An Overlooked Interaction: Reversible Tolvaptan-Associated Hepatotoxicity Due to Over-the-Counter Supplements

Naga Sumanth Reddy Gopireddy; Michelle Fravel; Lama Noureddine

doi:10.1016/j.kintcr.2026.100124

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An Overlooked Interaction: Reversible Tolvaptan-Associated Hepatotoxicity Due to Over-the-Counter Supplements

Journal article

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An Overlooked Interaction: Reversible Tolvaptan-Associated Hepatotoxicity Due to Over-the-Counter Supplements

Naga Sumanth Reddy Gopireddy, Michelle Fravel and Lama Noureddine

Kidney International Case Reports, 100124

09/08/2026

DOI: 10.1016/j.kintcr.2026.100124

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Abstract

Tolvaptan, a selective vasopressin V2 receptor antagonist, slows progression of autosomal dominant polycystic kidney disease (ADPKD) by reducing kidney volume and preserving renal function. Hepatotoxicity, manifesting as transaminase elevations >3× the upper limit of normal (ULN), affects approximately 4–5% of patients, necessitating Risk Evaluation and Mitigation Strategy (REMS) monitoring. Tolvaptan is metabolized via CYP3A4, making it vulnerable to interactions with over-the-counter supplements and beverages that inhibit this enzyme. We describe two patients with ADPKD on tolvaptan therapy who developed reversible transaminase elevations temporally associated with over-the-counter product use. Patient 1, a 42-year-old male, developed transaminitis after 33 months of stable tolvaptan therapy, coinciding with initiation of daily Athletic Greens (AG1) supplement use. Patient 2, a 42-year-old female, experienced alanine aminotransferase (ALT) elevation shortly after starting tolvaptan while regularly consuming Fresca, a grapefruit-flavored beverage. In both cases, liver enzymes normalized completely after discontinuation of the implicated products and temporary tolvaptan interruption. Both patients successfully resumed tolvaptan without recurrence after avoiding these products. CYP3A4-mediated interactions with over-the-counter supplements and grapefruit-containing beverages can cause reversible hepatotoxicity in ADPKD patients on tolvaptan. Clinicians should routinely screen for supplement and grapefruit product use, provide patient education on avoiding these agents, and maintain vigilant monitoring. Early detection and intervention allow for safe treatment interruption and successful rechallenge, enabling continuation of this disease-modifying therapy.

Athletic Greens

Autosomal dominant polycystic kidney disease (ADPKD)

CYP3A4

Drug Induced Liver Injury (DILI)

drug-supplement interaction

grapefruit

Hepatotoxicity

Tolvaptan

Details

Title: Subtitle: An Overlooked Interaction: Reversible Tolvaptan-Associated Hepatotoxicity Due to Over-the-Counter Supplements
Creators: Naga Sumanth Reddy Gopireddy
Michelle Fravel
Lama Noureddine
Resource Type: Journal article
Publication Details: Kidney International Case Reports, 100124
DOI: 10.1016/j.kintcr.2026.100124
ISSN: 3117-471X
Publisher: Elsevier Inc
Language: English
Electronic publication date: 09/08/2026
Academic Unit: Pharmacy Practice and Science; Nephrology; Internal Medicine
Record Identifier: 9985224435602771

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