Buyer Beware: Evidence-Based Evaluation of Dietary Supplements for Nephrolithiasis

Introduction

In the contemporary management of urinary stone disease, medical therapy can facilitate prevention of stone growth and new stone formation. ¹ For many patients, the use of medication or pharmacologic interventions may be preferable to surgery, is associated with minimal morbidity, and improves quality of life. However, due to the chronicity of stone disease, sustained adherence to medical therapies—high-volume fluid intake, long-term use of medication, and continual metabolic assessment—is generally poor, ² particularly among younger patients and those with lower socioeconomic status. ³ Furthermore, during acute stone episodes, pharmacologic interventions may not consistently facilitate spontaneous passage or stone dissolution for all stone types or locations. ^4,5

Numerous dietary supplements have recently been brought to the market with the purported benefit of kidney stone risk reduction. These products may be purchased without a prescription and make claims to reduce or prevent kidney stone formation. The use of these supplements, including vitamins, minerals, and herbs, is especially prevalent in the United States, where according to the U.S. Food and Drug Administration (FDA), three out of four individuals routinely consume dietary supplements. ⁶ The rising popularity of supplements has resulted in a 10-fold increase in the size of the industry in the past 25 years, from $4 billion to $40 billion. ⁷ However, the evidence for the varied claims that supplements may make is not always clear. Although the FDA is charged with overseeing the dietary supplement industry, the rigorous testing for safety and effectiveness that is required for prescription medications is not permitted by law for dietary supplements until after the products are marketed to consumers. ⁸ This relative lack of strict testing requirements, coupled with the large volume of brands and products on the market, makes effective regulatory oversight challenging and complicates patients' decisions to consume supplements and urologists' recommendations regarding their use.

The increasing overall prevalence of urinary stone disease suggests that patients' demand for dietary supplements may rise in parallel. Determining whether these supplements' claims to treat or prevent kidney stones are supported by evidence can help urologists provide more informed counseling to interested patients and avoid the morbidity of surgical intervention. This study aims to examine commercial dietary supplements marketed for kidney stones and assess the scientific evidence surrounding their use.

Materials and Methods

To capture a broad cross section of dietary supplements for kidney stones, two popular online marketplaces (Amazon and Google) were queried with stone-related key words (kidney stone, renal stone, ureter stone, ureteral stone, stone) with and without treatment-related terms (cure, dissolve, prevent, treatment, supplement). These online platforms were selected and used to mirror how patients may search for these products online. For each search, the first 50 product results were reviewed. Nonconsumable products and over-the-counter formulations of ion salts were excluded. All remaining products were assessed and included in the sample if the product description or label claimed to treat, cure, alleviate, or otherwise be used in the management of kidney stones. Products that did not have a publicly accessible label, including ingredients and instructions for use, were excluded.

For each product, product labels were reviewed to compile nonpharmacologically active ingredients, excluding vitamins and ion salts. The cost of a 30-day course of recommended treatment was assessed based on product's instructions for use. Each product's average consumer-assigned star rating was determined.

To assess the potential evidence for the ingredients, we queried MEDLINE/PubMed, Web of Science, and Google Scholar to capture data from published scientific literature, as well as books, monographs, scholarly websites, and other academic records. Each query consisted of the ingredient name and “kidney stone” or “stone” to narrow the results to stone-related studies. Non-English studies and conference proceedings were excluded. The abstract of each study was reviewed for relevance; the full text was reviewed to determine study design, form of administration, stone-related findings, and level of evidence. Two investigators independently performed the product reviews, literature searches, and evidence evaluation; differences were resolved by consensus. Descriptive statistics of the price, star rating, and ingredients of the supplements were determined using linear regression and Spearman correlation.

Ethical review was not required for this analysis of nonpatient public data.

Results

The initial queries returned 156 products related to nephrolithiasis. After 121 nonconsumable products (e.g., books, videos) and 8 dietary supplements without ingredient labels were excluded, 27 dietary supplements were included in the sample. Supplements made a variety of overlapping claims: 12 (44%) claimed to dissolve stones, 7 (26%) claimed to prevent stone formation, 6 (22%) claimed to reduce stone symptoms, and a majority (19, 70%) could be used to “support kidney health.” The mean 30-day cost was $32 (range $4–$189), and 10 (37%) supplements offered a money-back guarantee; the conditions eligible for a refund were unclear. In terms of consumer-assigned star ratings, most supplements were highly rated; the average rating was 4.2 stars on a five-star scale (range 3.4–5.0), and the majority of supplements (21 products, 78%) received ≥4 stars. There was no statistical association between the price and star rating of the supplements (p > 0.05). Table 1 summarizes the supplements included in the analysis.

