David A. Spector
Urinary stones are common in the United States. Although urologic intervention or nephrologic consultation may occasionally be required, most patients with stones can be evaluated, treated, and monitored by the primary care provider. This chapter reviews the various manifestations of stone disease, the types of urinary stones, the evaluation of patients with stones, the acute and chronic treatment of patients with urinary stones, and when to obtain consultation for these patients.
Presentation of Urinary Stone Disease
Patients with urinary stone disease may present with acute colic, persistent or recurrent urinary tract infection, isolated hematuria, no symptoms but a stone discovered incidentally on a radiograph taken for other purposes, or a prior history of stones.
Acute Colic
Presentation
Most patients with urinary stones at some time have an acute episode of colic. The stone, if obstructing, causes ureteral spasm, resulting in intermittent paroxysms of pain, which may range from barely noticeable to “the most
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severe in my life.” The location of the pain depends on the location of the stone in the ureter, but it is most often felt in the flank; then, as the stone moves distally, pain radiates in a characteristic pattern around the groin and into the testicles in men or into the labia majora in women. Dysuria and urgency may be present and nausea, vomiting, and other gastrointestinal (GI) symptoms might mistakenly suggest a primary GI problem. Examination reveals an uncomfortable, restless patient. There may be costovertebral tenderness as well as deep tenderness in the abdomen. More importantly, no signs of peritoneal irritation (guarding, rebound, rigidity) are present. Fever is not present unless infection has developed in the obstructed urinary tract. Urinalysis demonstrates microscopic (or gross) hematuria in 91% of cases (1). The presence of pyuria is important because chronic bacterial infection may be associated with the development of urinary stones; however, pyuria may be absent even if infection is present if there is complete urethral obstruction.
A patient with a history strongly suggestive of urinary stone disease may have another cause for the pain. A dissection of the aorta, acute back strain or lumbar disc disease, the passage of blood clots in the ureters (as in sickle cell disease or renal infarct), and, rarely, malingering should be considered. Malingerers are often difficult to identify; these patients may give a classic history of acute renal colic while relating a history of allergy to iodinated contrast dye, prohibiting the performance of an intravenous pyelogram (IVP). These patients may even contaminate the urine specimen they provide for analysis with blood (obtained from a fingerstick or oral injury). (For further information on malingering, see Chapter 21.)
Diagnosis and Management
The aims of management of urinary colic should be confirmation of the diagnosis, relief of discomfort, surveillance for infection, and determination of whether the stones will pass spontaneously or will require surgical removal. For decades, the IVP and abdominal plain film were the standard diagnostic procedures for patients with renal colic, but unenhanced helical computed tomography (CT) is now the imaging technique of choice for the examination of patients with suspected renal calculi (2,3). Although it is more expensive than IVP, unenhanced helical CT is faster, requires no contrast dye exposure, and has greater sensitivity (95%) and specificity (100%) for urinary stones than the IVP (2). Further, CT can give helpful information about other abdominal diseases if urinary stones are not present. On the other hand, IVP gives more information about anatomic urinary tract abnormalities that might predispose to stone formation (e.g., medullary sponge kidney, diverticula). In either case a plain abdominal film should be obtained to assess if the stone(s) is radiolucent (up to 90% of urinary stones are radiopaque) and therefore likely to represent a uric acid or indinavir stone, and as a baseline for future followup radiographs.
Several factors help in the decision whether to hospitalize a patient with renal colic, to obtain urgent urologic consultation, or to treat the patient at home: First, the patient with nausea and vomiting cannot be ensured of an adequate fluid intake or adequate oral analgesia and should be admitted to a hospital. Second, fever suggests infection proximal to an obstructing stone, and urgent urologic consultation should be obtained and hospitalization considered. Third, if the CT scan or IVP reveals a nonfunctioning kidney (completely obstructed ureter), a partially obstructed ureter from a solitary kidney, or urine extravasation, urgent urologic consultation should be obtained. Fourth, the size of the stone helps the clinician to predict whether urologic intervention is likely to be required. In general, stones that are smaller than 5 mm pass spontaneously, those between 5 and 10 mm have a 50% chance of passing spontaneously, and those larger than 10 mm usually require urologic intervention. Of all stones that become symptomatic, 80% are ureteral, and 85% to 90% of these pass spontaneously. Ureteral stones commonly lodge in the ureteropelvic junction, in the ureter at the pelvic brim where the ureter begins to pass over the iliac vessels, in the lower third of the ureter, or at the ureterovesical junction. Only 10% to 15% of ureteral stones require interventional treatment (4).
