Studies






Reference [3,5]
Risk factor Comment
General risk factors
Previous stone
  • In patients who have passed a kidney stone, the risk of recurrence is 40% at 5 years and 75% at 20 years
  • The risk appears to be greatest in patients who develop stones in childhood or adolescence
Male sex
  • Males have about twice the risk as women
White race
  • Whites have about 3 times the risk as blacks
Family history
  • Family history of stones increases risk
Obesity
  • Obesity is associated with elevated uric acid levels
  • Elevated uric acid levels increase the risk of calcium oxalate stones and uric acid stones
Diseases/Conditions
Hyperparathyroidism
  • Kidney stones occur in about 20% of patients with primary hyperparathyroidism
  • Elevated calcium levels lead to hypercalciuria and increased urinary pH
Gout
  • Elevated uric acid levels increase the risk of calcium oxalate stones and uric acid stones
Shortened bowel syndrome (e.g. bariatric surgery, intestinal resection)
  • Calcium binds oxalate in the intestine and decreases its absorption
  • In shortened bowel syndrome, fat malabsorption may increase the binding of calcium to fatty acids in the intestinal lumen
  • The loss of available calcium to bind oxalate can increase the absorption of oxalate in the colon leading to hyperoxaluria
  • Hyperoxaluria increases the risk of calcium oxalate stones
Pancreatic insufficiency
  • Calcium binds oxalate in the intestine and decreases its absorption
  • In pancreatic insufficiency, fat malabsorption may increase the binding of calcium to fatty acids in the intestinal lumen
  • The loss of available calcium to bind oxalate can increase the absorption of oxalate in the colon leading to hyperoxaluria
  • Hyperoxaluria increases the risk of calcium oxalate stones
Sarcoidosis
  • Sarcoidal macrophages convert 25-hydroxyvitamin D to its more active form, 1,25 dihydroxyvitamin D
  • Elevated vitamin D activity increases calcium absorption
  • Hypercalciuria occurs in 50% of patients with sarcoidosis
Renal tubular acidosis type 1
  • Renal tubular acidosis occurs when the nephron loses its ability to reabsorb bicarbonate and excrete acid
  • This leads to hypocitraturia and elevated urinary pH
Primary hyperoxaluria
  • Rare condition that leads to the overproduction of oxalate
  • 24-hour urine oxalate excretion > 75 mg/day in adults should raise suspicion
Anatomical abnormalities
  • Examples include: medullary sponge kidney (tubular ectasia), ureteropelvic junction obstruction, calyceal diverticulum, calyceal cyst, ureteral stricture, vesico-uretero-renal reflux, horseshoe kidney, ureterocele


Reference [3,5]
Dietary factor Comment
Low fluid intake
  • Low fluid intake (< 2.5 liters/day) may increase the risk for stones
High/low calcium intake
  • High calcium intake (> 1200 mg/day) may increase the risk for stones
  • Contrarily, low calcium intake (< 1000 mg/day) may increase the risk of stones by increasing the absorption of oxalate
High sodium intake
  • High sodium intake (> 5 grams/day) may increase the risk for stones
  • High sodium promotes stone formation through increased calcium excretion, decreased urinary citrate, and increased risk of sodium urate crystal formation
High purine intake
  • Purines are metabolized to uric acid
  • High purine intake can lead to hyperuricosuria and subsequent stone formation
  • High concentrations of purines are found in anchovies, sardines, herring, mackerel, scallops, mussels, waterfowl, organ meats, glandular tissue, gravies, and meat extracts
  • Moderate-high concentrations of purines are found in shellfish, fish, game meats, mutton, beef, pork, poultry, and meat-based soups and broths
High oxalate intake
Fruits and vegetables vs meats, cheese, and eggs
  • Fruits and vegetables confer an alkaline load on the kidneys and promote urinary citrate excretion (prevent stones)
  • Meats, fish, poultry, cheese, and eggs confer an acidic load on the kidneys and promote citrate reabsorption (stone promotion)
Vitamin C
  • Vitamin C is metabolized to oxalate
  • High vitamin C intake may increase urinary oxalate concentrations and lead to stone formation
Vitamin D
  • Vitamin D promotes calcium absorption and may increase urinary calcium excretion


