6 - Kidney Stones | Manual of Nephrology. Diagnosis and Therapy 6e

Editors: Schrier, Robert W.

Title: Manual of Nephrology, 6th Edition

> Table of Contents > 6 - The Patient with Kidney Stones

The Patient with Kidney Stones

Robert F. Reilly

Nephrolithiasis is a common disorder in the United States, with an annual incidence of 7 to 21 per 10,000 patients. Kidney stones account for approximately 1 in every 100 hospital admissions, with men affected three to four times more frequently than women. It is estimated that, by the age of 70, as many as 20% of all Caucasian men and 7% of all Caucasian women will form a stone. African Americans and Asians are affected less often. The peak incidence occurs between the ages of 20 and 30 years.

Kidney stones are a major cause of morbidity due to associated renal colic, urinary tract obstruction, urinary tract infection (UTI), and renal parenchymal damage. In the United States, calcium-containing stones make up approximately 90% of all stones; they contain primarily calcium oxalate, either alone or in combination with calcium phosphate. The remaining 10% are composed of uric acid, struvite-carbonate, and cystine.

A kidney stone can form only when urine is supersaturated with respect to a stone-forming salt. Interestingly, the urine in many normal subjects is often supersaturated with respect to calcium oxalate, calcium phosphate, or uric acid, yet stone formation does not occur. At least two other factors play a role in the pathogenesis of stone formation: heterogeneous nucleation and the presence in the urine of inhibitors of crystallization. The crystallization of a salt requires much less energy when a surface is present on which it can precipitate (heterogeneous nucleation), as opposed to crystallization that occurs in the absence of such a surface (homogeneous nucleation). In addition, normal urine contains a variety of inorganic and organic substances that act as inhibitors of crystallization. The most clinically important of these are citrate, magnesium, and pyrophosphate.

Sufficient energy must be generated for a crystal to form in solution. Once a crystal forms, it must either grow to sufficient size to occlude the tubular lumen or anchor itself to the urinary epithelium, which in turn provides a surface upon which it can grow. The typical transit time of a crystal in the nephron is on the order of 3 minutes, and this is too short a period for a crystal to nucleate, grow, and occlude the tubular lumen. A recent study of 19 stone formers shed additional light on how stones form in kidney. In 15 patients with idiopathic hypercalciuria the initial site of crystal formation, surprisingly, was in the basement membrane of the thin limb of the loop of Henle. The stone core was made up of calcium phosphate surrounded by calcium oxalate. The crystal deposit then eroded into the renal pelvis where it could be bathed in urine supersaturated with stone forming constituents. Why calcium phosphate would precipitate at the basolateral surface of the thin limb of the loop of Henle remains a mystery. Four of the 19 patients formed stones after intestinal bypass for obesity. In these patients, the mechanism for stone formation was different. Calcium phosphate crystals initially attached to the inner medullary collecting duct. The calcium phosphate core then acted as a nidus for calcium oxalate precipitation that resulted in luminal occlusion and growth along the inner medullary collecting duct out into the renal pelvis.

Initial presentation. A kidney stone most commonly presents with severe flank pain, sudden in onset, and often associated with nausea and vomiting. The radiation of the pain may provide some clue as to where in the urinary tract the stone is lodged. Stones in the ureteropelvic junction cause flank pain that may radiate to the groin, whereas stones lodged in the narrowest portion of the ureter, where it enters the bladder, are associated with signs of bladder irritation (dysuria, frequency, and urgency). Struvite-carbonate stones are, on

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occasion, incidentally discovered on abdominal radiograph. A careful abdominal examination and, in women, a pelvic examination, are important to rule out other potential causes of abdominal pain.

Laboratory evaluation should include a complete blood cell count, serum chemistries, and urinalysis. The white blood cell count may be mildly elevated but is generally less than 15,000 per mm³. A white blood cell count greater than 15,000 per mm³ is suggestive of another intraabdominal cause or an associated infection behind an obstructing calculus. An elevation of the blood urea nitrogen (BUN) and creatinine indicates prerenal azotemia, parenchymal renal disease, or obstruction of a solitary functioning kidney. A urinalysis should be performed routinely in any patient with abdominal pain. Microscopical hematuria is observed in approximately 90% of patients with nephrolithiasis.
Once the diagnosis is suspected based on the history, physical examination, and preliminary laboratory studies, establishing a definitive diagnosis is the focus of the next stage of the evaluation.
- A flat radiographic plate of the abdomen is often obtained and is capable of identifying radiopaque stones (calcium oxalate, calcium phosphate, struvite-carbonate, and cystine) that are greater than or equal to 2 mm in size. It will miss radiolucent stones, the most common of which are composed of uric acid, and stones that overlie the bony pelvis. For these reasons, an abdominal flat plate is most valuable in ruling out other intraabdominal processes.
- An ultrasound examination of the genitourinary tract often identifies stones in the renal pelvis; however, the majority of stones are lodged in the ureter, and the ultrasound examination often misses these.
- The intravenous pyelogram (IVP) was formerly considered the gold standard for the diagnosis of nephrolithiasis and is still of considerable value in the acute setting. Although the stone itself may not be visualized on an IVP, the site of the obstruction is regularly identified. Structural or anatomic abnormalities that may be present in the urinary tract, and renal or ureteral complications can be recognized. Disadvantages of the IVP include the need for intravenous contrast and the prolonged waiting time often required to visualize the collecting system on the side of the obstruction.
- Spiral computed tomography (CT), when available, is the test of choice in the patient with suspected nephrolithiasis. The advantages of spiral CT include higher sensitivity, faster scan times, and the lack of need for contrast.

