Amir Qaseem, MD, PhD; Paul Dallas, MD; Mary Ann Forciea, MD; Melissa Starkey, PhD; Thomas D. Denberg, MD, PhD; for the Clinical Guidelines Committee of the American College of Physicians (1)
* This paper, written by Amir Qaseem, MD, PhD; Paul Dallas, MD; Mary Ann Forciea, MD; Melissa Starkey, PhD; and Thomas D. Denberg, MD, PhD, was developed for the Clinical Guidelines Committee of the American College of Physicians. Individuals who served on the Clinical Guidelines Committee from initiation of the project until its approval were: Thomas D. Denberg, MD, PhD (Chair); Michael J. Barry, MD; Molly Cooke, MD; Paul Dallas, MD; Nick Fitterman, MD; Mary Ann Forciea, MD; Russell P. Harris, MD, MPH; Linda L. Humphrey, MD, MPH; Tanveer P. Mir, MD; Holger J. Schünemann, MD, PhD; J. Sanford Schwartz, MD; Paul Shekelle, MD, PhD; and Timothy Wilt, MD, MPH. Approved by the ACP Board of Regents on 23 November 2013.
Note: Clinical practice guidelines are “guides” only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians’ judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations.
Financial Support: Financial support for the development of this guideline comes exclusively from the ACP operating budget.
Disclosures: Authors followed the policy regarding conflicts of interest described at www.annals.org/article.aspx?articleid=745942. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=M13-2908. Any financial and nonfinancial conflicts of interest of the group members were declared, discussed, and resolved. A record of conflicts of interest is kept for each Clinical Guidelines Committee meeting and conference call and can be viewed at www.acponline.org/clinical_information/guidelines/guidelines/conflicts_cgc.htm.
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190. N. Independence Mall West, Philadelphia, PA 19106; e-mail, email@example.com.
Current Author Addresses:Drs. Qaseem and Starkey: 190 N. Independence Mall West, Philadelphia, PA 19106.Dr. Dallas: Virginia Tech Carilion School of Medicine, 1906 Bellview Avenue, Roanoke, VA 24014.
Dr. Forciea: University of Pennsylvania Health System, 3615 Chestnut Street, Philadelphia, PA 19104.
Dr. Denberg: Carilion Clinic, PO Box 13727, Roanoke, VA 24036.
Author Contributions:Conception and design: A. Qaseem, M.A. Forciea, T. Denberg.
Analysis and interpretation of the data: A. Qaseem, P. Dallas, M.A. Forciea, M. Starkey, T. Denberg.
Drafting of the article: A. Qaseem, P. Dallas, M.A. Forciea, M. Starkey, T. Denberg.
Critical revision of the article for important intellectual content: A. Qaseem, P. Dallas, M.A. Forciea, M. Starkey, T. Denberg.
Final approval of the article: A. Qaseem, P. Dallas.
Statistical expertise: A. Qaseem.
Administrative, technical, or logistic support: A. Qaseem, M. Starkey.
Collection and assembly of data: A. Qaseem, M. Starkey.
Qaseem A, Dallas P, Forciea MA, Starkey M, Denberg TD, for the Clinical Guidelines Committee of the American College of Physicians. Dietary and Pharmacologic Management to Prevent Recurrent Nephrolithiasis in Adults: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2014;161:659-667. doi: 10.7326/M13-2908
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Published: Ann Intern Med. 2014;161(9):659-667.
The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the comparative effectiveness and safety of preventive dietary and pharmacologic management of recurrent nephrolithiasis in adults.
This guideline is based on published literature on this topic that was identified using MEDLINE, the Cochrane Database of Systematic Reviews (through March 2014), Google Scholar, ClinicalTrials.gov, and Web of Science. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline include symptomatic stone recurrence, pain, urinary tract obstruction with acute renal impairment, infection, procedure-related illness, emergency department visits, hospitalizations, quality of life, and end-stage renal disease. This guideline grades the quality of evidence and strength of recommendations using ACP's clinical practice guidelines grading system. The target audience for this guideline is all clinicians, and the target patient population is all adults with recurrent nephrolithiasis (≥1 prior kidney stone episode).
