Pathophysiology and Management of Calcium StonesSangtae Park, MD, MPHa, Margaret S. Pearle, MD, PhDb,*

aDepartment of Urology, University of Washington Medical Center, Box 356510,1959 N.E. Pacific, Seattle, WA 98195, USA

bDepartment of Urology, The University of Texas Southwestern Medical Center,5323 Harry Hines Boulevard, J8.106, Dallas, TX 75390-9110, USA

Nephrolithiasis is a common disorder thataccounts for significant cost, morbidity, and lossof work. In the United States., the estimatedannual expenditure for the diagnosis and treat-ment of nephrolithiasis approached $2.1 billion in2000, almost certainly an underestimate, withouttaking into account lost wages and reduced workproductivity [1]. Indeed, there is a one in eight life-time chance of being diagnosed with urinarystones [2–4]. Although in most cases stones aresource of discomfort and inconvenience withoutsignificant risk to health, progressive loss of renalfunction can occur after repeated episodes ofstone disease. In a French study of over 1300 pa-tients newly requiring hemodialysis, 3.2% of caseswere directly related to stone disease [5].

With comprehensive evaluation, metabolic ab-normalities can be identified in over 90% of stoneformers, and the institution of preventive dietaryand medical measures has resulted in substantialreduction in stone recurrence rates [6,7]. A carefulmedical and dietary history, serologic tests, andurinalysis constitute the initial screening tools instone formers. Stone analysis by radiographiccrystallography or infrared spectrophotometry isan important component of this initial evaluation,because comprehensive metabolic testing may beforegone in lieu of more directed evaluation in pa-tients who have non–calcium-containing stonessuch as uric acid and cystine, in whom the under-lying pathophysiologic abnormalities are impliedby the stone composition [8]. In contrast, calcium

stones (calcium oxalate [CaOx] and calcium phos-phate) form as a result of a variety of environmen-tal risk factors and metabolic derangements, andidentification of these factors composes the main-stay of the evaluation and treatment plan for thesepatients.

Among the various stone compositions, cal-cium-containing stones represent approximately75% to 80% of upper tract stones. The remaining20% to 25% are composed of struvite, cystine,uric acid, and other stones [9]. In this article, theauthors review our current understanding of thepathophysiology of calcium stone disease, andpropose contemporary medical and dietary pro-phylactic regimens.

Pathophysiology

CaOx stones are the most common stone type(60% of all stones), followed by the calciumphosphate subtypes hydroxyapatite (20%) andbrushite (2%). Mixed calcium stones containingboth calcium phosphate and CaOx are common[10]. When over 30% of the stone volume is com-posed of calcium phosphate, it is classified as hy-droxyapatite or apatite, depending on the crystalmorphology.

The basis for calcium stone formation issupersaturation of urine with stone-forming cal-cium salts. A number of dietary factors andmetabolic abnormalities can change the composi-tion or saturation of the urine so as to enhancestone-forming propensity. Among the metabolicconditions are hypercalciuria, hypocitraturia, hy-peroxaluria, hyperuricosuria, and gouty diathesis(Table 1), and these conditions are reviewed in de-tail. Dietary factors also play a role in stone

* Corresponding author.E-mail address: margaret.pearle@utsouthwestern.edu

(M.S. Pearle).

0094-0143/07/$ - see front matter ! 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.ucl.2007.04.009 urologic.theclinics.com

Urol Clin N Am 34 (2007) 323–334

occurrence, and are discussed with regard to theirrole in preventing stone formation.

Hypercalciuria

Hypercalciuria is arguably the most importantpathophysiologic risk factor in calcium stoneformation. Urinary calcium raises ionic calciumconcentration and increases urinary saturation ofstone-forming calcium salts (calcium phosphateand CaOx). In addition, complexation of calciumwith urinary inhibitors such as citrate and glycos-aminoglycans reduces urinary inhibitory activity,thereby increasing stone risk.

Several lines of evidence support a pathogeneticrole for hypercalciuria in calcium stone formation.First, hypercalciuria is the most common abnor-mality identified in stone formers, occurring in35% to 65% of cases. Second, pharmacologictherapies aimed at reducing urinary calcium havebeen shown to reduce rates of recurrent stoneformation [11]. Finally, recent investigations sug-gesting that Randall’s plaques may represent po-tential precursors to calcium stones have shownthat plaques occur more commonly in stone for-mers, and that their number is directly correlatedwith urine calcium levels and number of stoneepisodes [12,13].

Hypercalciuria is defined as urinary calciumexcretion of greater than 200 mg daily. Althoughthe term ‘‘idiopathic hypercalciuria’’ has beenused to denote elevated urinary calcium, irrespec-tive of the underlying pathophysiologic mecha-nism, hypercalciuria can be more precisely

classified according to the site of primary meta-bolic derangement, whether intestine, kidney, orbone. Accordingly, hypercalciuria can be dividedinto three distinct subtypes: (1) absorptive hyper-calciuria (AH), characterized by intestinal hyper-absorption of calcium; (2) renal hypercalciuria(RH), resulting from impaired renal tubularcalcium reabsorption; or (3) resorptive hyper-calciuria, caused by bone demineralization [14].

Although hypercalciuria is classified accordingto the site of the primary defect in calciumtransport, secondary changes can occur at othersites; that is, renal calcium leak leads to secondaryhyperparathyroidism, which results in bone re-sorption and increased intestinal calciumabsorption.

Hypercalciuria has a rich genetic predisposi-tion. Nearly half of patients who have hyper-calciuria have a family history of stone disease[15]. Although studies suggest that multiple ge-netic defects can lead to the hypercalciuric pheno-type, in some cases a single gene defect has beenimplicated [16].

Absorptive hypercalciuriaAH occurs in approximately 55% of stone

formers, and is characterized by increased in-testinal absorption of calcium [17]. The positivecalcium balance suppresses parathyroid hormone(PTH) secretion and increases the renal filteredload of calcium, leading to increased urinary cal-cium excretion. AH is classified as Type I or II, ac-cording to the response to dietary calciumrestriction. AH Type I is diet-unresponsive,

Table 1Classification of underlying conditions in calcium stone formers

Condition Metabolic/environmental defect Prevalence

HypercalciuriaAbsorptive hypercalciuria Increased GI calcium absorption 20%–40%Renal hypercalciuria Impaired renal calcium reabsorption 5%–8%Resorptive hypercalciuria Primary hyperparathyroidism 3%–5%

Hyperuricosuric calcium nephrolithiasis Dietary purine excess, uric acid overproductionor overexcretion

10%–40%

Hypocitraturic calcium nephrolithiasisChronic diarrheal syndrome GI alkali loss dDistal RTA Impaired renal tubular acid excretion dThiazide-induced Hypokalemia and intracellular acidosis 10%–50%

Hyperoxaluric calcium nephrolithiasisPrimary hyperoxaluria Genetic oxalate overproduction dDietary hyperoxaluria Excessive dietary intake 2%–15%Enteric hyperoxaluria Increased GI oxalate absorption d

Gouty diathesis Low urine pH 10%–30%

Abbreviations: GI, gastrointestinal; RTA, renal tubular acidosis.