Once the diagnosis of urinary calculi is confirmed and complications ruled out, most patients can be treated at home. Although the colic associated with urinary calculi has traditionally been treated with narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs) may be more effective. This is so because NSAIDs block prostaglandins, which are known to induce ureteral muscle spasm. In a meta-analysis of randomized controlled trials, NSAIDs provided a greater reduction of pain and less side effects than narcotics (5). Further, NSAID-treated patients were less likely to require “rescue” analgesia. Patients may initially require parenteral administration of either class of analgesics, but rapid conversion to oral medications is usually possible. Indomethacin (Indocin or generic, 50 mg orally or by rectal suppository three to four times per day), ketorolac (Toradol, 10 mg every 4 to 6 hours orally; or 30 mg intravenously or intramuscularly every 6 hours), or diclofenac (Voltaren, 50 mg orally two to three times daily) all provide effective analgesia in renal colic (5). Since NSAIDs may cause GI side effects, simultaneous provision of an H2 receptor blocker or proton pump inhibitor (PPI) should be considered. Narcotics are a second choice for relief of renal colic. Oxycodone (generic, 5 mg, 1 to 3 tablets) or Tylox, which contains oxycodone and acetaminophen (1 to 3 capsules), every 3 to 4 hours, is a reasonable choice. If needed phenothiazine (e.g., Phenergan, 25 mg), given with the narcotic, provides additional relief by controlling any associated nausea. After pain is relieved, hydration with at
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least 2 to 3 liters of fluid daily will ensure good urinary flow and will help the stone to pass. All of the urine voided during the period of intermittent colic (usually several days) should be collected and strained through an old stocking, a fine-knit screen, or a filter paper so that the passed stone may be saved and analyzed (see below). Some patients may not realize that a passed “stone” may resemble sand more than a pebble.
If symptoms of colic are intermittent and well controlled at home, the patient should be monitored with a weekly radiograph of the abdomen to determine the progression of the stone. Average expected length of time to stone passage is dependent in part on stone size: for a stone ≤2 mm, 8.2 days; between 2 and 4 mm, 12.2 days; ≥4 mm, 22.1 days (6). Calcium channel blockers (CCBs) (e.g., nifedipine 30 mg slow release) or tamsulosin (e.g., Flomax 0.4 mg once daily) may significantly shorten the time to stone passage (7). If by 6 weeks the stone has not passed, it is unlikely that spontaneous passage will occur, and urologic consultation should be obtained. For occupational or social reasons, some patients want to consider earlier surgical removal and therefore ask their primary care providers to request urologic consultation sooner.
Stones that pass from the ureter into the bladder usually pass with ease through the urethra. In the event of a bladder outlet obstruction, a stone may be retained in the bladder (bladder stone), where it may grow and in time become an infection stone (see Struvite Stones).
Patient Requiring Urologic Referral
When a patient is referred to a urologist for stone removal, there are four options: extracorporeal shock wave lithotripsy (ESWL), percutaneous nephrostolithotomy (PCNL), rigid and flexible ureteroscopy, and open surgery. During ureteroscopy, lower ureteral stones may be removed with the use of a grasping forceps that is inserted through a cystoscope or ureteroscope or pulverized by ultrasonic, electrohydraulic, or laser lithotripsy. These procedures are similar to cystoscopic examination but require general or spinal anesthesia and hospitalization. These procedures have a success rate greater than 95% and a low rate of complications. Until the early 1980s, stones located more proximally required removal by open ureterolithotomy, open pyelolithotomy, or, in the case of a staghorn calculus, nephrolithotomy. However, PCNL and ESWL have supplanted traditional open stone removal operations. Both techniques give results similar to operative stone removal but are associated with less convalescence time and less morbidity.
PCNL requires that the patient be sedated and an IVP or ultrasound be performed to localize the kidney and the stone. Under fluoroscopy, a percutaneous nephrostomy tube is placed near the posterior axillary line. Subsequently, the tract is dilated and various nephroscopes, buckets, and forceps are used to extract the calculi. For struvite calculi (also called triple phosphate or “infection” stones; see later discussion), hemiacidrin (Renacidin) irrigation is sometimes useful to dissolve residual stones. Antegrade radiographs are performed to confirm stone removal and ureteral patency. Successful removal occurs with more than 95% of renal stones and 88% of ureteral stones. On the other hand, PCNL is associated with a significant incidence of complications, including major bleeding (5% to 12%), arteriovenous fistulae (0.6%), perforation/extravasation (5% to 26%), and fever or sepsis (3% to 11%) (8). Typically, a 2- to 3-day hospitalization is needed for a patient to undergo PCNL.
ESWL sometimes requires that the patient have anesthesia (usually spinal), but most often it is performed with only intravenous sedation, after which the stone is located by ultrasound or fluoroscopy. A shock wave, generated by an electrode similar to a spark plug, is focused by the lithotripter for a precise impact on the stone (Fig. 51.1). When the shock wave encounters calculus material that has different acoustic properties from surrounding tissue, a tensile force is produced that shatters that material. This treatment takes an average of 30 to 45 minutes. ESWL usually is done in outpatient settings. After ESWL, fragments of stone usually pass in the urine for a few days and cause mild colic. Retreatment is needed in a few patients, and macroscopic hematuria occurs transiently in most.
The selection of treatment modalities for a given patient depends in part on the characteristics of the stone being treated and in part on local resources and expertise. Where all modalities are available, ESWL used alone is the treatment of choice in 70% of patients. Patients who are suitable for treatment with ESWL are those who have single or multiple renal stones less than 20 mm in diameter, some patients with smaller staghorn stones (those in which the pelvis is not dilated), and some with stones located in the upper third of the ureter. Larger calculi, most staghorn calculi, and calculi composed of cystine (see later discussion) are usually treated by PCNL in combination with ESWL, or by open operation alone.
Results of ESWL are excellent. For patients with stones less than 10 mm in size that are located in the kidney or ureter, 90% become stone free or are left with small, asymptomatic residual fragments. Convalescence from ESWL requires several days. Most patients experience some flank discomfort from the trauma to the kidney. This discomfort often requires use of analgesics for a few days. Immediate complications of ESWL are uncommon, but renal or perirenal tissue injury has been demonstrated in experimental studies and suggested by MRI and tissue enzyme release in up to 85% of patients. Between 1% and 8% of patients develop new hypertension or experience an exacerbation of pre-existing hypertension within 3 years after
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ESWL treatment (9,10). The frequency of this complication may depend on the type of lithotripter.
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FIGURE 51.1. Series A: Schematic drawing of the technical arrangement of a modern lithotripter. (Adapted from Chaussy C, Schmiedt E, Jocham D. Nonsurgical treatment of renal calculi with shock waves. In: Roth RA, Finlayson BF (eds.) Stones Clinical management of Urolithiasis. Baltimore: Williams Wilkins, 1983 .) B: Photograph of a modern lithotripter. (Courtesy of Domier Medical Systems, Inc, Kennesaw, GA.) |
Other Patterns of Stone Presentation
Urinary stones usually produce symptoms that suggest acute colic, at least at some time in their course. When stones are discovered in patients who do not have colic, the same evaluation and management is indicated as when patients have acute colic (see Diagnostic Workup for Patients with Urinary Stone Disease).
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TABLE 51.1 Classification of Stone-Forming Patients by Type of Stone Passed |
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Types of Stones and Their Causes
There are four main types of urinary calculi: calcium oxalate or phosphate, uric acid, struvite–triple phosphate (magnesium ammonium phosphate), and cystine. Calcium stones are by far the most common. Table 51.1 shows the classification of stone-forming patients by the type of stone passed. Not shown in the table are uncommon stones made of xanthine, triamterene, indinavir, or nelfinavir.
It is important to be familiar with the metabolic disorders these patients may have. This understanding is helpful in planning a diagnostic evaluation and specific therapy (see later sections in this chapter). This is particularly true in the evaluation of the patient with the most common stone type, calcium.
Calcium Stones
Table 51.2 shows the metabolic and clinical disorders in calcium stone formers. This table shows that in almost 80% of patients who have had a calcium stone, a specific cause can be identified. In addition to the common disorders shown in the table, other metabolic disorders, such as hypocitraturia, may promote urinary calcium salt precipitation. Hypocitraturia is present as the sole metabolic abnormality in 10% (11) and as one of two or three abnormalities in 19% (12) of calcium stone formers. Urine pH, which affects the prevalence of many types of stones (see Urinalysis), has little influence on the formation of calcium oxalate stones, but formation of calcium phosphate stones
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is promoted at a pH greater than 6. The approach to these disorders is discussed later in this chapter.
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TABLE 51.2 Metabolic and Clinical Disorders in 978 Calcium Oxalate Stone Formers |
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Uric Acid Stones
Uric acid stones are caused by the high insolubility of undissociated uric acid (its pK of 5.7 means that 50% of uric acid is undissociated at pH 5.7 and 90% is undissociated at pH 4.7). Three factors are associated with uric acid stone formation: hyperuricosuria, highly acid urine, and low urinary volume. The lifetime incidence of uric acid stones in the general population is very low (Table 51.3). On the other hand, uric acid stones are very prevalent in patients who have gout, asymptomatic hyperuricemia, and hyperuricosuria, and probably in patients with a history of gout and no hyperuricemia. Many patients have passed uric acid stones long before a gouty attack has occurred. It is known that many patients with gout produce an abnormally high fraction of their daily acid load as titratable acid rather than as ammonium and therefore have an unusually low average urinary pH. Furthermore, patients with chronic diarrhea and those with excessive fluid loss from the skin may have highly concentrated urine, which predisposes them to the formation of uric acid calculi. Patients who have myeloproliferative disease and those with solid tumors that are undergoing lysis may have excessive uric acid excretion, which may be associated with uric acid stones and tubular plugs of urate. Patients with gout also have more calcium stones than people in the general population (13). The association may result from crystallization of uric acid, which then forms a nidus for calcium deposition.
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TABLE 51.3 Prevalence of Urate Stones in Various Populations |
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Struvite Stones (Infection Stones)
It is generally believed that infection stones form primarily as a consequence of the hydrolysis of urea and the production of ammonia by the bacterial enzyme, urease. The production of ammonia leads to a highly alkaline urine, which promotes the precipitation of magnesium, ammonium, and phosphate. These are the components of the infection-induced or struvite stone. Most urea-splitting organisms are Proteusspecies; however, Pseudomonas, Klebsiella, Staphylococcus, and some Escherichia coli strains are capable of producing urease. Struvite stones usually do not form de novo but almost always are a complication of another primary stone disease in which infection has become superimposed, and they are especially likely to grow into staghorn calculi (large stones that cannot pass the ureteropelvic junction and that form a cast of all or a portion of the pelvicaliceal system).
Cystine Stones
Cystine stones are rare and usually are seen in young patients, because the onset is usually in childhood. The stone forms because of crystallization of cystine when the urine is supersaturated with this substance, which occurs when
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there is an inherited defect in renal tubular resorption of filtered cystine. This is a particularly virulent form of stone disease and may be associated with staghorn calculi. In addition to cystinuria, there is usually urinary loss of other basic amino acids, including ornithine, lysine, and arginine. The disorder is an inherited autosomal recessive trait, although some heterozygous patients have excess cystine excretion, as shown in Table 51.4. Cystine is much less soluble in acid urine than it is in alkaline urine; therefore, cystine stones generally form when urine is acid and cystine excretion is greater than 400 mg/ 24 hours.
