loading
loading
NIH grant 1R01DK148495-01: Novel Predictors of Vascular Endothelial Growth Factor Signaling Pathway Inhibitor-Associated Proteinuria
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Shruti Gupta. Award: $881680.
Start: 2026-08-21T00:00:00.
PROJECT SUMMARY/ABSTRACT
Vascular endothelial growth factor (VEGF) signaling pathway inhibitors (VSPIs) have revolutionized the
treatment of a number of cancers; however, these drugs are associated with toxicities like proteinuria, which
can lead to cessation of potentially life-saving cancer therapy, as well as increased cardiovascular morbidity
and mortality. We previously found that high-grade VSPI-associated proteinuria (VSPI-proteinuria), defined as
≥2+ proteinuria on dipstick, a calculated urinary protein-to-creatinine ratio ≥1.0 g/g, or urine
microalbumin:creatinine ratio >300 mg/g, occurs in up to 42% of patients who initiate VSPIs. Despite the high
frequency and clinical importance of VSPI-proteinuria, clinical, biochemical, and genetic risk factors are not
well-understood. Our overall objective is to enhance prediction of VSPI-proteinuria, based on a better
understanding of its underlying mechanisms. Early identification of patients at risk of developing high-grade
VSPI-proteinuria will allow for closer monitoring and earlier implementation of targeted, anti-proteinuric
therapies, thereby minimizing treatment interruptions and improving both kidney outcomes and overall survival.
In Aim 1, we will derive and externally validate a risk prediction model for VSPI-proteinuria occurring in the
first 180 days following VSPI initiation using data from >15,000 patients treated with VSPIs from 2016-2025 at
Brigham (BWH)/Dana-Farber Cancer Institute (DFCI) and Massachusetts General Hospital (MGH) (derivation
cohort), as well as the Veterans Health Administration (validation cohort).
In Aim 2, we will prospectively collect blood and urine from VSPI-treated patients at baseline and 14 days
(±7) following VSPI initiation (n=400). We will measure 16 candidate blood and urinary biomarkers at both time
points, including circulating soluble urokinase plasminogen activator receptor (primary exposure), comparing
baseline-adjusted levels of each biomarker at 14 days in patients who do vs. do not develop VSPI-proteinuria.
Additionally, we will collaborate with OncoHost, a licensed SomaScan provider, to compare baseline-adjusted
levels of >7,000 proteins in blood and urine.
In Aim 3, we will examine whether clonal hematopoiesis of indeterminate potential (CHIP) and variants in
podocyte-related genes and complement pathway regulators are associated with VSPI-proteinuria using 2 well-
curated biorepositories: BioVU at Vanderbilt (n~300,000) and NIH’s All of Us (n~500,000).
Leveraging the multidisciplinary expertise of our team, along with the existing infrastructure and high volume
of VSPI-treated patients at our centers, we will refine risk prediction for VSPI-proteinuria and shed light on its
underlying mechanisms, with the goal of mitigating renal complications and preventing discontinuation of these
potentially life-saving anticancer therapies.document fetched 2026-08-30 02:46