Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

Подождите немного. Документ загружается.

348 Lowry and Nakada

stone management and initiation of allopurinol, the renal failure resolved (11). In the

other report, the patient was undiagnosed until after transplanted organ was rejected and

removed; the failure may have been prevented on appropriate therapy (10). In fact, both

patients had multiple previous surgeries for stone recurrence before renal failure and

transplantation. If 2,8-DHA had been properly diagnosed to begin with, these patients

may not have progressed to renal failure. When managed with proper medication, trans-

plantation of these patients is successful (4).

Additionally, the formation of 2,8-DHA stones may be exacerbated during preg-

nancy. A pregnant patient with APRT deficiency, who had stopped allopurinol therapy

on the advice of her obstetrician, presented with a 2,8-DHA steinstrasse. She was man-

aged conservatively with chronic ureteral stent changes until delivery, after which the

stones were removed. She experienced renal insufficiency, and her creatinine never

returned to normal (12). Females with APRT should be adequately counseled about the

potential fetal effects of allopurinol, as well as the possible risks to the mother associated

with discontinuation of allopurinol. Should patients continue through pregnancy, fluid

intake and urine output should be carefully monitored, especially at night when circadian

patterns increase risk of 2,8-DHA crystals in the urine.

Diagnosis may be accomplished with infrared spectroscopy. Quantitative 2,8-DHA

measurement of urine and determination of APRT activity in erythrocytes confirm exist-

ence of APRT deficiency. Quantitative 24 h 2,8-DHA measurements may also be used to

monitor treatment.

Treatment of 2,8-DHA calculi may be accomplished via any surgical modality, including

shock-wave lithotripsy (1). Prevention is accomplished with allopurinol therapy (300 mg/d)

and maintenance of urine output of at least 2.5 L/d (6). Dietary control has shown little

potential benefit (1,6), likely because the majority of adenine does not come from the

diet. However, a reported case described a child presenting in renal failure who was from

a commune where the primary diet was adenine rich lentils, grains, and vegetables. This

report could implicate high adenine intake as detrimental. Consequently, mild purine

restriction may be beneficial (4). Urinary alkalinization has no role; it has been described

as decreasing solubility of 2,8-DHA (11,13), although at physiologic urinary pH ranges,

is probably not detrimental, only ineffective at changing 2,8-DHA solubility (4).

2,8-DHA calculi should be suspected in all children with radiolucent stones, espe-

cially if presumed uric acid stones do not respond appropriately to treatment, or if

coexisting renal insufficiency develops. Brown smudges in diapers and small, yellow-

ish-brown, round urinary crystals suggest APRT deficiency. Suspicion, however, cannot

be limited to the pediatric population, as age presentation ranges from several months

old to the seventh decade (1).

Ammonium Acid Urate Stones (Fig. 2)

Stones composed primarily of ammonium acid urate (AAU) are rarely seen in North

American patients, and account for less than 1% of urinary stones (14). In multiple

studies, the prevalence of predominantly AAU stones has been shown to be in the range

of 0.3 % (14–16). In third world countries, endemic AAU lithiasis, predominantly in the

form of pediatric bladder calculi, is more common. Navajo Indians in the United States

and aboriginal children in Australia have also been identified with AAU calculi (17–19).

Pure AAU stones are radiolucent, but usually these stone types have a secondary com-

ponent which may make them faintly radiopaque.

Chapter 19 / Urinary Stones of Unusual Etiology 349

Risk factors for the formation of AAU stones include decreased urine volume,

hyperuricosuria, stasis (for bladder stones), and the moderate elevation in ammonium

excretion associated with low phosphorus intake or phosphorus malabsorption. Other

risk factors include high urinary ammonium levels (a result of the alkaline urine of

existing infection, or acidic urine owing to diet), hypokalemia, dehydration, or starva-

tion states (14). Commonly, more than one of these risk factors coexist. Dehydration

decreases urine output and can result in acid urine, and a diet with excessive meat causes

hyperuricosuria and acidic urine. Conditions that predispose to uric acid stones and

struvite stones also lead to AAU precipitation.

