Urolithiasis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has urolithiasis? What are the typical findings for this disease?

Although urolithiasis is more common in adults, the incidence of pediatric stone disease has been increasing in recent years and now accounts for 1/685 pediatric hospitalizations. Because younger children less commonly present with the typical flank pain seen in adults, clinicians are often late to diagnose stones in children.

The diagnosis of urolithiasis is confirmed by stone detection on imaging (noncontrast helical computed tomography [CT], ultrasonography, or radiography of the kidneys, ureter, and bladder) or retrieval of a passed stone. Hematuria (micro- or macroscopic) should raise clinical suspicion for urolithiasis, particularly if it is associated with renal colic and/or hydronephrosis. Early identification and intervention is important because urolithiasis may cause obstruction, which can lead to renal colic, obstructive pyelonephritis, and/or nephron loss in the developing kidney. Furthermore, pediatric patients with urolithiasis have a longer lifetime risk of stone recurrence and may require more extensive evaluation and aggressive prevention.

Physical examination for suspected urolithiasis should include:

Inspection and palpation of the external genitals and perineum to assess for signs of trauma or irritation.
Inspection and palpation of the abdomen. Upper quadrant tenderness can be a sign of renal tenderness from either obstructive uropathy or pyelonephritis, whereas tenderness in the suprapubic region may be a sign of cystitis or a stone in the distal ureter.
Assessment of costovertebral angle tenderness.

Presentation varies by age, with adolescents showing more typical adult symptoms, such as flank pain, and children younger than 5 years rarely having “classic” findings.

Abdominal/flank pain, gross hematuria in 60%
Asymptomatic in 15%, diagnosed incidentally through imaging for other purposes
Fever, dysuria, frequency, and urgency (symptoms of infection) in 15%
Positive family history in 35% to 40%

Stone burden appears more common with increasing age, with male sex (2:1 male-female ratio), in white children (very rare in Asian and African American groups), and in the southeastern United States, reflecting environmental influences (often referred to as the “stone belt”).

What other disease/condition shares some of these symptoms?

Abdominal/flank pain: Gastroenteritis, urinary tract infections (UTIs), appendicitis, pneumonia, irritation of the urinary tract or perineum, trauma

Hematuria: Nephritic disorders, hypercalciuria in the absence of stones, genitourinary (GU) tumors and infections, renal vein thrombosis, and parasites or foreign objects within the bladder

What caused this disease to develop at this time?

Seventy-five percent of children who have nephrolithiasis have an identified predisposition to stone formation: metabolic risk factors, anatomic anomalies, and infection are most common. Multiple factors may be found in any one child.

Metabolic abnormalities, in >50% of children with nephrolithiasis (e.g., distal renal tubular acidosis, partial or complete, cystinuria, primary hyperoxaluria)

Diuretic-related stones in infancy
Ceftriaxone-associated nephrolithiasis
Dietary abnormalities (e.g., poor fluid and/or citrate intake)
Nutrient absorption abnormalities (e.g., jejunoileal bypass, Crohn’s disease, intestinal resection, malabsorptive conditions, malnutrition leading to bladder stones)
Endocrine abnormalities (e.g., hyperparathyroidism, sarcoidosis)
Medications associated with stone formation (calcium supplements, vitamin D supplements, acetazolamide, ascorbic acid in large doses (>4 g/day), sulfonamides, indinavir, triamterine)

Anatomic abnormalities and urinary stasis, 32%(e.g., ureteropelvic junction obstruction or obstructive megaureter, neurogenic bladder, tubular ectasia/medullary sponge kidney, horseshoe kidney)

Infection, 4% of children with nephrolithiasis (urease-splitting organisms)

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Acute Work-Up

Urinalysis (including microscopic analysis) is perhaps the most important laboratory test in patients suspected of having urolithiasis.

The color and character can be an objective documentation of abnormality. The color of the urine can be affected by many drugs (phenazopyridine, rifampin, nitrofurantoin, L-dopa, methyldopa, metronidazole). Red discoloration of the urine can also be the result of betacyanin (beets), phenolphthalein (laxatives), vegetable dyes, concentrated urate, myoglobin (muscle injury), or hemoglobin (hemolysis) excretion. Hence, red urine is not sufficient to diagnose hematuria, and a microscopic analysis evaluating for erythrocytes in the urine is critical.

Specific gravity (normal range 1.003-1.030) can be a measure of how well-hydrated a patient is. Plasma specific gravity is 1.010. Urine specific gravities below this level may indicate overhydration, primary diabetes insipidus, or insufficient vasopressin levels. Urine specific gravity that is consistently near 1.010 (isosthenuria) can be a sign of renal injury (inability to concentrate urine) and is often seen in patients with sickle cell anemia.

Urine pH (normal 6.5) can be altered in conditions that predispose to stone formation. More acidic urine can be associated with uric acid stones, which dissolve in alkaline urine. Distal renal tubular acidosis is associated with persistently alkaline urine and can predispose to calcium phosphate stones. Alkaline urine, particularly in the setting of urinary infection, may be the result of urease-splitting bacteria, which can result in struvite (calcium triple phosphate) stones.

Leukocyte esterase and nitrites: Leukocyte esterase is an enzyme located in granulocytic leukocytes (white blood cells [WBCs]) and is predictive of pyuria (WBCs in urine). This can be falsely elevated after surgery or non-infectious inflammation in the GU tract. Nitrites are the products of coagulase-splitting bacteria that convert nitrates in the urine to nitrates. Only 40%-60% of common GU bacteria are coagulase positive; hence, this is not a sensitive test (it is specific, however), and combined with the leukocyte esterase test can be highly predictive of a urinary tract infection.

Microscopic analysis is critical in evaluating for erythrocytes, leukocytes, bacteria, and other cell types in the urine. Leukocytes in the urine can be indicative of a UTI or inflammation, as can bacteriuria. Erythrocytes may be present in the urine with many conditions (e.g., UTIs, stones, malignancy, nephritic renal disease). Squamous cell epithelium should not be present in large numbers in the urine and can be suggestive of a poor sample (including distal urethra and prepuce in men and vaginal introitus in women). Microscopic hematuria is present in 90% of children with urolithiasis.

Urine sediment showing crystals can yield information about the cause of the stones. Findings may include:

Calcium oxalate
Cystine crystals, diagnostic of cystinuria, are colorless, flat, and hexagonal
Calcium phosphate
Uric acid
Phosphate
Crystallization of drugs such as sulfadiazine and indinavir

Urine culture is essential for ruling out UTI as part of the differential diagnosis; if positive, stones that are superinfected are managed differently.

Evaluation for Underlying Risk Factors

Stone analysis can be performed on retrieved stones by specialized laboratories.

Metabolic evaluation is warranted in pediatric patients because of the high risk of stone recurrence and the longer lifetime risk for possible stone formation. Metabolic abnormalities are found in up to 76% of pediatric patients with stone disease. Evaluation should occur while the child is in the home environment, consuming his/her usual diet, after any infection has resolved. Low urine volume, elevated supersaturation of calcium phosphate, elevated supersaturation of calcium oxalate, and hypercalciuria are the most commonly identified abnormalities on 24-hour urine studies. Age appears to affect likelihood of underlying metabolic disease. Children <10 years are more likely to have a metabolic disorder including elevations in calcium, oxalate, and supersaturation of calcium phosphate, whereas children >10 years are more likely to have low urinary volume.

Initial work-up includes serum creatinine, electrolyte, bicarbonate, calcium, phosphorus, and uric acid determinations. If hypercalcemia or hyperphosphatemia is present, parathyroid hormone determinations should be obtained.

Twenty-four–hour urine collection should be obtained several weeks after infection or passage or treatment of stones, preferably in the home environment as the child consumes the usual diet. Urine is analyzed for sodium, calcium, urate, oxalate, citrate, creatinine, and cystine levels.

Would imaging studies be helpful? If so, which ones?

Imaging is especially important in patients with fever or a solitary kidney and when the diagnosis of a stone is in doubt. In children, ultrasonography and noncontrast helical CT are preferred to plain abdominal radiography.

Renal/bladder ultrasonography: This imaging study is useful for detecting radiolucent stones (e.g., uric acid stones) and obstruction, while avoiding radiation exposure and anesthesia and keeping costs low. Limitations include its user-dependent nature and difficulty detecting small stones (<5 mm), papillary and calyceal stones, and ureteral stones. A normal ultrasonogram is not adequate for ruling out urolithiasis in symptomatic children because it fails to identify stones in more than 40% of pediatric patients.

Noncontrast helical CT: This is the most sensitive radiographic modality for detecting urolithiasis, and it is superior for detecting ureteral stones, radiolucent stones, and small stones. Radiation settings can be adjusted for the size and weight of the younger child undergoing imaging to minimize radiation exposure.

Plain abdominal radiography: This is used when ultrasonography and CT are unavailable; it is adequate for radiopaque stones (e.g., calcium, struvite, cystine) but is limited in detecting radiolucent stones, small stones, stones overlying bony structures, and urinary obstruction.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

Expectant management

A trial of expectant management for spontaneous stone passage can be appropriate for children without signs of infection, intractable pain, solitary kidney or renal insufficiency, and for children with ureteral stones <4-5 mm in diameter. Calcifications in infants with neonatal nephrocalcinosis often spontaneously regress, warranting expectant management in the absence of obstruction or infection.

Pain control for renal colic can be achieved with acetaminophen and ibuprofen, and, if needed, oral narcotics such as oxycodone.

Ureteral stones >5 mm and renal calculi have much lower spontaneous passage rates and thus are treated more aggressively if proximal or associated with hydroureteronephrosis and symptoms.

Medical expulsive therapy

There are no specific pediatric guidelines for medical expulsive therapies (METs). A systematic review and meta-analysis of MET for pediatric urolithiasis demonstrated that MET results in an increased odds of spontaneous ureteral stone passage and a low rate of adverse events. The following modalities are used effectively in adults and are useful in children:

Calcium channel blockers such as nifedipine have not been studied for their safety or efficacy in children.
α1-adrenergic receptor antagonists (alpha-blockers) such as doxazosin and tiamulin have been used off label in children to facilitate passage of fragments through the intramural ureter. The efficacy is controversial; a recent abstract presented at the national meeting of the American Urological Association failed to show a positive impact of tamsulosin on stone passage in children. Although not approved by the US Food and Drug Administration for any of these indications in children, alpha-blockers (such as tamsulosin) have been studied and deemed safe for pediatric urologic disorders such as recalcitrant voiding dysfunction and neuropathic bladder.

Surgical approaches

The standard procedures for treating stones in children are similar to those for adults. As recurrence is a major concern for pediatric patients with nephrolithiasis, any management option should aim at eliminating all stone material.

Extracorporeal shock wave lithotripsy (ESWL): Safe for adults and children, including infants, ESWL is a preferred treatment for pediatric patients with proximal ureteral calculi, lower pole stones <1 cm, and non–lower pole stones <2 cm. The success rate is reported at 57%-92%. Cystine stones should not exceed 15 mm because these larger stones are harder. ESWL functions by generation and focus of shock-wave energy at a focal point, the calculus.
Ureterorenoscopy (URS): URS has become a first-line surgical treatment for stones of the mid- and distal ureter. Its use in the pediatric population has been facilitated by the development of smaller ureteroscopes and ureteroscopic instruments and small-caliber laser fibers.
Percutaneous nephrolithotomy (
PCNL): Larger and more complex calculi (>1.5 cm or >1 cm for lower-pole concrements), harder stone composition, and anatomic anomalies that impede good fragment clearance may warrant PCNL as a first-line therapy, despite its invasiveness. The “mini-perc” technique uses a smaller instrument and has even been successful in rendering children with staghorn calculi stone-free.
Laparoscopic and open surgery: These techniques are reserved for those who also need surgical correction of a urinary tract anatomic abnormality such as ureteropelvic junction obstruction or obstructive megaureter. Open surgery is more common in developing countries (14%) compared with developed countries (0.3%-5.4%), perhaps representing the cost-effectiveness of open surgery in developing regions.

Table I presents the treatment options for urolithiasis.

Table I.

Treatment	Indications	Advantages	Disadvantages
Expectant Management: Pain control with acetaminophen, ibuprofen, acetaminophen with codeine	No signs/symptoms of infection; absence of intractable pain, solitary kidney or renal insufficiency; ureteral stones <4-5 mm diameter	Lowest likelihood of adverse reactions due to treatment; cost-effective	Likelihood of spontaneous passage varies with stone size and location; larger and more proximal stones less likely to pass

Medical Explusive Therapy	Used in conjunction with pain control in stones that have high likelihood of passage	Avoids anesthesia risk, lower cost	No specific pediatric doses or guidelines
Calcium channel blockers: nifedipine
Alpha blockers: doxazosin, tamsulosin		Studied to be safe in children for other urologic disorders	Questionable efficacy in children

