Urolithiasis

Etiology

There are multiple types of kidney stones; however, 80% of stones are composed of calcium oxalate or phosphate. Other stone types include uric acid (9%), struvite (10%), and cystine (1%) stones and are significantly less common than stones composed of calcium oxalate or phosphate (80%).[2] The different types of stones occur due to varying risk factors such as diet, prior personal and family history of stones, environmental factors, medications, and the patient’s medical history.

Common risk factors for stone formation include poor oral fluid intake, high animal-derived protein intake, high oxalate intake (found in foods such as beans, beer, berries, chocolate, some nuts, some teas, soda, spinach, and potatoes), and high salt intake.[2] Oral hydration is recommended at a rate that produces approximately 2.5 L of urine per day, and acceptable choices for fluids include water, coffee, low sugar fruit juices except for tomato (high sodium content), grapefruit, and cranberry (high oxalate content). Consumption of citrate helps to prevent stone formation as it inhibits crystal aggregation by forming complexes with calcium salts within the urine. 60% of patients with calcium stones have been found to have hypocitraturia.[3][4] Low calcium intake has been shown to increase the risk of kidney stone formation, contrary to common belief. Decreased oral calcium intake will reduce calcium levels within the GI tract, which would otherwise be available to bind to oxalate. This, in turn, will increase oxalate absorption and excretion, increasing the risk of stone formation. Vitamin C intake and fish oil have also been shown to increase the risk of calcium stones.

A prior personal and family history of kidney stones will increase the patient’s risk of developing subsequent stones substantially. Procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy have shown a three-fold increase in calcium oxalate stone formation secondary to the malabsorptive post-surgical state, resulting in increased urinary oxalate levels, decreased production of urine, and decreased urine citrate.[5]

The presence of medical conditions such as chronic kidney disease, hypertension, gout, diabetes mellitus, hyperlipidemia, obesity, endocrine, and malignancies increase the risk of the development of kidney stones. Obesity, hyperlipidemia, and type 2 diabetes mellitus have a strong association with calcium oxalate and uric acid stones. Patients with histories of hyperlipidemia, hypertension, and type 2 diabetes mellitus often have diets that are high in animal-derived proteins, salt, and sugar, placing them at higher risk for stone formation. Insulin resistance in obesity and type 2 diabetes mellitus promotes metabolic changes that increase the risk of stone formation secondary to increased urinary calcium and uric acid excretion. A recent study evaluating 4500 patients with a history of kidney stones and insulin resistance showed increased urinary pH and decreased urinary acid excretion, promoting nephrolithiasis/urolithiasis. A prospective, large study followed participants over the years and assessed initial weight, weight gain, dietary exposure, BMI, and waist circumference and strongly showed that while increased BMI does raise the risk of symptomatic stone formation, increased weight due to adiposity in adulthood plays a very key role.[6][7]

Drug-induced urolithiasis is rare and only compromises 2% of stones. Common drugs include protease inhibitors used for the treatment of HIV (atazanavir and indinavir) and sulfadiazine. Protease inhibitor stones are poorly visualized on unenhanced CT scans and are gelatinous in material, making them often unsusceptible to lithotripsy. They typically cause a high-grade urinary obstruction requiring ureteral stenting.[8] Ceftriaxone has been shown to increase the risk of stone formation in patients who are on long-term therapy.[9]

Struvite stones, also known as infection stones, are less common and can form slowly and before becoming symptomatic. This type of stone can form into a staghorn or large calculus that overwhelms the renal collecting system. They are composed of magnesium ammonium phosphate and form secondary to elevated urine pH, and this is largely caused by the presence of Proteus or Klebsiella species, which are urease formers. Urea breakdown yields ammonia as a by-product, which increases the urinary pH (typically to more than 8) and facilitates struvite stone formation.[10]

Uric acid stone formation is related to low urinary uric acid levels, low urine pH, and low urinary volume. Most commonly, these patients will present as idiopathic uric acid stone formers; however, metabolic disorders such as diabetes and obesity will also increase the risk of uric acid stones. Low urinary pH will promote uric acid crystal formation and deposition, typically under a pH of 5.5. Diets rich in animal proteins will increase uric acid load and precipitation. Gout, certain neoplastic disorders, and chronic diarrhea are also associated with uric acid stone formation.[11]

