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This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of CME2, Inc. ("cme² ") and Contemporary Urology. cme² is accredited by the ACCME to provide continuing medical education for physicians.

cme² designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit?. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Target audience: Urologists.

Educational objectives

After completing the following CME activity, the reader should be able to:

• Identify patients at risk for the development of uric acid calculi.
• Manipulate the urinary volume, urinary acidity, and uric acid production for the patient with uric acid stone disease.
• Recognize the imaging characteristics of a uric acid stone.
• Create a plan for the medical and potentially surgical treatment for the patient with a symptomatic uric acid calculus.

To earn CME credit for ths activity

Participants should study the article and log onto www.contemporaryurology.com, where they must pass a post-test and complete an online evaluation of the CME activity. After passing the post-test and completing the online evaluation, a CME certificate will be e-mailed to them. The release date for this activity is February 1, 2007. The expiration date is February 1, 2008.

Faculty disclosures

Staff editors Nancy Lucas and Beverly Lucas disclose that they do not have any financial relationships with any manufacturer in this area of medicine.

The manuscript reviewers disclose that they do not have any financial relationships with any manufacturer in this area of medicine.

Author Dr. Lee discloses that he does not have any financial relationships with any manufacturer in this area of medicine. Author Dr. Stoller discloses that he has received research support from and is a speaker for Percutaneous Systems, Inc.

Resolution of conflict of interest

cme² has implemented a process to resolve conflicts of interest for each continuing medical education activity, to help ensure content objectivity, independence, fair balance, and that the content is aligned with the interest of the public. Conflicts, if any, are resolved through a peer review process.

Unapproved/off-label use discussion

Faculty may discuss information about pharmaceutical agents, devices, or diagnostic products that are outside FDA-approved labeling. This information is intended solely for CME and is not intended to promote off-label use of these medications. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information. Faculty are required to disclose any off-label discussion.

Keith L. Lee, MD

Dr. Lee is Clinical Fellow in Laparoscopy and Endourology, and Dr. Stoller is Professor and Vice Chairman in Urology, Department of Urology, University of California San Francisco.

Marshall L. Stoller, MD

Uric acid calculi are responsible for 10% of symptomatic urolithiasis cases in the United States. The chemical mechanism responsible for stone formation is well characterized (see "Mechanism of uric acid stone formation," page 4). As a result, specific and effective medical treatment is available. Advances in diagnosis and imaging as well as in identification of risk factors have enhanced our understanding of these common calculi and may direct medical alkalization and surgical treatment. This article provides an update on the epidemiology, pathology, and practical management of this often challenging condition.

RISK FACTORS

Approximately 1 in 20 women and 1 in 9 men in the United States will develop a kidney stone in their lifetime.¹ Uric acid calculi comprise roughly 10% of all kidney stones and continue to be a significant burden on patients and the healthcare system. The relative prevalence of uric acid calculi also appears to be growing and may be related to advancing age.² Worldwide, the prevalence of uric acid urolithiasis varies among nations, ranging from 4% in Sweden to 13% in the Sudan and 17% to 25% in Germany.^3-6 Within the United States, geographic variations are also seen.⁷ The cause for these differences are multifactorial, and researchers believe that dietary, cultural, racial, genetic, and environmental factors all contribute to the disparity.^8,9

Obesity has been shown to put men and women at increased risk for kidney stone formation. In a study of 3 large observational databases of more than 240,000 men and women, obese men (body mass index [BMI] > 30) had a relative risk for stone formation of 1.33 compared with men who were not obese.¹⁰ Two different databases demonstrated that the relative risk of stone formation is even more marked for obese women?1.90 and 2.09.¹⁰ Obesity is also associated with increased uric acid excretion and is inversely related to urinary pH.^11,12 Taken together, these findings suggest that obese patients are at high risk for developing uric acid stones. In a recent retrospective report by Preminger and colleagues, the prevalence of uric acid stones was as high as 63% in obese patients (BMI > 30) compared with 11% in controls.¹³