Management. After the diagnosis is established, subsequent management is determined by; (a) the presence or absence of associated pyelonephritis; (b) whether parenteral narcotics are required for pain control; and (c) the likelihood of spontaneous passage of the stone. Obstructing calculi can be managed with observation alone if pain can be controlled with oral analgesics and spontaneous passage is likely. Extracorporeal shock wave lithotripsy may need to be employed for stones lodged in the upper ureter. Calculi in the lower ureter can be removed via cystoscopy and ureteroscopy. Hospital admission is necessary if there is evidence of infection of the renal parenchyma; when nausea, vomiting, or severe pain preclude the use of oral analgesics; or the stone is unlikely to pass spontaneously. The likelihood of spontaneous passage is determined by the size of the stone and its location in the ureter (see Table 6-1). Small stones in the distal ureter will likely pass, whereas large stones in the upper ureter will likely require urologic consultation and intervention.

Table 6-1. Likelihood of Spontaneous Passage


	Likelihood of spontaneous passage

Size
>6 mm	25%
4 6 mm	60%
>4 mm	90%
Location
Upper ureter, >6 mm	1%
Upper ureter, <4 mm	81%
Lower ureter, <4 mm	93%

Types of stones

Calcium-containing stones make up 90% of all stones and are generally composed of a mixture of calcium oxalate and calcium phosphate. In mixed stones, calcium oxalate usually predominates, and pure calcium oxalate stones are more common than pure calcium phosphate stones. Calcium

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phosphate tends to precipitate in alkaline urine, as occurs with renal tubular acidosis (RTA), whereas the precipitation of calcium oxalate does not vary greatly with pH. Because urine is acidic in most patients, calcium oxalate stones are more common. The major risk factors for the formation of calcium-containing stones include hypercalciuria, hypocitraturia, hyperuricosuria, hyperoxaluria, low urine volume, and medullary sponge kidney. These risk factors can occur either alone or in combination. Their relative frequency is shown in Table 6-2.

Table 6-2. Risk Factors for Calcium-Containing Kidney Stones


Risk factor	Alone	Combined

Hypercalciuria	60%	80%
Low urine volume	10%	50%
Hypocitraturia	10%	50%
Hyperuricosuria	10%	40%
Hyperoxaluria	2%	15%

Hypercalciuria is defined as urinary calcium excretion greater than 250 mg per 24 hours in women and greater than 300 mg per 24 hours in men. Hypercalciuria is present in about two-thirds of patients with calcium-containing stones and may result from an increased filtered load, decreased proximal reabsorption, or decreased distal reabsorption of calcium. The proximal reabsorption of calcium parallels sodium reabsorption. Any situation that decreases proximal reabsorption of sodium such as extracellular fluid (ECF) volume expansion also decreases proximal reabsorption of calcium. Distal tubular reabsorption of calcium is stimulated by parathyroid hormone (PTH), thiazides, and amiloride, and inhibited by acidosis and phosphate depletion.

Hypercalciuria may be idiopathic or secondary to primary hyperparathyroidism, RTA, sarcoidosis, immobilization, Paget's disease, hyperthyroidism, milk-alkali syndrome, and vitamin D intoxication. The idiopathic group makes up 90% of all hypercalciuria. This category of patients is characterized by increased 1,25(OH)₂ vitamin D₃ concentration, suppressed PTH, and reduced bone mineral density. Three potential pathophysiologic mechanisms are postulated: increased intestinal absorption of calcium, decreased renal reabsorption of calcium or phosphorus, and enhanced bone demineralization. On the basis of a fast-and-calcium-load study, some authors advocate subdividing idiopathic hypercalciuria into absorptive hypercalciuria types I, II, and III, and renal leak hypercalciuria. The rationale for this approach is that the physiologic mechanism identified will help guide specific therapy. In practice, however, this is

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often unnecessary. In the past, increased intestinal absorption of calcium was treated with a low-calcium diet. This is no longer the case. Patients with idiopathic hypercalciuria often have reduced bone mass and are in negative calcium balance, which will be further exacerbated by a low-calcium diet. In addition, a reciprocal relationship exists between free calcium and free oxalate in the intestinal lumen. Calcium acts to bind oxalate in the intestine and reduce oxalate absorption. If oral intake of calcium is reduced, oxalate remains free in the intestinal lumen and its absorption increases. A recent study of recurrent stone formers comparing a low-calcium diet to a diet normal in calcium but low in sodium and protein showed that urinary oxalate and the risk for recurrent stone formation were increased in patients on the low-calcium diet. Finally, as shown in Table 6-3, the majority of randomized controlled studies showing that a given pharmacologic intervention reduces the risk of stone disease did not subdivide patients based on the results of a calcium load study.

