# Acute Kidney Injury with Immune Checkpoint Inhibitors and Beta-Lactam Antibiotics

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2024 · $83,884

## Abstract

PROJECT SUMMARY
Acute kidney injury (AKI) is emerging as an important immune related adverse event (IRAE) of immune
checkpoint inhibitors (ICI). ICIs are a revolutionary new class of cancer treatment used in over 17 types of
cancer and are treatment options in approximately 38% of cancer patients. Their role in therapy is expected to
expand to additional cancers as well as in maintenance regimens. As their use expands, the frequency of AKI
as an IRAE is also expected to increase. AKI is especially hazardous in cancer patients. In addition to
increased rates of CKD and related sequalae, it is associated with lower rates of remission, higher costs of
care, ineligibility to future chemotherapy, and higher cancer mortality. ICI induced AKI must be detected early to
prevent irreversible damage, however, risk factors and effective monitoring parameters have not been
identified. Though exact mechanisms remain unclear, evidence suggest that ICIs cause AKI primarily through
acute interstitial nephritis (AIN). Drug-drug interactions may be a primary driver of AIN during ICI therapy.
Studies of have repeatedly found that concomitant treatment of ICIs and other drugs suspected of causing AIN
are risk factors for ICI associated AKI. Beta-lactam antibiotics are critical supportive care agents in cancer
treatment and are also the leading cause of drug induced AIN. Beta-lactams cause AIN through formation of
drug-protein complexes that accumulate in renal interstitium, get presented as antigens to T-cells, which then
trigger inflammatory responses leading to AIN and AKI. ICIs may exaggerate this inflammatory response as
they set T-cells in a hyperactivate state leading to larger immune responses. Given the frequency of beta-
lactam use during ICIs treatment, this drug-drug interaction may be a primary driver of AKI in ICI users.
However, this potential drug-drug interaction remains unstudied in the literature. Understanding the
comparative risk of AIN with beta-lactam antibiotics versus key alternatives is essential for informing antibiotic
selection during ICI therapy. In Aim 1 of this study, we will use target trial emulation to evaluate whether, in
patients treated with ICIs, beta-lactams increase the rate of AKI versus fluroquinolones, an alternative to beta-
lactams that may carry a lower risk of AIN. In Sub-Aim 1a of this study, the treatment effect heterogeneity of
this drug-interaction will be evaluated using subgroup analysis, the prognostic score approach, and methods to
identify the optimal treatment rule. The accompanying training plan consists of both coursework as part of a
PhD program in epidemiology, application of advanced methods, and mentorship by expert clinician
researchers in renal pharmacoepidemiology, drug-drug interactions, nephrology, and oncology. This fellowship
will provide essential support to the trainee as she prepares for her career as an independent academic
pharmacoepidemiologist focused on studying nephrotoxicity in the cancer...

## Key facts

- **NIH application ID:** 10998392
- **Project number:** 1F32DK141217-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Haedi Thelen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $83,884
- **Award type:** 1
- **Project period:** 2024-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998392

## Citation

> US National Institutes of Health, RePORTER application 10998392, Acute Kidney Injury with Immune Checkpoint Inhibitors and Beta-Lactam Antibiotics (1F32DK141217-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10998392. Licensed CC0.

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