Uric Acid Nephrolithiasis

Article Author:
Manish KC
Article Editor:
Stephen Leslie
Updated:
9/22/2020 9:17:05 AM
For CME on this topic:
Uric Acid Nephrolithiasis CME
PubMed Link:
Uric Acid Nephrolithiasis

Introduction

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 conditions, dietary and environmental factors. [1][2][3][4]

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 age group. [5] Obesity, hyperglycemia (elevated blood sugar), metabolic syndrome and high blood pressure are frequently associated with uric acid calculi in Western countries. [6]

Etiology

The etiology of uric acid stones can be diverse and is classified as follows: [7]

  • Idiopathic: most common etiology, associated with metabolic disorders like obesity, diabetes mellitus, and aciduria (low urinary pH).
  • Acquired: less common, associated with low urinary pH and hyperuricosuria
    1. Gout
    2. Persistent diarrhea: Low urinary volume is seen instead of hyperuricosuria
    3. Cancer
    4. Dietary factors
  • Congenital: uncommon, associated with hyperuricosuria
    1. Lesch-Nyhan syndrome
    2. Von-Gierke disease
    3. URAT1 mutations

The occurrence of uric acid stones has risen considerably in patients suffering from metabolic syndromes. [4] 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 contributing cause is reduced hepatic ammonia synthesis.[8] Gout and/or hyperuricemia is associated with uric acid uropathy in 15 to 25% of uric acid nephrolithiasis patients. [9][10][11][12] A purine-rich diet, including substantial animal protein, increases the risk of uric acid nephrolithiasis. [11][13][14]

Uric acid is much less soluble at a low urinary pH (5 or less), whereas solubility greatly increases at a higher urinary pH (6.5 or more). [8]

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. [15][16] 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. [17]

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. [18][19] 

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%. The prevalence of uric acid stones has been found to be 6% in the white population, whereas it was 30% in the non-white population. [20][21] Environmental factors also influence the incidence 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. [21][22]

Pathophysiology

Factors related to the formation of uric acid stones include a 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). [23][24] 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 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. [25]

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 a low urinary pH. [26][27] 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. [27][28] Both of these conditions are characterized by hyperuricemia, a decrease in fractional excretion of uric acid, and persistently low urinary pH levels. Decreased urinary pH is associated with lower urinary ammonia excretion due to metabolic syndrome. This may also explain the observed association between obesity and aciduria. [29][30] The decrease in urine pH forms uric acid stones by inducing changes in the dissolution of uric acid and acid-base status. [31][32] 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 may lead to uric acid stone formation. Further, an increased urinary uric acid will not contribute to the formation of uric acid nephrolithiasis if the urine pH is increased. [33]

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 precipitation of uric acid crystals, which lead to stones. This explains why uric acid stones are more common in tropical and humid climates. [34][35]

Hyperuricosuria

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. [36][37][38]

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. [39] 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. [39][40][41]

Histopathology

Light microscopy of urine will sometimes show urinary crystallizations with characteristic rectangular or rhomboid-shaped uric acid crystals. [42]

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
  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. 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. [43][44] Comprehensive past medical and family history must be obtained focusing on problems related to uric acid stone formation like cancers, myeloproliferative neoplasms, inherited disorders related to hyperuricosuria, indigestion, and diarrhea. [45]

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.

Spot urine: To evaluate urine pH and routine urinalysis. Typical uric acid crystals can often be observed.

Blood workup: To evaluate creatinine, uric acid levels, eGFR, serum electrolytes, calcium, and complete blood count. [46]

Radiographic

After necessary 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 not clear. [47]

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. [48] 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 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. [49] Ultrasound has an overall 45% sensitivity and 88% specificity in the detection of kidney stones. [50]

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 Scan

Non-contrast enhanced computed tomography 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 stones. It can also reveal associated deformities even in the absence of uric acid stones. [51][52] Non-contrast is preferred because the contrast makes the urine white on the scans. Since stones are also white, adding contrast will hide the stones and make them harder to diagnose. It will also interfere with the 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.[9] Overall, urinary alkalinization is considered the single most effective therapy. The goal is to achieve a urine pH of 6 to 6.5.

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. A high intake of fluids to maintain adequate urinary output is useful to lower supersaturations and help prevent urinary stones. Recommendations to reduce obesity, appropriate management of high blood pressure and high blood sugar are also helpful in reducing the burden of uric acid kidney stones.

Medical Management [7]

  1. Increased fluid intake with adequate 24-hour urine output (2 to 2.5 L/day).
  2. Urinary alkalinization: Helps in the dissolution and prevention of all uric acid stones. The goal is urinary pH that is consistently around 6.5. Ultrasound and CT scans can be used to monitor the response to treatment.
    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 (reduced potassium urinary alkalinizer and citrate supplement. It includes sodium bicarbonate, magnesium citrate, and potassium citrate. Overall, about half the potassium of potassium citrate but equivalent citrate load.)
  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.[53] NSAIDs will interfere with platelet function and increase bleeding with some surgeries so check with urology before prescribing.  
  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%. [54][55]
  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 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. [56][57] 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 injected contrast (IV or injected via retrograde ureteral catheter) to make the stones visible.
  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, 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 Side Effect Management

Treatment with alkalinizing agents like sodium bicarbonate can increase sodium level 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. [58] Side effects from sodium bicarbonate can be controlled with the simultaneous use of acetazolamide, which also increases urinary alkalinization. [59] 

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 dissolvable packet has 10 mEq of citrate but only half the potassium of standard potassium citrate preparations. It is tasteless, available, and relatively inexpensive. It can be ordered online and is available without a prescription as it is officially classified as a "food".

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 7
  2. Maintaining adequate hydration and urine volume
  3. Reduction of hyperuricosuria to less than 600 mg/day with the usage of allopurinol or febuxostat. [60][61]
  4. Treatment of hyperuricemia to less than 6 mg/dL with the usage of 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 extracorporealshock wave lithotripsy include the need for retreatment, urinary tract infections, hematoma, and sepsis. Complications of ureteroscopy include stent pain, ureteral injury, retreatment, urinary tract infections, and sepsis. Complications of percutaneous nephrolithotomy include sepsis, hematuria, retroperitoneal hematoma formation, blood loss, and the need for arterial embolization. [46]

Consultations

Consultation with a nephrologist and a urologist can be done once the diagnosis is made. A urologic surgeon can be consulted in case any urinary tract complication arises. Diet experts can also be consulted to reduce the burden of uric acid in the patient’s diet.

Deterrence and Patient Education

Patients with uric acid calculi show similar clinical presentations as patients with calcium calculi. However, uric acid calculi have a different mechanism of stone formation, radiological diagnosis is more problematic, and management modalities are different. [47] First, uric acid calculi are radiolucent [62][63]; secondly, they are easily soluble with an appropriate alkalinizing medication  [43][64], and thirdly, there is a higher prevalence of uric acid calculi with certain conditions like obesity, gout and diabetes mellitus. [65][66] 

Patients should be educated on 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 are 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, adequate hydration, and management of conditions associated with higher uric acid production. [67]

Measures to prevent the recurrence of uric acid calculi should focus on the reduction of uric acid supersaturation in the urine. This includes interventions like increasing urine output to more than 2,000 ml per day, raising urine pH to at least 6.5 (preferably 7), reducing uric acid concentration in the urine, and using urinary alkalinizing agents like potassium citrate, sodium bicarbonate, and acetazolamide. [68]

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.

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