To cite this guideline:
Pearle MS, Goldfarb DS, Assimos DG et al: Medical management of kidney stones: AUA Guideline. J Urol 2014; 192: 316.

Published 2014; Reviewed and Validity Confirmed 2019

The purpose of the clinical guideline on Medical Management of Kidney Stones is to provide a clinical framework for the diagnosis, prevention and follow-up of adult patients with kidney stones based on the best available published literature. Topics covered include evaluation, diet therapy, pharmacologic therapy, and follow-up.

Guideline as it appears in The Journal of Urology® [pdf]
Unabridged version of this Guideline [pdf]
Español translated guideline courtesy of Confederacion Americana de Urologia (CAU) [pdf]

Margaret Sue Pearle, MD, PhD.; David S. Goldfarb, MD; Dean G. Assimos, MD; Gary Curhan, MD; Cynthia J Denu-Ciocca, MD; Brian R. Matlaga, MD; Manoj Monga, MD; Kristina Lea Penniston, PhD Glenn M. Preminger, MD; Thomas M.T. Turk, MD; James Robert White, PhD

Purpose

The purpose of this guideline is to provide a clinical framework for the diagnosis, prevention and follow-up of adult patients with kidney stones based on the best available published literature.

Methods

The primary source of evidence for this guideline was the systematic review and data extraction conducted as part of the Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review titled Recurrent Nephrolithiasis in Adults: Comparative Effectiveness of Preventative Medical Strategies (2012). That report included rigorous searches of MEDLINE, the Cochrane Database of Systematic Reviews, Google Scholar and ClinicalTrials.gov for English-language studies published from 1948 through November 2011 relevant to recurrent nephrolithiasis in adults. To augment and broaden the body of evidence provided in the original AHRQ report, the American Urological Association (AUA) conducted additional supplementary searches of PubMed and EMBASE for relevant articles published between January 2007 and November 2012 that were systematically reviewed using a methodology developed a priori. In total, these sources yielded 46 studies that were used to inform the statements presented in the guideline as Standards, Recommendations or Options. When sufficient evidence existed, the body of evidence for a particular clinical action was assigned a strength rating of A (high), B (moderate) or C (low). In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. While some of the statements in this guideline may be applicable to the pediatric population, this patient group was not the focus of our systematic review due to the limited number of relevant studies available.

Guideline Statements

Evaluation

1. A clinician should perform a screening evaluation consisting of a detailed medical and dietary history, serum chemistries and urinalysis on a patient newly diagnosed with kidney or ureteral stones. (Clinical Principle)

2. Clinicians should obtain serum intact parathyroid hormone (PTH) level as part of the screening evaluation if primary hyperparathyroidism is suspected. (Clinical Principle)

3. When a stone is available, clinicians should obtain a stone analysis at least once. (Clinical Principle)

4. Clinicians should obtain or review available imaging studies to quantify stone burden. (Clinical Principle)

5. Clinicians should perform additional metabolic testing in high-risk or interested first-time stone formers and recurrent stone formers. (Standard; Evidence Strength: Grade B)

6. Metabolic testing should consist of one or two 24-hour urine collections obtained on a random diet and analyzed at minimum for total volume, pH, calcium, oxalate, uric acid, citrate, sodium, potassium and creatinine. (Expert Opinion)

7. Clinicians should not routinely perform "fast and calcium load" testing to distinguish among types of hypercalciuria. (Recommendation; Evidence Strength: Grade C)

Diet Therapies

8. Clinicians should recommend to all stone formers a fluid intake that will achieve a urine volume of at least 2.5 liters daily. (Standard; Evidence Strength: Grade B)

9. Clinicians should counsel patients with calcium stones and relatively high urinary calcium to limit sodium intake and consume 1,000-1,200 mg per day of dietary calcium. (Standard; Evidence Strength Grade: B)

10. Clinicians should counsel patients with calcium oxalate stones and relatively high urinary oxalate to limit intake of oxalate-rich foods and maintain normal calcium consumption. (Expert Opinion)

11. Clinicians should encourage patients with calcium stones and relatively low urinary citrate to increase their intake of fruits and vegetables and limit non-dairy animal protein. (Expert Opinion)

12. Clinicians should counsel patients with uric acid stones or calcium stones and relatively high urinary uric acid to limit intake of non-dairy animal protein. (Expert Opinion)

