Continuing Education Activity

Uric acid nephrolithiasis is commonly seen with certain conditions like metabolic syndrome, obesity, diabetes mellitus, and hypertension. Increasing age, hot and dry environmental conditions, male sex, decreased urine volume and lower urinary pH are important risk factors for uric acid nephrolithiasis. Almost two-thirds of all uric acid kidney stones can be dissolved by increasing urinary pH and volume along with decreasing hyperuricosuria. This article reviews the evaluation and management of uric acid nephrolithiasis and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Outline the typical presentation and diagnosis of uric acid nephrolithiasis.
• Describe the pathophysiology of uric acid nephrolithiasis.
• Review the risk factors for developing uric acid nephrolithiasis.
• Summarize the importance of collaboration and communication amongst the interprofessional team to improve outcomes for patients with uric acid nephrolithiasis.

Introduction

Swedish pharmacist C. Scheele first identified what we now call "uric acid" as the primary acidic component of bladder stones in 1776. [1] Renal, and particularly bladder stones of this material, caused enormous pain and misery throughout history as the only therapy, until modern times, was dangerous, high risk surgery with substantial mortality rates. [2] Sir Isaac Newton and Michelangelo are two of many prominent historical figures who had recurrent uric acid kidney stones.

Nephrolithiasis is a frequent health problem in developed nations with a worldwide estimated 2 to 5% of people affected at least once in their lifetimes. In the United States, the overall lifetime risk for urinary stones in men is 10.6%, and for women, 7.6%. The majority of untreated patients suffer from periodic abdominal pain, urinary tract infections, and loss of kidney function; eventually leading to renal failure. Numerous conditions increase susceptibility to the nephrolithiasis, which includes genetic disorders, dietary and environmental factors. [3][4][5][6] Besides uric acid stone disease, elevated serum uric acid levels are also a risk factor for gout as well as cardiovascular disease, diabetes and chronic renal failure. [7][8]

Uric acid calculi make up 10 to 15% of all urinary tract stones with the overwhelming majority, 79%, presenting in men, most frequently in the 60 to 65 year old age group. [9] Obesity, hyperglycemia (elevated blood sugar), metabolic syndrome and high blood pressure are frequently associated with uric acid calculi in Western countries. [10]

Etiology

In humans, uric acid is the end product of purine metabolism. There are three sources of purines in humans: 1) cellular RNA from cell turnover, 2) metabolic hepatic synthesis and 3) dietary intake of high purine foods.  

Purine digestion produces xanthine which is converted to uric acid by the action of xanthine oxidase. Allopurinol works here; it blocks the effect of xanthine oxidase so uric acid production is reduced in favor of xanthine which is far more soluble than uric acid. In most other mammals, uric acid is further metabolized by uricase to allantoin, which is highly soluble and causes no pathology.

Endogenous uric acid synthesis is relatively stable at about 300 mg - 400 mg daily. The contribution of dietary sources can obviously vary, but generally, diet is responsible for 50% or less of total daily uric acid production. Total uric acid excreted daily on a typical Western diet is normally estimated at about 10 mg/kg body weight. [11] However, dietary factors, such as a high purine diet, can substantially increase urinary uric acid excretion by 50% or more. [12] While a high purine diet can increase uric acid production, since ammoniagenesis is intact there is adequate urinary pH buffering so uric acid stone formation is limited.  However, the hyperuricosuria leads to increased calcium oxalate urolithiasis. [13]

The etiology of uric acid stones can be diverse and is classified as follows: [14]

• Idiopathic: the most common etiology, associated with metabolic disorders:
  1. Aciduria (low urinary pH) is due to higher acid production and/or inadequate available buffers.
  2. Diabetes mellitus
  3. Metabolic syndrome
  4. Obesity
• Acquired: less common, associated with low urinary pH and hyperuricosuria:
  1. Gout
  2. Persistent diarrhea (Irritable Bowel Syndrome, GI Bypass Surgery). Low urinary volume and hypocitraturia is seen instead of hyperuricosuria
  3. Cancer (due to high cell turnover; especially during chemotherapy which causes increased necrosis of tumor cells and acute tumor lysis syndrome.) 
  4. Dietary factors. High purine sources include organ meats (liver, kidney), poultry, fish (herring, trout, sardines), and red meat.
  5. Medications: probenecid and sulfinpyrazone block renal reabsorption of uric acid.  Other uricosuric drugs include benzbromarone, indomethacin, losartan, and salicylic acid.
• Congenital: uncommon, associated with hyperuricosuria:
  1. Lesch-Nyhan syndrome
  2. Von-Gierke disease
  3. Type 1 collagen storage disease
  4. Hartnup disease
  5. Wilson's disease 
  6. Familial hypouricemic hyperuricosuria ("Renal uric acid leak") and URAT1 mutations [15][16]
  7. Sickle cell disease and other hemolytic anemias (due to high cell turnover) [17]

