title: African-American race modifies the influence of tacrolimus concentrations on acute rejection and toxicity in kidney transplant recipients.
abstract: OBJECTIVE
  To determine the effect of tacrolimus trough concentrations on clinical outcomes in kidney transplantation, while assessing if African-American (AA) race modifies these associations.
  
  
  METHODS
  Retrospective longitudinal cohort study of solitary adult kidney transplants.
  
  
  METHODS
  Large tertiary care transplant center.
  
  
  METHODS
  Adult solitary kidney transplant recipients (n=1078) who were AA (n=567) or non-AA (n=511).
  
  
  METHODS
  Mean and regressed slope of tacrolimus trough concentrations. Subtherapeutic concentrations were lower than 8 ng/ml.
  
  
  RESULTS
  AA patients were 1.7 times less likely than non-AA patients to achieve therapeutic tacrolimus concentrations (8 ng/ml or higher) during the first year after kidney transplant (35% vs 21%, respectively, p<0.001). AAs not achieving therapeutic concentrations were 2.4 times more likely to have acute cellular rejection (ACR) as compared with AAs achieving therapeutic concentrations (20.8% vs 8.5%, respectively, p<0.01) and 2.5 times more likely to have antibody-mediated rejection (AMR; 8.9% vs 3.6%, respectively, p<0.01). Rates of ACR (8.3% vs 6.7%) and AMR (2.0% vs 0.9% p=0.131) were similar in non-AAs compared across tacrolimus concentration groups. Multivariate modeling confirmed these findings and demonstrated that AAs with low tacrolimus exposure experienced a mild protective effect for the development of interstitial fibrosis/tubular atrophy (IF/TA; hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.47-1.32) with the opposite demonstrated in non-AAs (HR 2.2, 95% CI 0.90-5.1).
  
  
  CONCLUSIONS
  In contradistinction to non-AAs, AAs who achieve therapeutic tacrolimus concentrations have substantially lower acute rejection rates but are at risk of developing IF/TA. These findings may reflect modifiable time-dependent racial differences in the concentration-effect relationship of tacrolimus. Achievement of therapeutic tacrolimus trough concentrations, potentially through genotyping and more aggressive dosing and monitoring, is essential to minimize the risk of acute rejection in AA kidney transplant recipients.
authors.affiliation: Division of Transplant Surgery, College of Medicine, Medical University of South Carolina, Charleston, South Carolina.|Department of Pharmacy, Ralph H. Johnson VAMC, Charleston, South Carolina.
authors.forename: David J
authors.initials: DJ
authors.lastname: Taber
authors.affiliation: Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Mulugeta G
authors.initials: MG
authors.lastname: Gebregziabher
authors.affiliation: Division of Transplant, Nephrology, College of Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Titte R
authors.initials: TR
authors.lastname: Srinivas
authors.affiliation: Division of Transplant Surgery, College of Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Chavin
authors.affiliation: Division of Transplant Surgery, College of Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Prabhakar K
authors.initials: PK
authors.lastname: Baliga
authors.affiliation: Veterans Affairs HSR&D Health Equity and Rural Outreach Innovation Center (HEROIC), Ralph H. Johnson VAMC, Charleston, South Carolina.
authors.forename: Leonard E
authors.initials: LE
authors.lastname: Egede
mesh_terms: D000328:Adult; D001741:Black or African American; D001284:Atrophy / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D005355:Fibrosis / Q000139:chemically induced; D006084:Graft Rejection / Q000208:ethnology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000473:pathology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: African-American; acute rejection; kidney transplantation; tacrolimus; therapeutic drug monitoring