Table 6-3. Randomized Trials in Calcium-Containing Nephrolithiasis


Author	Treatment	Dose	Condition	No. of patients; length of follow-up	Risk reduction

Borghi	Water		First stone	199; 5 yr	55%
Laerum	Hydrochlorothiazide	25 mg b.i.d.	Noncategorized, recurrent	50; 3 yr	54%
Ettinger	Chlorthalidone	25 50 mg	Noncategorized, recurrent	54; 3 yr	48%
Ettinger	Allopurinol	100 mg t.i.d.	Hyperuricosuria, recurrent	60; 3 yr	45%
Barcelo	Potassium citrate	30 60 mEq	Hypocitraturia, recurrent	57; 3 yr	65%
Ettinger	Potassium-magnesium-citrate	42/21/63 mEq	Noncategorized, recurrent	64; 3 yr	81%
Ettinger	Potassium phosphate	1.4 g	Noncategorized, recurrent	71; 3 yr	None
Ettinger	Magnesium hydroxide	650 1,300 mg	Noncategorized, recurrent	52; 3 yr	None

In primary hyperparathyroidism, the filtered load of calcium is increased as a result of calcium release from bone and increased intestinal calcium absorption mediated by 1,25(OH)₂ vitamin D₃. An increase in the filtered calcium load overcomes the distal actions of PTH to increase tubular calcium reabsorption. In RTA, the decreased systemic pH results in increased calcium release from bone. In addition, acidosis directly inhibits distal nephron calcium reabsorption.

Macrophages in sarcoidosis produce 1,25(OH)₂ vitamin D₃, which leads to the increased intestinal absorption of calcium. Immobilization, Paget's disease, and hyperthyroidism cause hypercalciuria by releasing calcium from bone and increasing the filtered calcium load.

Hypocitraturia. Citrate combines in the tubular lumen with calcium to form a nondissociable but soluble complex. As a result, less free calcium is available to combine with oxalate. Citrate also prevents the nucleation and aggregation of calcium oxalate. Chronic metabolic acidosis from any cause enhances proximal tubular citrate reabsorption and decreases citrate concentration in urine; this is the mechanism whereby chronic diarrhea, RTA, and increased dietary protein load result in hypocitruria. Another important cause of hypocitruria is hypokalemia, which increases the expression of the sodium-citrate cotransporter present in the luminal membrane of the proximal tubule.
Hyperuricosuria. Uric acid and monosodium urate can act through several mechanisms to decrease the solubility of calcium oxalate in urine. They can act as a nidus upon which calcium salts can precipitate. Uric acid also binds naturally occurring macromolecular inhibitors and attenuates their activity. Finally, the addition of increasing concentrations of sodium urate to normal human urine can induce the precipitation of calcium oxalate via a poorly understood physiologic phenomenon known as salting out.
Hyperoxaluria. The etiologies of hyperoxaluria include enteric hyperoxaluria from inflammatory bowel disease, small bowel resection, or jejuno-ileal bypass; dietary excess (e.g., spinach, Swiss chard, rhubarb); and the rare genetic disorder primary hyperoxaluria. Urinary oxalate is derived from two major sources: 80% to 90% comes from endogenous production in liver, and the remainder is obtained from dietary oxalate or ascorbic acid. In enteric hyperoxaluria, the intestinal hyperabsorption of oxalate occurs via two mechanisms. First, free fatty acids complex with calcium and limit the amount of free calcium available to complex oxalate, thereby increasing the oxalate pool available for absorption. Second, bile salts and fatty acids increase the permeability of the colon to oxalate. Additional risk factors for stone formation in these patients include intestinal fluid losses that decrease urine volume, and intestinal bicarbonate and potassium losses that result in hypocitraturia.

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Low urinary volume. This is perhaps the most intuitively obvious of the risk factors for calcium-containing kidney stones. The lower the volume of solvent, the more likely that a given amount of salt will be supersaturating. This risk factor is particularly prominent in warm climates with low humidity.
Medullary sponge kidney should be suspected in women, or in men with no other risk factors for calcium-containing stones. Studies have shown that as many as 3% to 12% of patients with calcium-containing stones have this disorder. It has a prevalence of about 1 in 5,000 and affects males and females equally. The anatomic abnormality is an irregular enlargement of the medullary and inner papillary collecting ducts. The diagnosis is usually established in the fourth or fifth decade by an IVP that reveals radial, linear striations in the papillae or cystic collections of contrast media in ectatic collecting ducts. Patients present with stones or recurrent UTI, often associated with a distal RTA. Malformations of the terminal collecting duct result in urinary stasis that promotes crystal precipitation and attachment to the tubular epithelium.