Reference [3,5]
Medication Comment
Acetazolamide (Diamox®)
  • Acetazolamide causes urinary alkalinization which can promote stone formation
Allopurinol
  • Oxypurinol, a metabolite of allopurinol, has been shown to crystallize and form stones in case reports
Amoxicillin
  • In rare cases, amoxicillin has been found to promote crystalluria
Ceftriaxone (Rocephin®)
  • Ceftriaxone may combine with calcium to promote stone formation in the urine
Ephedrine
  • Cases of kidney stones containing ephedrine have been reported
Fenofibrate
  • Fenofibrate promotes uric acid excretion and could theoretically promote stone formation
Guaifenesin
  • Cases of kidney stones containing guaifenesin have been reported
Laxatives
  • Laxatives may promote stone formation through dehydration and hypocitraturia resulting from hypokalemia
Lithium
  • Lithium may cause hyperparathyroidism leading to increased calcium and hypercalciuria
Loop diuretics
  • Loop diuretics (furosemide, bumetanide, torsemide) increase urinary calcium concentrations and may increase the risk of stone formation
Losartan
  • Losartan promotes uric acid excretion and could theoretically promote stone formation
Indinavir (Crixivan®)
  • Indinavir may cause kidney stones
Probenecid
  • Probenecid promotes uric acid excretion into the urine
Quinolones (ciprofloxacin, levofloxacin, etc.)
  • Alkaline and/or concentrated urine may promote crystallization of quinolones
SGLT2 inhibitors
  • SGLT2 inhibitors promotes uric acid excretion and could theoretically promote stone formation
Sulindac
  • Metabolites of the NSAID sulindac have been found in some kidney stones
Sulpha drugs
  • Sulfa drugs have been shown to cause crystalluria
Topiramate (Topamax®)
  • Topiramate decreases urinary citrate excretion and increases urinary pH which in turn, may promote stone formation
Triamterene
  • The potassium-sparing diuretic triamterene has been found in kidney stones
  • See triamterene stones for more
Zonisamide
  • The anticonvulsant zonisamide increases the risk for kidney stone formation



References [1,2,6]
Major factors associated with kidney stone formation
Factor Causes Comment Normal urine range
Hypercalciuria
  • Familial idiopathic hypercalciuria
  • Hyperparathyroidism
  • Sarcoidosis
  • ↑ Vitamin D/Calcium intake
  • Loop diuretics
  • Increased urinary calcium promotes stone formation by increasing the amount of calcium available to bind to oxalate and phosphate [1]
Men: < 300 mg/day
Women: < 250 mg/day
Hyperoxaluria
  • Low dietary calcium
    (↑ oxalate absorption)
  • Fat malabsorption
    (bowel surgery, etc.)
  • High dietary oxalate intake
  • Primary hyperoxaluria
  • ↑ Vitamin C
    (metabolized to oxalate)
  • Oxalate is an end product of metabolism in humans. It is also found in foods and is absorbed from the intestine when consumed.
  • When intestinal oxalate is not bound to calcium, it is more readily absorbed. Deficiencies in unbound intestinal calcium can promote oxalate absorption. These deficiencies may occur through decreased calcium consumption, or in the setting of fat malabsorption (e.g. shortened bowel syndrome, bariatric surgery). Unabsorbed fats sequester calcium and decrease its availability to bind oxalate.
  • Increased oxalate absorption or production can lead to hyperoxaluria and stone formation [1,6]
< 40 mg/day
Hypocitraturia
  • Renal tubular acidosis
  • Hypokalemia
  • Medications
    (topiramate, acetazolamide)
  • Citrate is a weak acid that has two roles in preventing stone formation
  • Citrate permits base excretion without raising urinary pH. Citrate also forms a soluble complex with calcium and prevents it from forming crystals.
  • Low levels of urinary citrate can promote stone formation [2]
Men: > 450 mg/day
Women: > 550 mg/day
Hyperuricosuria
  • Obesity
  • Gout
  • ↑ Dietary purines
  • Uric acid is a byproduct of purine metabolism
  • Hyperuricosuria plays a role in the formation of two different types of stones. Uric acid promotes calcium stone formation by decreasing the solubility of calcium oxalate. Uric acid can also crystallize and form its own stones (uric acid stones). [1,2]
Men: < 800 mg/day
Women: < 750 mg/day
Urinary pH
  • Alkaline urinary pH (> 6.2) can promote calcium phosphate stone formation through supersaturation
  • Alkaline urinary pH also increases urinary citrate concentrations which helps prevent stones
  • Acidic urinary pH (< 5.5) promotes uric acid stone formation [1,2]
5.8 - 6.2

