Prevention of recurrent calcium stones in adults

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1 Official reprint from UpToDate Print Back Prevention of recurrent calcium stones in adults Author Gary C Curhan, MD, ScD Section Editor Stanley Goldfarb, MD Deputy Editor Theodore W Post, MD Last literature review for version 17.2: May 1, 2009 This topic last updated: April 14, 2009 INTRODUCTION Prevention of recurrent calcium stones (which are usually composed primarily of calcium oxalate) is aimed at decreasing the concentrations of the lithogenic factors (calcium and oxalate) and at increasing the concentrations of inhibitors of stone formation, such as citrate. Achieving these goals may require both dietary modification and the administration of appropriate drugs. Medical therapy (and metabolic evaluation) is usually undertaken in individuals who have formed more than one stone. Even if a patient has only passed one stone, it is important to review the imaging studies to determine if other stones are in the kidney since stone passage does not equal stone formation. At a minimum, those with a single kidney stone are encouraged to increase their fluid intake and are monitored periodically (usually by renal ultrasonography) for new stone formation (show radiograph 1). (See "The first kidney stone and asymptomatic nephrolithiasis in adults"). The management of patients with recurrent calcium stones will be reviewed here. The management of patients with other types of stones including of unknown composition, and risk factors for recurrent calcium stones are discussed separately. (See individual topic reviews and see "Evaluation of the adult patient with established nephrolithiasis and treatment if stone composition is unknown" and see "Risk factors for calcium stones in adults"). CALCIUM OXALATE STONES A variety of dietary modifications and drug therapies can affect the recurrence of calcium oxalate stones. Dietary modification From the viewpoint of diet, alterations in fluid, calcium, oxalate, animal protein, potassium, sucrose, fructose, sodium, phytate, and vitamin C intake may be beneficial [1]. (See "Risk factors for calcium stones in adults"). It remains unclear what role the intake of vitamin D plays in stone formation. The importance of a possible "stone clinic" effect following dietary recommendations should not be underestimated. One study found that 58 percent of 108 patients evaluated for kidney stones had, over a five year period, no evidence of active stone disease after a visit to the stone clinic in which minimal advice regarding diet and fluid intake was given [2]. Those patients who were metabolically inactive showed an increase in urine volume at follow-up versus no change in those who continued to form stones. Increase fluid intake Increasing fluid intake, spread throughout the day (although it is not essential that the patient wake up several times per night to urinate), will increase the urine flow rate and lower the urine solute concentration, both of which might protect against stone formation. In one prospective trial, 199 patients with a first calcium stone were randomly assigned to no therapy or recommendation of a high fluid intake to produce at least 2 liters of urine per day [3]. At five years, the incidence of new stone formation was significantly lower in the treated patients than in those in the control group (12 versus 27 percent). Similar findings were noted in another prospective study [4]. Stone formers who remained free of stones were noted to have a greater increase in urine volume than those who had recurrent disease (320 ml/day versus no change). Page 1 of 15

2 Type of fluid The risk of stone formation has been considered to be affected by the type of beverage consumed. However, data in support of these associations are limited and presented in more detail in a separate topic review. (See "Risk factors for calcium stones in adults"). - Grapefruit juice may be associated with an increased risk of stones, although a potential mechanism has not been identified. Although data are limited, avoidance of grapefruit and grapefruit juice may be reasonable in patients with calcium oxalate stones. - Coffee, tea and alcohol have been reported in prospective observational studies to be associated with a lower risk of stones. - Cranberry juice, advocated as prophylaxis against recurrent urinary tract infections, increased the urinary saturation of calcium oxalate when ingested in large amounts (one liter per day) [5]. Ingestion of moderate amounts is unlikely to be harmful, but there is no evidence that this beverage is beneficial for stone prevention. Reduce animal protein intake Adverse changes in urinary calcium, uric acid, and citrate excretion can be induced by a high protein diet, since the metabolism of sulfur-containing amino acids increases the daily acid load by generating sulfuric acid (show figure 1). Animal protein is much more likely to induce this effect than vegetable protein, since it has a higher sulfur content and therefore generates more acid [6]. (See "Risk factors for calcium stones in adults", see section on Protein for a discussion of how acid loading produces these changes). Thus, lowering animal protein intake will produce favorable changes in the urine [1]. However, it has not been proven that this will reduce the incidence of stone formation. In observational studies, a high animal protein diet is a risk factor for renal stones in men [7], but not in women [8,9]. In a randomized trial, reduced animal protein in association with higher dietary calcium and lower dietary sodium was associated with a reduced risk of stone recurrence [10]. Increase fruit and vegetable intake Foods that are rich in potassium, particularly fruits and vegetables, may be beneficial. Increasing dietary fruits and vegetables may reduce the risk of calcium oxalate stone formation, particularly in patients who self-select a diet that is low in fruits and vegetables. This benefit is primarily the result of increasing citrate excretion [11]. Limit dietary oxalate intake Some foods are high in oxalate and those should be avoided (eg spinach, rhubarb). In addition, some nuts and legumes are also high in oxalate and the intake should be limited (eg peanuts, cashews and almonds). However, there is scant evidence that low oxalate diets reduce the risk of stone formation. In prospective observational studies of individuals who have never had a stone, higher dietary oxalate only slightly increased the risk of incident stone formation in men and older women; there was no association in younger women [12]. Because of the documented health benefits of many foods that are traditionally considered high in oxalate (but still 10 mg or less per serving), strict oxalate restriction does not seem to be supported. Limit sodium intake Calcium is reabsorbed passively in the proximal tubule down the favorable concentration gradient created by the reabsorption of sodium and water. (See "Diuretics and calcium balance", for a review of renal calcium handling). Thus, a low sodium diet (to 80 to 100 meq/day) can enhance proximal sodium and calcium reabsorption, leading to a reduction in calcium excretion [10,13]. In one study, for example, lowering sodium intake from 200 to 80 meq/day diminished calcium excretion by as much as 100 mg/day (2.5 mmol/day) [13]. Although the independent contribution of lowering dietary sodium intake is unknown, it is part of a regimen that has been demonstrated to reduce recurrent stone formation [10]. Limit sucrose and fructose intake Sucrose has been shown to increase urine calcium independent of calcium intake and has been associated with an increased risk of stones [14]. Fructose intake also increases the risk of stone formation [15]. Page 2 of 15