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TABLE 51.4 Urinary Cystine Excretion |
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Natural History of Urinary Stone Disease
Urinary calculus disease is a chronic illness. Once a stone has formed there is a tendency for recurrence, and management should be tailored to the stone activity, the type of stone, and any associated metabolic abnormality.
Stone activity—the number of stones formed and the change in size of existing stones—is an important, although at times difficult, determination. It requires a yearly review of stones passed and removed, as well as an evaluation by abdominal radiography of the increase in size of known stones or of the appearance of new stones. The activity of urinary calculi depends on a number of factors: stone type, associated metabolic abnormality, treatment received (both specific and nonspecific), and age. Therefore, precise rates of recurrence cannot be given with accuracy.
Nevertheless, two studies have provided useful and corroborative information regarding the recurrence rate after passage of a first urinary stone. In one retrospective study of 515 patients who were monitored after a single (first) stone and were given no medications to prevent a recurrence, there was a 50% recurrence rate at approximately 9 years and approximately 75% recurrence by 25 years (14). These data are presented as a graph in Fig. 51.2. Another study of patients who passed their first calcium stone showed a recurrence in half of the patients by 5 years and in two-thirds by 9 years (15).
Therefore, it is suggested that evaluation for associated metabolic abnormalities be undertaken in every patient who has formed a new stone, because recurrence is likely, the basic assessment is noninvasive and inexpensive, and a workup may uncover an especially virulent or an important systemic disease or metabolic defect responsible for stone formation.
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FIGURE 51.2. Life-table calculation of the time course of recurrence after a first renal stone in 515 patients. (From Sutherland JW, Parks JH, Coe FL. Recurrence after a single renal stone in a community practice. Miner Electrolyte Metab 1985;11:267. ) |
Diagnostic Workup for Patients with Urinary Stone Disease
Evaluation of patients with stone disease can be accomplished entirely in an ambulatory setting. This evaluation depends on a directed history and physical examination, stone analysis, if the stone is available, and certain laboratory measurements. The extent of the evaluation of patients passing a first stone is somewhat controversial. Some suggest an abbreviated evaluation, because not all patients have recurrent stones and because all treatment modalities have potential side effects; others, citing the likelihood of eventual recurrence, fully evaluate patients after the first stone passage (see Coe et al., at http://www.hopkinsbayview.org/PAMreferences). The approach outlined in this section is a reasonable and commonly used method for evaluation of patients who have had a urinary calculus (16).
History
A directed medical history is important in determining the activity of stone disease as well as in providing clues to the nature of the stone. The number of passed stones, the frequency of attacks of colic or hematuria, and any history of infection should be obtained. Since most stones are composed of calcium, all conditions that might result in hypercalcemia must be considered, particularly
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hyperparathyroidism. Patients with chronic diarrheal illnesses, inflammatory bowel disease, or colostomy are predisposed to both calcium oxalate and urate stones. Previous abdominal radiographs and, most importantly, chemical analysis of prior stones should be obtained, if possible. The family history may provide a clue to cystine stones, uric acid stones (gout), and many calcium stones (e.g., those associated with idiopathic hypercalciuria). The dietary history may reveal excessive intake of sodium, animal protein, purine, or oxalate (see Types of Stones and Their Causes). High-protein meat diets are associated with production of metabolic acids (which leach bone and cause hypercalciuria), increased urine excretion of urate, and decreased excretion of urinary citrate, all of which may predispose to the development of stone disease. The approximate daily fluid intake is also an important part of the history. Some people ingest as little as 500 to 700 mL/day and therefore have concentrated urine most of the day. The medication history is important. For example, aspirin at high dosages (more than 5 g/day) and probenecid are associated with increased uric acid excretion and may cause a predisposition to uric acid calculi. On the other hand, use of the xanthine oxidase inhibitor allopurinol has led to development of xanthine stones. Use of calcium-containing antacids (e.g., Titralac, Tempo, Tums) as well as vitamins A and D and loop diuretics (e.g., furosemide) may be associated with hypercalciuria and calcium stone formation. Acetazolamide (Diamox) may be associated with the development of chronically alkaline urine and with a higher incidence of calculi made of calcium phosphate. Vitamin C at high dosages can cause hyperoxaluria and increase the risk of stones (17). Triamterene (contained in Dyazide) and its metabolites (18), as well as acyclovir, indinavir (19), and nelfinavir (20) have been found as a nidus in urinary calculi (or as the only constituent). Moreover, certain medications have been shown to decrease calcium excretion (e.g., thiazides) or uric acid excretion (e.g., allopurinol), whereas loop diuretics promote hypercalciuria and interfere with results of testing in a patient who is being evaluated for renal stone disease. The occupational history is important because exposure to excessive heat (and therefore fluid losses) and limited accessibility to fluids are factors that influence stone formation by decreasing urine output and by promoting the output of highly concentrated urine.
Physical Examination
Physical examination (when there is no colic) occasionally gives clues to specific problems. For example, band keratopathy (stippled calcification of the perimeter of the cornea, which may require a slit-lamp for visualization) may be seen in hyperparathyroidism, or there may be signs of sarcoidosis, hyperthyroidism, inflammatory bowel disease, neoplasia, or gouty arthritis.
