Nephrolithiasis – Causes, Symptoms, Diagnosis, Treatment

Urolithiasis is a common condition, and it accounts for a large number of hospital visits. It is frequently preventable by modification of risk factors and has numerous treatment options. This activity outlines the etiology, management, and treatment of urolithiasis and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Renal stones are formed within the kidneys, and this is called nephrolithiasis. Urolithiasis is a condition that occurs when these stones exit the renal pelvis and move into the remainder of the urinary collecting system, which includes the ureters, bladder, and urethra. Many patients with urolithiasis can be managed with expectant management, analgesic, and anti-emetic medications; however, stones that are associated with obstruction, renal failure, and infection require further increasingly critical interventions.[rx]

Types of Nephrolithiasis

• Calcium stones – Small asymptomatic stones in the kidney can be safely ignored, and if patients maintain good states of hydration, the risk of recurrent symptoms can be dramatically reduced ¹⁰. In all settings, a search for a possible underlying cause of hyperoxaluria/hypercalciuria should be sought and if present corrected when possible. Larger stones may be treated with extracorporeal shock wave lithotripsy (ESWL), percutaneous nephrostomy
• Struvite stones – Struvite stones are usually large (staghorn calculi) and result from infection. These stones need to be treated surgically and the entire stone removed, including small fragments, as otherwise, these residual fragments act as a reservoir for infection and recurrent stone formation.
• Uric acid stones – Uric acid stones usually are the result of low urinary pH, and hydration and elevation of urinary pH to approximately 6 are usually sufficient (note rendering the urine too alkali (e.g. pH >6.5) may result in calcium stone formation).
• Cystine stones – Cystine stones may be difficult to treat and are difficult to shatter with ESWL. Hydration and alkalinization are usually first-line therapy.

Causes of Nephrolithiasis

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 cysteine (1%) stones and are significantly less common than stones composed of calcium oxalate or phosphate (80%).[rx] 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, coffee, chocolate, some nuts, some teas, soda, spinach, potatoes), and high salt intake.[rx] 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, tea, beer, and 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.[rx][rx] 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.[rx]

The presence of medical conditions such as chronic kidney disease, hypertension, gout, diabetes mellitus, hyperlipidemia, obesity, endocrine, and malignancies increase the risk of 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.[rx][rx]

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.[rx] Ceftriaxone has been shown to increase the risk of stone formation in patients who are on long-term therapy.[rx]

Symptoms of Nephrolithiasis

The exact symptoms of urolithiasis depend on the location and size of the calculi in the urinary system. General signs and symptoms may include:

• Renal or ureteral colic
• Blood in the urine (hematuria)
• Urinary tract infection
• Abdominal pain
• This pain, known as renal colic, is often described as one of the strongest pain sensations known.^[rx]
• Renal colic caused by kidney stones is commonly accompanied by urinary urgency, restlessness, hematuria, sweating, nausea, and vomiting.
• It typically comes in waves lasting 20 to 60 minutes caused by peristaltic contractions of the ureter as it attempts to expel the stone.^[rx]
• The classical features of renal colic are sudden severe pain. It is usually caused by stones in the kidney, renal pelvis or ureter, causing dilatation, stretching, and spasm of the ureter.
• Pain starts in the loin about the level of the costovertebral angle (but sometimes lower) and moves to the groin, with the tenderness of the loin or renal angle, sometimes with haematuria.
• If the stone is high and distends the renal capsule then pain will be in the flank but as it moves down pain will move anteriorly and down towards the groin.
• A stone that is moving is often more painful than a stone that is static.
• The pain radiates down to the testis, scrotum, labia or anterior thigh.
• Whereas the pain of biliary or intestinal colic is intermittent, the pain of renal colic is more constant but there are often periods of relief or just a dull ache before it returns. The pain may change as the stone moves. The patient is often able to point to the place of maximal pain and this has a good correlation with the current site of the stone.
• Other symptoms which may be present include:
  • Rigors and fever.
  • Dysuria.
  • Haematuria.
  • Urinary retention.
  • Nausea and vomiting.

Stones in the kidneys can obstruct the urinary flow in the kidneys or the ureters, which can lead to severe flank pain and possibly blood in the urine. Stones in the bladder can lead to symptoms such as pain, as well as an increased urge and frequency of urination.

Diagnosis of Nephrolithiasis

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.

Lab Test and Imaging

Laboratory investigations typically carried out include^[rx]

• microscopic examination of the urine, which may show red blood cells, bacteria, leukocytes, urinary casts, and crystals;
• urine culture to identify any infecting organisms present in the urinary tract and sensitivity to determine the susceptibility of these organisms to specific antibiotics;
• complete blood count, looking for neutrophilia (increased neutrophil granulocyte count) suggestive of bacterial infection, as seen in the setting of struvite stones;
• renal function tests to look for abnormally high blood calcium levels (hypercalcemia);
• 24-hour urine collection to measure total daily urinary volume, magnesium, sodium, uric acid, calcium, citrate, oxalate, and phosphate;
• collection of stones (by urinating through a StoneScreen kidney stone collection cup or a simple tea strainer) is useful. Chemical analysis of collected stones can establish their composition, which in turn can help to guide future preventive and therapeutic management.

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

Urine analysis (UA)

• It is done 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.

Radiographic features

• These depend on the stone composition and vary according to modality. The much greater sensitivity of CT to tissue attenuation means that some stones radiolucent on plain radiography are nonetheless radiopaque on CT.

Plain radiograph

• 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.