324 PARK & PEARLE

whereas in AH Type II, urinary calcium normal-izes in response to a low calcium diet.

The pathophysiologic mechanism responsiblefor AH has not been elucidated. Vitamin D hasbeen postulated to play a pathogenetic role inintestinal calcium hyperabsorption; however, ke-toconazole-induced inhibition of vitamin D andsteroid metabolism has not produced a consistentclinical response, suggesting that vitamin D-de-pendent and independent processes may be in-volved [18]. Recently, mutations in the genecoding for a soluble form of adenylate cyclasewere identified in 40% of AH patients in whombone loss, especially of L2-4 vertebral bodies, con-tributed to the phenotype [19]. The mechanism ofaction of this protein and its role in AH has notyet been elucidated; however, together these datasuggest that AH is a complex polygenetic diseasethat requires further study.

Renal hypercalciuriaRH is caused by impaired renal tubular

reabsorption of calcium. Renal loss of calciumreduces serum calcium and secondarily stimulatesPTH secretion. Consequently, increased intestinalcalcium absorption caused by enhanced 1,25-[OH]2D synthesis and mobilization of calciumfrom bone caused by increased PTH lead to hy-percalciuria. Serum calcium remains normal be-cause the loss of calcium in the urine is o!set byenhanced intestinal calcium absorption and boneresorption. The pathogenesis of renal calciumleak is unknown. Several factors have been impli-cated in RH, including salt abuse and excessiveurinary prostaglandins [20,21]. RH is relativelyuncommon, occurring in approximately 9% ofstone formers.

Resorptive hypercalciuriaResorptive hypercalciuria is a rare cause of

stone disease that is most commonly associatedwith primary hyperparathyroidism. ExcessivePTH secretion from a parathyroid adenoma leadsto bone resorption, increased renal synthesis of1,25-[OH]2D (calcitriol), and enhanced intestinalabsorption of calcium. In a recent review of over20,000 reported cases [22], a solitary parathyroidadenoma was responsible for 89% of cases of pri-mary hyperparathyroidism; however, in 11% ofcases multiple adenomas or parathyroid carcino-mas were identified. Consequently, a neck ultra-sound and Technetium 99 m-sestamibi scan arerecommended to identify one or more abnormalglands. Post-parathyroidectomy normocalcemia

was achieved in 95% to 97% of patients in thisseries.

Other causesOther less common causes of hypercalciuria

include hypercalcemia of malignancy, sarcoidosis,hyperthyroidism, and vitamin D toxicity. Tumor-derived PTH related peptide (PTHrP) has beenshown to be the major pathogenic factor inhumoral hypercalcemia of malignancy, with de-tection of these molecules in 80% cases [23]. Todate, there have been no successful pharmacologicmeasures for suppressing the hypercalcemic e!ectsof PTHrP. A number of granulomatous diseases,including sarcoidosis, tuberculosis, and histoplas-mosis, have been reported to cause hypercalcemia,although sarcoidosis is the one most commonlyassociated with nephrolithiasis. The sarcoid gran-uloma produces 1,25-dihydroxyvitamin D3, whichcauses increased intestinal absorption of calcium,hypercalcemia, and hypercalciuria [24,25]. Sar-coidosis is suspected by clinical history (ie, historyof a persistent cough) and confirmed by measure-ment of serum vitamin D and calcitriol levels [26].This condition is e!ectively treated with cortico-steroids. Vitamin D toxicity is suspected by a his-tory of excessive vitamin D use, and is managedby restriction of vitamin D intake or limiting sun-light exposure.

Hypocitraturia

Citrate is the most abundant organic anion inhuman urine, and is a well-recognized inhibitor ofstone formation. Hypocitraturia is defined asurinary citrate excretion of less than 320 mg daily,although this is a somewhat arbitrary cuto!,because the acid-base status of the patientstrongly determines total citrate excretion. Hypo-citraturia is a well-known risk factor for calciumnephrolithiasis, and has been identified in 20% to60% of calcium stone formers [27].

The protective e!ect of citrate is threefold,arising from its bu!ering capacity, its ability tocomplex with calcium in solution, and its in-hibitory activity [28]. The bu!ering action of cit-rate is manifest during an alkali challenge, suchthat only a small rise in urinary pH occurs withan alkali load, thereby mitigating against calciumphosphate precipitation. Secondly, as an anion,citrate forms a soluble complex with calcium, re-ducing the ionic activity of calcium and decreasingurinary saturation of stone-forming calcium salts(CaOx and calcium phosphate). Finally, citrate di-rectly inhibits crystallization, aggregation, and

325PATHOPHYSIOLOGY AND MANAGEMENT OF CALCIUM STONES

agglomeration of CaOx and calcium phosphate,thereby further reducing stone formation.

Urinary citrate excretion is determined byacid-base status, and in particular, the intracellu-lar pH of renal proximal tubule cells [27]. Acidload promotes proximal tubular reabsorption ofcitrate and reduced citrate synthesis, leading tohypocitraturia, whereas alkali load reduces tubu-lar reabsorption and enhances citrate synthesis,thereby increasing urinary citrate excretion.Therefore, a logical and simple form of therapyfor hypocitraturic calcium stone formers is alkalicitrate [6].

A variety of pathologic states associated withacidosis leads to hypocitraturia. Distal renal tubu-lar acidosis (RTA) is associated with systemicacidosis, and is characterized by high urine pH(O6.8) and low serum bicarbonate and potassium[29]. Chronic diarrheal states are also associatedwith systemic acidosis because of alkali loss in thestool. Excessive animal protein provides an acidload that promotes bone loss and causes hypocitra-turia [30]. A recent study investigating the e!ects ofa high protein, low carbohydrate diet, typified bythe Atkins’ diet [31], demonstrated a significant re-duction in urine pH and citrate during both the in-duction and maintenance phases of the diet. Othercauses of acidosis associated with hypocitraturiaare thiazide-induced hypokalemia, which producesintracellular acidosis, and vigorous exercise, whichproduces lactic acidosis [32]. Finally, idiopathic hy-pocitraturia may represent an isolated abnormal-ity, unrelated to an acidotic state.

