dietary and medical management of recurrent nephrolithiasis

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EDUCATIONAL OBJECTIVE:Readers will apply interventions to reduce the risk of recurrent nephrolithiasis

Dietary and medical managementof recurrent nephrolithiasis

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 NUMBER 6 JUNE 2016 463

N and often re-curs. This review focuses on measures to

prevent recurrent stone formation. Some mea-sures apply to all patients, and some apply to

specic types of stones.

COMMON AND INCREASING

According to data from the 20072010 Na-tional Health and Nutrition Examination Sur-vey, the prevalence of nephrolithiasis in theUnited States was 10.6% in men and 7.1% inwomen. On average, 1 in 11 Americans willdevelop kidney stones at least once in theirlifetime.1

By race and sex, white men have the high-est incidence of nephrolithiasis and Asianwomen have the lowest. It is less common be-fore age 20 and peaks in incidence in the thirdand fourth decades of life.

The prevalence has steadily increased inthe past few decades (Table 1),1,2but the rea-sons are not clear. The trend may be due tochanges in diet and lifestyle, increasing preva-lence of obesity and diabetes, migration fromrural to urban areas, and global warming, withhigher temperature resulting in dehydrationand high urinary concentration of calciumand other stone-forming salts.3 Nephrolithi-asis is now recognized as a systemic disorder as-

sociated with chronic kidney disease, bone lossand fractures, increased risk of coronary arterydisease, hypertension, type 2 diabetes mellitus,and metabolic syndrome (Table 2).47

Without medical treatment, the 5-yearrecurrence rate is high, ranging from 35%to 50% after an initial stone event.8Annualmedical costs of care for kidney stones in theUnited States exceed $4.5 billion, with addi-tional costs from missed work. Therefore, this

REVIEW

doi:10.3949/ccjm.83a.15089

ABSTRACT

Dietary approaches and medical treatment can preventrecurrence of urinary stones. Some interventions are ap-

propriate for all types of stones, but there are particularrisk factors that may need directed therapy.

KEY POINTS

Nephrolithiasis is common and widespread, and its inci-dence and prevalence are increasing.

Calcium stones are the most common type, and of these,calcium oxalate stones predominate.

The most common risk factors for recurrent calciumstones are low urinary output, hypercalciuria, hyperoxal-

uria, hypocitraturia, and hyperuricosuria.

Less common types of stones are usually associated withgenetic abnormalities, infections, or medications.

SILVI SHAH, MDDepartment of Nephrology,University of Alabama at Birmingham

JUAN CAMILO CALLE, MDDepartment of Nephrology and Hypertension,Glickman Urological & Kidney Institute,Cleveland Clinic


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464 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 NUMBER 6 JUNE 2016

NEPHROLITHIASIS

condition has a considerable economic andsocial burden, which underscores the impor-

tance of prevention.9

MOST STONES CONTAIN CALCIUM

About 80% of kidney stones in adults containcalcium, and calcium oxalate stones are morecommon than calcium phosphate stones. Uricacid and struvite stones account for 5% to 15%,and cystine, protease inhibitor, triamterene,2,8-dihydroxyadenine (2,8-DHA) and xan-thine stones each account for less than 1%.10

Stones form when the urinary concentra-tion of stone-forming salts, which is inversely

proportional to urine volume, is higher thantheir saturation point, which is affected byurine pH. Acidic urine (low pH) predispos-es to the formation of uric acid and cystinestones, whereas alkaline urine (high pH) fa-vors calcium phosphate stones.

INCREASED FLUID INTAKE FOR ALL

High uid intake, enough to produce at least2.5 L of urine per day, should be the initialtherapy to prevent stone recurrence.11

Borghi et al12 randomly assigned 199 pa-tients who had a rst calcium stone to highoral uid intake or no intervention and fol-lowed them prospectively for 5 years. The re-currence rate was 12% in the treated group and27% in the control group. Another study, inpatients who had undergone shock wave litho-tripsy, found a recurrence rate of 8% in thoserandomized to increase uid intake to achieveurine output greater than 2.5 L/day, comparedwith 56% in those assigned to no treatment.13

Certain beverages increase the risk ofstones and should be avoided. Sugar-sweet-ened noncola soda and punch are associatedwith a 33% higher risk of kidney stones, andcola sodas are associated with a 23% higherrisk.14Prospective studies have shown that theconsumption of coffee, beer, wine, and orange

juice is associated with a lower likelihood ofstone formation.13,15Table 3 is a brief summary of the dietary

and pharmacologic interventions in the man-agement of recurrent nephrolithiasis.

