TABLE 1 Summary of Recommendations from the NIH Consensus Conference on the Evaluation of Stone Formers

Evaluation of patient with first stone episode History: medications, occupation, family history of stones or other kidney disease, inflammatory bowel disease (e.g., Crohn's disease) Diet: intake of protein, purines, sodium, fluids, oxalate and calcium Laboratory tests: electrolyte, blood urea nitrogen, creatinine, calcium, phosphate and uric acid levels, urinalysis, urine culture if indicated, stone analysis if available (if not, consider qualitative cystine screening) Radiology: plain radiographs, ultrasonography and/or intravenous pyelography (or helical computed tomography) to find more stones, radiolucent stones or anatomic abnormalities Consider: renal tubular acidosis, hyperparathyroidism and sarcoidosis Evaluation of patient with recurrent stone formation (and all children) Twenty-fourhour urine collection: volume, pH, levels of calcium, phosphorus, sodium, uric acid, oxalate, citrate, creatinine, calcium oxalate (supersaturation), calcium phosphate and uric acid Repeat as necessary: 24-hour urine collection and analysis to monitor response to dietary changes and effectiveness of treatment

NIH = National Institutes of Health. Information from Consensus conference. Prevention and treatment of kidney stones. Retrieved October 12, 1999, from the World Wide Web: http://odp.od.nih.gov/consensus/cons/067/067_intro.htm

First Stone Episode
Approximately 80 percent of kidney stones contain calcium. The majority of these stones are composed of calcium oxalate, with a minority containing calcium phosphate or admixtures of oxalate and phosphate salts. About 10 percent of stones are composed of uric acid (sometimes associated with a history of gout) or mixed uric acid and calcium. Another 10 percent are struvite stones, which develop exclusively in patients with urinary tract infections caused by urease-producing organisms, most typically Proteus species. Cystine accounts for no more than 1 percent of all stones. Cystine stones arise only in patients with cystinuria, an autosomal recessive disorder.1
Stone analysis is inexpensive (about $25) and is worth performing for first stones, those formed during preventive treatment and those occurring in conjunction with infection. If no stone is available for analysis, qualitative screening for urinary cystine should be performed at least once in younger patients.
Risk factors for nephrolithiasis are summarized in Table 2. Identifying a familial incidence of stones is useful because it indicates an increased risk of recurrence. Environmental or occupational factors and bowel surgeries such as ileostomy may be predisposing factors because of low urine volumes. Residents of the "stone belt" in the southeastern part of the United States also appear to be at higher risk for stone formation.3 In the stone belt, two mechanisms have been implicated: the hot climate causes increased perspiration and reduced urine volume, and exposure to sunlight activates vitamin D, stimulating the absorption of dietary calcium.

Drugs associated with kidney stone formation include triamterene (Dyrenium), sulfonamides, indinavir (Crixivan) and carbonic anhydrase inhibitors.

Drugs associated with stone formation include triamterene (Dyrenium) and the sulfonamides, which have low solubility. Calcium and vitamin D supplements cause hypercalciuria, and carbonic anhydrase inhibitors, which are used to treat glaucoma, increase the urinary pH and precipitate calcium phosphate. Indinavir (Crixivan), a protease inhibitor, can also crystallize and form stones in the urinary tract.4
Other important risk factors for calcium stones include hypercalciuria, hyperoxaluria and hypocitraturia. The major risk factors for uric acid stones are a low urinary pH and hyperuricosuria. Several dietary factors may contribute to these abnormalities and should be sought in the history.5,6
Animal protein is a major dietary constituent responsible for the relatively high prevalence of stones in populations of developed countries. Several mechanisms have been identified. Protein ingestion increases renal acid excretion. This, in turn, increases renal reabsorption of potential base, such as citrate, which is an endogenous inhibitor of calcium stone formation. Acid loads may be buffered in part by bone, which releases calcium to be excreted by the kidney. Finally, acid loading directly inhibits renal calcium reabsorption.5

TABLE 2 Risk Factors for Nephrolithiasis

Male gender (men constitute about two thirds of stone formers) Increasing age (risk increases until the age of 65 years) Low urine volume Occupational or situational factors: inadequate access to bathroom facilities or drinking water (e.g., delivery persons, sales persons), athletic activity, heat and sun exposure Bowel disease Geographic factors: residence in the "stone belt" of southeastern United States, or Mediterranean or Middle Eastern countries Hereditary factors and disorders: polycystic kidney disease, renal tubular acidosis, hyperparathyroidism, cystinuria, hypocitraturia, hypercalciuria Other renal disorders: infection (struvite calculus), medullary sponge kidney Dietary factors: increased intake of protein, salt or oxalate, decreased intake of calcium Hypercalciuria: hypercalcemia (hyperparathyroidism, sarcoidosis), increased intestinal absorption of calcium, renal leakage of calcium or phosphate, release of calcium from bone Hyperuricosuria: increased risk for calcium or urate stones Hyperoxaluria: primary hyperoxaluria, dietary intake of oxalate, enteric hyperoxaluria Hypocitraturia: increased protein intake, idiopathic Acidosis: acetazolamine (Diamox), renal tubular acidosis, bowel disease, protein loading

