# Repurposing Montelukast for Cardiac Surgery-Associated Acute Kidney Injury

> **NIH NIH U34** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $389,071

## Abstract

PROJECT SUMMARY/ABSTRACT
 Each year 500,000 patients undergo cardiac surgery in the United States, and acute kidney injury (AKI)
complicates recovery in 25% of patients. AKI is associated with subsequent postoperative arrhythmias, wound
infections, and sepsis, and independently predicts a 5-fold increase in death at 30 days. Despite advancements
in surgical technique and perioperative patient management, cardiac surgery-associated AKI (CSA-AKI) remains
a major problem and no therapies have been shown to improve clinical outcomes. While there are many reasons
that previous efforts to identify and validate new therapeutic targets for AKI have been unsuccessful, a key
feature is that discovery efforts were not primarily driven by human data. Leveraging BioVU (Vanderbilt's large-
scale DNA biobank), we performed a Phenome-Wide Association Study (PheWAS) based on ICD billing code
and genotype data in a disease-agnostic cohort of ~36,000 patients and identified novel genotype-phenotype
associations between single nucleotide polymorphisms in the gene that encodes the protein target of
montelukast (CYSTLR1) and AKI phenotypes. Montelukast is an anti-inflammatory leukotriene receptor
antagonist that is FDA approved to treat asthma and allergic rhinitis, and inflammation is a mechanism of AKI.
In additional preliminary studies montelukast reduces renal injury in preclinical models, urinary concentrations of
leukotrienes increase significantly during cardiac surgery and more so in patients who develop AKI, and patients
taking montelukast have a 38% reduction in AKI over time compared to patients not taking montelukast.
 To determine if montelukast can be repurposed to prevent CSA-AKI and potentially other forms of AKI in
subsequent initiatives, we will first perform a phase II trial to measure the effect of montelukast on CSA-AKI and
assess any safety events. To properly design and execute this phase II trial we assembled a multidisciplinary
team of physician scientists and staff with the relevant expertise and experience to accomplish four specific aims:
(1) Determine study cohort availability and baseline characteristics by simulating study cohorts using VUMC's
Synthetic Derivative; (2) Determine optimal montelukast dosing regimen and refine the trial's mechanistic studies
by measuring LTC4, LTD4, and LTE4 leukotriene subtypes in urine of patients who did and did not develop AKI
in a previous study; (3) Optimize study design to most efficiently recruit patients and test the hypothesis; and (4)
Complete all study startup tasks. The successful completion of this project will allow us to commence the clinical
trial immediately. Proving that a safe, affordable, generic drug can be used to prevent CSA-AKI is a major priority.
In addition, demonstration that the published and publicly available computational PheWAS algorithm is an
effective tool for drug repurposing will lead to additional medical treatments.

## Key facts

- **NIH application ID:** 10043764
- **Project number:** 1U34TR003298-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Frederic Tremaine Billings
- **Activity code:** U34 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,071
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043764

## Citation

> US National Institutes of Health, RePORTER application 10043764, Repurposing Montelukast for Cardiac Surgery-Associated Acute Kidney Injury (1U34TR003298-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10043764. Licensed CC0.

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