3 Calcium intake Although higher urine calcium is a common finding in stone formers, restricting calcium intake is not recommended. The decrease in free intestinal calcium can lead to increased absorption of dietary oxalate and enhanced oxalate excretion, due to decreased binding of oxalate by calcium in the intestinal lumen. The net effect may be increased supersaturation of the urine with respect to calcium oxalate and an enhanced tendency to stone formation. (See "Risk factors for calcium stones in adults", section on Dietary factors). The ability to help prevent new stone formation with a normal calcium intake was shown in part by a five year study that compared two diets among men with idiopathic hypercalciuria and recurrent calcium oxalate stones [10]. In this trial, 120 such men were randomly assigned to either a diet consisting of a normal amount of calcium (1200 mg/day [30 mmol/day]) and low amounts of animal protein (52 g/day) and salt (2900 mg/day [50 mmol/day] of sodium chloride) or a diet containing a low amount of calcium (400 mg/day [10 mmol/day]). At five years, a significantly lower risk of stone recurrence was observed among the group assigned to the normal-calcium, low animal-protein, low-salt diet (unadjusted relative risk of 0.49 with a CI of 0.24 to 0.98). This selective benefit likely arose because of a decrease in urinary oxalate excretion compared to an increase with the low calcium diet; the urine calcium actually decreased in both treatment arms. However, the independent effect of calcium is unclear given that the amounts of animal protein and salt ingested among those in the low calcium diet differed from that of patients in the normal calcium diet group. Nonetheless, the low calcium intervention was not beneficial and is not recommended. In addition to increasing stone formation, a low calcium diet may have a second deleterious effect in patients with idiopathic hypercalciuria: development of negative calcium balance [1,16]. This extra loss of calcium can exacerbate the already diminished bone density in some of these patients [16,17], a complication that may be due to enhanced bone resorption. It should be noted that calcium supplements do not appear to be effective in preventing recurrent stones and may even slightly increase risk [9]. (See "Risk factors for calcium stones in adults", section on Calcium). In patients with a history of stones who require calcium supplements (eg, for the treatment of osteoporosis), a suggested approach is to measure urinary calcium excretion before and approximately one month after starting the calcium supplement. If there is a clinically important increase in urinary calcium excretion, then the addition of a thiazide diuretic may be useful to reduce urinary calcium excretion (and to help maintain bone density). (See "Hypercalciuria" below). Other High dose vitamin C appears to increases urine oxalate excretion in certain individuals [18,19] and the risk of stone formation [20]; thus, high dose supplements should be avoided in those with higher urine oxalate excretion. Phytate appears to decrease the risk of stones in women [8]. Although not simply a matter of dietary intake, higher body mass index increases the risk of stone formation, particularly in women [21]. Therefore, weight control may be helpful in preventing stone recurrence. Drug therapy Drug therapy is indicated if the stone disease remains active (as evidenced by the formation of new stones, enlargement of old stones, or the passage of gravel) or if there is insufficient improvement in the urine chemistries despite attempted dietary modification over a three to six month period. The aim of therapy is to prevent further calcium oxalate precipitation; dissolution of already existing calcium stones is highly unlikely (in comparison to uric acid or cystine stones). Thus, passage of an existing stone does not necessarily reflect a therapeutic failure in a patient known to have renal stones prior to the institution of therapy. Initial drug therapy varies with the metabolic abnormality that is present: Thiazide diuretics to reduce urine calcium Allopurinol for hyperuricosuria Page 3 of 15

