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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 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.
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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 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: I W Gibson; W Gwinner; V Bröcker; B Sis; J Riopel; I S D Roberts; I Scheffner; G S Jhangri; M Mengel Journal: Am J Transplant Date: 2008-02-05 Impact factor: 8.086
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Authors: L C Racusen; K Solez; R B Colvin; S M Bonsib; M C Castro; T Cavallo; B P Croker; A J Demetris; C B Drachenberg; A B Fogo; P Furness; L W Gaber; I W Gibson; D Glotz; J C Goldberg; J Grande; P F Halloran; H E Hansen; B Hartley; P J Hayry; C M Hill; E O Hoffman; L G Hunsicker; A S Lindblad; Y Yamaguchi Journal: Kidney Int Date: 1999-02 Impact factor: 10.612
Authors: Lorraine C Racusen; Robert B Colvin; Kim Solez; Michael J Mihatsch; Philip F Halloran; Patricia M Campbell; Michael J Cecka; Jean-Pierre Cosyns; Anthony J Demetris; Michael C Fishbein; Agnes Fogo; Peter Furness; Ian W Gibson; Denis Glotz; Pekka Hayry; Lawrence Hunsickern; Michael Kashgarian; Ronald Kerman; Alex J Magil; Robert Montgomery; Kunio Morozumi; Volker Nickeleit; Parmjeet Randhawa; Heinz Regele; Daniel Seron; Surya Seshan; Stale Sund; Kiril Trpkov Journal: Am J Transplant Date: 2003-06 Impact factor: 8.086
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Authors: T F Mueller; G Einecke; J Reeve; B Sis; M Mengel; G S Jhangri; S Bunnag; J Cruz; D Wishart; C Meng; G Broderick; B Kaplan; P F Halloran Journal: Am J Transplant Date: 2007-10-17 Impact factor: 8.086
Authors: J M Gloor; S Sethi; M D Stegall; W D Park; S B Moore; S DeGoey; M D Griffin; T S Larson; F G Cosio Journal: Am J Transplant Date: 2007-07-03 Impact factor: 8.086
Authors: Timothy E Sweeney; Winston A Haynes; Francesco Vallania; John P Ioannidis; Purvesh Khatri Journal: Nucleic Acids Res Date: 2016-09-14 Impact factor: 16.971
Authors: André Costa Teixeira; Fábio Távora; Melissa Lou Fagundes de Deus E Silva; Renan Martins Gomes Prado; Ronaldo de Matos Esmeraldo; Tainá Veras de Sandes-Freitas Journal: Clin Exp Nephrol Date: 2020-11-26 Impact factor: 2.801