KIDNEY STONES










Reference [3,5]
GENERAL RISK FACTORS
Risk factor Comment
Previous stone
  • In patients who have passed a kidney stone, the overall risk of recurrence is 40% at 5 years and 75% at 20 years
  • See risk of recurrent stone below for more
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

Reference [3,5]
MEDICAL CONDITIONS
Medical condition Comment
Parathyroid disease
  • 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 [3,5,14]
DIETARY RISK FACTORS
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
  • Urinary calcium increases by approximately 40 mg/d for every 2300 mg/d increase in dietary sodium
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]
MEDICATIONS THAT PROMOTE STONE FORMATION
Medication Comment
Acetazolamide (Diamox®)
  • Acetazolamide is a carbonic anhydrase inhibitor, and it increases urinary alkalinization
  • Urinary alkalinization 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
Indinavir (Crixivan®)
  • Indinavir may cause kidney stones
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
Mesalamine
  • Cases of kidney stones, including kidney stones with 100% mesalamine content, have been reported during mesalamine therapy. Mesalamine stones are radiolucent, and therefore, are undetectable by X-ray or CT scan.
Orlistat (Xenical®)
  • Orlistat may indirectly promote stone formation by increasing oxalate absorption
Probenecid / Lesinurad
  • The gout medications probenecid and lesinurad promote 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 is a carbonic anhydrase inhibitor, and it increases urinary alkalinization
  • Urinary alkalinization can 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
Zonisamide (Zonegran®)
  • Zonisamide is a carbonic anhydrase inhibitor, and it increases urinary alkalinization
  • Urinary alkalinization can promote stone formation



  • Reference [15]
Annual risk of recurrent kidney stone
Stones passed Annual risk of recurrence
1 3.4%
2 7.1%
3 12.1%
≥ 4 17.6%








  • Percentages are based on a study in the U.S. (2010) that analyzed stones from 43,545 unique individuals. Stones with more than one mineral type were classified based on the predominant mineral (> 50%). [7]
  • References [1,2,3,7]
Kidney Stone Types
Calcium oxalate - 67% of stones
  • 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% of stones
  • 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% of stones
  • Uric acid stones are more common in men, obese patients, and diabetics
  • Acidic urine promotes uric acid stone formation [2]
  • Radiolucent
Struvite - 3% of stones
  • 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% of stones
  • 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% of stones
  • 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 radiopaque























Reference [3]
EAU recommendations for renal stone management
Observation
  • Nonobstructing 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 (also called ureteroscopy) is a procedure where an endoscope is passed through the urethra and bladder into the ureter and renal pelvis. The endoscope can deliver devices (e.g. laser) that fragment and/or retrieve stones.
  • Ureterorenoscopy can be used to treat all types of stones regardless of size and location. Complications of ureterorenoscopy include pain, bleeding, infection, and the need for a ureteral stent.
  • A small study (N=73) published in 2022 found that the removal of small (≤ 6 mm) asymptomatic stones during symptomatic stone removal lowered the risk of relapse. [PMID 35947709]
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
Observation
  • Stone passage
    • 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
  • Follow-up
    • Current guidelines do not make recommendations regarding follow-up in patients whose symptoms have resolved
    • A study that looked at 52 patients with ureteral stones whose pain had resolved at an average of 35 days after symptom onset found that 26% of these patients still had ureteral stones. Most of these patients did not have microscopic hematuria. [PMID 29107030]. In another study that looked at medically-treated ureteral stones, 37% of patients who reported cessation of pain still had ureteral stones, and 19% who reported that they observed the stone pass still had stones. In patients who reported both cessation of pain and observation of stone passage, 20% still had ureteral stones. [PMID 32271691] Lastly, a third study (N=220) looked at patients with ureteral stones < 9 mm in size. At 29 - 36 days after diagnosis, 20% of patients still had a persistent ureteral stone, and of these, 84% had no pain, and 40% had hydronephrosis. [PMID 34627871]
    • Given the high percentage of patients who still have stones after symptom resolution, follow-up imaging may be prudent to avoid the risks of silent ureteral obstruction
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 (also called ureteroscopy) is a procedure where an endoscope is passed through the urethra and bladder into the ureter and renal pelvis. The endoscope can deliver devices (e.g. laser) that fragment and/or retrieve stones.
  • Ureterorenoscopy can be used to treat all types of stones regardless of size and location. Complications of ureterorenoscopy include pain, bleeding, infection, and the need for a ureteral stent, which is sometimes placed to prevent the inflamed ureter from swelling and causing an obstruction. Stents are typically removed after 1 - 2 weeks.
  • A small study (N=73) published in 2022 found that the removal of small (≤ 6 mm) asymptomatic stones during symptomatic stone removal lowered the risk of relapse. [PMID 35947709]

