AUA: Evaluation and Medical Management of Stones (2019)

See Original AUA Guidelines

See 2016 CUA Guideline Notes on Evaluation and Medical Management of Stones

Diagnosis and Evaluation

Screening evaluation

• Patient with newly diagnosed kidney or ureteral stones should undergo:

1. History and Physical Exam
2. Laboratory (5)
   1. Urinalysis +/- culture
   2. Serum electrolytes (Na, K, Cl, HCO3)
   3. Serum calcium
   4. Serum creatinine
   5. Serum uric acid

• Same as CUA except for uric acid which is part of extended work-up in CUA

History and physical exam

• Conditions associated with stone disease (8):
  1. Obesity
  2. Hyperthyroidism
  3. Gout
  4. Renal tubular acidosis (RTA) type 1
  5. Diabetes mellitus type 2
  6. Bone disease
  7. Primary hyperparathyroidism
  8. Malabsorptive gastrointestinal states due to bowel resection, bariatric surgery or bowel or pancreatic disease
• Dietary history
  • Should include average daily intake of fluids (amount and specific beverages), protein (types and amounts), calcium, sodium, high oxalate-containing foods, fruits and vegetables and over-the-counter supplements.
    • Nutritional factors associated with stone disease, depending on stone type and risk factors, include
      • Calcium intake below or significantly above the recommended dietary allowance (RDA)
      • Low fluid intake
      • High sodium intake
      • Limited intake of fruits and vegetables
      • High intake of animal-derived purines
• Medications
  • Stone-provoking medications or supplements (9):
    1. Probenecid
    2. Some protease inhibitors
    3. Lipase inhibitors
    4. Triamterene
    5. Chemotherapy
    6. Vitamin C
    7. Vitamin D
    8. Calcium
    9. Carbonic anhydrase inhibitors such as topiramate, acetazolamide, zonisamide

Laboratory

• Urinalysis +/- culture
  • Dipstick
    • Assess urine pH and indicators of infection
    • Urine culture should be obtained in patients with a urinalysis suggestive of UTI.
    • The presence of high urine pH (>7.0) or urea-splitting organisms, such as Proteus species, raises the possibility of struvite stones.
  • Microscopic evaluation
    • Identify crystals pathognomonic of stone type.
• Serum chemistries (electrolytes (Na, K, Cl, HCO3), calcium, creatinine and uric acid)
  • May suggest underlying medical conditions associated with stone disease (e.g., primary hyperparathyroidism, gout, RTA type 1)
• Parathyroid hormone (PTH)
  • Indicated as part of the screening evaluation if primary hyperparathyroidism is suspected
    • Primary hyperparathyroidism should be suspected when (3):
      1. Mid-range PTH despite high or high normal serum calcium
      2. Increased urinary calcium
      3. Predominantly calcium phosphate stone composition
  • Measurement of vitamin D levels may be helpful as low vitamin D levels may mask primary hyperparathyroidism, or contribute to secondary hyperparathyroidism.
  • A high or high normal intact PTH in these settings should prompt further endocrine evaluation, imaging or referral for consideration of parathyroidectomy.
• Stone analysis
  • When a stone is available, a stone analysis should be obtained at least once.
    • Calcium phosphate stone composition associated with:
      1. RTA Type 1
      2. Primary hyperparathyroidism
      3. Medullary sponge kidney
      4. Use of carbonic anhydrase inhibitors

Imaging

• Imaging studies should be obtained and reviewed to quantify stone burden
• Conditions associated with nephrocalcinosis:
  1. RTA type 1
  2. Primary hyperparathyroidism
  3. Medullary sponge kidney
  4. Primary hyperoxaluria