AAU stones seen in third world countries are postulated to be multifactoral. The

combination of an acidic diet high in purines but low in phosphorus (perhaps owing to

dependence on breast milk), low fluid intake, and frequent diarrhea predisposes to a

urine with elevated concentrations of uric acid and ammonium, leading to AAU precipi-

tation (20,21). The secondary components in AAU calculi are generally uric acid or

calcium oxalate, but in the face of urinary infection with urea splitting organisms, the

urine alkalinization will support struvite formation as the secondary component (see

section on pediatric stones).

Pichette et al. analyzed 1346 stones and found 43 with some percentage of AAU, but

in only 3 of the 43 was AAU the dominant component (>50%) (14). They also observed

that the most common associated components were struvite (41%) and uric acid (35%).

Additionally, it was noted that in 75% of stones, the AAU was found as discrete deposits,

either intercrystalline or peripheral, mixed in with other stone constituents. The remain-

ing 25% of AAU was diffusely mixed with other stone components. Comparatively,

Soble et al. found that in 3400 stones, AAU was present in 44. In 11 of the 44, AAU was

the main component (mean of 44%). The most common secondary components were

uric acid (91%), calcium oxalate (63%), calcium phosphate (50%), and struvite (31%).

Fig. 2. Ammonium acid urate calculus (Courtesy of Mission Pharmacal, San Antonio, Texas).

350 Lowry and Nakada

The cohort was examined for risk factors: 41% were obese (BMI >30), 36% had recur-

rent urinary tract infections, 25% had inflammatory bowel disease, 13% were laxative

abusers, and 9% had a history of recurrent uric acid stones. These population groups of

AAU stone formers are consistent with the risk factors for AAU stone formation.

AAU formation in patients with laxative abuse has been well characterized by Dick

et al. (21). Eleven patients with documented laxative abuse were identified at two insti-

tutions. They were metabolically tested with serum studies and 24-h urine analysis.

Three of the patients had 24-h urine studies while taking laxatives and after a 1-mo hiatus

from laxatives. Serum electrolytes revealed normal parameters, except magnesium and

potassium, which were at the lower limit of normal, and bicarbonate, which was low in

five patients. Twenty-four-hour urine studies showed decrease in volume, sodium, potas-

sium, magnesium, phosphorus, uric acid, and citrate. In the three patients who submitted

a repeat study while not taking laxatives for a month, all values normalized. Laxative

abuse may cause metabolic acidosis, or alkalosis, depending on how long term and

regular the usage occurs and the amount of subsequent bicarbonate loss. Laxative abuse

produces a state similar to that of the endemic stone formation; low urine output, diarrhea

and resulting gastrointestinal (GI) electrolyte losses, sterile urine, and decreased phos-

phorus in the urine. The GI water and electrolyte loss produces a volume-contracted state

with potassium depletion and an intracellular acidosis, leading to low urine volume,

sodium, potassium, and citrate. Increased ammonia in the urine interacts with the urate,

which, because of the low urine sodium, becomes ammonium acid urate instead of the

usual soluble sodium urate (22).

HIV infected patients represent an additional group that is more predisposed to AAU

stone formation (23). In a small series of 11 stones formed by patients taking indinavir,

2 (18%) were composed of AAU. In a manner similar to that of laxative abusers, the

mechanism of AAU formation is thought to be related to the chronic diarrhea and mal-

nutrition.

Although the exact mechanisms for formation of AAU stones are not known, the renal

physiology surrounding AAU stone formation is well characterized. The pH at which a

minimum concentration of AAU will crystallize occurs at 6.2–6.3 (24). As the pH

increases, a higher concentration of AAU is required for stone crystals to form. At the

level of the nephron, ammonia is produced in the proximal convoluted tubule (PCT).

Ammonia is used by the kidney as an acid buffer. Increased amounts of ammonium are

excreted in states of metabolic acidosis, as well as potassium depletion, which is a form

of intracellular acidosis (25). Uric acid, which comes from urate in the serum, is freely

filtered at the glomerulus, and 99% reabsorbed in the PCT. Fifty percent of the original

filtered load is then secreted by the PCT, and all but 10% gets reabsorbed. After leaving

the nephron, the form of urate is pH dependent. At its dissociation constant, a pKa of 5.7,

uric acid and urate exist in a 50:50 ratio. As the pH increases, the urate predominates,

usually in the form of sodium urate.