ACP recommends management with increased fluid intake spread throughout the day to achieve at least 2 L of urine per day to prevent recurrent nephrolithiasis. (Grade: weak recommendation, low-quality evidence)
ACP recommends pharmacologic monotherapy with a thiazide diuretic, citrate, or allopurinol to prevent recurrent nephrolithiasis in patients with active disease in which increased fluid intake fails to reduce the formation of stones. (Grade: weak recommendation, moderate-quality evidence)
Nephrolithiasis is a condition in which kidney stones, formed from crystals precipitating from the urine, develop within the urinary tract when the urinary concentration of crystal-forming substances is high or that of substances that inhibit stone formation is low. Approximately 80% of adults with kidney stones have stones consisting primarily of calcium oxalate, calcium phosphate, or both. Other stones consist of struvite, uric acid, or cystine. The lifetime prevalence of nephrolithiasis is 13% for men and 7% for women (1, 2), with a 5-year recurrence rate after an initial event of 35% to 50% without treatment (3). Stones are caused by an interaction between genetics and environmental exposure (4).
Efforts to prevent the recurrence of nephrolithiasis target decreasing concentrations of the lithogenic factors (for example, calcium and oxalate) and increasing the concentrations of inhibitors of stone formation (for example, citrate). This is achieved by both dietary changes and appropriate pharmacologic approaches for preventing recurrent kidney stones. Dietary changes include increasing water intake, reducing dietary oxalate, reducing dietary animal protein and other purines, and maintaining normal dietary calcium.
The purpose of this American College of Physicians (ACP) guideline is to present the available evidence on the comparative effectiveness and safety of preventive dietary and pharmacologic management for recurrent nephrolithiasis. The target audience for this guideline is all clinicians, and the target patient population is all adults with recurrent nephrolithiasis (≥1 prior kidney stone episode). This guideline is based on a systematic evidence review (5) and an evidence report sponsored by the Agency for Healthcare Research and Quality (6).
This guideline is based on a systematic evidence review (5) that addressed the following key questions in adults with a history of nephrolithiasis:
Do results of baseline stone composition and blood and urine chemistries predict the effectiveness of diet and/or pharmacologic treatment on final health outcomes and intermediate stone outcomes, as well as reduce adverse effects?
Do results of follow-up blood and urine biochemistry measurements predict final health outcomes and intermediate stone outcomes in adults being treated to prevent recurrence?
What is the effectiveness and comparative effectiveness of different dietary therapies on final health outcomes and intermediate stone outcomes?
What is the evidence that dietary therapies to reduce risk for recurrent stone episodes are associated with adverse effects?
What is the effectiveness and comparative effectiveness of different pharmacologic therapies on final health outcomes and intermediate stone outcomes?
What is the evidence that pharmacologic therapies to reduce risk for recurrent stone episodes are associated with adverse effects?
The literature search included English-language trials identified by using MEDLINE, the Cochrane Database of Systematic Reviews (January 1948 to September 2012), Google Scholar, ClinicalTrials.gov, and Web of Science. The literature search was updated in March 2014, and no additional studies met the inclusion or exclusion criteria. Dietary interventions that were evaluated included intake of fluids, calcium, animal protein, sodium, fruit and fiber, purine, oxalate, potassium, soft drinks, citrus, or multicomponent diets. We also included empirical dietary interventions and those tailored according to patient demographics, comorbid conditions, baseline diet, baseline urine or blood biochemical testing, and/or stone type. Pharmacologic agents evaluated include medications approved by the U.S. Food and Drug Administration and available in the United States for prescription (for example, hydrochlorothiazide, chlorthalidone, indapamide, potassium citrate, potassium–magnesium citrate, sodium citrate, allopurinol, magnesium hydroxide, or acetohydroxamic acid [AHA]). For key questions 1, 2, 4, and 6, we considered final clinical health outcomes as the most important measures of treatment benefit, including symptomatic stone recurrence, pain, urinary tract obstruction with acute renal failure, infection, morbidity related to treatment of a recurrent stone, emergency department visits or hospitalizations for treatment of recurrent stones (for example, for renal colic or acute renal failure), quality of life (general or urologic), and end-stage renal disease. The next most important measures of treatment considered for key questions 1, 2, 4, and 6 were intermediate stone outcomes, including composite recurrence (combination of symptomatic or radiographically detected recurrence), recurrence detected only by scheduled radiographic imaging, and change in stone size. Evidence suggests that stones identified with imaging are associated with symptomatic recurrence. For key questions 3 and 5, adverse effects included any reported by eligible trials (for example, nausea, diarrhea, hypokalemia, weight change, hyperlipidemia, and hyperglycemia). Measures of treatment adherence were those reported by the individual trials (for example, self-report questionnaire, pill count, or as estimated by follow-up urine biochemical measures). Further details about the methods and inclusion and exclusion criteria applied in the evidence review are available in the full Agency for Healthcare Research and Quality report (6).
