Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial

Abstract

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.

Fig 1. Participant flowchart.

ESKD, end-stage kidney disease.

Fig 2. Kaplan–Meier curves of the percentages of patients with CAN in the 2 randomization arms.

Kaplan–Meier curves of the percentages of patients with CAN during the 3 years of follow-up in the MMF (red line) and in the AZA (blue line) groups in the overall patient population (A) and in patients who received a single kidney transplant (B) considered separately. AZA, azathioprine; CAN, chronic allograft nephropathy; CI, confidence interval; HR, hazard ratio; MMF, mycophenolate mofetil.

Fig 3. Kaplan–Meier curves of the percentages of patients with acute rejection episodes in the 2 randomization arms.

Kaplan–Meier curves of the percentages of patients with biopsy-proven acute clinical rejection (A) or biopsy-proven clinical or subclinical rejection (B) during the 3 years of follow-up in the MMF (red line) and in the AZA (blue line) groups. AZA, azathioprine; CI, confidence interval; HR, hazard ratio; MMF, mycophenolate mofetil.

Fig 4. GFR, blood CsA levels, platelets, and WBC counts at different time points after transplantation in the 2 randomization arms.

(A) GFR, (B) blood CsA C₀ and C₂ levels, (C) platelets, and (D) WBC counts at different time points after transplantation in the MMF (red) and in the AZA groups (blue). GFR data are reported as median and IQR; blood CsA levels, platelets, and WBC counts are reported as mean ± SEM. AZA, azathioprine; CsA, cyclosporine; GFR, glomerular filtration rate; IQR, interquartile range; MMF, mycophenolate mofetil; WBC, white blood cell.