# Mechanisms driving acute and chronic kidney function decline after immune checkpoint inhibitor therapy for cancer

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $682,247

## Abstract

PROJECT SUMMARY
Immune checkpoint inhibitors (ICIs) are revolutionizing cancer care, producing durable anti-tumor responses in
multiple cancer types; however, by unleashing T-cell responses, ICIs can lead to immune-related toxicities in
essentially any organ system, affecting 60-80% of recipients. It is conservatively estimated that 3-5% of
patients develop acute interstitial nephritis (AIN) after ICIs, and a recent study found that up to 40% of patients
that survive 2 years after receiving ICIs will experience rapid estimated glomerular filtration rate (eGFR) decline
(>3mL/min/year). Very little is known about the mechanisms of ICI-induced kidney injury, as all prior published
work in the field has been descriptive. Building on published studies showing distinctly high cytotoxic T-cell
activity in immune-related adverse events after ICIs, we hypothesize that AIN and chronic kidney disease
(CKD) that result from ICIs exist on a spectrum of T-cell mediated injury to the tubulointerstitial compartment of
the kidney. In Aim 1, we will enroll 25 patients with biopsy-proved ICI-induced AIN (ICI-AIN) and 25 patients
with clinically-adjudicated hemodynamic AKI after ICIs and use single-cell RNA sequencing of paired kidney
biopsy tissue, blood, and urine specimens to uncover mechanisms of ICI-induced AIN. Single-cell
transcriptional profiling of kidney tissue will offer insights into the cellular and molecular pathogenesis of ICI-
AIN as well as a clear benchmark against which to compare blood and urine signatures (Aim 1B). We will then
compare cell-based transcriptional biomarkers (Aim 1C) and cytokine biomarkers (Aim 1D) in blood and urine
of patients with biopsy-proven ICI-AIN to hemodynamic AKI after ICIs to identify biomarkers unique for ICI-AIN
and pathways to target in future interventional studies. In Aim 2, we will determine the relationship between
ICIs and long-term kidney injury by prospectively evaluating blood and urine biomarkers of kidney injury over
two years in ICI-treated patients with melanoma compared to control patients with early-stage melanoma who
undergo surgical resection alone and do not receive ICIs (Aim 2A). To understand mechanisms promoting
kidney function decline after ICIs, in Aim 2B, we will use scRNAseq to investigate the similarities between
immune and non-immune cell transcriptional programs in blood and urine among patients with >20% eGFR
decline after ICIs to patients with ICI-AIN from Aim 1B. In aggregate, the studies proposed will uncover
mechanisms of ICI-induced kidney injury, have strong potential to lead to non-invasive diagnostics for ICI-AIN,
and yield important biological insights into the role of T-cell disinhibition on kidney function. The proposal will
capitalize on the expertise of the Severe Immunotherapy Complications Service at Massachusetts General
Hospital (MGH), a first-of-its kind multidisciplinary team of oncologists and subspecialists studying immune-
related adverse events, and the tremendous ...

## Key facts

- **NIH application ID:** 10831491
- **Project number:** 5R01DK130839-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Meghan E. Sise
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $682,247
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831491

## Citation

> US National Institutes of Health, RePORTER application 10831491, Mechanisms driving acute and chronic kidney function decline after immune checkpoint inhibitor therapy for cancer (5R01DK130839-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10831491. Licensed CC0.

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