4 Potassium citrate for hypocitraturia Patient adherence to diet or medication may become an important issue over the long-term. The trials documenting benefit from these interventions required at least three years before the results were significant [22]. In an analysis of over 3000 patients followed in a well organized stone clinic at the University of Chicago, the reduction in urinary supersaturation remained constant or improved over time in those who adhered to yearly follow-up [22]. However, only 15 to 40 percent of patients complied with the follow-up requirements by three years. Adherence to long-term therapy among those who did not follow-up was unknown. Hypercalciuria Patients with high urine calcium that is not due to hypercalcemia (idiopathic hypercalciuria) and persistent active stone disease should be treated with a normal-calcium, low animalprotein, and low-salt diet [10], plus a thiazide diuretic such as hydrochlorothiazide or chlorthalidone (which has a longer half-life). The definition of hypercalciuria is arbitrary and the urinary calcium level at which one should consider treatment is not clear, because the relation between urine calcium and risk of stone formation is continuous; if there is evidence of ongoing stone formation, then the urine calcium should be lowered. Thiazide therapy can lower calcium excretion by as much as 50 percent. This is primarily by inducing mild volume depletion, leading to a compensatory rise in the proximal reabsorption of sodium, and therefore of passive calcium reabsorption [23,24]. The net effect may be a 90 percent reduction in the incidence of new stones (although there is also an appreciable improvement of 50 to 65 percent in placebo treated patients) [25-28]. In a meta-analysis of five trials of thiazide diuretics compared to standard treatment with increased water intake or a neutral potassium salt, thiazide therapy was associated with a significant reduction in the number of new stone recurrences (relative risk 0.62, 95% CI ) [28]. The full benefit may not be seen unless sodium intake is also restricted [23]. (See "Diuretics and calcium balance"). The diuretic is generally started at 25 mg/day of chlorthalidone or hydrochlorothiazide (or its equivalent) to minimize diuretic-induced complications, but most patients will require 50 to 100 mg/day to achieve adequate lowering of the urine calcium. Chlorthalidone can be given once daily, but hydrochlorothiazide at doses above 25 mg/day may need to be given twice daily because of its short half-life. Hypokalemia should be avoided, since low potassium levels reduce urinary citrate excretion (see "Hypocitraturia" below). A low calcium diet should be avoided because it increases the risk of stone formation (see "Calcium intake" above) [10]. The tendency toward positive calcium balance with a thiazide diuretic may have an additional beneficial effect: increasing bone mineralization and decreasing the incidence of hip fracture in older patients. (See "Drugs that affect bone metabolism"). This will also be helpful in patients who have mistakenly been on a low calcium and/or high sodium diet, both of which can lead to negative calcium balance and osteopenia in patients with higher urine calcium. (See "Risk factors for calcium stones in adults", section on Hypercalciuria). Urinary calcium and sodium excretion should be monitored after the institution of thiazide therapy. If the urine calcium remains higher than desired, a high sodium intake may be responsible and efforts should be made to reduce sodium excretion below 100 meq (2300 mg) per day. The potassium-sparing diuretic amiloride (5 to 10 mg/day) can also be added, since this drug may increase calcium reabsorption in the cortical collecting tubule, further lowering calcium excretion [29]. (See "Diuretics and calcium balance", section on Cortical collecting tubule and amiloride). Triamterene is typically avoided because of the rare possibility of precipitation. There are two alternatives if the urine calcium does not fall as desired or the thiazide is not well tolerated. One option is the administration of 60 to 80 meq of alkali per day as potassium bicarbonate or potassium citrate (citrate is rapidly metabolized to bicarbonate) [30]. Caution: Potassium supplements should not routinely be given with amiloride, since the combination can lead to potassium retention and hyperkalemia. Page 4 of 15

