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Kidney Week

Abstract: FR-PO117

The Kidney Protects Other Organs During Sepsis by Producing and Circulating Tamm-Horsfall Protein (Uromodulin)

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • LaFavers, Kaice A., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Micanovic, Radmila, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Hato, Takashi, Indiana University, Indianapolis, Indiana, United States
  • Khan, Shehnaz, Indina university of school of medicine Nephrology, Indianapolis, Indiana, United States
  • Winfree, Seth, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • El-Achkar, Tarek M., Indiana University, Indianapolis, Indiana, United States
Background

Acute kidney injury (AKI) significantly increases the mortality in patient with sepsis. Although retention of uncleared toxins could potentiate this effect, the loss of a protective factor released by the kidney could also play a role. Tamm-Horsfall Protein (THP) is uniquely made in the kidney. The majority of THP is secreted into the urine, but a portion is also released into the circulation. We previously showed that AKI is an acute state of THP deficiency and that circulating THP protects against systemic inflammation. Therefore, we propose that increased systemic release of THP from the kidney protects the organism with sepsis, and that the loss of THP is a major cause of increased mortality during septic AKI.

Methods

We used the cecal ligation and puncture (CLP) model of sepsis in THP+/+ and THP-/- mice and measured plasma THP in small patient cohorts admitted to the intensive care unit (ICU) with sepsis.

Results

In THP+/+ mice, the level of serum THP increases within 6 hours after CLP, and remains elevated up to 48 hours in surviving mice. This trend was also observed in ICU patients with sepsis, where increased plasma THP correlated with worsening SOFA scores (a measure of organ failure) within 48 hours of admission. We also detected high levels of THP in the bronchoalveolar lavage fluid of patients who had developed acute respiratory distress syndrome, whereas levels were undetectable in healthy controls, demonstrating that THP localizes to dysfunctional organs during sepsis. To study the effect of THP deficiency on mortality, we compared THP-/- to THP+/+ mice, and found that THP-/- mice have decreased survival (10% vs. 60% survival, respectively. p<0.05) within 48 hours after CLP. Additionally, treatment of THP-/- mice with purified exogenous THP restores survival to the levels seen in THP+/+ mice. Mechanistically, THP increases the phagocytic activity of macrophages, which could partially explain the benefits of THP in the setting of a systemic infection.

Conclusion

Our work strongly supports that THP potentiates a protective cross-talk between the kidney and other organs during sepsis, and underscores the importance of maintaining kidney health in septic patients. This work could lead to the development of a new therapy for sepsis by administering THP or modulating its potential targets.

Funding

  • NIDDK Support