functioning
lower poles.(135) The rate of open stone surgery at this
tertiary care facility is quoted at 5.4%, quite high by most
Uric Acid Stone Disease
1350
standards of other similar facilities both in the United
States and abroad (0.7 to 2.4%).(136-138) In a
retrospective review of stone surgery in Singapore, Sy and
colleagues noted in 2,651 operations for patients presenting
with urinary calculi, only 2% required open operations.
They again noted indications for open operations as
follows: complex stone burden requiring an anatrophic
nephrolithotomy and calicoplasty (15), 5 requiring
pyeloplasty with pyelolithotomy, 18 ureterolithotomies and
11 nephrectomies for non-functioning kidneys with
stones.(139)
Minimally invasive urologic surgery has seen
three eras currently in modern urologic practice. In this,
the third era of rapid procedural expansion almost every
type of open urologic operation is being reproduced by its
laparoscopic counterpart by pioneers in this field.(140)
Currently, every indication discussed in the transitional
papers on the role of open stone surgery are methodically
being removed by laparoscopic centers.(141)
Ureterolithotomy can be done laparoscopically with less
post-operative discomfort to the patient.(142) Obesity has
long been associated with an increased risk of both uric
acid stone formation and failure of shock wave lithotripsy.
Percutaneous ultrasonic nephrostolithotripsy can be very
difficult in these patients as well. Endourologic
innovations can successfully manage even massively obese
patients.(143) Laparoscopic pyelolithotomy and
concurrent pyeloplasty has been used successfully at the
Johns Hopkins University in 19 patients with 20 involved
kidneys. Immediate stone free status was achieved in 90%
of these patients and 80% remain stone free at a mean
follow-up of 12 months.(144) Of all the aforementioned
indications noted for open stone surgery, only complex
stone disease remains, but as with all things in medicine,
just wait. Kaouk and colleagues at the Urologic Institute of
the Cleveland Clinic Foundation have reported upon a
porcine model of cooled, ischemic anatrophic
nephrolithotomy with synchronous repair of the calyces.
Mean operative times were 125 minutes and the mean
blood loss was 68 cc. in 8 animals.(145) Buoyed by their
pre-clinical experiences, this same group has performed
this rather remarkable procedure on 2 patients.(146)
Despite all of the wondrous advances, the role of
laparoscopic stone surgery will probably continue to
decline to some small steady state because the urologic
armamentarium has even less invasive alternatives.(147)
For large, symptomatic upper tract uric acid
stones, percutaneous ultrasonic nephrostolithotripsy should
be considered. Indications for intervention are large stone
burdens and obstruction resulting in compromised renal
function or symptoms (pain, bleeding or infection). There
exist little or no data per se on the exact outcomes for
patients with uric acid stones, but this type of concretion is
easily fragmented with ultrasonic lithotrites.(148) Even in
patients with staghorn uric acid stones filling all areas
within the upper collecting system, successful debulking
can be done with stone free rates from 42 to 96%.
Combined “sandwich” strategies consisting of shock wave
lithotripsy following percutaneous debulking and second
look endoscopy further reduce the number and incidence of
residual fragments in active stone formers.(149) In
addition, once nephrostomy tubes have been placed and the
bulk of uric acid stone material has been removed,
secondary direct chemodissolution can be performed.
Almost any parentally available alkaline solutions can be
used to successfully dissolve remaining uric acid debris. 2
ampules of sodium bicarbonate added to a liter of half-
normal saline, the cardioplegic agents tromethamine and
tromethamine-E (organic buffer with pH of 10.6) are
usually available.(150)
Ureteroscopy is even less invasive than
percutaneous endorenal surgery, since small endoscopes
can be passed retrograde via the body’s naturally occurring
openings. Ureteroscope manufacturing has improved to the
point that diminutive instruments less than 3 mm. in
diameter and excellent optics are available. Virtually every
area within the kidney and ureter is thus amendable to this
type of therapy. In addition, reports of urologic
intervention with sub 8 Fr. (smaller than 3 mm. in
diameter) flexible ureteroscopic laser lithotripsy being
performed with the patients awake with intravenous
sedation alone are beginning to be reported.(151) A whole
host of energy-ablative technologies exist for ureteroscopic,
intracorporeal lithotripsy.(152) The gold standard has
become the holmium:YAG laser. The diminutive size,
wide range of power and clinical effectiveness have made
this modality the treatment of choice for urologist treating
stones.(153) One harbinger of risk has been raised by
Teichman regarding the laser light interaction with uric
acid. Since the mechanism of action of holmium:YAG
laser lithotripsy is a photothermal effect, breakdown
products of uric acid include cyanide. Despite this
potential, there have been no reported cases of cyanide
toxicity to date using the holmium:YAG laser.(154)
Shock wave lithotripsy has been a well-
established treatment for radiolucent or faintly opaque renal
and ureteral calculi. Some uric acid stones appear to break
up poorly but most series report significant fragmentation
with this least invasive modality. Some interesting
observations are apparent. First, it appears from studies in
vitro that pretreating patients with uric acid stones increases
the fragility of these stones and perhaps improves stone
free status.(155) Detailed evaluations stone fragmentation
in the past utilizing the Dornier HM-3 device shows fairly
uniform fragmentation of uric acid stones suggesting
disruption along concentric laminations within these
stones.(156) Shock wave lithotriptors can focus
radiolucent calculi at their F2 using either x-rays,
fluoroscopy and/or ultrasound. Ultrasound focusing
devices have an advantage since these stones are most
commonly radiolucent. Intravenous contrast administration
and retrograde contrast infusion have all been utilized to
aid in targeting these stones for shock wave
lithotripsy.(157-160) Treatment success has ranged from
76% to 82% stone free following these procedures.
Retreatments are noted to be common in about 15% to 20%
of patients possibly depending on the type of lithotriptor
utilized (more retreatments in the piezoelectric machines).
Finally, the rarer xanthine and 2,8-dihroxyadenine calculi
can be treated effectively with shock wave lithotripsy.
Uric Acid Stone Disease
1351
8. CONCLUSIONS
Uric acid stone disease is an ancient medical
condition. A lot has changed since Scheele and Pearson
recognized it chemically. Currently there is much interest
in the idiopathic uric acid stone formers and the possibility
that this may represent more subtle presentations for inborn
errors of metabolism. Since the purine metabolic pathways
are so complex, involving regulatory and feedback
mechanisms from both the salvage side and the de novo
synthesis pathways this should be no great surprise.
Genetic engineering may hold the future for the control of
this disease. It is now known that the administration of
recombinant urate oxidase to catalyze the conversion of
uric acid to the more soluble product allantoin has been
therapeutically utilized to prevent tumor lysis
syndrome.(63) For the rarer types of purine-derived stones
genetic alteration of the mutations causing these diseases might
be possible. Medical therapy, both chemolysis and
preventative are the hallmarks of therapy for this disease. For
those patients failing this the endourologic armamentarium is
rapidly expanding to the point that an open operation for uric
acid stone disease should be almost anecdotal.
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Key Words: Uric Acid, Calculi, Xanthine, 2-8
Dihydroxyadenine, Allopurinol, Purine, Metabolism,
Review
Send Correspondence to: Michael E. Moran, M.D.,
Capital District Urologic Surgeons, LLP, 319 So. Manning
Blvd., Suite 106, Albany, NY USA 12208, Tel: 518-438-
1019, Fax: 518-438-0981, E-mail: memoran2@juno.com