Molecular microscope strategy to improve risk stratification in early antibody-mediated kidney allograft rejection

Abstract

Antibody-mediated rejection (ABMR) is the leading cause of kidney allograft loss. We investigated whether the addition of gene expression measurements to conventional methods could serve as a molecular microscope to identify kidneys with ABMR that are at high risk for failure. We studied 939 consecutive kidney recipients at Necker Hospital (2004-2010; principal cohort) and 321 kidney recipients at Saint Louis Hospital (2006-2010; validation cohort) and assessed patients with ABMR in the first 1 year post-transplant. In addition to conventional features, we assessed microarray-based gene expression in transplant biopsy specimens using relevant molecular measurements: the ABMR Molecular Score and endothelial donor-specific antibody-selective transcript set. The main outcomes were kidney transplant loss and progression to chronic transplant injury. We identified 74 patients with ABMR in the principal cohort and 54 patients with ABMR in the validation cohort. Conventional features independently associated with failure were donor age and humoral histologic score (g+ptc+v+cg+C4d). Adjusting for conventional features, ABMR Molecular Score (hazard ratio [HR], 2.22; 95% confidence interval [95% CI], 1.37 to 3.58; P=0.001) and endothelial donor-specific antibody-selective transcripts (HR, 3.02; 95% CI, 1.00 to 9.16; P<0.05) independently associated with an increased risk of graft loss. The results were replicated in the independent validation group. Adding a gene expression assessment to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 1.01; 95% CI, 0.57 to 1.46; P<0.001; integrated discrimination improvement, 0.16; P<0.001). Compared with conventional assessment, the addition of gene expression measurement in kidney transplants with ABMR improves stratification of patients at high risk for graft loss.

Copyright © 2014 by the American Society of Nephrology.

Figures

Figure 1.

Kidney allograft histopathology at the time of rejection showing the distribution of graft injury lesions in the overall cohort of patients with ABMR. Note that all patients have intense microcirculation injury. Heat map is colored by thresholds representing (A) the histologic characteristics of patients with ABMR and (B) the mean Banff scores. ah, arteriolar hyalinosis; C4d, complement split product; cg, transplant glomerulopathy; cv, arterial fibrous intimal thickening score; g, glomerulitis; i, interstitial inflammation score; IFTA, interstitial fibrosis–tubular atrophy; ptc, peritubular capillary; t, tubulitis score; v, vasculitis.

Figure 2.

(A) Time to kidney transplant loss and (B) time to the progression of cg lesions after ABMR.

Figure 3.

Time of progression of cg lesions after acute ABMR according to (A) ABMR Molecular Score, (B) endothelial DSA-selective transcripts, (C) ptc Banff score, and (D) C4d deposition in the peritubular capillaries. Progression of transplant glomerulopathy lesions is defined by increase of cg Banff score≥1. High and low ABMR Molecular Scores and the endothelial DSA-selective transcripts were defined using the median values for the ABMR and endothelial DSA-selective transcripts as thresholds. A high ptc score was defined by a ptc Banff score≥2 compared with a low ptc score (

Figure 4.

Additive value of the molecular microscope (ABMR Molecular Score) for reclassification of risk of allograft failure (continuous net reclassification improvement). Blue lines in patients without graft failure indicate that the molecular microscope moved risk prediction in the correct (downward) direction (42/53=79.2%). Conversely, red lines in patients with graft failure indicate a correct (upward) change in risk assessment when using the molecular microscope (15/21=71.4%).