PREVENTING CALCIUM OXALATE STONES

Major urinary risk factors associated with cal-cium oxalate stones are hypercalciuria, hyp-eroxaluria, hyperuricosuria, hypocitraturia,and low urine volume.16Preventing calciumstones therefore depends on reducing the uri-

nary concentration of calcium and oxalate,increasing urinary levels of inhibitors such ascitrate, and increasing urine volume.

Reducing calcium excretionHypercalciuria has been traditionally denedas 24-hour urinary calcium excretion greaterthan 300 mg/day in men, greater than 250 mgin women, or greater than 4 mg/kg in men orwomen.17It is a graded risk factor, and the cut

Without

medical

treatment,the 5-year

recurrence rate

is 35% to 50%

TABLE 1

The prevalence of kidney stones is increasing

NHANESstudy period Men Women

197619802 4.9 0.42a 2.8 0.17a

198819942 6.3 0.56a 4.1 0.27a

200720101 10.6 (9.411.9)b 7.1 (6.47.8)b

a Percent prevalence standard error of the meanbPercent prevalence and 95% confidence intervalNHANES = National Health and Nutrition Examination Survey

TABLE 2

Systemic conditionsassociated with nephrolithiasis

Coronary artery diseaseChronic kidney disease and end-stage kidney disease

Bone disorders and fractures

Aortic calcification

Hypertension

Type 2 diabetes mellitus

Gout

Metabolic syndrome

Sarcoidosis

Renal tubular acidosis

Bowel disease and intestinal surgery

Renal and bladder anatomic anomaliesMedications

Genetic abnormalities


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SHAH AND CALLE

points used in published research and clinicallaboratories vary substantially. Some institu-tions use the same value for hypercalciuria inboth sexes, eg, greater than 200 mg/day.18

Excessive sodium intake is the most com-mon cause of hypercalciuria. Systemic condi-tions such as primary hyperparathyroidism,sarcoidosis, and renal tubular acidosis alsocause hypercalciuria but are uncommon.19Management depends on the underlying causeand includes dietary modications and phar-macologic therapy. Dietary modications have a pivotal rolein the management of recurrent stones thatare due to hypercalciuria.

Dietary calcium should not be restricted,since calcium reduces the excretion of urinary

oxalate by decreasing intestinal absorption ofoxalate. Guidelines from the American Uro-logical Association recommend a daily cal-cium intake of 1,000 to 1,200 mg.1120More-over, restriction of dietary calcium to less than800 mg/day (the current recommended dailyallowance for adults) can lead to negative cal-cium balance and bone loss.

Sodium intake also inuences hypercalci-uria. Calcium is reabsorbed passively in theproximal tubule due to the concentrationgradient created by active reabsorption of so-dium. A high sodium intake causes volume

expansion, leading to a decrease in proximalsodium and calcium reabsorption and enhanc-ing calcium excretion. A low-sodium diet(80100 mmol/day, or 1,8002,300 mg/day) isrecommended. This enhances proximal sodi-um and passive calcium absorption and leadsto a decrease in calcium excretion.21

Dietary protein increases the acid load byproduction of sulfuric acid and leads to hyper-calciuria by its action on bone and kidney. An-imal protein has a higher content of sulfur andgenerates a higher acid load compared withvegetable protein and has been associated withan increased incidence of stone formation, atleast in men.20,22 Borghi et al23 reported thatthe combination of restricted intake of ani-mal protein (52 g/day), restricted salt intake(50 mmol, or 2,900 mg/day of sodium chlo-ride), and normal calcium intake (30 mmol/day, or 1,200 mg/day) was associated with alower incidence of stone recurrence in menwith hypercalciuria compared with traditional

low-calcium intake (10 mmol, or 400 mg/day).Patients should therefore be advised to avoidexcessive intake of animal protein. Increasing the dietary intake of fruits andvegetables as in the Dietary Approach to StopHypertension (DASH) diet is benecial and

