Nephrolithiasis

Nephrolithiasis encompasses the formation of all types of urinary calculi in the kidney, which may be deposited along the entire urogenital tract, from the renal pelvis to the urethra. Risk factors include low fluid intake and high-sodium, high-purine, low-potassium diets, which can raise the calcium, uric acid, and oxalate levels in the urine and thereby promote stone formation. Urinary stones are most commonly composed of calcium oxalate. Less common stones are composed of uric acid, struvite (due to infection with urease-producing bacteria), calcium phosphate, or cystine. Nephrolithiasis manifests as sudden-onset colicky flank pain that may radiate to the groin, testes, or labia, commonly called renal or ureteric colic, and it is usually associated with hematuria. Diagnostics include spiral CT without contrast and/or ultrasound of the abdomen and pelvis to detect the stone, as well as urinalysis to assess for concomitant urinary tract infection (UTI) and serum BUN and creatinine to evaluate kidney function. Small stones that do not require urgent urological intervention can be managed with symptomatic treatment and a trial of medical expulsive therapy to promote spontaneous passage. If spontaneous passage appears unlikely or fails because of the size or location of the stone, first-line urological interventions include shock wave lithotripsy, ureterorenoscopy, and, in patients with large kidney stones, percutaneous nephrolithotomy. The most important preventive measure is adequate hydration. In addition, the analysis of passed stones may provide information to guide dietary changes and/or medical therapy (e.g., thiazide diuretics, urine alkalinization) that can prevent future stone formation.

• Sex: ♂ > ♀ ^[1]
• Peak incidence: 45–70 years ^[1]
• Risk factors for nephrolithiasis: See “Classification” below.
  • Personal or family history
  • Low fluid intake, dehydration
  • Loop diuretics
  • Postcolectomy and/or postileostomy

Epidemiological data refers to the US, unless otherwise specified.

Overview of kidney stones

Urine alkalizers (e.g., potassium citrate) prevent stones that form in acidic urine. Urine acidifiers (e.g., cranberry juice, betaine) prevent stones that form in alkaline urine.

Calcium oxalate stones ^[3]

• Types
  • Calcium oxalate monohydrate (whewellite): brown or black calculi
  • Calcium oxalate dihydrate (weddellite): light yellow calculi
• Etiology
  • Hypercalciuria: presence of elevated calcium levels in the urine
  • Hyperoxaluria: presence of elevated oxalate levels in the urine
    • Dehydration
    • Increased intake of dietary oxalate
    • Increased intestinal absorption of oxalate, e.g., due to fatty acid malabsorption (e.g., Crohn disease, ulcerative colitis, short bowel syndrome)
      • Calcium normally binds oxalate to form calcium oxalate, which is excreted via feces.
      • In conditions associated with fatty acid malabsorption due to impaired bile acid reabsorption, calcium preferentially binds free fatty acids, leading to excess free oxalate and, therefore, to increased oxalate absorption.
    • Vitamin C supplements
    • Ethylene glycol poisoning ^[4]
    • Pyridoxine deficiency ^[5]
    • Obesity
  • Hypocitraturia: decreased level of citrate in the urine
  • Hyperuricosuria: increased urinary excretion of uric acid
  • Develop in persistently acidic urine
• Diagnosis
  • Urine microscopy: dumbbell-shaped or octahedron-shaped crystals
  • X-ray (or CT): radiopaque stones
• Treatment ^[6][7]
  • Hydration
  • Dietary modification
    • Reduced intake of salt (mainly sodium) and animal protein
    • Reduced intake of oxalate-rich foods and supplemental vitamin C
    • Calcium intake should not be restricted (restriction increases risk of hyperoxaluria, and thereby, the risk for osteoporosis)
  • Thiazide diuretics for recurrent calcium-containing stones with idiopathic hypercalciuria (i.e., no hypercalcemia)
  • Urine alkalinization (e.g., with potassium citrate)
  • Possibly citrate supplementation

Crohn disease leads to increased oxalate absorption via malabsorption of fatty acids, which can ultimately cause nephrolithiasis.