Hyperoxaluria

Hyperoxaluria is defined as urinary oxalateexcretion of greater than 40 mg daily. Hyper-oxaluria is thought to increase the risk of stoneformation by increasing urinary saturation ofCaOx. Additionally, rat studies have implicatedoxalate in crystal growth and retention by meansof renal tubular cell injury mediated by lipidperoxidation and the generation of oxygen freeradicals [33]. Human studies of normal subjectsingesting large doses of oxalate, however, havenot shown increases in markers of oxidative stressor renal injury, and consequently the role of oxa-late-induced cell membrane damage in CaOxstone formation has not been fully elucidated [34].

The e!ect of oxalate on stone formation de-pends on the interaction between calcium andoxalate that takes place in the intestine and urine.In the intestine, oxalate absorption is modulated

by dietary oxalate and the formation of a poorlyabsorbed calcium-oxalate complex. In the settingof dietary calcium restriction, calcium-oxalatecomplex formation is reduced, thereby increasingluminal free oxalate that is absorbed from theintestine and excreted in the urine. In the urine,calcium-oxalate interaction results in formation ofa soluble complex that lowers ionic oxalateconcentration. Although historically urinary oxa-late was considered a more important contributorto CaOx stone formation than urinary calcium,a recent study demonstrated that urinary oxalateand urinary calcium contribute equally to theurinary saturation of CaOx [35].

Hyperoxaluria can be associated with primarydisorders in biosynthetic pathways (primary hyper-oxaluria), malabsorptive states (enteric hyperoxa-luria), excessive dietary oxalate intake (dietaryhyperoxaluria), or high substrate levels (excessivevitamin C). Primary hyperoxaluria is caused bya rare inherited autosomal recessive disorder inglyoxalate metabolism by which the normal con-version of glyoxalate to glycine is prevented,leading to oxidative conversion of excess glyoxalateto oxalate, an end product ofmetabolism. Systemicoxalosis ensues, and leads to excretion of markedlyhigh levels of urinary oxalate, increasing urinarysaturation of CaOx and causing stone formationand nephrocalcinosis. At diagnosis, 54% of hyper-oxaluric patients have had stones and 30% havenephrocalcinosis [36]. Without treatment, end-stage renal failure occurs by age 15 years in 50%of patients, with an overall mortality of 30% [37].

Two forms of primary hyperoxaluria havebeen identified, primary hyperoxaluria type 1(PH1) and primary hyperoxaluria type 2 (PH2),which di!er in the enzyme defect responsible forthe disease (Fig. 1). In the past, liver biopsy withimmunostaining for alanine-glyoxalate amino-transferase (AGT) or glyoxalate/hydroxypyruvatereductase (GRHPR) was required to diagnose thetype 1 and type 2 forms, respectively [38]. Cur-rently, a polymerase chain reaction using a serumsample can identify the three most commonmutations in the involved genes. Indeed, onestudy reported that 66% of patients who had hy-peroxaluria were diagnosed without the need forliver biopsy [39].

The diagnosis of primary hyperoxaluria shouldbe suspected in the calcium stone-forming child,or in adults with severe hyperoxaluria (greaterthan 100 mg/day), because nephrolithiasis is themost common presenting symptom of the disease.Transplantation of the kidney or liver is generally

326 PARK & PEARLE

required in patients who have end organ failure.Although current opinion holds that simultaneousliver transplantation is required to replete theunderlying hepatic enzymatic deficiency, renaltransplantation alone was associated with an84% 6-year survival, compared with a 56% sur-vival with combined liver-kidney transplant ina study of pediatric patients [40]. This di!erence insurvival may be confounded by higher disease se-verity in the combined transplant group, alongwith the more complicated postsurgical course inpatients with two transplanted organs.

The most common cause of hyperoxaluriaamong stone formers is intestinal disease/resectionassociated with a malabsorptive state. In thesetting of fat malabsorption, saponification offatty acids with luminal calcium reduces calcium-oxalate complex formation in the gut, increasingthe pool of unbound oxalate available for absorp-tion, and ultimately leading to hyperoxaluria. Inaddition, the poorly absorbed fatty acids and bilesalts are thought to increase colonic permeabilityto oxalate, further enhancing oxalate absorptionand urinary excretion [41]. Other urinary stonerisk factors associated with malabsorptive statesinclude low urine volume caused by dehydration,low urinary pH as a result of bicarbonate loss in

stool, hypocitraturia from metabolic acidosis,and low urinary magnesium from poor absorp-tion. Any condition associated with malabsorp-tion and chronic diarrhea may be associatedwith hyperoxaluria, including intestinal resection,inflammatory bowel disease, and celiac sprue.

A concerning and potentially increasing causeof enteric hyperoxaluria is bariatric surgical pro-cedures. The rise in the prevalence of obesity inNorth America led to a sixfold increase inbariatric surgery procedures between 1990 and2000 [42]. Jejunoileal bypass surgery, popularizedin the 1970s, was associated with a 39% rate ofnew stone occurrence during a 16-year mean fol-low-up in one study [43]. Urine collections in thesepatients demonstrated profound hyperoxaluria(mean 111 mg/day) and hypocitraturia (148 mg/day). Consequently, this operation was aban-doned because of the high risk of kidney stones,and in some cases, renal failure. Since then,many patients who had recalcitrant, frequentstones and profound hyperoxaluria or hypocitra-turia have undergone jejunoileal bypass reversal.Dhar and colleagues [44] showed that after surgi-cal reversal, hyperoxaluria resolved (with urinaryoxalate dropping from 112.5 mg pre-reversal to33.8 mg/day post-reversal), although mild

Glyoxalate

Oxalate

Glyoxalate

Oxalate

Glycolate Glycolate

Glycine

AGT

[PH Type 1]

LDH

GO

GO

LDH

GRHPR

[PH Type 2]

Ascorbic

Acid

Glycine

B6

PEROXISOME CYTOSOL

Fig. 1. Oxalate biosynthetic pathway. Type 1 primary hyperoxaluria is caused by a deficiency in peroxisomal alanineglyoxalate aminotransferase. Type 2 primary hyperoxaluria is caused by a defect in cytosolic glyoxalate reductase/hy-droxypyruvate reductase. AGT, alanine-glyoxalate aminotransferase; GHPHR, glyoxalate reductase-hydroxypyruvatereductase, GO, glycolate oxidase; LDH, lactate dehydrogenase.

327PATHOPHYSIOLOGY AND MANAGEMENT OF CALCIUM STONES

hypocitraturia persisted (22 mg/day pre-reversaland 227 mg/day post-reversal), albeit at levelsamenable to oral alkali citrate therapy.