13. Clinicians should counsel patients with cystine stones to limit sodium and protein intake. (Expert Opinion)

Pharmacologic Therapies

14. Clinicians should offer thiazide diuretics to patients with high or relatively high urine calcium and recurrent calcium stones. (Standard; Evidence Strength Grade B)

15. Clinicians should offer potassium citrate therapy to patients with recurrent calcium stones and low or relatively low urinary citrate. (Standard; Evidence Strength Grade B)

16. Clinicians should offer allopurinol to patients with recurrent calcium oxalate stones who have hyperuricosuria and normal urinary calcium. (Standard; Evidence Strength Grade B)

17. Clinicians should offer thiazide diuretics and/or potassium citrate to patients with recurrent calcium stones in whom other metabolic abnormalities are absent or have been appropriately addressed and stone formation persists. (Standard; Evidence Strength Grade B)

18. Clinicians should offer potassium citrate to patients with uric acid and cystine stones to raise urinary pH to an optimal level. (Expert Opinion)

19. Clinicians should not routinely offer allopurinol as first-line therapy to patients with uric acid stones. (Expert Opinion)

20. Clinicians should offer cystine-binding thiol drugs, such as alpha-mercaptopropionylglycine (tiopronin), to patients with cystine stones who are unresponsive to dietary modifications and urinary alkalinization, or have large recurrent stone burdens. (Expert Opinion)

21. Clinicians may offer acetohydroxamic acid (AHA) to patients with residual or recurrent struvite stones only after surgical options have been exhausted. (Option; Evidence Strength Grade B)

Follow-up

22. Clinicians should obtain a single 24-hour urine specimen for stone risk factors within six months of the initiation of treatment to assess response to dietary and/or medical therapy. (Expert Opinion)

23. After the initial follow-up, clinicians should obtain a single 24-hour urine specimen annually or with greater frequency, depending on stone activity, to assess patient adherence and metabolic response. (Expert Opinion)

24. Clinicians should obtain periodic blood testing to assess for adverse effects in patients on pharmacological therapy. (Standard; Evidence Strength Grade: A)

25. Clinicians should obtain a repeat stone analysis, when available, especially in patients not responding to treatment. (Expert Opinion)

26. Clinicians should monitor patients with struvite stones for reinfection with urease-producing organisms and utilize strategies to prevent such occurrences. (Expert Opinion)

27. Clinicians should periodically obtain follow-up imaging studies to assess for stone growth or new stone formation based on stone activity (plain abdominal imaging, renal ultrasonography or low dose computed tomography [CT]). (Expert Opinion)

Purpose

Kidney stone disease is a common malady, affecting nearly 1 in 11 individuals in the United States at some point in their lives, and there is evidence that the number of those who have had a stone is rising.¹ Unlike appendicitis and other surgical conditions, surgical treatment of stones is not the endpoint of the disease process, as stones are likely to recur, with at least 50% of individuals experiencing another stone within 10 years of the first occurrence.² For those who have experienced a stone or undergone surgical intervention for a stone, there is strong motivation to avoid a repeat episode. Consequently, these patients often seek advice from a variety of practitioners on how to prevent recurrent stones. However, misinformation abounds in the lay community and on the internet, and even medical providers often promulgate recommendations that are contrary to evidence-based medicine.³ This Guideline is aimed at practitioners from a variety of disciplines who are confronted with patients afflicted with stone disease, and it is based on a systematic review of the literature with respect to the evaluation, treatment and follow-up of first-time and recurrent stone formers. Patient preferences and goals must be taken into account by the practitioner when considering these guidelines, as the cost, inconvenience and side effects of drugs and dietary measures to prevent stone disease must be weighed against the benefit of preventing a recurrent stone.

Methodology

The primary source of evidence for this guideline was the systematic review and data extraction conducted as part of the Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review Number 61 titled Recurrent Nephrolithiasis in Adults: Comparative Effectiveness of Preventative Medical Strategies (2012). That report, prepared by the University of Minnesota Evidence-Based Practice Center (EPC), included searches of MEDLINE, the Cochrane Database of Systematic Reviews, Google Scholar, ClinicalTrials.gov and Web of Science for English-language studies published from 1948 through November 2011 relevant to the treatment of recurrent nephrolithiasis in adults.

