1. Recurrent Nephrolithiasis in Adults: Comparative Effectiveness of Preventive Medical Strategies Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2.  An introduction to recurrent kidney stones (recurrent nephrolithiasis) and to the various dietary and pharmacological interventions available for preventing the recurrence of kidney stones  Systematic review methods  The clinical questions addressed by the comparative effectiveness review  Results of studies and evidence-based conclusions about the relative benefits and adverse effects of currently available interventions to prevent kidney stone recurrence  Gaps in knowledge and future research needs  What to discuss with patients and their caregivers Outline of Material Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

3.  Nephrolithiasis is a condition in which hard masses (kidney stones) form within the urinary tract.  Formation of kidney stones may occur when:  The urinary concentration of crystal-forming substances (e.g., calcium, oxalate, uric acid) is high  The urinary concentration of substances that inhibit stone formation (e.g., citrate) is low  The lifetime incidence of kidney stones is approximately 13 percent for men and 7 percent for women.  Among adults with kidney stones, approximately 80 percent consist predominately of calcium oxalate and/or calcium phosphate stones. Background: Formation and Incidence of Kidney Stones Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

4.  Stones may be asymptomatic or may present with:  Abdominal and flank pain  Nausea and vomiting  Urinary tract obstruction  Infection Background: Clinical Presentation of Kidney Stones Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

5.  Genetic factors are thought to account for about half the risk of developing kidney stones.  Environmental risk factors include low fluid intake, low calcium intake, and high fructose intake.  The evidence for a role for increased animal protein intake, high sodium intake, increased sucrose intake, and low magnesium intake as risk factors for kidney stones is mixed.  Risk of kidney stones may be increased by medical conditions such as obesity, diabetes, primary hyperparathyroidism, gout, and anatomic abnormalities of the kidney. Background: Risk Factors for Kidney Stones Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

6.  Following an initial stone event, the 5-year recurrence rate in the absence of specific treatment is 35 to 50 percent.  Recurrence can be diagnosed by radiographic studies, by symptomatic recurrence, or by a composite definition that is a combination of symptomatic recurrence or radiographically detected recurrence.  Kidney stone recurrence increases the risk of developing chronic kidney disease. Background: Recurrence of Kidney Stones Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

7.  Dietary interventions that are suggested to prevent stone recurrence by altering concentrations of crystal-forming or crystal-inhibiting substances in urine include:  Increasing water intake, reducing dietary oxalate, reducing dietary animal protein and other purines, and maintaining normal dietary calcium  Pharmacological interventions that are suggested to prevent stone recurrence include:  Thiazide diuretics, citrate, indapamide (a thiazide-like diuretic), allopurinol, magnesium hydroxide, and acetohydroxamic acid Background: Interventions for Preventing Kidney Stone Recurrence Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

8.  Clinical uncertainty exists about the comparative effectiveness and adverse effects of pharmacological and dietary preventive treatments.  Current guidelines recommend pretreatment biochemical analysis of blood and urine.  However, it is unclear if using the results of these analyses to tailor treatment leads to better outcomes than empiric therapy.  The authors of this systematic review examined the evidence around these uncertainties. Background: Uncertainties Related to Interventions for Preventing Kidney Stone Recurrence Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

9.  Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.  The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/kidney-stones.cfm. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

10.  Key Question 1. 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 pharmacological treatment on final health outcomes and intermediate stone outcomes and reduce treatment adverse effects?  Key Question 2. In adults with a history of nephrolithiasis, what is the effectiveness and comparative effectiveness of different dietary therapies on final health outcomes and intermediate stone outcomes? Clinical Questions Addressed by This Comparative Effectiveness Review (1 of 3) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

11.  Key Question 3. In adults with a history of nephrolithiasis, what is the evidence that dietary therapies to reduce risk of recurrent stone episodes are associated with adverse effects?  Key Question 4. In adults with a history of nephrolithiasis, what are the effectiveness and comparative effectiveness of different pharmacological therapies on final health outcomes and intermediate stone outcomes? Clinical Questions Addressed by This Comparative Effectiveness Review (2 of 3) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

12.  Key Question 5. In adults with a history of nephrolithiasis, what is the evidence that pharmacological therapies reduce risk of recurrent stone episodes and are associated with adverse effects?  Key Question 6. In adults with a history of nephrolithiasis being treated to prevent stone recurrence, do results of followup blood and urine biochemistry measures predict final health outcomes and intermediate stone outcomes? Clinical Questions Addressed by This Comparative Effectiveness Review (3 of 3) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

13.  The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the Comparative Effectiveness Review Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

14.  A limited body of evidence suggests that the risk of stone recurrence is reduced by the following dietary interventions (please see Table 1 in slides 16 and 17 for details):  Increased fluid intake to maintain daily urine output of > 2 L/day  Advice to reduce soft drink intake, particularly in subjects with high baseline intake of soft drinks acidified solely by phosphoric acid but not by citric acid  Low-protein, low-sodium, decreased-oxalate, increased-water, and normal-calcium diet when compared with a low-calcium, decreased-oxalate, and increased-water diet  Tailored diet (based on a metabolic evaluation) when compared with an empiric diet Strength of Evidence: Low for these dietary interventions Dietary Interventions for Reducing the Risk of Kidney Stone Recurrence: Benefits (1 of 2) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

15.  High-fiber, reduced-animal protein diets and increased oligomineral water intake as isolated interventions did not have a statistically significant effect on stone recurrence. Strength of Evidence: Low Dietary Interventions for Reducing the Risk of Kidney Stone Recurrence: Benefits (2 of 2) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

16. Table 1. Effects of Dietary Interventions on Risk of Urinary Stone Recurrence (1 of 2) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm. InterventionComparator Mode of Detection ARR, NNT, RR (95% CI)SOE Increasing fluids to maintain urine output > 2 L per day (for individuals with a single prior calcium stone episode) No increase in fluids Composite*ARR = 15%, NNT = 7, RR = 0.45 (0.24 to 0.84) Low Eliminating soft drinks (based on a single study in men) No advice to reduce soft drink intake SymptomaticARR = 7%, NNT = 14, RR = 0.83 (0.71 to 0.98) Low ARR = 16%, NNT = 6, RR = 0.65 (0.49 to 0.87) Low Eliminating soft drinks acidified solely with phosphoric acid: subgroup analysis of participants who were frequent consumers of such soft drinks *Composite detection refers to stones detected by either symptoms or scheduled radiographs. ARR = absolute risk reduction: the difference in risk between the control group and the treatment group; NNT = number needed to treat: the number of patients to be treated to find the benefit in one patient more than in the control group; RR = relative risk; SOE = strength of evidence; 95% CI = 95-percent confidence interval

17. Table 1: Effects of Dietary Interventions on Risk of Urinary Stone Recurrence (2 of 2) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm. InterventionComparator Mode of Detection ARR, NNT, RR (95% CI)SOE Low-animal protein, low- sodium, decreased-oxalate, increased-water, and normal-calcium diet* Low-calcium, decreased-oxalate, and increased- water diet Composite † ARR = 18%, NNT = 6, RR = 0.52 (0.29 to 0.95) Low Tailored diet based on a metabolic evaluation** Empirical dietary recommendation CompositeARR = 13%, NNT = 8 RR = 0.32 (0.14 to 0.74) Low Low-animal protein, high- fiber, increased-bran, low- purine, increased-fluid, and adequate calcium diet Increased fluid intake and adequate calcium CompositeARR = -20%, NNT = 5 RR = 5.88 (1.39 to 24.92) Low * The recommended level of dietary calcium intake in this study was 1,200 mg per day. † Composite detection refers to stones detected by either symptoms or scheduled radiographs. ** Changes in risk according to the specific metabolic abnormality and dietary recommendation were not reported. ARR = absolute risk reduction: the difference in risk between the control group and the treatment group; NNT = number needed to treat: the number of patients to be treated to find the benefit in one patient more than in the control group; RR = relative risk; SOE = strength of evidence; 95% CI = 95-percent confidence interval

18.  Adverse effects, reported in terms of withdrawals for any cause, were low in trials evaluating increased fluid intake but high in long-term trials evaluating low-soft drink, high-fiber, low-animal protein, and multicomponent dietary interventions.  However, no significant differences in withdrawals between intervention and control groups were reported in these trials.  Other adverse events reporting was poor. Dietary Interventions for Reducing the Risk of Kidney Stone Recurrence: Adverse Effects Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