TABLE 3

Interventions to prevent recurrent kidney stones

DIETARY INTERVENTIONS

AllIncrease fluid intake to produce a urine volume of at least2.5 L/day

Calcium stones and hypercalciuriaLimit sodium intake to2,300 mg/day; consume at least 1,000 or 1,200 mg/day of dietarycalcium; restrict nondairy animal protein to 0.8 to 1 g/kg/day; in-crease intake of fresh fruits and vegetables

Calcium oxalate stones and relatively high urinary oxalateintakeLimit intake of oxalate-rich foods and maintain normalcalcium intake

Calcium oxalate stones and hypocitraturiaIncrease intakeof fruits and vegetables and limit nondairy animal protein

Uric acid stones or calcium stones with hyperuricosuriaLimit intake of nondairy animal protein to 0.8 to 1 g/kg/day

Cystine stonesLimit sodium intake to 2,300 mg/day and proteinintake to 0.81g/kg/day

PHARMACOLOGIC INTERVENTIONS

Hypercalciuria and recurrent calcium stonesThiazidediuretics

Recurrent calcium stones and hypocitraturiaPotassiumcitrate

Uric acid and cystine stonesPotassium citrate to alkalize urine

to optimal levelRecurrent calcium oxalate stones and hyperuricosuriaAllopurinol

Uric acid stonesDo not use allopurinol as first-line therapy, butconsider it in refractory cases

Type 1 hyperoxaluriaPyridoxine

Cystine stones unresponsive to conservative measuresOffer a cystine-binding thiol drug, eg, D-penicillamine or tiopronin.Pharmacotherapy should always be used in conjunction with conser-vative measures of dietary modification and urinary alkalization

Residual or recurrent struvite stones, and surgical inter-

ventions are contraindicated or refusedConsider ureaseinhibitors, acetohydroxamic acid


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NEPHROLITHIASIS

reduces the risk of stone recurrence, mainly byincreasing citrate excretion.24

Pharmacologic therapy in hypercalciuria.Thiazide diuretics are the mainstay of pharma-cotherapy for preventing recurrent stones inpatients with idiopathic hypercalciuria. Theyreduce the risk of stone recurrence by about50%, as reported in a recent meta-analysisthat looked at ve trials comparing thiazidediuretics with placebo.25They lower calciumexcretion by causing volume depletion, there-by increasing proximal sodium and passivecalcium reabsorption.

Chlorthalidone and hydrochlorothiazideare the thiazides commonly used to treat hy-percalciuria. The dosage is titrated to the uri-nary calcium excretion, and a common mis-

take is to use doses that are too low. They areusually started at 25 mg/day, but often requirean increase to 50 to 100 mg/day for adequatelowering of urinary calcium. Care should be taken to avoid hypokale-mia. If it occurs, it can be corrected by add-ing the potassium-sparing diuretic amiloride(510 mg/day), which increases calcium re-absorption in collecting ducts or, in patientswith hypocitraturia, potassium citrate-potas-sium bicarbonate. (Sodium salts should beavoided, since they increase renal calciumexcretion.)26

Management of hypercalciuria with met-abolic causes, which include primary hyper-parathyroidism and chronic acidemia. Pa-tients who have hypercalciuria from primaryhyperparathyroidism are treated with para-thyroidectomy.27 Chronic metabolic acidosiscauses hypercalciuria by loss of bone calciumand hypocitraturia by increasing active proxi-mal absorption of citrate. Potassium citrateor potassium bicarbonate is used to preventstones in such patients; sodium salts should beavoided.28