Uric acid stone formers with urinary tract infections from urea splitting organisms are

at risk for AAU formation. When these patients have sterile urine, normal ammonium,

hyperuricosuria, and any pH, AAU will not form. However, in the face of urinary infec-

tion with urea splitting organisms, the increased pH and elevated ammonium make AAU

formation (with struvite) likely if enough urate is present (14,21). This situation must be

considered in patients with urinary tract infections who are afflicted with the Lesch–

Nyhan syndrome, as these patients are uric acid stone formers. Some may treat Lesch–

Chapter 19 / Urinary Stones of Unusual Etiology 351

Nyhan patients with urinary tract infections with temporary allopurinol to decrease the

amount of urate, lowering the chance of AAU stone formation (26).

Treatment of these stones, after elimination of existing stones, is aimed at prevention.

Acute stones may be successfully treated with SWL, although slow dissolution with

cessation of laxatives and proper fluid intake has been described (21). After initial

treatment, risk factors must be identified for preventive counseling and treatment. Patients

should have follow-up with multiple twenty-four urine studies to ensure adequate treat-

ment and compliance. Patients with diarrhea from ileostomies must maintain proper

urine volume and electrolyte replacement, and must be followed with 24-h urine studies.

Recurrent urinary infections must be eliminated, especially in patients who form uric

acid stones. Uric acid stone patients need treatment with alkalinization, volume and if

hyperuricosuric, dietary restriction and allopurinol. Ammonium acid urate stones are

rare, and occur in discrete situations. Stone analysis provides definitive diagnosis.

Awareness of the conditions that predispose their formation will prevent confusion with

other radiolucent stone types.

Xanthine Stones

Primary xanthine stones are found only in patients with hereditary xanthinuria.

Xanthinuria is a metabolic disorder of purine metabolism, which is passed on in an

autosomal recessive pattern. This disorder is characterized by a deficiency of xanthine

oxidase, which prevents the conversion of hypoxanthine to xanthine, and further pre-

vents xanthine from being converted into uric acid (Fig. 3). Serum and urine uric acid

levels are extremely low (serum 0.8–1.0) (27,28), and the uric acid precursors, xanthine

Fig. 3. Uric acid metabolism.

352 Lowry and Nakada

and hypoxanthine, are elevated. After being excreted, xanthine precipitates in the urine

to form stones. Hypoxanthine, being more soluble, does not form stones. Stone forma-

tion is the primary manifestation of this disease, and occurs in approximately one-third

of affected patients (27).

Xanthine stones are radiolucent, but can be detected by using computed tomography

(CT) (29). Usual excretion of xanthine and hypoxanthine is between 10 and 20 mg/24 h,

but during allopurinol therapy, these amounts may exceed 150 mg. However, in patients

with excess production of urate, the values can be as high as 700 mg/24 h (30). The

solubility of xanthine increases from a concentration of 5 mg/100 mL at a pH of 5 to

13 mg/100 mL at a pH of 7 (31). This relatively moderate increase in solubility places

more importance on increased urinary output and dietary purine restriction, rather than

on pH modulation as the primary therapy for prevention of xanthine stones. Analysis of

xanthine stones have revealed stones of xanthine mixed with oxypurinol in patients

treated with xanthine oxidase inhibitors (32) and stones made of almost pure xanthine

(27). They are described as faintly radiopaque (27,32).

Secondary xanthine stones are also formed under several specific circumstances. Patients

with Lesch–Nyhan syndrome have a deficiency of the enzyme hypoxanthine guanine

phosphoribosyl transferase (HGPRT), which is important in the purine salvage pathway

(Fig. 1). Without HGPRT, hypoxanthine cannot be taken back into the salvage pathway,

and is consequently metabolized by xanthine oxidase (XO) to uric acid, the end product

of the pathway. As a result, Lesch-Nyhan patients are hyperuricemic and hyperuricosuric.