More recently, Roux-en-Y gastric bypass sur-gery or various forms of gastric banding havebecome the bariatric operations of choice. Asplinand Coe [45] collected 24-hour urine specimensfrom 132 gastric bypass patients, and found sig-nificantly higher urinary oxalate levels (83 ! 2mg/day) in this group of patients compared withcontrol groups of either unselected calcium stoneformers or non-stone formers (39 mg ! 2 mgand 34 mg ! 1 mg, respectively; P ! .001 forboth comparisons); however, oxalate levels werenot quite as high as those seen in jejunoileal by-pass patients (102 mg ! 4 mg/day). Severe hyper-oxaluria (O100 mg/day) was identified in 23%of bypass patients, compared with 0.5% of unse-lected stone formers. CaOx supersaturation, thedriving force for kidney stone formation, washigher in gastric bypass patients (12.1 ! 0.5 mg)than in unselected stone formers (9.0 ! 0.1 mg),non-stone formers (7.4 ! 0.8 mg), and jejunoilealbypass patients (8.9 ! 1.1 mg).

In a sobering study, Nelson and associates [46]identified 23 patients who had enteric hyperoxalu-ria after gastric bypass surgery, manifest by eitheroxalate nephropathy or the formation of CaOxstones. Indeed, 2 patients ultimately required he-modialysis. With the exponential increase in bari-atric surgery for the treatment of morbid obesity,we are likely to see a rise in the incidence of hyper-oxaluria and CaOx stone formation. With longerfollow-up of patients undergoing Roux-en-Y gas-tric bypass or gastric banding, a better under-standing of the associated urinary derangementsand their treatment will become possible.

Hyperoxaluria in the absence of intestinaldisease can occur from excessive dietary intakeof oxalate-rich foods such as nuts, chocolate,brewed tea, spinach, and rhubarb. Severe calciumrestriction may reduce intestinal oxalate binding,thereby increasing intestinal oxalate absorption.Excessive vitamin C intake has also been shown toincrease oxalate excretion by in vivo conversion ofascorbate to oxalate [47]; however, observationalstudies of two large cohorts did not demonstratean increased incidence of stone disease amongsubjects consuming the highest amounts of vita-min C [48,49].

Oxalate-degrading bacteria such as Oxalo-bacter formigenes have been shown to colonizethe intestine of normal individuals, and may re-duce intestinal oxalate. Absence of these bacteria

has been linked to increased urinary oxalate levels[50] and higher rates of stone formation in stoneformers [51]. The contribution of oxalate-degrad-ing bacteria to CaOx stone formation has notbeen fully elucidated.

Hyperuricosuria

Hyperuricosuria can lead to CaOx stone for-mation by heterologous nucleation on the surfaceof monosodium urate crystals [52]. Hyperuricosu-ria is defined as urinary uric acid exceeding 600mg daily. The most common cause of hyperurico-suria is increased dietary purine intake, becauseuric acid is the end product of purine metabolism.Numerous other acquired and hereditary diseasescan lead to hyperuricosuria, however, includinggout, myelo- and lymphoproliferative disorders,multiple myeloma, hemolytic disorders, andhemoglobinopathies.

The pathophysiology of hyperuricosuric CaOxnephrolithiasis is intimately related to urinary pH.At pH less than 5.5, poorly soluble undissociateduric acid precipitates, leading to uric acid or CaOxstone formation. At pH greater than 5.5, uric acidis found predominantly in its dissociated form,increasing urinary saturation of monosodiumurate and promoting CaOx stone formationthrough heterogeneous nucleation [53]. Further-more, monosodium urate has been shown tobind to urinary inhibitors, thereby reducing uri-nary inhibitory activity and indirectly promotingCaOx crystallization [54].

Gouty diathesis

Gouty diathesis refers to uric acid stone forma-tion associated with primary gout [55]. The invari-ant feature of this disorder is low urine pH, whichpromotes the precipitation of the sparingly solu-ble, undissociated form of uric acid, leading touric acid stone formation. Gouty diathesis is alsoa risk factor for CaOx stone formation, however.Although uric acid, which is favored at low pH,is not as e"cient as monosodium urate in promot-ing CaOx stone formation, it too leads to CaOxcrystallization by way of heterogeneous nucle-ation. Although the etiology of low urine pH inthese stone formers has not been fully elucidated,an association has recently been established be-tween uric acid stone formation and non–insulin-dependent diabetes [56]. Insulin resistance, thecause of non-insulin diabetes, has been shown toimpair renal ammoniagenesis, which in turn re-duces urinary ammonium and lowers urine pH.

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Treatment

Dietary modification

Hosking and colleagues [57] coined the term‘‘stone clinic e!ect’’ to describe the reduction instone formation seen with dietary measures alone.Dietary modification can reduce urinary excretionof stone constituents or increase urinary inhibi-tors. In low-risk stone formers, dietary measuresalone may be su"cient to prevent stone recurrencewithout the need for drug therapy; however, die-tary modification should always accompany drugtherapy in patients who have more severe disease.A number of dietary factors have been shown toinfluence stone formation, including fluids, so-dium, animal protein, calcium, and oxalate.

FluidsA high fluid intake reduces urinary saturation

of stone-forming calcium salts and dilutes pro-moters of CaOx crystallization. In two largeobservational studies, a high fluid intake wasinversely related to risk of kidney stone formation[58,59]. Furthermore, a prospective, randomizedtrial assessing the e!ect of a high fluid intake[60] showed a 55% reduction in stone recurrencerates in the group adhering to a high fluid intakecompared with the control group, who receivedno specific recommendations. In general, patientsare recommended to consume enough fluid tomaintain a urine output of at least 2 L daily.The fluid intake required to produce the targeturine volume varies according to the activity levelof the patient and the weather.

Not all beverages are comparable with regardto their beneficial e!ect. Alcoholic beverages,co!ee, and tea were shown in observation studiesto reduce the risk of stone formation [61,62]. In-terestingly, grapefruit juice was shown in thesesame studies to be associated with a 40% higherrisk of stone formation. This finding is counterin-tuitive, because citrus fruits have been thought tobe beneficial in preventing stone formation as a re-sult of their high citrate content. Although no ran-domized clinical trials have evaluated the e!ect ofspecific fruit juices on rates of incident or recur-rent stone formation, a number of metabolic stud-ies have investigated the e!ect of citrus fruit juiceson urinary stone risk factors. The key factor in thee!ect of citrus juices on stone-forming risk is thecation accompanying the citrate, which determinesthe net alkali load delivered, and subsequently theurinary pH and citraturic response. Citrate isalmost completely metabolized to bicarbonate.

If the accompanying cation is hydrogen ion, thealkalinizing e!ect of citrate is neutralized. Potas-sium-rich fruit juices such as orange juice [63],but not potassium-poor juices, like cranberry juice[64], provide organic anions that are metabolizedto alkali, thereby increasing urinary pH andcitrate. Although lemonade, which is replete withcitric acid was shown in one metabolic studyof subjects on a random diet to increase urinarycitrate [65], another study in which subjects weremaintained on a controlled metabolic diet [66]showed no increase in urine pH or citrate withlemonade consumption. Grapefruit juice, whichhas a high potassium content, was shown toincrease urinary citrate, but the e!ect on urinarysaturation of CaOx was o!set by a concomitantincrease in urinary oxalate, such that overall therewas no change in the relative saturation of CaOxbetween the control and grapefruit phases ofstudy.

