1. Patients:
Patients were recruited from 12 renal units in Shanghai, China. They were aged 18-65 with biopsy-confirmed primary IgAN in recent 3 months, and with any one of the following cases: 24-UPE>1.0g/day; eGFR<60ml/min/1.73m2(calculated by CKD-MDRD equation); and renal histological lesions defined as Lee’s IV, or glomerulus and/or segmental sclerosis ≥ 40%. Patients with anyone of the following conditions were excluded: (a) rapidly progressive IgAN (IgAN with rapid renal function loss, characterized histopathologically by necrotizing capillaritis or active crescent formation>50%); (b) secondary IgAN such as Henoch-Schonlein purpura nephritis, hepatitis-associated glomerulonephritis, and lupus nephritis, diabetic nephropathy, etc.; (c) receiving immunosuppressive and cytotoxic drugs for over 1 weeks or corticosteroid more than 20mg/day for more than 4 weeks within 6 months; (d) eGFR <30ml/min/1.73m2; (e) malignancy, HIV infection, acute central nervous system diseases, serious gastrointestinal diseases; (f) pregnancy or lactation. This study was approved by local ethics committees and all patients provided written informed consent before enrollment.
2. Procedures:
Before randomly allocation, eligible patients were enrolled into a 3-month run-in phase, during which, RAS blockade was optimised by adjusting ACEIs and ARBs to a maximum recommended dose or maximum tolerated dose (in keeping with established clinical practice), to a target blood pressure of less than 130/80 mmHg. At the end of run-in, patients according to the inclusion criteria were randomly allocated to LEF plus low-dose prednisone (LEF group) or conventionally accepted-dose prednisone group (prednisone group). All patients continued optimised ACEIs or ARBs treatment throughout the trial. Patients in LEF group received LEF 40mg/day for 3 days, after which the dose was reduced to 20 mg/day and administered for 12 months, combined with oral prednisone 0.5-0.8mg/kg/day for 8-12 weeks with a maximum daily dose of 40mg. Then prednisone was tapered by 5mg, 2.5mg to a maintenance dose of 10mg per day. Patients in prednisone group received oral prednisone 1mg/kg/day for 8-12 weeks, which was tapered by 5mg, 2.5mg to a maintenance dose of 10mg per day. The maximum daily dose of prednisone was 60mg. The followed-up is 12 months. During the treatment, when the disease relapsed, it is allowed to maintain the prednisone unchanged for 4 weeks, or increase to the dose before relapsing for 2-4 weeks and, if necessary, a temporary methylprednisolone was allowed (<1g). During the follow-up period, the patients were retreated with the original regimen when the disease relapsed.
3. Allocation
Patients will be randomly assigned to either the LEF group or the prednisone group at a 1:1 allocation ratio, using a computer generated randomisation schedule of permuted blocks of random sizes ranging from 4 to 10. The creation of the randomisation sequentially numbered will be performed by persons not else involved in the trial. The final enrolment and subsequent allocation of participants will be conducted by investigators not taking part in any outcome assessment, who will be blinded to the randomisation sequence at all times during the intervention period. Outcome assessors will not take part in any of the processes related to allocation.
4. Outcome
Patients were randomized to LEF group or prednisone group using a computer algorithm method of permuted blocks. Demographics and baseline characteristics were collected at month 0. When recording clinical and laboratory characteristics at month 3, month 6, month 9, month12, month 24, the medications and adverse events were recorded at the same time. Standardised questionnaires at each visit were used to ask patients about the presence of specific LEF-related and corticosteroid-related adverse events.
The primary outcome is 24h UPE and secondary outcomes were sALB, Scr, and eGFR.
Complete remission (CR) was defined as 24h UPE<0.3g/d, with stable Scr (changes in Scr £15% of baseline values) and sALB ≥ 35g/L; partial remission (PR) was defined as 24h UPE decreased by 50% of the baseline value and ≥ 0.3g/d, with stable Scr and sALB ≥ 30g/L; No response (NR) was defined as a 24h UPE > 3.5 g/d, or < 50% reduction in baseline value, or Scr doubled. Relapse was defined as the reappearance of overt proteinuria, defined as > 1.0 g/d or an increase of > 50% from the lowest level of proteinuria after remission[14, 15].
5. Statistical analysis
Normal distribution variables were expressed by means ± SD and compared by t-test or ANOVA. Non-parametric variables were represented as median with range, and the either the Mann-Whitney U test or the Kruskal-Wallis test was used. The chi-square test was employed for the categorical variables. Statistical analyses were performed using SPSS 13.0, with p-values <0.05 considered statistically significant.