KIDNEY STONES










Reference [3,5]
GENERAL RISK FACTORS
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, which increase the risk of calcium oxalate stones and uric acid stones

Reference [3,5]
MEDICAL CONDITIONS
Parathyroid disease
  • Kidney stones occur in about 20% of patients with primary hyperparathyroidism, which causes elevated calcium levels, 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)
  • Under normal conditions, calcium binds oxalate in the intestines and prevents its absorption. Short bowel syndrome causes fat malabsorption, increasing free fatty acids in the intestinal lumen. Fatty acids sequester calcium and prevent it from binding oxalate, thereby indirectly increasing oxalate absorption.
Pancreatic insufficiency
  • Under normal conditions, calcium binds oxalate in the intestines and prevents its absorption. Pancreatic insufficiency causes fat malabsorption, increasing free fatty acids in the intestinal lumen. Fatty acids sequester calcium and prevent it from binding oxalate, thereby indirectly increasing oxalate absorption.
Sarcoidosis
  • Hypercalciuria, which occurs in 50% of patients with sarcoidosis, is caused by sarcoidal macrophages that convert 25-hydroxyvitamin D to its more active form, 1,25 dihydroxyvitamin D
Renal tubular acidosis type 1
  • Renal tubular acidosis causes hypocitraturia and elevated urinary pH
Primary hyperoxaluria
  • Primary hyperoxaluria is a rare condition that causes oxalate overproduction
  • 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
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 stone risk, while low calcium intake (< 1000 mg/day) may also promote stone formation by increasing oxalate absorption
High sodium intake
  • High sodium intake (> 5 grams/day) may promote stone formation by decreasing urinary citrate and increasing calcium excretion and sodium urate crystal formation
  • Urinary calcium increases by approximately 40 mg/d for every 2300 mg/d increase in dietary sodium
High purine intake
  • Dietary purines, which are metabolized to uric acid, can cause hyperuricosuria and promote stone formation
  • High amounts of purines are found in anchovies, sardines, herring, mackerel, scallops, mussels, waterfowl, organ meats, glandular tissue, gravies, and meat extracts. Moderate-to-high amounts 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 that promotes urinary citrate excretion and stone prevention
  • Meats, fish, poultry, cheese, and eggs confer an acidic load on the kidneys that promotes citrate reabsorption and stone formation
Vitamin C
  • Vitamin C is metabolized to oxalate, and high intake may increase urinary oxalate concentrations, promoting stone formation
Vitamin D
  • Vitamin D promotes calcium absorption, increasing urinary calcium excretion

Reference [3,5]
MEDICATIONS THAT PROMOTE STONE FORMATION
Acetazolamide (Diamox®)
  • Acetazolamide, a carbonic anhydrase inhibitor, promotes stone formation through urinary alkalinization
Allopurinol
  • The allopurinol metabolite oxypurinol can crystallize in the urine and form stones
Amoxicillin
  • In rare cases, amoxicillin has been found to promote crystalluria
Ceftriaxone (Rocephin®)
  • Ceftriaxone may combine with calcium in the urine and promote stone formation
Ephedrine
  • Cases of kidney stones containing ephedrine have been reported
Fenofibrate
  • Fenofibrate promotes uric acid excretion, which theoretically can 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 hypokalemia-induced hypocitraturia
Lithium
  • Lithium may cause hyperparathyroidism, which increases calcium levels and the risk of hypercalciuria
Loop diuretics
  • Loop diuretics promote renal calcium excretion
Losartan
  • Losartan promotes renal uric acid excretion
Mesalamine
  • Cases of kidney stones, including some with 100% mesalamine content, have been reported during mesalamine therapy. Mesalamine stones are radiolucent, making them undetectable by X-ray or CT scan.
Orlistat (Xenical®)
  • Intestinal calcium binds oxalate and inhibits its absorption. Orlistat blocks fat absorption, increasing luminal free fatty acids that sequester calcium and prevent it from binding oxalate.
Probenecid
  • Probenecid promotes reanl uric acid excretion
Quinolones antibiotics (ciprofloxacin, levofloxacin, etc.)
  • Alkaline and/or concentrated urine may promote quinolone crystallization
SGLT2 inhibitors
  • SGLT2 inhibitors promotes renal uric acid excretion
Sulindac
  • Sulindac metabolites have been found in kidney stones
Sulpha drugs
  • Sulfa drugs have been shown to cause crystalluria
Topiramate (Topamax®)
  • The anticonvulsant topiramate is a mild carbonic anhydrase inhibitor that increases urinary alkalinization
Triamterene
  • The potassium-sparing diuretic triamterene has been found in kidney stones. See triamterene stones for more.
Zonisamide
  • The anticonvulsant zonisamide is a carbonic anhydrase inhibitor that increases urinary alkalinization