Additional metabolic testing

• High-risk or interested first-time stone formers and recurrent stone formers should undergo additional metabolic testing
  • High-risk and/or recurrent stone formers include those with (different list than CUA):
    1. Family history of stone disease
    2. Malabsorptive intestinal disease or resection
    3. Recurrent UTIs
    4. Obesity
    5. Medical conditions predisposing to stones (e.g., RTA Type 1, primary hyperparathyroidism, gout, diabetes mellitus type)
    6. Solitary kidney; considered "high-risk" because of the serious implications of obstruction in a solitary kidney
• Metabolic testing should consist of one or two 24-hour urine collections obtained on a random diet and analyzed at minimum for (9): volume, pH, creatinine, sodium, potassium, calcium, oxalate, uric acid, and citrate (CUA includes magnesium but not pH)
  • In stone formers with known cystine stones or a family history of cystinuria or for those in whom cystinuria is suspected, urinary cystine should additionally be measured.
  • 24-hour urine testing can be used to inform and monitor treatment protocols
  • Either one or two 24-hour urines may be obtained, although 2 collections are preferred by the Panel
  • The accuracy of a 24-hour urine collection should be assessed prior to interpretation of results.
    • To assess the adequacy of collection, 24-hour urinary creatinine excretion, taking into account patient gender and body weight, as well as patient recall of the start and end times of his or her collection,should be considered
  • Markers of protein intake, such as urine urea nitrogen or urinary sulfate, are reflective of animal protein intake and can be used to assess dietary adherence.
  • Urinary potassium measured at baseline can be compared to urinary potassium obtained during follow-up to gauge compliance with medication regimens.
  • Primary hyperoxaluria should be suspected when urinary oxalate excretion > 75 mg/day in adults without bowel dysfunction. These patients should be considered for referral for genetic testing and/or specialized urine testing
  • Fast and calcium load testing should not be performed routinely to distinguish among types of hypercalciuria

Management

Diet Therapies

1. Fluid intake that will achieve a urine volume of > 2.5 liters daily (same as CUA) is recommended in all stone formers
   • An RCT of recurrent calcium oxalate stone formers randomized to a high fluid intake vs. no specific recommendations found signifianctly reduced stone recurrence rates in the high fluid intake group (12% vs. 27%, respectively, at 5 years)
   • Although there is no definitive threshold for urine volume and increased risk, an accepted goal is ≥2.5 liters of urine daily.
     • Because of insensible losses and varying intake of fluid contained in food, a universal recommendation for total fluid intake is not appropriate
   • Alcoholic beverages, coffee, decaffeinated coffee, tea and wine have been shown to be associated with a lower risk of stone formation, while sugar-sweetened beverages demonstrated an increased risk.
     • The only specific beverage that has been evaluated for an effect on stone recurrence in an RCT is soft drinks; the group avoiding soft drinks demonstrated a marginally lower rate of stone recurrence at the end of the 3-year trial but the effect appeared to be limited to those consuming primarily phosphoric acid-based (e.g. colas) rather than citric acid-based soft drinks
2. Limiting sodium intake (target of ≤100 mEq (2,300 mg)) is recommended in patients with calcium stones and relatively high urinary calcium
   • Dietary salt (sodium chloride) is linked to urinary calcium excretion
3. Consuming 1,000-1,200 mg per day of dietary calcium is recommended in patients with calcium stones and relatively high urinary calcium
   • A lower calcium diet in the absence of other specific dietary measures is associated with an increased risk of stone formation
     • In the case of calcium oxalate stones, a potential mechanism to explain this apparent paradox is that lower calcium intake results in insufficient calcium to bind dietary oxalate in the gut, thereby increasing oxalate absorption and urinary oxalate excretion.
   • In contrast, the RDA of calcium, defined as 1,000-1,200 mg/day for most individuals, was shown to be associated with reduced risk
   • Total calcium intake should not exceed 1,000-1,200 mg daily
     • If a patient with calcium urolithiasis uses calcium supplements, 24-hour urine samples should be collected on and off the supplement.
       • If urinary supersaturation of the calcium salt in question increases during the period of supplement use, the supplement should be discontinued.
4. Limiting intake of oxalate-rich foods and maintaining normal calcium consumption is recommended in patients with calcium oxalate stones and relatively high urinary oxalate
   • Urinary oxalate is also modulated by calcium intake, which influences intestinal oxalate absorption
   • Other factors that may contribute to higher urinary oxalate include vitamin C (ascorbic acid is metabolized to oxalate) and other over-the-counter nutrition supplements.
5. Increasing intake of fruits and vegetables and limiting non-dairy animal protein is recommended in patients with calcium stones and relatively low urinary citrate
   • Urinary citrate excretion is determined by acid-base status; conditions such as metabolic acidosis, renal tubular acidosis and chronic diarrhea, and some medications, such as carbonic anhydrase inhibitors, may promote hypocitraturia
     • Acidosis can arise from a diet that is inordinately rich in foods with a high potential renal acid load such as meats, fish, poultry, cheese, eggs, and to a lesser extent, grains.
     • Dietary citrate increases urinary citrate excretion
   • Although a number of fruits and juices have been evaluated for their effect on urinary stone risk factors, none have been prospectively evaluated in an RCT assessing actual stone formation.
6. Limiting intake of non-dairy animal protein may help reduce stone recurrence in patients with uric acid stones or calcium stones and relatively high urinary uric acid
   • Urinary uric acid is derived from both endogenous and exogenous sources
     • Diet-derived purines account for an ≈30% of urinary uric acid
   • If diet assessment suggests that purine intake is contributory to high urinary uric acid, patients may benefit from limiting high- and moderately high purine containing foods.
     • "High purine" foods are generally considered specific fish and seafood (anchovies, sardines, herring, mackerel, scallops and mussels), water fowl, organ meats, glandular tissue, gravies and meat extracts.
     • "Moderately-high" sources of purines include other shellfish and fish, game meats, mutton, beef, pork, poultry and meat-based soups and broths
7. Patients with cystine stones should be counselled to increase fluid intake and limit sodium and protein intake
   • High fluid intake is particularly important in cystine stone formers; the target for urine volume is typically higher than that recommended to other stone formers; oral intake of ≥4 L/day is often required
   • Lower sodium intake has been shown to reduce cystine excretion
   • Limiting animal protein intake is of benefit in patients with cystine stones