Animal protein is also the major dietary source of purines, the precursors of uric acid. Excessive intake of animal protein is therefore associated with hyperuricosuria, a condition present in some uric acid stone formers. More importantly, uric acid solubility is largely determined by the urinary pH. As the pH falls below 5.5 to 6.0, the solubility of uric acid decreases, and uric acid precipitates, even if hyperuricosuria is not present.7 One last important link between dietary protein and stones is the decrease in calcium oxalate solubility caused by uric acid. As a result, hyperuricosuria is also associated with calcium stone formation.
Another dietary risk factor for stones is sodium ingestion, although no controlled studies have shown that sodium restriction prevents stone formation. Increases in urinary sodium excretion cause increased urinary calcium excretion through renal mechanisms and increased calcium mobilization from bone.6 Higher sodium excretion rates also increase uric acid excretion and decrease urinary citrate excretion. Therefore, patients should be warned about added table salt and the salt content of processed meats, cheese, canned foods, soy sauce, baked goods and restaurant food.
Endogenous metabolism contributes a larger proportion of urinary oxalate than does dietary intake. Nonetheless, patients should be asked about their intake of foods with a high oxalate content, such as nuts, chocolate and dark-green leafy vegetables. Rhubarb, beets and okra are especially high in oxalate. Tomato sauce and jams are concentrated and can also contribute to excess urinary oxalate.
Measuring the oxalate content and determining the bioavailability of dietary oxalate present some technical problems. As a result, some dietary information may be misleading. Surprisingly, beverages such as tea or beer, thought to increase urinary oxalate excretion, may actually protect against stone disease.8,9 Finally, restriction of oxalate intake has been shown to reduce urinary oxalate levels, but not to prevent stone formation.
Calcium intake, particularly through dairy products, may be associated with hypercalciuria and stone formation. However, inverse relationships between dietary calcium and stone formation have been demonstrated, in that groups of men and women with the highest calcium intake have been shown to have nearly one half the rate of stones as groups with the lowest intake.10,11 One explanation for this phenomenon is that dietary calcium binds in the intestinal lumen with dietary oxalate, forming an insoluble, nonabsorbable complex. The reduction in urinary oxalate levels that occurs with increased intake of dietary calcium is proportionally more important than the increased urinary calcium levels. Like oxalate, some dietary calcium may also be less bioavailable.

Laboratory Evaluation
After a first episode of nephrolithiasis, a reasonable laboratory evaluation includes routine serum chemistries, including a blood urea nitrogen level, a creatinine level, electrolyte measurements and calcium, phosphate and uric acid levels. Children with stones should probably be referred to a urologist or nephrologist for further evaluation. Adult patients with a solitary kidney, struvite stones, abnormal renal function or renal tubular acidosis probably also require further evaluation.

Primary hyperparathyroidism is more common in women and older adults. It should be considered in a patient who forms stones and is found to have a high-normal or elevated serum calcium level.

Primary hyperparathyroidism, which is more common in women and older adults, should be considered in patients who have a high-normal or elevated serum calcium level (10 mg per dL or greater [0.25 mmol per L]). The preferred screening test for primary hyperparathyroidism is the intact parathyroid hormone level. High-normal serum calcium levels do not completely rule out this condition.12 Stone formation resulting from hypercalciuria may occasionally be a first presenting sign of sarcoidosis, often without hypercalcemia.
Urinalysis should be performed in patients with a first stone, and urine cultures should be obtained if infection is suspected. The presence of hexagonal cystine crystals may lead to the diagnosis of cystinuria. A low urinary pH is associated with uric acid stone formation, and a high urinary pH accompanied by a low serum bicarbonate concentration may occur with distal (type I) renal tubular acidosis. These patients are at risk for renal insufficiency. Calcium phosphate stones often occur in patients with renal tubular acidosis or hyperparathyroidism.

Compared with intravenous pyelography, helical computed tomography is faster and more sensitive in the diagnosis of kidney stones. It also does not require the use of intravenous contrast material.

After the acute episode has resolved, imaging of the kidneys with ultrasonography or helical computed tomographic (CT) scanning is recommended to screen for conditions such as polycystic kidney disease or asymptomatic stones such as staghorn calculus (Figure 1). Unlike calcium stones, uric acid stones are radiolucent (unless mixed with calcium) and therefore are not visualized using plain radiographic techniques.13 These stones can be visualized directly on helical CT scans. Helical CT scanning is faster and more sensitive than intravenous pyelography (IVP), and it does not require the use of intravenous contrast material.14 It is more expensive than IVP, but the cost should decrease as the study becomes more widely available.