Reducing oxalate excretionHyperoxaluria has traditionally been denedas urinary oxalate excretion of more than 45mg/day. However, the optimal cutoff point forurinary oxalate excretion is unclear, as is theoptimal cutoff for hypercalciuria. The risk ofstone formation has been shown to increasewith oxalate excretion even above 25 mg/day,which is within the normal limit.18

Idiopathic hyperoxaluria. High dietaryoxalate intake, especially when associatedwith low calcium intake, leads to idiopathichyperoxaluria. However, the contribution ofabnormal endogenous oxalate metabolism isuncertain. Ingested calcium binds to oxalatein the intestinal tract and reduces both the ab-sorption of intestinal oxalate absorption andthe excretion of urinary oxalate.29 High di-etary oxalate intake has usually been regardedas a major risk factor for kidney stones.

Taylor and Curhan,30in a prospective study,reported a mild increase in the risk of stones inthe highest quintile of dietary oxalate intakecompared with the lowest quintile for men(relative risk [RR] 1.22, 95% condence in-terval [CI] 1.031.45) and older women (RR

1.21, 95% CI 1.011.44). They also demon-strated that eating eight or more servings ofspinach per month compared with fewer thanone serving per month was associated with asimilar increase of stone risk in men (RR 1.30,95% CI 1.081.58) and older women (RR1.34 95% CI 1.11.64). In contrast, spinachand dietary oxalate intake did not increase therisk of nephrolithiasis in young women. Theauthors concluded that the risk associatedwith oxalate intake was modest, and their datadid not support the contention that dietaryoxalate is a major risk factor for kidney stones.

Higher oxalate intake increases urinaryoxalate excretion and presumably the risk ofnephrolithiasis. Limiting dietary oxalate toprevent stones is recommended if habituallyhigh dietary intake of oxalate is identied orfollow-up urine measurements show a de-crease in oxalate excretion.31Foods rich in ox-alate include spinach, rhubarb, nuts, legumes,cocoa, okra, and chocolate.

The DASH diet, which is high in fruitsand vegetables, moderate in low-fat dairyproducts, and low in animal protein, is aneffective dietary alternative and has been as-sociated with a lower risk of calcium oxalatestones.24Consuming fruits and vegetables in-creases the excretion of urinary citrate, whichis an inhibitor of stone formation. Also, it hasbeen proposed that the DASH diet containsunknown factors that reduce stone risk. Taylor et al32prospectively examined therelationship between the DASH diet and theincidence of kidney stones and found that the

Acidic urine

predisposes

to uric acid andcystine stones;

alkaline urine

favors calcium

phosphate

stones


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SHAH AND CALLE

diet signicantly reduced the risk of kidneystones. The relative risks of occurrence of kid-ney stones in participants in the highest quin-tile of the DASH score (a measure of adher-ence to the DASH diet)compared with thelowest quintile were 0.55 (95% CI 0.460.65)for men, 0.58 (95% CI 0.490.68) for olderwomen, and 0.60 (95% CI 0.520.70) foryounger women, which the authors charac-terized as a marked decrease in kidney stonerisk.

Vitamin C intakeshould be restrictedto90 mg/day in patients who have a history ofcalcium oxalate stones. Urivetzky et al33foundthat urinary oxalate excretion increased by 6to 13 mg/day at doses of ascorbic acid greaterthan 500 mg.

Pyridoxine (vitamin B6), a coenzyme of al-anine-glyoxylate aminotransferase (AGT), in-creases the conversion of glyoxylate to glycineinstead of oxalate and is used in the treatmentof type 1 primary hyperoxaluria (see below).34However, its effect in preventing stones in id-iopathic hyperoxaluria is not well known, andit has not been studied in a randomized con-trolled trial. In a prospective study, Curhan etal35reported that high intake of pyridoxine (>40 mg/day) was associated with a lower risk ofstone formation in women, but no such ben-et was found in men.