These metabolic abnormalities are treated with urinary alkalinization and allopurinol,

which inhibits xanthine oxidase, lowering the uric acid production and decreasing the

incidence of uric acid stone formation. However, in rare cases, the inactivation of xan-

thine oxidase by allopurinol may lead to the formation of stones by an excess of xanthine,

the precursor to uric acid (30,32). Attempts at dissolution of allopurinol induced xan-

thine stones with alternating acidic and basic solutions has been described in vitro, but

has not been developed into clinical treatment (32). Some have used high dose allopu-

rinol in the face of urinary tract infection for Lesch–Nyhan patients to decrease the risk

of ammonium acid urate stones, and have reported xanthine stones as an effect of this

therapy(33).To date, the optimal prevention of xanthine stones in Lesch–Nyhan patients

on allopurinol therapy is achieved by continuing allopurinol, but placing added empha-

sis on their hydration and alkalinization.

Another situation in which secondary xanthine stones have been described is with the

use of allopurinol to treat the state of hyperuricemia seen in hematopoetic malignancies.

The urate overproduction seen in hematopoetic malignancies comes from cell break-

down, which result in uric acid excretion up to four-times normal, especially during the

rapid cell lysis associated with chemotherapy or radiotherapy (34). The side effects of

nausea and vomiting can interfere with proper fluid intake, or worse cause dehydration,

further increasing the risk of stone formation in this patient population. Rarely, the use

of allopurinol for inhibition of XO to decrease the uric acid in these patients will result

in excess xanthine accumulation and xanthine stone formation.

The formation of xanthine stones in the hematopoetic malignancy patient population

is through a similar mechanism by which the Lesch–Nyhan patients form xanthine

stones. Unlike Lesch–Nyhan patients, who fail to properly metabolize uric acid precur-

sors via the purine salvage pathway, the metabolic abnormality in patients with

hematopoetic malignancies is urate overproduction. The excess urate overloads the

Chapter 19 / Urinary Stones of Unusual Etiology 353

purine salvage pathway, leading to uric acid production as the method of ridding the

body of the excess by-products released by the malignancy. The massive uric acid

excretion places these patients at risk for uric acid urolithiasis, and to prevent this,

patients are prophylactically treated with allopurinol, alkalinization, and increased

diuresis (3000 mL/d) before the initiation of chemotherapy (35). Paradoxically, the

allopurinol used to prevent uric acid stones can lead to excess accumulation of xanthine,

leading to xanthine urolithiasis. These stones rarely form when patients adhere to rec-

ommended fluid intake.

Formation of xanthine stones has been described in patients with uric acid nephroli-

thiasis or gout who are treated with allopurinol (36). Certainly, with the administration

of allopurinol, the excess xanthine and hypoxanthine will be excreted in the urine. However,

allopurinol does not completely inhibit XO at usual doses. Consequently, one will rarely see

serum urate levels drop below 3 mg/dL or urinary urate levels below 250 mg/d. Xanthine

stones are not likely to form at these levels (28). Patients with uric acid nephrolithiasis

or gout on allopurinol therapy can further decrease their risk by adhering to recom-

mended fluid intake.

Acute stone episodes should be managed in the usual manner to control symptoms.

If operative therapy is required, xanthine stones may be treated endourologically or by

shockwave lithotripsy (SWL)(37). Outside of the patient population with hereditary

xanthinuria, xanthine stones are quite rare, even in the specific instances, described here,

which increase the risk of secondary xanthine stones. Primarily, preventive therapy is

achieved through adequate intake of fluids. Urine alkalinization also increases xanthine

solubility in the urine.

MEDICATION-RELATED STONES

Ephedrine Stones

Ephedrine and its metabolites, pseudoephedrine and norephedrine, have recently

been shown to be capable of forming urinary calculi (38). This initial report resulted from

a patient who chronically abused ephedrine containing medication, and ingested up to

120 ephedrine containing tablets daily (25 mg/tablet). Subsequent reports outline small

series of patients with ephedrine stones, many of whom abuse the medication for stimu-

latory effects (39,40). Often a history of drug or alcohol abuse may be elicited. Claims

of euphoria, increased energy, heightened sexual tension, weight reduction, and addition

of muscle mass are justification given by those abusing ephedrine (39). Some patients

receive ephedrine in drugs made for bronchodilating effects, which become less noticed

after long term use. Patients then increase the dosage, leading to the high doses that cause

calculi (39).

