title: Untreated rejection in 6-month protocol biopsies is not associated with fibrosis in serial biopsies or with loss of graft function.
abstract: Donor age, calcineurin inhibitor nephrotoxicity, and acute rejection are the most significant predictors of chronic allograft nephropathy. Protocol biopsies, both in deceased- and living-donor renal grafts, have shown that cortical tubulointerstitial fibrosis correlates with graft survival and function. The impact of not treating subclinical acute rejection (SAR) is less clear. In this study, 126 de novo renal transplant recipients were randomly assigned to receive area-under-the-curve-controlled exposure of either a cyclosporine or a tacrolimus-based immunosuppressive regimen that included steroids, mycophenolate mofetil, and basiliximab induction. Protocol biopsies were taken before and 6 and 12 mo after transplantation. The prevalence of SAR was determined retrospectively. Fibrosis was evaluated by quantitative digital analysis of Sirius red staining in serial biopsies. Donor age correlated significantly with tubulointerstitial fibrosis in pretransplantation biopsies and inferior graft function at month 6 (rtau = -0.26; P = 0.033). Acute rejection incidence was 11.5%, and no clinical late rejection occurred. The prevalence of SAR at 6 mo was 30.8% but was not associated with differences in serial quantitative Sirius red staining at 6 or 12 mo, proteinuria, or progressive loss of GFR up to 2 yr. No differences were found in donor variables, histocompatibility, rejection history, or exposure of immunosuppressants. Controlled individualized calcineurin inhibitor exposure and subsequent tapering resulted in a low early acute rejection rate and prevented late acute rejection. Because, by design, we did not treat SAR, these results provide evidence that asymptomatic infiltrates in 6-mo surveillance biopsies may not be deleterious in the intermediate term. There is need for reliable biomarkers to prove that not all cell infiltrates are equivalent or that infiltrates may change with time.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Eduard M
authors.initials: EM
authors.lastname: Scholten
authors.forename: Ajda T
authors.initials: AT
authors.lastname: Rowshani
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.forename: Frederike J
authors.initials: FJ
authors.lastname: Bemelman
authors.forename: Michael
authors.initials: M
authors.lastname: Eikmans
authors.forename: Erik
authors.initials: E
authors.lastname: van Kan
authors.forename: Marko J
authors.initials: MJ
authors.lastname: Mallat
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Janto
authors.initials: J
authors.lastname: Surachno
authors.forename: Ineke J
authors.initials: IJ
authors.lastname: ten Berge
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Bajema
authors.forename: Johan W
authors.initials: JW
authors.lastname: de Fijter
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001706:Biopsy / Q000379:methods*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000009:adverse effects; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced; D005260:Female; D005355:Fibrosis; D006084:Graft Rejection / Q000175:diagnosis / Q000188:drug therapy*; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000502:physiology; D016030:Kidney Transplantation / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000009:adverse effects
chemical_list: D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D016559:Tacrolimus