This guideline rates the quality of evidence and strength of recommendations using ACP's guideline grading system (Table 1). Details of the ACP guideline development process can be found in ACP's methods paper (7).
Table 1. The American College of Physicians’ Guideline Grading System
Results from 1 good-quality (8) and 28 fair-quality trials (9–35) showed that current evidence is insufficient to conclude that assessing baseline stone composition, blood chemistry, or urine chemistry before initiating pharmacologic or dietary interventions reduces stone recurrence.
Evidence is insufficient from 1 good-quality (8) and 15 fair-quality trials (9, 11–14, 18–21, 27, 28, 30, 32–34) to conclude that monitoring stone composition, blood chemistry, or urine chemistry once pharmacologic or dietary interventions have been initiated reduces stone recurrence.
Eight fair-quality trials were identified that assessed the effectiveness of dietary therapies on recurrent kidney stones (28–35). Most studies assessed treatment in patients with calcium stones. Low-quality evidence showed that increased fluid intake; reduced soft drink intake (particularly soda acidified by phosphoric acid); and a high-calcium, low-protein, low-sodium multicomponent diet compared with a control diet reduced stone recurrence. Further, a tailored diet compared with an empirical diet reduced stone recurrence. A summary of the evidence is presented in Table 2.
Table 2. Evidence for Prevention of Stone Recurrence With Dietary and Pharmacologic Interventions
Low-quality evidence from 1 study (33) showed that patients with calcium stones who increased fluid intake to achieve more than 2 L of urine per day had less composite stone recurrence than the control group (12.1% vs. 27.0%; follow-up, 60 months). Another trial (29) of radiographic stone recurrence in patients with calcium stones showed a nonstatistically significant decrease in stone recurrence in patients with increased fluid intake compared with no treatment (8.0% vs. 55.6%; follow-up, 24 to 36 months).
Oligomineral water is a type of mineral water often marketed for diuretic properties. Low-quality evidence from 1 study (31) of radiographic stone recurrence showed that patients with calcium stones who were assigned to drink more than 2 L of a particular brand of mineral water each day (Fiuggi brand oligomineral water) that contained 15 mg of calcium per liter versus tap water with 55 to 130 mg of calcium per liter showed that 17.0% had recurring stones compared with 22.9%, respectively. No studies assessed the effect of other types of mineral or oligomineral waters on stone recurrence.
Low-quality evidence from 1 study (35) showed that patients (any stone type) with baseline soft drink consumption of more than 160 mL per day who were instructed to abstain from drinking soda had a reduced risk for symptomatic stone recurrence compared with no treatment (33.7% vs. 40.6%). Subgroup analysis showed that the benefit was limited to patients who drank soda that was acidified by phosphoric acid (typically colas) rather than those acidified by citric acid (typically fruit-flavored sodas) (29.7% vs. 45.6%).
Three RCTs (30, 32, 34) reported mixed results in comparing multicomponent diets with control diets in patients with calcium stones. One fair-quality study (34) showed that 24.0% of patients on a multicomponent diet (low animal protein, high fiber, increased bran, and low purine) had composite stone recurrence compared with 4.1% of those on a control diet. Patients on the multicomponent diet also had a higher rate of composite stone recurrence (7.1 vs. 1.2 per 100 person-years). One fair-quality trial (30) showed that 20.0% of patients on a diet that included normal to high calcium, low animal protein, and low sodium had composite stone recurrence compared with 38.3% of patients on a low-calcium control diet. A third fair-quality study (32) showed that fewer patients who received an extensive metabolic evaluation and subsequent dietary modification had increased composite stone recurrence than patients who received a limited biochemical evaluation with general dietary recommendations (6.2% vs. 19.1%).
Low-quality evidence from 1 study (28) of patients with calcium stones showed no statistically significant difference between composite stone recurrence for those on a high-fiber diet (increase baseline fiber intake to 25 g per day through increased fruit, fiber, and whole grain consumption) compared with patients on their usual diet. Two other trials (32, 34) of patients assigned to high fiber intake as part of a multicomponent diet compared with a control diet reported conflicting results.