The exact mechanism for this increased risk remains a topic of research, and obesity-associated insulin resistance may play a pivotal role in patients with recurrent uric acid stones. Abate and co-workers demonstrated that patients with recurrent uric acid calculi are "severely insulin resistant" and have low renal acid-buffering capacity and high urinary acidity.¹⁴ Others have shown that patients with diabetes are 2.2 times more likely to harbor uric acid stones than nondiabetic patients (28.5% vs 13.2%, respectively). Again, this difference was more marked in women than in men (3.8 vs 1.7, respectively).¹⁵

IMAGING AND DIAGNOSIS

Uric acid calculi are radiolucent on traditional flat-plat radiography. Prior to CT, diagnosis was made by intravenous urography or retrograde pyelography. Stones show up faintly on scout films and appear as filling defects with contrast. Today, unenhanced CT has replaced traditional radiography because of CT's high sensitivity in stone detection. Uric acid stones are radiodense on CT and can be easily identified. Radiographic characterization by CT can further differentiate uric acid stones from calcium stones. Uric acid calculi are less dense and image in the range of 300 to 350 HU compared with 650 to 2,250 HU for calcium oxalate stones.^16,17 US and MRI are inferior to CT in sensitivity and have limited applications. Nevertheless, an advantage of US and MRI is the absence of radiation, which may be useful in patients who are pregnant.

MEDICAL MANAGEMENT

One factor that contributes to uric acid stone formation is the total amount of uric acid to be eliminated. Minimizing dietary animal protein intake will decrease exogenous sources and help patients whose primary cause for uric acid stone is purine gluttony. Endogenous purine production can oversaturate the kidney's elimination capacity in a patient with a myeloproliferative disorder or a malignancy, or who is undergoing chemotherapy, or who has experienced massive weight loss after gastric bypass surgery, or who is in a catabolic state. To prevent uric acid stone formation, manipulation of urinary volume, urinary acidity, and uric acid production are necessary.

Urinary volume. Increasing urinary volume makes intuitive sense since doubling urinary volume will double the amount of urate species that the kidneys can excrete. Clinically, this may be simple to achieve in compliant patients whose primary problem is low dietary fluid intake. For most, only modest increases in 24-hour urine output (500 mL/d) can be achieved in the outpatient setting. For inpatients undergoing chemotherapy where tumor lysis and high endogenous uric acid production are anticipated, aggressive intravenous hydration will help minimize risk of uric acid supersaturation. In patients with inflammatory bowel disease, chronic diarrhea, or ileostomy bowel diversion, dehydration continues to be a major problem.

Urinary acidity. The most important factor in the pathogenesis of uric acid stones is urinary acidity. Uric acid saturation is pH-dependent and, as such, patients with metabolic acidosis or any metabolic state leading to acidic urine will be at increased risk for stone formation.

Within the distal nephron, acid is primarily excreted in the form of ammonium: NH ₃ + H ⁺ ↔NH ₄ ⁺

A defect in ammonium excretion may be a mechanism for acidic urine in patients with uric acid stones, obesity, insulin-resistance, or diabetes.^11,14,18,19

Diets rich in animal proteins are not only high in purine but also high in organic acids. It has been shown that popular weight loss diets that are high in animal protein and low in carbohydrates (for example, Atkins or South Beach) are associated with marked acid loads to the kidneys, putting patients with uric acid stones at increased risk for recurrence.²⁰

TABLE 1 Urinary alkalinization

Clinically, alkalization can be achieved with sodium bicarbonate (650 mg, 3 times a day) or with commercial baking soda (1 to 2 teaspoons, 3 times a day).²² Patients should check their urinary pH levels at home with pH test strips until a consistently alkaline pH is noted. For patients with congestive heart failure, cirrhosis, or hypertension, in whom a sodium load may not be tolerated, potassium citrate (10 to 20 mEq, 3 times a day) is effective.²³ Use of oral alkalization for uric acid stone dissolution is effective, with success rates ranging from 70% to 80%. With optimal alkalization, uric acid stones will dissolve at a rate of approximately 1 cm per month as measured by plain radiography (IVP). The treating physician must remember that patient education and motivation are critical to success.²⁴