Pharmacologic Therapies

Calcium or calcium phosphate stones

• Thiazide diuretics should be offered to patients with recurrent calcium or calcium phosphate stones and hypercalcuria
  • Specific drugs and dosages associated with a hypocalciuric effect:
    • Hydrochlorothiazide (25mg orally, twice daily; 50mg orally, once daily)
    • Chlorthalidone (25mg orally, once daily)
    • Indapamide (2.5mg orally, once daily).
  • Potassium supplementation (either potassium citrate or potassium chloride) may be needed when thiazide therapy is employed because of the hypokalemic effects of these medications
    • The addition of amiloride or spironolactone may avoid the need for potassium supplementation.
    • Triamterene, although it is potassium-sparing, should be avoided as stones of this compound have been reported.
• Potassium citrate therapy should be offered to patients with recurrent calcium or calcium phosphate stones and hypocitraturia
  • Calcium stone-forming patients with normal citrate excretion but low urinary pH may also benefit from citrate therapy
    • There is also a risk that higher urine pH can promote calcium phosphate stone formation, or change calcium oxalate stone formers to calcium phosphate stone formers.
  • Potassium citrate is preferred over sodium citrate, as the sodium load in the latter may increase urine calcium excretion. However, other agents such as sodium bicarbonate or sodium citrate should be considered if the patient is at risk for hyperkalemia.

Recurrent calcium stones

• Allopurinol should be offered to patients with recurrent calcium oxalate stones who have hyperuricosuria and normal urinary calcium
  • Hyperuricemia is not a required criterion for allopurinol therapy
  • In addition to medication, specific recommendations about limiting non-dairy animal protein may maximize the efficacy of allopurinol.
• Thiazide diuretics and/or potassium citrate should be offered to patients with recurrent calcium stones in whom other metabolic abnormalities are absent or have been appropriately addressed and stone formation persists
  • Both thiazides and potassium citrate therapy have been shown to prevent recurrent stones in patients with normal range urinary calcium and citrate, respectively
  • For patients with no identified risk factors for nephrolithiasis, potassium citrate may be the preferred first-line therapy, given its relatively low side effect profile.

