Clinical Practice Guideline
Developed for the
Aerospace Medical Association
by their constituent organization
Overview: Urinary stone disease is the third most frequent urinary tract disorder, exceeded in frequency only by infections and prostatic disease. Men are affected more frequently than women, with a ratio of 2:1. Incident rates are highest in non-Hispanic Caucasians, followed by Hispanics, then African-Americans and other racial/ethnic groups. Initial presentation most commonly occurs in the third and fourth decades. The incidence of urolithiasis is increasing for both men and women, such that 13% of men and 7% of women will be diagnosed with a kidney stone during their lifetime. Diet and fluid intake are important factors in the development of urinary stones. Persons with diets high in protein and/or sodium may have higher rates of stone disease, and persons in sedentary occupations have a higher incidence of stones than manual laborers. Genetic factors also contribute to urinary stone formation, such as for patients with cystinuria and renal tubular acidosis.
The disease’s clinical course is usually that of a gradual onset of flank, abdominal or back pain over an hour or more before acute colic pain onset. Pain (renal colic) usually is described as sharp, severe and localized to the flank and may be associated with nausea and/or vomiting. It may occur episodically and radiate anteriorly over the abdomen or be referred to the ipsilateral testis or labium. If the stone becomes lodged at the ureterovesical junction the patient may complain of marked urinary urgency and frequency. Stone size does not correlate well with severity of symptoms. Urinalysis usually reveals microscopic or gross hematuria.
EVALUATION OF NEPHROLITHIASIS
In initial evaluation, the first radiograph usually obtained is the plain kidney-ureter-bladder (KUB) film. Unenhanced helical computed tomography (CT) is the most sensitive imaging method to confirm (99% diagnostic accuracy) the diagnosis of a urinary stone in a patient with acute flank pain; it also helps with the measurement of stone density and may guide treatment—stones with density > 1000 Hounsfield units respond less well to lithotripsy. Due to potential hazards of increased radiation exposure, CT scans should be used sparingly and judiciously. If a KUB is sufficient for performing follow-up, then it should be used in lieu of CT. Intravenous pyelogram (IVP) is used very infrequently now but can also be helpful in diagnosis and treatment planning. Ultrasound is a noninvasive method for demonstrating both the urinary stone and the resultant hydronephrosis and has a high specificity, but low sensitivity.
Urinary calculi are polycrystalline aggregates composed of varying amounts of crystalloid and a small amount of organic matrix. There are five major types of urinary stones: calcium oxalate, calcium phosphate, struvite, uric acid, and cystine. The following requirements are needed for urinary stone formation: (1) formation of a crystal nidus through nucleation, (2) retention of the nidus within the urinary tract, and (3) growth of the nidus to a size sufficient to cause symptoms or be visible on imaging. For crystals to occur, the urine needs to be supersaturated with the salt in consideration. Intermittent supersaturation, as seen during periods of dehydration or after meals, is sufficient. Stone formers as a group excrete larger crystals and crystal aggregates than non-stone formers and have lower levels of stone inhibitors.
Approximately 75% of renal stones are composed of calcium oxalate. Furthermore, approximately 50-75% of patients with calcium oxalate stones have hypercalciuria, the most common urinary abnormality predisposing to this type of stone disease. Etiologies of hypercalciuria include metabolic acidosis (RTA), hyperthyroidism, malignancies with bone metastases, corticosteroid treatment, vitamin D excess (exogenous or diseases such as sarcoidosis), and hyperparathyroidism. Approximately 5% of individuals with hypercalciuria have primary hyperparathyroidism. A significant number of hypercalciuric patients are classified with “idiopathic hypercalciuria,” which is a diagnosis of exclusion made when the particular etiology of the hypercalciuria cannot be identified. Hypercalciuria is diagnosed with the help of a 24-hour urinary calcium excretion; the upper limit of normal is 4mg (0.1mmol)/kg body weight in patients of either sex.
Hyperoxaluria may predispose to the formation of calcium oxalate stones and hyperuricosuria may predispose to the formation of uric acid stones, calcium stones, or a combination of both. Hyperoxaluria will result in an elevated urinary oxalate level. Normal level for both males and females is about 45mg/day. If due to dietary excess (spinach, rhubarb, Swiss chard, cocoa, beets, peppers, wheat germ, pecans, peanuts, okra, chocolate and lime peel) the maximum would be 50-60mg/day. A level above 60mg/day should be considered abnormal. Hyperuricosuria will display an elevated urinary uric acid level. Levels greater than 800mg (4.8mmol)/day in men and 750mg (4.5mmol) in women may predispose to calcium oxalate stone formation via heterogeneous nucleation or reduction of naturally occurring urinary inhibitors.