Urinalysis
The urinalysis provides a simple assessment that may give specific direction to the determination of the cause of the urinary calculus. It is important that the urinalysis be complete, including the determination of pH. The pH is usually acid in patients with a uric acid or a cystine stone and is invariably alkaline in patients with struvite stones. Also, the pH may suggest the presence of renal tubular acidosis. Because the first voided morning urine is usually acid, a urine pH greater than 6.0 in such a specimen suggests the possibility of renal tubular acidosis. The microscopic analysis may show hematuria (although this is often absent in the intercritical period), crystals, or evidence of infection. Crystals of cystine have the appearance of a benzene ring and are highly suggestive of cystinuria. Other crystals are more variable and are not diagnostic but may give a clue to the stone composition in patients with lithiasis (see Coe et al., athttp://www.hopkinsbayview.org/PAMreferences for photographs of typical examples). In patients with calcium stones crystalluria, when repeatedly found in early morning urine samples, the finding is highly predictive of stone recurrence (21).
Stone Analysis
If a stone is available, it should be analyzed to determine its composition, because the stone type determines the approach to evaluation and treatment. Stones can be analyzed inexpensively at commercial laboratories and may be mailed without preservative for this purpose.
Laboratory Assessment
A laboratory assessment is important even for patients in whom a stone is available for analysis (Table 51.5). This evaluation is necessary because it is increasingly recognized that many patients have more than one metabolic disorder that predisposes them to stone formation. For example, struvite stones often start as some other primary stone type, most often calcium; patients with a calcium oxalate stone may have hypercalciuria, hyperuricosuria, or hypocitraturia. Patients usually comply with the testing necessary for proper evaluation of a metabolic disorder if they understand the ease with which it can be accomplished, the substantial rate of recurrent calculi, and the effectiveness of specific therapy for metabolic problems (see Preventive Treatment of Urinary Calculus Disease). The 24-hour urine volume and individual constituents provide objective guides about when the most basic interventions, such as increasing fluid intake (if urinary volume is low) or decreasing salt intake (if sodium excretion is high), are useful (see General Measures) and provide baseline data to ascertain the effectiveness of treatment at followup.
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TABLE 51.5 Laboratory Assessment of Patients with Urinary Calculia |
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Laboratory assessment of patients who have formed urinary calculi is simple and noninvasive and can be performed easily in the office. It is important that this initial evaluation be accomplished without modifying the patient's diet or habits so that an underlying process associated with urinary calculus disease is not masked. The reasons for obtaining most of the studies listed in Table 51.5 are self-evident. Measurement of serum calcium should be repeated at least once, and ionized calcium should be determined if possible, because the latter is a more accurate index of hypercalcemia. Urinary creatinine is measured to monitor the completeness of collections (normally approximately 1 g of creatinine is excreted in 1 day, more if patients are muscular and less if they are wasted) and to estimate the glomerular filtration rate. Urinary sodium (reflecting dietary intake) is measured because increased urinary sodium excretion promotes hypercalciuria. Urinary citrate is measured because citrate combines with calcium to form a soluble complex, thus reducing the availability of calcium for crystallization with oxalate or phosphate, and it also directly inhibits crystallization of these substances.
Several commercially prepared 24-hour urine kits have become available (from UroCor Inc., Oklahoma City, Oklahoma, or Mission Pharmacal Co., San Antonio, Texas) that allow for measurement of all urinary constituents listed in Table 51.5 (including pH and cystine as well as the state of saturation of the patient's urine for compounds that might crystallize and become stones) from a single 24-hour urine sample. These convenient kits, which include jugs for urine, are mailed directly to the patient, who returns a sample portion of the 24-hour urine to the company for analysis. Two separate baseline 24-hour collections should be obtained, since a single collection may miss identifying one or more risk factors because of day-to-day variations in urine constituents (21).
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TABLE 51.6 Situations in which Hyperoxaluria May Be Expected |
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An IVP, if not done previously as part of the evaluation of an episode of acute colic, could be done as part of the search for underlying structural disease (e.g., anatomic abnormality of the lower urinary tract, medullary sponge kidney).
In addition to the laboratory assessment outlined in Table 51.5, serum parathyroid hormone concentration should be measured if hypercalcemia or hypophosphatemia is present, or if stone analysis indicates that the stone is made up of calcium phosphate. Finally, urinary oxalate should be measured when hyperoxaluria is suspected (Table 51.6).
Hypercalciuria
Patients with hypercalciuria without hypercalcemia deserve special attention because they are seen commonly and because of the variable pathogenesis of their stones. Table 51.7 lists the causes of hypercalciuria that may not be associated with hypercalcemia. Most patients have idiopathic hypercalciuria from either a renal leak (renal hypercalciuria, 5% of stone formers) or excessive GI absorption of calcium (absorptive hypercalciuria). In the latter instance, which is far more common, there is excess GI absorption (and then excretion) of calcium after the ingestion of calcium. The differentiation of renal from absorptive hypercalciuria requires the use of an oral calcium tolerance test(22), which is not routinely recommended in a general medical office practice but might be performed by a nephrologist or urologist specializing in stone disease. However, it is important to be aware that some patients with absorptive hypercalciuria may have normal calcium excretion if they inadvertently restrict their calcium intake on the day of the urine collection. Therefore, it is
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advantageous to ensure that the patient continues his or her usual diet for at least a few days before and during the metabolic evaluation.
