title: Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients.
abstract: This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR).
  
  
  
  Adult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model.
  
  
  
  Fourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6-month biopsy (13% vs. 50%).
  
  
  
  Transplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dirk Jan A R
authors.initials: DJ
authors.lastname: Moes
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rogier R
authors.initials: RR
authors.lastname: Press
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P Consultants BV), Leiden, The Netherlands.
authors.forename: Oliver
authors.initials: O
authors.lastname: Ackaert
authors.affiliation: Leiden Academic Center for Drug Research (LACDR), Leiden, The Netherlands.|Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P Consultants BV), Leiden, The Netherlands.
authors.forename: Bart A
authors.initials: BA
authors.lastname: Ploeger
authors.affiliation: Department of Nephrology, Academic Medical Center Amsterdam, The Netherlands.
authors.forename: Frederike J
authors.initials: FJ
authors.lastname: Bemelman
authors.affiliation: Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P Consultants BV), Leiden, The Netherlands.
authors.forename: Cheikh
authors.initials: C
authors.lastname: Diack
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Judith A M
authors.initials: JA
authors.lastname: Wessels
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tahar
authors.initials: T
authors.lastname: van der Straaten
authors.affiliation: Leiden Academic Center for Drug Research (LACDR), Leiden, The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Department of Nephrology, University Medical Center Groningen, The Netherlands.
authors.forename: Jan-Stephan F
authors.initials: JS
authors.lastname: Sanders
authors.affiliation: Department of Nephrology, Academic Medical Center Amsterdam, The Netherlands.
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Homan van der Heide
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henk Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: de Fijter
mesh_terms: D000328:Adult; D000906:Antibodies / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D016572:Cyclosporine / Q000627:therapeutic use; D051799:Delayed Graft Function / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D006084:Graft Rejection / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015994:Incidence; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors
chemical_list: D000906:Antibodies; D015415:Biomarkers; D007166:Immunosuppressive Agents; D016572:Cyclosporine
keywords: Acute rejection; Delayed graft function; Pharmacogenetics; Pharmacometrics; Renal transplantation; Subclinical rejection