The occurrence of uric acid stones has risen considerably in patients suffering from metabolic syndrome. [6] Uric acid stones are commonly seen in patients with hyperuricosuria, but overall, aciduria is the most common underlying etiology. The cause of aciduria is thought to be due to diet-dependent as well as diet-independent causes such as metabolic syndrome, which tends to produce a net acid load. Another underlying factor is reduced hepatic ammonia synthesis. [18] This causes an increase in net acid excretion as there is less ammonia buffering of excess acid. [19]

Gout and/or hyperuricemia is associated with uric acid uropathy in 15 to 25% of uric acid nephrolithiasis patients. [20][21][22][23] A purine-rich diet, including substantial animal protein, further increases the risk of uric acid nephrolithiasis. [22][24][25]

Uric acid is much less soluble at a low urinary pH (5.5 or less), whereas solubility greatly increases at a higher urinary pH (especially at pH of 6.5 or more). [18] Diurnal variations also play a role as the lowest urine production and lowest urinary pH both occur in the early morning so this is when uric acid crystals are most likely to form. [11]

Hyperuricosuria increases the risk of calcium oxalate stone formation while reductions in hyperuricosuria with allopurinol and similar agents have shown a significant benefit in reducing recurrent calcium oxalate nephrolithiasis. [26][27]. There are several proposed physiochemical mechanisms for this: [28]

• Uric acid crystalluria reduces crystallization inhibitors and acts a nidus for heterogenous calcium oxalate nucleation.  
• Dissolved uric acid in a solution can promote precipitation crystallization which increases calcium oxalate crystal formation leading to calculi.

Epidemiology

Uric acid stones account for about 10% of all urinary stones in the United States and 5 to 40% of all stone cases globally. [29][30] The annual economic burden associated with uric acid nephrolithiasis has risen from $1.3 billion in the year 1994 to $2 billion in the year 2000 despite advancements in treatment and patient care. [31]

The prevalence of uric acid uropathy varies with age, gender, and environmental factors. For example, people aged more than 65 were found to suffer from uric acid stones twice as often as younger patients. Males are affected up to three times more than females, but this is changing as more women are developing this disorder. [32][33] Uric acid stone formers tend to have a somewhat greater risk of recurrences and stone related surgeries than patients with calcium urolithiasis.[34]

The incidence of uric acid stones has been found to be 6% in the white population, whereas it was 30% in the non-white population. [35][36]

Uric acid stones vary with ethnic groups. For example, about 50% of ethnic Hmong patients (from Laos and Thailand) were found to be affected by uric acid stones, whereas, among non-Hmong patients from the same country, the rate was only 10%. [37] In the Middle East, some regions report that uric acid comprises one-third of all urinary calculi. [38] Most Asian countries have very low rates of uric acid stones, such as India where the reported incidence is <1%. [39] However, there are a few exceptions such as Okinawa which has a relatively high incidence of uric acid stones, accounting for 15% of all urinary calculi produced on the island. [40] These differences are due to genetic, dietary, and climate-based factors. 

Environmental factors also influence the frequency of uric acid disorders and stone formation. The prevalence of uric acid stones was found to be 9% among factory workers laboring in a hot environmental condition, whereas it was only 0.9% among people working the same job at standard room temperature. [36][37]

Pathophysiology

Factors related to the formation of uric acid stones include a persistent decrease in urine pH, hypovolemia, and hyperuricosuria (defined as 24-hour urinary excretion of uric acid more than 750 mg/day in females and 800 mg/day in males). [41][40] It should be pointed out that these values derive from statistical analyses of numerous 24-hour urine tests from "normal" individuals and not from supersaturation ratios, crystallization rates or other sources. For most practical purposes, 800 mg/day is a reasonable level in most patients without aciduria or hyperuricemia. When being treated for high uric acid levels, the "optimal" level of urinary uric acid is no more than 600 mg/day. [42]

