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Kidney Week

Abstract: TH-PO083

The Role of C5aR vs. C3 in Thrombotic Microangiopathy, Ischemic Kidney Necrosis, and AKI Induced by Cholesterol Crystal Embolism

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

  • Zhao, Danyang, Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, Germany
  • Anders, Hans J., Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, Germany
  • Mammadova-Bach, Elmina, Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, Germany
Background

Certain thrombotic microangiopathies (TMA) respond to inhibition of complement factor C5, which abrogates formation of the membrane attack complex and hence impairs host defense. Inhibition of C5a receptor (C5aR) avoids this safety problem and still controls autoimmune systemic vasculitis. We speculated that targeting C5aR could be sufficient also in TMA, e.g., related to cholesterol crystal embolism (CCE) .

Methods

We induced experimental TMA in C3-/-, C5aR-/- or wildtype mice by injecting CC into the left kidney artery of mice and analyzed thrombotic angiopathy, drop in measured glomerular filtration rate (GFR), and ischemic necrosis 24 hours after CCE.

Results

In wildtype mice, CC injection caused diffuse TMA followed by a consistent drop of GFR compared to baseline and ischemic kidney necrosis. Genetic deficiency in C3 convertase profoundly attenuated TMA and hence GFR drop and ischemic kidney necrosis indicating a key role of the complement system in CCE-related TMA. Genetic deficiency of C5aR attenuated TMA, GFR drop and ischemic necrosis to the same extent indicating that C5aR provides the main contribution of the complement system to the pathogenesis of TMA.

Conclusion

We conclude that targeting the C5a/C5aR axis could be sufficient to attenuate also TMA for which a better safety profile would be expected as compared to C5 inhibition.

Funding

  • Clinical Revenue Support