Abstract: SA-PO182
Plasma Sialic Acid as a Marker for Kidney Function Decline in Preclinical Models of AKI
Session Information
- AKI: Mechanisms - III
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Darshi, Manjula, Janssen Research and Development LLC, Boston, Massachusetts, United States
- Meng, Rong, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Myshkin, Eugene, Janssen Research and Development LLC, Boston, Massachusetts, United States
- Camacho, Raul, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Du, Fuyong, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Ma, Li-Jun, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Ho, George, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Liu, Jianying, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Li, Qiu, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Albarazanji, Kamal Ahmed, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Watrous, Jeramie, Sapient Bioanalytics, San Diego, California, United States
- Long, Tao, Sapient Bioanalytics, San Diego, California, United States
- Jain, Mo, Sapient Bioanalytics, San Diego, California, United States
- Nawrocki, Andrea R., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Reilly, Dermot F., Janssen Research and Development LLC, Boston, Massachusetts, United States
Background
Acute kidney injury (AKI) occurs in approximately 10–15% of hospitalized patients leading to high degree of mortality in clinic and is a major risk factor for CKD development and progression. Novel biomarkers could improve diagnosis and help define molecular pathways associated with AKI.
Methods
Untargeted metabolomics was performed on plasma samples from rat and mouse AKI models induced by ischemia reperfusion injury (IRI) using Rapidfire high throughput LC-MS technology. Samples from lean Sprague Dawley (SD) rats, and lean C57Bl/6J mice were collected 24 hours after IRI surgery using bilateral clamping. We also developed an obese and diabetic model of IRI, uninephrectomized (Unx) obese ZSF1 rats which are more susceptible to AKI compared to lean ZSF1 rats. AKI was confirmed by increased plasma Creatinine (pCr), increased kidney injury markers (KIM-1 and NGAL) and a decline in Glomerular Filtration Rate. Plasma sialic acids and creatinine levels were validated by targeted LC-MS/MS methods. Sialic acids were also measured in a Cecal slurry (CS)-induced Sepsis model of AKI in mice.
Results
A total of 20,472 spectral features were extracted from untargeted metabolomics and 123 of them were assigned putative annotations based on m/z and RT with the library of standards. Principal component analysis of the annotated metabolites showed distinct separation between AKI and control groups in all 3 models of IRI. Several gut-microbiome derived metabolites, uremic toxins and sialic acids were significantly increased across all models of AKI and correlated highly with plasma creatinine. Validation of free sialic acid using targeted LC-MS confirmed that plasma sialic acids are significantly increased in AKI and strongly correlated positively with plasma creatinine (Pearson r2: 0.95 in CS, 0.91 in SD rat IRI, 0.77 in mouse IRI, and 0.60 in ZSF IRI, p<0.0001) in both IRI and sepsis models of AKI.
Conclusion
Increases in circulating free sialic acid, consistently observed in preclinical models for IRI or sepsis induced AKI, may be due to impaired filtration and could serve as a surrogate marker for AKI diagnosis