Struvite stones, also called infection stones, represent 10-20% of renal stones. They consist of magnesium, ammonium and phosphate, mixed with carbonate. Two conditions must exist for the crystallization of struvite: urine pH of >7.2 and ammonia in the urine. This is caused by urea-splitting bacteria with the generation of ammonia. The usual causative bacteria include Proteus, Klebsiella, Pseudomonas species and Enterococci (excluding E. coli). Those who produce only struvite stones may present with large stones that cause bleeding, obstruction, or infection without stone passage. Struvite stones require complete surgical removal and possibly long-term antibiotics.
Calcium phosphate stones represent around 5% of all stones; these can be caused by renal tubular acidosis or hyperparathyroidism. The laboratory tests for this stone type are blood pH and serum bicarbonate level. If metabolic acidosis is present, along with 24-hour urinary pH > 6.5, hypercalciuria and hypocitraturia treatment is indicated. Therapy is initiated with potassium alkali and close monitoring of urinary pH, citrate and calcium. Uric acid stones also account for 5% of all stones. These usually occur in the presence of low urinary pH (5.1-5.9) and urinary uric acid levels > 1200mg (7.1mmol) excreted daily. Treatment is accomplished by raising the urinary pH to 6.0-6.5 with potassium citrate and treating with allopurinol.
Cystine stones represent less than 1% of all stones. This etiology is secondary to a hereditary defect of amino acid transport. Cystine stones are often multiple, large and may form staghorns. The peak clinical expression is in the third and fourth decade. Cystine stones form because cystine is poorly soluble in the range of normal urinary pH. A level > 250 mg/24 hours is usually diagnostic of cystinuria. Hydration and alkalinization of the urine above pH of 7.5 is considered first-line treatment. If volume plus pH adjustment are insufficient, treatment with penicillamine or tiopronin is utilized (these are not aeromedically acceptable medications in the military).
Observational studies describe the natural history of asymptomatic renal calculi. The risks for development of pain or need for intervention depend in part on stone size and location, with larger stones more likely to require intervention. In a 2004 review of 300 patients, the risk for progression of stones was followed for a mean of 3.26 years. In this report, 77% experienced disease progression, which was defined as the need for surgical intervention, development of pain, or stone growth on serial imaging. These investigators identified that renal pelvic stones (which are free-floating) incurred the greatest risk of surgical intervention. An earlier report describes a similar rate of symptomatic events; with 32% of 107 patients with asymptomatic stones developing symptoms over a mean follow up of 31.6 months and 17% requiring surgical intervention. A 2010 study demonstrated that approximately 1 in 5 adults with asymptomatic urolithiasis will experience symptoms during a 10-year period. This equates to an approximate 2% risk/year of symptomatic stone disease.
While some have advocated observation for lower pole calculi based on the theory that gravity will prevent them from migrating, the above 2004 study did not find a significant difference in need for intervention based on stone location in upper, interpolar or lower pole calyces. A newer study in 2007 described 24 patients with asymptomatic lower pole stones who were followed for an average of 53 months and found that 33% experienced stone growth and 11% required intervention due to pain, obstruction or persistent gross hematuria. The rate of stone growth correlated positively with initial size of stone.
Many have raised the question of whether there is a stone size threshold below which the risk for symptoms and progression is negligible, or at least less than the risks of a stone treatment intervention. This issue has been investigated through observational studies of residual fragments after various stone procedures, including extracorporeal shock wave lithotripsy (ESWL), percutaneous nephrolithotomy (PN) and ureteroscopy. Some have designated small residual calculi with the term “clinically insignificant residual fragments” (CIRF), and various authors have attempted to identify a size below which intervention should be discouraged. The size threshold for CIRFs has been reported variously, from less than 2 mm to 4 mm. There is a tendency to observe these small fragments for a number of reasons. Many settle in lower pole calyces and are held stationary by gravity. It can be difficult to eradicate smaller stones, especially when they are 2 mm or less, because they are harder to localize on fluoroscopy and harder to engage with ureteroscopic baskets. The majority of stones 4 mm or less will pass spontaneously, so the cost and risk of surgical intervention are felt to exceed the benefits of treating these smaller stones for many patients.