Low-quality evidence from 1 study (28) showed no difference between a diet low in animal protein (<3 servings of meat or fish per week and <100 g of milk products per day) and a control diet for risk for composite recurrent stones (47.8% for both groups) in patients with calcium stones. Three other trials included low animal protein as part of a multicomponent diet compared with a control diet; 2 of these found a lower risk for recurrent stones (30, 32), whereas the other (34) found a higher risk for recurrent stones with the multicomponent diet.
One trial (30) in patients with calcium oxalate stones found that fewer patients treated with a multicomponent diet including normal or high calcium intake (1200 mg/d) had recurrent stones than those on a low-calcium diet (400 mg/d); further, patients on a multicomponent diet including low sodium intake (50 mmol/d) were less likely to experience stone recurrence than those on the control diet. Multicomponent diets including low purine intake were assessed in 2 trials (32, 34) with mixed results. No included studies addressed a low-oxalate diet.
Evidence showed that withdrawals from studies for any cause were low because of increased fluid intake. However, withdrawals were high in long-term trials evaluating soft drink intake, high fiber intake, low animal protein intake, and multicomponent dietary interventions. Most trials had poor reporting of adverse events.
Average withdrawals from the 2 trials (29, 33) were 9.5% (range 0% to 10.0%) and were similar between increased fluid intake and no treatment. One trial (29) reported no withdrawals due to adverse events.
One study (31) reported no withdrawals from either group, and they did not report adverse events.
One study (35) reported that 8.7% of patients instructed to abstain from soft drinks withdrew compared with 5.5% of patients given no treatment (relative risk, 1.57 [95% CI, 1.00 to 2.49]).
No increased risk for withdrawals for multicomponent dietary interventions compared with control was found, and the average from 3 trials was 16.4%. One trial reported that 5.0% of withdrawals were due to adverse events for the multicomponent diet compared with 11.7% for the control diet, including hypertension (2.0% vs. 12.0%; relative risk, 0.14 [CI, 0.02 to 1.13]), stroke (2.0% vs. 0%), and gout (2.0% vs. 0%) (30). Another trial reported an 18% withdrawal rate for the multicomponent diet compared with 29% for the control diet and no adverse events were reported (34).
One study (28) reported no increase in withdrawals for patients on the high-fiber diet compared with the control diet (55.0% vs. 61.7%).
One study (28) reported no increase in withdrawals for a low-protein diet compared with a control diet (58.2% vs. 61.7%).
A total of 20 (1 good-quality and 19 fair-quality) trials (8–27) assessed pharmacologic therapy for reducing stones. Both control and therapy groups were instructed to increase fluid intake. Most studies assessed treatment in patients with calcium stones. Thiazide, citrate, and allopurinol treatment decreased stone recurrence.
Moderate-quality evidence from 6 fair-quality trials compared thiazide diuretic with placebo (13, 14, 27) or control (9–11) in patients with recurrent calcium stones. The results showed that the risk for composite stone recurrence was lower in persons treated with thiazide than placebo or control (24.9% vs. 48.5%) (9–13, 27). No significant differences were found in the risk for recurrence between the different types of thiazides studied or varying dosages.
Moderate-quality evidence was derived from 6 trials comparing citrate monotherapy with placebo (8, 19) or control (15–18) in patients with nephrolithiasis (calcium stones in 5 of 6 studies; stone type not specified for 1 study). Pooled data from 4 trials (8, 15, 16, 19) showed that composite stone recurrence was lower in patients treated with citrate than placebo or control (11.1% vs. 52.3%). Results were similar for different types of citrate used, including potassium citrate (16, 19), potassium–magnesium citrate (8), and potassium–sodium citrate (15). One fair-quality trial (18) showed no difference between citrate and control for risk for radiographic stone recurrence.
Moderate-quality evidence from 4 trials that compared allopurinol monotherapy with placebo (20, 21) or control (22, 23) in patients with calcium oxalate stones showed a reduced risk for composite stone recurrence with allopurinol. Two trials (20, 23) reporting on composite stone recurrence showed that risk for recurrence was lower in patients treated with allopurinol than placebo (33.3% vs. 55.4%). One fair-quality study (20) showed a reduction in symptomatic stone recurrence (10.3% vs. 29.0%), although they found no difference in recurrence of radiographic stones between the treatments.