Decreased Urinary pH

Uric acid urinary stones are frequently seen in conditions where there is a consistently low urinary pH. Almost all individuals with uric acid nephrolithiasis present with aciduria. [43][44] In the absence of congenital or acquired conditions that increase susceptibility to uric acid stones, most affected patients are found to develop idiopathic uric acid renal stones or gout. [44][45] Both of these conditions are characterized by hyperuricemia, a decrease in fractional excretion of uric acid, and persistently low urinary pH levels. This may also explain the observed association between obesity and aciduria. [46][47] The decrease in urine pH forms uric acid stones by inducing changes in the dissolution of uric acid and acid-base status. [48][49] In other words, uric acid solubility is heavily dependent on pH. A persistent decrease in urine pH (usually to 5.5 or less) even with the normal level of urinary uric acid secretion will lead to uric acid stone formation. Further, an increased urinary uric acid will not contribute to the formation of uric acid urolithiasis if the urine pH is increased to 6.0 - 6.5 as this greatly increases uric acid solubility. [50]

Decreased urinary pH (aciduria) is associated with lower urinary ammonia excretion due to metabolic syndrome. In the proximal convoluted tubule, insulin increases glutamine metabolism resulting in the production of ammonia (NH3) which then forms ammonium ions (NH4+) in the presence of free hydrogen. Ammonium is the primary urinary acid buffer; so when this is deficient, due to proximal renal tubular steatosis and lipotoxity or from lower insulin levels in patients with metabolic syndrome or diabetes, the patient will develop aciduria. [19][51][19][52][53]

Decreased Urine Output

A decrease in urine output increases highly concentrated urinary solutes and supersaturation that increase susceptibility to crystal and stone formation. This leads to the precipitation of uric acid crystals, which lead to stones. This explains why uric acid stones are more common in tropical and humid climates. [54][55]

Hyperuricosuria

Uric acid is almost completely filtered by the renal glomerulus, then mostly reabsorbed in the proximal convoluted tubule. About 10% of the filtered uric acid is ultimately excreted in the urine. In the presence of normal or low normal urinary pH, hyperuricosuria can form pure uric acid stones or mixed urinary stones composed of urate and calcium oxalate (Calcium phosphate generally requires a more alkaline environment to form stones). An increase in the concentration of monosodium urate induces the formation of calcium oxalate crystals. Hyperuricosuria often results from a disturbance in dietary factors (so-called purine gluttony). Congenital renal hypouricemic hyperuricosuria is seen due to mutations in the URAT1 channel. [56][57][58]

Crystallization Inhibitors

Many components in urine suppress the crystallization of urate and thus inhibit urinary stone formation. The most significant of these is citrate, which lowers urinary pH, but there are also several glycoproteins and glycosaminoglycans present in urine, which specifically suppress precipitation of urate crystals. [59] A decrease in the concentration of urinary glycosaminoglycans has been demonstrated in many patients with uric acid stones. The reason behind the increased formation and development of uric acid stones in the absence of glycosaminoglycans is still not completely understood. [59][60][61]

Histopathology

Light microscopy of urine will sometimes show urinary crystallizations with characteristic rectangular or rhomboid-shaped uric acid crystals. [62] Finding such crystals, along with an acidic urinary pH of 5.5 or less, is suggestive but not diagnostic of uric acid urolithiasis.

History and Physical

History

Characteristic features of uric acid nephrolithiasis include:

1. Abdominal pain
2. Flank pain with radiation towards the groin
3. Nausea and/or emesis
4. High purine (meat) diet
5. Gout
6. Obesity
7. Diabetes or metabolic syndrome
8. Personal or family history of nephrolithiasis

Physical Examination

1. Costovertebral angle tenderness
2. Presence of urinary crystals
3. Hematuria (gross or microscopic). However, 15% of all patients with stones may not demonstrate even microscopic hematuria.
4. Aciduria
5. Physical examination findings associated with certain specific conditions like cancer or various metabolic syndromes can be seen.