In one report, nanobacteria were isolated from 30 of 30 calcium-containing stones. Nanobacteria are members of the Proteobacterium family, and they grow in protein- and lipid-free environments. They are capable of nucleating carbonate apatite directly on their surfaces at physiologic pH. This finding awaits confirmation from other laboratories. A subsequent study failed to culture nanobacteria from 10 upper urinary tract stones.

Uric acid stones represent approximately 5% of all cases of nephrolithiasis in Western countries. The highest incidence has been reported from Israel and the Middle East, where as many as 75% of all kidney stones consist solely of uric acid. This may be the result of the arid climate and reduced urinary volume. Uric acid is the major metabolic end product of purine metabolism in humans. Unlike most other mammals, humans do not express uricase, which degrades uric acid into the much more soluble allantoin. Uric acid stones are the most common radiolucent stone.
- Pathophysiology. The principal determinant of uric acid crystallization is its relative insolubility at acidic pH. Uric acid is a weak organic acid with two dissociable protons. The first has a pK_a of 5.5, and the second a pK_a of 10. As a result, only the first proton is dissociated in urine. At a pH of less than 5.5, the undissociated acid predominates, and it is more likely to crystallize (solubility 80 mg/L). As pH increases, uric acid dissociates into the more soluble sodium urate (solubility 1 gm/L). Because of the great increase in solubility with increasing pH, uric acid stones are the only kidney stones that can be completely dissolved with medical therapy. The main determinants of uric acid solubility are pH, concentration, and other cations present in urine. A higher sodium concentration decreases, whereas an increased potassium concentration increases, uric acid solubility. This may explain the complication of calcium-containing stone formation that can develop during sodium alkali therapy but not during treatment with potassium alkali. Sodium-containing alkalis also increase urinary calcium excretion secondary to ECF volume expansion.
- Signs and symptoms. Patients with uric acid stones exhibit a lower mean urinary pH and ammonium ion excretion rate. As many as 75% demonstrate a mild defect in renal ammoniagenesis in response to an acid load. Urinary buffers other than ammonia are titrated more fully than in unaffected individuals, with a resultant urine pH approximating 4.5.
  
