Recurrent Nephrolithiasis in Adults: Comparative Effectiveness of Preventive Medical Strategies

Recurrent Nephrolithiasis in Adults: Comparative

Effectiveness ofPreventive Medical Strategies

Prepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

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.

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


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


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


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


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


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


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


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)


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?


Fink HA, Wilt TJ, Eidman KE, et al. AHRQ Comparative Effectiveness Review No. 61.

Available at http://www.effectivehealthcare.ahrq.gov/kidney-stones.cfm.

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?




The strength of evidence was classified into four broad categories:

Rating the Strength of Evidence From the Comparative Effectiveness Review


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)


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)


Table 1. Effects of Dietary Interventions on Risk of Urinary Stone Recurrence (1 of 2)


Intervention Comparator

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

Symptomatic

ARR = 7%, NNT = 14,RR = 0.83 (0.71 to 0.98)

Low

ARR = 16%, NNT = 6,RR = 0.65 (0.49 to 0.87)

LowEliminating 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

Table 1: Effects of Dietary Interventions on Risk of Urinary Stone Recurrence (2 of 2)


Intervention ComparatorMode 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

Composite ARR = 13%, NNT = 8RR = 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

Composite ARR = -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

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


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)


Citrate reduces the risk of calcium stone recurrence (composite): ARR = 41 percent; NNT = 3 (RR = 0.25 [95% CI, 0.14 to 0.44]).


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]).


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.




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.


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



*Composite endpoint = stones detected either by symptoms or scheduled radiographs

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


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)



* The strength of evidence for these findings was not rated.

** Composite endpoint = stones detected either by symptoms or scheduled radiographs.

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)


*The strength of evidence for these findings was not rated.

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*


*The strength of evidence for these findings was not rated.

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)


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.



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




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)



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)



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 andTheir Caregivers


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Recurrent Nephrolithiasis in Adults: Comparative Effectiveness of Preventive Medical Strategies