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Kidney Week

Abstract: FR-PO998

The Yin and Yang of Acute Rejection in Kidney Allografts

Session Information

  • Transplantation: Basic
    October 25, 2024 | Location: Exhibit Hall, Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 2101 Transplantation: Basic

Authors

  • Khan, Zahraa, Weill Cornell Medicine, New York, New York, United States
  • Li, Carol Y., Weill Cornell Medicine, New York, New York, United States
  • Wright, Sheavonnie, Weill Cornell Medicine, New York, New York, United States
  • Devito, Alex, Weill Cornell Medicine, New York, New York, United States
  • Montecillo, Mia, Weill Cornell Medicine, New York, New York, United States
  • Dadhania, Darshana M., Weill Cornell Medicine, New York, New York, United States
  • Muthukumar, Thangamani, Weill Cornell Medicine, New York, New York, United States
  • Suthanthiran, Manikkam, Weill Cornell Medicine, New York, New York, United States
Background

Acute rejection undermines the life - prolonging benefit of kidney transplantation. We and others have demonstrated that acute rejection is exemplified by proinflammatory effectors such as cytopathic granzyme B, perforin and pro - inflammatory cytokines such as interferon gamma and interleukin 2. Because preclinical models have elucidated the essential role of negative regulators of immunity such as CTLA4 and PD1 in limiting inflammation, we tested the hypothesis that acute rejection is also associated with the over expression of the prototypic negative regulator CTLA4. We tested our novel postulate by urinary cell mRNA profiling, an accurate reflector of immune events in a rejecting kidney allograft.

Methods

We isolated RNA from biopsy matched urine samples, reverse transcribed to cDNA and measured absolute mRNA levels of CTLA4 using preamplification enhanced real time quantitative PCR assays in 58 biopsy - matched urine samples from 52 recipients with acute T cell mediated rejection and 176 biopsy matched urine samples from 158 recipients with biopsies without rejection features (NR).

Results

The median (IQR) absolute copy number of CTLA4 mRNA in TCMR - biopsy matched 58 urine samples was 720 copies (197 - 2906) per microgram of total RNA compared to 167 copies (12.5 – 448) per microgram of total RNA in NR - biopsy matched 176 urine samples (P - value < 0.0001). Figure 1, the Box and Whisker plots, in addition to showing the distribution of CTLA4 mRNA copy numbers stratified by biopsy diagnosis, show significant overexpression of 18S normalized, log10 transformed CTLA4 mRNA in urine samples matched to TCMR biopsies compared to urine samples matched to NR biopsies (P-value <0.0001). Figure 2, Receiver operating Characteristic Curve analysis showed urinary cell level of CTLA4 discriminates TCMR biopsy matched urine from NR biopsy – matched urine samples and the area under the curve (AUROC) was 0.71 (95% Confidence interval 0.63 – 0.8, P-value < 0.0001) to distinguish TCMR from NR.

Conclusion

Our finding demonstrating over expression of CTLA4 mRNA during an episode of acute T cell mediated rejection has identified a counter regulatory mechanism to limit the proinflammatory forces associated with acute rejection. The finding also advances a mechanistic rationale for the use of CTLA4-Ig for the treatment of acute TCMR.