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Abstract: FR-OR007

Urinary Proteomic Biomarker Profiling of AKI in Patients with Cancer Receiving Immune Checkpoint Inhibitors

Session Information

Category: Onconephrology

  • 1600 Onconephrology

Authors

  • Asby, Sarah C., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver, Colorado, United States
  • Gupta, Shruti, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Zhuang, Yonghua L., University of Colorado Cancer Center, Aurora, Colorado, United States
  • Huang, Yuxin, University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver, Colorado, United States
  • Wells, Sophia L., Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Thompson, Lauren E., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver, Colorado, United States
  • Wen, Xia, Rutgers Ernest Mario School of Pharmacy Department of Pharmacology & Toxicology, Piscataway, New Jersey, United States
  • Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center Department of Medicine, New York, New York, United States
  • Aleksunes, Lauren, Rutgers Ernest Mario School of Pharmacy Department of Pharmacology & Toxicology, Piscataway, New Jersey, United States
  • Joy, Melanie S., University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver, Colorado, United States
Background

Immune Checkpoint Inhibitor-associated acute kidney injury (ICI-AKI) is an immune-related adverse event that commonly presents as acute tubulointerstitial nephritis (ATIN), although glomerular and vascular pathologies are also observed. ICI-AKI is difficult to diagnose on clinical features alone, often requiring a kidney biopsy to confirm diagnosis. This diagnostic gap presents the need for identification of non-invasive biomarkers of ICI-AKI. We conducted a discovery study of novel ICI-AKI biomarkers through high-throughput proteomic profiling of clinical urine samples.

Methods

Urine proteomics was performed using the SomaLogic SomaScan 7k platform and an orthogonal Luminex panel, using samples from 3 academic cancer centers. 3 groups were evaluated: Pre-treatment Control/No Toxicity (n=6), ICI-Exposed/Stable Kidney Function for treatment cycles 2–7 (n=15), and ICI-Exposed/Biopsy-proven ICI-AKI (n=23) and analyzed as shown (Figure).

Results

ICI-Exposed/Biopsy-proven ICI-AKI cases were significantly older (mean 70 ± 7 yrs, p=0.002) and predominantly male (91%, p=0.007) compared to Control (60 ± 10 yrs, 83% male) and ICI-Exposed/Stable Kidney Function cohorts (57 ± 14 yrs, 47% male). Unadjusted analysis identified 1,822 differentially abundant proteins (FDR<0.05) among all 3 cohorts. Enrichment analysis of significant proteins revealed signatures of neutrophil degranulation, leukocyte trafficking, and TNF signaling (FDR<0.05). Comparison with 4 ICI-AKI urine proteomics publications identified concordant candidates (CXCL9, CXCL11, and IL-6) in ICI-Exposed/Biopsy-proven ICI-AKI cases. Luminex validation confirmed significant SomaLogic-identified proteins (p<0.05) including reductions in EGF and increases in TIMP-1 in the ICI-Exposed/Biopsy-proven ICI-AKI cohort compared to the ICI-Exposed/Stable Kidney Function cohort.

Conclusion

This study identified a biologically coherent set of candidate urinary ICI-AKI biomarkers encompassing immune trafficking, inflammatory signaling, and tubular injury pathways, with cross-platform validation of potential leading candidates.

Acknowledgment

Clinical urine samples were collected at the University of Colorado Cancer Center, Mass General Brigham, and Memorial Sloan Kettering Cancer Center. Urine proteomic profiling was performed using the SomaLogic SomaScan platform in Boulder, CO. Statistical analyses were performed by the Biostatistics and Bioinformatics Shared Resource at the University of Colorado Cancer Center on the Anschutz Medical Campus in Aurora, CO.

Funding

  • NIDDK Support