Stone clearance and stone-free rates after ESWL vary considerably, ranging from 30-60% (depending on the ESWL machine and imaging used to detect fragments), and it is likely that residual retained fragments contribute to a persistent risk for growing stones in those treated with ESWL alone. Much higher stone-free rates can be achieved with physical extraction of stones via ureteroscopy or PN, but to date there has not been a randomized prospective trial investigating ureteroscopy vs. observation for asymptomatic renal stones.
There have been several studies in the past decade looking at the natural history of residual fragments after ESWL. Most have shown that a significant number of such patients develop stone growth and a symptomatic episode requiring intervention. Many urologists continue to advocate observation with close follow-up for patients with residual stones < 4 mm after an intervention due to the high rate of spontaneous passage of such stones. Despite consequential rates of stone growth, development of symptoms, and need for intervention, this is a safe and cost-effective management plan when patients have ready access to emergency medical and urology care. It is important to note that, while these smaller stones frequently pass spontaneously, they do not pass painlessly.
TREATMENT OF NEPHROLITHIASIS
In most cases, stones < 5 mm in diameter will pass spontaneously but will take variable time to do so depending on their location at presentation. Hydration is helpful to facilitate passage of small stones.
Ureteral stones: Prediction of spontaneous stone passage is difficult. Stones less than 5 mm in diameter often pass spontaneously, especially in the distal ureter. In such cases, conservative observation with pain medication is appropriate for the first four weeks, as long as no infection is present. In a 1999 study of 75 subjects, 95% of stones < 4 mm passed spontaneously within 40 days, and 50% of subjects with stones > 5 mm required intervention for refractory symptoms or failure of the stone to pass. Spontaneous passage of ureteral stones can be facilitated with hydration and oral alpha-1 adrenergic antagonists (not approved for use while on flying status).
Individuals with large stones (not likely to pass), evidence of infection, refractory symptoms or high-grade obstruction should be considered for intervention. Persistent ureteral obstruction for > 4 weeks can increase the likelihood of renal damage in previously normal kidneys. If spontaneous stone passage has failed, therapeutic intervention is required. Ureteroscopic stone extraction or ESWL is used to extract or fragment stones from the proximal, mid or distal ureter. Complications during ureteroscopic extraction increase as the duration of conservative observation increases beyond six weeks. Percutaneous removal can be used for ureteral stones but is generally reserved for those too large to be treated effectively for ureteroscopy or when the ureter cannot be accessed from the lower urinary tract. Open surgery and blind basket extraction have fallen out of favor as ureteral and nephroscopes have improved in capability. Indications for earlier intervention include intractable pain, fever, or persistent nausea and vomiting.
Renal stones: Retained stones in the renal parenchyma, renal cyst, or calyceal diverticulum rarely migrate into the collecting system and therefore should be followed with serial abdominal radiographs and/or ultrasound. If calculi are growing or becoming symptomatic, intervention should be considered. Direct visualization with ureteroscopy may be required to determine if stones are free-floating in the collecting system or retained in parenchyma or other enclosed spaces. Renal stones in a papillary duct or more distal part of the collecting system, such as Randall’s plaques are more likely to enter the collecting system. However, removal of these calculi may not be possible if they cannot be visualized. Renal stones < 2 cm in diameter can be treated successfully with ureteroscopy, ESWL, or PN. Larger stones and those located in lower pole calyces may not respond well to ESWL but can be successfully treated with ureteroscopy or PN, depending on patient anatomy and other clinical considerations.
Prevention of recurrence: Those afflicted with stone disease are encouraged to remain well-hydrated (>2L/day) and maintain a diet restricted in sodium and animal protein intake. Excess intake of oxalates and purines can increase the incidence of stones in predisposed individuals. Medical therapy is dictated by a metabolic evaluation that includes 24-hour urine collection for a variety of stone-forming metabolites, as well as an assessment of parathyroid function and calcium metabolism. Medical therapy is effective in reducing the risk for future nephrolithiasis, and can also reduce the growth and risk of existing stones becoming symptomatic. Treatment may include a thiazide diuretic for hypercalciuria, allopurinol or potassium citrate for hyperuricosuria and potassium citrate for hypocitraturia, depending on factors identified by a metabolic evaluation. In the absence of a defined metabolic abnormality, empiric therapy with potassium citrate has also been shown to reduce the risk of future symptomatic episodes.