5 Via an unknown mechanism, raising the plasma bicarbonate concentration increases calcium reabsorption and lowers calcium excretion [31,32]. For this to occur, however, the potassium salt must be given; the volume expansion induced by sodium bicarbonate or sodium citrate will increase sodium and therefore calcium excretion, counteracting the effect of the elevation in the plasma bicarbonate concentration [31-33]. The administration of potassium citrate or potassium bicarbonate may have an additional beneficial effect by increasing the urinary excretion of citrate, a potent inhibitor of calcium stone formation (see below). The second option is the administration of neutral phosphate (orthophosphate), which may reduce the excretion of calcium and increase the excretion of inhibitors of crystallization (such as pyrophosphate). However, there are no randomized trials documenting the effectiveness of this strategy in preventing stone recurrence. (See "No metabolic abnormality" below). Hyperuricosuria Elevated urinary excretion of uric acid has been thought to promote calcium oxalate stone formation [25,34,35], but there is controversy regarding the role of uric acid [36]. The lack of importance of uric acid excretion was suggested in a study of 3350 men and women, which revealed no difference in mean 24-hour uric acid excretion between individuals with and without a history of stones [36]. Multivariate analyses adjusting for other urinary factors revealed no increased likelihood of being a stone former among those with higher urine uric acid. To the contrary, there was a significant inverse association between 24-hour uric acid excretion and the likelihood of stone formation in men. Despite the latter findings, a randomized trial and observational studies have shown benefit from allopurinol in calcium stone-formers with hyperuricosuria [34,37,38]. In the randomized trial, 60 patients with hyperuricosuria and normocalciuria were assigned to allopurinol or placebo [34]. Allopurinol therapy significantly reduced the likelihood of calcium oxalate stone recurrence (0.12 versus 0.26 per patient per year with placebo) (show figure 2). These two apparently conflicting studies raise the possibility that allopurinol may lower the risk through a mechanism other than reducing uric acid excretion. In the past, it was suggested that uric acid may act as a nidus for calcium oxalate stone formation, and alkali therapy with potassium citrate (60 to 80 meq/day) was proposed to be theoretically beneficial, since raising the urine ph above 6.0 will convert insoluble uric acid to the much more soluble urate salt [39,40]. However, uric acid is no longer believed to act as a nidus. No trials address the benefits of alkali therapy in preventing recurrent calcium oxalate stone formation among patients with hyperuricosuria. Hypocitraturia Increasing urinary citrate excretion is the goal in patients with hypocitraturia, since citrate inhibits stone formation by forming a poorly dissociable but soluble complex with calcium, thus reducing the amount of calcium available for binding with oxalate or phosphate. Citrate excretion can be enhanced by alkalinizing the plasma by the daily administration of 30 to 80 meq of potassium citrate or potassium bicarbonate [39,41]. In a controlled study of 57 patients, for example, the incidence of new stone formation was lower in hypocitraturic patients treated with potassium citrate (0.1 versus 1.1 events per patient year in the placebo group) [41]. This benefit was associated with an approximate doubling of citrate excretion. In contrast to the beneficial effect of potassium citrate or potassium bicarbonate, a nonalkalinizing salt such as potassium chloride does not increase citrate excretion in normokalemic subjects [39]. Although orange juice is a good source of potassium and citrate, it has some undesirable effects: it does not lower calcium excretion; it modestly raises oxalate excretion; and the increase in caloric intake could lead to weight gain [42]. By comparison, lemon juice appears to be an effective source of citrate [43,44]. In one report, for example, the ingestion of 4 ounces of lemon juice concentrate per day (mixed with tap water as lemonade for a total volume of 2 liters) resulted in increased urinary citrate levels in 11 of 12 patients (average increase of 142 to 346 mg/day, although it remained in the low range) who were either noncompliant or intolerant of conventional citrate replacement therapy [43]. Active therapy also decreased urinary calcium excretion and did not alter urinary oxalate excretion. Sugar-sweetened lemonade should be avoided because of the additional calories. Further studies of the impact on actual stone formation are required before this approach can be routinely recommended to prevent stone recurrence. Page 5 of 15

