Nephrolithiasis is a chronic condition for which preventive dietary and pharmacological interventions play an important management role. Traditionally, providers have screened for metabolic abnormalities on the results of a 24-hour urine collection, which can give insight into the pathophysiology of stone formation and help the provider identify specific interventions.¹ While it is known that clinicians at least modify and tailor pharmacologic treatment based on testing,² only 1 observational study has shown a reduction in stone events among recurrent, stone-forming patients who received testing.³ Three studies have reported no differences in rates of recurrent stone events between patients with and without 24-hour testing.^4-6 Accordingly, the American College of Physicians did not endorse testing,⁷ stating the evidence is insufficient to conclude testing is beneficial. However, it should be noted that those guidelines predated these more recent studies.

There is the possibility that initiating pharmacological therapy without 24-hour urine testing—also called empirical therapy—may be beneficial to reducing kidney stone recurrence.⁸ The rationale for empirical therapy is supported by several randomized controlled diet and pharmacologic trials in which the identification of baseline urinary calcium, oxalate, and citrate did not predict symptomatic kidney stone recurrence.⁹ Some positive trials of citrate therapy did not require the intervention group to have low urinary citrate. The same was true for several thiazide trials that did not require elevated urinary calcium as an inclusion criteria. The only positive diet intervention trial by Borghi et al did not require more than elevated urinary calcium among eligible participants (and was performed only in men).

No prior trials have compared selective vs empirical pharmacological intervention strategies. The only study comparing empirical vs selective therapy was a diet-only intervention study among patients who had a first-time stone event.¹⁰ At 3 years, stone recurrence occurred in 7% of the selective therapy group and 23% of the empirical therapy group. However, a major flaw of this study was significant follow-up bias: only follow-up visits and 24-hour urine testing were performed in the selective therapy group. The empirical therapy group had sparse follow-up during the study.

Within this context, we initiated a National Institutes of Health–funded clinical trial to test selective and empirical prevention strategies among recurrent kidney stone formers (see Figure). We call this study the URINE Study: Urinary supersaturation in a Randomized trial among Individuals with Nephrolithiasis comparing Empirical vs selective therapy (clinicaltrials.gov identifier: NCT05365477). The study design and interventions were chosen based on consensus feedback from the EDGE Research Consortium. After randomization, participants in the empirical arm receive dietary counseling regarding intakes of fluids, sodium, sugary beverages, and animal protein, and they are prescribed indapamide and potassium citrate. Participants in the selective arm receive dietary counseling and medication specific to their 24-hour urine values, with adjustment of the interventions based on follow-up 24-hour urine testing at week 4. At week 8, a repeat 24-hour urine test will be performed to assess the primary outcomes of calcium oxalate and calcium phosphate supersaturation. Secondary outcomes assessed will include individual 24-hour urine parameters, side effects, and adherence.

We anticipate this study will determine the impact of empirical vs selective therapy on urinary supersaturation and acquire sufficient foundational data toward a future prospective study to assess symptomatic stone events. If selective therapy is beneficial for kidney stone prevention, then clinicians need the evidence to support using it. Empirical therapy, if established as an effective strategy, would lower the barrier for clinicians outside of urology and nephrology to promptly intervene without needing the expertise and specialized knowledge to interpret a 24-hour urine test. We also note that 24-hour urine testing may not be accessible for patients who are under-insured and is not available in many locations around the world. In these settings, empirical therapy may be the only choice. In summary, the answer to the question of comparative effectiveness of empirical vs selective therapy for kidney stone prevention directly affects every patient with kidney stone disease.