Unmasking Liver Risks: Over-the-Counter Supplements Trigger Transient Hepatotoxicity in Patients with ADPKD on Tolvaptan

Introduction: Tolvaptan, a V2 receptor antagonist, slows autosomal dominant polycystic kidney disease (ADPKD) progression by reducing kidney volume and preserving renal function. Hepatotoxicity affects ~4–5% of patients. Tolvaptan is metabolized via CYP3A4, making it vulnerable to interactions with over-the-counter (OTC) products. We report two ADPKD cases with transient liver enzyme elevation due to such interactions—with a greens supplement and a grapefruit-containing beverage. Case Description: Case 1: A 42-year-old M with ADPKD began tolvaptan (45/15 mg daily) in Dec 2021 for CKD G3A1 (eGFR 66, SCr 1.38). In Sept 2024, after 18 months, ALT rose (61→41 U/L) with concurrent Athletic Greens use. eGFR declined to 54 (SCr 1.63), but cystatin C eGFR was stable. ALT normalized 4 weeks after stopping both tolvaptan and the supplement. Tolvaptan was restarted safely. Case 2: A 42-year-old F with ADPKD began tolvaptan (45/15 mg) in Apr 2023 for CKD G2A1 (eGFR 64, SCr 1.04). Mild ALT rise (34→38→26 U/L) occurred early, resolving after stopping Fresca (grapefruit-containing). Tolvaptan was resumed at 30/15 mg or 15/15 mg safely. Discussion: Tolvaptan metabolism via CYP3A4 makes it susceptible to interactions with common supplements and beverages. Both patients experienced reversible transaminitis likely triggered by CYP3A4 inhibition. Discontinuing the offending agents led to normalization of liver tests, allowing for safe tolvaptan reinitiation. These cases emphasize the importance of educating patients about OTC and dietary interactions and the necessity of monitoring liver function during therapy. CYP3A4-mediated interactions with OTC supplements can cause transient hepatotoxicity in ADPKD patients on tolvaptan. Early detection and intervention allow for safe treatment interruption and rechallenge.