AUA Stone Prevention Recommendations
All stones
  • 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
  • No urine abnormality
    • 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

  • Price (month supply): $ = < $50; $$ = $50 - $100; $$$ = $100 - $150
  • Reference [5, Manufacturer's package insert]
Medications to Prevent Kidney Stones
Allopurinol
  • Dosage forms
    • 100 and 300 mg tablet ($)
  • Dosing
Potassium citrate
  • Dosage forms
    • Potassium citrate (Urocit-K®)
      • 5, 10, 15 mEq tablet ($)
  • Dosing
    • Urine citrate < 150 mg/day - 60 mEq/day given as 30 mEq twice daily or 20 mEq three times a day
    • Urine citrate > 150 mg/day - 30 mEq/day given as 15 mEq twice daily or 10 mEq three times a day
    • Give with meals or within 30 minutes after a meal
    • Monitor renal function and serum potassium closely (at least every 4 months)
    • Monitor urinary pH and citrate every 4 months
    • Target urinary pH is 6 - 7. Long-term use at a dose of 60 mEq/day raises urinary citrate by ∼ 400 mg/day and increases pH by ∼ 0.7 units
Thiazide diuretics
  • Dosage forms
    • HCTZ - 12.5, 25, 50mg ($)
    • Chlorthalidone - 15, 25, 50mg ($)
    • Indapamide - 1.25, 2.5mg ($)
  • Dosing
    • 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


Tamsulosin vs Placebo for Ureteral Stone Passage, JAMA Internal Medicine (2018) [PubMed abstract]
  • The study enrolled 512 patients presenting to the ER with newly-diagnosed, symptomatic ureteral stones < 9 mm in diameter
Main inclusion criteria
  • Symptomatic ureteral stone < 9 mm in diameter confirmed on CT scan
Main exclusion criteria
  • Concurrent UTI
  • Prior ureter/kidney surgery
Baseline characteristics
  • Average age 40 years
  • Average stone size - 3.8 mm
  • Stone size ≤ 4 mm - 74% of patients
  • Stone location: Ureterovesical junction - 44% | Distal ureter - 24% | Proximal ureter 17%
Randomized treatment groups
  • Group 1 (267 patients) - Tamsulosin 0.4 mg once daily for 30 days
  • Group 2 (245 patients) - Placebo once daily for 30 days
Primary outcome: The primary outcome was passage of a ureteral stone within 28 days after randomization, as determined by the participant’s visualization or physical capture of the stone
Results

Duration: 28 days
Outcome Tamsulosin Placebo Comparisons
Primary outcome 49.6% 47.3% p=0.60
Stone passed on follow-up CT (N=238) 83.6% 77.6% p=0.24
Surgery for stone 6.5% 6.9% p=0.89
  • 7.4% of patients in the placebo group crossed over to tamsulosin
  • In subgroup analysis, there was no significant difference in passage rates for stones > 5 mm in diameter (p=0.45)
  • In subgroup analysis, there was no significant difference in passage rates for stone location, although upper ureter stones showed a trend towards significance (Tamsulosin - 41.8%, Placebo - 29.4%, p=0.17)