FIGURE 1. Helical computed tomographic scan showing a 3-cm staghorn calculus (arrow) composed of calcium oxalate and located in the right renal pelvis. No associated hydronephrosis is present.

A 24-hour urine collection with measurement of relevant analytes is not generally indicated in most patients with a first stone. Generic therapeutic recommendations can be made without these data. Moreover, patients may not accept drug therapy after a single episode. A 24-hour urine collection may be warranted if a single stone was large, was associated with significant morbidity or occurred in an older patient more vulnerable to the adverse effects of acute urolithiasis and intervention.15 Cystinuria and primary hyperoxaluria, which are associated with more severe stone recurrences and more morbidity,16 should be ruled out in children with stones.

Therapeutic Recommendations
After a first stone episode, up to 50 percent of patients have at least a second stone within 10 years, and up to 80 percent have more stones within 20 to 30 years.17 These data, combined with the memory of the pain, inconvenience and cost of the first acute stone episode, may motivate some patients to comply with suggested modifications in diet and fluid intake.
Treatment options are summarized in Table 3. The most important aspect of stone prevention is increased urine volume.8 Patients understand the concept that increased urine volume dilutes urinary constituents, and they are often able to achieve urine volumes of 2 to 2.5 L per day. This goal requires daily ingestion of 2.5 to 3 L of fluids to account for stool and insensible fluid losses. Fluid intake should be increased when perspiration is increased (e.g., with exercise and heat). Thirst is not a sufficient indicator of adequate hydration.

Patients who have had a kidney stone should be encouraged to drink 2.5 to 3 L of fluid per day.

At least 8 to 12 oz of fluid should be ingested at bedtime, because urinary concentration usually occurs during sleep. Water is the preferred beverage. Citrus juices also appear to diminish the risk of stone formation, although the benefit of increased urinary citrate excretion is accompanied by a concomitant increase in urinary oxalate that may mitigate the net effect.18,19 Asking patients to periodically measure and record their own urine volumes using a soda bottle or a 24-hour collection jug may help to communicate the desired goal.
Although the effects of dietary changes on individual urinary components such as sodium and calcium are relatively well established, controlled trials demonstrating preventive efficacy are lacking. Restriction of daily salt intake to 2 g of sodium, animal protein intake to 8 oz and oxalate intake to as low as tolerated are all potentially useful, achievable goals. In particular, these restrictions are indicated if dietary excesses are uncovered in the history. Restriction of dairy products to reduce dietary calcium intake is no longer appropriate advice.

TABLE 3 Summary of Strategies for Preventing Calcium and Urate Nephrolithiasis

Calcium stones 1. In all patients, increase fluid intake to yield an output of at least 2 L of urine per day. 2. In the patient with hypercalciuria: Dietary restriction of protein, oxalate and sodium; no restriction of dietary calcium Medication: thiazides, usually given with potassium citrate; amiloride (Midamor) 3. In the patient with hypocitraturia: Dietary restriction of protein and sodium Potassium citrate supplementation (sodium citrate if potassium citrate is not tolerated) 4. In the patient with hyperoxaluria: Dietary restriction of oxalate 5. In the patient with hyperuricosuria: Dietary restriction of purine (i.e., protein) Allopurinol (Zyloprim) Uric acid stones 1. Increasing fluid intake is less important for the prevention of uric acid stones than calcium stones. 2. In the patient with a low urinary pH level: Dietary restriction of protein and sodium Alkalinization of urine with potassium citrate (sodium citrate if potassium citrate is not tolerated) 3. In the patient with hyperuricosuria: Dietary restriction of protein and sodium Alkalinization of urine with potassium citrate if urinary pH level is low Allopurinol in selected situations

Patients may object to the combination of restricted intake of some vegetables (to lower urinary oxalate excretion) and animal protein (to lower urinary calcium and uric acid excretion). Similarly, patients already restricting saturated fat and beef intake for cardiovascular purposes may be disheartened to learn that dietary restrictions to prevent stones extend to fish, fowl and pork. Moderation, not elimination, should be the message.20
Recurrent Stone Formation

Laboratory Evaluation
Patients with recurrent stones should undergo a more detailed evaluation, including a 24-hour urine collection. Accurate diagnosis depends on the methods used to determine the relevant urinary electrolytes. The urine collection may be performed while patients follow their usual diet. Optimally, more than one collection should be made to account for day-to-day variability. To ensure proper handling, it is important to use a laboratory that specializes in the determination of lithogenicity (i.e., the likelihood of urinary stone formation).
The data obtained from analysis of the urine should include calculation of any supersaturation of relevant stone components. Supersaturation is a computed value that indicates the likelihood of crystallization given the concentration of relevant ions and the urinary pH. This value correlates well with stone composition and alleviation in response to treatment of the stone-forming state.21 It also allows the net effect of treatment and diet to be integrated into a single number that the physician and patient can use for long-term follow-up.
Hypercalciuria is the most common cause of calcium stones. Determining a specific cause of hypercalciuria using special diets and calcium binders is a technique best left to the research setting.22 Classifying patients with this technique is unwieldy and costly. Hypercalciuria can be treated in a nonspecific manner. Low-calcium diets and calcium binders such as sodium cellulose phosphate have no proven utility and may result in diminished bone density.