Calcium-containing stones are radiopaque:

• calcium oxalate +/- calcium phosphate
• struvite (triple phosphate) – usually opaque but variable
• pure calcium phosphate

Lucent stones include:

• uric acid
• cystine
• medication (indinavir is best known) stones
• pure matrix stones (although may have a radiodense rim or center)

Fluoroscopy

• Intravenous urography (IVU) is a traditional radiographic study of the renal parenchyma, pelvicalyceal system, ureters, and urinary bladder. It involves the administration of intravenous contrast. This exam has been largely replaced by non-contrast CT.

Ultrasound

• 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.[rx] 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.
• Ultrasound is frequently the first investigation of the urinary tract, and although by no means as sensitive as CT, it is often able to identify calculi. Small stones and those close to the corticomedullary junction can be difficult to reliably identify. Ultrasound compared to CT KUB reference showed a sensitivity of only 24% in identifying calculi. Nearly 75% of calculi not visualized were <3 mm. Features include
• echogenic foci
• acoustic shadowing
• twinkle artifact on color Doppler
• color comet-tail artifact

​Pulsed wave (PWD) and color flow Doppler (CFD) are further sonographic modalities that may act as a diagnostic aid, and assess for the presence of complications;

• ureteric jets in obstructive uropathy tend to be shorter, slower, and occur less often suggested cutoff values vary; the combination of fewer than 1.5 jets per minute, with peak velocities below 19.5 cm/s and jet durations less than 2.5 seconds have specificities ranging between 87 and 97%
• the renal resistive index (RI) is significantly higher in obstructed kidneys contralateral unaffected renal RI comparison useful elevation in RI may precede pelvicalyceal dilation

CT Scan

• 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

On CT almost all stones are opaque but vary considerably in density.

• calcium oxalate +/- calcium phosphate: 400-600 HU
• struvite (triple phosphate): usually opaque but variable
• pure calcium phosphate: 400-600 HU
• uric acid: 100-200 HU
• cystine: opaque

Two radiolucent stones are worth mentioning

• medication (protease inhibitor (indinavir)) stones radiolucent and usually undetectable on non-contrast CT  characterized on delayed phase as a filling defect in the ureter
• pure matrix stones 99% of renal tract calculi are visible on a non-contrast CT. Given that one of the commonest sites for a stone to become lodged is the vesicoureteric junction, some centers perform the study in the prone position to establish if the stone is retained within the intravesical component of the ureter or has already passed into the bladder itself.

Dual-energy CT

• Dual-energy CT is a technique allowing the composition of the calculus to be determined, by assessing stone attenuation at two different kVp levels. Each CT vendor has its own algorithms for the use of dual-energy CT for assessing stone composition. Dual-energy CT may be useful in detecting stones concealed by the opacification of the collecting system. Dual-energy CT has also been shown to predict the success of extracorporeal shock wave lithotripsy.

MRI

• It 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.[rx]

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.[rx]

Treatment of Nephrolithiasis

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.[rx] 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, have been shown to be 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.[rx][rx][rx] Overall, the size of the stone largely contributes to how long the stone will take to pass, and its likelihood of passing spontaneously.

• Less than or equal to 2 mm stones, 8 days for mean passage and passage rate of 87%
• 3 mm stones, 12 days for mean passage and passage rate of 76%
• Between 4 – 6 mm, 22 days for mean passage and passage rate of 60%
• 7 mm stone with a passage rate of 48%
• 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.[rx] Flexible ureteroscopy is a good option for lower pole stones between 1.5 and 2 cm in size.[rx] Additionally, it is an ideal choice of treatment for patients taking anticoagulant/antiplatelet medications.

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 to 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.[rx]

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.[rx] 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 ~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.[rx]

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.[rx]

Initial management of acute presentation

• Non-steroidal anti-inflammatory drugs (NSAIDs), usually in the form of diclofenac IM or PR, should be offered first-line for the relief of the severe pain of renal colic. NSAIDs are more effective than opioids for this indication and have less tendency to cause nausea. However, if parenteral morphine is required in severe renal colic pain, this works quickly and can provide pain relief in the time taken for an NSAID to work. If opioids are needed then a Cochrane review concluded that it should not be pethidine.
• Provide antiemetics and rehydration therapy if needed.
• The majority of stones will pass spontaneously but may take 1-3 weeks; patients who have not passed a stone or who have continuing symptoms should have the progress of the stone monitored at a minimum of weekly intervals to assess the progression of the stone.
• Conservative management may be continued for up to three weeks unless the patient is unable to manage the pain, or if he or she develops signs of infection or obstruction.
• Medical expulsive therapy may be used to facilitate the passage of the stone. It is useful in cases where there is no obvious reason for immediate surgical removal. Calcium-channel blockers (eg, nifedipine) or alpha-blockers (eg, tamsulosin) are given. A corticosteroid such as prednisolone is occasionally added when an alpha-blocker is used but should not be given as monotherapy.^[rx]

Managing patients at home

• All patients managed at home should drink a lot of fluids and, if possible, void urine into a container or through a tea strainer or gauze to catch any identifiable calculus.
• Analgesia: paracetamol is safe and effective for mild-to-moderate pain; codeine can be added if more pain relief is required. Paracetamol and codeine should be prescribed separately so they can be individually titrated.
• Patients managed at home should be offered fast-track investigation initiated by the hospital on receipt of a letter or email completed by the general practitioner.
• Patients should ideally receive an appointment for radiology within seven days of the onset of symptoms.
• An urgent urology outpatient appointment should be arranged for within one week if renal imaging shows a problem requiring intervention.

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