Eligible studies included RCTs and large prospective observational trials of patient populations limited to adults aged 18 years or older with a history of one or more past kidney stone episodes. Studies addressing acute pain management and treatment to promote expulsion of stones were excluded. Full details of the AHRQ search strategies and inclusion/exclusion criteria can be found in the original report.

To augment and broaden the body of evidence provided in the AHRQ report, AUA conducted additional supplementary searches of PubMed and EMBASE for relevant articles published between January 2007 and November 2012, which were systematically reviewed using a methodology developed a priori. Study populations were limited to adults 18 years or older with one or more past kidney stone episodes. No limitations on study design were set, however the search protocol prioritized RCTs, CCTs and prospective studies with a comparison group. A total of 3,760 abstracts were obtained, from which 24 articles were selected for full-text review. All dietary and pharmacologic therapies were acceptable, with the exception of interventions addressing acute pain management for urolithiasis, treatment to promote expulsion of ureteral stones, pharmacological agents not approved by the FDA for use in the United States, and finally imaging for suspected acute renal colic. Outcomes of interest included stone recurrence (symptomatic/asymptomatic detection through imaging) and other clinical outcomes relevant to kidney stones: changes in stone size, residual stone clearance, intermediate biochemical changes in urine or blood, quality of life, morbidity related to treatment of recurrent stones as well as adverse event outcomes.

Overall, this supplementary review identified 18 studies to complement the 28 RCTs identified by the AHRQ report. Data on study design, treatment parameters (e.g., dose, administration protocols, follow-up durations), patient characteristics (i.e., age, gender, race, stone composition), adverse events, and primary outcomes (as defined by study authors) were extracted to evidence tables for analysis and synthesis by the methodologist.

Quality of Studies and Determination of Evidence Strength. Quality of individual studies was rated as high, moderate, or low based on instruments tailored to specific study designs. Randomized controlled trials (RCTs) were assessed using the Cochrane Risk of Bias instrument.⁴ Conventional diagnostic cohort studies, diagnostic case-control studies, or diagnostic case series that presented data on diagnostic test characteristics were evaluated using the QUADAS-2 tool⁵ that evaluates the quality of diagnostic accuracy studies. Cohort studies with a comparison of interest were evaluated with the Newcastle-Ottawa scale.⁶

The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes consideration of study design, individual study quality, consistency of findings across studies, adequacy of sample sizes, and generalizability of samples, settings and treatments for the purposes of the guideline. The AUA categorizes body of evidence strength as Grade A (well-conducted RCTs or exceptionally strong observational studies), Grade B (RCTs with some weaknesses of procedure or generalizability or generally strong observational studies) or Grade C (observational studies that are inconsistent, have small sample sizes or have other problems that potentially confound interpretation of data).

AUA Nomenclature: Linking Statement Type to Evidence Strength. The AUA nomenclature system explicitly links statement type to body of evidence strength and the Panel's judgment regarding the balance between benefits and risks/burdens.⁷ Standards are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade A or Grade B evidence. Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade C evidence. Options are non-directive statements that leave the decision to take an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears relatively equal or appears unclear; the decision is based on full consideration of the patient's prior clinical history, current quality of life, preferences and values. Options may be supported by Grade A, B or C evidence.

In some instances, the review revealed insufficient publications to address certain questions from an evidence basis; therefore, some statements are provided as Clinical Principles or as Expert Opinions with consensus achieved using a modified Delphi technique if differences of opinion emerged.⁸ A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge and judgment for which there is no evidence.

Limitations of the Literature. The Panel proceeded with full awareness of the limitations of the kidney stone literature. These limitations include heterogeneous patient groups, small sample sizes, lack of studies with diagnostic accuracy data, lack of RCTs or controlled studies with patient outcome data, and use of a variety of outcome measures. Overall, these difficulties precluded use of meta-analytic procedures or other quantitative analyses. Instead, narrative syntheses were used to summarize the evidence for the questions of interest.

Panel Selection and Peer Review Process. The Panel was created by the American Urological Association Education and Research, Inc. (AUA). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chair and Vice Chair who in turn appointed the additional panel members, all of whom have specific expertise with regard to the guideline subject. Once nominated, panel members are asked to record their conflict of interest (COI) statements, providing specific details on the AUA interactive web site. These details are first reviewed by the Guidelines Oversight Committee (GOC), a member sub-committee from the PGC consisting of the Vice Chair of the PGC and two other members. The GOC determines whether the individual has potential conflicts related to the guideline. If there are no conflicts, then the nominee's COI is reviewed and approved by the AUA Judicial and Ethics (J&E) committee. A majority of panel members may not have relationships relevant to the guideline topic.