These clinical features are 80% sensitive and 99% specific in determining urinary stones but are not specific for uric acid calculi. [63][64] Comprehensive past medical and family history should be obtained, focusing on problems related to uric acid stone formation like cancers, myeloproliferative neoplasms, inherited disorders related to hyperuricosuria, indigestion, and chronic diarrhea. [65]

Evaluation

Laboratory

24-hour urine collection: To evaluate the uric acid level, urine pH, citrate excretion, and volume. Urine pH below 5.5 is usually seen with uric acid nephrolithiasis.  Hyperuricosuria is not necessarily associated with hyperuricemia which should be investigated separately with a serum sample. Hyperuricosuria is usually defined as daily urinary uric acid excretion >800 mg for men and >750 mg for women.

On careful review, having different normal values based exclusively on gender makes very little sense as there is nothing that would justify using sex alone to differentiate normal from abnormal chemistry with regards to uric acid crystallization or stone formation.  Ultimately, it is the chemistry that determines stone risk.  If temperature, uric acid content, fluid volume, concentration, and pH are identical between two specimens, should gender alone determine that one patient (female) is diagnosed with hyperuricosuria and will form stones while the other patient (male) is normal and not expected to produce stones? Would not body weight, uric acid concentration, or renal function be better parameters to help determine the presence of hyperuricosuria? There is a similar problem with hypercalciuria. In our practice, we typically will use a daily urinary excretion of 800 mg as being sufficient to consider treatment in uric acid and calcium oxalate stone formers. 

Spot urine: To evaluate urine pH and routine urinalysis. Typical uric acid crystals can often be observed on microscopic urinalysis given sufficient aciduria.

Blood workup: To evaluate creatinine, uric acid levels, GFR, serum electrolytes, calcium, and a complete blood count. [66]

Radiographic

After necessary fluid resuscitation and pain control, imaging is performed. Urgent radiological investigations are done in patients with signs of infection, solitary kidneys, and when the diagnosis is unclear. [67] Intravenous pyelograms, which used to be the "gold standard" imaging modality for kidney stones, are rarely used today for an evaluation of possible urinary calculi. CT scans can identify and locate stones much faster and do not require IV contrast to do so. 

Plain Abdominal X-ray (kidney, ureter, and bladder or KUB)

The KUB is simple, quick, and extremely useful in tracking stones over time. However, uric acid stones are radiolucent, which will not typically show up on standard plain abdominal x-ray films but can be easily identified by CT scan. [68] The KUB is still very useful since a stone that is visible on the CT but is not seen on the plain abdominal film would suggest the presence of a uric acid stone. If the urine pH is low (5.5 or less), then a presumptive diagnosis of uric acid stone disease can be made.

Ultrasonography

Ultrasound is easily available, cheap, free from harmful ionizing radiation, and can be performed easily at the bedside. It can easily diagnose kidney stones if they are large enough (more than 0.4 cm), identify hydronephrosis, echogenicity, and other abnormal renal changes. However, it cannot differentiate hydronephrosis from ureteropelvic junction obstruction or the benign extra-renal pelvis. It also cannot identify ureteral stones or differentiate uric acid from calcium stones. Ultrasound can also be used to measure the resistive index, which is elevated in the presence of any obstructive uropathy on the affected side. [69] Ultrasound has an overall 45% sensitivity and 88% specificity in the detection of kidney stones. [70]

The combination of a KUB and a renal ultrasound is very helpful in the diagnosis of renal stone disease, especially where a CT scan is not available for some reason. This combination has sometimes been called a "poor man's CT scan". 

Non-Contrast Computed Tomography (CT) Scan

Non-contrast enhanced computed tomography (CT) scan of the kidney is the standard imaging modality in the diagnosis of nephrolithiasis. It is more precise and effective than intravenous urography or ultrasound. It can identify the size and density as well as the location of any kidney or ureteral stones. It can also reveal associated deformities even in the absence of uric acid stones. [71][72] Pure uric acid stones will typically have CT measurements of about 500 Hounsfield units while calcium stones are usually about 900 Hounsfield units. [73] Stone patients who have a urinary pH of 5.5 or less and whose stones are about 500 Hounsfield units or less can reliably be diagnosed as having uric acid stones.[73]

Non-contrast CT scan studies, often referred to as the "renal colic CT scan", are preferred because the contrast makes the urine "white" on the images. Since stones will also appear white, adding contrast will tend to hide the stones and make them harder to locate and diagnose. It will also interfere with the follow-up KUB which will now only show contrast and not the stone, making it useless for tracking unless it is done prior to the CT scan which is what we recommend in all cases of abdominal pain with any of the following:

• Personal or family history of kidney stones
• Flank pain
• Abdominal pain that has moved
• Constant patient movement
• Hematuria
• Crystalluria
• Urinary tract infection

Treatment / Management

Management of uric acid kidney stones includes lifestyle changes, medical treatment focusing on decreasing uric acid production and excretion, and urinary alkalinization.[20] Overall, urinary alkalinization is considered the single most effective therapy. The goal is to achieve a urine pH of 6 to 6.5. For uric acid kidney stones, renal ultrasonography can be used for tracking as the calculi will not be visible on a standard KUB.