Based on the ingredient labels, 56 unique ingredients were identified. Most supplements (17, 63%) contained multiple active ingredients, averaging 5.6 ingredients per product (Table 1). The number of active ingredients was not statistically associated with the price or star rating of the supplements (p > 0.05). After reviewing the literature on each of these ingredients, we found that nine ingredients (16%) had any published studies about their use in stone disease, and of these, only five ingredients (9%) had exclusively studies supporting their use in stone disease. The large majority of the ingredients (47, 84%) had no available scientific evidence for their use in treating or preventing kidney stones.

The 56 ingredients were categorized based on the kind of studies that were identified in the literature search: ingredients evaluated in human studies, those in animal studies, and those without any published studies for use in stone disease. Six ingredients had ≥1 human studies in the literature: Phyllanthus niruri, cranberry, green tea leaf, pomegranate, Tribulus terrestris, and citric acid. These six ingredients were found in up to 20 supplements in the sample. Similarly, in the nonexclusive animal study category, six ingredients had ≥1 animal studies in the literature, and these six ingredients were found in up to 20 products. Finally, no scientific studies were identified about the remaining 47 ingredients, each of which was included in up to 7 of the supplements. Price and star rating were not statistically associated with containing any active ingredient with human or animal studies, or with containing only active ingredients with human or animal studies (all p > 0.05). Table 2 summarizes the categories of studies for the ingredients.

There were 18 scientific publications in the literature about the treatment and prevention of kidney stones using the identified ingredients. Of these, six animal and human studies (33%) showed mixed or no benefit in stone disease. Seven animal studies (39%) and five human studies (28%) supported the ingredient's use in kidney stones. The majority of these studies were small, nonrandomized trials involving fewer than 30 patients, with a primary outcome of alterations in the biochemical composition of the serum or urine. The human studies are summarized in Supplementary Table S1. No statistical association was found between supplements containing any active ingredients supported by scientific studies and their price or star rating (p > 0.05).

Overall, among the 27 supplements, 18 (67%) consisted partially or entirely of ingredients with conflicting, refuting, or absent evidence of benefit in stone disease.

Discussion

In the setting of an increasing prevalence of urinary stone disease among adults, numerous dietary supplements claiming to treat or prevent stones have become commercially available. In this study of dietary supplements with specific claims of benefit for kidney stones, we found that two-thirds of the supplements contained active ingredients that were not supported by scientific evidence for use in stone disease. Of the 56 ingredients that were identified on product labels, only 9 (16%) had published studies about their effects in humans or animal studies. Despite variable costs and high consumer satisfaction with the products, there was no statistical relationship with the number of ingredients or with having an ingredient supported by scientific evidence.

This is the first study assessing the breadth of and evidence for commercially available dietary supplements marketed for the treatment and prevention of kidney stone disease. Consumer demand for dietary supplements, and complementary and alternative medicine in general, continues to rise overall. In the United States, the National Health and Nutrition Examination Survey has longitudinally surveyed the population regarding dietary supplements in adults and children since 1971, demonstrating a consistent upward trend in overall use and in the number of supplemental products consumed by individuals. ⁹ The common prevalence of urologic conditions impacting quality of life, such as benign prostatic hyperplasia and erectile dysfunction, has likely augmented the use of dietary supplements among urology patients. A study of the evidence supporting dietary supplements labeled for lower urinary tract symptoms related to prostatic enlargement found that nearly three-quarters of the products contained one or more ingredients not supported by scientific evidence. ¹⁰ The most common ingredient in the supplements was saw palmetto, which, despite several randomized, placebo-controlled trials showing no benefit in reducing symptom scores, ^11,12 continues to be widely used by patients. Similarly, among dietary supplements marketed to increase testosterone levels, only one-quarter were supported by evidence to be effective, while 10% contained ingredients that were implicated in lowering testosterone levels. ¹³

Prior studies of over-the-counter nutraceuticals have concluded inconsistent or poor overall benefit in stone disease. For instance, an in vitro analysis of probiotic formulations claiming to contain Oxalobacter formigenes did not identify any oxalate-degrading organisms when grown in culture, suggesting unlikely benefit in oxalate stone formers. ¹⁴ In addition to physiologic efficacy, economic considerations may also motivate patients to try nonprescription alternatives. Potassium citrate is frequently used as a urine alkalinizing agent to reduce lithogenic risk, compared with prescription-strength formulations, over-the-counter alkalinizing agents appear to be substantially less expensive, although they potentially contain fewer citrate alkali equivalents. ¹⁵ In our study, the presence or absence of evidence-based support for the ingredients or product was not associated with product price or consumer ratings, on which patients may rely to make purchasing decisions. Furthermore, many labels recommend taking the supplements two to three times daily (Table 1), each with multiple glasses of water; it is possible that any perceived benefit of the supplements could be achieved through guideline-recommended water gluttony, ¹ although the evidence review could not definitively confirm this.