Ephedrine stones are radiolucent, but may be visualized by CT. They are easily

fragmented with SWL (39). To improve diagnosis, attention must be given to obtaining

a proper drug history and social history for previous substance abuse. Treatment is aimed

at reduction of ephedrine intake, and increase of urinary output.

Substance abuse counseling is recommended for abusers of ephedrine or users with

a history of substance abuse not only to prevent further stone episodes, but also to avoid

more serious sequelae of ephedrine abuse. The potential for major complications exist,

including but not limited to death, myocardial infarction, stroke, respiratory depression,

seizure, hypertension, cardiac arrhythmia, and headache. Over 100 ephedrine stones

354 Lowry and Nakada

were identified at a single stone analysis company (L. Herring) between January 1996

and June 1997, out of over 166,000 samples (40). Although the incidence was only

0.064%, one must believe that this represents only a small portion of the ephedrine

abusers who form stones.

Guaifenesin Stones

Approved by the FDA for over the counter use in 1989, guaifenesin is a common compo-

nent of cough/cold medications, which often contain ephedrine (41). Guaifenesin containing

urinary calculi were first noted in 1999 (42,39). Specifically, the guaifenesin metabolite,

β-(2-methoxyphenoxy)-lactic acid, is the component found in the calculi (42). The majority

of the affected patients were abusers of the offending medications (refer to the section on

ephedrine stones). Many were abusing the medication for the effect of the ephedrine. Because

the FDA, in 1994, limited the amount of pure ephedrine that may be contained in medication

(43), abusers take larger amounts of predominantly guaifenesin containing preparations for

the effect of the minor component, ephedrine (42). Some, however, were taking customary

doses of the medications, but were simultaneously taking numerous preparations that con-

tained guaifenesin, resulting in excessive guaifenisin intake (42).

Patients using prescribed amounts as directed by the manufacturer for the treatment

of colds, coughs, or allergies are at almost no risk of forming stones composed of

guaifenesin. Like ephedrine stones, guaifenesin stones are radiolucent, but can be seen

on CT scanning. They are easily fragmented with SWL (39).

Indinavir Stones (Fig. 4)

Indinavir stones were first described in 1995 (44–46). Used in the treatment of the HIV

virus, indinavir competitively inhibits HIV protease and decreases viral load by 90–99%.

Indinavir is commonly used with reverse transcriptase inhibitors such as nucleoside

analogues and/or nonnucleoside reverse transcriptase inhibitors as part of a multi-drug

antiretroviral regimen. Indications for use of antiretroviral therapy in HIV infected

individuals include acute HIV syndrome, symptomatic disease, and asymptomatic dis-

ease with low CD4+ T cell counts or with elevated HIV titer. Treatment may also be

offered to uninfected individuals for the purpose of postexposure prophylaxis following

an exposure to HIV (47).

Indinavir is predominantly excreted in the feces after hepatic metabolism. Nineteen

percent, however, is excreted in the urine (48). Patients taking this medication may form

indinavir crystals in their urine, leading to stone formation. Indinavir crystals are very

distinctive, with a fan-shaped or starburst type of appearance. They have been described

in 20% of patients on indinavir (49). When examined with microscopy, crystalluria has

been reported to occur in over 30% of patients on indinavir therapy (50). Indinavir stones

were first thought to have an incidence of 2–12 % (51–53); however, much higher rates

of over 40% have also been reported (54). In populations of patients on indinavir therapy,

the average time to stone episodes has varied from 21 wk (range 6–50) (55) to 11 mo

(range 4–19) (56).

The etiology of stones among patients taking indinavir was examined in a group of

11 patients who passed a stone that underwent analysis (23). Of these 11, only 4 patients

(36%) had stones with indinavir as a detected component; the remainder was composed

of calcium oxalate (3), calcium phosphate (1), ammonium acid urate (2), and uric acid

Chapter 19 / Urinary Stones of Unusual Etiology 355

(1). Additionally, nine patients taking indinavir underwent 24-h urine testing, which

revealed hypocitraturia (3), hyperoxaluria (2), hypomagnesuria (2), hypercalciuria (1),

and hyperuricosuria (2). Although previous stone history was not discussed and the

patient numbers were limited, this series reveals abnormal urine testing and the forma-

tion of stones primarily from components other than indinavir. This data suggests that

stone formation by patients on indinavir therapy may have a substantial metabolic com-

ponent, in addition to the effects of urinary indinavir excretion.