Evidence from 2 fair-quality trials showed no statistically significant difference in symptomatic or radiographic stone recurrence between AHA treatment compared with placebo or control group (24, 25) in patients with struvite stones. The overall quality of evidence for this outcome was graded as insufficient because of the small number of recurrent stone events and imprecise risk estimates.
Low-quality evidence from 1 fair-quality study (27) showed that risk for composite stone recurrence in patients with calcium stones treated with magnesium was nonstatistically significantly lower than placebo (29.4% vs. 45.2%) and nonstatistically significantly higher than thiazide diuretic (29.4% vs. 14.3%).
Evidence from 1 trial (9) showed no difference in risk for composite stone recurrence between treatment with thiazide plus citrate compared with thiazide monotherapy (30.0% vs. 32.0%). The overall quality of evidence for this outcome was graded as insufficient because of the small number of recurrent stone events and imprecise risk estimates.
Low-quality evidence from 1 study (11) showed that the risk for composite stone recurrence was similar in patients with recurrent calcium oxalate treated with thiazide plus allopurinol compared with thiazide monotherapy (12.5% vs. 15.8%).
Evidence related to harms of pharmacologic therapies were derived largely from trials reporting on withdrawals from the studies or withdrawals due to adverse events, and trials were variable. Specific adverse event reporting was poor.
Pooled data from 7 fair-quality trials (9–14, 27) showed an increase in withdrawals for thiazides compared with placebo or control (17.0% vs. 8.0%; relative risk, 1.77 [CI, 1.12 to 2.82]), and more withdrawals due to adverse events were in the thiazide treatment group (8.0% vs. 1.0%). Four trials (10, 13, 14, 27) reported adverse events as a composite outcome, including orthostasis, gastrointestinal upset, erectile dysfunction, fatigue, and muscle symptoms, although the list of adverse events was different for each study. One of two trials reporting risk for composite adverse events according to treatment group found an increase with thiazide treatment (27, 34). No adverse events were reported for more than 1 patient in any of the other trials.
Data from 4 trials (1 good and 3 fair quality) showed an increased risk for withdrawal for citrate therapy compared with placebo or control (36.0% vs. 20.0%) (8, 17–19) and an increased risk for withdrawals due to adverse events (15.0% vs. 2.0%).
Two fair-quality trials showed no increased risk for withdrawals (31.0% vs. 42.0%) and no increased risk for withdrawals due to adverse events (4.0% vs. 8.0%) when comparing allopurinol with placebo (20, 23).
Two fair-quality trials reported withdrawal rates for 63% for patients receiving AHA therapy versus 46% for placebo (24, 25) and an increased risk for withdrawals due to adverse events for AHA compared with placebo (22.0% vs. 5.0%). An increased risk for any adverse event with AHA versus placebo (64.0% vs. 32.0%) was found, including anemia (18.0% vs. 8.0%) (24, 25), headache (9.0% vs. 4.0%) (25), and alopecia (9.0% vs. 2.0%) (25). Results for tremor (25.0%) and deep venous thrombosis (16.0%) each were reported only for the AHA group in 1 trial (26).
One fair-quality trial (27) found no increased risk for withdrawal for magnesium compared with placebo (18.0% vs. 17.0%). Rates of withdrawal due to adverse events were 6.0% for the magnesium group and 3.0% for the placebo group.
One fair-quality trial reported no withdrawals for either the thiazide plus citrate group or the thiazide treatment groups, and this study did not report adverse events (9).
One fair-quality trial (11) reported withdrawal rates of 4.0% in the thiazide plus allopurinol group, 24.0% in the thiazide-only group, and 16.0% in the control group. Withdrawals due to adverse events were reported in 8% of patients in the thiazide group and none for thiazide plus allopurinol or control groups.
Increased fluid intake was shown to decrease stone recurrence by at least half with no reported side effects. Decreasing soft drink intake in men with a high baseline intake of soft drinks acidified by phosphoric acid also decreased stone recurrence. Other dietary interventions, including low-protein diets and multicomponent interventions, showed mixed results. Pharmacologic therapies plus increased fluid intake was effective, and thiazide, citrate, and allopurinol treatment resulted in a statistically significant decrease in stone recurrence. No trials were identified that directly compared these treatments with each other. Clinical outcomes and adverse events were sparsely reported, but they were more common for pharmacologic than nonpharmacologic therapies. Evidence was insufficient to determine the effect of dietary or pharmacologic therapy based on stone composition or blood and urine chemistries. Most studies included only patients with calcium stones, and no trials assessed treatment in patients with uric acid or cystine stones. See the Figure for a summary of the recommendations and clinical considerations.