In the postsurgical setting where small residual fragments remain after percutaneous nephrolithotomy, intravenous alkalization with one sixth molar sodium lactate and direct nephrostomy tube irrigation with alkaline fluid can be used. Similarly, alkalization after shock wave lithotripsy can be effective in dissolving stone fragments. Nevertheless, with advances in endourologic techniques, the practice of prolonged chemolysis is not cost effective.²⁵

Uric acid production. With the exception of dalmatians and perhaps the river otter, humans are the only mammal prone to uric acid stones.^26,27 We lack the enzyme uricase, which breaks down uric acid to allantoin, a purine end-product that is 10 to 100 times more soluble than uric acid.²⁸ In a state of homeostasis, uric acid production is matched by excretion, and uric acid stones do not form. In catabolic states or in patients with myeloproliferative disorders or in those undergoing chemotherapy, nucleic acid turnover is high, and the incidence of uric acid calculi can be upwards of 40%.²⁹ Patients with gout also produce more uric acid than normal and have a higher prevalence of stone disease, in the range of 10% to 20%. Although uric acid production is only part of the puzzle?as not all patients with gout will form stones, and not all patients with uric acid stones are simply uric acid overproducers?stone risk can be minimized by lowering uric acid levels with medications such as allopurinol.

Allopurinol is a xanthine oxidase inhibitor that blocks the natural conversion of xanthine to uric acid and can also decrease de novo purine synthesis. It is most beneficial for stone patients with hyperuricosuria (>1,000 mg/d), and its use results in a "shift to the left" with increased production of the more soluble xanthine precursor. The usual dose of allopurinol is 300 mg a day, but it should be lowered in patients with renal insufficiency. For patients undergoing chemotherapy, allopurinol should be started several days in advance along with hydration and urinary alkalization.

Allopurinol is generally well tolerated. Minor side effects include gastrointestinal irritation, alteration of liver function, and skin rash. A rare and severe allergic response resulting in hemorrhagic skin lesions, epidermal necrolysis, and vasculitis (Stevens-Johnson syndrome) can occur. Patients who report a rash or pruritus with allopurinol should discontinue the medication and be closely followed.

Other medications that alter uric acid metabolism and urate solubility such as rasburicase (a recombinant urate oxidase) and febuxostat (a nonpurine selective xanthine oxidase inhibitor) are being used in patients at risk for tumor lysis syndrome and in those with gout.^30-32 Such medications can be alternatives for patients with allopurinol allergies, and they may one day find clinical applications in the medical management of uric acid stone disease. Currently, rasburicase has been approved for use in pediatric cancer patients to lower plasma uric concentrations and manage tumor lysis syndrome. Its use as a treatment for gout is off-label. Febuxostat has not been approved by the FDA.

SURGICAL MANAGEMENT

Despite effective medical therapy for patients with uric acid stones, those with mixed stone compositions and acute presentation may not respond. In such cases, traditional surgical therapy is effective. Uric acid calculi are considered "soft" stones that are amenable to treatment with extracorpeal shock wave lithotripsy and endoscopic techniques.³³ Interestingly, when using endoscopic techniques, the application of a holmium:YAG laser can create subclinical levels of cyanide. Investigators have varied pulse energy in an effort to minimize cyanide production; however, this technique remains controversial.^34,35 Nevertheless, due to the minute levels generated and irrigation fluid use in endourology, cyanide remains a theoretical concern but no clinical case of cyanide poisoning has been reported.

