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Kidney Week

Abstract: PO0275

Quantitative Proteomics Analysis Identifies Novel Markers of AKI, CKD, and AKI-to-CKD transition in Human Kidneys

Session Information

Category: Acute Kidney Injury

  • 102 AKI: Clinical, Outcomes, and Trials

Authors

  • Madhavan, Sethu M., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
  • Shapiro, John P., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
  • Eadon, Michael T., Indiana University Purdue University at Indianapolis, Indianapolis, Indiana, United States
  • El-Achkar, Tarek M., Indiana University Purdue University at Indianapolis, Indianapolis, Indiana, United States
  • Dagher, Pierre C., Indiana University Purdue University at Indianapolis, Indianapolis, Indiana, United States
  • Poggio, Emilio D., Cleveland Clinic, Cleveland, Ohio, United States
  • Toto, Robert D., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
  • Parikh, Chirag R., Johns Hopkins University, Baltimore, Maryland, United States
  • Wilson, Francis Perry, Yale University School of Medicine, New Haven, Connecticut, United States
  • Kiryluk, Krzysztof, Columbia University, New York, New York, United States
  • Rovin, Brad H., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
  • Parikh, Samir V., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States

Group or Team Name

  • Kidney Precision Medicine Project (KPMP)
Background

The etiology of AKI is multifactorial and is associated with in-hospital mortality and progression to CKD. Molecular phenotypes that are shared across AKI, CKD and the transition are unclear but may characterize common injury mechanisms that can be targeted for kidney preservation. We hypothesize that molecular interrogation of the kidney tubulointersitium (TI) will identify proteomic signatures that reflect AKI, AKI to CKD transition and CKD progression.

Methods

Frozen kidney biopsies from 4 CKD and 3 AKI patients obtained from recruitment sites in the Kidney Precision Medicine Project were used for this study and compared to nephrectomy controls (n=4). TI was isolated using laser microdisseciton and recovered proteins were submitted for HPLC MS/MS proteomic analysis using Orbitrap eclipse mass spectrometer. Label-free quantification and global normalization of spectral count data was performed to determine changes in protein expression.

Results

Protein signatures demonstrating cell proliferation and migration (MAP1B, PPFIBP1, RASAL1, NT5C2, PITPNM1, S100A4, XRN1, MNDA, SRM, MAMDC2) and extracellular matrix regulatory proteins (VCAN, POSTN, TNC, PXDN, ITGB6, THBS2, FBLN5, COLGALT1) were upregulated in AKI while cell-cell adhesion and extracellular matrix expansion (COL7A1, POSTN, FBLN5, ELN, VCAN, FERMT3, A1BG, MRC1, CP, STAB1, TIMP3, ITIH3, MFAP4, TNC), cell proliferation (MAP1B, PTPRC, NIBAN1, FUBP1, S100A, PPFIBP1, ARHGDIB) and inflammation markers (C2, SAMHD1, IL16, C7) were upregulated in CKD compared to controls. Overall, 57% and 28% of up- and downregulated proteins in AKI, were shared in CKD and may reflect AKI to CKD transition.

Conclusion

Proteomic analysis of the TI identified known and novel markers specific to AKI and CKD. Additionally, activation of common inflammatory and extracellular matrix remodeling proteins in AKI and CKD settings suggests that unified pathways activated in the TI could underlie AKI to CKD progression. The causal role of these candidate markers in the pathogenesis of AKI and CKD needs to be better defined, but if validated, targeting these pathways could help arrest tissue injury and limit disease progression. This work is ongoing.

Funding

  • NIDDK Support