Enteric hyperoxaluria. About 90% ofdietary oxalate binds to calcium in the smallintestine and is excreted in the stool. The re-maining 10% is absorbed in the colon and issecreted in urine. Hyperoxaluria is frequentlyseen with fat malabsorption from inammatorybowel disease, short gut syndrome, and gastricbypass surgery. In these conditions, excess fatbinds to dietary calcium, leading to increasedabsorption of free oxalate in the colon.36

Treatment is directed at decreasing intes-tinal oxalate absorption and should includehigh uid intake and oral calcium supple-ments. Calcium carbonate or citrate causesprecipitation of oxalate in the intestinal lu-men and is prescribed as 1 to 4 g in three tofour divided doses, always with meals. Calci-um citrate is preferred over calcium carbon-ate in stone-formers because of the benet ofcitrate and calcium citrates higher solubilityand greater effectiveness in the presence ofachlorhydria.37Patients should be advised to

avoid foods high in oxalate and fat. Primary hyperoxaluria is caused by inher-ited inborn errors of glyoxylate metabolism thatcause overproduction of oxalate and urinaryoxalate excretion above 135 to 270 mg/day.

Type 1 primary hyperoxaluria is the mostcommon (accounting for 90% of cases) and iscaused by reduced activity of hepatic peroxi-somal AGT. Type 2 is from a deciency of glyoxylate re-ductase-hydroxypyruvate reductase (GRHPR).

Type 3 is from mutations in the HOGA1gene, which codes for the liver-specic mito-chondrial 4-hydroxy-2-oxoglutarate aldolaseenzyme involved in degradation of hydroxy-proline to pyruvate and glyoxalate.38

High uid intake to produce a urinary vol-

ume of 3 L/day reduces intratubular oxalate de-position and should be encouraged. Potassiumcitrate (0.15 mg/kg), oral phosphate supple-ments (3040 mg/kg of orthophosphate), andmagnesium oxide (500 mg/day/m2) inhibit pre-cipitation of calcium oxalate in the urine.39,40Pyridoxine, a coenzyme of AGT, increases theconversion of glyoxylate to glycine instead ofoxalate and is prescribed at a starting dose of5 mg/kg (which can be titrated up to 20 mg/kgif there is no response) in patients with type 1primary hyperoxaluria. About 50% of patientswith type 1 respond successfully to pyridoxine,and a 3- to 6-month trial should be given inall patients in this category.34AGT is presentonly in hepatocytes, and GRHPR is found inmultiple tissues; therefore, combined liver-kidney transplant is the treatment of choicein patients with type 1 primary hyperoxaluria,whereas isolated kidney transplant is recom-mended in patients with type 2.41

Reducing uric acid excretionHyperuricosuria is dened as uric acid excre-tion of greater than 800 mg/day in men andgreater than 750 mg/day in women. The association of hyperuricosuria withincreased risk of calcium oxalate stone forma-tion is controversial. Curhan and Taylor,18ina cross-sectional study of 3,350 men and wom-en, reported that there was no difference inmean 24-hour uric acid excretion in individu-als with and without a history of stones.

The mechanism by which uric acid leadsto calcium oxalate stones is not completely

Excessive

sodium

intake is themost common

cause of

hypercalciuria


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NEPHROLITHIASIS

Do not restrict

calcium intake

in calciumoxalate

stone-formers

known and could be the salting out of cal-cium oxalate from the urine.42

Dietary purine restriction, ie, limiting intakeof nondairy animal protein to 0.8 to 1 g/kg/day,is the initial dietary intervention.11Allopurinolis the alternative approach if the patient is notcompliant or if dietary restriction fails.43

In a study by Ettinger et al,4460 patientswith hyperuricosuria and normocalciuria wererandomized to receive allopurinol (100 mgthree times daily) or a placebo. The allopuri-nol group had a rate of calculus events of 0.12per patient per year, compared with 0.26 inthe placebo group.

Increasing citrate excretionHypocitraturia is a well-known risk factor for

the formation of kidney stones. It is usuallydened as a citrate excretion of less than 320mg/day for adults.

Citrate prevents formation of calciumcrystals by binding to calcium, thereby lower-ing the concentration of calcium oxalate be-low the saturation point.45

Diet therapy. Patients with calcium oxa-late stones and hypocitraturia should be en-couraged to increase their intake of fruits andvegetables, which enhances urinary citrate ex-cretion, and to limit their intake of nondairyanimal protein.11

The use of citrus products in preventingstones in patients with hypocitraturia is con-troversial, however, and needs to be studiedmore.