Uric acid stones

• Etiology
  • Hyperuricemia and hyperuricosuria
    • Gout
    • High cell turnover (e.g., tumor lysis syndrome, myelodysplastic syndrome)
  • Diabetes mellitus, metabolic syndrome
  • Chronic diarrhea
  • ↓ Urine volume; , e.g., due to dehydration (often seen in desert climates)
  • Develop in persistently acidic urine ^[8]
• Diagnosis
  • Urine microscopy: rhomboid/needle-shaped crystals
  • X-ray: radiolucent stones
  • CT: can be visible but are usually only minimally visible (not as visible as calcium stones)
  • US and/or intravenous pyelogram may also be helpful in diagnosis
• Treatment
  • Hydration
  • Oral chemolitholysis (e.g., potassium citrate) via urine alkalinization
  • Low-purine diet
  • Allopurinol

Uricosuric agents (e.g., probenecid) increase the excretion of uric acid, which can accelerate the formation of stones.

Uric acid stones are radiolUcent (x-ray negative).

Struvite stones (magnesium ammonium phosphate stones)

• Etiology
  • Upper UTI with urease-producing bacteria such as Proteus mirabilis, Klebsiella, Staphylococcus saprophyticus, and/or Pseudomonas
    • These bacteria convert urea to ammonia → elevated ammonia causing alkaline urine → precipitation of the ammonium magnesium phosphate salt → crystal and stone formation
    • Can form very large stones that fill the entire renal pelvis and calyces (staghorn calculi)
  • Use of indwelling catheter increases risk
  • Develop in persistently alkalic urine
• Diagnosis
  • Urine microscopy: rectangular prisms (coffin lid-appearance) indicate struvite stones
  • X-ray (or CT)
    • Weakly radiopaque stones
    • Possibly staghorn calculi
• Treatment
  • Antibiotic treatment of urinary tract infections
  • Hydration
  • Urine acidification
  • Usually require surgical stone removal

Urinary tract infections can lead to the formation of struvite stones, but struvite stones also increase the risk of urinary tract infections.

Calcium phosphate stones ^[3]

• Types
  • Carbonate apatite
  • Brushite
• Etiology
  • Hyperparathyroidism (brushite)
  • Type 1 renal tubular acidosis (brushite)
  • Upper urinary tract infections (carbonate apatite)
  • Develop in persistently alkalic urine
• Diagnosis
  • Urine microscopy: wedge-shaped crystals
  • X-ray (or CT): radiopaque stones
• Prevention
  • Hydration
  • Thiazide diuretics
  • Diet low in sodium
  • Urine acidification (carbon apatite stones)

Cystine stones ^[9]

• Etiology
  • Autosomal recessive defect in cystine-reabsorbing PCT transporter → impaired proximal renal tubular absorption of dibasic amino acids → cystinuria → cystine stone formation (as cystine is poorly soluble)
  • Develop in persistently acidic urine
• Clinical features: recurrent kidney stones (manifesting with e.g., flank pain) starting in childhood
• Diagnosis
  • Urine microscopy: hexagonal crystals
  • X-ray (or CT)
    • Weakly radiopaque stones
    • Possibly staghorn calculi
  • Positive cyanide nitroprusside test
• Prevention
  • Hydration
  • Diet low in sodium
  • Urine alkalinization
  • Chelating agents (e.g., penicillamine) for refractory cases
  • Tiopronin

To remember that cystine crystals are hexagonal, think “The Cystine Chapel has six sides.”

Xanthine stones

• Etiology: xanthinuria
  • Hereditary deficiency of xanthine oxidase → failure to convert xanthine to uric acid
  • Allopurinol
• Diagnosis
  • Urine microscopy: amorphous crystals
  • Urine pH: plays little role in diagnosis ^[10]
  • X-ray: radiolucent stones (require further evaluation with CT, US, and/or intravenous pyelogram)
• Treatment: reduced dietary intake of purines

2,8-Dihydroxyadenine stones

• Etiology: increased urinary 2,8-dihydroxyadenine concentration due to hereditary deficiency of adenine phosphoribosyltransferase
• Treatment: allopurinol OR febuxostat

Ammonium urate stones

• Etiology: urinary tract infection, malabsorption, hypokalemia
• Treatment
  • Antibiotic treatment of UTI as indicated
  • Urine acidification

Drug-induced stones

Can be caused by:

• Crystallization of drug compounds in the urine, which is most commonly associated with:
  • Aciclovir
  • Indinavir
  • Sulfonamides
  • Fluoroquinolones
  • Ceftriaxone
• Stone formation due to alterations in urine composition, which are most commonly associated with:
  • Acetazolamide
  • Furosemide
  • Topiramate
  • Vitamin D, vitamin A
  • Aluminium magnesium hydroxide
  • Calcium