CONCLUSION

Uric acid calculi make up 10% of kidney stones, and remain the stone type most effectively managed and prevented medically. Urinary alkalization with oral potassium citrate and sodium bicarbonate are well tolerated and can effectively increase the urinary pH level to 6 to 6.5. Avoiding dehydration and minimizing uric acid production can further decrease stone risk. With optimal medical management, a pure uric acid stone can be expected to dissolve completely in the majority of compliant patients.

Mechanism of uric acid stone formation

Uric acid is an end product of purine metabolism in humans. It is a weak acid that dissociates into anionic urate and a proton at physiologic pH: Uric acid ↔H ⁺ + urate ^-

The undissociated form of uric acid is poorly soluble, while the dissociated form, anionic urate, is highly soluble. Thus, the overall solubility depends on how much undissociated uric acid is present, which is determined by urinary pH. The pH at which half of the uric acid dissociates is termed the pKa. The pKa is temperature-dependent and for uric acid, it is 5.5 at 38?C and 5.35 at 37?C.^1-3

As an illustrative example, roughly 100 mg/L of undissociated uric acid will dissolve in urine at 37?C and a pH of 5.35. At this pH level, an additional 100 mg/L of urate species in the form anionic urate will be in solution. Thus, a total of 200 mg/L of urate species will remain in solution. Any higher concentration can lead to precipitation of undissociated uric acid crystals. It is important to note that uric acid solubility is very much pH-dependent. When pH increases from 5 to 6, the equation is driven to the right, with solubility increasing more than 3-fold and more than 24-fold going from a pH of 5 to 7.2.

To put this into context, the typical Western diet consists of 500 mg/L of uric acid daily. Exogenous sources of purine are derived from dietary intake of animal protein and can increase dramatically with purine gluttony. Endogenous sources from de novo purine synthesis and tissue catabolism generate 300 to 400 mg/d.³ Approximately two thirds of the uric acid load is eliminated by the kidneys with the other third by the intestine, skin, hair, and nails. Thus, approximately 600 mg of uric acid must be excreted in the urine each day. When the urinary pH is 6 or higher, the urinary excretion capacity is not reached, and crystallization does not occur. In the setting of an acidic urinary pH of 5.35 or less, only 200 mg/L (from our example) of urate species can be eliminated in solution. A urinary volume of at least 3 L is required to prevent crystallization.

In this oversimplified example, excess uric acid will crystallize out of urine and form stones. In reality, stone formation is much more complex, and not all patients with hyperuricosuria or gout form stones. Similarly, not all patients with normal levels of uric acid excretion are free from uric acid stones. Risk factors may include diurnal variations in urinary pH and dehydration with periodic stone growth at times of increased urine acidity and dehydration. Heteronucleation with calcium stones can also occur in the setting of normal uric acid excretion levels.

REFERENCES

1. Coe FL, Evan A, Worcester E. Kidney stone disease. J Clin Invest. 2005;115(10):2598-2608.

2. Finlayson B, Smith A. Stability of first dissociable proton of uric acid. J Chem Eng Data. 1974;86:355.

3. Shekarriz B, Stoller ML. Uric acid nephrolithiasis: current concepts and controversies. J Urol. 2002;168(4 pt 1):1307-1314.

UROlogic

• In the United States, uric acid stones comprise approximately 10% of all kidney stones, and their prevalence appears to be increasing.
• Obesity and diabetes are associated with a greater risk for uric acid stones in both men and women.
• Uric acid stone formation is highly pH dependent, and only occurs in the setting of acidic urine.
• Uric acid stones are radiolucent on KUB x-rays but are easily seen on CT.
• Unlike calcium-based stones, uric acid stones will dissolve with alkalinization. Success rates are upwards of 80%. The goal of alkalization is to achieve a consistent urinary pH level of 6 to 6.5.
• Allopurinol blocks the conversion of xanthine to uric acid. This can increase overall urate excretion because the former is much more soluble.
• Severe allergic reactions can occur with allopurinol, and all patients must be advised to stop taking this medication in the setting of new skin rashes or pruritus.

REFERENCES

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