Cystine stones are rare and occur due to an inborn congenital disorder causing mutations in 2 genes, SLC3A1 and SLC7A9. These mutations cause defective cystine metabolism and transport, resulting in cystinuria and stones. They typically present in childhood or adolescence, but some cases have even been shown in infants. Of note, cystine stones can also form staghorn calculi.[12]

Epidemiology

Urolithiasis is a common condition and affects about 1 out of 11 people in the U.S. It is estimated to create a $5 billion expenditure on the health care system and is responsible for approximately 1 million emergency department (ED) visits annually. Its prevalence is rising and primarily affects the working-age population. Men present more commonly than women, 10.6% vs. 7.1%. Obese and overweight individuals compared to normal-weight individuals present more commonly, and studies showed that obesity was an equalizer in the formation of kidney stones when comparing men to women. Variations between different ethnicities have been seen, however white, non-Hispanic males have the highest prevalence per recent studies, followed by Hispanic and then black non-Hispanic individuals. Females are more likely than males to form struvite stones because they have urinary tract infections more frequently.

A recurrence rate of up to 50% has been seen five years from the initial episode of symptomatic urolithiasis.[13][14][1]

Pathophysiology

Urolithiasis occurs when crystals that the stone is composed of supersaturate the urine due to being present in a high concentration and begin to collect and crystallize within the parenchyma of the kidney, forming the renal calculi. These crystals will aggregate together and continue to enlarge with the potential to migrate into the ureter and become symptomatic. If the stone causes an obstruction and does not allow for the passage of urine through the ureter, hydronephrosis can occur secondary to upstream dilation of the ureter and renal pelvis. The most common location for a stone to obstruct is near the ureteropelvic junction (UPJ) because in this region the diameter of the ureter is very narrow. There are two other areas of ureteral narrowing, the first being where the ureter crosses over the iliac vessels and the second at the ureterovesical junction (UVJ). Stones are painful within the ureter because as they pass through the ureter, increased luminal tension and hydronephrosis will lead to prostaglandin release, resulting in colicky pain associated with the condition. 

Crystal nucleation and growth are key factors in the production of all types of kidney stones. Nucleation is when crystals begin to compound together to initiate stone formation. Supersaturation of the urine with organic materials contributing to stone formation is a driving force of this mechanism.

There are two theories, free particle vs. fixed particle, that describe the growth and aggregation of crystals. The free particle mechanism states that the crystals will increase in size and aggregate within the urine of the tubules. These aggregates enlarge and block urine outflow from tubular openings, which promotes the formation of smaller stones. Alternatively, the fixed particle mechanism states that stones formed attached to calcific plaques called Randall plaques. These plaques are rooted deeply within the basement membrane of the loop of Henle. The cause of the initial formation of Randall’s plaque is unknown.[15][16][17]

History and Physical

Regardless of the type of stone, patients present with a similar array of symptoms, ranging from asymptomatic to critically ill. The presentation includes sudden to gradual onset, unilateral colicky abdominal/flank pain that often waxes/wanes, hematuria (90% microscopic on UA), nausea, vomiting, and fever.

The abdominal exam typically shows a soft, non-distended abdomen. Depending on the location of the pain within the urinary tract, pain can range from flank pain when near the ureteropelvic junction to groin/scrotal/labial pain if the stone is at the ureterovesical junction. Pediatric patients may present with irritability, crying, fevers, and vomiting. Awake and alert patients are often restless due to the pain and shift around incessantly to find a position of comfort.

In severe cases, stones can cause urinary obstruction and/or can become a source of sepsis. In these patients, symptoms are more severe and include mild confusion to obtundation secondary to severe metabolic abnormalities. In patients that do present with severe infection or sepsis, hemodynamic instability is often present.

Evaluation

Appropriate labwork to be ordered in the initial evaluation of a patient with suspected urolithiasis is as follows:

Urine analysis (UA) with microscopy (can show gross blood or + microscopic hematuria, +/-leukocyte esterase, +/- nitrites +WBC), urine HCG (all women of reproductive age), CBC, CMP, lactic acid, lipase, amylase, blood cultures (if the patient has +SIRS criteria).

The choice of imaging modality can be selected using factors such as the patient's body habitus, pregnant state, cost, and consideration of radiation exposure.