SodiumA high salt intake increases stone risk by

reducing renal tubular calcium reabsorption andincreasing urinary calcium. In addition, highurinary sodium increases urinary saturation ofmonosodium urate, and reduces urinary citratevia sodium-induced bicarbonate loss. Conse-quently, inhibitory activity against CaOx andcalcium phosphate is reduced, monosodiumurate-induced CaOx crystallization is enhanced,and urinary saturation of CaOx and calciumphosphate is increased. Furthermore, high urinarysodium reduces the e"cacy of thiazide treatmentfor hypercalciuria by blunting the hypocalciurice!ect. The benefit of concomitant restriction ofsalt and animal protein in reducing urinarycalcium was demonstrated in a randomized trial[67]. In general, salt intake should be limited to2000 to 3000 mg daily.

Animal proteinAnimal protein provides an acid load because

of the high content of sulfur-containing aminoacids. As such, a high protein intake reduces urinepH and citrate and enhances urinary calciumexcretion via bone resorption and reduced renalcalcium reabsorption [68]. Additionally, the pu-rine load potentially increases urinary uric acid,and increases the risk of CaOx stone formation.

Observational studies have shown a positivecorrelation between animal protein consumptionand new stone formation in men but not women[58,59]. Interestingly, a randomized trial

329PATHOPHYSIOLOGY AND MANAGEMENT OF CALCIUM STONES

comparing a low animal protein, high fiber, highfluid intake with a high fluid intake alone ina group of first-time CaOx stone formers showeda higher rate of stone formation in the low proteingroup compared with the control group [69]. Thecontrol group instructed on a high fluid intakealone had a higher urinary volume than the studygroup, however, which could have confounded re-sults. In contrast, Borghi and colleagues [67] dem-onstrated a lower rate of stone formation inhypercalciuric stone formers maintained on a nor-mal calcium, low protein, low sodium diet com-pared with subjects maintained on a high fluiddiet alone. Restriction of animal protein (redmeat, fish, poultry) to no more than two servingsdaily is recommended.

CalciumTraditionally, calcium restriction has been

recommended to reduce urinary calcium andurinary saturation of CaOx; however, two largecohort studies [58,59] and a randomized trial [67]showed a protective e!ect of a high/normal cal-cium intake against incident/recurrent stone for-mation. The protective e!ect of a high calciumintake in both studies was attributed to the declinein urinary oxalate that results from reduced intes-tinal oxalate absorption in the face of increasedluminal calcium-oxalate complex formation.However, urinary oxalate levels depend on dietarycalcium and oxalate intake and the state of intes-tinal calcium absorption. By concomitantly re-stricting calcium and oxalate in the diet, the risein urinary oxalate associated with dietary calciumrestriction can averted [70]. Indeed, a retrospectivestudy of a large number of calcium stone formers[71] demonstrated that a short-term program ofbroad dietary modification, including both cal-cium and oxalate restriction, resulted in a signifi-cant decline in urinary calcium in hypercalciuricpatients, without a change in urinary oxalate. Ina long-term retrospective study of 28 hypercalciu-ric calcium stone formers, dietary calcium and ox-alate restriction, along with a thiazide diuretic andpotassium citrate, reduced urinary calcium with-out raising urinary oxalate, and reduced urinarysaturation of CaOx and stone formation [72].Thus, hypercalciuric patients may be optimallytreated with a program of modest calcium and ox-alate restriction, along with pharmacologic ther-apy. Severe calcium restriction should be alwaysbe avoided so as to prevent a negative calciumbalance; however, mild calcium restriction to noless than one serving of dairy daily should be

part of a program of broad dietary modificationin patients who have hypercalciuria.

Normocalciuric patients, on the other hand, donot benefit from dietary calcium restriction, andtherefore a liberal calcium intake is recommendedin this group of patients [71].

OxalateThe relative contribution of dietary oxalate

and endogenous oxalate production to urinaryoxalate is controversial. Dietary oxalate has beenestimated to account for 10% to 50% of urinaryoxalate, depending on dietary calcium and oxalateintake and the bioavailability of oxalate in foods[34]. CaOx stone formers who have mild hyperox-aluria have been shown to have increased intesti-nal absorption and renal excretion of oxalate,which may account for their increased risk ofstone formation [73]. In general, restriction of ox-alate-rich foods, such as nuts, chocolate, tea, anddark roughage is recommended.

Vitamin C has been implicated in calciumstone formation because of in vivo conversion ofascorbic acid to oxalate. A metabolic trial dem-onstrated a 20% to 33% increase in urinaryoxalate with the consumption of 2 g of vitaminC daily. Likewise, a large male cohort studyshowed a 41% increased risk of stone formationin men consuming 1 g or more of vitamin C dailycompared with those consuming less than 90 mgdaily [74]. As such, limitation of vitamin C supple-ments to 500 mg or less daily is recommended.

Drug therapy

For those patients in whom conservative di-etary measures fail or those who have moreaggressive stone disease or identifiable metabolicabnormalities, pharmacologic therapy, along withdietary measures, should be initiated. Drug ther-apies aimed at correcting underlying metabolicderangements can reduce the likelihood of re-current stone formation. In some cases, medicaltherapies are initiated empirically, without regardto the metabolic background of the patient. Thebenefit of targeted versus empiric medical therapyhas never been formally addressed; however, forthe purposes of this discussion, drug therapies arereviewed with respect to the abnormalities theyare targeted to correct.

Thiazide diureticsThiazide diuretics are reserved for patients

who have severe hypercalciuria (urinary calciumO275 mg/day) or for patients who have mild

330 PARK & PEARLE

hypercalciuria and reduced bone mineral density.The hypocalciuric action of thiazides is attributedto enhanced calcium reabsorption in the distalrenal tubule. In addition, thiazide-induced extra-cellular sodium depletion promotes sodium andcalcium reabsorption in the proximal renal tubule,further reducing urinary calcium. As such, a highsodium intake can attenuate the hypocalciuricaction of thiazide diuretics.

