title: Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody.
abstract: Understanding rates and determinants of clinical pathologic progression for recipients with de novo donor-specific antibody (dnDSA), especially subclinical dnDSA, may identify surrogate endpoints and inform clinical trial design. A consecutive cohort of 508 renal transplant recipients (n = 64 with dnDSA) was studied. Recipients (n = 388) without dnDSA or dysfunction had an eGFR decline of -0.65 mL/min/1.73 m(2) /year. In recipients with dnDSA, the rate eGFR decline was significantly increased prior to dnDSA onset (-2.89 vs. -0.65 mL/min/1.73 m(2) /year, p < 0.0001) and accelerated post-dnDSA (-3.63 vs. -2.89 mL/min/1.73 m(2) /year, p < 0.0001), suggesting that dnDSA is both a marker and contributor to ongoing alloimmunity. Time to 50% post-dnDSA graft loss was longer in recipients with subclinical versus a clinical dnDSA phenotype (8.3 vs. 3.3 years, p < 0.0001). Analysis of 1091 allograft biopsies found that dnDSA and time independently predicted chronic glomerulopathy (cg), but not interstitial fibrosis and tubular atrophy (IFTA). Early T cell-mediated rejection, nonadherence, and time were multivariate predictors of IFTA. Independent risk factors for post-dnDSA graft survival available prior to, or at the time of, dnDSA detection were delayed graft function, nonadherence, dnDSA mean fluorescence intensity sum score, tubulitis, and cg. Ultimately, dnDSA is part of a continuum of mixed alloimmune-mediated injury, which requires solutions targeting T and B cells.
authors.affiliation: Department of Medicine, University of Manitoba, Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Wiebe
authors.affiliation: Department of Pathology, University of Manitoba, Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: I W
authors.initials: IW
authors.lastname: Gibson
authors.affiliation: Department of Pediatrics and Child Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: T D
authors.initials: TD
authors.lastname: Blydt-Hansen
authors.affiliation: Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Pochinco
authors.affiliation: Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: P E
authors.initials: PE
authors.lastname: Birk
authors.affiliation: Department of Medicine and Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Ho
authors.affiliation: Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Karpinski
authors.affiliation: Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.|Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Goldberg
authors.affiliation: Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Storsley
authors.affiliation: Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: D N
authors.initials: DN
authors.lastname: Rush
authors.affiliation: Departments of Medicine and Immunology, University of Manitoba, Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: P W
authors.initials: PW
authors.lastname: Nickerson
mesh_terms: D000208:Acute Disease; D000328:Adult; D000367:Age Factors; D064591:Allografts / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D015331:Cohort Studies; D051799:Delayed Graft Function / Q000276:immunology*; D018450:Disease Progression; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007518:Isoantibodies / Q000032:analysis / Q000276:immunology*; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000379:methods; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012737:Sex Factors; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D066027:Transplant Recipients; D016896:Treatment Outcome
chemical_list: D007518:Isoantibodies
keywords: Alloantibody; compliance/adherence; rejection: T cell-mediated (TCMR); rejection: antibody-mediated (ABMR); rejection: chronic