Dietary Interventions

High intake of fruits and vegetables, low intake of purine-rich diets and animal proteins are necessary to reduce the burden of uric acid production in patients with uric acid nephrolithiasis. Orange juice and lemonade are often recommended but very large amounts are necessary for any meaningful change in urinary pH. [74] A high intake of fluids to maintain adequate urinary output (>2,000 ml daily) is useful to lower supersaturations and help prevent kidney stones. Recommendations to reduce obesity, appropriate management of hypertension, and high blood sugar are also helpful in reducing the burden of uric acid kidney stones.

Medical Management [14]

1. Increased fluid intake with adequate 24-hour urine output (2,000 to 2,500 ml/day). A minimum of 2,000 ml of the daily urinary volume is recommended and 2,500 ml or more is considered optimal. 
2. Urinary alkalinization: Helps in the dissolution and prevention of all uric acid stones. The goal is a urinary pH that is consistently around 6.5. Ultrasound and CT scans can be used to monitor the response to treatment. Potassium citrate is usually preferred but sodium citrate and sodium bicarbonate can also be used.  However, sodium-based alkalinizing agents will tend to increase urinary calcium excretion and may promote the formation of calcium-based nephrolithiasis. [75]
   1. Potassium citrate: 15 to 30 mEq, two or three times a day
   2. Sodium bicarbonate: 500 to 1000 mg three times a day
   3. Acetazolamide: 500 mg per day (lowers urinary pH but also lowers citrate excretion)
   4. Litholyte (urinary alkalinizer and citrate supplement with reduced potassium content. It includes sodium bicarbonate, magnesium citrate, and potassium citrate. Overall, about half the potassium of potassium citrate but equivalent citrate load.) Cytra-2 is similar.
3. Xanthine oxidase inhibitors are used in patients with hyperuricemia or hyperuricosuria. Adjust as needed for optimal serum uric acid levels of 6 mg/dl or less and urinary levels of 600 mg/day or less.
   1. Allopurinol: 100 to 300 mg per day, the usual dose is 300 mg
   2. Febuxostat: 40 to 80 mg per day (typically used when the patient does not tolerate allopurinol for some reason) 
4. Analgesic use: Patients with acute nephrolithiasis should be managed with adequate analgesia after ruling out an acute abdominal surgical condition and obstructive pyelonephritis (pyonephrosis). Non-steroidal anti-inflammatory drugs (NSAIDS) are preferred to opioids as NSAIDs can be used as monotherapy and they have an additional anti-prostaglandin effect. On the other hand, opioids like pethidine increase vomiting, reduce bowel motility, and also require higher doses to show therapeutic effects. [76] NSAIDs will interfere with platelet function and increase bleeding with some surgeries.  
5. Medical expulsive therapy: The use of selective alpha-blockers, such as tamsulosin, has been shown to help facilitate spontaneous stone passage. This benefit is most useful for smaller stones in the distal ureter. The overall benefit appears to facilitate spontaneous stone passage by about 30%. [77][78]
6. Antibiotics: Their use in stone cases with fever, sepsis, or infection is obvious, but some experts suggest adding a brief, low level of antibiotics as prophylaxis upon diagnosis as patients can develop potentially dangerous infections later that complicate their treatment. 

Surgical Management

Surgical management is done when medical treatment fails or urinary tract infections develop. [79][80] A urinary infection with a blocked kidney from a stone is a surgical emergency and should be addressed urgently. It may require emergent drainage by a double J stent placed cystoscopically or a percutaneous nephrostomy. Overall, most cases can be managed as outpatients.

1. Extracorporeal shock wave lithotripsy: for calcific and radio-opaque kidney stones less than 2 cm. Uric acid stones can be treated also but will need contrast (IV or injected via retrograde ureteral catheter) to make the stones visible for targeting.
2. Ureteroscopic stone laser fragmentation and retrieval: for kidney and ureteral stones less than 2 cm.
3. Percutaneous nephrolithotomy: for larger kidney stones (greater than 2 to 2.5 cm).