This study has several limitations. First, we found no studies or trials directly assessing the efficacy or outcomes of the specific products that were included in this analysis, so we cannot surmise that the inclusion of ingredients with scientific evidence supporting their use in kidney stone disease should necessarily result in the expected benefit. Second, product prices and consumer star ratings may be highly variable over time, particularly in online platforms such as the ones we queried to develop our sample. Our cross-sectional price and rating data may not reflect longitudinal trends, and star ratings are subject to biases of raters and manufacturers. However, based on the universally high star ratings of nearly all the supplements, it is unlikely that accounting for the variation would result in clinically or statistically meaningful differences. Third, we did not include non-English-language publications and evidence sources in our assessment. Scientific analyses of the herbal and alternative medicine ingredients in the supplements, which may be influenced by geographic or cultural factors, could have been missed by our search criteria. We did use Google Scholar to capture nonjournal sources, such as books, monographs, and other academic sources. Although we did not include the clinical entities “nephrolithiasis” or “urolithiasis” in our search terms, our results likely include and are representative of the existing literature on the ingredients. Finally, Amazon and Google do not make detailed product sales data publicly accessible, so it was challenging to estimate how large the market for stone supplements actually is to assess its economic impact. However, the rising prevalence of stone disease in adults, coupled with the relatively large number of unique dietary products that were found during the searches, suggests that the demand for supplements to treat and prevent stones remains high.

Despite these limitations, this study has important implications. Dietary supplements are likely to remain popular among patients who prefer nonsurgical management of their urologic conditions. While advances in ureteroscopic lithotripsy and percutaneous nephrolithotomy have reduced the morbidity of stone surgery, ureteral stent-related symptoms, including flank pain and irritative lower urinary tract symptoms, may adversely impact patients' quality of life. ¹⁶ Patients may also encounter increased expense ¹⁵ and perceive negative health-related quality of life associated with the side effects of medications commonly prescribed in stone disease, ¹⁷ such as potassium citrate and thiazides, despite contrary evidence of experienced changes in quality-of-life parameters among patients taking these medications compared with nontakers. ¹⁸ For patients who are interested in dietary supplements and other complementary therapies, urologists should counsel that for the majority of ingredients, there are inadequate or absent data to give patients evidence-based recommendations. The commercial proliferation of new supplements suggests that rigorous trials for each product may be infeasible, but additional studies of commonly used ingredients would improve the strength of these recommendations.

The less stringent regulation of dietary supplements compared with prescribed substances by the FDA increases the likelihood that some products may improperly contain pharmacologic ingredients. ¹⁹ For instance, the FDA has issued numerous warnings against commercial supplements for low testosterone and erectile dysfunction, often marketed as “male enhancement” products. In 2018 alone, 37 FDA Public Notifications were issued for 37 sexual enhancement products, which were adulterated with traces of phosphodiesterase-5 inhibitors. ²⁰ Even when the FDA recalls tainted supplements, the regulatory action may not result in elimination from the marketplace; one study of recalled supplements showed that 6 months after the recall, two-thirds remained tainted with banned substances. ²¹ The different regulatory processes governing dietary supplements also make it possible for manufacturers to rebrand and relabel products frequently, which may contribute to consumer confusion and potential harm. Furthermore, injury due to dietary supplements is not theoretical; one study of the U.S. emergency departments estimated that 23,000 emergency visits annually are attributable to adverse events associated with dietary supplements. ²²

Finally, the purity of listed ingredients in each product and the consistency of the concentration contained in each tablet are not subject to the same standards as prescription drugs. While the FDA oversees regulations for manufacturing practices, the responsibility for ensuring product safety lies with the manufacturer, and the agency specifically does not analyze the content of dietary supplements or enforce that the content matches the amount declared on the label. ⁸ It is prudent to advise patients that, in the context of looser FDA oversight and the proliferation of products in the commercial marketplace, the absence of demonstrated negative effects of dietary supplements in the literature does not necessarily mean that these products do not cause harm.

Conclusions

Among commercial dietary supplements claiming to treat or prevent kidney stones, two-thirds contained ingredients with conflicting or no scientific evidence to support these claims. Patients who wish to use these supplements in the management of stone disease should be counseled that for the majority of ingredients, the absence of scientific evidence about their use in stone disease does not imply benefit and cannot rule out potential harm.