Pretransplant Recipient Circulating CD4+CD127lo/- Tumor Necrosis Factor Receptor 2+ Regulatory T Cells: A Surrogate of Regulatory T Cell-Suppressive Function and Predictor of Delayed and Slow Graft Function After Kidney Transplantation

Transplantation. 2016 Feb;100(2):314-24. doi: 10.1097/TP.0000000000000942.

Abstract

Background: Delayed graft function (DGF) and slow graft function (SGF) are ischemia-reperfusion-associated acute kidney injuries (AKI) that decrease long-term graft survival after kidney transplantation. Regulatory T (Treg) cells are protective in murine AKI, and their suppressive function predictive of AKI in kidney transplantation. The conventional Treg cell function coculture assay is however time-consuming and labor intensive. We sought a simpler alternative to measure Treg cell function and predict AKI.

Methods: In this prospective observational cohort study, pretransplant recipient circulating CD4+CD25+CD127lo/- and CD4+CD127lo/- tumor necrosis factor receptor 2 (TNFR2)+ Treg cells were measured by flow cytometry in 76 deceased donor kidney transplant recipients (DGF, n = 18; SGF, n = 34; immediate graft function [IGF], n = 24). In a subset of 37 recipients, pretransplant circulating Treg cell-suppressive function was also quantified by measuring the suppression of autologous effector T-cell proliferation by Treg cell in coculture.

Results: The TNFR2+ expression on CD4+CD127lo/- T cells correlated with Treg cell-suppressive function (r = 0.63, P < 0.01). In receiver operating characteristic curves, percentage and absolute number of CD4+CD127lo/-TNFR2+ Treg cell predicted DGF from non-DGF (IGF + SGF) with area under the curves of 0.75 and 0.77, respectively, and also AKI (DGF + SGF) from IGF with area under the curves of 0.76 and 0.72, respectively (P < 0.01). Prediction of AKI (DGF + SGF) from IGF remained significant in multivariate logistic regression accounting for cold ischemic time, donor age, previous transplant, and pretransplant dialysis modality.

Conclusions: Pretransplant recipient circulating CD4+CD127lo/-TNFR2+ Treg cell is potentially a simpler alternative to Treg cell function as a pretransplant recipient immune marker for AKI (DGF + SGF), independent from donor and organ procurement characteristics.

Trial registration: ClinicalTrials.gov NCT01232816.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / blood
  • Acute Kidney Injury / immunology*
  • Acute Kidney Injury / physiopathology
  • Acute Kidney Injury / therapy
  • Area Under Curve
  • Biomarkers / blood
  • Cells, Cultured
  • Coculture Techniques
  • Delayed Graft Function / blood
  • Delayed Graft Function / immunology*
  • Delayed Graft Function / physiopathology
  • Delayed Graft Function / therapy
  • Female
  • Flow Cytometry
  • Humans
  • Immunophenotyping / methods
  • Interleukin-7 Receptor alpha Subunit / blood
  • Interleukin-7 Receptor alpha Subunit / immunology*
  • Kidney / immunology*
  • Kidney / metabolism
  • Kidney / physiopathology
  • Kidney Transplantation / adverse effects*
  • Logistic Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Odds Ratio
  • Phenotype
  • Predictive Value of Tests
  • Prospective Studies
  • ROC Curve
  • Receptors, Tumor Necrosis Factor, Type II / blood
  • Receptors, Tumor Necrosis Factor, Type II / immunology*
  • Renal Dialysis
  • Risk Factors
  • T-Lymphocytes, Regulatory / classification
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Time Factors
  • Transplant Recipients*
  • Treatment Outcome

Substances

  • Biomarkers
  • Interleukin-7 Receptor alpha Subunit
  • Receptors, Tumor Necrosis Factor, Type II
  • TNFRSF1B protein, human

Associated data

  • ClinicalTrials.gov/NCT01232816