One study46 demonstrated that lemonjuice was benecial in hypocitraturic nephro-lithiasis: 4 oz/day of lemon juice concentratein the form of lemonade was associated withan increase in urinary citrate excretion to 346mg/day from 142 mg/day in 11 of 12 patientswho participated. Odvina47 compared the effects of orangejuice with those of lemonade on the acid-baseprole and urinary stone risk under controlledmetabolic conditions in 13 volunteers. Orangejuice was reported to have greater alkalinizingand citraturic effects and was associated withlower calculated calcium oxalate supersatura-tion compared with lemonade.

Lemonade therapy may be used as adjunc-tive treatment in patients who do not complywith or cannot tolerate alkali therapy. How-

ever, we advise caution about recommendingcitrus products, as they can increase oxalateexcretion. Pharmacotherapy includes alkali therapy.

Barcelo et al

48

compared the effects of potas-sium citrate and placebo in 57 patients withcalcium oxalate stones and hypocitraturia. Pa-tients treated with potassium citrate had a rateof stone formation of 0.1 event per patient peryear, compared with 1.1 in the placebo group. Many forms of alkaline citrate are avail-able. Potassium citrate is preferred over so-dium citrate since the latter may increaseurine calcium excretion.49 Treatment is usu-ally started at 30 mEq/day and is titrated toa maximal dose of 60 mEq/day for a urinarycitrate excretion greater than 500 mg/day.

Common side effects are abdominal bloat-ing and hyperkalemia (especially with renalinsufciency), and in such cases sodium-basedalkali, sodium citrate, or sodium bicarbonatecan be prescribed.

PREVENTING CALCIUM PHOSPHATESTONES

Risk factors for calcium phosphate stones aresimilar to those for calcium oxalate stones(other than hyperoxaluria), but calcium phos-phate stones are formed in alkaline urine (usu-ally urine pH > 6.0), often the result of distalrenal tubular acidosis. Preventive measuresare similar to those for calcium oxalate stones.

Alkali therapy should be used with cau-tion because of its effect on urinary pH andthe risk of precipitation of calcium phosphatecrystals.50Use of potassium citrate was foundto be associated with increases in both urinarycitrate excretion and calcium phosphate su-persaturation in hypercalciuric stone-formingrats.51 It is therefore challenging to managepatients with calcium phosphate stones and

hypocitraturia. Alkali administration in thissetting may diminish the formation of newstones by correcting hypocitraturia, but atthe same time it may increase the likelihoodof calcium phosphate stone formation by in-creasing the urinary pH. When the urine pHincreases to above 6.5 with no signicantchange in urine citrate or urine calcium excre-tion, we recommend stopping alkali therapy.


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SHAH AND CALLE

PREVENTING URIC ACID STONES

Clinical conditions associated with uric acidstones include metabolic syndrome, diabetesmellitus, gout, chronic diarrheal illness, and

conditions that increase tissue turnover anduric acid production, such as malignancies.Other risk factors for uric acid stone forma-tion are low urine volume, low uric pH, andhyperuricosuria. Abnormally acidic urine is the most com-mon risk factor. Metabolic syndrome and dia-betes mellitus reduce ammonia production,resulting in a lower urinary pH, which predis-poses to uric acid stone formation. Chronicdiarrhea also acidies the urine by loss of bi-carbonate. Similarly, in gout, the predispos-ing factor in uric acid stone formation is the

persistently acidic urine due to impaired am-monium excretion.52Uric acid precipitates toform uric acid stones in a low urinary pH evenwith normal excretion rates of 600 to 800mg/day and a urinary volume of 1 to 1.5 L.53

Therefore, apart from increasing uid in-take, urinary alkalization is the cornerstoneof management of uric acid stones. Potassiumcitrate is the preferred alkali salt and is startedat a dose of 30 mEq/day for a goal urinary pHof 6 to 6.5.47

