title: A Time-to-Event Model for Acute Kidney Injury after Reduced-Intensity Conditioning Stem Cell Transplantation Using a Tacrolimus- and Sirolimus-based Graft-versus-Host Disease Prophylaxis.
abstract: There is a paucity of data evaluating acute kidney injury (AKI) incidence and its relationship with the tacrolimus-sirolimus (Tac-Sir) concentrations in the setting of reduced-intensity conditioning (RIC) after allogeneic stem cell transplantation (allo-HSCT). This multicenter retrospective study evaluated risk factors of AKI defined by 2 classification systems, Kidney Disease Improving Global Outcome (KDIGO) score and "Grade 0-3 staging," in 186 consecutive RIC allo-HSCT recipients with Tac-Sir as graft-versus-host disease prophylaxis. Conditioning regimens consisted of fludarabine and busulfan (n = 53); melphalan (n = 83); or a combination of thiotepa, fludarabine, and busulfan (n = 50). A parametric model, with detailed Tac-Sir consecutive blood levels, describing time to AKI was developed using the NONMEM software version 7.4. Overall, 81 of 186 (44%) RIC allo-HSCT recipients developed AKI with a cumulative incidence of 42% at a median follow-up of 25 months. Time to AKI was best described using a piecewise function. AKI-predicting factors were melphalan-based conditioning regimen (HR, 1.96; P < .01), unrelated donor (HR, 1.79; P = .04), and tacrolimus concentration: The risk of AKI increased 2.3% per each 1-ng/mL increase in tacrolimus whole blood concentration (P < .01). In multivariate analysis, AKI grades 2 and 3 according to KDIGO staging were independent risk factors for 2-year nonrelapse mortality (HR, 2.8; P = .05; and HR, 6.6; P < .0001, respectively). According to the KDIGO score, overall survival decreased with the increase in severity of AKI: 78% for patients without AKI versus 68%, 50%, and 30% for grades 1, 2, and 3, respectively (P < .0001). In conclusion, AKI is frequent after Tac-Sir-based RIC allo-HSCT and has a negative impact on outcome. This study presents the first predictive model describing time to AKI as a function of tacrolimus drug concentration.
authors.affiliation: Department of Hematology, Fundación de Investigación INCLIVA, Hospital Clínico Universitario, Valencia, Spain; Department of Hematology, Hospital Universitari I Politècnic la Fe, Valencia, Spain. Electronic address: jlpinana@gmail.com.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Piñana
authors.affiliation: Pharmacy Department, Hospital Clínico Universitario, Valencia, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Perez-Pitarch
authors.affiliation: Department of Hematology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Garcia-Cadenas
authors.affiliation: Department of Hematology, Hospital Universitari Vall D'Hebron, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Barba
authors.affiliation: Department of Hematology, Fundación de Investigación INCLIVA, Hospital Clínico Universitario, Valencia, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Hernandez-Boluda
authors.affiliation: Department of Hematology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Esquirol
authors.affiliation: Department of Hematology, Hospital Universitari Vall D'Hebron, Barcelona, Spain.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Fox
authors.affiliation: Department of Hematology, Fundación de Investigación INCLIVA, Hospital Clínico Universitario, Valencia, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Terol
authors.affiliation: Biochemical Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Queraltó
authors.affiliation: Biochemical Department, Hospital Universitari Vall D'Hebron, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Vima
authors.affiliation: Department of Hematology, Hospital Universitari Vall D'Hebron, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Valcarcel
authors.affiliation: Pharmacy Department, Hospital Clínico Universitario, Valencia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ferriols-Lisart
authors.affiliation: Department of Hematology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Sierra
authors.affiliation: Department of Hematology, Fundación de Investigación INCLIVA, Hospital Clínico Universitario, Valencia, Spain; Department of Medicine, School of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Solano
authors.affiliation: Department of Hematology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Martino
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000328:Adult; D000368:Aged; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D019172:Transplantation Conditioning / Q000379:methods*; D055815:Young Adult
chemical_list: D020123:Sirolimus; D016559:Tacrolimus
keywords: Acute kidney injury; Allogeneic stem cell transplantation; Parametric modeling of time-to-event data; Reduced intensity conditioning; Sirolimus; Tacrolimus; Time-to-event analysis