Nephrolithiasis

7 Interesting Facts of Nephrolithiasis

1. Most common kidney stone composition is calcium oxalate, followed by calcium phosphate, uric acid, struvite, and cystine
2. Noncontrast CT of abdomen and pelvis is the gold standard imaging test; however, secondary risks from radiation exposure should prompt consideration of alternative imaging, particularly in pediatric or pregnant patients
3. Urinalysis should be performed to look for blood, crystals, and signs of infection
4. For initial presentation of nephrolithiasis, laboratory studies for renal function and serum calcium, phosphate, and uric acid levels are recommended to identify underlying metabolic abnormalities
5. Conservative management of nephrolithiasis involves aggressive hydration and dietary modification
6. Pharmacologic treatment includes analgesics, medical expulsive therapy, and drugs aimed at correcting specific metabolic abnormalities
7. Urologic intervention is determined by size, location, and composition of the stone; it is undertaken when condition does not respond to conservative management

Pitfalls

• Chronic nephrolithiasis is rarely a cause of chronic pain. Other causes of back, flank, or abdominal pain should be sought in patients presenting with these symptoms and radiographic evidence of renal stones without hydronephrosis
• Abdominal aortic aneurysm should be ruled out with ultrasonography or CT imaging if severe back or flank symptoms are present without evidence of hydronephrosis or ureteral stone. Consider ruling out abdominal aortic aneurysm even if a stone is noted
• Renal and ureteral calculi may not be visualized on kidney-ureter-bladder radiographs or abdominal plain radiographs; use of ultrasonography or CT imaging should be considered if clinical suspicion exists

Nephrolithiasis involves supersaturation of urinary sediment of various possible compositions in the urinary system

Classification

• Kidney stones are typically classified by chemical composition
  • Calcium oxalate or calcium phosphate stones
    • Most common type of stone composition (more than 80% of stones) 
    • Typically contain calcium oxalate, either alone or in combination with calcium phosphate
  • Struvite stones
    • Account for 10% to 25% of stones 
    • Typically form in presence of urea-splitting bacteria in setting of chronic urinary tract infections
  • Uric acid stones
    • Account for less than 10% of stones 
    • Often form in relationship to gout or obesity
  • Cystine stones
    • Account for 2% of stones 
    • Typically related to cystinuria, an autosomal recessive disease

Clinical Presentation

History

• Asymptomatic when in kidney; frequently noted incidentally on abdominal imaging performed for unrelated reasons
• Acute renal colic occurs when a stone causes obstruction by moving into the ureter
  • Severe flank pain is a common presentation
  • Abdominal pain can be presenting complaint
• Nausea or vomiting may occur
• Fever and chills may be reported if a coexisting urinary tract infection is present
• Bladder symptoms (eg, urinary frequency, nocturia, dysuria, hesitancy) can occur if stone migrates to distal ureter, near bladder
• Urethral pain may occur if stone migrates to urethra

Physical examination

• Pain typically involves ipsilateral flank, groin, or lumbar areas
• As stones migrate, pain can involve ipsilateral abdominal or inguinal region
• Pain can radiate to ipsilateral testicle
• Gross hematuria can exist with or without pain
• Fever may be present with coexisting urinary tract infection

Causes

• Hypercalciuria
  • Elevated urinary calcium levels increase risk for calcium oxalate and calcium phosphate stones (higher than 250 mg/day in women; higher than 300 mg/day in men)
• Hyperoxaluria
  • Elevated urinary oxalate levels increase risk for calcium oxalate stones (higher than 45 mg/day)
• Hyperuricosuria
  • Elevated urinary uric acid levels increase risk for uric acid stones (higher than 750 mg/day in women; higher than 800 mg/day in men)
  • Often coexists with conditions resulting in hyperuricemia (eg, gout)
• Hypocitraturia
  • Citrate inhibits stone aggregation; therefore, low urinary levels may increase risk for stones of all types
• Cystinuria
  • Autosomal recessive trait that causes excessive excretion of cystine, ornithine, lysine, and arginine
• Urinary tract infection from urea-splitting organisms increases risk for struvite stones

Risk factors and/or associations

Age

• Males: peak incidence is age 30 to 60 years
• Females: peak incidence is age 20 to 30 years

Sex

• Risk is approximately double for males 

Genetics 

• Family history of nephrolithiasis confers a 2-fold higher risk, but basis for this genetic influence is uncertain for most cases 
• Monogenic disorders associated with hypercalciuria account for 10% and 2% of pediatric and adult patients with kidney stones, respectively 
  • Primary hyperoxaluria (OMIM #259900) 
    • Autosomal recessive disorder caused by mutations in AGXT (alanine–glyoxylate and serine–pyruvate aminotransferase), leading to hepatic enzyme deficiencies that result in overproduction of oxalate
    • Cardinal manifestations of recurrent urolithiasis or progressive nephrocalcinosis begin in first decade of life
  • Cystinuria (OMIM #220100) 
    • Autosomal recessive disorder caused by mutations in SLC31A or SLC7A9 (solute carrier family members), resulting in increased urinary excretion of cystine
    • Clinical features include onset in adolescence, often complicated by obstructive uropathy and pyelonephritis
  • Dent disease (OMIM #300009, #300555) 
    • X-linked recessive disorder caused by mutations in CLCN5 (chloride voltage-gated channel 5) or OCRL1 (OCRL inositol polyphosphate-5-phosphatase), leading to hypercalciuria and low-molecular-weight proteinuria
    • Calcium oxalate and calcium phosphate stones develop in first decade of life
• Polygenic disorders associated with hypercalciuria include: 
  • Idiopathic hypercalciuria
  • Idiopathic calcium oxalate urolithiasis

Ethnicity/race

• Risk in black populations is approximately 35% that in white populations 

Other risk factors/associations

• Obesity
  • Relative risk for stone formation in men with BMI greater than 30 kg/m² versus BMI 21 to 22.9 kg/m² is approximately 1.3 
  • Relative risk for stone formation in women with BMI greater than 30 kg/m² versus BMI less than 25 kg/m² is approximately 1.6 to 1.8 
• Primary hyperparathyroidism 
  • Calcium stone disease is the most common clinical manifestation of primary hyperparathyroidism
  • Approximately 15% to 20% of patients with primary hyperparathyroidism develop a kidney stone; 3% of patients with nephrolithiasis have primary hyperparathyroidism
• Renal tubular acidosis
  • Approximately 25% of patients with distal renal tubular acidosis experience nephrolithiasis caused by hypercalciuria, higher urine pH, and lower urinary citrate excretion 
• Gout
  • Approximately 2-fold increased risk in patients with gout 
• Diabetes mellitus
  • Approximately 2-fold increased risk in patients with diabetes (particularly uric acid related to nephrolithiasis) 
• Inflammatory bowel disease (eg, Crohn disease, ulcerative colitis) 
  • Nephrolithiasis occurs in approximately 20% of surgery-naive patients
  • Calcium oxalate stones are most common
• Surgical resection of small or large intestine for treatment of:
  • Obesity
    • Roux-en-Y gastric bypass surgery is associated with approximately 1.7-fold increased risk of nephrolithiasis, versus obese controls 
  • Inflammatory bowel disease 
    • Extensive ileal resection or ileostomy formation increases risk of calcium oxalate stones
      • Excessive intestinal absorption of oxalate occurs as a result of malabsorbed fatty acids binding dietary calcium. Colonic mucosa becomes more permeable to oxalate owing to exposure to bile acids. Enteric hyperoxaluria results in elevated urinary oxalate levels
    • Colon resection with ileostomy increases risk of uric acid stones
• Dietary risks
  • Fluid intake
    • Low fluid intake (less than 1 L/day) results in low urinary volumes, supersaturation of urinary components, and spontaneous crystallization of lithogenic salts; promotes stone formation of all types 
  • Calcium intake 
    • Low dietary calcium intake can increase risk for calcium oxalate stones
      • Low-calcium diets increase incidence of stone formation. Dietary calcium binds oxalate in the gastrointestinal tract and prevents its absorption, whereas inadequate calcium intake can cause excessive gastrointestinal absorption and increased renal excretion of oxalate
    • Calcium supplements can increase risk of calcium stone disease 
      • Excessive intake of calcium and vitamin D in the form of supplements can increase risk of stone formation
  • Protein intake
    • A diet high in animal protein reduces excretion of citrate, increases excretion of calcium and uric acid, and thereby increases risk of calcium stones 
  • Sodium intake
    • A high-sodium diet can increase risk of stones owing to an increase in calcium excretion 
• Medications that increase risk of stone recurrence include:
  • Atazanavir
  • Carbonic anhydrase inhibitors (eg, acetazolamide, topiramate)
  • Triamterene
  • Felbamate

How is Nephrolithiasis diagnosed?

• Diagnosis is based on suggestive history, presence of hematuria on urinalysis, and demonstration of calculus on imaging 
  • Noncontrast CT of pelvis is the preferred imaging study for most patients to identify precise location and size of urinary stones
  • Renal ultrasonography is preferred in children and pregnant patients
• At time of first stone, all patients should undergo laboratory testing for renal function, urinalysis, and mineral levels (ie, calcium, phosphorus, uric acid) 
• 24-hour urine sample to identify stone composition is recommended for patients with recurring stones and those who are considered to be at high risk. Elevated risk factors include: 
  • Family history of stone disease
  • Recurrent urinary tract infections
  • Pediatric stone formation
  • Obesity
  • Malabsorptive intestinal disease
  • History of gastric bypass surgery
  • Solitary kidney
  • Other medical conditions that can predispose to stone formation (eg, primary hyperparathyroidism, gout, type 2 diabetes mellitus, or distal renal tubular acidosis)
• Consider unusual genetic causes in young patients with the following circumstances: 
  • Decreased glomerular filtration rate
  • Proteinuria
  • Extremely high 24-hour urine oxalate excretion