Renal ultrasound is a method that can be used to assess urolithiasis and is an ideal initial imaging study of choice in pediatric and pregnant patients to avoid radiation.[18] This form of imaging will identify stones within the kidneys, pyeloureteric, and vesicoureteric junctions, and identify hydronephrosis secondary to obstructive urolithiasis. Doppler jet can also be used to assess urinary flow. The sensitivity and specificity of ureteric stones are 57% and 97.5%. Stones will appear echogenic (bright white) on ultrasound. A large body habitus can significantly limit the visualization of stones. Assessment of the size of the stone can also be operator-dependent.

X-ray of kidney, ureter, and bladder (KUB) can be used to assess for radiopaque stones (calcium phosphate and oxalate), but not radiolucent stones (uric acid and cystine), and it has a sensitivity and specificity of 45% and 85%, respectively. Despite low yield in an acute setting, KUB is most helpful in monitoring for stone growth over time.

CT abdomen/pelvis without contrast has become the ideal study of choice to assess for ureterolithiasis if the patient can tolerate radiation, with sensitivity and specificity of 95% and 98%. It is possible that stones less than 3 mm in size might not be detected, as they may slip through the imaging slices of the CT scanner. CT will provide visualization of every type of stone, except for stones that are formed secondary to HIV medications (protease inhibitors). CT scan is also useful in that it can help to predict therapeutic response to shock wave lithotripsy, as stones that have higher attenuation on CT will likely require an increased number of shocks and less successful response to the treatment itself. BMI must be taken into consideration when selecting a standard dose vs. low dose CT scan, and current guidelines state that a low dose CT scan is not recommended for patients with a BMI of more than 30.

MRI is another option for imaging urolithiasis. It is better in sensitivity (82%) and specificity (98%) than ultrasound and KUB but is inferior to CT. MRI is reliable for determining hydronephrosis, but a stone may not always be visualized because it relies on identifying calcifications and signal voids. The benefit of MRI is that it provides 3D imaging without radiation, and it is a good second-line imaging option for pregnant and pediatric patients to be used adjunctively to ultrasound. The cons of MRI with respect to the diagnosis of urolithiasis are that it is three times as expensive as CT, time-consuming, and not readily available in the ED where the majority of these patients will present.[19]

A validated risk assessment tool has been derived and validated called the STONE score, which stratifies patients in a low, moderate, or high probability of having a stone using five criteria; sex, timing origin, nausea, and erythrocytes.[20]

Treatment / Management

The treatment of urolithiasis is based upon the patient's acute presentation and includes both conservative medical therapies and surgical interventions. Often when patients present, pain control is an important intervention. Oral and IV anti-inflammatory medications (NSAIDs) are indicated as first-line treatments for pain. Opioids can be used, but are reserved for refractory pain. IV lidocaine has also been studied as an effective pain control option.[21] Nausea and vomiting should be treated with IV antiemetic medications such as ondansetron, metoclopramide, promethazine, to name a few. Medical expulsive therapy, or MET, includes alpha-blockers, such as doxazosin and tamsulosin, which is a useful adjunct to facilitate passage of larger (5-10 mm) stones but has not shown to be beneficial in the passage of smaller ones. IV crystalloid fluids can be given to patients who appear dehydrated due to persistent vomiting, but have not been shown to facilitate stone passage.

Approximately 86% of stones will pass spontaneously within 30-40 days.[22][23][22] Overall, the size of the stone largely contributes to how long the stone will take to pass, and its likelihood of passing spontaneously.

1. Less than or equal to 2 mm stones, 8 days for mean passage and passage rate of 87%
2. 3 mm stones, 12 days for mean passage and passage rate of 76%
3. Between 4-6 mm, 22 days for mean passage and passage rate of 60%
4. 7 mm stone with a passage rate of 48%
5. 8-9 mm stone with a passage rate of 25% 

Patients with urolithiasis can present with varying degrees of illness/complications associated with the condition. Patients with small stones, physiologic bloodwork, no signs of infection, or acute obstruction can be managed using MET. 

Patients presenting with large stones, or if the presentation is consistent with acute renal failure, oliguria/anuria, SIRS criteria, associated infection, or a history of the solitary kidney is present, may require urgent/emergent urologic intervention. Intractable pain or vomiting, inability to tolerate oral intake, pregnancy, or pediatric patients may require hospitalization for closer observation.

Further interventions should be discussed with urology emergently, and an appropriate plan of care should be made according to the patient's risk factors, medical history, acute presentation, and urologist's comfort and preference. There are various methods of acute urologic interventions, including extracorporeal shockwave lithotripsy (ESWL), flexible ureteroscopy (URS), and percutaneous nephrolithotomy (PCNL).