Stones usually form in the collecting ducts of the kidneys but may be deposited along the entire urogenital tract from the renal pelvis to the urethra. Their localization and size determine the specific symptoms. Small kidney stones may also be asymptomatic and detected incidentally. ^[11]

• Severe unilateral and colicky flank pain (renal colic) ; ^[12]
  • Radiates anteriorly to the lower abdomen, groin, labia, testicles, or perineum
  • Paroxysmal or progressively worsening ^[13]
  • The area around the kidneys may be tender on percussion (costovertebral angle tenderness)
• Hematuria
• Nausea, vomiting, and reduced bowel sounds
• Dysuria, frequency, and urgency
• Passage of gravel or a stone
• Patients are usually unable to sit still and move around frequently (opposed to patients with peritonitis, who usually prefer to lie still)

Depending on the location of the stone, nephrolithiasis may resemble conditions such as appendicitis or testicular torsion.

Approach ^[14][15][16]

• Clinical suspicion: Consider nephrolithiasis in patients with unilateral colicky flank pain associated with nausea, vomiting, and/or hematuria.
  • See “Approach to the management of acute abdominal pain” for the general evaluation of patients with flank pain.
  • For patients presenting with hematuria, see also “Diagnostics” in “Hematuria.”
• Initial diagnostics
  • Laboratory studies: CBC, BMP, urinalysis , β-hCG
  • Imaging studies: CT abdomen and pelvis without contrast preferred if imaging is indicated
• Further evaluation
  • Determine stone composition.
  • Identify metabolic risk factors with a dietary history and laboratory studies.

Laboratory studies ^[14][15]

• CBC: ↑ WBC count ^[17]
• BMP
  • Typically within normal limits
  • Elevated BUN and creatinine suggest an acute kidney injury.

Laboratory studies are not necessary for the diagnosis of nephrolithiasis, but they may help narrow the differential diagnosis and identify complicating factors (e.g., acute kidney injury, UTI).

Urinalysis ^[15][17]

• Nonspecific findings of nephrolithiasis
  • Gross or microscopic hematuria
  • Crystalluria
• Nonspecific urinalysis findings of UTI, e.g., positive leukocyte esterase or nitrites, leukocyturia, bacteriuria
• Findings suggestive of stone composition
  • Alkaline urine (pH > 7.5–8) suggests struvite stones associated with urease-producing organisms. ^[18][19]
  • Acidic urine (pH < 4.5–5.5) may indicate uric acid stones. ^[20]

Imaging studies ^[21][22][23]

• Recommendations in this section are consistent with the 2015 American College of Radiology (ACR) appropriateness criteria for acute-onset flank pain with suspicion of stone disease. ^[21]
• In general, an initial presentation suspicious for nephrolithiasis requires confirmatory CT imaging.
• Imaging is also indicated for acute flank pain of uncertain etiology, e.g., to rule out AAA.
• Routine CT is controversial in young patients with uncomplicated presentations of renal colic , especially those with a history of nephrolithiasis. ^{[21][24][25][26]}

CT abdomen and pelvis without contrast and ultrasound of the abdomen and pelvis are the preferred diagnostic tests for nephrolithiasis in patients for whom imaging is indicated.

CT abdomen and pelvis without IV contrast

CT has the highest accuracy of the imaging modalities to identify kidney stones.

• Type: low-dose, helical (spiral) CT without contrast
• Indication: first-line for nonpregnant patients with suspected nephrolithiasis
• Findings ^[21]
  • Calculus size , location, density , and degree of obstruction
  • Hydronephrosis and/or hydroureter
  • Perinephric fat stranding

Hydronephrosis and/or hydroureter without calculi may suggest a recently passed kidney stone. ^[21]

The addition of IV contrast may help to differentiate ureteral stones from phleboliths and increases the likelihood of detecting alternative causes of abdominal pain (e.g., appendicitis, diverticulitis). However, IV contrast reduces the sensitivity for kidney stones to ∼ 80% compared to > 95% in CT without contrast. ^[21]

Ultrasound abdomen and pelvis

• Indications: suspected nephrolithiasis in patients for whom radiation exposure should be minimized (e.g., pregnant patients, pediatric patients, those with recurrent stones)
• Findings
  • Obstructive uropathy (e.g., hydronephrosis, hydroureter, perinephric fluid) ^[21]
  • Stone: hyperechoic signal with acoustic shadowing ^[17]
  • Twinkle artifact: intense multicolored signal behind a stone seen when using color Doppler technique
  • Absence of ureteral jet : suggests an obstructing stone

X-ray kidney, ureter, and bladder (KUB)

• Indications: follow-up for previously identified radiopaque stones after the initiation of treatment
• Findings: radiographic densities (e.g., stones, phleboliths, vascular calcifications)

Because KUB sensitivity is proportional to stone size, it is usually only suitable for larger stones.