  Those with defects in ammoniagenesis, such as the elderly and patients with polycystic kidney disease, are at increased risk for uric acid lithiasis. The second most important risk factor is decreased urine volume. Hyperuricosuria is the least important risk factor and is seen in less than 25% of patients with recurrent uric acid stones.
- A definitive diagnosis is established through stone analysis. The diagnosis is suggested by the presence of a radiolucent stone, although xanthine and 2,8-dihydroxyadenosine stones can also be radiolucent, or by the presence of uric acid crystals in unusually acidic urine.
Struvite-carbonate stones are also known as infection stones and are composed of a mixture of magnesium ammonium phosphate (struvite: MgNH₄PO₄ 6H₂O) and carbonate apatite [Ca₁₀(PO₄)₆CO₃]. Of all stones, 10% to 15% are estimated to be struvite-carbonate stones. This is likely an overestimate, however, given that these figures are based on reports from chemical stone analyses, and a greater proportion of stones chemically analyzed are obtained from surgical specimens. It is likely that struvite-carbonate stones make up no more than 5% of kidney stones. Their presence is also known as stone cancer because, before more recent therapeutic advances, they were the cause of numerous operations, renal failure, and death. Struvite-carbonate stones are the most common cause of staghorn calculi, although cystine, calcium oxalate, and urate stones may occasionally form staghorns. Struvite-carbonate becomes supersaturating in urine only in one circumstance: infection by urea-splitting organisms that secrete urease. The most common urease-producing bacteria include Proteus, Morganella, Providencia, Pseudomonas, and Klebsiella. Escherichia coli and Citrobacter do not produce urease.
- Risk factors. Women with recurrent UTI and patients with spinal cord injury, other forms of neurogenic bladder, or ileal diversions of the ureter are most prone to the formation of struvite-carbonate stones. Men with indwelling bladder catheters and complete spinal cord transection are at highest risk.
- Signs and symptoms. Struvite stones may present in a variety of ways, including fever, hematuria, flank pain, recurrent UTI, and septicemia. They can grow to a very large size and fill the renal pelvis as a staghorn calculus. The carbonate apatite component makes them radio-opaque. Rarely, if ever, do they pass spontaneously, and 25% are discovered incidentally. If untreated, they result in loss of the affected kidney in 50% of cases.
- Pathophysiology. For struvite-carbonate stones to form, the urine must be alkaline, with a pH greater than 7.0 and supersaturated with ammonium hydroxide. Bacterial urease hydrolyzes urea to ammonia and carbon dioxide. The ammonia then hydrolyzes spontaneously to form ammonium hydroxide; the carbon dioxide hydrates to form carbonic acid and, subsequently, bicarbonate. At high pH, the bicarbonate loses its proton to become carbonate. UTI with a urease-producing organism is the only situation in which urinary pH, ammonium, and carbonate are elevated simultaneously. The bacteria produce supersaturation in their own immediate environment. Crystals form around clusters of bacteria, and bacteria permeate every crevice of a struvite-carbonate stone. The stone itself is an infected foreign body.
Cystine stones. Cystinuria is the result of an autosomal recessive defect in the proximal tubular and jejunal reabsorption of the dibasic amino acids cysteine, ornithine, lysine, and arginine. Excessive amounts of these amino acids are excreted in urine, but clinical disease is due solely to the poor urinary solubility of cystine. Cystine is a dimer of cysteine. Cystine stones make up less than 1% of all calculi in adults but may constitute as many as 5% to 8% of all kidney stones in children. The prevalence of cystinuria is approximately 1 per 15,000 in the United States. Pure cystine stones form only in homozygotes. A normal adult excretes less than 19 mg of cystine per gram of creatinine in 24 hours. Cystine stones are radio-opaque due to the sulfhydryl moiety of cysteine.
- Pathophysiology. The solubility of cystine is approximately 250 mg per L, and this rises with increasing urinary pH. The pK_a of cysteine is 6.5; therefore, a gradual increase in solubility occurs as urinary pH rises
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  from 6.5 to 7.5. Supersaturation occurs at cystine concentrations greater than 250 mg per L. If the cystine concentration can be maintained below 200 mg per L, cystine stones should not form. Because homozygotes excrete 800 to 1,000 mg of cystine per day, at least 4 L of urine is required at normal urinary pH to keep the cystine concentration within the soluble range.
- Signs and symptoms. Cystine stones begin to form in the first to fourth decades. Patients tend to have bilateral obstructive staghorn calculi with associated renal failure. Characteristic hexagonal crystals may be identified, particularly in the first morning urine, which is usually acidic. Heterozygotes can form stones either with no cystine or with cystine as only a minor component, given that cystine can act as a nidus for the crystallization of both calcium oxalate and calcium phosphate.
Drug-related stones. A variety of drugs can precipitate in urine, including sulfonamides, triamterene, acyclovir, and the antiretroviral agent indinavir. Microscopic hematuria occurs in up to 20% of patients on indinavir. Nephrolithiasis develops in 3%, and 5% experience either dysuria or flank pain that resolves when the drug is discontinued. Reports show that patients with flank pain may have abnormal CT scans with a decrease in contrast excretion in the medullary rays.

Approximately 1 in 2,000 stones are ephedrine stones. These can result from either abuse of over-the-counter cold formulations or the ingestion of Ma-huang. Ma-huang is prepared from the dried stems of ephedra and is rich in ephedrine, norephedrine, pseudoephedrine, and norpseudoephedrine. It is contained in a variety of health food store preparations. The FDA has recently banned the sale of ephedrine-containing products.

Evaluation of the patient
- Calcium-containing stones. The first question to be addressed in the patient with calcium-containing stones is whether the stone disease is simple or complicated. Simple disease is defined as a single stone in the absence of an associated systemic disorder. Complicated calcium-containing stone disease is present if the patient has multiple stones, evidence of the formation of new stones, enlargement of old stones, or the passage of gravel. This distinction is made based on the initial evaluation. A history should be obtained, looking for a family history of stone disease, skeletal disease, inflammatory bowel disease, and UTI. Environmental risk factors are evaluated, such as fluid intake, urine volume, immobilization, diet, medications, and vitamin ingestion. A physical examination is performed. Initial laboratory evaluation includes blood chemistries, urinalysis, and a flat radiographic plate of the abdomen to assess stone burden. Stone analysis should always be carried out if the patient has saved the stone. Stone analysis is inexpensive. It is also the only way to establish the diagnosis of a specific disorder and often helps to direct therapy. In addition, it was shown that in 15% of cases, analyses of 24-hour urines would not have predicted the chemical composition of the stone.
  
  In the patient with complicated disease, two to three measurements of serum calcium should be performed. If any of these serum calcium levels is above 10 mg per dL, PTH concentration should be evaluated. Blood chemistries are examined. An IVP may be indicated to rule out structural abnormalities that predispose to stone formation. A first morning void urine should be examined for cystine crystals. At least two 24-hour urine collections should be obtained on the patient's usual diet for calcium, citrate, uric acid, oxalate, sodium, phosphate, volume, pH, and creatinine. Further therapeutic intervention depends on the results of these collections. Normal values for 24-hour urine collection are shown in Table 6-4. If a therapeutic intervention is undertaken, a 24-hour urine collection should be repeated in 6 to 8 weeks to verify its expected effect and then repeated on a yearly basis.
  