The recommended dosages of commonly usedthiazide diuretics for a normal sized adult arehydrochlorothiazide 25 mg twice daily or chlor-thalidone 25 to 50 mg daily. An alternative, non-thiazide diuretic, indapamide (1.25–2.5 mg daily),has a similar mechanism of action to thiazides andhas been shown in a randomized trial be e!ectivein reducing stone recurrence [7]. The use of thia-zides may be limited in 30% to 50% of patientsby side e!ects, including fatigue, dizziness, impo-tence, musculoskeletal symptoms, or gastrointesti-nal complaints. Because thiazides can depleteserum potassium, the addition of a potassium sup-plement is recommended. Thiazide-induced hypo-kalemia can also lead to intracellular acidosis andhypocitraturia, and therefore the use of potassiumcitrate (10–20 mEq twice daily) can prevent bothhypokalemia and hypocitraturia.

A number of randomized trials have demon-strated a benefit of thiazide diuretics and indapa-mide in reducing the rate of stone recurrence incalcium stone formers [7,75–78]. Interestingly, insome of these trials, thiazides were successfullyused unselectively, without regard to urinary cal-cium levels [7,75]. In a meta-analysis of random-ized medical therapy trials [11], a 21% riskreduction in stone recurrence rates was demon-strated with the initiation of thiazides orindapamide.

Potassium citratePotassium citrate is e!ective in the treatment

of patients who have calcium stones and normalurinary calcium. By providing an alkali load,potassium citrate increases urinary pH and cit-rate, thereby increasing urinary inhibitory activ-ity, and perhaps reducing urinary calcium. Ina randomized trial, potassium citrate was shownto reduce stone recurrence rates by 75% amonghypocitraturic stone formers [6].

In patients who have gouty diathesis, potas-sium citrate raises urinary pH and reduces uricacid-induced CaOx stone formation. For patientswho have hyperuricosuric CaOx nephrolithiasisand who are unable to tolerate allopurinol,

potassium citrate therapy has been shown to bee!ective in reducing stone recurrence rates [79].

Potassium citrate is prescribed at a startingdose of 10 mEq three times daily, or 20 mEq twicedaily. Potassium citrate can be used for treatmentof patients who have hypocitraturia, or fornormocalciuric calcium stone formers regardlessof other associated abnormalities. In patients whohave hypercalciuria, potassium citrate is pre-scribed along with a thiazide diuretic or indapa-mide to prevent thiazide-induced hypokalemiaand hypocitraturia.

For patients who have enteric hyperoxaluria,potassium citrate therapy can raise urine pH andcitrate; however, dosages higher than those usedfor idiopathic calcium nephrolithiasis (up to 120mEq daily) may be required. Furthermore, be-cause of the rapid intestinal transit associated withchronic diarrheal syndromes, a liquid form ofpotassium citrate may be better absorbed.

AllopurinolIn calcium stone formers who have moderate

to severe hyperuricosuria and in whom dietarymodification fails, allopurinol has been shown toreduce urinary uric acid levels and prevent re-current stone formation [80]. Allopurinol is a xan-thine oxidase inhibitor that prevents theconversion of hypoxanthine to xanthine, the pre-cursor of uric acid. The medication is generallywell-tolerated, and side e!ects are limited to irre-versible liver enzyme elevation and skin rash. Be-cause of a risk of progression to Stevens-Johnsonsyndrome, report of a skin rash with allopurinolshould prompt immediate cessation of the drug.

PyridoxineVitamin B6, or pyridoxine, promotes the

conversion of glyoxalate to glycine, thereby re-ducing the substrate for oxalate production [81].Pyridoxine (100 to 400 mg daily) is most oftenused for the treatment of primary hyperoxaluria.Because the elevated urinary oxalate levels associ-ated with enteric hyperoxaluria are derived pri-marily from intestinal oxalate hyperabsorption,reduction of endogenous oxalate production bypyridoxine is likely to be of limited value. In thesepatients, a regimen of dietary oxalate restriction,potassium citrate therapy, and calcium supple-mentation is e!ective in reducing urinary oxalate,correcting the metabolic acidosis and hypocitratu-ria, and restoring normal calcium balance.

331PATHOPHYSIOLOGY AND MANAGEMENT OF CALCIUM STONES

Summary

Calcium-containing stones are the most fre-quent stone type identified. The pathophysiologyof calcium stone formation is complex and oftenmultifactorial; however, systematic identificationof underlying metabolic abnormalities and theinitiation of dietary and pharmacologic prophy-lactic regimens can successfully correct stone riskfactors and reduce the likelihood of stonerecurrence.

References

[1] Clark JY, Thompson IM, Optenberg SA. Economicimpact of urolithiasis in the United States. J Urol1995;154(6):2020–4.

[2] Pak CY. Kidney stones. Lancet 1998;351(9118):1797–801.

[3] Preminger GM.Renal calculi: pathogenesis, diagno-sis, and medical therapy. Semin Nephrol 1992;12(2):200–16.

[4] Sierakowski R, Finlayson B, Landes RR, et al. Thefrequency of urolithiasis in hospital discharge diag-noses in the United States. Invest Urol 1978;15(6):438–41.

[5] Jungers P, Joly D, Barbey F, et al. ESRD caused bynephrolithiasis: prevalence, mechanisms, and pre-vention. Am J Kidney Dis 2004;44(5):799–805.

[6] Barcelo P, Wuhl O, Servitge E, et al. Randomizeddouble-blind study of potassium citrate in idiopathichypocitraturic calcium nephrolithiasis. J Urol 1993;150(6):1761–4.

[7] Borghi L, Meschi T, Guerra A, et al. Randomizedprospective study of a nonthiazide diuretic, indapa-mide, in preventing calcium stone recurrences. J Car-diovasc Pharmacol 1993;22(Suppl 6):S78–86.

[8] Pak CY, Poindexter JR, Adams-Huet B, et al. Pre-dictive value of kidney stone composition in the de-tection of metabolic abnormalities. Am J Med 2003;115(1):26–32.

[9] Pak CY. Etiology and treatment of urolithiasis. AmJ Kidney Dis 1991;18(6):624–37.

[10] Mandel NS, Mandel GS. Urinary tract stone diseasein the United States veteran population. II. Geo-graphical analysis of variations in composition.J Urol 1989;142(6):1516–21.

[11] Pearle MS, Roehrborn CG, Pak CY. Meta-analysisof randomized trials for medical prevention of cal-cium oxalate nephrolithiasis. J Endourol 1999;13(9):679–85.

[12] Kim SC, Coe FL, Tinmouth WW, et al. Stone for-mation is proportional to papillary surface coverageby Randall’s plaque. J Urol 2005;173(1):117–9.

[13] Kuo RL, Lingeman JE, Evan AP, et al. Urine cal-cium and volume predict coverage of renal papillaby Randall’s plaque. Kidney Int 2003;64(6):2150–4.

[14] Pak CY, OataM, Lawrence EC, et al. The hypercal-ciurias. Causes, parathyroid functions, and diagnos-tic criteria. J Clin Invest 1974;54(2):387–400.