Summary of the American College of Physicians guideline on dietary and pharmacologic management to prevent recurrent nephrolithiasis in adults.
ESRD = end-stage renal disease.
Recommendation 1: ACP recommends management with increased fluid intake spread throughout the day to achieve at least 2 L of urine per day to prevent recurrent nephrolithiasis. (Grade: weak recommendation, low-quality evidence)
Low-quality evidence showed that increased fluid intake is associated with a reduction in stone recurrence. Evidence also did not show any difference between tap water and a specific brand of mineral water (Fiuggi brand oligomineral water). People who already drink recommended amounts of liquids and those in whom increased fluid intake is contraindicated should not be directed to increase their fluid intake further. Although some low-quality evidence shows that a decrease in the consumption of soft drinks is associated with a reduced risk for stone recurrence, this benefit was limited to patients who drank soft drinks acidified by phosphoric acid, such as colas, but not for drinks acidified by citric acid, such as fruit-flavored sodas.
Recommendation 2: ACP recommends pharmacologic monotherapy with a thiazide diuretic, citrate, or allopurinol to prevent recurrent nephrolithiasis in patients with active disease in which increased fluid intake fails to reduce the formation of stones. (Grade: weak recommendation, moderate-quality evidence)
Moderate-quality evidence showed that thiazide diuretics, citrates, and allopurinol reduce the risk for recurrence of composite calcium stones. Combination therapy with these agents was not more beneficial than monotherapy. Although biochemistry and some observational data on stone recurrence suggest that the choice of treatment could be based on the type of metabolic abnormality, evidence from randomized, controlled trials is lacking to correlate the drug of choice and stone type to the prevention of stone recurrence. Most patients have calcium stones, and evidence showed that thiazide diuretics, citrates, and allopurinol all effectively reduced recurrence of this stone type. Note that the available evidence evaluated higher doses of thiazides (hydrochlorothiazide, 50 mg; chlorthalidone, 25 or 50 mg; indapamide, 2.5 mg) to prevent recurrent nephrolithiasis. The use of lower doses of thiazides is associated with fewer adverse effects, but their effectiveness in preventing stone recurrence compared with higher doses is not known. All of the medications are associated with adverse events, which are summarized in Table 2.
The current evidence from randomized trials is insufficient to evaluate the benefits of knowing the stone composition, urine chemistry, and blood chemistry related to the effectiveness of treatment. The guidelines committee is aware that observational data show an association of stone composition and biochemistry with stone recurrence; moreover, physiologic knowledge suggests that interventions targeting stone composition, biochemistry, or both can favorably alter biochemical composition that leads to stone formation. Clinicians often select pharmacologic therapy on the basis of method of action: Thiazide diuretics reduce urinary calcium and are often prescribed for patients with hypercalciuria, citrates bind to calcium and decrease urine acidity, and allopurinol decreases uric acid in urine. Almost all studies analyzed in the evidence review included only patients with calcium stones, which are the most common stone type. Although biochemistry suggests a relationship between pharmacologic method of action and stone type, no randomized, controlled trials link biochemical testing to outcomes. Our recommendations do not include patients with suspected hyperparathyroidism or other rare cases.
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David S. H. Bell, MD
November 20, 2014
Pharmacologic Management of Nephrolithiasis Qaseem et al in their clinical guideline from the American College of Physicians did not indicate under what circumstances citrates, thiazides or allopurinol should be utilized to avoid a recurrence of nephrolithiasis.1 Obviously if hypercalciuria is present thiazide diuretics should be utilized. However, utilization of thiazides in the presence of uricosuria may be counterproductive. With uricosuria, allopurinol should be utilized but allopurinol and citrates may also be successfully utilized in the absence of either hypercalciuria or uricosuria. In the obese, insulin resistant or type 2 diabetic patients there is a high frequency of an acidic urine due to hyperinsulinemia inducing both a decreased production of ammonia in the proximal tubule and decreasing clearance of sodium. The resulting lower urine PH can result in uric acid "coming out" of solution and crystallizing.2 While in the obese, insulin resistant or diabetic subjects the majority of calculi are composed of calcium oxylate the proportion of uric acid stones is higher than in controls (35.8% versus 11.3%).3 Normal excretion of uric acid is less than 800 mg/day but in the presence of an acid urine uric acid can crystallize at levels of as low as 200 mg/day. In this situation the most effective therapies to prevent the formation of stones are allopurinol to reduce uricosuria and citrates to neutralize the acid urine. In the absence of an analysis of a previous stone or hypercalciuria the presence of a low urine PH should suggest that therapy with allopurinol and/or a citrate will result in a decreased formation of calculi.4References:1) Qaseem A, Dallas P, Forciea MA, Starkey M, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Dietary and pharmacologic management to prevent recurrent nephrolithiasis in adults: a clinical practice guideline from the american college of physicians. Ann Intern Med(2014)161(9):659-67.2) Sakhaee K1, Adams-Huet B, Moe OW, Pak CY. Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Int(2002)62(3):971-9.3) Daudon M1, Traxer O, Conort P, Lacour B, Jungers P. Type 2 diabetes increases the risk for uric acid stones. J Am Soc Nephrol(2006)17(7):2026-33.4) Bell DS. Beware the low urine pH--the major cause of the increased prevalence of nephrolithiasis in the patient with type 2 diabetes. Diabetes Obes Metab(2012)14(4):299-303.
Amy E. Krambeck, John C. Lieske
December 2, 2014
We read with interest the recent Clinical Practice guidelines from the American College of Physicians (ACP) for the Prevention of Kidney Stones in Adults. The recommendations for drinking at least 2 L of fluid per day and the use of thiazide diuretics, citrate, or allopurinol when fluids alone are insufficient mirror recent guidelines released by the American urological Association (AUA). However, several features of the ACP recommendations are in disagreement with those of the AUA. For example, baseline stone composition is not recommended by ACP, nor is 24-hour urine analysis for stone risk factors. Kidney stone analysis by infrared spectroscopy is relatively inexpensive and very precise and, in our opinion, essential to properly diagnose the form of kidney stone disease. For example, a thiazide diuretic would not be helpful for patient with uric acid kidney stones or someone with cystinuria, both of which can be determined by stone analysis alone. Furthermore, a 24-hour urine analysis can help to guide logical therapeutic choices and specific dietary advice for an individual patient. For example, pharmacotherapy may not be helpful for individuals where a very low urine volume is the only major risk factor, and individuals with enteric hyperoxaluria need very specific therapy geared towards dietary measures to reduce oxalate loads. In these cases allopurinol or thiazide would probably not have any benefit. Although rare, certain genetic conditions associated with stone disease such as primary hyperoxaluria can be diagnosed by extreme abnormalities noted on 24 hour urine studies. Early intervention in such diseases can slow disease progression. These are just a few situations in which urine studies would be diagnostic and extremely helpful for management of patients, and demonstrate potential flaws in the minimalistic approach recommended by the ACP. Like many disorders, kidney stone disease is complicated with a variable phenotype. The ACP guidelines do little to acknowledge or highlight these issues. Current studies indicate that less than 10% of individuals with kidney stone disease undergo a full metabolic workup to prevent further stone formation (1). The approach implied by the ACP guidelines will do little to increase the rate of appropriate metabolic evaluations or help to abate the rising stone disease incidence in the United States (2). In contrast, the AUA guidelines appear to be more balanced and, in general, contain much more useful advice for a physician faced with a patient suffering from recurrent kidney stones. Amy E. Krambeck, MDAssociate Professor of UrologyJohn C. Lieske, MDProfessor of MedicineFellow American College of PhysiciansMayo Clinic O’Brien Urology Research CenterRochester, MNReferences1. Milose JC, Kaufman SR, Hollenbeck BK, Wolf JS, Jr., Hollingsworth JM. Prevalence of 24-hour urine collection in high risk stone formers. The Journal of urology. 2014;191(2):376-80.2. Scales CD, Jr., Smith AC, Hanley JM, Saigal CS. Prevalence of kidney stones in the United States. European urology. 2012;62(1):160-5.