Therapeutic Recommendations
One study found that the treatment of patients with recurrent stones is cost effective.23 The authors of this study calculated the costs of diagnostic testing, therapeutic procedures and medications in 1,092 unselected patients before and after metabolic evaluation and specific drug therapy. The drugs used, such as thiazides, potassium citrate and allopurinol (Zyloprim), are all relatively inexpensive. The savings achieved by the use of medical therapy and the resultant significant reduction in urologic procedures and hospitalizations amounted to $2,158 per patient per year. Given the proven benefit of prophylaxis, Medicare and most managed-care organizations typically cover the costs of diagnosis and these particular medical treatments.

The usual starting dosage of both hydrochlorothiazide and chlorthalidone for the purpose of lowering urinary calcium excretion is 25 to 50 mg once daily, with the dosage increased up to 50 mg twice daily as dictated by the results of repeated 24-hour urine collections

The pharmacologic treatment of calcium stones requires lowering urinary calcium excretion with thiazides and increasing the inhibitory activity of urine by increasing urinary citrate excretion. Hydrochlorothiazide and chlorthalidone are useful for achieving lower urinary calcium levels,24 with the latter perhaps offering a more prolonged effect. The usual starting dosage of each agent is 25 to 50 mg once daily, with the dosage increased up to 50 mg twice daily as dictated by the results of repeated 24-hour urine collections.
The major side effect of thiazides is hypokalemia, which leads to reductions in urinary citrate excretion. Therefore, thiazide therapy is usually accompanied by potassium citrate supplementation to replace potassium and replenish urinary citrate. The need to restrict dietary salt intake to minimize kaliuresis and maximize the effect of reducing calciuria should be reemphasized. Potassium citrate comes in oral tablets and liquid forms (with various flavors to improve palatability). The usual dosage is 20 to 30 mEq taken twice daily as needed.
Another approach to hypokalemia is to add amiloride (Midamor), a potassium-sparing diuretic that may also have a minor effect in reducing urinary calcium excretion. Triamterene should not be used because it is poorly soluble and is associated with stone formation through precipitation of the drug.
Hypocitraturia is another major contributor to calcium stone disease.25 Potassium citrate supplementation can suffice to treat this condition. Potassium is the preferred citrate preparation because the sodium salt can increase urinary calcium excretion. Potassium citrate therapy may be limited by gastrointestinal intolerance, particularly in older patients and patients with dyspepsia. A recent formulation of magnesium and potassium citrate may minimize this side effect.26
Hyperuricosuria may also be an independent risk factor for calcium stones. In patients with this condition, allopurinol can be effective in reducing the ability of uric acid to facilitate the crystallization of calcium oxalate if other risk factors are not identified.27
Uric acid stones are most often appropriately treated with potassium citrate, which causes an increase in the urinary pH and, thereby, an increase in uric acid solubility. Allopurinol therapy is reserved for use in patients with hyperuricosuria, rather than low urinary pH level, as the dominant feature. Even in patients with hyperuricosuria, citrate therapy may be preferred, because excess uric acid can be solubilized at a more alkaline pH.7

Osteoporosis and Stone Disease

Calcium restriction has not been shown to decrease stone formation and may actually worsen osteoporosis.

One potential issue is the significant incidence of osteoporosis in patients with stone disease and hypercalciuria.28 Mobilization of bone calcium may, in fact, be a primary cause of hypercalciuria.28 Many studies have shown that stone formers have lower bone density than nonstone formers matched by age and gender.29 Although the abnormality may be common, the bone disease usually appears to be mild, only rarely producing clinical signs.30 The syndrome may worsen with calcium restriction,29 which does not clearly prevent stone formation.
Bone density may increase with the administration of thiazides, which appear to have some beneficial effect on fracture rates.31 Bisphosphonates such as alendronate (Fosamax) may also be beneficial. The bisphosphonates, which are now standard therapy for osteoporosis, also reduce urinary calcium excretion.32 Therefore, therapy with thiazides and bisphosphonates may permit calcium supplementation in older stone formers who are at risk for osteoporosis.
Calcium citrate is the preferred agent for calcium supplementation in postmenopausal women with stone disease. Although urinary calcium excretion increases with the administration of this calcium salt, urinary citrate levels also increase.33 Supplementation using orange juice fortified with calcium citrate and calcium maleate is not associated with an increase in urinary calcium oxalate supersaturation.34

The Authors

DAVID S. GOLDFARB, M.D.,
is associate professor of clinical medicine and urology at New York University School of Medicine and co-director of the kidney stone prevention and treatment program at New York University Medical Center, both in New York City. He is also assistant chief of nephrology, director of hemodialysis and director of the metabolic stone clinic at the New York Department of Veterans Affairs Medical Center, New York City. Dr. Goldfarb graduated from Yale University School of Medicine, New Haven, Conn. He completed a residency in internal medicine and a fellowship in nephrology at New York University Medical Center.