Findings: Tamsulosin did not significantly increase the stone passage rate compared with placebo. Our findings do not support the use of tamsulosin for symptomatic urinary stones smaller than 9 mm. Guidelines for medical expulsive therapy for urinary stones may need to be revised.
Tamsulosin vs Placebo for Distal Ureteral Stones, Annals of EM (2016) [PubMed abstract]
  • A study in the Annals of Emergency Medicine enrolled 403 patients with distal ureteral stones who presented to the ER with ureteral colic
Main inclusion criteria
  • Distal ureteral stone ≤ 10 mm on CT scan (distal ureter defined as distal to the sacroiliac joint)
Main exclusion criteria
  • GFR < 60 ml/min
  • Temp > 100.4°F
Baseline characteristics
  • Median stone size - 3.8 mm
  • Stones 5-10 mm in size - 26%
  • Vesicoureteric junction stone - 64%
Randomized treatment groups
  • Group 1 (198 patients) - Tamsulosin 0.4 mg once daily for 28 days
  • Group 2 (195 patients) - Placebo once daily for 28 days
  • A prespecified subgroup analysis comparing stone < 5 mm to stones 5-10 mm was performed. Randomization was stratified by stone size (< 5 mm and 5-10 mm)
Primary outcome: The coprimary outcomes were stone expulsion and time to stone expulsion. Stone expulsion was defined as absence of stone on repeated, noncontrast, limited pelvic CT at 28 days. Time to stone expulsion in days was defined as self-reported definitive passage of the calculus or first day of a pain-free 48-hour period, with calculus absent on repeated CT.
Results

Duration: 28 days
Outcome Tamsulosin Placebo Comparisons
Stone expulsion (overall) 87% 82% diff 5%, 95%CI [-3 to 13]
Stone expulsion for stones < 5 mm (N=239) 88% 89.5% diff -1.5%, 95%CI [-9.5 to 6.5]
Stone expulsion for stones 5 - 10 mm (N=77) 83% 61% diff 22%, 95%CI [3.1 to 41.6]
Median time to stone passage (overall) 7 days 11 days p=0.10
  • About 19% of patients in each group had no follow-up CT or had urologic intervention

Findings: We found no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.
Tamsulosin vs Nifedipine vs Placebo for Kidney Stones (Lancet 2015) [PubMed abstract]
  • A study in the Lancet enrolled 1167 patients with newly diagnosed kidney stones presenting to hospitals with ureteral colic
Main inclusion criteria
  • 18 - 65 years of age
  • One kidney stone ≤ 10 mm in diameter in either ureter identified on CT scan
Main exclusion criteria
  • Sepsis
  • GFR < 30 ml/min
  • Need for immediate intervention
Baseline characteristics
  • Average age 42 years
  • Average stone size 4.5 mm
  • Stone size: ≤ 5 mm - 75% | > 5 mm - 25%
  • Location: Upper ureter 24% | Middle ureter 11% | Lower ureter 65%
Randomized treatment groups
  • Group 1 (391 patients) - Tamsulosin 0.4 mg once daily for 28 days
  • Group 2 (387 patients) - Nifedipine 30 mg once daily for 28 days
  • Group 3 (389 patients) - Placebo once daily for 28 days
Primary outcome: Spontaneous stone passage in 4 weeks (defined as the absence of need for additional interventions to assist stone passage at 4 weeks after randomisation)
Results

Duration: 4 weeks
Outcome Tamsulosin Nifedipine Placebo Comparisons
Primary outcome 81% 80% 80% p>0.05
Average number of days to stone passage 16.5 16.2 15.9 p>0.05
  • Subgroup analyses that considered stone size and stone location found no significant effect of either intervention when compared to placebo. These analyses were underpowered.

Findings: Tamsulosin 400 μg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic