Middle-Aged Woman With Ureteral Calculi

For 3 months, a 46-year-old woman had had intermittent right-sided loin pain. She had no dysuria, increased frequency or urgency, daytime wetting or dampness, nocturia, or bed-wetting. There was no change in the color or the odor of her urine. She had no history of trauma. Her medical history was unremarkable.

On examination, she was afebrile. Mild tenderness was noted over the right flank. The remainder of the physical examination findings were normal.

Urinalysis revealed 0 to 4 white blood cells (WBCs) and 10 red blood cells per high-power field. There were no casts or crystals. A urine culture was negative. A plain radiograph of the abdomen showed an opacity on the right side at the level of the third lumbar vertebra (L3), in a position compatible with a ureteral calculus (Figure 1). The opacity measured 10 3 13 mm. The diagnosis of a ureteral calculus was confirmed with a nonenhanced helical CT scan (Figure 2).

The patient’s serum calcium, phosphate, alkaline phosphatase, uric acid, electrolyte, and creatinine levels were normal. The prothrombin and activated partial thromboplastin times were also normal.

She was treated with extracorporeal shock wave lithotripsy (ESWL). After 2 sessions of ESWL, some residual fragments of the ureteral calculi remained. An 8F semirigid ureteroscope was introduced into the right ureter (Figure 3). The stone was fragmented by holmium:yttrium-aluminum-garnet (Ho:YAG) laser, and the fragments were removed by basket extraction (Figure 4).

Stone analysis revealed 80% calcium oxalate and 20% calcium phosphate. An intravenous pyelogram obtained 3 months after ureteroscopy showed no evidence of residual stone or of stricture of the ureter.

EPIDEMIOLOGY OF
URETERAL CALCULI
Urinary calculi develop in about 8% to 12% of the population.^1-3 Between the ages of 30 and 60 years, the annual age-adjusted incidence for men and women is approximately 1.1 and 0.36 per 1000 individuals, respectively.⁴ The incidence increases with age.5

The lifetime recurrence rate is about 50%.2 Once a stone recurs, the relapse rate increases and the interval between recurrences decreases.6 Recurrence is more common with a young age of onset and with a positive family history.⁶

Urolithiasis is 3 to 4 times more common in whites than in African Americans.⁴ The incidence is higher in certain regions, perhaps because of genetic and environmental factors. The environmental factors may include hot climate with consequent dehydration and sun exposure with increased vitamin D levels.

ETIOLOGY
Idiopathic calcium calculi account for 70% to 80% of urinary stones.⁴ Calcium oxalate stones are much more common than calcium phosphate stones. Calcium oxalate stones are thought to develop from Randall plaques, which are lesions that arise from the basement membrane of the loop of Henle and expand to protrude through the urothelium into the papillae.⁶

Calcium stones develop in the presence of hypercalciuria, which can result from increased calcium absorption from the GI tract, increased renal tubular excretion, bone resorption, or a combination
of these factors. Intestinal hyper­absorption in conjunction with a low bone density and reduced bone formation is the most common abnormality.⁶ Renal tubular acidosis also contributes to hypercalciuria.

Hypercalcemia from a variety of causes can produce hypercalciuria. Hyperparathyroidism is the most common cause of hypercalcemia; it accounts for calcium stones in 5% of patients.⁴ Other hypercalcemic conditions that can result in calcium stones include hypervitaminosis D, immobilization, milk-alkali syndrome, Cushing syndrome, sarcoidosis, and malignancy.

Metabolic causes of urolithiasis include inherited disorders of uric acid, cystine, and oxalate metabolism; these account for about 5% to 10% of cases.^4,6 Urinary tract infection (UTI), urinary tract obstruction, and neurogenic bladder predispose to stone formation. Medications such as triamterene, indinavir, and acyclovir are also associated with stone formation.

CLINICAL MANIFESTATIONS
A ureteral calculus can be asymptomatic or painful. The classic presentation is the sudden onset of intense ipsilateral flank pain that is often severe enough to make the patient writhe.^2,3 The pain sometimes radiates across the abdomen to the groin and into the testicle in males or the labia majora in females.⁷ Nausea and vomiting are common. Blood is often visible in the urine.

Depending on the position, a calculus can mimic other diseases. A stone located in the right ureteropelvic junction can mimic acute cholecystitis; in the right lower ureter, acute appendicitis; in the left lower ureter, acute diverticulitis; and in the vesicoureteral junction, acute cystitis.⁸ Urgency and frequency can develop when the calculus is in the distal urethra.⁹

The pain almost always occurs on the same side as the underlying pathology. Rarely, the pain might be generalized or felt on the contralateral side, a phenomenon known as “mirror pain.”^10,11

CLINICAL EVALUATION

History. The younger the patient, the higher the likelihood that the stone is caused by a metabolic disorder, such as cystinuria, primary hyperoxaluria, an inborn error of uric acid metabolism, or renal tubular acidosis. Uric acid calculi and idiopathic calcium calculi are more common in males, whereas primary hyperparathyroidism and renal tubular acidosis are more common in females.⁴

The history should include the location, time of onset, character, severity, duration, and radiation of the pain. A history of gross hematuria points to the urinary tract as the origin of the pain. Increased urinary frequency, dysuria, urgency, and malodorous urine suggest a UTI.¹² The presence of fever, nausea, vomiting, lethargy, and loss of appetite suggests kidney infection, the possibility of urosepsis, and the need for prompt intervention.

A detailed dietary history is important. Excessive intake of sodium, calcium, oxalate, or protein, and a low intake of fluid can predispose to the formation of calculi.⁴ A drug history is necessary to identify medications that can cause urolithiasis.

A past history of urolithiasis can provide clues to the diagnosis; note the types and success of previous treatments. Suspect struvite lithiasis if there is a history of recurrent UTIs with urease-producing bacteria.⁴ A family history of cystinuria, xanthinuria, primary hyper­oxaluria, or renal tubular acidosis suggests the corresponding dis­order. About half of patients with idiopathic hypercalciuria have a family history of kidney stones.⁶

Physical examination. Tenderness of the costovertebral angle or lower abdominal quadrant may be present.² The blood pressure and heart rate are usually elevated secondary to pain. The presence of fever raises the possibility of pyelonephritis or urosepsis.

A spinal defect; abnormalities in the motor power, tone, or reflexes in the lower extremities; and absence of the anal wink indicate a neurogenic bladder. Moon facies, buffalo hump, truncal obesity, and hypertension suggest Cushing syndrome. Hyperreflexia, ankle clonus, spasticity, extrapyramidal movements, and self-mutilation point to Lesch-Nyhan syndrome. The presence of gouty trophi and arthritis suggests gout.

DIAGNOSTIC EVALUATION

Urinalysis. Microscopic or gross hematuria, WBCs and bacteria, or crystalluria may be noted. Calcium oxalate crystals can be bipyramidal, ovoid, biconcave, or dumbbell-shaped; are birefringent; and appear as bright specks with polarized microscopy.⁴ Uric acid crystals are rhomboid, biconvex, or barrel-shaped. Cystine crystals are hexagonal.

WBCs and bacteria suggest a UTI.¹² A urine culture should be ordered if a UTI is suspected.

The urine pH should be determined. A urine pH of less than 5.5 favors the formation of uric acid stones. A urine pH of higher than 8 is associated with urease-producing bacteria.⁴ A 24-hour urine collection for calcium, phosphorus, uric acid, oxalate, cystine, citrate, sodium, magnesium, and creatinine should be ordered.

Imaging studies. Although 90% of stones are radio-opaque in plain radiography with a kidney-ureter-bladder (KUB) view,⁹ in real life only about 60% to 70% of stones can be seen with plain radiography. This is because some of the stones may be obscured by an overlying bone or bowel shadow, for example. Magnesium ammonia phosphate (struvite) and cystine calculi are less radiodense and are more difficult to visualize.9 Uric acid, orotic acid, xanthine, triamterene, dihydroxy­adenine, and indinavir calculi are radiolucent and might not be seen on a plain radiograph.⁹ A phlebolith or fecalith can be mistaken for a ureteral calculus and vice versa.

For a patient with acute ureteral colic, an nonenhanced CT scan is the preferred diagnostic imaging study.^9,13 The sensitivity and specificity of nonenhanced helical CT to diagnose ureterolithiasis are 95% to 96% and 98% to 100%, respectively.¹³ An nonenhanced helical CT scan does not require radiocontrast, obtains all the necessary images in less than 1 minute, detects calculi as small as 1 mm, offers detailed anatomic information, and provides information on differential renal function.^8,9 CT allows determination of the Hounsfield unit, which correlates with the fragility of the stone.⁶ The disadvantages of nonenhanced helical CT are ionizing radiation and cost.¹⁴

Most stones appear as radio­dense calcifications and have high attenuation, which makes the identification straightforward.¹⁴ Indinavir calculi, which are radiolucent, might be undetectable on CT.¹⁴ The signs of ureteral obstruction include hydroureter, hydronephrosis, periureteral edema, unilateral renal enlargement, and fluid in the perinephric and paranephric space.^9,13

Ultrasonography has a sensitivity of 93% for renal stones but might not detect stones that are smaller than 3 mm.¹⁴ Both ultrasonography and CT have high sensitivity in detecting obstruction. An ultrasound scan coupled with a plain radiograph with a KUB view is a reasonable alternative when CT is not available.

Other laboratory studies. Serum calcium, phosphorus, alkaline phosphatase, uric acid, creatinine, blood urea nitrogen, sodium, potassium, chloride, and albumin levels and total carbon dioxide content should be determined. Measurement of serum parathyroid hormone is recommended for patients who have a high serum calcium level and a low serum phosphorus level. A ureteral calculus that has been passed or removed should be sent for analysis.
MANAGEMENT

Conservative therapy. A meta-analysis by the American Urological Association Clinical Guidelines Panel found that the overall spontaneous passage rate for calculi smaller than 5 mm in the proximal ureter, mid-ureter, and distal ureter is 25%, 45%, and 75%, respectively.¹⁵ Most investigators recommend 6 weeks as the maximal duration to allow a stone to pass spontaneously, because of the risk of renal damage and ureteral stricture.¹⁶ Patients with a stone that has a low probability of spontaneous passage should be offered intervention.

