Background/Purpose: To report the 10-year outcome of patients with lupus nephritis (LN) treated with combined prednisolone with mycophenolate mofetil (MMF) or tacrolimus (TAC) as induction in a randomized controlled trial (RCT).

Methods: Patients with active LN were randomized to receive MMF (2-3g/day) (N=76) or TAC (0.1-0.06mg/kg/day) (N=74) in combination with high-dose prednisolone (0.6mg/kg/day for 6-8 weeks and tapered) as induction therapy between 2005 and 2012.  Complete renal (CR) or good partial renal responders were switched to azathioprine (AZA) (2mg/kg/day) for maintenance.  We hereby report the 10-year outcomes of the patients in terms of renal flares (proteinuric/nephritic), renal function decline (drop in eGFR by ≥30% from baseline), development of chronic kidney disease (CKD) stage 4/5 (eGFR< 30ml/min) and mortality.  Factors affecting renal prognosis were studied by Cox regression analysis.  Renal parameters (urine P/Cr ratio [uPCr], eGFR) at different time points from 6 to 24 months were studied for their predictive value of a poor renal prognosis by ROC analysis.

Results: 150 patients (92% women) were studied (age 35.5±12.8 years, ISN/RPS class III±V 36%; IVG/S±V 46%; pure V 19%, activity and chronicity score 8.2±3.4 and 2.6±1.6, respectively). At entry, 67% patients had eGFR< 90ml/min.  The rate of CR at 6m was 59% in MMF and 62% in the TAC group (p=0.71).   Maintenance AZA was given to 79% patients.  After a follow-up of 118.2±42 months, proteinuric and nephritic renal flares occurred in 34% and 37% of patients treated with MMF and 53% and 30% in those treated with TAC, respectively.  There was a total of 77 renal flares in 43 (57%) MMF-treated patients (0.11/patient-year) and 92 renal flares in 46 (62%) patients treated with TAC (0.12/patient-year; p=0.44).  The cumulative risk of renal flare in patients treated with MMF/AZA was 28% at 3 years, 42% at 5 years and 58% at 10 years, whereas the corresponding figures for those treated with TAC/AZA was 32% at 3 years, 53% in 5 years and 66% in 10 years (p=0.43).  Time to first renal flare was 70.4±47.1 months in MMF group and 65.2 ±50 months in the TAC group (p=0.61).  The cumulative incidence of a composite outcome of eGFR decline by ≥30%, development of CKD stage 4/5 or death at 5 and 10 years was 24% and 33%, respectively, in patients treated with MMF, and 17% and 33%, respectively, in those treated with TAC (p=0.90).  Factors significantly associated with this outcome were first time lupus nephritis (HR 0.26[0.11-0.59]; p=0.001), uPCR at 6m (HR 1.33[1.02-1.76]; p=0.04) and eGFR at 6m (HR 0.98[0.97-0.997]; p=0.02).  ROC analysis demonstrated that an eGFR cut-off of 80ml/min (AUC 0.70; sensitivity 0.64, specificity 0.66) and uPCR cut-off of 0.75 (AUC 0.73; sensitivity 0.69, specificity 0.74) at month 18 best predicted CKD stage 4/5 or decline of eGFR by ≥30%.

Conclusion: Long-term data of our RCT showed that TAC remained non-inferior to MMF as induction therapy of LN in terms of renal flares, renal function decline and mortality.  Relapsed renal disease, lower eGFR and more proteinuria post-induction therapy were associated with a poorer outcome.  An uPCR ≤0.75 and eGFR of >80ml/min at 18 months best predicted a better outcome at 10 years, and should be considered as a target for induction/consolidation therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/long-term-outcome-of-a-randomized-controlled-trial-comparing-tacrolimus-with-mycophenolate-mofetil-as-induction-therapy-of-severe-lupus-nephritis/