Differential Diagnosis

Renal stones can mimic several other possible differential diagnoses that occur in the same anatomical region. Differential diagnoses of uric acid nephrolithiasis include:

1. Acute pyelonephritis
2. Acute Appendicitis
3. Pelvic inflammatory disease
4. Intestinal obstruction
5. Ectopic pregnancy
6. Acute cholecystitis
7. Biliary colic
8. Constipation
9. Costochondritis
10. Calcium, cystine, xanthine, and matrix nephrolithiasis
11. Hydronephrosis
12. Ureteropelvic junction (UPJ) obstruction

Pertinent Studies and Ongoing Trials

There are three ongoing interventional clinical trials in the United States in the uric acid nephrolithiasis:

1. Renal uptake of fatty acids in patients with idiopathic uric acid nephrolithiasis.
2. Pathophysiology of uric acid nephrolithiasis.
3. Pathogenesis of uric acid nephrolithiasis: role of pioglitazone/weight loss.

Toxicity and Adverse Effect Management

Treatment with alkalinizing agents like sodium bicarbonate can increase sodium levels and cause fluid overload, which can be life-threatening in patients with high blood pressure, congestive cardiac failure, and liver cirrhosis. High sodium can also increase the risk of calcium oxalate calculi by promoting calcium and sodium excretion. [81] Side effects from sodium bicarbonate can be controlled with the simultaneous use of acetazolamide, which also increases urinary alkalinization. [82] 

Potassium citrate is the primary urinary alkalinizing agent, but there can be problems in patients with renal failure who have hyperkalemia or who cannot swallow larger tablets. It may also be costly for those without insurance, especially since there are no current pharmaceutical industry indigent programs providing potassium citrate. "Litholyte" is a commercially available citrate supplement and urinary alkalinizer. It is composed of potassium citrate, magnesium citrate, and sodium bicarbonate. Each packet of dissolvable crystals has 10 mEq of citrate but only half the potassium of standard potassium citrate preparations. It is tasteless, available by mail, and relatively inexpensive. It can be ordered online and is available without a prescription as it is officially classified as a "food".

Medical Oncology

Recombinant urate oxidase or uricase (rasburicase) is available for intravenous administration to control the very high serum levels of uric acid that are initially produced when chemotherapy drugs are started in certain types of highly proliferative cancers; usually aggressive non-Hodgkins lymphomas and leukemias that would otherwise cause "tumor lysis syndrome". [83] The syndrome is characterized by nausea, vomiting, diarrhea, muscle cramps, weakness, tingling or numbness, and fatigue. Besides severe hyperuricemia, it is also associated with hyperkalemia, hyperphospatemia and hypocalcemia. If severe and untreated, the syndrome can be lethal.  With rasburicase, the serum uric acid is metabolized to allantoin which is far more soluble. Rasburicase is quite expensive and, with its mandatory IV administration requirement, is only rarely used clinically except for highly selected cases. [84] 

Prognosis

Medical treatment for the dissolution of existing uric acid stones is very effective. Prognosis of uric acid nephrolithiasis is usually good if proper treatment is followed consistently. Recurrent uric acid nephrolithiasis can be prevented by adopting good dietary habits, avoiding dehydration, treating hyperuricosuria and/or hyperuricosuria, and proper usage of alkalinizing agents. Almost 2/3rd of uric acid stones can be dissolved by adopting the following measures:

1. Treating aciduria by maintaining urine pH at 6.5 - 7. If this is not feasible or possible, try to get the urine pH at least up to 6. [81][85]
2. Maintaining adequate hydration and urine volume.
3. Reduction of hyperuricosuria to less than 600 mg/day with the use of allopurinol or febuxostat. [86][87]
4. Treatment of hyperuricemia to less than 6 mg/dL by using allopurinol or febuxostat.