FREDRIC L. COE, M.D.,
is chief of the renal section and professor of medicine and physiology at University of Chicago Pritzker School of Medicine, where he earned his medical degree. He completed a residency in internal medicine at Michael Reese Hospital and Medical Center, Chicago, and a fellowship in nephrology at the University of Texas Southwestern Medical School at Dallas.

New Insights into Causes and Treatments of Kidney Stones

STEVEN J. SCHEINMAN
State University of New York
Health Science Center at Syracuse

Recent findings have provided insight into the molecular basis of kidney stone formation and entirely changed our approach to management of calcium stones. Understanding the role of genetic factors and the various promotors and inhibitors of stone formation should lead to more effective prophylaxis and treatment of other types of stones as well.

Dr. Scheinman is Professor of Medicine and Chief, Division of Nephrology, State University of New York Health Science Center at Syracuse College of Medicine.

Kidney stones are an ancient affliction. They were mentioned in the Hippocratic Oath, and one was found in an Egyptian mummy. In the past several years, we have begun to decipher the genetic basis of hereditary kidney diseases and to understand how endogenous and dietary factors interact to inhibit or promote stone formation. Some of the findings have challenged our long-held views on treatment of hypercalciuria and calcium stones. Studies suggesting that symbiotic bacteria may be involved in stone formation have yet to be confirmed but serve as a reminder that causes as well as treatments of kidney stones are still being defined.
Risk Factors for Stone Formation

Normal urine is supersaturated with calcium oxalate, the primary constituent of most kidney stones. Stones do not usually form, however, unless there is a deficiency of an endogenous inhibitor of stone formation; an overexcretion of stone constituents; a persistent imbalance in urinary pH; or an obstruction in the urinary tract. In some cases, the underlying problem is simply poor fluid intake leading to concentrated urine. For many patients, hereditary factors are important.
The composition of the stones often provides clues to the underlying abnormality (Table 1). In North America, 70% to 80% of stones are composed of calcium oxalate, for which the most significant risk factors are hypercalciuria, hyperoxaluria, hypocitraturia, and hyperuricosuria. In one study involving nearly 3,500 patients, hypercalciuria was found in more than 40% of those with stones but only 7% of controls. The relative risk ratio was greater than 9:1, more than twice that in hypocitraturia (3.8:1) or hyperoxaluria (4.3:1), and more than four times that observed in studies of dietary factors affecting stone formation (<2:1).

Table 1. Underlying Pathology of Common Kidney Stones

Composition	Cause
Calcium oxalate	Hypercalciuria Hypocitraturia Hyperoxaluria Hyperuricosuria
Calcium phosphate	Renal tubular acidosis
Uric acid	Hyperuricosuria Persistently acidic urine
Struvite	Urease-producing bacterial infection
Cystine	Cystinuria

* Adapted from Coe et al, 1992

Urine pH is also important. Calcium phosphate stones, for example, are most likely to form at persistently high pH, and uric acid and cystine stones at persistently low pH.