Aeromedical Concerns: The pain of renal colic can be severe and is potentially incapacitating in flight. A few cases of some degree of in-flight incapacitation have been reported. Missions have been curtailed due to renal colic in aircrew. The aviation environment can be conducive to renal calculi formation; conditions of dehydration, extremes of temperature, sedentary work and adverse dietary factors are commonly experienced by aircrew members.
Medical Work-up: The aviator needs to submit a complete history to include possible etiologic events; attempts to catch the stone, and complete work-up done at the time of the episode. Any history of prior episodes prior to going on flying status needs to be reported, as does any family history of stones or personal history of gout, low fluid intake, high animal protein intake, high salt intake, low calcium intake or use of vitamin D supplements. History of all medications used, prescription and over-the-counter, is also necessary. Lab evaluation is critical and includes:
Stone analysis; urinalysis, including urine pH and urine culture; one complete 24-hour urine assessment should be done while on patient’s usual diet for urine volume, calcium, oxalate, uric acid, citrate, magnesium, phosphorus, urine sodium, and creatinine excretion; serum electrolytes, blood urea nitrogen (BUN), serum creatinine, calcium, phosphate, and uric acid; and parathyroid hormone level. Urine creatinine is measured to determine the accuracy of urine collection. Any imaging studies performed, such as KUB and unenhanced helical computed tomography or IVP or ultrasound need to be provided. Nephrology and urology consults are important and need to address the likelihood of any retained stone entering the collecting system.
Air Force: In the US Air Force, renal stones, or a history of renal stones, is disqualifying for all flying classes and no waiver is required for a single episode in a trained aviator. An unrestricted waiver is also allowed for retained stones provided they are in the renal parenchyma, renal cyst, or calyceal diverticulum with no possibility of migrating into the collecting system, when metabolic and renal function are normal and the aviator is asymptomatic. These aviators are typically followed every 6-12 months for a change in the size of the calculus, and if stable over a year, annual follow up is deemed safe. The same protocol is followed for asymptomatic stones found incidentally on imaging studies. In cases where the calculus is retained in a papillary duct or more distal part of the collecting system waiver is unlikely.
Army: History of urinary tract stone formation or retention of urinary tract stone within collecting system is disqualifying for aircrew. The condition is discussed in the Renal Stones APL. Army concerns parallel those of the Air Force, though there are few operational missions flown single-pilot in the Army which decreases the aeromedical risk. The work-up includes 24 hour urine chemistry, standard urinalysis, analysis if possible and imaging after stone passage. A urology consultation is critical to assess propensity for stone formation in the future. With regard to applicants for flight training, waivers are not generally granted, though have been. For rated aircrew members with a history of a solitary unilateral kidney stone that has resolved and a normal metabolic work-up, no waiver is generally required. Waivers are granted for the presence of retained stones provided they are in the renal parenchyma, the metabolic work-up and renal function are normal, and the patient is asymptomatic. Retained stones within the calyx must be too large to pass into the ureter. If the metabolic work-up is abnormal, a waiver may be requested if the metabolic condition can be controlled with approved medication. Difficulty in controlling a metabolic abnormality may result in a permanent disqualification.
Navy: Many causes of, or associated conditions seen with nephrolithiasis are treatable and are frequently waived. Certain conditions are considered more problematic in the aviation arena such as:
1. Recurrent stones (2 stones in one year)
2. Cysteine stones
3. Hypercalcuria (absorptive, type one and type three)
4. Retained stones in the collecting system
These conditions are considered disqualifying (CD) and a waiver is not recommended in applicants. Waiver is generally not recommended in designated aviation personnel, but considerations are made on a case-by-case basis.
Waiver is generally recommended for designated aviation personnel with:
1. Calcium Oxalate, Calcium Phosphate, Uric Acid, and Struvite stones
2. Retained stones in the renal parenchyma
3. Recurrent stones greater than 12 months apart
Applicants: An applicant with a history of a single renal stone or renal stones greater than 60 months apart may apply for aeromedical waiver consideration. The applicant must be stone free for one year prior to application. The waiver submission requires:
2. Blood chemistries. A Metabolic Workup Worksheet is available for flight surgeons to
record the flyer’s laboratory data and should be submitted with the waiver request.