6 required before this approach can be routinely recommended to prevent stone recurrence. Contrary to popular belief, cranberry juice does not seem to increase urinary citrate levels. This was demonstrated in a study of 24 individuals (12 of whom had prior calcium oxalate stones), in which urinary citrate excretion was the same during water (the control intervention) and cranberry juice intake [5]. A possible explanation for the lack of effect is the low potassium content of cranberry juice. Alkalinization raises citrate excretion by diminishing the uptake of filtered citrate by the proximal tubular cells [45]. The mechanism by which this occurs is related in part to the chemical form of citrate that is present in the lumen. Citrate can exist at a physiologic ph either as a divalent or trivalent anion. Proximal citrate reabsorption (via a sodium-citrate cotransporter in the luminal membrane) preferentially occurs as the divalent anion. Raising the ph in the tubular lumen converts the divalent form into the less reabsorbable trivalent form: Citrate(2-) + HCO3- > Citrate(3-) + CO2 + H2O Increasing the systemic ph may enhance citrate excretion by a second mechanism. The associated intracellular alkalosis will diminish citrate metabolism within the cells. The ensuing elevation in the cell citrate concentration will create a less favorable concentration gradient for passive citrate movement from the tubular lumen into the cell [5,46]. The net effect is decreased citrate uptake and increased citrate excretion. In addition to the effect on ph, some of the administered citrate may be excreted directly before being metabolized to bicarbonate [47]. Thus, potassium citrate has a slightly greater citraturic effect than potassium bicarbonate [39,47]. On the other hand, metabolic acidosis diminishes citrate excretion due to enhanced citrate reabsorption [45]. This effect is mediated both by conversion of citrate(3-) to the more reabsorbable citrate(2-) and by increased citrate metabolism (due to upregulation of the enzyme ATP citrate lyase) within the cells [46]. Hypocitraturia probably contributes to the stone formation that is relatively common in patients with untreated type 1 renal tubular acidosis (see "Nephrolithiasis in renal tubular acidosis"). Care must be taken when providing alkali supplements in patients with calcium phosphate stones (see below). Hypokalemia, as may be produced by a thiazide diuretic for example, has a similar stimulatory effect on citrate reabsorption. Potassium moves out of the cells to repair the extracellular deficit and electroneutrality is maintained in part by the movement of extracellular hydrogen into the cells. The intracellular acidosis will enhance citrate metabolism, thereby lowering the cell citrate concentration and creating a more favorable gradient for citrate reabsorption [47,48]. It is therefore desirable to correct hypokalemia in recurrent stone formers. Hyperoxaluria High urine oxalate can result from ingestion of a diet high in oxalate or factors that can be converted to oxalate (eg, vitamin C) and/or from increased GI absorption of dietary oxalate (enteric hyperoxaluria). Treatment in individuals with enteric hyperoxaluria is directed toward diminishing intestinal oxalate absorption [25,49]. The initial regimen consists of a high fluid intake, potassium citrate to correct metabolic acidosis if present, and oral calcium carbonate or citrate (1 to 4 g/day) with meals to bind oxalate in the intestinal lumen. Although some of the calcium is absorbed, there is a proportionately greater fall in oxalate excretion. (See "Risk factors for calcium stones in adults") A low-fat, low-oxalate diet is another modality that may be helpful in this disorder by reducing the quantity of fatty acids and free oxalate in the colon. However, only recently have reliable data on the oxalate content of foods become available ( and restriction of diet may lead to inadequate nutrition in these patients who have malabsorption and/or a short bowel syndrome. (See "Risk factors for calcium stones in adults") Cholestyramine, which binds both bile acids and oxalate, can also be used, but side effects may be limiting. Although it is has been postulated that manipulation of enteric flora (as with lactic acid bacteria or Oxalobacter formigenes) may also reduce dietary oxalate absorption and urinary oxalate excretion, a randomized placebo-controlled trial found that lactic acid bacteria failed to reduce urinary oxalate excretion Page 6 of 15

7 randomized placebo-controlled trial found that lactic acid bacteria failed to reduce urinary oxalate excretion [50-52]. No metabolic abnormality Some patients with recurrent calcium stones have no identifiable metabolic abnormality [25,36,53,54]. However, careful analysis has shown that these patients frequently have more calcium, more oxalate, and/or less citrate in the urine than normals, although no value meets the traditional definition of abnormal [36,53]. This is the likely explanation for these patients with no metabolic abnormality, because there appears to be a graded increase in stone risk that begins when the rate of urinary excretion is still within the normal range. This important principle was illustrated in a cross-sectional observational study of 3350 men and women, of whom 2237 had a history of nephrolithiasis [36]. Although the stone composition was unknown in many cases, the demographics of the participants suggest that approximately 80 percent were likely to have had calcium oxalate stones. The following results were noted in the different biochemical categories; most of the values were significantly different from the comparator: Compared to a 24-hour urinary calcium excretion below 100 mg in older women, the relative risk of being a stone former was 1.52 at a urinary calcium of 150 to 199 mg/day, 1.84 at a urinary calcium of 200 to 249 mg/day, and 1.93 at a urinary calcium of 250 to 299 mg/day. The relative risk increased further at clearly hypercalciuric levels: 2.68 and 4.94 at urinary calcium of 300 to 349 and greater than 350 mg/day, respectively. Similar results were observed for men and younger women. Compared to a 24-hour urinary oxalate below 20 mg, the relative risk of being a stone former was 1.59 at a urinary oxalate of 25 to 29 mg/day and 2.51 at a urinary oxalate of 30 to 39 mg/day. Urinary oxalate excretion above 45 mg/day has generally been considered to represent hyperoxaluria. Compared to a 24-hour urinary citrate below 300 mg, the relative risk of being a stone former was 0.72 at a urinary citrate of 300 to 399 mg/day, 0.63 at a urinary citrate of 400 to 499 mg/day, and 0.50 at a urinary citrate of 500 to 599 mg/day. Hypocitraturia has often been defined as citrate excretion below 320 mg/day. Stone formers also tend to have a lower urine volume, another factor that could promote stone formation. In one report, for example, patients with a first stone and who subsequently formed another stone had a baseline daily urine output that was 250 to 350 ml less than those who did not form another stone [3]. In some patients, the only abnormality may be a low urine volume leading to high concentration of calcium and oxalate. This emphasizes the importance of considering the concentrations of urinary factors and not simply the absolute amount of excretion. As an example, even if the urine calcium is not in the traditionally accepted hypercalciuric range, the urine calcium concentration will be high when the urine volume is low. If the urine volume cannot be consistently maintained at a higher level, the urine calcium must therefore be reduced to lower the calcium concentration. There is some suggestive evidence that lowering calcium excretion with a thiazide diuretic may be beneficial, even in patients who are not hypercalciuric [26,27]. The possible benefit of potassium citrate in this setting remains to be determined. Summary From the viewpoint of diet, alterations in fluid, calcium, oxalate, potassium, phytate, animal protein, sucrose, fructose, sodium, and vitamin C intake may be beneficial. We therefore recommend the following: Sufficient fluid intake distributed throughout the day to produce at least 2 liters of urine per day, including drinking at night (although it is not essential that the patient wake up several times per night to urinate). This will increase the urine flow rate and lower the urine solute concentration, both of which may protect against stone formation. Page 7 of 15

8 protect against stone formation. To reach this goal, the best strategy is to recommend how much additional fluid the patient should drink based on his or her 24 hour urine volume. As an example, if the total urine volume is 1.5 liters, then we recommend two additional 8 ounce (240 ml) glasses of fluid each day to reach the goal of at least 2 liters of urine output per day. Limiting animal protein in the diet. Although it has not been proven that a low protein diet will reduce the incidence of stone formation, a high animal protein diet is a risk factor for renal stones in men [7], but not in women [8,9]. Limiting dietary sodium to 100 meq/day. A low sodium diet can enhance proximal sodium and calcium reabsorption, leading to a reduction in calcium excretion. Increasing dietary potassium intake, as this substantially decreases risk in men and older women. Limiting dietary sucrose and fructose. Limiting dietary oxalate and vitamin C in patients with calcium oxalate stones. However, excessive limitation is not likely to be helpful; patients should continue to consume a wide variety of fruits and vegetables. Drug therapy is indicated if the stone disease remains active (as evidenced by the formation of new stones, enlargement of old stones, or the passage of gravel) or adequate improvements are not realized in urinary chemistries despite attempted dietary modification over a three to six month period. Initial drug therapy varies with the metabolic abnormality that is present: Thiazide diuretics for reducing urinary calcium excretion Allopurinol for hyperuricosuria Potassium citrate for hypocitraturia MONITORING OF RESPONSE The 24-hour urine is an essential component of the initial evaluation and guides recommendations for prevention. The response to dietary or drug therapy is monitored by repeat 24- hour urine collections. It is essential that all the relevant urinary factors be monitored in individuals with calcium oxalate stones as they often have more than one urinary abnormality. Although remnant stones may theoretically consume urinary constituents and thus lower their measured urinary concentration, the potential error from a stone being present is much less than the variability due to dietary intake [55,56]. (See "Evaluation of the adult patient with established nephrolithiasis and treatment if stone composition is unknown", section on 24-hour urine collections). The goal of therapy is to reverse the abnormalities detected during the initial work-up (eg, low urine volume, hypercalciuria, hypocitraturia, and hyperoxaluria). We routinely obtain at least one and preferably two 24-hour urine collections at six to eight weeks after therapy has begun to assess the impact of the intervention. If the desired changes have taken place, repeat values are obtained at six months and then at yearly intervals [22]. If urinary abnormalities persist, additional therapy is required. (See "Patient information: Collection of a 24-hour urine specimen"). It is important to emphasize that it is urinary supersaturation that must be reduced, not simply the concentration of a particular reactant (such as calcium). Supersaturation can be calculated from the 24-hour urine collection when performed in an experienced laboratory. Although the supersaturation is not perfectly predictive, it can be used as a guide to monitor the overall impact of the interventions. An absolute cutoff for "abnormal" supersaturation has not been defined, rather the risk decreases as the supersaturation decreases. (See "Evaluation of the adult patient with established nephrolithiasis and treatment if stone composition is unknown", section on 24-hour urine collections). Another component of monitoring is periodic imaging. Helical computed tomography (CT) is the most sensitive and specific imaging modality (relative to plain X-ray and ultrasound) to assess the number, size Page 8 of 15

9 sensitive and specific imaging modality (relative to plain X-ray and ultrasound) to assess the number, size and location of stones. However, CT is associated with higher radiation exposure and cost. Thus, ultrasound or KUB is frequently used to determine if new stones have formed or previous stones have increased in size. Ultrasound or KUB should be performed at one year and, if negative, every two to four years thereafter depending on the severity of persistent urinary abnormalities. We choose ultrasound or KUB depending on which the stone was best seen to allow for comparability. Limiting radiation exposure is important, as individuals with recurrent stones often have undergone multiple imaging procedures around the times of acute stone events. CALCIUM PHOSPHATE STONES In general, patients with calcium phosphate stones have the same risk factors as those with calcium oxalate stones (except for hyperoxaluria); as a result, therapy for recurrent stone formation is similar in most cases [57]. However, most calcium phosphate stone formers have a persistently elevated urine ph (usually above 6.0) often due to overt or incomplete type 1 renal tubular acidosis. Although the administration of alkali (preferably potassium citrate) in this setting may diminish the frequency of stone growth or new formation, it could also increase the risk by raising the urine ph, thereby increasing the likelihood of calcium phosphate crystal formation. Therefore, alkali therapy must be undertaken with caution. Urine ph and citrate should be monitored, and supplemental alkali should be discontinued if urine ph rises above 6.5 without a substantial increase in the urine citrate. (See "Nephrolithiasis in renal tubular acidosis"). STONE COMPOSITION NOT KNOWN In some patients, the stone composition remains unknown. The evaluation and management of such patients is discussed elsewhere. (See "Evaluation of the adult patient with established nephrolithiasis and treatment if stone composition is unknown"). INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Kidney stones in adults"). We encourage you to print or this topic review, or to refer patients to our public web site, which includes this and other topics. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Taylor, EN, Curhan, GC. Diet and fluid prescription in stone disease. Kidney Int 2006; 70: Hosking, DH, Erickson, SB, Vanden Berg, CJ, et al. The stone clinic effect in patients with idiopathic calcium urolithiasis. J Urol 1983; 130: Borghi, L, Meschi, T, Amato, F, et al. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: A 5-year randomized prospective study. J Urol 1996; 155: Strauss, AL, Coe, FL, Deutsch, L, Parks, JH. Factors that predict relapse of calcium nephrolithiasis during treatment: A prospective study. Am J Med 1982; 72: Gettman, MT, Ogan, K, Brinkley, LJ, et al. Effect of cranberry juice consumption on urinary stone risk factors. J Urol 2005; 174: Breslau, NA, Brinkley, L, Hill, KD, Pak, CY. Relationship of animal protein-rich diet to kidney stone formation and calcium metabolism. J Clin Endocrinol Metab 1988; 66: Curhan, GC, Willett, WC, Rimm, EB, Stampfer, MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993; 328: Curhan, GC, Willett, WC, Knight, EL, Stampfer MJ Dietary factors and the risk of incident kidney stones in younger women: Nurses'Health Study II. Arch Intern Med 2004; 164: Curhan, GC, Willett, WC, Speizer, FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med 1997; 126:497. Page 9 of 15

10 10. Borghi, L, Schianchi, T, Meschi, T, Guerra, A. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 2002; 346: Meschi, T, Maggiore, U, Fiaccadori, E, et al. The effect of fruits and vegetables on urinary stone risk factors. Kidney Int 2004; 66: Taylor, EN, Curhan, GC. Oxalate intake and the risk for nephrolithiasis. J Am Soc Nephrol 2007; 18: Muldowney, FP, Freaney, R, Moloney, MF. Importance of dietary sodium in the hypercalciuria syndrome. Kidney Int 1982; 22: Lemann, J Jr, Piering, WF, Lennon, EJ. Possible role of carbohydrate-induced calciuria in calcium oxalate kidney-stone formation. N Engl J Med 1969; 280: Taylor, EN, Curhan, GC. Fructose consumption and the risk of kidney stones. Kidney Int 2008; 73: Bataille, P, Achard, JM, Fournier, A, et al. Diet, vitamin D and vertebral mineral density in hypercalciuric calcium stone formers. Kidney Int 1991; 39: Asplin, JR, Donahue, S, Kinder, J, Coe, FL. Urine calcium excretion predicts bone loss in idiopathic hypercalciuria. Kidney Int 2006; 70: Massey, L. Ascorbate increases human oxaluria and kidney stone risk. J Nutr 2005; 135: Traxer, O. Effect of ascorbic acid consumption on urinary stone risk factors. J Urol 2003; 170: Taylor, EN, Stampfer, MJ, Curhan, GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol 2004; 15: Taylor, EN, Stampfer, MJ, Curhan, GC. Obesity, weight gain, and the risk of kidney stones. JAMA 2005; 293: Parks, JH, Asplin, JR, Coe, FL. Patient adherence to long-term medical treatment of kidney stones. J Urol 2001; 166: Nijenhuis, T, Hoenderop, JG, Loffing, J, Van Der, Kemp AW. Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transport proteins in kidney. Kidney Int 2003; 64: Nijenhuis, T, Vallon, V, van der, Kemp AW, et al. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005; 115: Coe, FL, Parks, JH, Asplin, JR. The pathogenesis and treatment of kidney stones. N Engl J Med 1992; 327: Ettinger, B, Citrov, JT, Livermore, B, Dolman, LI. Chlorthalidone reduces calcium oxalate calculus recurrence but magnesium hydroxide does not. J Urol 1988; 139: Laerum, E, Larsen, S. Thiazide prophylaxis of urolithiasis. A double-blind study in general practice. Acta Med Scand 1984; 215: Escribano, J, Balaguer, A, Pagone, F, et al. Pharmacological interventions for preventing complications in idiopathic hypercalciuria. Cochrane Database Syst Rev 2009; :CD Alon, U, Costanzo, LS, Chan, JC. Additive hypocalciuric effects of amiloride and hydrochlorothiazide in patients treated with calcitriol. Miner Electrolyte Metab 1984; 10: Pak, CY, Peterson, R, Sakhaee, K, et al. Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in thiazide-unresponsive hypercalciuric nephrolithiasis. Am J Med 1985; 79: Lemann, J Jr, Gray, RW, Pleuss, JA. Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men. Kidney Int 1989; 35: Sakhaee, K, Nicar, M, Hill, K, Pak, CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int 1983; 24: Preminger, GM, Sakhaee, K, Pak, CY. Alkali action on the urinary crystallization of calcium salts: Page 10 of 15