  Table 6-4. Normal Values for 24-Hour Urine Collection
  
  Substance Male (mg/24 hr) Female (mg/24 hr)
  
  Calcium <300 <250
  
  Uric acid <800 <750
  
  Citrate >200 >400
  
  Oxalate <40 <40
- Uric acid stones. The etiologies of uric acid stones can be subdivided into three pathophysiologic groups based on risk factors. Low urine volume
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  contributes to uric acid stones in gastrointestinal disorders such as Crohn's disease, ulcerative colitis, diarrhea, ileostomies, and dehydration. Acidic urinary pH plays an important role in primary gout and gastrointestinal disorders. Hyperuricosuria is divided into those with hyperuricemia (primary gout, enzyme disorders, myeloproliferative diseases, hemolytic anemia, and uricosuric drugs) and those without hyperuricemia (dietary excess).
  
  Primary gout is an inherited disorder most likely transmitted in an autosomal dominant fashion with variable penetrance. It is associated with hyperuricemia, hyperuricosuria, and a persistently acid urine. In affected patients 10% to 20% have uric acid stones, and in 40% kidney stones precede the first attack of articular gout. Because the urine is always acidic, the risk of uric acid lithiasis varies directly with serum and urine uric acid concentration.
  
  Uric acid stones are typically round and smooth and are more likely to pass spontaneously than calcium-containing stones, which are often jagged. They are also radiolucent, as are xanthine, hypoxanthine, and 2,8-dihydroadenine stones. Xanthine, hypoxanthine, and 2,8-dihydroadenine stones should be suspected if a radiolucent stone fails to dissolve with alkali therapy.
- Struvite-carbonate stones. Seventy-five percent of all staghorn calculi are composed of struvite-carbonate. Struvite-carbonate stones are large and less radiopaque than calcium-containing stones. As with any kidney stone, the definitive diagnosis can only be established on chemical analysis, but a diagnosis of struvite-carbonate stones should be strongly suspected in any patient with an infected alkaline urine. In the presence of an infected acid urine and a staghorn calculus, one should consider the possibility that the two are unrelated and that the calculus may be either calcium-containing or a uric acid stone. Stone analysis and culture should be carried out in all patients after either percutaneous nephrolithotomy or extracorporeal shock wave lithotripsy. Some patients, especially ambulatory men, have stones that contain a mixture of struvite-carbonate and calcium oxalate. These patients should always undergo a complete metabolic evaluation, because virtually all of them have an underlying metabolic defect, and they are probably at higher risk for stone recurrence, even with complete removal of the stone.
  
  Proteus mirabilis accounts for more than one-half of all urease-producing infections. Stone culture, when possible, is important, because culture of the urine is not always completely representative of the organisms present in the stone. If no organisms are cultured, then the possibility of infection with Ureaplasma urealyticum, which is often difficult to culture, should be considered.
- Cystine stones. The presence of characteristic hexagonal crystals in a first morning void urine is diagnostic of cystinuria, although this is a very infrequent finding. The simplest and most rapid screening test for cystinuria is the sodium-nitroprusside test, which has a lower limit of detection of 75 mg per gram of creatinine. The nitroprusside complex binds to sulfide groups and may yield a false positive result in patients taking sulfur-containing drugs. Phosphotungstic acid has also been used as an alternative screening test. Patients with a positive screening test should undergo 24-hour urine cystine quantitation. Cystine stones are usually less radiodense
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  on radiography than calcium-containing or struvite-carbonate stones. They typically have a homogeneous structure without striation.
Treatment
- Calcium-containing stones. The treatment of calcium-containing stones is determined by whether the patient has simple or complicated disease. The American College of Physicians advises that the patient with a single, isolated stone and no associated systemic disease be managed with nonspecific forms of therapy alone, including increased fluid intake and a diet normal in calcium. This approach is approporiate in patients at low risk of recurrence. One may consider, however, performing more extensive studies in those patients at high risk for recurrence (Caucasian males; 63% will form a second stone within 8 years) or in those who may experience substantial morbidity with a recurrence (kidney transplant patient).
  
  The patient with complicated disease is managed with both nonspecific and specific treatment. Specific therapy varies depending on the assessment of risk factors derived from the analysis of 24-hour urines.
  - Nonspecific therapeutic options include manipulation of fluid intake and diet. Increasing fluid intake is the cheapest way to reduce urinary supersaturation with calcium oxalate and phosphate. In a prospective randomized trial of 199 first-time stone formers followed for a 5-year period, the risk of recurrent stone formation was reduced from 27% to 12% by raising urinary volume to more than 2 L per day with water ingestion. The average increase in urine volume in patients advised to increase fluid intake is approximately 300 mL per day.
    
    Before 1993, the majority of patients with calcium-containing stones were advised to restrict dietary calcium. More recent studies, however, in both men and women suggest that a low-calcium diet may actually increase the risk of forming calcium-containing stones. The postulated mechanism is that ingested calcium aids in complexing dietary oxalate, and a reduction in dietary calcium results in a reciprocal increase in the intestinal absorption of oxalate. As a result, urinary supersaturation of calcium oxalate increases. In these studies, however, the ingestion of a diet high in calcium was also associated with an increased intake of magnesium, potassium, and phosphate, which may have acted as a confounding variable in reducing stone risk. A recent prospective, randomized, controlled trial compared patients on a low-calcium diet to those on a normal calcium, low-sodium, low-protein diet. The relative risk for kidney stone formation was reduced by 51% in those on the normal calcium diet. As predicted, urinary oxalate increased in the low-calcium group, compatible with the reciprocal relationship hypothesis.
    
    Another study examined the effects of the Atkins diet on risk factors for calcium-containing stone disease. Net acid excretion increased by 56 mEq per day, urinary citrate decreased from an average of 763 mg to 449 mg, urinary pH fell from 6.09 to 5.67, and urinary calcium increased from 160 mg to 248 mg. Patients with a history of kidney stones should avoid this highly lithogenic diet.
    
    Based on these findings, the most prudent approach is to consume a diet that is normal in calcium. The question of whether supplemental calcium increases the risk of nephrolithiasis in women is controversial. One report has suggested that any use of supplemental calcium raises the relative risk of stone disease approximately 20%. The risk in this study, however, did not increase with increasing dose. Although the relative risk of kidney stone formation is increased by supplemental calcium, one should bear in mind that women, in general, are at low risk for kidney stone formation.
  - Specific forms of treatment are directed by the results of the 24-hour urine studies. Therapy is focused around agents shown to reduce the relative risk of stone formation in randomized, placebo-controlled clinical trials with greater than 1 year of follow up (results shown in Table 6-3).
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    This is important because of the stone clinic effect. After patients present for evaluation of nephrolithiasis, the subsequent period is often associated with a reduced risk for new stone formation (the stone clinic effect ). This is the result of at least two factors: (a) regression to the mean and (b) increased adherence to nonspecific forms of treatment. Trials with less than 12 to 24 months of follow up should be viewed with skepticism if no effect is detected. At the start of treatment, patients at high risk for recurrence may have stones that are too small to be detected radiographically but that grow and subsequently are identified as new stones. Because calcium-containing stones are often difficult to prevent from increasing in size once a nidus is established, this could minimize the treatment effect in high-risk patients. Agents that were shown to be effective in randomized, placebo-controlled trials with a long duration of follow up include thiazides, allopurinol, potassium citrate, and potassium magnesium citrate.
    - Hypercalciuria is managed initially with thiazide diuretics. Thiazides act directly to increase distal calcium reabsorption and indirectly to increase calcium reabsorption in the proximal tubule by inducing a state of mild volume contraction. Volume contraction must be maintained and hypokalemia avoided in order for thiazide diuretics to remain maximally effective. Thiazides generally reduce urinary calcium by approximately 50%. The doses used in studies that show an effect are high, 25 mg of hydrochlorothiazide twice a day or 50 mg of chlorthalidone once a day. If they are ineffective, noncompliance with the low-sodium diet is usually the reason. This can be monitored with a 24-hour urine for sodium. Amiloride acts independently of thiazides at a more distal site and can be added if required. Two randomized, controlled trials in recurrent stone formers demonstrated a reduction in the risk of new stone formation with thiazide diuretics. Although all patients in these trials were calcium-containing stone formers, the minority were actually hypercalciuric. This suggests that thiazides may have additional effects beyond reducing urinary calcium or that the reduction of urinary calcium, even in the absence of hypercalciuria, may reduce the risk for recurrent kidney stone formation. Some have argued that the effect of thiazide diuretics may diminish with time, but this does not appear to be the case.
      
      In patients who cannot tolerate thiazide diuretics, other potential therapies include sodium cellulose phosphate and orthophosphate. These are often poorly tolerated. Slow-release neutral phosphate appears to be better tolerated and may become the second-line agent of choice. Randomized, controlled trials of potassium acid phosphate and magnesium hydroxide showed no benefit when compared to placebo.
    - Hypocitraturia is managed with potassium citrate or potassium-magnesium citrate. Each of these agents reduced the relative risk of stone formation in randomized controlled trials. Potassium-magnesium citrate may be especially beneficial in patients receiving thiazide diuretics, because potassium and magnesium losses induced by the diuretic are repleted. Patients with struvite-carbonate stones should not be given citrate, because it may increase the deposition of magnesium ammonium phosphate and carbonate apatite. Citrate may also increase the intestinal absorption of aluminum in patients with renal failure. Potassium-magnesium citrate is not currently clinically available. Citrate preparations are often difficult for patients to tolerate secondary to diarrhea. Slow release preparations such as Urocit -K are well tolerated but are relatively expensive. In patients with urinary citrate levels of less than 150 mg per 24 hours, 60 mEq should be administered daily in divided doses with meals. If the urinary citrate is greater than 150 mg per 24 hours, the dose is 30 mEq per day.
    - Hyperuricosuria is probably best managed with allopurinol. Whether alkalinization is of benefit is unclear, because heterogeneous nucleation and salting out can both be initiated by sodium urate. Citrate may reduce calcium oxalate precipitation in this setting, but this remains to be proven.
    - Hyperoxaluria is managed with a low-oxalate diet. Enteric hyperoxaluria should be initially treated with a low-fat, low-oxalate diet. If this is unsuccessful, calcium carbonate, cholestyramine, or both can be added.
    - Urinary volume should be increased to at least 2 L per day. This is best accomplished by drinking water, which is the only liquid shown to reduce the rate of stone formation in randomized, controlled clinical trials. If the patient will not drink water, lemonade is a sensible, although unproven, alternative. Lemon juice is high in citrate and low in oxalate.
      
