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

José Luis Piñana, Alejandro Perez-Pitarch, Irene Garcia-cadenas, Pere Barba, Juan Carlos Hernandez-Boluda, Albert Esquirol, María Laura Fox, María José Terol, Josep M. Queraltó, Jaume Vima, David Valcarcel, Rafael Ferriols-Lisart, Jorge Sierra, Carlos Solano, Rodrigo Martino

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Abstract

© 2017 The American Society for Blood and Marrow Transplantation 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.
Original languageEnglish
Pages (from-to)1177-1185
JournalBiology of Blood and Marrow Transplantation
Volume23
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017

Keywords

  • Acute kidney injury
  • Allogeneic stem cell transplantation
  • Parametric modeling of time-to-event data
  • Reduced intensity conditioning
  • Sirolimus
  • Tacrolimus
  • Time-to-event analysis

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    Piñana, J. L., Perez-Pitarch, A., Garcia-cadenas, I., Barba, P., Hernandez-Boluda, J. C., Esquirol, A., Fox, M. L., Terol, M. J., Queraltó, J. M., Vima, J., Valcarcel, D., Ferriols-Lisart, R., Sierra, J., Solano, C., & Martino, R. (2017). 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. Biology of Blood and Marrow Transplantation, 23(7), 1177-1185. https://doi.org/10.1016/j.bbmt.2017.03.035