title: Within-Patient Variability in Tacrolimus Blood Levels Predicts Kidney Graft Loss and Donor-Specific Antibody Development.
abstract: BACKGROUND
  Lack of adherence to immunosuppressive drugs is a risk factor for development of de novo donor-specific antibodies (dnDSA) and can contribute to antibody-mediated rejection and graft loss. Moreover, nonadherence is the main determinant of immunosuppressive drug level variability. High intrapatient variability of tacrolimus relates to a worse outcome in transplant recipients through unknown mechanisms. We hypothesized that a high within-patient variability of tacrolimus could increase the rate of dnDSA development and contribute to further death-censored graft loss (DCGL).
  
  
  METHODS
  We included 310 adult renal transplants receiving twice-daily tacrolimus throughout their first posttransplant year, with (1) at least 3 blood trough levels available to calculate coefficient of variation (CV) from month 4 to 12, (2) graft survival longer than 1 year, and (3) absence of pretransplant DSA. The dnDSA were analyzed in sera at 1, 3, and 5 years and around 6 month before the last follow-up visit or graft loss by single-antigen beads.
  
  
  RESULTS
  During the follow-up, 53 patients lost their graft excluding death. A total of 116 patients (37.4%) had a CV greater than 30% and 39 (12.6%) developed dnDSA. Coefficient of variation greater than 30% (hazards ratio, 2.613; 95% confidence interval, 1.361-5.016; P = 0.004) independently related to DCGL. Acute rejection, re-transplant and CV greater than 30% (hazards ratio, 2.925; 95% confidence interval, 1.473-5.807; P = 0.002) were the only variables related to dnDSA development by Cox regression analysis.
  
  
  CONCLUSIONS
  Tacrolimus level variability is a strong risk factor for dnDSA development and DCGL. Variability must be added to the current monitoring of kidney transplant recipients due to its relationship with adherence and to graft outcome.
authors.affiliation: 1 Nephrology Service, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain. 2 Immunology Service, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain. 3 Clinical Pharmacology Service, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Rodrigo
authors.forename: David San
authors.initials: DS
authors.lastname: Segundo
authors.forename: Gema
authors.initials: G
authors.lastname: Fernández-Fresnedo
authors.forename: Marcos
authors.initials: M
authors.lastname: López-Hoyos
authors.forename: Adalberto
authors.initials: A
authors.lastname: Benito
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Ruiz
authors.forename: Maria-Angeles
authors.initials: MA
authors.lastname: de Cos
authors.forename: Manuel
authors.initials: M
authors.lastname: Arias
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood*; D007518:Isoantibodies / Q000096:biosynthesis*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000097:blood*; D014019:Tissue Donors
chemical_list: D007166:Immunosuppressive Agents; D007518:Isoantibodies; D016559:Tacrolimus