      This approach, directed at both specific and nonspecific risk factor reduction for calcium-containing stone disease, was shown to decrease the frequency of recurrent stone formation and reduce the number of cystoscopies, surgeries, and hospitalizations.
- Uric acid stones. Therapy for uric acid stones is directed at the three major risk factors for uric acid lithiasis (decreased urine pH, decreased urine volume, hyperuricosuria). First, urine volume should be increased to 2 to 3 L per day. Second, the urine should be alkalinized to a pH of 6.5 using potassium citrate. The starting dose is 30 mEq b.i.d., to be titrated upward according to urinary pH. More than 80 to 100 mEq is rarely required. Sodium alkali therapy should be avoided, because it may result in hypercalciuria. In one study of 12 patients, alkali therapy resulted in a dissolution of stones within a period of 3 weeks to 5 months. Increases in urinary pH above 6.5 should be avoided. If the first morning void urine remains acidic, acetazolamide (250 mg) can be added at bedtime.
  
  If hyperuricosuria is present, dietary purine consumption should be reduced. Allopurinol should only be used when stones recur despite fluid and alkali administration, or if uric acid excretion is above 1,000 mg per day. When allopurinol is administered for massive uric acid overproduction, adequate hydration must be maintained to avoid the precipitation of xanthine crystals.
- Struvite-carbonate stones. Open surgical removal was formerly the treatment of choice for staghorn struvite-carbonate calculi. The recurrence rate, however, 6 years after surgery is 27%, and UTI persists in 41%. A second pyelolithotomy carries substantial morbidity. More recently, the combination of percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy has decreased morbidity substantially and is now the treatment modality of choice. Total elimination of the stone remains a challenge, because of the inability to remove small, bacteria-containing particles that act as nidi for further crystal growth. After complete removal, chronic culture-specific antimicrobial agents are indicated as prophylaxis against recurrent infection. If a struvite-carbonate stone is not removed in its entirety, the patient will continue to have recurrent UTI, and the stone will regrow. Stone growth in the majority of patients with residual fragments progresses despite antibiotic treatment. It can be slowed by reducing the bacterial population, but the chance of cure with antibiotics alone is remote. Urease inhibitors, such as acetohydroxamic acid, reduce urinary saturation of struvite-carbonate and prevent stone growth and may, on occasion, cause dissolution of existing stones. These agents, however, are associated with a variety of severe complications including hemolytic anemia, thrombophlebitis, and nonspecific neurologic symptoms (e.g., disorientation, tremor, headache).
- Cystine stones. Water is the hallmark of treatment for cystinuria. The required dose should be based on the patient's urinary cystine excretion.
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  The goal is to reduce the urinary cystine concentration below 250 mg per L. This often requires a urine output of at least 4 L per day. Two 8-oz glasses of water should be ingested every 4 hours. When patients void during the night, they should drink two glasses of water. The urine can be periodically examined for cystine crystals to assess the adequacy of fluid intake.
  
  Urinary alkalinization may be of some benefit. The dissociation constant of cystine is 6.5. As a result, a pH of 7.5 is required for 90% of cystine to take the ionized form. At this pH, the risk of calcium phosphate stones is increased. As a result, alkalinization should be viewed as an ancillary measure. Potassium citrate is the agent of choice and is preferable to sodium-containing alkali because ECF volume expansion increases cystine excretion.
  
  If these measures are ineffective, then either d-penicillamine, alpha-mercaptopropionylglycine, or captopril can be tried. These compounds are thiols that bind preferentially to cysteine, forming compounds that are more soluble than cysteine-cysteine dimers (cystine). Alpha-mercaptopropionylglycine causes fewer complications than d-penicillamine. d-Penicillamine also binds pyridoxine, and thus pyridoxine (50 mg per day) should be administered to prevent deficiency. Zinc supplements can usually prevent the anosmia and loss of taste that often occurs with d-penicillamine. Captopril has fewer side effects than either d-penicillamine or alpha-mercaptopropionylglycine, but may be less effective in reducing urinary cystine.