Indinavir crystals form at a pH of 7 (57) and are soluble at a pH of 4.5 in vitro (56).

Although such an acidic pH is difficult to obtain in vivo, short term acidification of 2–3 d

for treatment of stone episodes has been suggested (51) to help partially dissolve stones to

facilitate passage. Acidification may result in deposition of uric acid crystals (56), fur-

ther exacerbating episodes, although risk is small in the short term. The metabolic

acidosis and hypocitraturia caused by urinary acidification may also result in calcium

oxalate supersaturation (58). Increasing the intake of citrate containing fluids (lemon-

ade) may decrease the risk of stone calcification. Concern has been raised regarding the

hypothetical risk of virus mutation and subsequent development of resistance during

temporary cessation of indinavir (47), but no evidence exists to support this.

Pure indinavir calculi are radiolucent and are unique in that they are not visualized on

spiral CT scanning (59). On gross appearance, pure indinavir stones are brown and have

a pliable, puttylike consistency.

Conservative management successfully treats most stone episodes. Treatment con-

sists of hydration, analgesics, and temporary withdrawal of indinavir (60–62). Tempo-

rary urinary acidification may be considered. One must keep a low threshold for emergent

stent placement, as these patients may be dangerously immunosuppressed. After reso-

lution of a stone episode, indinavir may be restarted and increased oral hydration may

be initiated (61).

Fig 4. Indinivir calculus (Courtesy of Mission Pharmacal, San Antonio, Texas).

356 Lowry and Nakada

If conservative measures fail, indinavir stones may be fragmented and removed endo-

scopically. Shock wave lithotripsy has been used to successfully treat indinavir stones (56).

It is not understood why some patients taking indinavir form urinary crystals and

stones whereas others do not. Risk factors for the formation of indinavir stones are

unknown. At this time, adequate hydration, 2 L daily, is the best prevention (54,64). To

minimize recurrence, patients with stones of mixed composition or with a history of

stones may benefit from metabolic evaluation. HIV patients need continuation of

indinavir for optimal treatment of their disease, and because almost 10% of patients have

discontinued the use of indinavir because of nephrolithiasis, maximal effort must be

given to prevention of stones in this patient population.

Nelfinavir Stones

The most recent medication to cause stone formation is nelfinavir, a protease inhibitor

used for the treatment of the HIV virus. Before 2002, nephrolithiasis owing to protease

inhibitors as an etiology had only been described with indinavir. However, stones com-

posed of nelfinavir have now been reported (65).

Similar to indinavir stones, those composed of nelfinavir are radiolucent. However,

in contrast to indinavir calculi, nelfinavir stones are visible on CT scan (65). Nelfinavir

stones are successfully fragmented with SWL, or may be treated with other forms of

stone ablation.

In one report, a patient had a short course of indinavir therapy and changed to nelfinavir

because of intolerable side effects. Subsequently, the patient developed a large renal

pelvis calculus. The stone composition was 99% nelfinavir and 1% indinavir. As only

1–2% on nelfinavir is excreted in the urine, compared to 20% of indinavir, it was pos-

tulated that indinavir crystals may have provided the nidus for nelfinavir stone formation

(65,66).

Patients on other lithogenic medications and patients with a history of nephrolithiasis

who also have a need for nelfinavir may benefit from metabolic evaluation and surveil-

lance to keep stone episodes minimized.

Oxypurinol Stones

Oxypurinol was an early xanthine oxidase inhibitor, but was abandoned in favor of

allopurinol, in part owing to the improved urinary solubility of allopurinol. Oxypurinol

is the primary metabolite of allopurinol and is excreted via the kidneys. Although

allopurinol is broken down into an oxypurinol component, about half is excreted as

allopurinol, keeping the oxypurinol excretion lower than if oxypurinol were the only

drug administered (67). The presence of oxypurinol has been detected in stones pro-

duced by patients with the Lesch–Nyhan syndrome who were on allopurinol therapy

(68). Oxypurinol as a primary stone constituent, mixed with xanthine (increased excre-

tion owing to the xanthine oxidase inhibitor) and uric acid, has also been described in

patients on high dose allopurinol (600 mg/d) for prophylaxis of uric acid stones (69).