Surgical Approaches		More likely to eliminate all stone material on first attempt	Requires anesthesia, higher cost
ESWL	Proximal ureter, renal lower pole stones <1 cm, non–lower pole stones <2 cm	Well-studied as safe overall for adults and children; success rate 57%-92%; effect of ESWL on girls’ developing ovaries not known	Lower success rates for harder stones (cystine, calcium oxalate monohydrate) and lower pole stones
URS	Mid- and distal ureter	Availability of smaller ureteroscopic instruments and smaller caliber laser fibers for pediatric patients	Often requires ureteral stent placement temporarily; second examination with anesthesia for stent removal
PCNL	Larger, more complex stones (>1.5 cm or >1 cm in lower pole), harder stone composition, anatomic anomalies	Better access to difficult stones; “mini-perc” uses smaller instrument, proved successful for even staghorn calculi	More invasive than ESWL, URS; postoperative fever, bleeding, risk of injuring adjacent intraabdominal structures
Laparoscopic and open surgery	More common in developing countries	Can correct urinary tract anatomic abnormalities; more cost-effective in developing countries	Most invasive modality

EWSL = extracorporeal shock wave lithotripsy; PCNL = percutaneous nephrolithotomy; URS = ureterorenoscopy

What are the adverse effects associated with each treatment option?

Anesthesia risk: In all children younger than 14 years of age, anesthesia is required for all procedural approaches. Thus, it is best to use the approach that is most likely to be successful after one attempt. All treatment options carry the risk of incomplete stone removal, with lower pole stones often requiring additional treatment regardless of treatment modality. In older children (>14 years) ESWL may be performed with intravenous sedation at the discretion of the anesthesiologist, child, and family.

ESWL: Short-term minor effects include bruising, hematuria, renal colic, perinephric hematoma, and temporarily reduced glomerular filtration rate. There is no evidence of these effects lasting long-term. Despite concern that high-energy impact may negatively impact kidney development, studies have shown ESWL to have no effect on a child’s renal function or blood pressure and no evidence of renal scarring.

PCNL: Postoperative fever (30%) and bleeding can occur (subsequent transfusion rates 0%-23.9%); there is the risk of renal pelvis (or ureteropelvic junction) injury/rupture and a small chance of percutaneous access traversing large bowel, diaphragm, pleura, spleen, and liver.

URS: There is a very low risk of vesicoureteral reflux and ureteral strictures. Ureteroscopy and stone treatment often necessitate placement of a ureteral stent on completion of the procedure and subsequent endoscopy under anesthesia for removal of the ureteral stent.

What are the possible outcomes of this disease?

Renal stones may remain in the same position for a long time, potentially years, without growing or causing symptoms. In general, however, they may grow, particularly if the risk factor for stone development is not resolved, and they may also move. If the size is such that passage past the points of GU tract narrowing (the ureteropelvic junction, the ureterovesical junction, and the ureter as it passes over the iliac vessels) is impeded, they can cause renal colic as they obstruct the flow of urine down the ureter. The stone can potentially pass spontaneously.

If the patient has signs of pyelonephritis or renal failure with an obstructing stone, an emergent urologic consultation must be conducted to decompress the renal pelvis or ureter with either a ureteral stent or a percutaneous nephrostomy expeditiously. Decompression, with or without concurrent treatment of the stone, is also warranted for patients in whom outpatient expectant therapy (or medical expulsive therapy) has failed or for those who have renal colic refractory to reasonable analgesia.

Please note, obstruction in a solitary kidney (anatomically or functionally—as exhibited by a poorly functioning contralateral kidney) always merits urgent urologic evaluation because these patients should not be offered expectant management.

Obstruction that is associated with pyelonephritis merits urgent decompression. Also urinary obstruction that has been present for longer than 4 to 6 weeks should be resolved in an expedited fashion because obstruction beyond this time frame in animal models has demonstrated irreversible kidney damage.

Residual stone fragments can become symptomatic and act as a nidus for new stone growth. Once a stone develops, the child is at increased risk for the development of further stones. Thus, a stone work-up is helpful in identifying modifiable risk factors.

What causes this disease and how frequent is it?

See section “What caused this disease to occur at this time?” for a full list of risk factors and predisposing conditions.

Environmental factors center around hydration.

Seasonal variation occurs with respect to stone formation. The highest incidence of stones occurs in the hot, dry months of the year when there is relative dehydration.
Geographically, the highest incidence of stones occurs in the southeastern United States.
Stone formation generally increases with age.

Infection can influence stone formation; urease-splitting pathogens are the cause of magnesium ammonium phosphate (struvite) and carbonate apatite stones, forming 15% of all stones. Proteus, Klebsiella, Pseudomonas, and Staphylococcus species are the most important urease producers and are transmitted similarly to other uropathogens.

Genetically transmitted metabolic disorders are a cause of recurrent urolithiasis. Recent studies have identified multiple single-gene disorders and candidate genes. These disorders are rare and do not account for most patients with stone disease; however they help elucidate the pathophysiology of stone formation:

Human soluble adenylate cyclase gene (sAC), which senses bicarbonate ions, has been implicated in families with severe absorptive hypercalciuria.
Calcium-sensing receptor gene (CASR) polymorphisms have been associated with autosomal dominant hypocalcemia and hypercalciuria.
Tight junction protein claudin-16 (CLDN16) mutations are associated with familial hypomagnesemia and hypercalciuria.
Chloride channel gene (CLCN5) mutations lead to X-linked nephrolithiasis of Dent disease.
Proteins associated with sodium phosphate may also play a role in nephrolithiasis.
There is an ongoing search for the multiple genes involved in idiopathic hypercalciuria and nephrolithiasis. Through genetic studies and earlier identification of affected children and children of stone formers, more aggressive prophylactic management can be pursued.

How do these pathogens/genes/exposures cause the disease?

Urease-producing pathogens raise the pH of the urine as a result of steady ammonia and CO₂ catalyzed by bacterially produced urease. In this alkaline milieu, intrabacterial and peribacterial crystal growth is facilitated.

See above for discussion of genetic effects on metabolism and urolithiasis.

What complications might you expect from the disease or treatment of the disease?

Urolithiasis can lead to obstruction and hydronephrosis, infection and urosepsis, and corresponding sequelae in severe cases.

Complications from treatment are discussed above.

How can this disease be prevented?

Identifying modifiable dietary risk factors is the first step in preventing urolithiasis. All patients with stone disease, regardless of underlying abnormalities, may benefit from:

Increased water intake
Avoidance of excess sodium, meat, and oxalate intake
Normal dietary calcium intake (with inadequate calcium consumption, less is available to bind oxalate, which increases the risk of calcium oxalate urolithiasis)
Increased citrate intake through orange juice, real lemonade, or citrate supplements

Specific metabolic abnormalities may have targeted preventive therapies.

With calcium oxalate and calcium phosphate forming up to 65% and 30% of stones, respectively, hypercalciuria is the most common abnormality found. If associated hypercalcemia exists, it should be explored for underlying cause and treated because low bone density can be associated.

Thiazide diuretics should be considered in the treatment of calcium based stones and persistent hypercalciuria refractory to reduction in salt intake. Monitor for side effects of hypokalemia and hypocitraturia.

Potassium citrate supplementation or increasing citrus fruit intake (orange juice, lemonade) is useful for patients with calcium oxalate stones and concomitant hypocitraturia, as well as children with uric acid stones.

Hyperoxaluria, accounting for 20% of metabolic abnormalities identified in children, results from bile and fat malabsorption; treatment with potassium citrate addresses the metabolic acidosis, and calcium supplementation may decrease oxalate absorption from the intestines. Primary hyperoxaluria is an inborn error of metabolism treated definitively with liver transplantation.

Uric acid stones, composing 8% of pediatric stones, can be controlled by increasing urinary pH with potassium citrate (10 mEq tablets 3 times daily) or with a trial of allopurinol (for hyperuricosuria, 100-300 mg/d). The cause is often idiopathic or from rapid cell turnover associated with tumor lysis syndrome, myeloproliferative/lymphoproliferative disorders, or inborn errors of metabolism.

Cystine stones associated with cystinuria, which occurs in 7% of children with stones, can be treated with aggressive hydration and alkalinization of urine, but children with this inherited defect often require multiple stone procedures during their lifetimes. Penicillamine or tiopronin can be used to maintain a pH of more than 6.5. Captopril is an alternative.

Struvite (infection) stones may warrant prophylactic antibiotics targeting the predominant organism. Acetohydroxamic acid is a urease inhibitor that can be used for chronic infection with urease-splitting organisms. The recommended initial dose for children is 10 mg/kg/d divided every 6 to 8 hours by mouth on empty stomach and then titrate to patient response.

Referral to a pediatric urologist is appropriate for patients with complicated or recurrent urolithiasis. Patients with small uncomplicated ureteral or renal calculi may be followed as outpatients by their primary care providers.

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