title: The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy.
abstract: BACKGROUND
  This study investigated the mechanisms involved in development of donor-specific antibody (DSA) and/or C4d-negative transplant glomerulopathy (TGP) by allograft gene expression profiles using microarrays.
  
  
  METHODS
  This cohort study was conducted in kidney transplant recipients. Patients were eligible for inclusion if they required a clinically indicated biopsy at any time point after their transplant. They were then classified according to their histopathology findings and DSA and C4d results. Eighteen chronic antibody-mediated rejection (CAMR), 14 DSA+/C4d- TGP, 25 DSA-/C4d- TGP, and 47 nonspecific interstitial fibrosis/tubular atrophy (IFTA) biopsy specimens were identified. In a subset of patients from the study population, biopsy specimens in each group and normal transplant kidney specimens were analyzed with Affymetrix Human Gene 1.0 ST Arrays.
  
  
  RESULTS
  The mean sum score of glomerulitis and peritubular capillaritis increased from 0.28±0.78 in IFTA specimens to 0.75±0.85 in DSA-/C4d- TGP specimens, 1.71±1.49 in DSA+/C4d-/TGP specimens, and 2.11±1.74 in CAMR specimens (P<0.001). During a median follow-up time of 2 (interquartile range, 1.4-2.8) years after biopsy, graft loss was highest in CAMR specimens (27.8%) compared to IFTA specimens (8.5%), DSA+/C4d- TGP specimens (14.3%), and DSA-/C4d- TGP specimens (16%) (P=0.01). With use of microarrays, comparison of the gene expression profiles of DSA-/C4d- TGP specimens with glomerulitis + peritubular capillaritis scores > 0 to normal and IFTA biopsy specimens revealed higher expression of quantitative cytotoxic T cell-associated transcripts (QCAT). However, both CAMR and DSA+/C4d- TGP specimens had higher expression of not only QCAT but also IFN-γ and rejection-induced, constitutive macrophage-associated, natural killer cell-associated, and DSA-selective transcripts. Endothelial cell-associated transcript expression was upregulated only in CAMR biopsy specimens.
  
  
  CONCLUSIONS
  These results suggested that DSA+/C4d- TGP biopsy specimens may be classified as CAMR. In contrast, DSA-/C4d- TGP specimens showed increased cytotoxic T cell-associated transcripts, suggesting T cell activation as a mechanism of injury.
authors.affiliation: Division of Pediatric Nephrology,, †Montefiore-Einstein Center for Transplantation,, ‡Department of Pathology,, §Computational Genomics Facility, Department of Genetics, and, ‖Division of Nephrology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hayde
authors.forename: Yi
authors.initials: Y
authors.lastname: Bao
authors.forename: James
authors.initials: J
authors.lastname: Pullman
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: R Brent
authors.initials: RB
authors.lastname: Calder
authors.forename: Monica
authors.initials: M
authors.lastname: Chung
authors.forename: Daniel
authors.initials: D
authors.lastname: Schwartz
authors.forename: Michelle
authors.initials: M
authors.lastname: Lubetzky
authors.forename: Maria
authors.initials: M
authors.lastname: Ajaimy
authors.forename: Graciela
authors.initials: G
authors.lastname: de Boccardo
authors.forename: Enver
authors.initials: E
authors.lastname: Akalin
mesh_terms: D000328:Adult; D064591:Allografts; D001706:Biopsy; D015935:Complement C4b / Q000032:analysis*; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival; D006648:Histocompatibility; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007518:Isoantibodies / Q000032:analysis*; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D055806:Microvessels / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000032:analysis*; D011237:Predictive Value of Tests; D012307:Risk Factors; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D013997:Time Factors
chemical_list: D007518:Isoantibodies; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d
references.citation: J Mol Diagn. 2010 Sep;12(5):653-63
references.pmid: 20688906
references.citation: Am J Transplant. 2010 Mar;10(3):464-71
references.pmid: 20121738
references.citation: Transplantation. 2012 Aug 27;94(4):345-51
references.pmid: 22820699
references.citation: Am J Transplant. 2010 Aug;10(8):1812-22
references.pmid: 20659089
references.citation: Am J Transplant. 2009 Oct;9(10):2312-23
references.pmid: 19681822
references.citation: Am J Transplant. 2009 May;9(5):1230-6
references.pmid: 19422348
references.citation: Clin J Am Soc Nephrol. 2007 Nov;2(6):1261-7
references.pmid: 17942771
references.citation: Kidney Int. 2011 Oct;80(8):879-85
references.pmid: 21697808
references.citation: Hum Immunol. 2012 Dec;73(12):1218-25
references.pmid: 22863448
references.citation: Am J Transplant. 2011 Jan;11(1):56-65
references.pmid: 21199348
references.citation: Am J Transplant. 2008 Apr;8(4):819-25
references.pmid: 18261174
references.citation: Am J Transplant. 2008 Apr;8(4):753-60
references.pmid: 18294345
references.citation: Am J Transplant. 2012 May;12(5):1168-79
references.pmid: 22300601
references.citation: Am J Transplant. 2012 May;12(5):1180-91
references.pmid: 22390872
references.citation: Transplantation. 2013 Feb 27;95(4):580-8
references.pmid: 23274969
references.citation: Am J Transplant. 2012 Mar;12(3):563-70
references.pmid: 22300494
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Am J Transplant. 2007 Jul;7(7):1743-52
references.pmid: 17564636
references.citation: Hum Pathol. 2012 Jan;43(1):69-80
references.pmid: 21777946
references.citation: J Am Soc Nephrol. 2007 Apr;18(4):1046-56
references.pmid: 17360947
references.citation: Am J Transplant. 2007 Sep;7(9):2124-32
references.pmid: 17608832
references.citation: Am J Transplant. 2011 Oct;11(10):2123-31
references.pmid: 21827618
references.citation: Am J Transplant. 2003 Jun;3(6):708-14
references.pmid: 12780562
references.citation: Am J Transplant. 2010 Nov;10(11):2442-52
references.pmid: 20977635
references.citation: Kidney Int. 1999 Feb;55(2):713-23
references.pmid: 9987096
references.citation: Am J Transplant. 2012 Jun;12(6):1551-63
references.pmid: 22335458
references.citation: Kidney Int. 2012 Aug;82(3):321-9
references.pmid: 22513824
references.citation: Transplantation. 2011 Mar 15;91(5):552-9
references.pmid: 21150704
references.citation: Am J Transplant. 2009 Nov;9(11):2561-70
references.pmid: 19775320
references.citation: Am J Transplant. 2003 Sep;3(9):1116-20
references.pmid: 12919091
references.citation: Am J Transplant. 2007 Dec;7(12):2712-22
references.pmid: 17941957