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Abstract: FR-PO095

Increased Expression of the Ca2+ Channel Orai1 and IL-17 in Blood CD4+ Cells in Critically Ill Patients with AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Mehrotra, Purvi, Indiana School of Medicine, Indianapolis, Indiana, United States
  • Neyra, Javier A., University of Kentucky Medical Center, Lexington, Kentucky, United States
  • Basile, David P., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Acute kidney injury (AKI) affects up to 50% of critically ill patients and is associated with high mortality rates approaching 60%. In surviving patients, reduced kidney function is reversible, however AKI increases the risk developing of chronic kidney disease (CKD). IL-17, a pro-inflammatory cytokine secreted by CD4+T cells (Th17 cells), has been linked to the activation of the store-operated calcium channel, Orai1.Th17 cells, have been associated with various autoimmune diseases such as psoriasis and SLE and also in delayed graft function. In rodent models of kidney injury, Th17 cells have been shown to enhance the severity of AKI and AKI-to-CKD transition. However, no direct evaluation of Th17 cells has been conducted in AKI patients.

Methods

Prospective, case-control study of critically ill patients with AKI (KDIGO stage ≥2, n=9) and ICU matched-controls without AKI (n=8). Matching criteria included age, gender and baseline eGFR. Venous blood was collected 12-24 hours post AKI diagnosis and 12-24 h ICU admission and analyzed for expression of CD4+/IL17+ cells and the expression and activity of Orai1.

Results

The percent of CD4+/IL17+ was significantly higher in AKI patients (0.98%±0.11) vs ICU controls (0.15%±0.06, p<0.05). In addition, there was a enhancement in the expression of Orai1, from 3.5% in ICU controls vs with 30% in the AKI group. To determine if the increase in Orai1 expression was involved in mediating IL17 activity, we isolated CD4+ cells and stimulated in vitro for ~12 hours with either elevated extracellular sodium (170mM) and/or AngII (10-7M), which was previously shown to enhanced IL17 production in kidney T cells of post-AKI rats. In blood from AKI patients, there was significant increase in IL17 producing CD4+ in response to in vitro stimulation (from 2.3% to 5.2%, p<0.05). Furthermore, the increased IL17 response from blood of AKI patients was completely blocked by the inclusion of the Orai1/SOCE inhibitor YM58483 (p<0.05 vs. stimulated). Interestingly, there was no IL17 response in CD4+ cells from ICU controls without AKI.

Conclusion

These results suggest that circulating Th17 cells are activated early in critically ill patients with AKI vs ICU controls without AKI. Th17 cells and/or IL17 may represent a target as a potential early biomarker of AKI in the ICU, and Orai1 may represent a therapeutic target.

Funding

  • NIDDK Support