Proteomic analysis of human kidney biopsies unveils emerging acute kidney injury very early after liver graft reperfusion.

BACKGROUND

Acute kidney injury (AKI) is a frequent complication after liver transplantation (LT) and is associated with morbidity, mortality, and late development of chronic kidney disease. Risk factors for AKI after LT include patient, perioperative and graft-related factors. The exact renal molecular mechanisms behind AKI in LT are unclear.

METHODS

Alterations in the proteome were investigated in kidney biopsies from 21 patients undergoing LT using quantitative proteomics. The most upregulated protein was validated using immunohistochemistry. In addition, serum levels of interleukin (IL)-33, insulin-like growth factor binding protein (IGFBP)-7 and high-mobility group box (HMGB)-1 were analyzed. In silico data validation was performed using 14 recently published proteomics and transcriptomics datasets.

RESULTS

In post-reperfusion biopsies, we identified 731 differentially regulated proteins between patients with and without AKI. The most upregulated pathways were related to inflammation, integrin signaling and extracellular matrix (ECM) remodeling. The most downregulated pathways were traceable to a mitochondrial origin. HMGB-1 was found to be already upregulated (15%) 2 h after LT in patients who later developed AKI. The AKI group also showed upregulation of the alarmin IGFBP-7, caspases 1, 4 and 8, nuclear factor kappa B subunits, and the inflammasome adaptor protein PYCARD. Circulating IL-33 and HMGB-1 (but not IGFBP-7) increased during LT but returned to normal levels within 24 h. Altogether, these findings indicate ongoing inflammatory signaling activity in the kidneys of LT recipients who ultimately develop moderate or severe AKI shortly after liver graft reperfusion.

CONCLUSIONS

LT induces extensive alarmin signaling and ECM remodeling in the kidneys of recipients who develop postoperative AKI. Further strategies to curtail this phenomenon are mandated. Trial registration https://www.researchweb.org/is/en/vgr/project/278585 , Registered 24 May 2022 (Retrospectively registered).