This single-center randomized controlled trial at Mount Sinai West will enroll 80 patients undergoing percutaneous nephrolithotomy for calcium oxalate stones. Participants will be randomized to receive either empiric therapy or selective therapy guided by 24-hour urine evaluation. The primary outcome is change in calcium oxalate supersaturation at 4 weeks, aiming to determine whether empiric therapy can provide outcomes comparable to selective therapy while simplifying access to prevention.

This is a single-center, randomized controlled trial evaluating the effectiveness of empiric versus selective medical therapy for the prevention of calcium oxalate kidney stones. The study will enroll 80 patients at Mount Sinai West undergoing percutaneous nephrolithotomy (PCNL) for predominantly calcium oxalate stones. Participants will be randomized postoperatively to receive either empiric therapy (based on stone composition and urinalysis) or selective therapy (based on 24-hour urine metabolic evaluation). The primary endpoint is the change in calcium oxalate supersaturation (ssCaOx) at 4 weeks post-treatment. The study is designed to determine whether an empiric approach can achieve comparable outcomes to selective therapy while simplifying access to preventive treatment.

Inclusion Criteria:

• Adult age of 18 years
• Diagnosed with kidney stones and scheduled for PCNL.
• Calcium Oxalate Stone Former
• Pre-operative CT-scan within 90 days of surgery and stone density with > 1000 Hounsfield units
• Non-pregnant or breastfeeding
• Able and willing to provide informed consent.
• Pre-operative eGFR greater than 70 mL/min/1.73 m² -Negative pre-operative urine culture

Exclusion Criteria:

• Documented history of gastric or intestinal bypass, liver disease, history of gastrointestinal malabsorptive disease (Crohn's disease, ulcerative colitis, and short-gut syndrome)
• Hyperparathyroidism -Renal tubular acidosis
• Active kidney stone prevention treatment (use of thiazides, alkaline therapy, or low oxalate diet) at the time of surgery
• History of hypokalemia or baseline hypotension
• Allergy to medications used in trial or sulfa-containing medications
• Patient prescribed thiazide, loop diuretics, carbonic anhydrase inhibitors, xanthine oxidase inhibitors, active Vitamin D, bisphosphonates, denosumab, glucocorticoids, or potassium supplementation

Individual participant data will not be shared because all results are part of standard clinical care, and participants have access to their own medical records.