Margaret S. Pearle, David S. Goldfarb
University of Texas Southwestern, Dallas, TX, NYU School of Medicine, New York, NY
December 22, 2014
Writing guidelines when there is a paucity of medical evidence
To the Editor,
We were disappointed by the recent Clinical Practice guidelines from the American College of Physicians (ACP) about prevention of recurrent nephrolithiasis.(1) The guidelines were based exclusively on randomized controlled trial-generated evidence, which had been summarized in a recent review sponsored by the Agency for Healthcare Research and Quality.(2) That valuable review documented that there was a relative paucity of high quality evidence regarding kidney stone prevention. The members of the American Urological Association’s guideline panel on Medical Management of Kidney Stones therefore recognized that, if the trial data were limited, useful guidelines require access to a broader set of data than could be derived solely from randomized controlled trials.(3) The resulting AUA guidelines, in contrast to the ACP guidelines, relied not only on the AHRQ review but also in part on extensive studies of urine and crystal chemistry, renal physiology, pharmacology, and nutrition. They also rely, of course, on the extensive experience of a diverse group of experts, whose “expert opinion” we understand is considered a flawed body of lore. Nonetheless we believe the AUA guidelines provide a more practical basis for practitioners and patients to prevent recurrent kidney stones, a practice which needs to be advanced in an era of increasing stone prevalence.(4)
Margaret S. Pearle MD
Professor of Urology,
University of Texas Southwestern,
Chair, AUA Guidelines Panel, Medical Management of Kidney Stones
David S. Goldfarb MD, FACP
Professor of Medicine and Physiology
NYU School of Medicine,
New York, NY
Vice-Chair, AUA Guidelines Panel, Medical Management of Kidney Stones
1. Qaseem A, Dallas P, Forciea MA, Starkey M, Denberg TD. Dietary and pharmacologic management to prevent recurrent nephrolithiasis in adults: a clinical practice guideline from the american college of physicians. Ann Intern Med. 2014;161(9):659-67.
2. Fink HA, Wilt TJ, Eidman KE, Garimella PS, MacDonald R, Rutks IR, et al. Recurrent Nephrolithiasis in Adults: Comparative Effectiveness of Preventive Medical Strategies. Rockville MD; 2012.
3. Pearle MS, Goldfarb DS, Assimos DG, Curhan G, Denu-Ciocca CJ, Matlaga BR, et al. Medical management of kidney stones: AUA guideline. J Urol. 2014;192(2):316-24.
4. Scales CD, Smith AC, Hanley JM, Saigal CS. Prevalence of kidney stones in the United States. Eur Urol. 2012;62(1):160-5.
Amir Qaseem, MD,PhD, Howard A. Fink, MD, MPH, Thomas D. Denberg, MD, PhD
American College of Physicians
January 30, 2015
IN RESPONSE: Dr. Bell raised an important issue and suggests that ACP should offer guidance on what drugs to use under specific circumstances. We acknowledge in the guideline that biochemistry suggests a linkage between the mode of action of the various drugs and stone type. However, results were mixed about whether baseline biochemistry measures predicted treatment effectiveness for reducing stone recurrence risk or efficacy of dietary or pharmacologic treatments compared with control for recurrent stone outcomes. In addition, no RCTs compared risk for stone recurrence between treatments according to follow-up biochemistry measures or changes from pretreatment biochemistry values. A post hoc analysis of one RCT, described in the evidence review on which this guideline was based (1), suggested that the benefit of allopurinol treatment was limited to patients with baseline hyperuricemia or hyperuricosuria. However, this was the only available evidence from an RCT linking stone biochemistry to recurrent stone outcomes, it was only for 1 drug, and the analysis was post hoc. As we point out in the guideline, we are aware that many physicians do select medications based on stone type, for example, allopurinol for uric acid stones, and we do not discourage that practice. Drs. Krambeck and Lieske also suggest that ACP should have recommended biochemical testing to determine stone type, and suggest that such testing is inexpensive and is recommended by other organizations. However, as stated above, ACP cannot make an evidence-based recommendation in light of what is currently shown in the studies. Further, just because a test or intervention is inexpensive, it does not mean we should do it without evidence, as costs do add up. References1. Fink HA, Wilt TJ, Eidman KE, Garimella PS, MacDonald R, Rutks IR, et al. Medical management to prevent recurrent nephrolithiasis in adults: a systematic review for an American College of Physicians Clinical Guideline. Ann Intern Med. 2013; 158:535-43. Amir Qaseem, MD, PhD, MHAAmerican College of Physicians, Philadelphia, PennsylvaniaHoward A. Fink, MD, MPHMinneapolis Veterans Affairs Medical Cente, Minneapolis, MNThomas D. Denberg, MD, PhDCarilion Clinic, Roanoke, Virginia
Nephrology, Guidelines, Nephrolithiasis, Urological Disorders.
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