  • 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. [7]
  • References [1,2,3,7]
Kidney Stone Types
Calcium oxalate - 67% of stones
  • Most kidney stones are calcium oxalate stones, although they often contain some amount of calcium phosphate. Calcium oxalate stones are harder than other stones, making them more resistant to shockwave therapy. [1,2,3]
  • Imaging: Radiopaque
Calcium phosphate (apatite) - 16% of stones
  • Calcium phosphate stones have two different crystalline structures, apatite and brushite. Apatite stones are more common than brushite stones. Calcium phosphate stones often contain some amount of calcium oxalate. [3]
  • Imaging: Radiopaque
Uric acid - 8% of stones
  • Risk factors for uric acid stones include male sex, obesity, diabetes, and acidic urine [2]
  • Imaging: Radiolucent
Struvite - 3% of stones
  • Struvite stones, which form in the setting of chronic urinary infections, are composed of magnesium ammonium phosphate. They are caused by urea-splitting organisms (e.g. Proteus, Klebsiella, Pseudomonas) that promote stone formation by altering urinary ammonium and bicarbonate concentrations. [2]
  • Imaging: Mildly radiopaque
Calcium phosphate (brushite) - 0.9% of stones
  • Calcium phosphate stones have two different crystalline structures, apatite and brushite. Brushite stones are less common than apatite stones but carry a higher risk of recurrence. They are also harder and more resistant to shockwave therapy. [3]
  • Imaging: Radiopaque
Cystine stones - 0.4% of stones
  • Cystine stones are caused by congenital defects in renal amino acid transporters that lead to high urinary cysteine concentrations (> 100 mg in a 24-hour urine). Young age of presentation and a strong family history of stones should raise suspicion for cystine stones. Cystine stones are harder and more resistant to shockwave therapy [1,2,3]
  • Imaging: Mildly radiopaque
Staghorn stones - rare
  • Stones that fill at least 2 renal calyces are called staghorn stones because they are shaped like a male deer (stag) rack (see staghorn stone illustration). They are most often formed from struvite stones, and large ones can cause renal obstruction and failure. [2]
  • Imaging: Typically radiopaque



Illustration of factors associated with kidney stone formation



















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 (e.g. X-ray, US, etc.), yearly follow-up may be sufficient
  • Optimal follow-up intervals have not been defined
Shockwave lithotripsy (SWL)
  • SWL uses high-energy, pulsatile sound waves delivered externally to crush the stones
  • SWL works best for stones < 20 mm in size located 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 is a procedure where a small incision is made in the skin, a catheter is inserted into the kidney, and stones are removed manually
  • PNL is recommended for stones ≥ 20 mm in size. 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 the 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)
  • Oral urinary alkalinizers, including potassium bicarbonate and citrate, can be used to dissolve 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. A study published in 2023 found that HCTZ had no significant effect on kidney stone recurrence (see thiazides for kidney stone prevention).
  • 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
    • A study published in 2023 found that HCTZ had no significant effect on kidney stone recurrence (see thiazides for kidney stone prevention)
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
    • STUDY: A study published in 2023 found that HCTZ had no significant effect on kidney stone recurrence (see thiazides for kidney stone prevention).


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