3. 24 hour urine metabolic workup documented and submitted on the Metabolic Workup
4. Stone analysis (if stone obtained)
5. Urology consult
6. IVP or imaging study
7. KUB is required at the time of application to an aviation training program
Any member diagnosed with a primary or recurrent renal stone requires the following workup:
2. Blood chemistries (Metabolic Workup Worksheet).
3. IVP or imaging study
4. 24-hour urine metabolic workup. See Metabolic Workup Worksheet for required labs and normal values. Note that member must meet normal values on this worksheet regardless of local laboratory norms.
5. Stone analysis (if available).
The condition is Not Considered Disqualifying (NCD) and the member may be found Physically Qualified (PQ) if ALL of the following conditions are met:
1. This is the member’s first renal stone or more than 60 months have passed since the last stone
2. The stone is a single stone
3. The member is completely stone free (no retained stones), as confirmed by imaging study
4. All labs required by the Metabolic Workup Worksheet are normal
6. Member must be grounded for:
a. 2 weeks after spontaneous passage
b. 4 weeks following stone manipulation/lithotripsy
c. 12 weeks following open surgery and must be found fit for full duty by urology
The following conditions are CD and require a waiver:
1. Recurrent stones (less than 60 months apart)
2. Cysteine stones
3. Hypercalcuria (absorptive, type one and type three)
4. Multiple stones
5. Retained stones (regardless of location)
6. Any abnormality noted on the Metabolic Workup Worksheet
Waivers are considered on a case by case basis. Waiver submission must include:
1. Renal stone workup as noted above
2. Urology Consult
3. Any metabolic abnormalities should be evaluated and/or treated as indicated prior to waiver submission
Civilian: A stone should be recovered if possible and sent to analysis. Information should confirm that metabolic and renal functions are normal and should be performed locally. This should include KUB, IVP, spiral CT scan of the kidneys, urinalysis, 24-hour urine sample after normal diet along with a 12-hour fasting blood specimens. The urine and blood samples should be checked for calcium, magnesium, phosphorus, uric acid, and creatinine. In addition, the blood should be checked for sodium, potassium, chloride, and bicarbonate, and the urine should be checked for oxalate, citrate, pH, sodium nitroprusside for citrate, and volume.
A solitary passed stone with no retained stones is a condition that the FAA will permit an AME to issue an airman without a requirement to defer the issuance. They expect the AME to have all the information mentioned above and provide that with the examination. The FAA will grant an authorization for airmen who have retained stones. The airman should demonstrate that the stone (s) have been present for at least six months. When a decision is made to grant an authorization the size and location of the stone is also taken into consideration. If an airman has recurrent stone formation and passage without evidence of a predisposing condition, the case will be reviewed on its merits. Consultation with FAA Urology may result.
Air Force: Query of AIMWTS review revealed 532 submitted cases for stone disease. There were 13 FC I/IA cases, 294 FC II cases, 2 FC IIU cases, and 223 FC III cases. Within the total were 51 disqualification dispositions: 8 were FC I/IA, 7 were FC II, and 36 were FC III. Of the 51 disqualification cases, 21 were disqualified primarily for diagnoses other than the stone disease and 30 were primarily for the stone disorders. Included in this total were cases of recurrent stone formation, retained stones, and multiple symptomatic episodes.
Army: Nephrolithiasis is a common diagnosis among rated Army aviators. Between 2009 and 2011 there was an average rated aviator population of 14,919 as identified by having an annual flight physical. During this period, there was an average of 343.3 cases carrying the diagnosis of renal stone each year, yielding an average one year period prevalence of 230.1 cases per 10,000 aircrew. Among rated aircrew there was an average annual incidence of 57.3 cases and almost the same incidence (48.3) among applicants. There were no suspensions issued in the rated population during this period and only a total of 4 applicants were denied a waiver during this 3 year study period; however there was a large percentage of applicants who did not pursue a work-up once they were told nephrolithiasis is a disqualifying condition.
Navy: Not available at this time
Civilian: As of December 2011, there were 4,083 First Class, 3,202 Second Class, and 10,189 Third Class airmen with the diagnosis of Urolithiasis in the FAA system.
ICD 9 codes for renal stones
Calculus of kidney and ureter
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Prepared by Drs Amy Gammill, Edith Canby-Hagino, and Dan Van Syoc
May 21, 2012