The AUA conducted an extensive peer review process. The initial draft of this Guideline was distributed to 107 peer reviewers of varying backgrounds; 40 responded with comments. The panel reviewed and discussed all submitted comments and revised the draft as needed.

Once finalized, the Guideline was submitted for approval to the PGC. It was then submitted to the AUA Board of Directors for final approval. Funding of the panel was provided by the AUA. Panel members received no remuneration for their work.

Background

Although calculi can form de novo anywhere within the urinary tract, including the kidneys, bladder and prostate, the pathophysiology related to stone formation differs according to the site of origin. The focus of this Guideline is on renal calculi as these stones are the main source of morbidity, cost and resource utilization associated with urinary tract calculi.

Kidney stone disease is a common condition. According to the most recent National Health and Nutrition Examination Survey (NHANES), the overall prevalence of self-reported kidney stones in the period 2007-2010 was 8.8%, with a higher prevalence among men (10.6%) than among women (7.1%).¹ This prevalence represents a 70% increase over the last reported prevalence (5.2%) derived from an NHANES sample (1988-1994), and the increased prevalence was observed across all age groups and in both sexes. However, prevalence data pose some problems. Unlike other conditions, like appendicitis, for which the diagnosis is readily apparent and can be confirmed by a pathology report, stone disease can be asymptomatic and occurs intermittently and repeatedly. Some individuals harbor undiagnosed stones and require no medical attention, while others necessitate repeated medical encounters for a single stone. Consequently, stone prevalence depends on the metric used as a surrogate for stone disease (e.g., hospital discharges for a diagnosis of stones, self-reported stones, stones identified on autopsy studies, stones identified on unrelated imaging studies as well as the sensitivity of the imaging modality used to diagnose stones). Most of these surrogates likely underestimate stone prevalence because of failure to detect asymptomatic stones, because of spontaneously passed stones that never involve health care resources, or because a stone was not substantiated by imaging studies or by the documentation of a passed stone despite a history of classic stone symptoms. As such, true stone prevalence is difficult to determine, and the best we can do is to define the parameter measured to determine prevalence.

Historically, kidney stones have occurred more commonly in men than in women. However, by any number of metrics, the gender gap in stone disease is closing.^9-11 Administrative data from the Nationwide Inpatient Sample showed a decline in the male-to-female ratio among hospital discharges with a primary diagnosis of kidney or ureteral stone from 1.7:1 in 1997 to 1.3:1 in 2002.¹¹ The change in the male-to-female ratio is thought to reflect a disproportionate increase in stone disease among women, rather than a decline among men.⁹ The reasons for the observed rise in stone disease among women are not certain, but the impact of obesity, a known risk factor for kidney stones, was found to be greater in women than in men.¹²

Stone disease has been linked to systemic conditions, although it is not clear if stone disease is a cause of these disorders or if it is a consequence of the same conditions that lead to these disorders. Overweight/obesity,^{1, 12} hypertension¹³ and diabetes¹⁴ have all been shown to be associated with an increased risk of stone disease.

With the increase in the prevalence of stone disease, the cost associated with diagnosis, treatment and follow-up of individuals with stones has risen accordingly. Using claims data from 25 large employers as part of the Urologic Disease in America Project, Saigal and colleagues estimated that the annual incremental health care cost per individual associated with a diagnosis of nephrolithiasis in year 2000 was $3,494, thereby resulting in a total direct cost of nephrolithiasis among the employed population of $4.5 billion.¹⁵ Additionally, since stone disease primarily affects the working-age population, the total direct and indirect costs associated with nephrolithiasis, taking into account the cost of lost workdays, was estimated at $5.3 billion that year.

Diet and lifestyle likely impact the risk of developing stones. The beneficial effect of dietary moderation in reducing the risk of recurrent stones was demonstrated by Hoskings and co-workers, who found a reduction in stone recurrence rate among 108 idiopathic calcium oxalate stone formers who were encouraged to maintain a high fluid intake and avoid "dietary excess".¹⁶ At a mean follow-up of 63 months, 58% of patients showed no new stone formation. Although there was no control group in this study, the favorable effect of dietary modification on stone formation was termed the "stone clinic effect," and it comprises the standard against which pharmacologic therapy is measured.