Stone types
Stone type % of stones
(see footnote)
Comment Radiology
Calcium oxalate 67%
  • The majority of kidney stones are calcium oxalate stones
  • Calcium oxalate stones often contain some amount of calcium phosphate
  • Calcium oxalate stones are harder and more resistant to shockwave therapy [1,2,3]
Radiopaque
Calcium phosphate
(apatite)
16%
  • Calcium phosphate stones occur in 2 different forms - apatite and brushite
  • Apatite stones are far more common than brushite stones
  • Calcium phosphate stones often contain some amount of calcium oxalate [3]
Radiopaque
Uric acid 8%
  • Uric acid stones are more common in men, obese patients, and diabetics
  • Acidic urine promotes uric acid stone formation [2]
Radiolucent
Struvite 3%
  • Struvite stones are composed of magnesium ammonium phosphate
  • Struvite stones form in the setting of chronic urinary infections with certain urea-splitting organisms (e.g. Proteus, Klebsiella, Pseudomonas)
  • Infecting organism alter urinary ammonium and bicarbonate concentrations promoting stone formation [2]
Mildly radiopaque
Calcium phosphate
(brushite)
0.9%
  • Calcium phosphate stones occur in 2 different forms - apatite and brushite
  • Brushite stones are far less common than apatite stones
  • Brushite stones have a higher risk of recurrence
  • Brushite stones are harder and more resistant to shockwave therapy [3]
Radiopaque
Cystine stones 0.4%
  • Cystine stones occur in patients who have congenital defects in renal amino acid transporters
  • These defects lead to high urinary concentrations of cysteine (> 100 mg in a 24-hour urine)
  • Family history and young age of presentation should raise suspicion for cystine stones
  • Cystine stones are harder and more resistant to shockwave therapy [1,2,3]
Mildly radiopaque
Staghorn stones rare
  • Staghorn stones are large renal stones that extend into and take the shape of at least 2 renal calyces (see staghorn illustration). This gives the stone the shape of a male deer (stag) rack.
  • Staghorn formation is most commonly seen with struvite stones
  • Large staghorn stones may lead to renal obstruction and failure [2]
Typically opaque













Reference [3]
Imaging studies for kidney stones
Study Comment Accuracy
Non-contrast-enhanced CT scan
  • Preferred imaging study for diagnosing kidney stones
  • Able to detect uric acid stones
  • Can detect stone density, inner structure of the stone, and skin-to-stone distance (important information for shockwave therapy)
  • Low-dose CT scans can be used in patients with BMI < 30
Sensitivity: 97%
Specificity: 95%
Ultrasound
  • Does not expose patient to radiation so is preferred in certain situations (e.g. pregnancy)
Renal stones
Sensitivity: 45%
Specificity: 88%
Ureteral stones
Sensitivity: 45%
Specificity: 94%
X-ray (KUB)
  • A plain film X-ray of the abdomen will show radiopaque stones
  • Typically used to follow stone progression after diagnosis with a CT scan
Sensitivity: 44 - 77%
Specificity: 80 - 87%
Intravenous pyelogram (IVP)
  • An IVP is performed by giving the patient IV contrast and then taking X-rays of the kidneys, ureters, and bladder (KUB)
  • The contrast makes the urinary system visible on the X-ray
  • IVP used to be the preferred method for detecting kidney stones, but it has largely been replaced by CT scans


Laboratories to consider in patients with kidney stones
Study Comment Normal range
Urinalysis
  • All patients should have a urinalysis
  • Symptomatic ureteral stones typically cause gross or microscopic hematuria
  • In one study (n=140), 85% of patients presenting to the ER with documented urinary lithiasis had hematuria on urinalysis. When a positive urinalysis or a positive urine dipstick was used as criteria, 94% of patients had hematuria. [13]
  • Urinary signs of infection should be investigated promptly
Serum electrolytes, calcium level
  • All patients should have serum electrolytes and calcium levels checked
  • Elevated calcium levels should raise suspicion for hyperparathyroidism
  • Reduced serum bicarbonate and elevated chloride should raise suspicion for renal tubular acidosis type 1
Uric acid, serum
  • Uric acid levels should be checked in high-risk patients (e.g. gout, obesity)
  • Male: 3.7 - 8.6 mg/dl
  • Female: 2.5 - 7.1 mg/dl
24-hour urine testing
  • Recurrent and high-risk stone formers should have 24-hour urine testing. First-time stone formers may also elect to be tested.
  • 24-hour urine should be obtained while consuming a random diet
  • The AUA recommends that 24-hour urine testing include the following: urine volume, pH, calcium, oxalate, uric acid, citrate, sodium, potassium, and creatinine
  • Creatinine is measured to assess compliance with 24-hour collection
  • Potassium may be used to assess compliance with medications
  • Sodium is measured to assess dietary sodium intake
  • Calcium, oxalate, uric acid, citrate, and pH are risk factors for stone formation - see factors in stone formation above
  • Urine volume: > 1500 ml/day
  • Urine pH: 5.8 - 6.2
  • Calcium:
    • < 300 mg/day (men)
    • < 250 mg/day (women)
  • Oxalate:
    • 7 - 44 mg/day (men)
    • 4 - 31 mg/day (women)
  • Uric acid: 250 - 750 mg/day
  • Citrate: 320 - 1240 mg/day
  • Sodium: 40 - 220 mmol/day
  • Potassium: 25 - 125 mmol/day
  • Creatinine:
    • 20 - 24 mg/kg/day (men)
    • 15 - 19 mg/kg/day (women)
Stone analysis
  • If stone is available, stone analysis should be performed to determine the type of stone
Parathyroid hormone (PTH)
  • Primary hyperparathyroidism should be considered when calcium level is high or high-normal
  • Intact PTH (active form) should be drawn
15 - 65 pg/ml
Cystine, 24-hour urine
  • In patients where cystine stones are suspected
10 - 100 mg/day



Reference [3]
EAU recommendations for renal stone management
Treatment Comments
Observation
  • Non-obstructing renal stones may be followed with observation only
  • If stones remain stable after 6 months of observation (X-ray, US, etc.), then yearly follow-up may be sufficient
  • There is no consensus guideline regarding optimal follow-up intervals
Shockwave lithotripsy (SWL)
  • SWL involves crushing the stone with high-energy, pulsatile sound waves that are delivered externally (extracorporeal) and focused on the stone
  • SWL works best for stones that are < 20 mm, and for stones that are in the renal pelvis or upper/middle calices
  • Complications of SWL include renal colic, regrowth of residual fragments (up to 59% of patients), bacteriuria, hematoma formation, and steinstrasse (accumulation of stone fragments in the ureter that do not pass)
Percutaneous nephrolithotomy (PNL)
  • PNL involves making a small incision in the skin, inserting a catheter into the kidney, and removing the stone manually
  • PNL is recommended for stones ≥ 20 mm. It may also be preferred for lower pole stones.
  • Complications of PNL include infection, bleeding, and urinoma (urine-filled cyst formed from leakage of urine into retroperitoneum)
Ureterorenoscopy
  • Ureterorenoscopy involves running an endoscope through the urethra and bladder, up the ureter, and into the renal pelvis. The endoscope may be used to deliver devices (e.g. laser) that can fragment the stone and/or retrieve it.
  • Ureterorenoscopy can be used to treat all types of stones regardless of size or location
  • Complications include pain, bleeding, infection, and need for ureteral stent
Urinary alkalinization
(uric acid stones)
  • Urinary alkalinization via oral therapies can be used to treat uric acid stones
  • Patients are given either potassium bicarbonate or potassium citrate, and these medications induce an alkaline urine that dissolves uric acid stones


Reference [3,10]
EAU recommendations for ureteral stone management
Treatment Comments
Observation
  • For stones up to 4 mm in size, 95% will pass spontaneously within 40 days
  • For stones 5 - 10 mm in size, approximately 61% will pass spontaneously within 28 days of becoming symptomatic
  • Stones ≥ 10 mm generally will not pass
  • Patients should have follow-up within 14 days to assess stone position and check for hydronephrosis