MRI abdomen and pelvis with or without IV contrast

• Indications: suspected nephrolithiasis in patients for whom radiation exposure should be minimized (e.g., pregnant patients or children)
• Findings: similar to CT

Intravenous pyelogram (IVP)

• Indications: rarely indicated given the broad availability of CT
• Findings
  • Provides a complete outline of the urinary tract system
  • Size and location of stone, degree of obstruction

Further evaluation ^[14][16]

For initial episodes of nephrolithiasis, patients should undergo a limited metabolic evaluation to rule out underlying systemic disorders and guide preventative therapy. This workup is typically unnecessary following repeat visits for renal colic where the underlying etiology is already known.

• Dietary history: fluid intake, protein, calcium, sodium, fruits, vegetables, high-oxalate foods, over-the-counter supplements
• Laboratory studies: BMP , calcium , uric acid , urinalysis
• Stone composition analysis ^[27]
• 24-hour urine profile
  • Measures saturation of stone-forming salts and other parameters, such as total volume, pH, and creatinine
  • Dietary changes, medical therapies, or additional testing may be recommended based on the results.

Provide patients with a first-time diagnosis of nephrolithiasis with a urine strainer at the time of discharge to collect passed stones for compositional analysis during their follow-up.

• Pain
  • Causes of acute abdomen (See “Differential diagnoses of acute abdominal pain.”)
  • Causes of acute back pain (E.g., see “Nonspinal causes of acute back pain.”)
  • Causes of testicular pain (See “Differential diagnosis of scrotal pain.”)
• Other findings or clinical features
  • Causes of hydronephrosis (See “Upper urinary tract obstruction.”)
  • Urinary tract infection: cystitis or pyelonephritis
  • See also “Hematuria.”

The differential diagnoses listed here are not exhaustive.

Recommendations in this section are consistent with the 2016 American Urological Association (AUA) guideline on the surgical management of kidney stones and the 2019 AUA guideline on the medical management of kidney stones. ^[14][28]

Approach ^[22][28]

• Initiate symptomatic management prior to confirmatory imaging for patients with renal colic.
• Consult urology urgently for interventional treatment in the following cases:
  • Uncontrolled symptoms (e.g., intractable pain, inability to tolerate PO)
  • Large stones (> 10 mm)
  • Infected kidney stones (e.g., signs of sepsis in combination with high-grade obstruction)
  • Acute renal failure
  • Solitary kidney or kidney transplant with obstruction
• Attempt a trial of conservative management for patients with small (≤ 10 mm), uncomplicated stones.
  • Offer medical expulsive therapy in addition to symptomatic treatment.
  • Treat concomitant UTI, if present.
  • Interventional treatment is indicated if conservative management is unsuccessful after 4–6 weeks.
• Disposition: Most patients with uncomplicated nephrolithiasis can be treated successfully with conservative management during an emergency department visit of a few hours.
  • Admit patients requiring urgent urology consult and intervention.
  • Ensure outpatient urology follow-up for all patients eligible for discharge (e.g., no indications for urgent urology consult, resolved symptoms, no complications).
• Tailor recurrence prevention measures to the type of stone; see “Prevention” for details.

The larger the stone, the less likely it is to pass spontaneously.

Obstructing nephrolithiasis with suspected infection requires urgent urology consultation and management. ^[28]

Symptomatic management ^[17][22]

• Analgesia
  • First-line: NSAIDs, e.g., ketorolac ^[29]
  • Second-line: opioids, e.g., morphine
• Antiemetics, e.g., ondansetron (off-label)
• Intravenous fluids for dehydration

Conservative management ^[22][28]

• Initiate medical expulsive therapy (MET).
  • First-line: tamsulosin (alpha blocker, off-label) ^[28]
    • Relieves ureter muscle spasms
    • Promotes the passage of ureteral stones ≤ 10 mm
    • Reduces the need for analgesics
  • Alternative: nifedipine; (calcium-channel blocker, currently not routinely recommended)
• Provide antibiotic treatment if urinalysis indicates a UTI; for specific recommendations, see:
  • “Antibiotic treatment of complicated lower UTI”
  • “Empiric antibiotic therapy for complicated pyelonephritis”

Interventional management ^[28]

Overview

The choice of interventional treatment is based on the size and location of the stone, suspected infection, and shared decision-making.