A number of dietary measures have been evaluated for their effect on stone formation. Unfortunately, few RCTs have compared the incorporation of specific dietary measures with no recommendations on recurrence rates in groups of well-defined stone formers. Those that have made such comparisons typically utilized multicomponent diets such that the independent effects of individual components cannot be determined.^17-19 However, a single RCT found reduced stone recurrence rates among recurrent calcium oxalate stone formers randomized to a high fluid intake compared to a comparable group given no specific recommendations (12% versus 27%, respectively, at 5 years), validating the long held notion that high fluid intake reduces the likelihood of stone recurrence.²⁰ The only specific beverage that has been evaluated for an effect on stone recurrence in an RCT is soft drinks, for which a group of 1,009 stone formers with a baseline soft drink consumption exceeding 160 ml daily were randomized to avoid soft drinks or continue their typical beverage consumption.²¹ The group avoiding soft drinks demonstrated a marginally lower rate of stone recurrence at the end of the three-year trial (58.2% versus 64.6%, respectively, p=0.023), but the effect appeared to be limited to those consuming primarily phosphoric acid-based (e.g. colas) rather than citric acid-based soft drinks.

Multicomponent diets have been evaluated for their effect on stone recurrence by combining dietary measures thought to individually reduce stone recurrence rates. A multicomponent diet consisting of normal calcium, low sodium, low animal protein intake was shown to be superior to a low calcium diet in preventing stone recurrence in hypercalciuric, recurrent calcium oxalate stone-forming men (20% versus 38% recurrence rate at 5 years, respectively).¹⁷ However, the independent effects of calcium, sodium and animal protein could not be assessed. Another multicomponent diet comprised of high fluid, high fiber, low animal protein intake surprisingly was not shown to be superior to a high fluid diet in preventing stone recurrence in a group of 102 first-time calcium oxalate stone formers.¹⁹ However, the control group was found to have higher urine volumes than the study group at two out of three visits, confounding the results. Another RCT also found no benefit of a low animal protein diet in reducing stone recurrence rates among 175 idiopathic calcium stone formers randomized to one of three groups: low animal protein diet, high fiber diet or a control group with no recommendations.²² There was no significant difference in recurrence rates among the three groups at the conclusion of the four-year trial. Consequently, only the combined effect of low sodium, low animal protein, normal calcium intake has been shown to reduce the likelihood of stone recurrence compared to low calcium intake. It remains unclear how much each of the dietary components contributes to the beneficial effect of the diet. Furthermore, the benefit of these diets was only definitively demonstrated in recurrent calcium stone-forming men.

In the absence of large numbers of well-designed RCTs for the evaluation of dietary measures on stone recurrence, three large cohort studies have been extensively analyzed to determine the independent effect of a variety of foods and supplements on incident stone formation: the Nurses' Health Study I (NHS I) comprised of 121,700 female registered nurses age 30-55, the Nurses' Health Study II (NHS II) comprised of a slightly younger cohort of 116,671 female registered nurses age 25-42 and the Health Professionals Follow-up Study (HPFS) comprised of 51,529 male health professionals age 40-75 years. In all three cohorts, subjects completed food frequency questionnaires and biennial surveys inquiring about different aspects of their health, including whether they had ever been diagnosed with a kidney stone.^23-32 These epidemiologic studies have implicated low calcium intake^{23, 24, 28, 29} (women and younger men), low fluid intake,^{23, 24, 28, 29} sugar-sweetened beverages³³ and animal protein^{23, 24, 28, 29} (men with a BMI >25 mg/kg²) as risk factors for the development of a first-time stone.

Other dietary measures have been evaluated in small metabolic trials, which in some cases validate the findings of large epidemiologic studies and RCTs, but sometimes do not. The endpoint of these studies is the effect of therapy on urinary stone risk factors, rather than actual stone formation, despite a clear lack of validation of these parameters as proxies for stone formation. Consequently, this Guideline focused primarily on RCTs using actual stone formation rate as the primary outcome, although the benefit of some therapies was inferred from the effect on urinary stone risk factors; the later treatment recommendations were made with a lower strength of evidence.

Drug therapies, primarily directed against specific metabolic abnormalities, have been shown to be superior to placebo, or no-treatment control groups, in randomized trials.³⁴ Unfortunately, RCTs in stone disease are relatively sparse, likely because the relative infrequency of the event requires long periods of observation. However, for the purposes of this guideline we focused on published RCTs to derive recommendations regarding pharmacologic therapy aimed at preventing stone recurrence. Interestingly, the benefit of directed medical therapy aimed at specific underlying metabolic abnormalities over empiric therapy administered without regard to metabolic background, has never been proven. Indeed, several RCTs have demonstrated a benefit of therapy in unselected groups of patients despite drug therapy targeted to address a specific metabolic abnormality, e.g., thiazides^{35, 36} or potassium magnesium citrate.³⁷ Thiazide diuretics, the best-studied drug therapy for stone prevention, along with high fluid intake, have been shown to reduce stone recurrence rates in recurrent calcium stone formers.³⁸ The effect is not necessarily limited to hypercalciuric stone formers, although even in trials in which patients were not selected on the basis of hypercalciuria, hypercalciuria was likely the most common metabolic abnormality. Along with high fluid intake, alkali citrate^{37, 39} and allopurinol^{40, 41} have each been shown to be effective in reducing the risk of calcium stones, although the effect of allopurinol is limited to hyperuricosuric and/or hyperuricemic patients. Thus, to be strictly accurate, recommendations by the Panel would have to be restricted to the specific groups of stone formers studied in the limited RCTs (i.e., hypercalciuric, recurrent calcium stone-forming men) to recommend a normal calcium, low animal protein, low sodium diet.¹⁷ However, in some cases, recommendations were broadened to include the larger stone-forming population, although the recommendation was supported with lower strength of evidence. Further study will be necessary to determine if these recommendations hold for women or for normocalciuric stone formers.

Diet therapy has never been compared head-to-head with pharmacologic therapy. As such, recommendations by the Panel incorporate drugs and/or diet therapy in select circumstances, until the superiority of one over the other can be demonstrated and to allow individualization for particular patients.

A clinician should perform a screening evaluation consisting of a detailed medical and dietary history, serum chemistries and urinalysis on a patient newly diagnosed with kidney or ureteral stones. (Clinical Principle

Clinicians should obtain serum intact parathyroid hormone (PTH) level as part of the screening evaluation if primary hyperparathyroidism is suspected. Clinical Principle

When a stone is available, clinicians should obtain a stone analysis at least once. Clinical Principle

Clinicians should obtain and review available imaging studies to quantify stone burden. Clinical Principle

Clinicians should perform additional metabolic testing in high-risk or interested first-time stone formers and recurrent stone formers. Standard; Evidence Strength: Grade B

Metabolic testing should consist of one or two 24-hour urine collections obtained on a random diet and analyzed at minimum for total volume, pH, calcium, oxalate, uric acid, citrate, sodium, potassium and creatinine. Expert Opinion

Clinicians should not routinely perform “fast and calcium load� testing to distinguish among types of hypercalciuria. Recommendation; Evidence Strength: Grade C

Clinicians should recommend to all stone formers a fluid intake that will achieve a urine volume of at least 2.5 liters daily. Standard; Evidence Strength: Grade B

Clinicians should counsel patients with calcium stones and relatively high urinary calcium to limit sodium intake and consume 1,000-1,200 mg per day of dietary calcium. Standard; Evidence Strength Grade: B

Clinicians should counsel patients with calcium oxalate stones and relatively high urinary oxalate to limit intake of oxalate-rich foods and maintain normal calcium consumption. Expert Opinion

Clinicians should encourage patients with calcium stones and relatively low urinary citrate to increase their intake of fruits and vegetables and limit non-dairy animal protein. Expert Opinion

Clinicians should counsel patients with uric acid stones or calcium stones and relatively high urinary uric acid that limitation of intake of non-dairy animal protein may help reduce stone recurrence. Expert Opinion

Clinicians should counsel patients with cystine stones to limit sodium and protein intake. Expert Opinion

Clinicians should offer thiazide diuretics to patients with high or relatively high urine calcium and recurrent calcium stones. Standard; Evidence Strength Grade B

Clinicians should offer potassium citrate therapy to patients with recurrent calcium stones and low or relatively low urinary citrate. Standard; Evidence Strength Grade B

Clinicians should offer allopurinol to patients with recurrent calcium oxalate stones who have hyperuricosuria and normal urinary calcium. Standard; Evidence Strength Grade B