19.  Thiazide diuretics reduce the risk of calcium stone recurrence (composite endpoint*): absolute risk reduction (ARR) = 29 percent; number needed to treat (NNT) = 3 (relative risk [RR] = 0.53 [95-percent confidence interval (95% CI), 0.41 to 0.68]).  Hydrochlorothiazide, chlorthalidone, and indapamide each reduce the risk of recurrent stones, but no trial directly compared thiazide agents to each other.  No trial directly compared different dosages of agents, and no trial assessed the lower thiazide doses often used to treat hypertension. Strength of Evidence: Moderate *Composite endpoint = stones detected either by symptoms or scheduled radiographs Pharmacological Interventions for Reducing the Risk of Kidney Stone Recurrence: Benefits (1 of 3) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

20.  Citrate reduces the risk of calcium stone recurrence (composite): ARR = 41 percent; NNT = 3 (RR = 0.25 [95% CI, 0.14 to 0.44]). Strength of Evidence: Moderate  Allopurinol reduces the risk of calcium stone recurrence in patients with elevated blood and urine uric acid levels (composite): ARR = 22 percent; NNT = 5 (RR = 0.59 [95% CI, 0.42 to 0.84]). Strength of Evidence: Moderate  There is no additional benefit from adding citrate to thiazide in patients (composite), 35 percent of whom had hypercalciuria and 15 percent of whom had hypocitraturia. Strength of Evidence: Low Pharmacological Interventions for Reducing the Risk of Kidney Stone Recurrence: Benefits (2 of 3) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

21.  Treatment with magnesium did not reduce the risk (composite endpoint*) of stone recurrence when compared with placebo. ˜™™No statistically significant difference in the risk of stone recurrence was observed. Strength of Evidence: Low  The evidence about acetohydroxamic acid treatment for preventing stone recurrence (detected radiographically) in patients with chronic urinary tract infections and struvite stones is insufficient to permit conclusions; however, this does not exclude the possibility that the drug does not work. Strength of Evidence: Insufficient Pharmacological Interventions for Reducing the Risk of Kidney Stone Recurrence: Benefits (3 of 3) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm. *Composite endpoint = stones detected either by symptoms or scheduled radiographs

22.  When compared with participants given placebo or control treatments, patients given thiazide, citrate, or acetohydroxamic acid were more likely to withdraw from trials and to withdraw due to adverse effects.„„  Participants treated with allopurinol were not more likely than control group participants to withdraw from trials overall or to withdraw due to adverse effects.  Patients given high-dose magnesium were more likely to withdraw due to adverse effects (all due to diarrhea) when compared with placebo groups.„„  Specific adverse effects were poorly reported. U.S. Food and Drug Administration labels should be consulted when using these agents. Pharmacological Interventions for Reducing the Risk of Kidney Stone Recurrence: Adverse Effects Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

23.  Almost no randomized controlled trials (RCTs) reported stone recurrence outcomes between treatments for subgroups stratified by baseline biochemistry levels.  In two RCTs limited to patients with calcium stones and hyperuricosuria or hyperuricemia, those randomized to allopurinol versus a control had a significantly lower risk of recurrent stones using composite endpoints** (33.3% vs. 55.4%; relative risk = 0.59 [95-percent confidence interval, 0.42 to 0.84]). Baseline Blood and Urine Biochemical Evaluations To Predict Stone Recurrence* (1 of 2) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm. * The strength of evidence for these findings was not rated. ** Composite endpoint = stones detected either by symptoms or scheduled radiographs.

24.  Limited evidence suggests that baseline calcium, oxalate, and citrate do not appear to predict efficacy of diet and pharmacological interventions on recurrent stone outcomes.  Otherwise, the evidence is limited to determine the effect of baseline values of urine magnesium, phosphate, potassium, pH, or supersaturation of calcium oxalate, uric acid, or calcium phosphate on predicting treatment efficacy. Baseline Blood and Urine Biochemical Evaluations To Predict Stone Recurrence* (2 of 2) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm. *The strength of evidence for these findings was not rated.