Laboratory 

• Standard and microscopic urinalysis
  • Hematuria (more than 3 RBCs per high-power field) is present in more than 80% of patients with nephrolithiasis 
  • Crystals may be present in urine sediment and suggest stone composition; nonetheless, chemical stone analysis is recommended for first stone 
    • Hexagonal crystals suggest cystine stones
    • Coffin lid–shaped crystals suggest struvite stones
    • Dumbbell or envelope-shaped crystals suggest calcium oxalate stones
    • Square or rectangular crystals suggest uric acid stones
  • Pyuria and bacteriuria indicate infection
• Urine dipstick testing
  • Hematuria can be detected, although test specificity is less than that of formal microscopic urinalysis (thus higher potential for false-positive results)
  • Dipstick positivity for leukocyte esterase and nitrite suggests infection
  • Uric acid stones are usually associated with low urine pH, whereas calcium phosphate stones are most often associated with high urine pH 
• Serum laboratory tests for first passed stone include:
  • Serum levels of electrolytes, BUN, creatinine, calcium, phosphorus, and uric acid
  • Evaluate parathyroid hormone levels if serum calcium measurements are elevated
• Chemical stone analysis by x-ray crystallography or infrared spectroscopy should be performed with a patient’s first passed stone to help guide long-term management 
• 24-hour urine testing
  • Performed with chemical stone analysis to properly categorize patients and guide long-term management
  • Assess for total volume, pH, and levels of calcium, oxalate, uric acid, citrate, sodium, phosphorus, and creatinine 
    • Ideal 24-hour urine values 
      • Volume: more than 2.5 L
      • pH: more than 5.5 and less than 7 (24-hour specimen not required)
      • Calcium: less than 300 mg or more than 3.5 to 4 mg/kg in men; less than 250 mg or more than 3.5 to 4 mg/kg in women
      • Oxalate: less than 40 mg
      • Sodium: less than 3000 mg
      • Uric acid: less than 800 mg in men; less than 750 mg in women
      • Citrate: more than 320 mg
      • Phosphorus: less than 1100 mg
      • Creatinine: more than 15 mg/kg in men; more than 10 mg/kg in women (to ensure adequacy of collection)
  • Ideally performed 6 weeks after stone passage or treatment
  • Suspect primary hyperoxaluria when urinary oxalate excretion exceeds 75 mg/day in adults without bowel dysfunction 

Imaging 

• CT scan of abdomen and pelvis
  • Noncontrast CT represents most sensitive test for identifying precise location and size of all stone types (ie, radiolucent, radiopaque)
  • Considered gold standard imaging test for assessment of suspected renal colic 
  • Useful for projecting stone burden, as estimated by sum of stone volume measurements 
  • Identifies stones that are radiolucent on traditional kidney-ureter-bladder radiographs and IV pyeloureterogram
  • Newer variations of CT imaging can limit radiation exposure. However, for patients in whom it is desirable to limit radiation exposure (ie, pregnant women, children, patients undergoing frequent radiography), consider ultrasonography first
• Ultrasonography
  • Aids in determining stone position and size in the kidney, ureteropelvic junction, and ureterovesical junction; performs poorly in localizing calculi within ureter
  • Can assess for hydronephrosis as surrogate for ureteral obstruction
  • Imaging test of choice in children and pregnant women
• Kidney-ureter-bladder radiographs 
  • Identifies radiopaque renal and ureteral stones containing calcium; however, stones are often obscured by stool, vertebrae, or abdominal gas
  • Primarily useful study for patients with known history of nephrolithiasis
    • Poor sensitivity (approximately 50%) and specificity (approximately 75%) in patients with first stone renders kidney-ureter-bladder radiography insufficiently reliable for primary diagnostic study 
    • Kidney-ureter-bladder radiography is a reliable imaging study to assess stone recurrence or stone clearance for patients with known radiopaque stone disease 
• IV pyeloureterogram
  • Contrast-enhanced radiograph series that evaluates function, excretion, and drainage capability of upper urinary tract
  • CT imaging is preferred when kidney stones are suspected; IV pyeloureterogram is reserved for cases where imaging is needed to detect kidney stones associated with structural abnormalities (eg, medullary sponge kidney) 
  • Disadvantages of IV pyeloureterogram include iodinated contrast material requirement, increased amount of ionizing radiation, and lengthy image acquisition time

Other diagnostic tools

• Evaluation for systemic conditions
  • For patients with calcium oxalate stones and hypercalciuria, consider testing to exclude the following: 
    • Hyperparathyroidism, hyperthyroidism, sarcoidosis, vitamin D excess, calcium supplements, prolonged immobilization, malignant neoplasms, distal renal tubular acidosis, primary hyperoxaluria, enteric hyperoxaluria, inflammatory bowel disease, chronic pancreatitis, vitamin C supplements, chronic diarrhea, urinary infection, gouty diathesis, cystinuria
  • For patients with calcium oxalate stones and hyperoxaluria, consider testing to exclude the following: 
    • Primary hyperparathyroidism, prolonged immobilization, incomplete distal renal tubular acidosis, vitamin C excess, chronic diarrhea, chronic pancreatitis, Crohn disease, gastric bypass procedures, small bowel resections, nephrocalcinosis, primary hyperoxaluria
  • For patients with calcium oxalate stones, consider testing to exclude the following: 
    • Gout, uricosuric agents, dietary purine overload, rare transporter diseases, catabolic states

Differential Diagnosis

Most common

• Acute cholecystitis 
• Acute appendicitis
• Acute cystitis
• Acute pyelonephritis
• Abdominal aortic aneurysm

Treatment Goals

• Ameliorate pain
• Restore proper hydration status
• Relieve any renal or ureteral obstruction caused by calculi
• Prevent recurrence

Admission criteria

Anuria or acute kidney injury owing to bilateral obstruction

• Acute kidney injury: an abrupt (within 48 hours) reduction in kidney function marked by an absolute increase in serum creatinine level of at least 0.3 mg/dL (at least 26.4 μmol/L), a percentage increase in serum creatinine of at least 50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 mL/kg/hour for more than 6 hours) 

Need for urgent surgical intervention, as indicated in the following situations:

• Intractable pain or vomiting despite drug therapy and IV hydration
• Pregnancy; if preterm labor is detected or for intractable pain or vomiting
• Stone in setting of urinary tract infection or sepsis
• Unilateral obstruction in a patient with solitary functioning kidney

Criteria for ICU admission

• Sepsis

Recommendations for specialist referral

• Urologist consultation should be considered for patients with:
  • Intractable pain or vomiting despite drug therapy and IV hydration
  • Pregnancy
  • First episode of kidney stone
  • Patients with solitary kidney
  • Ureteral stones larger than 5 mm
  • Stones that have not passed despite 1 week of conservative management
  • Anatomic variations (eg, ureteral stricture, diminished lumen size) that make spontaneous passage unlikely
  • Urinary tract infection or sepsis
    • Evidence of sepsis in the setting of an obstructing ureteral stone requires urgent urologist consultation to consider drainage treatment using ureteral stent or percutaneous nephrostomy tube placement

Treatment Options

Conservative management is indicated if stone size and patient anatomy suggest reasonable chance of spontaneous passage

• Smaller stones (smaller than 5 mm) located in middle to distal ureter are most likely to pass spontaneously 
• Initial suggested treatment for ureteral stone smaller than 5 mm includes:
  • IV fluids to restore hydration status, particularly for patients with chronic underlying kidney disease, and for those receiving NSAIDs
  • Pain management with NSAIDs as standard analgesics and opioids as rescue medications
  • Medical expulsive therapy (ie, administration of drugs to facilitate stone passage)
    • α₁-antagonists are effective in reducing time to stone passage 

Conservative measures of lifestyle changes (eg, increasing water intake, modifying dietary intake of calcium and protein) should be used to prevent recurrence of kidney stones in all patients with stone formation

Pharmacotherapy also may be used to prevent recurrence of kidney stones. Offer the following options to patients, as appropriate: 

• Thiazide diuretics
  • Patients with high urinary calcium level (absolute or relative elevation) and recurrent calcium stones
• Potassium citrate therapy
  • Patients with recurrent calcium stones and low urinary citrate level (absolute or relative)
  • Patients with uric acid or cystine stones: to raise urinary pH to 6 and 7, respectively
• Thiazide diuretics and/or potassium citrate
  • Patients with recurrent calcium stones in whom other metabolic abnormalities are absent or have been appropriately addressed and yet stone formation persists
• Allopurinol
  • Patients with recurrent calcium oxalate stones who have hyperuricosuria and urinary calcium levels within reference range
• α-Mercaptopropionylglycine (tiopronin)
  • Patients with cystine stones that are unresponsive to dietary modifications and urinary alkalinization, or those with large recurrent stone burdens
• Acetohydroxamic acid
  • Patients with residual or recurrent struvite stones only after surgical options have been exhausted

Interventional procedures (ie, ureteroscopy, extracorporeal shock wave lithotripsy, percutaneous nephrolithotomy)

• Indications for interventional therapy include:
  • Failure of conservative management
  • Intractable pain or vomiting despite analgesic drug therapy
  • Pregnancy, if preterm labor is detected or for intractable pain or vomiting
  • Solitary kidney
  • Most stones greater than 10 mm, and many of those between 5 and 10 mm in size
  • Stones that have not passed despite 1 week of conservative management
  • Stone in setting of urinary tract infection or sepsis
  • Anatomic variations (eg, ureteral stricture, diminished lumen size) that make spontaneous passage unlikely
  • Struvite stones (to ensure complete removal of stone for underlying urinary infection to be eradicated)
• Selection of specific intervention is based upon stone size, stone location, stone composition, and urologist recommendation 
  • Ureteroscopy: ideal procedure for lower pole renal calculi smaller than 1 cm, most ureteral stones, and particularly distal ureteral stones
  • Extracorporeal shock wave lithotripsy: ideal procedure for calculi smaller than 2 cm in patients with normal collecting system anatomy
  • Percutaneous nephrolithotomy: ideal procedure for stones larger than 2 cm and staghorn calculi
• Ureteral stents are placed when there is suspicion of coexisting urinary tract infection or when a ureteroscope will not pass to allow for ureteral dilation. Routine stenting is not recommended 

Infected stones should be treated with a course of antibiotics; empiric therapy may be started in advance of tailored drugs 

• Common urease-producing bacterial genera include Proteus, Haemophilus, Corynebacterium, and Klebsiella

Drug therapy

• Acute management
  • Analgesics 
    • NSAIDs are effective for pain relief and used as first line treatment for acute renal colic
      • Ketorolac
        • Multiple-dose treatment
          • Ketorolac Tromethamine Solution for injection; Adolescents 17 years weighing less than 50 kg: 15 mg IV/IM every 6 hours. Max: 60 mg/day. Total systemic therapy should not exceed 5 days.
          • Ketorolac Tromethamine Solution for injection; Adolescents 17 years weighing 50 kg or more: 30 mg IV/IM every 6 hours. Max: 120 mg/day. Total systemic therapy should not exceed 5 days.
        • Single-dose treatment
          • Ketorolac Tromethamine Solution for injection; Children† and Adolescents† 2 to 16 years: 0.5 mg/kg/dose IV (Max: 15 mg/dose) or 1 mg/kg/dose IM (Max: 30 mg/dose); higher single IV doses of 1 mg/kg/dose (Max: 30 mg/dose) have been used.
            • Off-label use in this age group
          • Ketorolac Tromethamine Solution for injection; Adolescents 17 years weighing less than 50 kg: 15 mg IV or 30 mg IM.
          • Ketorolac Tromethamine Solution for injection; Adolescents 17 years weighing 50 kg or more: 30 mg IV or 60 mg IM.
    • If ketorolac is ineffective or cannot be administered, opioids are an effective alternative
      • Morphine
        • Morphine Sulfate Solution for injection; Neonates† and Infants younger than 6 months: Initially, 0.03 to 0.1 mg/kg/dose IV, IM, or subcutaneously every 3 to 4 hours PRN. Titrate to pain relief.
          • Off-label use in neonates
        • Morphine Sulfate Solution for injection; Infants 6 months and older, Children, and Adolescents: 0.05 to 0.2 mg/kg/dose IV, IM, or subcutaneously every 2 to 4 hours PRN. Begin at lower end of dosage range and titrate to effect. Usual Max: 4 mg for children, 8 mg for adolescents; individualize dose.
        • Morphine Sulfate Solution for injection; Adults: Initially, 2 to 10 mg/70 kg IV, IM, or subcutaneously every 3 to 4 hours PRN. Titrate to pain relief. Higher dose recommended when giving IM or subcutaneously (10 mg IM or subcutaneously every 4 hours PRN; dosage range: 5 to 20 mg IM or subcutaneously every 4 hours PRN). Geriatric or debilitated patients may need lower dose and/or longer dosing interval.
      • Hydromorphone
        • Hydromorphone Hydrochloride Solution for injection; Infants >= 6 months of age† and Children† and Adolescents† weighing < 50 kg: 0.015—0.02 mg/kg IV q2—4h OR a 0.006 mg/kg/hour IV infusion in opioid-naive patients. Titrate to pain relief.
          • Off-label use in this age group
        • Hydromorphone Hydrochloride Solution for injection; Children† and Adolescents† weighing >= 50 kg: 0.2—1 mg IV q2—4h OR a 0.3 mg/hour IV infusion. Opioid-naive patients will require lower dosages. Titrate to pain relief.
          • Off-label use in this age group
        • Hydromorphone Hydrochloride Solution for injection; Adults: Initially, 0.2—1 mg IV q2—3h. Give slowly over 2—3 minutes. Opioid-naive patients will require lower dosages. Use the lower the initial dose in geriatric or debilitated patients (e.g., 0.2 mg). Titrate to pain relief.
      • Oxycodone
        • Oxycodone Hydrochloride Oral solution; Children† and Adolescents† 5 years or older: 0.2 mg/kg PO then 0.1 to 0.3 mg/kg PO every 3 to 4 hours has been used successfully for acute bone fracture pain management. In 1 study, 0.2 mg/kg PO given 30 minutes before wound care procedures reduced associated pain in children aged 5 to 14 years (16.6 to 56 kg). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Off-label use in this age group
        • Oxycodone Hydrochloride Oral solution; Adults: 5 to 15 mg PO every 4 to 6 hours PRN for opioid-naive patients; for chronic, severe pain, consider dosing on scheduled basis every 4 to 6 hours. Convert opioid-tolerant patients considering the potency of prior opioid therapy. Use the same dose and dosing regimen to convert between RoxyBond immediate-release tablets and other oxycodone immediate-release formulations. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Hydrocodone
        • Hydrocodone Bitartrate, Ibuprofen Oral tablet; Adolescents 16 years and older: 1 tablet PO every 4 to 6 hours PRN. Max: 5 tablets/day.
  • Medical expulsive therapy 
    • May be attempted with ureteral stones smaller than 10 mm in diameter for 4 to 6 weeks if pain is controlled, kidney function is normal, and there is no evidence of urinary tract infection or ureteral obstruction 
    • α₁-antagonists facilitate stone passage by promoting ureteral smooth muscle relaxation
      • Tamsulosin
        • Greater efficacy for facilitating passage of larger stones (5-10 mm) whose size and location are known 
        • Tamsulosin Hydrochloride Oral capsule; Children and Adolescents: Pediatric patients with radiopaque lower ureteral stones of 10 or 12 mm or smaller have received the following doses: tamsulosin 0.4 mg PO at bedtime for children older than 4 years and 0.2 mg PO at bedtime for children 4 years or younger, given for 28 days or until definite stone passage (i.e., evidence of stone on urine straining). Tamsulosin is given in addition to standard analgesia (e.g., ibuprofen). Most patients receiving tamsulosin pass stones earlier and with less pain than if no tamsulosin is received. Mild somnolence is common.
        • Tamsulosin Hydrochloride Oral capsule; Adults: Adults with radiopaque lower ureteral stones of 10 mm or smaller have received tamsulosin 0.4 mg PO at bedtime for 28 days or until definite stone passage (i.e., evidence of stone on urine straining) in addition to standard analgesia (e.g., NSAID, etc.) in clinical studies. data suggest that patients with stones of 5 to 10 mm pass stones earlier and with less pain than if no tamsulosin is received; thus, this treatment may be considered. Tamsulosin may offer little benefit over placebo if the stones are less than 5 mm.
      • Silodosin
        • Off-label indication; safety not established for pediatric patients
        • Greater efficacy than tamsulosin for distal ureteral calculi in terms of stone expulsion rate and time to stone expulsion with better control of pain 
        • Silodosin Oral capsule; Adults†: 8 mg PO once daily.
      • Alfuzosin
        • Off-label indication; safety not established for pediatric patients
        • Effective for expulsive therapy of ureteral stones smaller than 10 mm; equivalent to tamsulosin in effectiveness and safety
        • Alfuzosin Oral capsule; Adults†: 10 mg PO once daily.
  • Antibiotics should be administered in cases of suspected infected stone 