Clinicians should offer thiazide diuretics and/or potassium citrate to patients with recurrent calcium stones in whom other metabolic abnormalities are absent or have been appropriately addressed and stone formation persists. Standard; Evidence Strength Grade B

Clinicians should offer potassium citrate to patients with uric acid and cystine stones to raise urinary pH to an optimal level. Expert Opinion

Clinicians should not routinely offer allopurinol as first-line therapy to patients with uric acid stones. Expert Opinion

Clinicians should offer cystine-binding thiol drugs, such as alpha-mercaptopropionylglycine (tiopronin), to patients with cystine stones who are unresponsive to dietary modifications and urinary alkalinization, or have large recurrent stone burdens. Expert Opinion

Clinicians may offer acetohydroxamic acid (AHA) to patients with residual or recurrent struvite stones only after surgical options have been exhausted. Option; Evidence Strength Grade B

Clinicians should obtain a single 24-hour urine specimen for stone risk factors within six months of the initiation of treatment to assess response to dietary and/or medical therapy. Expert Opinion

After the initial follow-up, clinicians should obtain a single 24-hour urine specimen annually or with greater frequency, depending on stone activity, to assess patient adherence and metabolic response. Expert Opinion

Clinicians should obtain periodic blood testing to assess for adverse effects in patients on pharmacological therapy. Standard; Evidence Strength Grade: A

Clinicians should obtain a repeat stone analysis, when available, especially in patients not responding to treatment. Expert Opinion

Clinicians should monitor patients with struvite stones for reinfection with urease-producing organisms and utilize strategies to prevent such occurrences. Expert Opinion

Clinicians should periodically obtain follow-up imaging studies to assess for stone growth or new stone formation based on stone activity (plain abdominal imaging, renal ultrasonography or low dose computed tomography [CT]). Expert Opinion

For a disease with relatively high incidence and prevalence, research in the prevention of kidney stone disease is surprisingly sparse. The reasons for the paucity of work have not been investigated but may relate to the facts that kidney stones are sporadic; that the associated pain and discomfort are transient; that recurrence rates in individuals may be high but episodes of renal colic may be separated by years; by a perception, right or wrong, that the pharmaceutical industry is not likely to find substantial profit in stone prevention. The recent AHRQ-sponsored review of medical management identified only 28 RCTs performed through 2012.³⁸

The interest in kidney stones has grown in recent years in two important respects, and we hope that these factors will stimulate further interest in understanding and treating stone disease. First, kidney stones appear to be increasing in prevalence.¹ Hypotheses regarding this phenomenon range from changes in diet (more salt and less dairy); the growing epidemics of metabolic syndrome, diabetes and obesity; the effects of global warming and the elimination of Oxalobacter formigenes by widespread exposure to antibiotics in the food supply and elsewhere. Prospective monitoring of kidney stone development in populations for whom these sorts of exposures are recorded would be most critical for learning more about the etiologies and root causes of stone disease.

Second, stones have consistently been shown to be associated with more morbidity than previously expected. Associations with coronary artery disease,¹⁵¹ hypertension¹³ and diabetes¹⁴ have led to questions about which of these factors are simply associations, and which, if any, are actually in the causal pathways. If stones precede these co-morbidities, we need to understand that relationship; if stones are another indicator of a metabolic alteration resulting from weight gain, we need to advance our efforts to intervene in our patients' diet and exercise regimens. The impression that stones may have more lasting effects or arise from factors that themselves are cardiovascular risk factors may help patients understand that renal colic is perhaps a sentinel event.

With those newsworthy trends in mind, perhaps the effort to prevent stones needs to be broadened to other populations of practitioners. Many patients never see a urologist, most never see a nephrologist, and few are evaluated and personally counseled regarding individualized regimens to address stone prevention. Primary care practitioners and physician extenders are experts at counseling weight loss, exercise and smoking cessation. If research regarding implementation of stone prevention regimens in emergency rooms and primary care offices advanced, stone recurrence could be the purview of a vastly larger pool of practitioners. Along with the potential to prevent and relieve human suffering, there is ample reason to believe that kidney stone prevention research could have economic impact as well.¹⁵ A wide range of healthcare providers are capable of implementing such strategies without a very sophisticated view of urine chemistry.

