Acute kidney injury with immune checkpoint inhibitors and beta-lactam antibiotics

Ended Project Grant Awarded Last action

Award ID
F32DK141217
Recipient
Awarding agency
Obligated
$166,217

Award facts

Completion date
Place of performance
Pennsylvania, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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 population.

Transactions

Action Obligated Date
Amendment -$1,551
Amendment $83,884
Amendment $83,884
Original award $0

Quick answers

Who received award F32DK141217?

F32DK141217 was awarded to The Trustees Of The University Of Pennsylvania by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on December 7, 2024.

How much is award F32DK141217 worth?

$166,217 has been obligated on F32DK141217.

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