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TABLE 51.7 Causes of Hypercalciuria That May Not Be Associated with Hypercalcemia |
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Preventive Treatment of Urinary Calculus Disease
General Measures
Patients who have formed even a single stone should be educated about the nature of urinary calculi, their natural history, the importance of regular surveillance, and the effectiveness of therapy. Eliminating dietary excesses or deficiencies will probably help control calcium stone formation in many patients (17). Increasing fluid intake has long been a mainstay of treatment of all types of urinary calculi. In a randomized, prospective study of nearly 200 patients, increasing fluid intake to achieve a daily urine volume of greater than 2 liters reduced recurrence of calculi by more than 50% during 5 years of followup (23).
The decision to use specific therapy (especially pharmacologic therapy) must be made on an individual basis. The rate of stone recurrence for a large population of patients may not apply to an individual patient. It is prudent to use only general and dietetic therapeutic measures if the patient has passed only a single stone and has no evidence of urinary stones on radiography. However, for recurrent stone formers and for patients with radiographic evidence of stones, more specific measures should be used (see later discussion).
Diet
Diet can play a role in most conditions in which stones form. Because obtaining a detailed diet history is often impractical in the office, it is usually helpful to have a dietitian or nutritionist evaluate the patient, both to determine dietary excesses or deficiencies and to begin to plan dietary therapy, depending on the results of the evaluation for metabolic abnormalities. Specific dietary restrictions are discussed under the various stone types.
Fluid Intake
A low urine volume, reflecting low fluid intake, and/or excess body fluid loss is common in many stone formers. Regardless of the type of stone that has been formed, patients should maintain a high intake of fluids to ensure a urinary output of at least 2 liters daily. This high urinary output prevents supersaturation, and the high flow rate may wash out small crystalline formations before they produce any obstructive or irritative symptoms.
Patients who have had several urinary stones are likely to continue to do so. Such patients should be prescribed a high fluid intake throughout the day and night (24). This can be accomplished by having the patient drink 2 to 4 L through the day and then take one or two glasses of water before retiring. This should result in a nocturnal diuresis necessitating voiding 3 to 4 hours later, at which time a further ingestion of one or two glasses of water will continue the diuresis until morning. Older patients may not require the intake of fluid before retiring to bed since there is an age-related change in solute diuresis resulting in natural nocturia in the elderly. Although this method may be annoying to the patient, once the habit is formed it is a small nuisance compared with subsequent stone formation. Continuing to encourage patients is critical to the success of the treatment program.
Avoidance of Dehydration
Patients should be counseled to avoid dehydration, and the resulting concentrated urine, when participating in sports or during travel or work.
Specific Therapy for Calcium Stone Formers
Calcium is present in most urinary calculi, and hypercalciuria is the most common disorder uncovered during the evaluation of patients with urinary calculus disease. In addition to the general measures described earlier in this chapter, there are several specific therapies.
Dietary Measures
Because dietary calcium restriction usually results in a fall in urinary calcium excretion, it has been advocated for patients with calcium stones and hypercalciuria. However, no controlled studies have confirmed the efficacy of this measure. In fact, in two large epidemiologic analyses,
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dietary calcium was found to be inversely related to the risk of developing renal calculi, with a 46% reduction of risk in men and a 35% reduction of risk in women who ingested dietary calcium in the highest versus the lowest quintile (25,26). Furthermore, in a randomized trial, men receiving a normal calcium diet (with restricted salt and animal protein) had less chance of recurrent stones than men on a low calcium diet (27). Although the mechanism whereby higher dietary calcium might protect against stones is uncertain, it is known that greater calcium binding of gut oxalate results in decreased oxalate absorption and reduced urinary oxalate excretion. Further, apart from the probable increase in urinary stones, dietary calcium restriction may actually cause significant adverse side effects, such as negative calcium balance, reduced bone mineral density, and osteoporosis. Therefore, dietary calcium restriction is no longer recommended as a general policy in treating calcium stones. On the other hand, supplemental calcium (e.g., calcium carbonate tablets) has been shown to be a risk factor for renal calculi and should be avoided in patients with renal stones (26).
A number of authorities suggest limiting animal protein intake to 1 g/kg daily in patients with renal calculi. In addition to increasing calcium excretion, dietary animal protein intake increases excretion of uric acid and lowers urinary citrate excretion (probably because of acid production consequent to animal protein catabolism). These latter two changes predispose to formation of calcium stones. A direct relationship has been demonstrated between animal protein intake and calcium stone formation (25,26). A randomized trial in men who experienced recurrent urinary calculi in association with hypercalciuria showed a significant reduction in stone recurrence over 5 years in those who restricted animal protein (529 mg/day) and salt intake compared with those on a low-calcium diet (27).
Similar circumstantial data suggest that high dietary potassium intake and the prevention of hypokalemia may independently reduce the risk of calcium stones. Potassium bicarbonate, but not sodium bicarbonate, reduces calcium excretion (28), and potassium deprivation increases calcium excretion (29). Furthermore, a higher dietary potassium intake is associated with a 50% reduction in the risk of calcium stones (25). It seems sensible, then, to avoid hypokalemia and, when alkali (citrate) is indicated, to provide it as the potassium salt (seePotassium Citrate). Finally, because dietary sodium chloride enhances calciuria, all patients with calcium stones should have modest restriction of dietary salt.
Thiazide Diuretics
Thiazide administration has been shown to result in a fall in urinary calcium excretion by as much as 50% to 60% within a day or two. Thiazides are an ideal theoretical choice (if hypokalemia is avoided) in the treatment of renal hypercalciuria, but thiazides also seem to be effective in absorptive hypercalciurias and even in patients with calcium stones associated with normal calcium excretion. Many studies attest to a 60% to 90% efficacy of a thiazide in reducing the frequency of calcium stones in all types of stone formers. Although there are serious methodologic concerns about some of these studies (30), two prospective trials demonstrated at least a 50% reduction in stone recurrence in patients taking thiazide (31,32), and most experts consider thiazide the drug of choice in hypercalciurics. However, because of their tendency to raise serum calcium, thiazides should be avoided in patients who are already hypercalcemic (e.g., those with hyperparathyroidism or sarcoidosis).
Any thiazide diuretic may be used, but trichlormethiazide (2 to 4 mg) or hydrochlorothiazide (25 to 50 mg) twice daily, or chlorthalidone (25 to 50 mg) once daily are most commonly prescribed. However, the exact dosage of thiazide to be used for the prevention of urinary calculi is uncertain. The incidence of side effects was almost 35% in one early study (33) in which a 50-mg dose of hydrochlorothiazide was given twice a day, the regimen that usually resulted in maximal hypocalciuria. Most side effects were seen soon after initiation of the drug. Intolerance of thiazides can be limited to less than 10% of patients by increasing the dosage gradually and reducing it if side effects develop. Although thiazides increase the plasma uric acid concentration (see Chapter 76), this is not detrimental to patients with urate stones. Chapter 50 provides a discussion of management of the hypokalemic complications of thiazides. If a potassium-sparing diuretic is used, amiloride, 5 to 10 mg daily, is the drug of choice, either alone or in a preparation containing amiloride and hydrochlorothiazide (e.g., Moduretic). Triamterene should not be given because of the association of this agent with the formation of urinary calculi (see earlier discussion in History). The best choice for prevention or treatment of thiazide-induced hypokalemia is the addition of oral potassium citrate (see next section). This provides both potassium and base. The latter increases urinary citrate, which is reduced as a consequence of thiazide therapy (34). Citrate therapy has also been useful in hypercalciuric patients who continue to form stones despite thiazide therapy, presumably by increasing urinary citrate concentration (see next section) (35).
Potassium Citrate
Potassium citrate (e.g., Polycitra-K, Urocit-K) is useful in many metabolic conditions associated with renal stones. It is prescribed at a dosage of 0.5 to 2 mEq/kg/day in two to four doses daily. Potassium citrate is available as Polycitra-K solution (2 mEq potassium per milliliter) or crystal packets (30 mEq potassium per packet) to be mixed in water or
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juice, and as Urocit-K tablets (5 or 10 mEq potassium per tablet). Its usefulness results from the alkalinizing effect on the urine (for calcium stones associated with renal tubular acidosis, hyperuricosuria, and diarrheal syndromes, and for uric acid and cystine stones); from an increase in urinary citrate, a natural inhibitor of stone formation (for calcium stones associated with hypocitraturia); and from a mild reduction in calciuria. In a placebo-controlled prospective, randomized trial, 30 to 60 mEq potassium citrate daily reduced stone events by 90% compared with placebo and to pretreatment rates in hypocitraturic calcium stone formers (36).
The goals of treatment are to provide enough base to increase urinary pH to 6.0 and 7.0 and to restore normal urinary citrate excretion (more than 320 mg/day and as close as possible to the normal mean of 640 milligrams per day). A 24-hour urinary citrate excretion or urinary pH measurement should be obtained to determine the adequacy of the initial dosage. Once an acceptable level is achieved, it should be confirmed every 6 to 12 months.
Orthophosphate (Inorganic Phosphate)
The administration of inorganic phosphate (e.g., K-Phos) has been shown to reduce urinary calcium and the formation of calcium stones, in part by complexing gut calcium and thereby decreasing calcium absorption, and in part by increasing urine inhibitors of stone formation. Although some trials suggest that orthophosphate reduces renal calculi (37), others do not, and no controlled trial is available. Because of the large doses required and the high incidence of gastrointestinal side effects, this therapy is discouraged for patients without consultation from a nephrologist.
Cellulose Phosphate
Taken with meals, this ion-exchange resin (Calcibind) binds calcium so that it is not absorbed. Early studies suggested that this agent might be useful in hyperabsorptive hypercalciuria, but the only controlled trial did not show efficacy (30). Because the incidence of significant side effects, including osteoporosis, may be high, cellulose phosphate is not recommended without consultation with a nephrologist.
Patients with Calcium or Uric Acid Stones Who Are Found to Have Hyperuricosuria
Patients with calcium stones who have hyperuricosuria and those who have mixed calcium and uric acid stones should be treated as if they had pure uric acid stones.
If purine gluttony is present, hyperuricosuria can be modified by dietary restriction of purine-rich foods, such as liver, kidney, and fish roe. However, dietary excess is not often the problem, and other approaches are necessary.