25.  No randomized controlled trials (RCTs) prospectively compared subsequent stone recurrence outcomes between treatments stratified by followup biochemistry levels or by changes in these measures from pretreatment baseline.  No eligible pharmacological RCT reported followup urine supersaturation levels and their role in predicting reduced risk of recurrent stones with drug treatment.  Followup measurement of the urine calcium level after dietary treatment is unlikely to be a reliable predictor of treatment efficacy for reducing the risk of stone recurrence.  Followup measurement of the urine calcium level after thiazide treatment may not be a reliable predictor of treatment efficacy for reducing risk of stone recurrence. Followup Blood and Urine Biochemical Evaluations To Predict Stone Recurrence* Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm. *The strength of evidence for these findings was not rated.

26.  The published evidence regarding the effectiveness of dietary interventions to reduce the risk of recurrence of calcium stones is limited. There is low-strength evidence that:  Fluid intake to maintain urine excretion of > 2 liters per day may provide a clinically significant reduction in risk of stone recurrence.  Abstaining from soft drinks or eliminating soft drinks acidified solely with phosphoric acid but not by citric acid (based on a single study in men) reduces risk of stone recurrence in frequent consumers.  A normal-calcium, low-sodium, low-animal protein diet may reduce the risk for stone recurrence, but the independent effect of increasing dietary calcium has not been determined.  High-fiber and reduced-animal protein diets may not help prevent stone recurrence.  The effectiveness of other dietary interventions is not clear. Conclusions (1 of 3) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

27.  Among the pharmacological interventions, thiazide diuretics, citrate, and allopurinol — each combined with increased fluid — reduce the risk of calcium stone recurrence more than increased fluid intake alone.  Allopurinol treatment reduced the rate of stone recurrence for patients with elevated blood or urine levels of uric acid.  Thiazides or citrates may be the preferred initial therapy over allopurinol in patients with calcium stones and no hyperuricosuria or hyperuricemia.  Patients receiving pharmacological interventions may experience adverse effects that lead to withdrawal from treatment. Conclusions (2 of 3) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

28.  Clinical studies have not clearly established the general utility of baseline or followup blood and 24-hour urine biochemical evaluations in predicting stone recurrence.  Regarding applicability, nearly all trials:  Were limited to patients with a history of calcium stones  Were conducted primarily in young to middle-aged men  Excluded participants with biochemical abnormalities  Excluded individuals with specific conditions that could predispose them to stone formation  Were limited by the absence of reported data on patient characteristics Conclusions (3 of 3) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

29. A review of randomized controlled trials (RCTs) to assess benefits and of RCTs and observational studies to assess adverse effects revealed a number of gaps in knowledge seen in these types of studies.  There is no direct evidence from RCTs about whether diets that increase calcium or lower sodium, oxalate, or purine (independent of other dietary components) reduce the risk of recurrent stones.  It is unknown whether the efficacy of dietary interventions differs as a function of participant characteristics.  Direct comparisons of dietary interventions to each other, of pharmacological interventions to each other, and between these two types of interventions are rare or absent.„„ Gaps In Knowledge (1 of 2) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

30.  The effect of dietary and pharmacological interventions on stone types other than calcium stones—and of acetohydroxamic acid for other than struvite stones—is unexamined in randomized controlled trials that report the effects of these treatments on the risk of stone recurrence.  No trial assessed the effectiveness of lower thiazide doses, often used to treat hypertension, for reducing the risk of recurrent stones.  Studies are needed to formally test whether the risk for stone recurrence after either dietary or pharmacological treatment can be stratified based on blood and urine biochemical measures, either at baseline or at followup. Gaps In Knowledge (2 of 2) Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

31.  That kidney stones have a high chance of recurring if not managed properly  The importance of maintaining daily fluid intake to achieve urine output of > 2 L per day  The benefits and adverse effects of medicines for preventing kidney stone recurrence  Dietary changes that may be beneficial in preventing kidney stone recurrence (eliminating soft drinks acidified solely with phosphoric acid, increasing calcium-rich foods, and limiting oxalate-containing foods) What To Discuss With Your Patients and Their Caregivers Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61. Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.