Uric acid stones

• Allopurinol should not be routinely offered as first-line therapy to patients with uric acid stones
  • Most patients with uric acid stones have low urinary pH rather than hyperuricosuria as the predominant risk factor
    • First-line therapy for patients with uric acid stones is alkalinization of the urine with potassium citrate.
  • Allopurinol may be considered as an adjunct when alkalinization is not successful or for patients who continue to form uric acid stones despite adequate alkalinization of the urine.

Uric acid and cystine stones

• Potassium citrate should be offered to patients with uric acid and cystine stones to raise urinary pH to an optimal level
  • For uric acid stone formers, a urine pH of 6.0 (CUA targets 6.5) should be achieved
  • For cystine stone formers, a urine pH of 7.0 (CUA targets >7.0) should be achieved

Cystine stones

• First-line therapy for patients with cystine stones:
  • Increased fluid intake
  • Restriction of sodium and protein intake
  • Urinary alkalinization
• Cystine-binding thiol drugs, such as alpha-mercaptopropionylglycine (tiopronin), should be offered to patients with cystine stones who are unresponsive to dietary modifications and urinary alkalinization, or have large recurrent stone burdens.
  • Tiopronin is possibly more effective and associated with fewer adverse events than d-penicillamine and should be considered first.
  • Captopril, another thiol agent, has not been shown to be effective for the prevention of recurrent cystine stones

Struvite stones

• Acetohydroxamic acid (AHA) may be offered to patients with residual or recurrent struvite stones only after surgical options have been exhausted.
  • Patients treated for struvite stones may still be at risk for recurrent UTIs after stone removal, and in some patients surgical stone removal is not feasible.
  • The use of a urease inhibitor, AHA, may be beneficial in these patients, although the extensive side effect profile may limit its use. In particular, patients taking this medication should be closely monitored for phlebitis and hypercoagulable phenomena

Follow-up

• A single 24-hour urine specimen for stone risk factors should be obtained within 6 months of the initiation of treatment to assess response to dietary and/or medical therapy
• After the initial follow-up, a single 24-hour urine specimen should be obtained annually or with greater frequency, depending on stone activity, to assess patient adherence and metabolic response
  • If patients remain stone free on their treatment regimen for an extended period of time, discontinuation of follow-up testing may be considered.
• Periodic blood testing should be obtained to assess for adverse effects in patients on pharmacological therapy.
  • Thiazide therapy may promote hypokalemia and glucose intolerance
  • Allopurinol and tiopronin may cause an elevation in liver enzymes
  • AHA and tiopronin may induce anemia and other hematologic abnormalities
  • Potassium citrate may result in hyperkalemia
  • Patients with undiagnosed primary hyperparathyroidism may develop hypercalcemia after initiation of thiazide therapy
• Repeat stone analysis, when available, should be obtained especially in patients not responding to treatment
• Patients with struvite stones should be monitored for reinfection with urease-producing organisms and utilize strategies to prevent such occurrences.
  • Monitoring should include surveillance urine culture testing on a periodic basis. In some cases, recurrences may be reduced with long-term, prophylactic antibiotic therapy
• Clinicians should periodically obtain follow-up imaging studies to assess for stone growth or new stone formation based on stone activity (plain abdominal imaging, renal ultrasonography or low dose CT).

Questions

1. What is the recommended workup in a patient with a newly diagnosed kidney stone?
2. What conditions are associated with stone disease?

References

• Pearle, Margaret S., et al. "Medical management of kidney stones: AUA guideline." The Journal of urology 192.2 (2014): 316-324.