    • Initial empiric regimens can include 1 of the following:
      • Amoxicillin/clavulanate
        • Amoxicillin Trihydrate, Clavulanate Potassium Oral tablet; Adults (every 12 hour regimens): 500 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours for mild/moderate infections and 875 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours for severe infections.
      • Cefixime
        • Cefixime Oral tablet; Adults: 400 mg/day PO divided every 12 to 24 hours for 3 to 7 days.
      • Ciprofloxacin
        • Ciprofloxacin Hydrochloride Oral tablet; Adults: 250 to 500 mg PO every 12 hours for 7 to 14 days. Clinical guidelines suggest treatment for 7 days for acute outpatient pyelonephritis and for 7 for 14 days for catheter-associated UTI.
    • Antibiotics can be tailored to causative organism following identification of pathogen and susceptibilities on urine culture
• Chronic management
  • Pharmacotherapy to prevent stone recurrence is lifelong
    • Thiazide diuretics
      • Indicated for reducing incidence of stone recurrence in patients with high urinary calcium levels and recurrent calcium stones
      • Hydrochlorothiazide
        • Hydrochlorothiazide Oral tablet; Adults: 50 mg PO, given 1 to 2 times per day, has been used.
    • Potassium citrate
      • Indicated for:
        • Inducing urinary alkalization and subsequent stone dissolution in patients with uric acid and cystine stones
        • Augmenting urinary citrate levels in patients with calcium stones who have urinary citrate levels that are low or within reference range on 24-hour urine testing
      • Remains as first line therapy for patients with uric acid stones
      • Must monitor potassium levels periodically for hyperkalemia:
        • Within 4 to 6 weeks after starting therapy, or dosage increase
        • Thereafter, every 6 months 
      • Oral solution (oral solution; contains 2 mEq/mL of potassium and 2 mEq/mL of bicarbonate)
        • Potassium Citrate, Citric Acid Monohydrate Oral solution; Children and Adolescents: 5 to 15 mL PO 4 times daily, given after meals and at bedtime. Dilute dose with at least 120 mL of water before administration. Monitor urinary pH to titrate dosage.
        • Potassium Citrate, Citric Acid Monohydrate Oral solution; Adults: 15 to 30 mL PO 4 times daily, given after meals and at bedtime. Dilute dose with at least 240 mL of water before administration. Monitor urinary pH to titrate dosage.
      • Oral tablets (potassium citrate extended-release tablets; e.g., Urocit-K)
        • To restore normal urinary citrate in adult patients with mild-moderate hypocitraturia (150 mg/day or more)
          • Potassium Citrate Oral tablet, extended-release; Adults: 10 mEq PO 3 times daily with meals. Max: 100 mEq/day.
        • To restore normal urinary citrate in adult patients with severe hypocitraturia (less than 150 mg/day)
          • Potassium Citrate Oral tablet, extended-release; Adults: 20 mEq PO 3 times daily with meals (or 15 mEq PO 4 times daily with meals). Max: 100 mEq/day.
    • Allopurinol
      • Indicated for reducing uric acid excretion and conferring a lower risk of stone reformation in patients with hyperuricosuric (more than 800 mg/day) calcium oxalate and uric acid stone disease, to be used on a lifelong basis
      • Allopurinol Oral tablet; Adults: 200 to 300 mg PO once daily or in divided doses. Adjust dose according to control of hyperuricosuria using 24-hour urinary urate determinations.
    • Acetohydroxamic acid
      • Urease inhibitor
      • Indicated for patients with residual or recurrent struvite stones only after surgical options have been exhausted
        • Acetohydroxamic Acid Oral tablet; Adolescents and Children: Detailed studies regarding dosage and dose intervals have not been established. Begin with 10 mg/kg/day PO, administered in 2—3 divided doses given on an empty stomach, and titrate as to obtain optimum therapeutic effect/reduce the risk of side effects. Max dose is 15 mg/kg/day, not to exceed 1.5 g/day PO, regardless of body weight.
        • Acetohydroxamic Acid Oral tablet; Adults: 250 mg PO q6—8h given on an empty stomach (range: 10—15 mg/kg/day PO; usual starting dose: 12 mg/kg/day PO). Max: 1.5 g/day, regardless of body weight.
    • α-Mercaptopropionylglycine (tiopronin)
      • Indicated for cystinuria patients with urinary cystine levels above 500 mg/day, particularly for patients with 1 of the following:
        • Unresponsiveness to dietary modification and urinary alkalinization
        • Large recurrent stone burdens
      • Complications include:
        • Agranulocytosis
        • Aplastic anemia
        • Thrombocytopenia
      • Safety not established for pediatric patients aged 9 years or younger
      • Tiopronin Oral tablet; Children† 2 to 8 years: Off-label use reported. Initially, 15 mg/kg/day PO administered in 3 divided doses at least 1 hour before or 2 hours after meals. Adjust dosage to amount required to reduce urinary cystine concentration to below its solubility limit (usually less than 250 mg/L). Consider lower initial dose in patients who developed severe toxicity to d-penicillamine. Usual maintenance dose: 20 to 40 mg/kg/day PO. One smaller report noted a mean dose of 24.65 mg/kg/day PO (range 13.8 to 51 mg/kg/day). The dosage required to achieve target level depended on the patient’s body weight, and older children required a lower dose to achieve target level. Continue conservative measures such as high fluid intake, alkali administration, and dietary modification.
      • Tiopronin Oral tablet; Children and Adolescents 9 years and older: Initially, 15 mg/kg/day PO administered in 3 divided doses at least 1 hour before or 2 hours after meals. Adjust dosage to amount required to reduce urinary cystine concentration to below its solubility limit (usually less than 250 mg/L). Consider lower initial dose in patients who developed severe toxicity to d-penicillamine. Usual maintenance dose: 20 to 40 mg/kg/day PO. One smaller report noted a mean dose of 24.65 mg/kg/day PO (range 13.8 to 51 mg/kg per day). Usual Max: Not reported, but in general do not exceed adult usual maximum of 2,000 mg/day PO. Continue conservative measures such as high fluid intake, alkali administration, and dietary modification.
      • Tiopronin Oral tablet; Adults: 800 mg/day PO initially, administered in 3 divided doses at least 1 hour before or 2 hours after meals. Adjust to reduce urinary cystine concentration; usually less than 250 mg/L. Average daily dose: 1,000 mg/day. Usual Adult Max: Rarely exceeds 2,000 mg/day PO; up to 3,000 mg has been reported in rare patients.

