title: A Computational Gene Expression Score for Predicting Immune Injury in Renal Allografts.
abstract: BACKGROUND
  Whole genome microarray meta-analyses of 1030 kidney, heart, lung and liver allograft biopsies identified a common immune response module (CRM) of 11 genes that define acute rejection (AR) across different engrafted tissues. We evaluated if the CRM genes can provide a molecular microscope to quantify graft injury in acute rejection (AR) and predict risk of progressive interstitial fibrosis and tubular atrophy (IFTA) in histologically normal kidney biopsies.
  
  
  METHODS
  Computational modeling was done on tissue qPCR based gene expression measurements for the 11 CRM genes in 146 independent renal allografts from 122 unique patients with AR (n = 54) and no-AR (n = 92). 24 demographically matched patients with no-AR had 6 and 24 month paired protocol biopsies; all had histologically normal 6 month biopsies, and 12 had evidence of progressive IFTA (pIFTA) on their 24 month biopsies. Results were correlated with demographic, clinical and pathology variables.
  
  
  RESULTS
  The 11 gene qPCR based tissue CRM score (tCRM) was significantly increased in AR (5.68 ± 0.91) when compared to STA (1.29 ± 0.28; p < 0.001) and pIFTA (7.94 ± 2.278 versus 2.28 ± 0.66; p = 0.04), with greatest significance for CXCL9 and CXCL10 in AR (p <0.001) and CD6 (p<0.01), CXCL9 (p<0.05), and LCK (p<0.01) in pIFTA. tCRM was a significant independent correlate of biopsy confirmed AR (p < 0.001; AUC of 0.900; 95% CI = 0.705-903). Gene expression modeling of 6 month biopsies across 7/11 genes (CD6, INPP5D, ISG20, NKG7, PSMB9, RUNX3, and TAP1) significantly (p = 0.037) predicted the development of pIFTA at 24 months.
  
  
  CONCLUSIONS
  Genome-wide tissue gene expression data mining has supported the development of a tCRM-qPCR based assay for evaluating graft immune inflammation. The tCRM score quantifies injury in AR and stratifies patients at increased risk of future pIFTA prior to any perturbation of graft function or histology.
authors.affiliation: Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA 94017, United States of America.
authors.forename: Tara K
authors.initials: TK
authors.lastname: Sigdel
authors.affiliation: Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA 94017, United States of America; Kidney Transplant Unit, Bellvitge University Hospital, UB, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Bestard
authors.affiliation: Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA 94017, United States of America.
authors.forename: Tim Q
authors.initials: TQ
authors.lastname: Tran
authors.affiliation: Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA 94017, United States of America.
authors.forename: Szu-Chuan
authors.initials: SC
authors.lastname: Hsieh
authors.affiliation: Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA 94017, United States of America.
authors.forename: Silke
authors.initials: S
authors.lastname: Roedder
authors.affiliation: Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA 94017, United States of America.
authors.forename: Izabella
authors.initials: I
authors.lastname: Damm
authors.affiliation: Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA 94017, United States of America.
authors.forename: Flavio
authors.initials: F
authors.lastname: Vincenti
authors.affiliation: Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA 94017, United States of America.
authors.forename: Minnie M
authors.initials: MM
authors.lastname: Sarwal
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D064591:Allografts; D002648:Child; D003198:Computer Simulation; D005260:Female; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D018448:Models, Immunological