Genetic Causes
The genes responsible for several uncommon but important kidney stone diseases have been cloned, including those for cystinuria, primary hyperoxaluria, hereditary distal renal tubular acidosis, X-linked nephrolithiasis (Dent's disease), and hereditary hypomagnesemia-hypercalciuria. Each of these diseases is inherited as a single mendelian trait and has clinical features that distinguish it from other causes of kidney stones. Understanding the pathophysiology of these unusual diseases has provided a framework for elucidating the more common conditions underlying stone formation.
Cystinuria. The presence of cystine in urinary tract stones is patho-gnomonic of cystinuria. Three types of cystinuria have been identified. All are inherited autosomal recessive traits that impair renal reabsorption of cystine. Type I disease is caused by a mutation in the solute carrier family 3 gene, SLC3A1. The gene or genes responsible for types II and III have not yet been identified.
Primary Hyperoxaluria. Like cystinuria, primary hyperoxaluria occurs in more than one form. Type I disease is inherited as an autosomal recessive trait and is caused by a mutation in the gene for alanine:glyoxalate aminotransferase. Inactivation or impairment of this enzyme's activity increases the risk of calcium oxalate stones and nephrocalcinosis leading to renal failure. Other complications stem from the systemic deposition of oxalate in blood vessels, bone marrow, connective tissues, nerves, brain, and heart--but, interestingly, not in liver, where oxalate is produced.
In patients homozygous for type I disease, the oxalate excretion rate is often extremely elevated, typically exceeding 250 mg/day in adults. This is higher than usually seen in adults with hyperoxaluria caused by bowel disease (100-250 mg/day) or excessive oxalate in the diet (45-100 mg/day). The heterozygous parents of patients with primary hyperoxaluria excrete normal amounts of oxalate (<45 mg/day).
Type II disease, which is rarer, milder, and less well understood than type I, is associated with a deficiency in D-glycerate dehydrogenase activity. The specific genetic defect has not been identified, nor has the gene been cloned. Usually, the only manifestation of the deficiency is nephrolithiasis.
Hereditary Distal Renal Tubular Acidosis. The inherited autosomal dominant form of distal renal tubular acidosis (dRTA) is caused by mutations in a gene for the basolateral anion exchanger (AE1) responsible for bicarbonate transport. A separate gene encoding the B1 subunit of proton-ATP-ase has been implicated in the autosomal recessive form. These two genes do not account for all cases of hereditary dRTA, however, which suggests that others have yet to be found.
Systemic acidosis calls on the body's buffers, including the minerals in bone. This increases the amount of calcium and phosphate presented to the kidney for excretion. Another reason for increased calcium excretion in dRTA is that acidosis directly inhibits the reabsorption of calcium in the renal tubules. Furthermore, the hypokalemia that occurs in dRTA reduces urinary citrate excretion. The persistently high urinary pH that results favors the formation of calcium phosphate, rather than calcium oxalate, stones.
dRTA should be suspected in any patient with calcium phosphate stones. Essential tests include measurements of 24-hour urinary citrate excretion and urine pH. Low levels of citrate do not necessarily indicate dRTA, but normal levels virtually exclude the disorder.
X-Linked Nephrolithiasis (Dent's disease). The first molecular defect associated with hypercalciuric stone formation was in the voltage-gated chloride channel protein, ClC-5. The product of a gene on the X chromosome, ClC-5 is predominantly expressed in the kidney, primarily in the subapical endosomes of proximal tubule cells (Figure 1).

In Dent's disease, defects in the ClC-5 channel inhibit chloride entry into the endosomes. This prevents the acidification needed for post-endocytotic degradation of low-molecular-weight proteins. Other impaired functions in the proximal tubules may reflect abnormal recycling of membrane proteins. ClC-5 is also expressed in the medullary thick ascending limb of Henle's loop and in intercalated cells of the collecting duct, but the impact of ClC-5 dysfunction in these segments is not clear.
The abnormalities of calcium metabolism seen in Dent's disease resemble those in idiopathic hypercalciuria. Levels of 1,25-dihydroxyvitamin D are often elevated, and intestinal absorption of dietary calcium is increased. In some patients, the hypercalciuria persists even during fasting. Other cardinal features of Dent's disease clearly distinguish it from common idiopathic hypercalciuria: patients (almost all of whom are male) have low-molecular-weight proteinuria and other signs of renal proximal tubular dysfunction such as glycosuria, aminoaciduria, or phosphaturia. Many also have progressive renal failure, and some have overt rickets.
Bartter Syndrome. Another hypercalciuric condition, Bartter syndrome, is associated with mutations in several different genes, one of which encodes ClC-Kb, a chloride channel protein in the same family as ClC-5 (Figure 2). In this case, the voltage-gated channel is on the basolateral side of cells of the thick ascending limb of Henle's loop. Other genes associated with the syndrome also encode membrane proteins, including the bumetanide-sensitive Na+-K+-2Cl- cotransporter (NKCC2) and the apical potassium channel (ROMK) in the medullary thick ascending limb. Mutations in these genes impair solute absorption in the very segment where much of calcium reabsorption occurs. Although patients with Bartter syndrome have hypercalciuria, and often nephrocalcinosis, they do not have kidney stones, possibly because of polyuria and dilute urine.
Hereditary Hypomagnesemia-Hypercalciuria. The gene responsible for hereditary hypomagnesemia-hypercalciuria, a syndrome characterized by magnesium and calcium wasting in the urine, nephrolithiasis, nephrocalcinosis, and muscle weakness, was recently cloned by R.P. Lifton and colleagues. It encodes a protein, paracellin-1, that may function either as a component or a regulator of a cation channel for paracellular reabsorption of magnesium and calcium in the loop of Henle and distal tubule. The discovery of this novel gene is tremendously exciting, since paracellin-1 is the first example of a specific protein involved in paracellular ion transport (see Figure 2 ).
This syndrome differs from Gitelman syndrome, which is also characterized by hypomagnesemia, in that patients are hypercalciuric rather than hypocalciuric. Gitelman syndrome is caused by mutations inactivating the sodium chloride cotransporter protein NCCT, the same protein that is inhibited by thiazide diuretics. The mutations thus have the same effect as treating with thiazides--calcium reabsorption in the distal tubule is stimulated, and stones do not form.
Idiopathic Hypercalciuria. Up to 40% of patients with idiopathic hypercalciuria have a family history of kidney stones. In the general population (hypercalciuric people included), urine calcium excretion is a continuous variable, which suggests that minor variations (polymorphisms) in multiple genes are involved. Charles Pak and colleagues described several different metabolic patterns in hypercalciuric patients: Three groups of patients had excessive intestinal calcium absorption, and two groups had renal calcium leak, one with and one without secondary hyperparathyroidism. This heterogeneity also suggests multiple pathologic mechanisms, possibly involving genes such as those for the calcium-sensing receptor, renal sodium-phosphate cotransporter, vitamin D-receptor, renal 1-alpha-hydroxylase (vitamin D-activating enzyme), or factors affecting bone mineralization.