Complications

Uric acid stones are associated with certain complications like obstruction of the urinary tract leading to renal failure and sepsis. Treatment-related complications with extracorporeal shock wave lithotripsy include the need for retreatment, urinary tract infections, hematoma, steinstrasse and sepsis. Complications of ureteroscopy include stent pain, ureteral injury, retreatment, urinary tract infections, urinoma formation and sepsis. Complications of percutaneous nephrolithotomy include sepsis, hematuria, retroperitoneal hematoma formation, blood loss, and the need for arterial embolization to control excessive bleeding. [66]

Consultations

Consultation with a urologist should be done once the diagnosis is established.  Nephrology can be consulted if there is renal failure. A consultation with a local healthcare expert on medical stone prevention testing and prophylactic treatment should be considered in all patients who have a history of stones and are interested in minimizing future stone production.  Depending on the community, this could be a urologist, nephrologist, endocrinologist, or internist; whichever individual healthcare practitioner has sufficient interest and experience in the medical treatment and prophylaxis of nephrolithiasis. 

Deterrence and Patient Education

Patients with uric acid calculi show similar clinical presentations as patients with calcium stones. However, uric acid calculi have a different mechanism of stone formation, radiological diagnosis is more problematic, and management modalities are different. [67] First, uric acid calculi are radiolucent [88][89]; secondly, they are easily soluble with adequate dosing of an appropriate alkalinizing medication, [63][90] and thirdly, there is a higher prevalence of uric acid calculi associated with certain conditions like obesity, gout and diabetes mellitus. [91][92] 

Patients should be educated on the various factors related to the prevention of uric acid nephrolithiasis like adequate fluid intake and dietary control. Adherence to medications also plays a vital role in the management of uric acid nephrolithiasis.

Pearls and Other Issues

The incidence of uric acid nephrolithiasis is rising. The association between uric acid calculi and decreased urine pH has been observed for a long time. Currently, the relationship between uric acid nephrolithiasis and different metabolic conditions and their pathogenesis has been explained. Various conditions like metabolic syndrome, diabetes mellitus, increased dietary purine intake, inherited uric acid disorders, and diseases related to problems in ammonia formation have been found to be related to a decrease in urine pH (aciduria). Climate changes like global warming also appear to have contributed to an increased incidence of uric acid calculi.

There are three different non-surgical modalities to treat uric acid calculi: increase urinary pH, achieve adequate hydration, and manage conditions associated with higher uric acid production. [93]

Measures to prevent the recurrence of uric acid calculi should focus on the reduction of urinary uric acid supersaturation. This includes interventions like increasing urine output to more than 2,000 ml per day, raising urinary pH to at least 6.5 if possible, reducing uric acid concentration in the urine, and using urinary alkalinizing agents like potassium citrate and sodium bicarbonate. Acetazolamide and topiramate are not generally recommended as they cause metabolic acidosis which reduces urinary citrate excretion and tends to cause calcium phosphate stone production. [81][94] 

Uric acid stone formers should be screened for diabetes and metabolic syndrome due to the strong association between these entities. [58]

Summary

Uric acid nephrolithiasis is a growing problem that includes about 10% of all urinary calculi. It is associated with metabolic syndrome, obesity, and diabetes. High purine diets also tend to promote these stones. Presentation and initial treatment is similar to other urinary calculi. [95] Diagnosis is primarily by CT scan of the abdomen, preferably without contrast. Uric acid stones can be reliably diagnosed if the urine pH is <5.5 and the Hounsfield Units for the stone is 500 units or less.  Pure uric acid calculi will typically not be visible on plain abdominal x-rays (KUB).  

The majority of uric acid stones are formed under conditions of excessive aciduria rather than hyperuricosuria.  Prophylactic treatment is with urinary alkalkinization which is primarily done with potassium citrate.  Sodium bicarbonate, sodium citrate, and magnesium citrate can be substituted for alkalinization if potassium citrate is not tolerated well or otherwise unacceptable due to hyperkalemia. "Cytra-2" and "Litholyte" are low potassium urinary alkalinizers that can be alternatives for potassium citrate as needed. Sufficient alkalinization can also dissolve existing stones, but urinary pH needs to be at least 6.1 and optimally at least 6.5 or more to achieve dissolution.

If hyperuricsuria or hyperuricemia is found, then allopurinol or febuxostat (Uloric) can be used. 

Enhancing Healthcare Team Outcomes

The diagnosis and management of uric acid nephrolithiasis require coordination among various health care professionals like nephrologists, radiologists, urologists, primary care providers, nurses, and pharmacists. In most cases, conservative treatment with uric acid dissolving medications helps to resolve the nephrolithiasis. However, in the case of urinary obstructions and accompanying renal failure or infection, urology surgical help is required for further management. The prognosis is good in most of the cases, and patient recovery is rapid.