Patients with hyperuricosuria are also ad-

vised to restrict their protein intake to nomore than 0.8 to 1 mg/kg/day.If the above measures fail, patients are

treated with a xanthine oxidase inhibitor, ie,allopurinol or febuxostat, even if their uricacid excretion is normal.54

PREVENTING STRUVITE STONES

Struvite stones contain magnesium ammo-nium phosphate and are due to chronic up-per urinary tract infection with urea-splittingbacteria such as Proteus, Klebsiella, Pseudomo-nas, and enterococci. Urea hydrolysis releaseshydroxyl ions, resulting in alkaline urine thatpromotes struvite stone formation. Early de-tection and treatment are important, sincestruvite stones are associated with morbidityand rapid progression.

Medical treatment of struvite stones is usu-ally unsuccessful, and the patient is referred toa urologist for surgical removal of the stones,the gold standard treatment.55Long-term use

of culture-specic antibiotics to prevent newstone growth is not well studied. Medical ther-apy by itself is preferred in patients who refusestone removal or cannot tolerate it. Ureaseinhibitors such as acetohydroxamic acid havebeen successful in preventing or slowing stonegrowth, but their use is limited by frequentside effects such as nausea, headache, rash,and thrombophlebitis.56

CYSTINE STONES

Cystine stones occur in people with inheriteddefects of renal tubular and intestinal trans-port of cysteine and dibasic amino acids thatcause excessive excretion of urinary cystine,ie, 480 to 3,600 mg/day.

Cystine is formed from two cysteine mol-ecules linked by a disulde bond. The solubil-ity of cystine is pH-dependent, with increasedsolubility at higher urinary pH. The goal is tomaintain a urinary cystine concentration be-low its solubility level by keeping the cystineconcentration below 243 mg/L and the urinecystine supersaturation (the ratio of the urinecysteine concentration to the cysteine solubil-ity in the same sample) less than 0.6.57Thera-py is aimed at increasing daily urinary volumeto 3 L and urine alkalization to pH above 7, inorder to increase cystine solubility by 300%.58

Overnight dehydration should be pre-vented, and patients should be encouragedto wake up at least once a night to void anddrink additional water. Sodium restriction to100 mmol/day (2,300 mg/day) and moderateprotein restriction to 0.8 to 1 g/kg/day are as-sociated with decreased cystine excretion, butlong-term studies demonstrating their benetin preventing cystine stones are lacking.59

A thiol-containing drug,eg, D-penicilla-mine (0.52 g/day) or tiopronin (4001,200mg/day), should be added to the conservativemeasures if they have not been effective for3 months or if there is history of noncompli-ance.60Thiol-containing drugs have a sulfhy-dryl group that reduces the disulde bond, andthey form soluble disulde cysteine-drug com-plexes with greater ability to solubilize cystinein alkaline urine. They must always be used inconjunction with uid and alkali therapy.61 Both drugs have severe and common adverseeffects including leukopenia, aplastic anemia,

The DASH diet

lowers the risk

of calciumoxalate stones


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NEPHROLITHIASIS

fever, rash, arthritis, hepatotoxicity, pyridoxinedeciency, and proteinuria (membranous ne-phropathy). However, tiopronin seems to havea lesser incidence of side effects.62Regular moni-toring of complete blood cell counts, liver en-zymes, and urine protein should be done.

Captoprilcontains a sulfhydryl group, andthe captopril-cysteine disulde is more soluble

than cysteine alone. The amount of captoprilthat appears in the urine is low, and doses of150 mg/day are usually required to reduce cys-teine excretion, which can lead to hypoten-sion. The efcacy of captopril in treating cys-tine stones is unproven, and this drug is usedonly if patients cannot tolerate other thiol-containing drugs.63

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ADDRESS: Juan Camilo Calle, MD, Department of Nephrology and Hyper-

tension. Glickman Urological and Kidney Institute. Q7, Cleveland Clinic,

9500 Euclid Avenue, Cleveland, OH 44195; [email protected]

dietary and medical management of recurrent nephrolithiasis

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