Uric acid stone formation can be significantly modified by increasing the urinary pH. Increasing the pH of the urine from 4.5 to 5.5 or 6.5 increases uric acid dissociation from 15% to 40% and 80%, respectively. Alkalinization can be accomplished by the administration of sodium bicarbonate several times a day. However, because sodium bicarbonate often causes gastrointestinal discomfort and gas, citrate salts (e.g., Polycitra-K solution, which contains 2 mEq of base per milliliter, as previously discussed) are more palatable and therefore preferable. Most patients require 10 mL three times a day, but the dosage should be adjusted as necessary based on the results of regular urine pH testing. The metabolism of citrate results in the generation of bicarbonate. During the initial week of treatment and periodically thereafter, the patient should be taught to measure the urinary pH several times a day using simple pH strips to ensure proper alkalinization (urine pH greater than 6.5).
Should these agents not be effective in controlling recurrence of uric acid stones, if the urine pH cannot be kept above 6.5, or if uric acid excretion is greater than 650 mg/day, allopurinol (which decreases uric acid production) may be used and effectively reduces stone recurrence. Allopurinol (Zyloprim, available in 100- and 300-mg tablets) should be initiated at a dosage of 100 mg once a day and raised to a level that controls uric acid excretion (to less than 500 or 600 mg/day); doses greater than 300 mg are divided in two daily doses. Complications from allopurinol are unusual (minor skin rash, drug fever, precipitation of an acute gouty attack), but the drug can have serious side effects and should be discontinued if a skin rash or fever occurs, because fatal systemic vasculitis has been reported. The use of allopurinol is especially important as a preventive measure in patients who have excess uric acid excretion because of a myeloproliferative disease or in anticipation of tumor lysis during treatment of neoplastic disease.
Hyperoxaluria
In patients with hyperoxaluria, the aim is to lower oxalate excretion (normal excretion is less than 45 mg/day). Treatment depends to some extent on the cause of hyperoxaluria. Reduction of foods with high oxalate content (spinach, rhubarb, chard, nuts, cocoa, and chocolate) helps in many cases of mild hyperoxaluria. The most common setting of severe hyperoxaluria and oxalate stones is in patients with malabsorption, especially in cases of ileal resection. In such circumstances, gut calcium, which ordinarily precipitates with oxalate, binds instead to fats, allowing oxalate to be readily absorbed. Treatment in such circumstances may be complicated and might include reducing dietary oxalate and fat, supplementing calcium and
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magnesium, prescribing cholestyramine resin to bind oxalate, administering potassium citrate, and recommending high fluid intake. Nephrology consultation for help in managing this complex problem is appropriate.
Cystinuria
Stone formers with cystinuria generally have virulent disease and are best treated in consultation with a nephrologist. Usually it is necessary to increase urine output to at least 3 L/day and to raise urinary pH in a manner similar to that used in patients with uric acid stones (see Uric Acid Stones). If stone activity continues, one may use D-penicillamine, tiopronin (which has fewer side effects), or the angiotensin-converting enzyme (ACE) inhibitor captopril, all of which form complexes with cystine and prevent its precipitation.
Struvite or Infection Stones
Infection stones, composed of a combination of magnesium ammonium phosphate (struvite) and calcium carbonate-apatite, are particularly virulent. Untreated patients with infected staghorn calculi often develop sepsis and require urgent nephrectomy. Among 177 consecutive patients with staghorn calculi, renal-related death occurred in 67% of those patients who refused treatment, in 3% of those who were treated without clearance of stone fragments, and in none of those who had complete clearance of fragments (38). In view of this morbidity and mortality and with the recent advance in techniques for controlling infection stones, early urologic referral for surgical intervention is imperative. The goal of surgery in such patients is to remove the stone totally, as suggested by an American Urologic Association consensus panel (39). This may be accomplished by a variety of approaches, including PCNL, ESWL, combinations of PCNL and ESWL, and open surgery, as discussed earlier. There are inherent advantages and disadvantages to each technique, and ultimately the choice for a given patient must depend on a number of considerations, including the size and location of the stone or stones and the preference of the surgeon. The mortality rate for these procedures in experienced hands is less than 1%. The success of any treatment is best determined by CT scanning, which can detect stones as small as 1 mm.
In addition to the surgical treatment of infection stone disease, medical therapy is an important adjunct. Associated metabolic abnormalities should be sought and treated. Specific antimicrobial therapy is necessary in conjunction with surgery, and, where stones cannot be removed surgically, suppressive therapy with antimicrobials may decrease for a period the incidence of septicemia. The use of oral agents that prevent infecting bacteria from splitting urea (urease inhibitors) has been shown to decrease recurrence of some struvite stones by preventing the formation of highly alkaline urine caused by the ammonium produced by urea-splitting organisms. Acetohydroxamic acid (Lithostat) may be used as an adjunct to antimicrobial therapy and surgery in patients with struvite stones. Acetohydroxamic acid, 250 mg, three to four times a day or a total dosage of 10 to 15 mg/kg/day (but never more than 1.5 g/day) should be used only when the patient is infected with urea-splitting organisms, as evidenced by a high urinary pH. Because of its teratogenic effects, it is contraindicated in pregnant women. Also it is not effective in the presence of moderate renal failure (i.e., creatinine 2.5 mg/dL or higher, or creatinine clearance 20 mL/minute or less). Side effects occur in almost 30% of patients and some are serious, such as thrombophlebitis and hemolysis. Experience with the drug is still limited, and consultation with a urologist is appropriate before prescribing it.
Urinary Calculi in Patients without an Identifiable Metabolic Disorder
Approximately 10% to 15% of stone formers are found after evaluation not to have an identified metabolic disorder and may respond to general measures and to treatment with thiazides and/or potassium citrate, as outlined previously (40).
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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