Metabolic and Mechanical Causes
Bone Metabolism in Hypercalciuria. Many patients, particularly those with the highest rates of calcium excretion, excrete more calcium than they absorb from the diet. The calcium balance can become more negative when dietary calcium is restricted. In such cases, much of the calcium lost is derived from bone. There are several cytokines in bone, including tumor necrosis factor alpha and interleukins 1-alpha, 1-beta, and 6, that by regulating osteoclastic resorption might play a role in hypercalciuria. In a rat model of idiopathic hypercalciuria, treatment with a bone resorption inhibitor, the bisphosphonate alendronate, decreased calcium excretion. The loss of calcium from bone as a possible cause of hypercalciuria continues to be the focus of active research and may present new avenues for therapeutic intervention.
Crystallization Inhibitors. Normal urine contains inhibitors that protect against kidney stones, particularly calcium oxalate stones. Among the most prominent is citrate, which, by forming a soluble complex with calcium, reduces the amount of calcium available to form an insoluble complex with oxalate. Other substances inhibit one or more phases of stone formation in vitro, including several urinary proteins (e.g., Tamm-Horsfall protein, uropontin, prothrombin F1 peptide, and nephrocalcin) and glycosaminoglycans (chondroitin sulfate and heparan sulfate). However, the clinical relevance of some of these has yet to be determined.
Adhesion of Crystals to Urothelial Cells. Under normal conditions, the urine flows too fast to allow crystals to aggregate to form stones. As a result, any microcrystals in the urine are excreted without attaining much size. Conditions that promote binding to the urothelium allow the microcrystals to become large enough to cause problems.
The tip of the renal papilla appears to be a particularly favorable site for crystal adhesion. In 1937, A. Randall was the first to describe calcific plaques, now known as Randall's plaques, involving the interstitium and epithelium of the papillary tip. Similar calcification of the papillary tip occurs in rats when the epithelium is damaged by induction of hyperoxaluria. The binding properties of calcium oxalate crystals have also been studied in renal epithelial cell cultures. Among the many substances that inhibit binding in vitro are citrate, nephrocalcin, uropontin, chondroitin sulfate, heparan sulfate, and hyaluronic acid.
Harmful and Helpful Bacteria. A Finnish research group has recently proposed that nanobacteria promote calcific pathology by acting as a nidus for crystal formation. These organisms, the smallest cell-walled bacteria known, are less than 0.1 µm in diameter. They produce a shell of calcium phosphate (apatite), and the investigators found evidence of such shells in human kidney stones. Although intriguing, more study is needed before this mechanism of stone formation can be widely accepted.
When urine is infected with urease-producing bacteria, urea is hydrolyzed to carbon dioxide and ammonia. A urine pH above 8.0 indicates such an infection, usually involving Proteus, Klebsiella, enterococci, or Pseudomonas species, but not Escherichia coli. This change in the chemistry of the urinary tract favors the precipitation of magnesium ammonium phosphate stones. These stones, called struvite, often form when the urinary tract is functionally or anatomically obstructed. Any type of stone in the urinary tract can harbor bacteria, which makes the infection more difficult to eradicate and increases the risk of struvite formation. Like cystine stones, struvite can grow into large staghorn calculi that fill the entire renal pelvis. In this way, stones, obstruction, and infection become mutually perpetuating, making removal of the stone(s) by surgery or lithotripsy necessary.
Certain other bacteria may have a more positive effect. Oxalobacter formigenes, a gram-negative anaerobe found in human feces, degrades oxalate to carbon dioxide and formate and could potentially reduce dietary oxalate absorption. The stools of patients who have had jejunoileal bypass surgery contain less O. formigenes than normal, probably because of an excess of bile salts in the intestinal lumen. If it can be definitively shown that oxalate absorption and bacterial titers are correlated, measures to increase O. formigenes growth in the intestinal lumen might prove to be a novel strategy for preventing calcium oxalate stone formation.

Management Guidelines
Because all patients with kidney stones benefit from diluting the urine, drinking more fluids remains the mainstay of therapy. Other dietary and pharmacologic management decisions depend on the chemical composition of the stone and urine (Table 2). In monitoring the course of therapy, it is important to keep in mind that urine volume is a therapeutic variable. The only useful marker for estimating the adequacy of a 24-hour urine collection is the creatinine content.