We note that although both dietary manipulation¹⁷ and medications such as thiazides, allopurinol and citrate³⁸ have all been shown to have efficacy in kidney stone prevention, the relative merits of diet and medications have never been compared head-to-head. There may be important patient-centered variables that determine which stone formers are best able to adhere to a medication and respond favorably and which prefer dietary manipulation. Determination of the characteristics of patients who do well incorporating one or the other or both would provide an important aid to practitioners interested in prescribing successful preventive strategies. Whether modifying these exposures will change stone prevalence must be examined.

Furthermore, it is hopeful that the revolution in genetics will lend power to the diagnosis and prevention of disease, and progress is indeed being made slowly. The recent discovery of mutations in CYP24A1, the gene encoding the 24-hydroxylase that inactivates 1,25-dihydroxy vitamin D, as a cause of hypercalcemia and kidney stones,^152-154 serves as an example that genetics can uncover important genotype-phenotype correlations. Rare genetic causes of kidney stones are being thoroughly investigated and may yield insights into the mechanisms and treatments of more common idiopathic disease affecting wider populations.¹⁵⁵ However the genetic basis for the widespread prevalence of kidney stones in the United States remains relatively unsolved.

Finally, we are only just beginning to understand the potential importance of the intestinal microbiome in the determination of urinary chemistry. Clearly dietary intake is not the sole variable influencing urinary output; an appropriate complement of intestinal microbiota will serve an important role. We have been most familiar with Oxalobacter formigenes, an obligate metabolizer of its only substrate, oxalate; its presence is associated with prevention of stones and its absence with increased urinary oxalate and more stones.¹⁵⁶ How the microbiome influences urinary lithogenicity and whether we can safely and productively manage the human microbiome using probiotics, prebiotics, fecal transplants and other strategies will be examined in the coming years.

In summary, there is no dearth of important kidney stone research questions to be raised. Kidney stones now appear to be related to chronic conditions that require a long-term view by a broad range of physicians, physician extenders and patients. They may be associated with adverse effects that either precede or follow stones; the directionality of those relationships needs to be understood. Strong evidence from an admittedly low number of clinical trials demonstrates that stones are indeed preventable.³⁵ There is now not only a need for new research into the causative and exacerbating factors associated with stones, but also a need to ensure that the acquired knowledge to prevent stones is shared with every stone former in a clinical setting.

Clinical Effectiveness Protocols for Imaging in the Management of Ureteral Calculous Disease: AUA Technology Assessment

Additional Educational Resources

Medical Management of Kidney Stones – Clinical Problem Solving (CPS) Protocol

Patient Educational Resources

Kidney Stones Filtered Resources

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This document was written by the Medical Management of Kidney Stones Guidelines Panel of the American Urological Association Education and Research, Inc., which was created in 2013. The Practice Guidelines Committee (PGC) of the AUA selected the committee chair. Panel members were selected by the chair. Membership of the committee included urologists and other clinicians with specific expertise on this disorder. The mission of the committee was to develop recommendations that are analysis-based or consensus -based, depending on Panel processes and available data, for optimal clinical practices in the treatment of kidney stones. Funding of the committee was provided by the AUA. Committee members received no remuneration for their work. Each member of the committee provides an ongoing conflict of interest disclosure to the AUA. While these guidelines do not necessarily establish the standard of care, AUA seeks to recommend and to encourage compliance by practitioners with current best practices related to the condition being treated. As medical knowledge expands and technology advances, the guidelines will change. Today these evidence-based guidelines statements represent not absolute mandates but provisional proposals for treatment under the specific conditions described in each document. For all these reasons, the guidelines do not pre-empt physician judgment in individual cases. Treating physicians must take into account variations in resources, and patient tolerances, needs, and preferences. Conformance with any clinical guideline does not guarantee a successful outcome. The guideline text may include information or recommendations about certain drug uses ('off label') that are not approved by the Food and Drug Administration (FDA), or about medications or substances not subject to the FDA approval process. AUA urges strict compliance with all government regulations and protocols for prescription and use of these substances. The physician is encouraged to carefully follow all available prescribing information about indications, contraindications, precautions and warnings. These guidelines and best practice statements are not in-tended to provide legal advice about use and misuse of these substances. Although guidelines are intended to encourage best practices and potentially encompass available technologies with sufficient data as of close of the literature review, they are necessarily time-limited. Guidelines cannot include evaluation of all data on emerging technologies or management, including those that are FDA-approved, which may immediately come to represent accepted clinical practices. For this reason, the AUA does not regard technologies or management which are too new to be addressed by this guideline as necessarily experimental or investigational.