title: Fibrosis with inflammation at one year predicts transplant functional decline.
abstract: Lack of knowledge regarding specific causes for late loss of kidney transplants hampers improvements in long-term allograft survival. Kidney transplants with both interstitial fibrosis and subclinical inflammation but not fibrosis alone after 1 year have reduced survival. This study tested whether fibrosis with inflammation at 1 year associates with decline of renal function in a low-risk cohort and characterized the nature of the inflammation. We studied 151 living-donor, tacrolimus/mycophenolate-treated recipients without overt risk factors for reduced graft survival. Transplants with normal histology (n = 86) or fibrosis alone (n = 45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, whereas those with both fibrosis and inflammation (n = 20) exhibited a decline in GFR and reduced graft survival. Immunohistochemistry confirmed increased interstitial T cells and macrophages/dendritic cells in the group with both fibrosis and inflammation, and there was increased expression of transcripts related to innate and cognate immunity. Pathway- and pathologic process-specific analyses of microarray profiles revealed that potentially damaging immunologic activities were enriched among the overexpressed transcripts (e.g., Toll-like receptor signaling, antigen presentation/dendritic cell maturation, IFN-γ-inducible response, cytotoxic T lymphocyte-associated and acute rejection-associated genes). Therefore, the combination of fibrosis and inflammation in 1-year protocol biopsies associates with reduced graft function and survival as well as a rejection-like gene expression signature, even among recipients with no clinical risk factors for poor outcomes. Early interventions aimed at altering rejection-like inflammation may improve long-term survival of kidney allografts.
authors.affiliation: Department of Surgery, Division of Transplantation Surgery, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Walter D
authors.initials: WD
authors.lastname: Park
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Griffin
authors.forename: Lynn D
authors.initials: LD
authors.lastname: Cornell
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Cosio
authors.forename: Mark D
authors.initials: MD
authors.lastname: Stegall
mesh_terms: D000328:Adult; D001706:Biopsy; D015331:Cohort Studies; D005260:Female; D005355:Fibrosis; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000502:physiology; D006084:Graft Rejection / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009393:Nephritis / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology; D011237:Predictive Value of Tests; D011379:Prognosis
references.citation: Am J Transplant. 2006 May;6(5 Pt 1):1025-32
references.pmid: 16611340
references.citation: Transplantation. 2009 Jan 27;87(2):290-5
references.pmid: 19155987
references.citation: Bioinformatics. 2004 Nov 1;20(16):2778-86
references.pmid: 15166021
references.citation: Am J Transplant. 2005 Mar;5(3):573-81
references.pmid: 15707413
references.citation: Curr Opin Nephrol Hypertens. 2008 Mar;17(2):149-55
references.pmid: 18277147
references.citation: Mol Med. 2008 May-Jun;14(5-6):276-85
references.pmid: 18286166
references.citation: Annu Rev Med. 2007;58:369-85
references.pmid: 17002551
references.citation: J Am Soc Nephrol. 2003 Dec;14(12):3278-87
references.pmid: 14638927
references.citation: Am J Transplant. 2007 Dec;7(12):2712-22
references.pmid: 17941957
references.citation: Am J Transplant. 2009 May;9(5):989-97
references.pmid: 19422328
references.citation: Transplantation. 2007 Jun 15;83(11):1466-76
references.pmid: 17565320
references.citation: J Am Soc Nephrol. 1998 Nov;9(11):2129-34
references.pmid: 9808101
references.citation: Am J Transplant. 2006 Sep;6(9):2006-12
references.pmid: 16796717
references.citation: Am J Transplant. 2005 Jun;5(6):1405-14