• Infected stones: ureteral stenting or percutaneous nephrostomy to relieve obstruction; delayed definitive management
• Ureteral stones
  • Ureterorenoscopy (URS): first-line for mid- or distal ureter stones
  • OR extracorporeal shockwave lithotripsy (ESWL)
• Renal stones > 20 mm OR lower renal pole stones > 10 mm: percutaneous nephrolithotomy (PCNL)

Procedures

The need for follow-up imaging after conservative or interventional management depends on the symptoms, stone type, and intervention modality.

• Keep patient NPO.
• Provide symptomatic management (e.g., analgesia, antiemetics).
• Obtain CT abdomen and pelvis without IV contrast if indicated (e.g., first presentation of renal colic, flank pain with uncertain diagnosis).
• Evaluate for indications for urgent interventional management of nephrolithiasis.
• Consider conservative management with medical expulsive therapy.
• Refer to urology for follow-up and further workup of etiology of nephrolithiasis.

• Recurrent urinary tract infections → risk of pyelonephritis, urosepsis, and perinephric abscess
• Urinary obstruction → inflammation of the kidney and hydronephrosis → permanent glomerular damage if left untreated
• Acute kidney injury ^[11]

We list the most important complications. The selection is not exhaustive.

• Stone size and location determine the likelihood of spontaneous passage: Stones ≤ 5 mm tend to pass spontaneously, while stones ≥ 10 mm are unlikely to do so, especially if located in the pyelon or proximal ureter. ^[8]
• 50% of patients may have a new episode of nephrolithiasis within 10 years. ^[1]

• Hydration: sufficient fluid intake (≥ 2.5 L/day) ^[31]
• Diet
  • For calcium stones:
    • Reduced consumption of salt and animal protein ^[31]
    • Reduced consumption of oxalate-rich foods and supplemental vitamin C: for oxalate stones ^[32][33]
    • Calcium intake should not be restricted (restriction increases risk of hyperoxaluria, and thereby, the risk for osteoporosis)
  • For uric acid stones: low in purine
  • For cystine stones: low in sodium
• Chemoprophylaxis
  • Calcium stones
    • Thiazide diuretic for recurrent calcium-containing stones with idiopathic hypercalciuria (i.e., no hypercalcemia) ^[31][34]
    • Allopurinol in the case of high urine uric acid
  • Uric acid stones: allopurinol ^[31]
  • Cystine stones: tiopronin
  • Struvite stones: antibiotic treatment for UTI
• Change urinary pH: depends on stone composition
  • Urine alkalinization: a treatment regimen to raise urinary pH to 6.5–7.5
    • Achieved via diet rich in fruits and vegetables or supplementation of potassium citrate
    • Used to prevent recurrence of calcium oxalate, uric acid, and cystine stones
  • Urine acidification: a treatment regimen to lower the urinary pH to ≤ 7
    • Achieved via intake of cranberry juice or betaine or a diet rich in dairy products, grains, or meat
    • Used to prevent recurrence of calcium phosphate and struvite stones

Low calcium diets increase the risk of calcium-containing stone formation because they increase oxalate reabsorption.

Nephrolithiasis in pregnancy

• Epidemiology: ∼ 1:3000 pregnancies ^[35][36]
• Risk factors
  • ↑ Calcium excretion, ↓ excretion of magnesium and citrate
  • ↑ Urine pH
  • Urinary stasis due to hormonal changes (e.g., due to increased progesterone levels)
  • Late pregnancy: ↓ fluid intake resulting from ↓ bladder capacity due to altered position and increasing size of uterus
• Clinical features: See above.
• Diagnostics: Renal ultrasonography is preferred.
• Treatment
  • Focuses on pain control because the majority of stones pass spontaneously (for details on analgesia during pregnancy, see “Overview of analgesics to avoid during pregnancy”)
  • Surgical interventions are similar to those for nonpregnant individuals (see “Conservative management” and “Interventional management” in “Treatment”).

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