Medical expulsive therapy (MET)
  • MET is treatment with alpha blockers or nifedipine to facilitate stone passage. These medications theoretically inhibit ureteral contractions and thereby allow stones to pass easier.
  • In randomized controlled trials, their effects have been null to marginal (see studies for more)
  • The EAU recommends alpha blockers (typically tamsulosin 0.4 mg/day) to help facilitate stone passage and to reduce pain. Tamsulosin is typically prescribed for one month.
Shockwave lithotripsy (SWL)
  • SWL involves crushing the stone with high-energy, pulsatile sound waves that are delivered externally (extracorporeal) and focused on the stone
  • SWL may be used to treat all types of ureteral stones
  • Complications of SWL include renal colic, bacteriuria, hematoma formation, and steinstrasse (accumulation of stone fragments in the ureter that do not pass)
Ureterorenoscopy
  • Ureterorenoscopy involves running an endoscope through the urethra, bladder, and into the ureter. The endoscope may be used to deliver devices (e.g. laser) that can fragment the stone and/or retrieve it.
  • Ureterorenoscopy can be used to treat all types of ureteral stones
  • Ureteral stents are sometimes placed after ureterorenoscopy to prevent the inflamed ureter from swelling and causing an obstruction. Stents are typically removed after 1 - 2 weeks.
  • Complications include pain, bleeding, infection, and need for ureteral stent



AUA recommendations for stone prevention
Stone type Urine findings Treatment
All types
  • Fluid intake to achieve a urine volume of 2.5 liters a day
Calcium stones High urinary calcium
  • Limit sodium intake to < 2300 mg/day
  • Consume 1000 - 1200 mg of calcium a day
  • Thiazide diuretics should be offered to patients with recurrent stones
High urinary oxalate
Low urinary citrate
  • Increase intake of fruits and vegetables and limit non-dairy animal protein to 0.8 - 1 g/kg/day
  • Potassium citrate should be offered to patients with recurrent stones
High urinary uric acid
  • Limit intake of non-dairy animal protein to 0.8 - 1 g/kg/day
  • *Limit purine intake (see footnote)
  • Allopurinol should be offered to patients with recurrent calcium oxalate stones, hyperuricosuria, and normal urinary calcium
None
  • Thiazide diuretics and/or potassium citrate should be offered to patients with recurrent stones who have no metabolic abnormalities and in those who have stones despite appropriate treatment of abnormalities
Uric acid stones Low urinary pH
  • Potassium citrate should be offered to raise urinary pH to an optimal level (pH of 6 - 7)
  • Allopurinol should not be offered as a first-line agent since the underlying stone-promoting abnormality is low urinary pH
  • If stones recur despite alkalinization of the urine, then allopurinol may be considered
Cystine stones High urinary cystine
  • Limit sodium intake to < 2300 mg/day
  • Limit protein intake to 0.8 - 1 g/kg/day
  • Potassium citrate should be offered to raise urinary pH to an optimal level (pH of > 7.0)
  • Cystine-binding thiol drugs (e.g. tiopronin) may be offered to patients who form stones despite dietary modification and urinary alkalinization

Medications
Medication Dosage form/Price Dosing
Thiazide diuretics
  • HCTZ - 12.5, 25, 50mg ($)
  • Chlorthalidone - 15, 25, 50mg ($)
  • Indapamide - 1.25, 2.5mg ($)
  • HCTZ - 25 mg twice daily or 50 mg once daily
  • Chlorthalidone - 25 mg once daily
  • Indapamide - 2.5 mg once daily
  • Monitor for and treat hypokalemia because it may worsen hypocitraturia
  • See thiazide diuretics for more information
Potassium citrate
  • Potassium citrate (Urocit-K®)
    • 5, 10, 15 mEq tablet ($$-$$$)
  • Urine citrate < 150 mg/day - 60 mEq/day given as 30 mEq twice daily or 20 mEq three times a day
  • Urine citrate > 150 mg/day - 30 mEq/day given as 15 mEq twice daily or 10 mEq three times a day
  • Give with meals or within 30 minutes after a meal
  • Monitor renal function and serum potassium closely (at least every 4 months)
  • Monitor urinary pH and citrate every 4 months
  • Target urinary pH is 6 - 7. Long-term use at a dose of 60 mEq/day raises urinary citrate by ∼ 400 mg/day and increases pH by ∼ 0.7 units
Allopurinol
  • 100 and 300mg tablet ($)
  • 100 - 300 mg once daily