[15] Coe FL, Parks JH, Moore ES. Familial idiopathichypercalciuria. N Engl J Med 1979;300(7):337–40.

[16] Moe OW, Bonny O. Genetic hypercalciuria. J AmSoc Nephrol 2005;16(3):729–45.

[17] Pak CY, Britton F, Peterson R, et al. Ambulatoryevaluation of nephrolithiasis. Classification, clinicalpresentation and diagnostic criteria. Am J Med1980;69(1):19–30.

[18] Breslau NA, Preminger GM, Adams BV, et al. Useof ketoconazole to probe the pathogenetic impor-tance of 1,25-dihydroxyvitamin D in absorptivehypercalciuria. J Clin Endocrinol Metab 1992;75(6):1446–52.

[19] Reed BY, Gitomer WL, Heller HJ, et al. Identifica-tion and characterization of a gene with base substi-tutions associated with the absorptive hypercalciuriaphenotype and low spinal bone density. J Clin Endo-crinol Metab 2002;87(4):1476–85.

[20] Breslau NA, McGuire JL, Zerwekh JE, et al. Therole of dietary sodium on renal excretion and intesti-nal absorption of calcium and on vitamin D metab-olism. J Clin Endocrinol Metab 1982;55(2):369–73.

[21] Cirillo M, Ciacci C, Laurenzi M, et al. Salt intake,urinary sodium, and hypercalciuria. Miner Electro-lyte Metab 1997;23(3–6):265–8.

[22] Ruda JM, Hollenbeak CS, Stack BC Jr. A system-atic review of the diagnosis and treatment of primaryhyperparathyroidism from 1995 to 2003. Otolaryng-ol Head Neck Surg 2005;132(3):359–72.

[23] Chattopadhyay N. E!ects of calcium-sensing recep-tor on the secretion of parathyroid hormone-relatedpeptide and its impact on humoral hypercalcemia ofmalignancy. Am J Physiol Endocrinol Metab 2006;290(5):E761–70.

[24] Bell NH, Stern PH, Pantzer E, et al. Evidence thatincreased circulating 1 alpha, 25-dihydroxyvitaminD is the probable cause for abnormal calciummetabolism in sarcoidosis. J Clin Invest 1979;64(1):218–25.

[25] Hendrix JZ. Abnormal skeletal mineral metabolismin sarcoidosis. Ann Intern Med 1966;64(4):797–805.

[26] Adams JS. Vitamin D metabolite-mediated hyper-calcemia. Endocrinol Metab Clin North Am 1989;18(3):765–78.

[27] Hamm LL, Hering-Smith KS. Pathophysiology ofhypocitraturic nephrolithiasis. Endocrinol MetabClin North Am 2002;31(4):885–93, viii.

[28] Pak CY. Citrate and renal calculi: an update. MinerElectrolyte Metab 1994;20(6):371–7.

[29] Laing CM, Toye AM, Capasso G, et al. Renal tubu-lar acidosis: developments in our understanding ofthe molecular basis. Int J Biochem Cell Biol 2005;37(6):1151–61.

[30] Amanzadeh J, Gitomer WL, Zerwekh JE, et al. Ef-fect of high protein diet on stone-forming propensityand bone loss in rats. Kidney Int 2003;64(6):2142–9.

332 PARK & PEARLE

[31] Reddy ST, Wang CY, Sakhaee K, et al. E!ect oflow-carbohydrate high-protein diets on acid-basebalance, stone-forming propensity, and calcium me-tabolism. Am J Kidney Dis 2002;40(2):265–74.

[32] Sakhaee K, Nigam S, Snell P, et al. Assessment ofthe pathogenetic role of physical exercise in renalstone formation. J Clin Endocrinol Metab 1987;65(5):974–9.

[33] Ravichandran V, Selvam R. Increased lipid peroxi-dation in kidney of vitamin B-6 deficient rats. Bio-chem Int 1990;21(4):599–605.

[34] Holmes RP, Assimos DG. The impact of dietaryoxalate on kidney stone formation. Urol Res 2004;32(5):311–6.

[35] Pak CY, Adams-Huet B, Poindexter JR, et al. Rapidcommunication: relative e!ect of urinary calciumand oxalate on saturation of calcium oxalate. Kid-ney Int 2004;66(5):2032–7.

[36] Hoppe B, Langman CB. A United States survey ondiagnosis, treatment, and outcome of primaryhyperoxaluria. Pediatr Nephrol 2003;18(10):986–91.

[37] Cochat P, Gaulier JM, Koch Nogueira PC, et al.Combined liver-kidney transplantation in primaryhyperoxaluria type 1. Eur J Pediatr 1999;158(Suppl2):S75–80.

[38] Milliner DS,Wilson DM, Smith LH. Phenotypic ex-pression of primary hyperoxaluria: comparative fea-tures of types I and II. Kidney Int 2001;59(1):31–6.

[39] Rumsby G,Williams E, Coulter-MackieM. Evalua-tion of mutation screening as a first line test for thediagnosis of the primary hyperoxalurias. KidneyInt 2004;66(3):959–63.

[40] Saborio P, Scheinman JI. Transplantation for pri-mary hyperoxaluria in the United States. KidneyInt 1999;56(3):1094–100.

[41] Dobbins JW, Binder HJ. E!ect of bile salts and fattyacids on the colonic absorption of oxalate. Gastro-enterology 1976;70(6):1096–100.

[42] Trus TL, Pope GD, Finlayson SR. National trendsin utilization and outcomes of bariatric surgery.Surg Endosc 2005;19(5):616–20.

[43] Annuk M, Backman U, Holmgren K, et al. Urinarycalculi and jejunoileal bypass operation.A long-termfollow-up. Scand J Urol Nephrol 1998;32(3):177–80.

[44] Dhar NB, Grundfest S, Jones JS, et al. Jejunoilealbypass reversal: e!ect on renal function, metabolicparameters and stone formation. J Urol 2005;174(5):1844–6.

[45] Asplin J, Coe F. Hyperoxaluria in bariatric surgerypatients with urolithiasis. J Urol 2006;175(Suppl):334–5.

[46] Nelson WK, Houghton SG, Milliner DS, et al. En-teric hyperoxaluria, nephrolithiasis, and oxalate ne-phropathy: potentially serious and unappreciatedcomplications of Roux-en-Y gastric bypass. SurgObes Relat Dis 2005;1(5):481–5.

[47] Traxer O, Huet B, Poindexter J, et al. E!ect of ascor-bic acid consumption on urinary stone risk factors.J Urol 2003;170(2 Pt 1):397–401.

[48] Curhan GC, Willett WC, Rimm EB, et al. A pro-spective study of the intake of vitamins C and B6,and the risk of kidney stones in men. J Urol 1996;155(6):1847–51.