Nondrug and supportive care

For acute renal colic, supportive care should include IV fluids to hydrate those with volume contraction and to prevent nephrotoxicity associated with NSAIDs 

• Hydration should largely be aimed at repleting volume in patients who are dehydrated or who have an elevated serum creatinine; forced diuresis is not recommended

Lifestyle modifications for chronic management

• Advise increased fluid intake to reach urine volume of at least 2 L daily (total daily fluid intake of approximately 2.5 L) and reduce risk of recurrent stone formation 
• Provide dietary recommendations based on categorization of stone type, history, and laboratory testing (including 24-hour urinalysis and stone composition) 
  • Calcium stones
    • Maintain intake of at least 1200 mg/day calcium from food, with low (2-3 g/day) amount of dietary sodium 
    • For patients with calcium oxalate stones, aim for dietary oxalate intake of 40 to 50 mg/day 
      • Examples of oxalate content in selected foods are available online from the Harvard School of Public Health 
  • Uric acid and cystine stones
    • Limit nondairy animal protein (0.8-1.4 mg/kg/day) and increase alkali-rich foods (eg, fruits) 

Procedures

Ureteroscopy 

General explanation

• Uses narrow diameter scope to access upper urinary tract in retrograde fashion
• Combined with laser fragmentation or basket extraction to treat ureteral and renal stones
• Successful resolution of ureteral obstruction and reduction in stone burden is observed in more than 90% of cases
• Compared with extracorporeal shock wave lithotripsy, ureteroscopy has higher likelihood of achieving stone-free state, but with higher complication rate and longer hospital stay 

Indication

• Unsuccessful resolution of ureteral obstruction with conservative treatment

Contraindications

• Untreated urinary tract infections
• Uncorrected bleeding diathesis

Complications

• Ureteral avulsion and strictures (rare; less than 1%) 

Extracorporeal shock wave lithotripsy 

General explanation

• Uses shock waves generated outside body to treat renal and ureteral stones
• Success rates are highest (80%-90%) with calculi in renal pelvis and ureteropelvic junction 

Indication 

• Renal calculi less than 2 cm, particularly suitable for:
  • Patients for whom sudden symptoms of stone passage may prompt dangerous situations (eg, airline pilots, military personnel)
  • Patients with solitary kidney
  • Patients with hypertension, diabetes, or other medical conditions that predispose to renal insufficiency

Contraindications

• Untreated urinary tract infections
• Uncorrected bleeding diathesis
• Abdominal aortic aneurysm
• Morbid obesity
• Pregnancy

Complications

• Pain with passage of fragments 

Percutaneous nephrolithotomy

General explanation

• Uses narrow diameter scope with percutaneous approach to access kidney
• Procedure of choice for stones larger than 2 cm
• More effective than extracorporeal shock wave lithotripsy for kidney stone management, but requires longer hospital stay and is associated with more complications 
• Bilateral synchronous percutaneous nephrolithotomy is a potential endourologic approach for patients with bilateral stone disease; requires careful patient selection, counseling, and preferably should be performed in endourology centers with large case volumes 

Indication

• Unsuccessful resolution of ureteral obstruction with conservative treatment
• Obstruction cannot be broken up effectively by extracorporeal shock wave lithotripsy or ureteroscopy
• Large (greater than 2 cm) or irregularly shaped stones