references.pmid: 15888048
references.citation: Curr Opin Organ Transplant. 2009 Feb;14(1):34-9
references.pmid: 19337144
references.citation: N Engl J Med. 2003 Jul 10;349(2):125-38
references.pmid: 12853585
references.citation: Am J Transplant. 2007 Nov;7(11):2538-45
references.pmid: 17908280
references.citation: Am J Kidney Dis. 1997 Nov;30(5):646-52
references.pmid: 9370179
references.citation: J Am Soc Nephrol. 2003 Apr;14(4):1046-52
references.pmid: 12660340
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15448-53
references.pmid: 17873064
references.citation: Nephrol Dial Transplant. 2009 Aug;24(8):2567-75
references.pmid: 19398767
references.citation: Am J Transplant. 2008 Mar;8(3):547-56
references.pmid: 18294151
references.citation: Transplantation. 1996 Nov 15;62(9):1235-41
references.pmid: 8932263
references.citation: BMC Genomics. 2008 Feb 08;9:71
references.pmid: 18261221
references.citation: Am J Transplant. 2002 Nov;2(10):913-25
references.pmid: 12482143
references.citation: Transplant Rev (Orlando). 2008 Apr;22(2):131-40
references.pmid: 18631866
references.citation: Nat Immunol. 2008 Mar;9(3):239-44
references.pmid: 18285775
references.citation: Annu Rev Immunol. 2009;27:451-83
references.pmid: 19105661
references.citation: Am J Transplant. 2004 Aug;4(8):1289-95
references.pmid: 15268730
references.citation: Kidney Int. 1999 Feb;55(2):713-23
references.pmid: 9987096
references.citation: N Engl J Med. 2003 Dec 11;349(24):2326-33
references.pmid: 14668458
references.citation: Transplantation. 2008 Sep 15;86(5):681-5
references.pmid: 18791449
references.citation: Am J Transplant. 2004 Sep;4(9):1475-89
references.pmid: 15307835
references.citation: Am J Transplant. 2007 Nov;7(11):2483-95
references.pmid: 17908279
references.citation: Am J Transplant. 2005 May;5(5):1130-6
references.pmid: 15816896
references.citation: Pediatr Nephrol. 2009 Aug;24(8):1465-71
references.pmid: 18584214
references.citation: Kidney Int. 2007 Sep;72(6):690-7
references.pmid: 17597702
references.citation: Am J Transplant. 2008 Jul;8(7):1423-33
references.pmid: 18510637
references.citation: Am J Transplant. 2009 Aug;9(8):1859-67
references.pmid: 19563338
references.citation: Am J Transplant. 2007 Oct;7(10):2221-6
references.pmid: 17848174
references.citation: J Am Soc Nephrol. 2009 May;20(5):1149-60
references.pmid: 19389845
references.citation: Am J Transplant. 2007 Mar;7(3):512-7
references.pmid: 17250556
references.citation: N Engl J Med. 2005 Dec 1;353(22):2342-51
references.pmid: 16319383
references.citation: Am J Transplant. 2005 Oct;5(10):2464-72
references.pmid: 16162196
references.citation: Am J Transplant. 2006 Apr;6(4):747-52
references.pmid: 16539631
references.citation: Transplantation. 2007 Feb 27;83(4):448-57
references.pmid: 17318078
references.citation: Semin Immunol. 2004 Feb;16(1):3-9
references.pmid: 14751757
references.citation: Am J Transplant. 2009 Nov;9(11):2597-606
references.pmid: 19843035
references.citation: Am J Transplant. 2009 Mar;9(3):527-35
references.pmid: 19191769
references.citation: Transplantation. 2008 Jul 27;86(2):192-9
references.pmid: 18645476
references.citation: Am J Transplant. 2009 Mar;9(3):517-26
references.pmid: 19191772
references.citation: Am J Transplant. 2008 Mar;8(3):637-46
references.pmid: 18294160
references.citation: Transpl Int. 2009 Mar;22(3):293-302
references.pmid: 19017305
references.citation: J Am Soc Nephrol. 2004 Dec;15(12):3270-1
references.pmid: 15579532
references.citation: Microbes Infect. 2000 Mar;2(3):295-304
references.pmid: 10758406
references.citation: Am J Transplant. 2006 Jun;6(6):1342-54
references.pmid: 16686758
references.citation: Clin Transplant. 2005 Aug;19(4):518-21
references.pmid: 16008598
references.citation: BMC Genomics. 2007 Mar 30;8:88
references.pmid: 17397532
references.citation: Am J Transplant. 2009 Aug;9(8):1802-10
references.pmid: 19519809