[49] Curhan GC, Willett WC, Speizer FE, et al. Intakeof vitamins B6 and C and the risk of kidneystones in women. J Am Soc Nephrol 1999;10(4):840–5.

[50] Troxel SA, Sidhu H, Kaul P, et al. Intestinal oxalo-bacter formigenes colonization in calcium oxalatestone formers and its relation to urinary oxalate.J Endourol 2003;17(3):173–6.

[51] Mikami K, Akakura K, Takei K, et al. Associationof absence of intestinal oxalate degrading bacteriawith urinary calcium oxalate stone formation. Int JUrol 2003;10(6):293–6.

[52] Grover PK, Marshall VR, Ryall RL. Dissolvedurate salts out calcium oxalate in undiluted humanurine in vitro: implications for calcium oxalate stonegenesis. Chem Biol 2003;10(3):271–8.

[53] Grover PK, Ryall RL. Urate and calcium oxalatestones: from repute to rhetoric to reality. MinerElectrolyte Metab 1994;20(6):361–70.

[54] Pak CY, Holt K, Zerwekh JE. Attenuation bymonosodium urate of the inhibitory e!ect of glycos-aminoglycans on calcium oxalate nucleation. InvestUrol 1979;17(2):138–40.

[55] Levy FL, Adams-Huet B, Pak CY. Ambulatoryevaluation of nephrolithiasis: an update of a 1980protocol. Am J Med 1995;98(1):50–9.

[56] Maalouf NM, Cameron MA,Moe OW, et al. Novelinsights into the pathogenesis of uric acid nephroli-thiasis. Curr Opin Nephrol Hypertens 2004;13(2):181–9.

[57] Hosking DH, Erickson SB, Van den Berg CJ, et al.The stone clinic e!ect in patients with idiopathic cal-cium urolithiasis. J Urol 1983;130(6):1115–8.

[58] Curhan GC, Willett WC, Rimm EB, et al. A pro-spective study of dietary calcium and other nutrientsand the risk of symptomatic kidney stones. N EnglJ Med 1993;328(12):833–8.

[59] Curhan GC,Willett WC, Speizer FE, et al. Compar-ison of dietary calcium with supplemental calciumand other nutrients as factors a!ecting the risk forkidney stones in women. Ann Intern Med 1997;126(7):497–504.

[60] Borghi L, Meschi T, Amato F, et al. Urinary vol-ume, water and recurrences in idiopathic calciumnephrolithiasis: a 5-year randomized prospectivestudy. J Urol 1996;155(3):839–43.

[61] Curhan GC, Willett WC, Rimm EB, et al. Prospec-tive study of beverage use and the risk of kidneystones. Am J Epidemiol 1996;143(3):240–7.

[62] Curhan GC,Willett WC, Speizer FE, et al. Beverageuse and risk for kidney stones in women. Ann InternMed 1998;128(7):534–40.

[63] Wabner CL, Pak CY. E!ect of orange juice con-sumption on urinary stone risk factors. J Urol1993;149(6):1405–8.

333PATHOPHYSIOLOGY AND MANAGEMENT OF CALCIUM STONES

[64] Gettman MT, Ogan K, Brinkley LJ, et al. E!ect ofcranberry juice consumption on urinary stone riskfactors. J Urol 2005;174(2):590–4.

[65] Seltzer MA, Low RK, McDonald M, et al. Dietarymanipulation with lemonade to treat hypocitraturiccalcium nephrolithiasis. J Urol 1996;156(3):907–9.

[66] Goldfarb DS, Fischer ME, Keich Y, et al. A twinstudy of genetic and dietary influences on nephroli-thiasis: a report from the Vietnam Era Twin (VET)Registry. Kidney Int 2005;67(3):1053–61.

[67] Borghi L, Schianchi T, Meschi T, et al. Comparisonof two diets for the prevention of recurrent stones inidiopathic hypercalciuria. N Engl J Med 2002;346(2):77–84.

[68] Fellstrom B, Danielson BG, Karlstrom B, et al. Ef-fects of high intake of dietary animal protein onmineral metabolism and urinary supersaturation ofcalcium oxalate in renal stone formers. Br J Urol1984;56(3):263–9.

[69] Hiatt RA, Ettinger B, Caan B, et al. Randomizedcontrolled trial of a low animal protein, high fiberdiet in the prevention of recurrent calcium oxalatekidney stones. Am J Epidemiol 1996;144(1):25–33.

[70] Heller HJ, Doerner MF, Brinkley LJ, et al. E!ect ofdietary calcium on stone forming propensity. J Urol2003;169(2):470–4.

[71] Pak CY, Heller HJ, Pearle MS, et al. Prevention ofstone formation and bone loss in absorptive hyper-calciuria by combined dietary and pharmacologicalinterventions. J Urol 2003;169(2):465–9.

[72] Pak CY, Odvina CV, Pearle MS, et al. E!ect ofdietary modification on urinary stone risk factors.Kidney Int 2005;68(5):2264–73.

[73] Krishnamurthy MS, Hruska KA, Chandhoke PS.The urinary response to an oral oxalate load inrecurrent calcium stone formers. J Urol 2003;169(6):2030–3.

[74] Taylor EN, Stampfer MJ, Curhan GC. Dietary fac-tors and the risk of incident kidney stones in men:new insights after 14 years of follow-up. J Am SocNephrol 2004;15(12):3225–32.

[75] Ohkawa M, Tokunaga S, Nakashima T, et al. Thia-zide treatment for calcium urolithiasis in patientswith idiopathic hypercalciuria. Br J Urol 1992;69(6):571–6.

[76] Laerum E, Larsen S. Thiazide prophylaxis ofurolithiasis. A double-blind study in generalpractice. Acta Med Scand 1984;215(4):383–9.

[77] Ettinger B, Citron JT, Livermore B, et al. Chlortha-lidone reduces calcium oxalate calculous recurrencebut magnesium hydroxide does not. J Urol 1988;139(4):679–84.

[78] Wilson DR, Strauss AL, Manuel MA. Comparisonof medical treatments for the prevention of recurrentcalcium nephrolithiasis. Urol Res 1984;12:39.

[79] Pak CY, Peterson R. Successful treatment ofhyperuricosuric calcium oxalate nephrolithiasiswith potassium citrate. Arch Intern Med 1986;146(5):863–7.

[80] Ettinger B, Tang A, Citron JT, et al. Randomizedtrial of allopurinol in the prevention of calciumoxalate calculi. N Engl J Med 1986;315(22):1386–9.

[81] Milliner DS, Eickholt JT, Bergstralh EJ, et al. Re-sults of long-term treatment with orthophosphateand pyridoxine in patients with primary hyperoxalu-ria. N Engl J Med 1994;331(23):1553–8.

334 PARK & PEARLE