Contraindications

• Uncorrected coagulopathy

Complications 

• Fever
• Transfusion

Ureteral stent 

General explanation

• Ureteral stents are used to keep ureter patent and kidney drained after ureteroscopy
• Not recommended routinely, but may be performed as a primary procedure for ureteral stones requiring intervention at facilities where ureteroscopy or lithotripsy are unavailable
• Complications of stents include the following:
  • Urinary tract infection
  • Stent migration
  • Encrustation
  • Stent breakage

Indication

• Ureteral obstruction with suspicion of coexisting urinary tract infection or urosepsis
• Inability to pass ureteroscope

Special populations

• Pregnant patients 
  • Imaging should be restricted to ultrasonography, and if additional information is required, a limited 3-shot IV pyeloureterogram can be performed in an effort to limit radiation exposure to fetus 
    • Rapidly dividing cells of fetus are most susceptible to the teratogenic effects of radiation during first trimester
    • Mean fetal radiation exposure for limited IV pyeloureterogram is 0.17 cGy
    • Doses of less than 5 cGy do not appear to cause intrauterine growth restriction or other fetal anomalies
    • Risk of malignancy, miscarriage, or major malformations is negligible in fetuses exposed to 50 mGy or less
  • If conservative management fails, intervention in the form of ureteral stent, percutaneous nephrostomy placement, and ureteroscopy with laser are acceptable options 
    • Each procedure has advantages and disadvantages; preference for intervention remains controversial and at discretion of urologist
      • Temporary drainage with ureteral stent or percutaneous nephrostomy tube is recommended for infected stones, large stone burden, multiple stones, or altered anatomy
      • Ureteroscopy is the recommended intervention if significant length of pregnancy remains

Monitoring

• Ongoing monitoring of patients with history of kidney stones
  • Assessment of response to dietary and/or medical therapy
    • Obtain 24-hour urinalysis 6 months after initial dietary or medication therapy has started, then yearly thereafter
    • Repeat more frequently if stone burden increases over time despite initial medical therapy
      • Stone burden can be estimated by sum of stone volume measurements as detected on noncontrast CT of abdomen and pelvis 
    • Continued follow-up of all patients, particularly those with a stone unlikely to pass spontaneously because of its size (greater than 5 mm), is necessary to avoid complications of infection and renal impairment
  • Assessment for adverse drug effects
    • During treatment with thiazides, monitor for hypokalemia with periodic potassium measurements within 4 to 6 weeks after start of therapy and every 6 months thereafter
    • During treatment with potassium citrate, monitor for hyperkalemia with periodic potassium measurements within 4 to 6 weeks after start of therapy and every 6 months thereafter
    • During treatment with allopurinol, monitor liver enzyme levels within 4 to 6 weeks after start of therapy and every 6 months thereafter
    • During treatment with tiopronin, monitor CBC, serum albumin level, and liver enzyme levels at 3- to 6-month intervals
• Monitoring incidentally discovered asymptomatic renal stones 
  • Surveillance is sufficient for most stones; only about half of patients will become symptomatic over 5 years, and about half of those will spontaneously pass the stone
  • Monitoring regimen
    • No formal guidelines exist; however, those patients at highest risk for conversion to symptomatic stone need the most intensive monitoring. Risk increases in patients with the following:
      • Stones in renal pelvis
      • Stones larger than 15 mm
      • Solitary kidney
      • History of urinary tract reconstruction
      • Immunodeficiency
    • Although formal guidelines do not exist, a reasonable strategy is to monitor serum creatinine level annually and perform plain kidney-ureter-bladder radiographs (for radiopaque stones), ultrasonography, or CT of abdomen and pelvis every 1 to 2 years 
      • Stone radiopacity can be determined by analyzing the CT scout image that usually is performed as part of the initial evaluation 
  • Patients who become symptomatic and require surgery have much higher stone-free rates after percutaneous nephrolithotomy compared with extracorporeal shock wave lithotripsy 

Complications

• Sepsis
• Renal failure is a potential complication in patients with sepsis, bilateral obstructing ureteral calculi, or unilateral stone obstruction with solitary kidney (Related: Acute kidney injury)
• Large impacted ureteral calculi can cause a ureteral stricture

Prognosis

• Stone resolution
  • Nearly all patients can be relieved of the ureteral calculi that cause acute renal colic
    • Most important factors predicting spontaneous stone passage are stone size and location 
    • Approximate spontaneous passage rates are as follows:
      • Ureteral stones less than 5 mm: about 70% 
      • Ureteral stones 5 to 10 mm: about 50% 
  • Recurrence is common, and often patients with multiple stones on presentation never become stone free
  • Incidentally discovered asymptomatic renal stones
    • Over 5 years, about half of cases progress (defined as symptomatic stone events, increase in size on serial imaging, or need for intervention), but most of those do not reach the point of requiring surgery
      • Cases in which stones are larger than 15 mm and located in renal pelvis are most likely to progress
    • A large burden of asymptomatic renal stones rarely results in long-standing sequelae
• Associated morbidities
  • 2-fold higher risk of developing chronic kidney disease and end-stage renal disease 
    • Struvite and uric acid stones are particularly linked to development of chronic kidney disease 

Prevention

• Increasing fluid intake to reach urine volume of at least 2 L daily (total daily fluid intake of approximately 2.5 L) may reduce risk of initial episode or recurrence of nephrolithiasis 
• Long-term (eg, 5-year) adherence to diets that contain normal levels of calcium, low protein, and low sodium may reduce numbers of stone recurrences in patients with idiopathic hypercalciuria