Table 2. Urine Levels1 Monitored in Patients with Calcium Oxalate or Unidentified Stones

Calcium Oxalate Citrate Uric acid Magnesium Sodium Creatinine

1Routine laboratory tests of 24-hr urine collection. Specialized laboratories may also be able to provide supersaturation ratios for calcium oxalate, calcium phosphate, and uric acid.

Cystinuria. Adequate fluid intake is especially important in patients with cystinuria, in whom stones can form overnight. Cystine is so insoluble that the patient must drink large volumes of fluid, five or more liters a day, around the clock to maintain a continuously dilute urine. The standard treatment with drugs such as penicillamine or tiopronin that form soluble complexes with cystine often cannot be tolerated because of unpleasant, and sometimes severe, side effects. Alternative therapy with captopril is better tolerated but not as effective.
Hypercalciuria. In the past, the guidelines for treating hypercalciuria emphasized restricting calcium intake. Our views have completely changed, however, as we have recognized the dangers of inadequate calcium in the diet. Epidemiologic studies conducted by Gary Curhan and colleagues showed that low calcium intake (<800 mg/day) is associated with an increased risk of stones. The likely explanation is that, because calcium binds to oxalate in the intestinal lumen, more dietary oxalate is absorbed when less calcium is present (Figure 3). The protective effect of additional calcium was observed only when it was obtained in the diet and not from supplements, probably because supplements are not usually taken with meals. Another reason that an adequate calcium intake is important is that hypercalciuric, stone-forming patients tend to have lower than normal bone-mineral density. They thus have a higher than normal risk of bone demineralization and, possibly, fractures as they age.

Since natriuresis significantly increases urinary calcium excretion, all hypercalciuric patients should reduce dietary sodium intake to two grams a day (the same as in hypertension). In some patients, merely restricting sodium intake will reduce daily calcium excretion to normal levels (<300 mg in men, <250 mg in women, and 4 mg/kg in children). Sodium excretion of more than 100 mEq/day indicates noncompliance with the prescribed restriction.
Management of hypercalciuria usually requires use of a thiazide diuretic to stimulate calcium reabsorption in the renal distal tubule. Among the thiazides available, chlorthalidone and indapamide have the advantage of 24-hour action. The patient's response should be monitored by measurement of 24-hour calcium excretion levels. Excessive sodium consumption will reduce or even eliminate the thiazide's benefit. It will also increase the risk of hypokalemia, which increases the risk of stone formation by reducing urinary citrate excretion. If hypokalemia occurs, amiloride may be added to or substituted for the thiazide.
Although hyperparathyroidism accounts for only a small percentage of patients with hypercalciuria, diagnosis is important, because the condition can be cured with surgery (or potentially treated with calcimemetic agents). Failure to diagnose hyperparathyroidism engenders risk of nephrocalcinosis, bone disease, and such nonspecific symptoms as weakness. For this reason, all patients with even a single calcium-containing stone should have their serum calcium level measured.
Hypocitraturia. One of the most common conditions causing stones is hypocitraturia, which occurs in all patients with calcium phosphate stones resulting from dRTA and in many patients with calcium oxalate stones without acidosis. Unless hyperkalemia is present, hypocitraturia is treated with potassium citrate. Potassium rather than sodium alkali is used, since potassium deficiency reduces citrate excretion and sodium loading increases calcium excretion. The adequacy of this therapy should be monitored in 24-hour urine collections. The dosage should be adjusted continually to maintain a normal pH of 6.5 to 7.0 and bring the citrate level up to the normal range.
Hyperoxaluria. Management of hyperoxaluria involves restriction of oxalate intake. The results of efforts to restrict oxalate-enriched foods such as chocolate, nuts, spinach, berries, and beets are sometimes disappointing--even in the most conscientious patients. Unfortunately, little is known about the bioavailability of oxalate from dietary sources. Pyridoxine therapy can be effective in reducing oxalate excretion in patients with primary hyperoxaluria and might be helpful in other cases as well.
Hyperuricosuria. Allopurinol has been shown to prevent the recurrence of calcium oxalate stones in patients with hyperuricosuria and is the treatment of choice for all patients with hyperuricosuria, whether their stones are calcium oxalate, uric acid, or mixed. Avoidance of dietary purine in fish, fowl, and meat, especially organ meat, may also help to reduce uric acid excretion.

Conclusion
Medical therapy for the underlying causes of kidney stones, such as the use of thiazides for hypercalciuria, potassium citrate for hypocitraturia, or allopurinol for hyperuricosuria, will reduce the rate of stone recurrence. Increased water intake will also reduce the frequency of recurrence, as has been demonstrated in a randomized prospective trial. Rational dietary therapy is also beneficial.
The financial benefits of reducing stone recurrence far outweigh the costs of diagnostic evaluation and therapy. All patients with recurrent stones should have a full metabolic evaluation. For those who do not respond to medical treatment, new surgical techniques, including extracorporeal shock-wave lithotripsy, percutaneous nephrolithotomy, ureteroscopy, and laser lithotripsy, are improvements over older surgical options for this painful disease.