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Kidney Week

Abstract: TH-PO081

AKI-Induced Circulating TNFR1/2 Elevations Correlate with Persistent Kidney Injury and Progression to Fibrosis

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Arthanarisami, Akshayakeerthi, Washington University in St Louis, St Louis, Missouri, United States
  • Komaru, Yohei, Washington University in St Louis, St Louis, Missouri, United States
  • Katsouridi, Charikleia, Washington University in St Louis, St Louis, Missouri, United States
  • Schumacher, Julian, Washington University in St Louis, St Louis, Missouri, United States
  • Ning, Liang, Washington University in St Louis, St Louis, Missouri, United States
  • Abdelmageed, Mai, Washington University in St Louis, St Louis, Missouri, United States
  • Herrlich, Andreas, Washington University in St Louis, St Louis, Missouri, United States
  • Kefalogianni, Eirini, Washington University in St Louis, St Louis, Missouri, United States
Background

Elevated levels of circulating Tumor-Necrosis-Factor-Receptors 1 and 2 (cTNFR1/2) predict CKD progression. Whether acute kidney injury drives cTNFR1/2 elevations and whether they predict disease outcomes after AKI remains unknown.

Methods

We used AKI patient serum and urine samples, mouse models of kidney injury (ischemic, obstructive, toxic) and progression to fibrosis, nephrectomy, and related single cell RNA-sequencing datasets.

Results

We show that TNFR1/2 serum and urine levels are highly elevated in all mouse models of kidney injury tested, beginning within one-hour post-injury, and correlate with its severity. Consistent with this, serum and urine TNFR1/2 levels are increased in AKI patients and correlate with severity of kidney failure. Interestingly, the extracellular particle (EP)-bound forms of cTNFR1/2 correlate with renal function better than their soluble forms. TNF neutralization does not affect early cTNFR1/2 elevations, suggesting that cTNFR1/2 levels do not reflect injury-induced TNF activity. Kidney tissue expression of TNFR1/2 after AKI is only mildly increased and bilateral nephrectomies lead to strong cTNFR1/2 elevations, suggesting release of these receptors by extrarenal sources. cTNFR1/2 remain elevated for weeks after severe kidney injury and at these later timepoints cTNFR1/2 correlate to remaining kidney injury. During AKI-to-CKD transition, kidney expression of TNFR1/2 and cTNFR2 levels, correlate with development of fibrosis.

Conclusion

Our data demonstrate that AKI drives acute increases in cTNFR1/2 serum levels which negatively correlate with kidney function, in particular their EP-bound forms. Sustained TNFR1/2 elevations after kidney injury during AKI-to-CKD transition correlate with persistent tissue injury and progression to kidney fibrosis.

Funding

  • Private Foundation Support