Flexible URS is the most common method used and involves an endoscopic approach passed through the lower urinary tract system into the ureters and calyces. This technique allows for the visualization of the urinary tract and the retrieval of an obstructing stone.[24] Flexible ureteroscopy is a good option for lower pole stones between 1.5 and 2 cm in size.[25] Additionally, it is an ideal choice of treatment for patients taking anticoagulant/antiplatelet medications.(B3)

ESWL is a technique in which an x-ray is used to target stone location, and shockwaves from an energy source are used to fragment the stone into smaller pieces that can be passed into the urine. This technique may require follow-up ureteral stent placement to facilitate fragment passage. This technique typically requires IV sedation or general anesthesia but can be performed on an outpatient basis. Cystine stones may be resistant to treatment.

PCNL is often reserved for patients that fail or have contraindications to URS or ESWL. This method is preferred for stones greater than 20 mm in size, staghorn calculi, and stones in patients with a history of chronic kidney disease. Large stones located in the kidney and proximal ureter are often treated using this technique. General or spinal anesthesia is used, and a small puncture wound is placed in the flank skin overlying the stone, followed by a ureteroscope to retrieve the stone. Contraindications to PCNL include current pregnancy, bleeding disorders, and active urinary tract infections.[25]

Acute renal obstruction with signs of urinary tract infection is a urologic emergency. This will require emergent decompression to prevent permanent renal damage and worsening of infection. The two options currently present for this are indwelling ureteral catheter and placement of a nephrostomy tube.

In patients who have calcium urolithiasis, medications such as thiazide diuretics, citrate salts (potassium citrate), and lifestyle modifications are beneficial in long-term management.[26] Struvite stones will largely require surgical intervention and close follow-up with urology. The cornerstone of cystine stone urolithiasis is lifestyle modification, including increasing fluid intake to optimize urinary output to around 3 liters per day and minimizing animal protein and sodium intake. Potassium citrate and thiol drugs have also been beneficial in patients with a history of cystine stones. Uric acid stones can be managed with increased fruit, and vegetable intake decreased animal protein intake, and initiation of potassium citrate and uric acid lowering medications such as allopurinol to prevent recurrence of stones.[27]

Outpatient management can be assisted by testing to determine the etiology of urolithiasis which includes testing focused on abnormalities in the serum (serum calcium, phosphorus, oxalate, sulfate, magnesium, citrate, cysteine, ammonium, vitamin D levels, lactate dehydrogenase, and parathyroid hormone) and the urine (urine electrolytes, pH, uric acid, creatinine, and calcium). These tests allow for further stone analysis to improve further management.[21]

Differential Diagnosis

The use of an objective clinical prediction rule for kidney stones in the form of STONE criteria is advisable. Patients with a high STONE score are more likely to have kidney stones and vice versa. Following are some important differentials to be considered in a patient presenting with the above-mentioned features:

• Lower urinary tract infection
• Pyelonephritis 
• Renal abscess 
• Renal artery aneurysm 
• Appendicitis 
• Diverticulitis 
• Mesenteric ischemia
• Pancreatitis
• Cholecystitis
• Small bowel obstruction
• Ovarian torsion
• Dysmenorrhea
• Ectopic pregnancy 
• Spontaneous abortion 
• Pelvic inflammatory disease (PID)
• Constipation

Prognosis

Most patients presenting with urolithiasis have an excellent prognosis.

Asymptomatic/calyceal stones (non-struvite) typically do not require acute intervention and can be monitored over time with a routine evaluation with ultrasound or KUB. 

Stones that are less than 5-6 mm can usually pass spontaneously and can be treated using medical management (anti-emetics, analgesia, increased oral fluid intake, and alpha-receptor antagonists [i.e., tamsulosin]).[23] Patients with small stones should be counseled on risk factor modification to prevent stone recurrence.

Larger stones may require more invasive techniques such as shock wave lithotripsy, percutaneous nephrolithotomy, or a combination of the two. These patients have a good prognosis and should be counseled on risk factor management.

Infected stones have a good prognosis with early acute intervention, including antibiotics, hemodynamic stabilization, and interventions to remove the septic stone.

Complications

Complications include acute renal failure secondary to obstruction, anuria, urinary tract infection with renal obstruction, and sepsis.