11 33. Preminger, GM, Sakhaee, K, Pak, CY. Alkali action on the urinary crystallization of calcium salts: Contrasting responses to sodium citrate and potassium citrate. J Urol 1988; 139: Ettinger, B, Tang, A, Citron, JT, et al. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med 1986; 315: Ettinger, B. Does hyperuricosuria play a role in calcium oxalate lithiasis?. J Urol 1989; 141: Curhan, GC, Taylor, EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int 2008; 73: Favus, MJ, Coe, FL. The effects of allopurinol treatment on stone formation on hyperuricosuric calcium oxalate stone-formers. Scand J Urol Nephrol Suppl 1980; 53: Coe, FL. Treated and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria, or no metabolic disorder. Ann Intern Med 1977; 87: Sakhaee, K, Alpern, R, Jacobson, HR, Pak, CY. Contrasting effects of varying potassium salts on renal citrate excretion. J Clin Endocrinol Metab 1991; 72: Pak, CY, Peterson, R. Successful treatment of hyperuricosuric calcium oxalate nephrolithiasis with potassium citrate. Arch Intern Med 1986; 146: Barcelo, P, Wuhl, O, Servitge, E, et al. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol 1993; 150: Wabner, CL, Pak, CY. Effect of orange juice consumption on urinary stone risk factors. J Urol 1993; 149: Seltzer, MA, Low RK, McDonald, M, et al. Dietary manipulation with lemonade to treat hypocitraturic calcium nephrolithiasis. J Urol 1996; 156: Penniston, KL, Steele, TH, Nakada, SY. Lemonade therapy increases urinary citrate and urine volumes in patients with recurrent calcium oxalate stone formation. Urology 2007; 70: Hamm, LL. Renal handling of citrate. Kidney Int 1990; 38: Melnick, JZ, Srere, PA, Eishourbagy, NA, et al. Adenosine triphosphate citrate lyase mediates hypocitraturia in rats. J Clin Invest 1996; 98: Sakhaee, K, Alpern, R, Poindexter, J, Pak, CY. Citraturic response to oral citric acid load. J Urol 1992; 147: Levi, M, McDonald, LA, Preisig, PA, Alpern, RJ. Chronic K depletion stimulates rat renal brush-border membrane Na-citrate cotransporter. Am J Physiol 1991; 261:F Williams, HE. Oxalic acid and the hyperoxaluric syndromes. Kidney Int 1978; 13: Lieske, JC, Goldfarb, DS, De Simone, C, Regnier, C. Use of a probiotic to decrease enteric hyperoxaluria. Kidney Int 2005; 68: Hoppe, B, Beck, B, Gatter, N, et al. Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1. Kidney Int 2006; 70: Goldfarb, DS, Modersitzki, F, Asplin, JR. A randomized, controlled trial of lactic acid bacteria for idiopathic hyperoxaluria. clin J Am Soc Nephrol 2007; 2: Parks, JH, Coe, FL. A urinary calcium-citrate index for the evaluation of nephrolithiasis. Kidney Int 1986; 30: Curhan, G, et al. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int 2001; 59: Laube, N, Pullmann, M, Hergarten, S, Hesse, A. Influence of urinary stones on the composition of a 24-hour urine sample. Clin Chem 2003; 49: Laube, N, Pullmann, M, Hergarten, S, et al. The alteration of urine composition due to stone material present in the urinary tract. Eur Urol 2003; 44: Gault, MH, Chafe, LL, Morgan, JM, et al. Comparison of patients with idiopathic calcium phosphate and calcium oxalate stones. Medicine (Baltimore) 1991; 70:345. Page 11 of 15

12 GRAPHICS Kidney stone Ultrasonography showing a stone in the renal pelvis of the right kidney (arrow). Page 12 of 15

13 Protein load increases urine stone-forming tendency The institution of a high protein diet (2 g/kg per day) in normal men adversely effects the metabolic parameters determining the risk of calcium stone formation. There is an increase in the urinary excretion of calcium and uric acid and a reduction in that of citrate. Data from Kok, DJ, Iestra, JA, Doorenbos, CJ, Papapoulos, SE, J Clin Endocrinol Metab 1990; 71:861. Page 13 of 15

14 Allopurinol prevents stones in hyperuricosuria When compared to placebo, allopurinol protects against new stone formation in hyperuricosuric calcium oxalate stone formers. Data from Ettinger, B, Tang, A, Citron, JT, et al, N Engl J Med 1986; 315:1386. Page 14 of 15

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