Empiric Versus Selective Prevention Strategies for Kidney Stone Disease

Randomized Trial of Empiric Versus Selective Prevention Strategies for Kidney Stone Disease

The aims of this study are to 1) Conduct a randomized clinical trial of selective versus empiric diet plus pharmacologic therapy in high-risk stone formers and 2) Determine adverse effects from, and adherence to selective and empiric strategies.

Study Overview

• Status: Completed
• Conditions: Nephrolithiasis; Kidney Stones
• Intervention / Treatment: Behavioral: Empiric Therapy: Diet; Drug: Empiric Therapy: Drug; Behavioral: Selective Therapy: Diet; Drug: Selective Therapy: Drug

Detailed Description

Diet and pharmacologic interventions for preventing future kidney stone episodes are effective, however clinical guideline panels disagree on whether clinicians should perform selective therapy: performing 24-hour urine testing to guide choosing interventions to correct abnormal urinary parameters. The alternative strategy is empiric therapy: applying interventions without 24-hour urine testing. While 24-hour urine testing is considered the standard of care by nephrology and urology specialties for higher risk patients, the American College of Physicians does not recommend 24-hour urine testing.

This is a randomized clinical trial of selective versus empiric therapy for patients with presumed idiopathic calcium stone disease, representing >80% of the kidney stone population. The primary outcome is change in urinary supersaturation, which associates with symptomatic stone recurrence. We will recruit patients with presumed idiopathic calcium stone disease with at least 2 stone events within the previous 5 years. Participants will be randomly assigned to empiric diet plus thiazide with potassium citrate daily, or to selective diet plus pharmacologic therapy based on the 24-hour urine abnormalities identified at baseline and adjusted during follow-up. The primary outcomes will be the calculated calcium oxalate and calcium phosphate supersaturations. In addition, we will determine adverse effects from, and adherence to, selective and empiric strategies.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Two or more symptomatic kidney stone events in the last 5 years
• Adult

Exclusion Criteria:

• Medullary sponge kidney or renal tubular acidosis
• Untreated urinary obstruction
• Primary hyperparathyroidism
• Primary hyperoxaluria
• Pregnancy
• Inflammatory bowel disease or bowel resection
• Sarcoidosis
• Cystinuria
• Prior stone composition with uric acid, struvite, cystine, carbonate apatite
• Use of specific medications (thiazides, topiramate, xanthine oxidase inhibitors, citrate, bicarbonate)
• Chronic kidney disease stage 3 or higher (eGFR<60)
• Gouty arthritis or 3 gout episodes in 1 year
• Known allergy to study medications
• Hypokalemia or hyponatremia at screening.
• Age < 18 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Empiric Therapy; Diet intervention and drug intervention not based on 24 hour urine results	Behavioral: Empiric Therapy: Diet; Diet: High water intake - at least 2.5 liters daily Reduce sugar-sweetened cola intake to ≤3 cans per week. Reduce salt intake to <2000mg sodium daily Reduce red meat intake to two 4-ounce portions per week Normal calcium intake: 3 servings of dairy products (or their equivalents) per day Increase vegetable and fruit intake to ≥5 servings per day Reduce oxalate intake to <100 mg/day; Drug: Empiric Therapy: Drug; Drug(s): indapamide 1.25mg and potassium citrate 15mEq daily.
Experimental: Selective Therapy; Diet intervention and drug intervention based on 24 hour urine results	Behavioral: Selective Therapy: Diet; Diet: Volume <2.5L Increase fluid intake to ≥ 2.5L/d, based on specific urine volume Calcium >250mg male, >200mg female Reduce red meat intake to two 4-oz portions/wk; reduce sodium intake to<2000mg/d, avoid vitamin D + calcium supplements Oxalate >40mg Reduce dietary oxalate intake to <100 mg/d; increase fiber intake to 25-35 g/d Citrate <450mg male, <550mg female Reduce red meat intake to two 4-oz portions/wk; increase fruit and vegetable intake to ≥5 svgs/d pH<5.8 Reduce red meat intake to two 4-oz portions/wk; increase fruit and vegetable intake to ≥5 svgs/d Uric acid >800mg male, >750mg female Reduce red meat intake to two 4- oz portions/wk; increase fruit and vegetable intake to ≥5 svgs/d Sodium >150mmol Reduce sodium intake to <2000mg/d Sulfate > 80mEq or urine urea nitrogen >14g Reduce red meat intake to three 3-4 oz portions/wk; increase fruit and vegetable intake to ≥5 svgs/d; Drug: Selective Therapy: Drug; Drug(s): For calcium >250mg male, >200mg female: indapamide 1.25mg and potassium chloride 20mEq. At 1 month if persistent, then increase to indapamide 2.5mg and potassium chloride 20mEq. For citrate <450mg male, <550mg female: potassium citrate 15mEq BID. At 1 month if persistent, then increase to potassium citrate 30mEq BID. For pH<5.8: potassium citrate 15mEq BID. At month if persistent, then increase to potassium citrate 30mEq BID. For uric acid >800mg male, >750mg female: allopurinol 300mg. If both elevated calcium and low pH: indapamide 1.25mg and potassium citrate 15mEq BID If both elevated calcium and low citrate: indapamide 1.25mg and potassium citrate 15mEq BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Calcium oxalate supersaturation	Calculated calcium oxalate supersaturation in urine	Baseline compared to two months
Calcium phosphate supersaturation	Calculated calcium phosphate supersaturation in urine	Baseline compared to two months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Uric acid supersaturation	Calculated uric acid supersaturation in urine	Baseline compared to two months
24hr urine parameters	Urinary volume, calcium, oxalate, potassium, citrate, pH, uric acid, and sodium	Baseline compared to two months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kidney stone events	Assessment of short term kidney stone events by self report and clinical imaging, if available	Baseline to 2 months
Adverse events	Assessment of adverse events - subjective and new hypokalemia, hyponatremia, hypomagnesemia, gouty arthritis or requiring uric acid lowering therapy, newly developed overt diabetes mellitus, allergic reactions, abnormal heart rate and blood pressure.	Baseline to 2 months
Diet adherence	Food diaries	Baseline to 2 months
Medication adherence	Pill counts	Baseline to 2 months
24hr urine parameters from baseline to month 1	Calculated urinary supersaturations of calcium oxalate, calcium phosphate, uric acid, and urinary volume, calcium, oxalate, potassium, citrate, pH, uric acid, and sodium	Baseline to 1 month
24hr urine parameters from month 1 to month 2	Calculated urinary supersaturations of calcium oxalate, calcium phosphate, uric acid, and urinary volume, calcium, oxalate, potassium, citrate, pH, uric acid, and sodium	1 month to 2 months

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Ryan Hsi, MD, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 4, 2022
• Primary Completion (Actual): September 26, 2025
• Study Completion (Actual): March 31, 2026

Study Registration Dates

• First Submitted: May 4, 2022
• First Submitted That Met QC Criteria: May 4, 2022
• First Posted (Actual): May 9, 2022

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Prevention
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Calculi; Pathological Conditions, Anatomical; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urolithiasis; Urinary Calculi; Pathological Conditions, Signs and Symptoms; Kidney Calculi; Nephrolithiasis
• Other Study ID Numbers: 200238

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes