PMID- 34166370
OWN - NLM
STAT- MEDLINE
DCOM- 20211004
LR  - 20211210
IS  - 1549-1676 (Electronic)
IS  - 1549-1277 (Print)
IS  - 1549-1277 (Linking)
VI  - 18
IP  - 6
DP  - 2021 Jun
TI  - Mycophenolate mofetil versus azathioprine in kidney transplant recipients on 
      steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic 
      randomized trial.
PG  - e1003668
LID - 10.1371/journal.pmed.1003668 [doi]
LID - e1003668
AB  - BACKGROUND: We compared protection of mycophenolate mofetil (MMF) and 
      azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft 
      nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose 
      cyclosporine (CsA) microemulsion maintenance immunosuppression. METHODS AND 
      FINDINGS: ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 
      Italian transplant centers, compared the outcomes of 233 consenting recipients of 
      a first deceased donor kidney transplant induced with low-dose thymoglobulin and 
      basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 
      mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week 
      steroid. In patients without acute clinical or subclinical rejections, CsA dose 
      was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by 
      intention to treat. Participants were included between June 2007 and July 2012 
      and followed up to August 2016. Between-group donor and recipient 
      characteristics, donor/recipient mismatches, and follow-up CsA blood levels were 
      similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 
      48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA 
      (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 
      (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on 
      AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven 
      subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. 
      Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft 
      survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) 
      [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse 
      events (AEs) were not significantly different between groups. Chronicity scores 
      other than CAN predict long-term graft outcome. Study limitations include small 
      sample size and unblinded design. CONCLUSIONS: In this study, we found that in 
      deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF 
      had no significant benefits over AZA. This finding suggests that AZA, due to its 
      lower costs, could safely replace MMF in combination with minimized 
      immunosuppression. TRIAL REGISTRATION: ClinicalTrials.gov NCT00494741; EUDRACT 
      2006-005604-14.
FAU - Ruggenenti, Piero
AU  - Ruggenenti P
AUID- ORCID: 0000-0002-8394-0879
AD  - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
AD  - Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy.
FAU - Cravedi, Paolo
AU  - Cravedi P
AUID- ORCID: 0000-0001-7837-0923
AD  - Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New 
      York, United States of America.
FAU - Gotti, Eliana
AU  - Gotti E
AD  - Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy.
FAU - Plati, Annarita
AU  - Plati A
AD  - Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy.
FAU - Marasa, Maddalena
AU  - Marasa M
AUID- ORCID: 0000-0003-0712-2329
AD  - Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy.
FAU - Sandrini, Silvio
AU  - Sandrini S
AD  - Unit of Nephrology, ASST degli Spedali Civili di Brescia, Brescia, Italy.
FAU - Bossini, Nicola
AU  - Bossini N
AD  - Unit of Nephrology, ASST degli Spedali Civili di Brescia, Brescia, Italy.
FAU - Citterio, Franco
AU  - Citterio F
AUID- ORCID: 0000-0003-0489-6337
AD  - Unit of Kidney Transplantation, Fondazione Policlinico Universitario Agostino 
      Gemelli IRCCS, Roma, Italy.
FAU - Minetti, Enrico
AU  - Minetti E
AUID- ORCID: 0000-0001-9143-8021
AD  - Unit of Nephrology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy.
FAU - Montanaro, Domenico
AU  - Montanaro D
AD  - SOC di Nefrologia, Dialisi e Trapianto Renale della Azienda Ospedaliero 
      Universitaria "S. Maria della Misericordia," Udine, Italy.
FAU - Sabadini, Ettore
AU  - Sabadini E
AD  - Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy.
FAU - Tardanico, Regina
AU  - Tardanico R
AD  - Unit of Nephrology, ASST degli Spedali Civili di Brescia, Brescia, Italy.
FAU - Martinetti, Davide
AU  - Martinetti D
AUID- ORCID: 0000-0001-5839-1612
AD  - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
FAU - Gaspari, Flavio
AU  - Gaspari F
AUID- ORCID: 0000-0001-5941-3481
AD  - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
FAU - Villa, Alessandro
AU  - Villa A
AD  - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
FAU - Perna, Annalisa
AU  - Perna A
AUID- ORCID: 0000-0002-9257-0283
AD  - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
FAU - Peraro, Francesco
AU  - Peraro F
AUID- ORCID: 0000-0002-5569-5300
AD  - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
FAU - Remuzzi, Giuseppe
AU  - Remuzzi G
AUID- ORCID: 0000-0002-6194-3446
AD  - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
LA  - eng
SI  - ClinicalTrials.gov/NCT00494741
SI  - EudraCT/2006-005604-14
PT  - Clinical Trial, Phase III
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Pragmatic Clinical Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210624
PL  - United States
TA  - PLoS Med
JT  - PLoS medicine
JID - 101231360
RN  - 0 (Immunosuppressive Agents)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Azathioprine/*administration & dosage/adverse effects
MH  - Cyclosporine/*administration & dosage/adverse effects
MH  - Drug Therapy, Combination
MH  - Female
MH  - Graft Rejection/diagnosis/immunology/*prevention & control
MH  - Graft Survival/*drug effects
MH  - Humans
MH  - Immunosuppressive Agents/*administration & dosage/adverse effects
MH  - Italy
MH  - *Kidney Transplantation/adverse effects
MH  - Male
MH  - Middle Aged
MH  - Mycophenolic Acid/*administration & dosage/adverse effects
MH  - Prospective Studies
MH  - Time Factors
MH  - Treatment Outcome
PMC - PMC8224852
COIS- The authors have declared that no competing interests exist.
EDAT- 2021/06/25 06:00
MHDA- 2021/10/05 06:00
PMCR- 2021/06/24
CRDT- 2021/06/24 17:23
PHST- 2020/02/27 00:00 [received]
PHST- 2021/05/23 00:00 [accepted]
PHST- 2021/06/24 17:23 [entrez]
PHST- 2021/06/25 06:00 [pubmed]
PHST- 2021/10/05 06:00 [medline]
PHST- 2021/06/24 00:00 [pmc-release]
AID - PMEDICINE-D-20-00648 [pii]
AID - 10.1371/journal.pmed.1003668 [doi]
PST - epublish
SO  - PLoS Med. 2021 Jun 24;18(6):e1003668. doi: 10.1371/journal.pmed.1003668. 
      eCollection 2021 Jun.