These stones are described as radiolucent (69). Oxypurinol has not been described as a

constituent with calcium stones. In fact, there is no interaction between oxypurinol and

either calcium or oxalate at oxypurinol concentrations expected with therapeutic doses

of allopurinol (70).

The presence of oxypurinol as a stone constituent is primarily seen in patients using

high dose (600 mg/d) allopurinol. Patients with oxypurinol as a stone constituent may

Chapter 19 / Urinary Stones of Unusual Etiology 357

benefit from a decrease in the allopurinol dosing, although, because these stones are

uncommonly rare, the risks and benefits in modification of allopurinol dosing should be

carefully considered. Metabolic studies of 24-h uric acid excretion will reveal how much

of an advantage, if any, exists with increased doses of allopurinol. This can be compared

to the increased oxypurinol excretion resulting from increased allopurinol dosing;

approximately half of an allopurinol dose is excreted as oxypurinol. One report (69)

showed, with constant diet, uric acid excretion falling from 481 to 346 to 334 mg/d on

0, 300, and 900 mg allopurinol daily. On the same respective allopurinol doses,

oxypurinol excretion increased from 0 to 243 to 440 mg/d, and xanthine excretion

increased from 6 to 47 to 145 mg/d. The patient identified in this report showed only a

minute benefit in uric acid excretion with an allopurinol increase of 300 to 900 mg/d, yet

the daily excretion of oxypurinol and xanthine increased by over 80% and 200% respec-

tively. In this instance, the 3% decrease in uric acid excretion must be weighed against

the 80% increase in oxypurinol excretion in this patient who produced stones made of

oxypurinol (major constituent) and xanthine.

If high allopurinol doses reveal a treatment advantage as seen with 24-h urine analy-

sis, a decrease of the allopurinol dose might place the patient at risk for other clinical

problems. Increasing urine output to dilute urinary oxypurinol concentration may better

serve the patient. Twenty-four hour urine studies will help guide therapy on an individual

basis. Continued radiolucent stone formation while on allopurinol therapy should raise

suspicion to other types of stones, and oxypurinol must be considered as a possibility.

For accurate stone analysis, special notation should be made on analysis requests to

reflect this suspicion.

Silicate Stones

Silicate urinary calculi occur exclusively in patients taking large amounts of magne-

sium silicate antacids. In 1912, silica stones were first found in cattle living in sandy

areas (71). The first human patient with silicate stones was reported in 1953 (72). This

patient had gastric ulcers and ingested 2 g daily of magnesium trisilicate, an antacid.

Subsequently, other reports of silicate stones have been presented, all involving patients

with a history of silicate abuse (73–76). Invariably, sufferers of silicate stones also have

associated upper gastrointestinal disease such as esophagitis, gastric ulcers, gastritis, or

hiatal hernia, prompting them to abuse magnesium trisilicate antacids.

No report exists linking an episode of silicate stones to any source other than silicate

antacids. The only report suggesting another etiology was regarding a patient who died

in the months before establishment of silicate antacids as an etiology. This patient’s

family reported no knowledge of abdominal pain or antacid use; this is the only reported

case of silicate stones in a patient not on silicate antacid therapy (77). It has also been

postulated, although never reported, that methyl polysiloxane, or dimethicone, used for

prevention of flatulence, may be a source of urinary silica (77).

As in other unusual stones, failure to suspect silicate stones leads to a delay in diag-

nosis and prevention. A 1973 report outlines a 5-yr delay in diagnosis in a patient with

multiple stone passages; part of the explanation for the delay was poor quality of stone

analysis (74). The gross appearance of silica stones can resemble the gross appearance

of calcium oxalate jackstones. Electron microscopy, however, reveals the subtle differ-

ence of the spikes blending into the body in silica, whereas they appear more demarcated

from the body on calcium oxalate jackstones (78). This reinforces the value of quality