Therapies that increase urine flow expedite passage of a stone. However, a Cochrane review failed to find evidence-based data that diuretic and high-volume fluid therapy is beneficial for the treatment of adult patients with uncomplicated acute ureteral colic.¹⁷

NSAIDs, such as indomethacin and diclofenac sodium, and opioids, such as morphine, meperidine, and tramadol, are indicated for acute ureteral colic.¹⁸ NSAIDs inhibit prostaglandin synthesis and result in reduction in vasodilatation, intrarenal pressure, and urinary tract inflammation.¹⁸ Adverse effects include GI hemorrhage and renal impairment, especially in patients with existing renal damage.¹⁸ Opioids offer more effective pain relief. Adverse effects of these agents include nausea, vomiting, urinary retention, and constipation. Respiratory depression and hypotension can occur with high doses.¹⁸

Medical expulsive therapy. Patients with small calculi, especially in the lower ureter, might benefit from adjuvant medical expulsive therapy.16 Studies have shown that calcium channel blockers, such as nifedipine, a1-blockers, such as tamsulosin, and corticosteroids can enhance expulsion of ureteral cal­culi.^11,18-21 Nifedipine blocks the calcium influx necessary for smooth muscle contraction and thereby eliminates the fast uncoordinated component of ureteral smooth muscle contraction but does not affect the slower peristaltic rhythm.^16,19 The medication should be used with caution in patients with cardiovas­cular disease because of the risk of hypotension.¹⁸

Tamsulosin blocks α₁-receptors, which are present in high density in the distal ureter.¹⁹ This leads to selective relaxation of ureteral smooth muscle, with subsequent inhibition of ureteral spasms and dilatation of the ureteral lumen.²⁰ Corticosteroids are often used in conjunction with a calcium channel blocker or an a1-blocker to reduce ureteral inflammation and edema and to facilitate expulsion of the calculus.^9,21

Surgical management. Active intervention is usually indicated for ureteral calculi larger than 7 mm, calculi that cause complete ureteral obstruction, persistent pain despite adequate medication, and failure of conservative therapy.²² The options for surgical management of a ureteral calculus include ESWL and ureteroscopy.

ESWL is often preferred because the therapy is less invasive, is associated with lower morbidity, and can be performed without general anesthesia.¹⁶ ESWL is the first-line treatment for ureteral calculi that are 10 mm or smaller.^2,9 This procedure works best for proximal ureteral calculi, for calculi composed of calcium oxalate dehydrate, and for struvite fragments. ESWL is less effective in fragmenting calculi that have an attenuation value on helical CT of greater than 1000 Hounsfield units, such as cystine and calcium oxalate monohydrate calculi.² Contraindications to ESWL include pregnancy, uncontrolled coagulopathy, uncontrolled hypertension, and febrile UTI.²³

Advances in flexible ureteroscopes and the introduction of the Ho:YAG laser have made ureteroscopy a safe and minimally invasive procedure in the management of ureteral calculi of all composition and sizes.^2,24 The procedure has a higher success rate than ESWL.²⁵ Flexible ureteroscopes allow access to all locations, including the lower pole of the kidney. The Ho:YAG laser can be introduced through the smallest-caliber endoscopes and can fragment any stone.⁶ Complications are rare; they include ureteral perforation, ureteral avulsion, ureteral mucosal abrasion, ureteral stricture, and steinstrasse.24

The routine use of stents after ureteroscopy to reduce ureteral edema, to facilitate the passage of residual fragments of calculi, and to decrease the risk of ureteral structure has been questioned.^24,26 Some urologists suggest that a ureteral stent is not necessary after uncomplicated ureteroscopy.^24-26
Patients with urosepsis require intravenous hydration, parenteral antibiotic therapy, and close observation, since septic shock can intervene. These patients often need emergency percutaneous nephrostomy or placement of a ureteral stent to drain the upper tract. Other indications for surgical drainage include persistent pain despite conservative management, obstruction of a solitary kidney, and deterioration in glomerular filtration rate.

PREVENTION
Counsel adolescents and adults with ureteral calculi to increase their fluid intake to achieve a urine output of more than 2 L per day.²⁷ Patients with oxalate calculi should avoid foods with a high content of oxalate, such as rhubarb, wheat bran, spinach, beetroot, cocoa, and nuts.²² Those with uric acid calculi should avoid foods rich in urate, such as red meat, liver, kidneys, and sardines.²²

To reduce the risk of recurrence of calcium calculi, excessive restriction of calcium intake is not recommended.^2,22 Instead, consumption of citrus fruit helps increase the level of urinary citrate, which forms a complex with calcium and minimizes the likelihood of calcium calculi formation.18 Advise patients to avoid excessive salt intake, because a high sodium load increases calcium excretion in the kidney.²⁸