Efficacy And Safety Of RAS Inhibitor Combined With Sinomenine Hydrochloride In The Treatment Of IgA Nephropathy

Background:Immunoglobulin A nephropathy(IgAN)is the most common form of primary glomerulonephritis in China.KDIGO(Kidney Disease:Improving Global Outcomes)guidelines recommend that patients with IgA nephropathy with urine protein>0.5 g/24h should be treated with renin-angiotensin system(RAS)inhibitor-based optimization therapy for at least 3 months,regardless of whether they have hypertension.However,studies have shown that about 70%of patients still had urinary protein>0.75 g/24h after 6 months of optimal therapy.Sinomenine hydrochloride is a monomeric alkaloid extracted from the traditional Chinese medicine which has various pharmacological effects such as anti-inflammatory and immunosuppressive.There is a lack of evidence-based medical evidence on whether RAS inhibitors combined with sinomenine hydrochloride can improve the efficacy of lowering urinary protein excretion.Objective:1.Retrospective observation:To compare the efficacy of RAS inhibitor combined with sinomenine hydrochloride and RAS inhibitor alone in IgA nephropathy.2.Multicenter RCT(Randomized Controlled Trial)study:To evaluate the efficacy and safety of losartan potassium combined with sinomenine hydrochloride in IgA nephropathy.Methods:1.Retrospective observation:1227 patients with primary IgA nephropathy diagnosed by renal biopsy from 2007 to 2021 at the Third Xiangya Hospital of Central South University were collected.A total of 97patients who met the inclusion and exclusion criteria and had complete clinical data.All patients with 24 h urine protein>0.5 g/24h and e GFR(Estimated Glomerular Filtration Rate)≥30 ml/min/1.73m~2.51 patients were treated with RAS inhibitor alone(group A)and 46 patients were treated with RAS inhibitor combined with sinomenine hydrochloride(group B).The observation indicators were the change of 24 h urine protein and effective rate after 6 months of treatment.Effective is defined as 24-h urinary protein≤0.5 g or 24-h urinary protein reduction rate≥30%.Effectiveness was defined as 24-hour urine protein≤0.5 g or 24-hour urine protein decrease rate≥30%.2.Multicenter RCT:The study was initiated and led by the Third Xiangya Hospital of Central South University,with participants from six different regional tertiary care hospitals in Hunan Province and Zhejiang Province.The study randomly enrolled 109 patients with primary IgA nephropathy,all with urine protein 0.5-2.0 g/24h and e GFR≥60 ml/min/1.73m~2,including 37 cases in the group treated with sinomenine hydrochloride extended-release tablets alone(group A);36 cases in the group treated with Losartan Potassium alone(group B);and 36 cases in the group treated with Losartan Potassium combined with sinomenine hydrochloride extended-release tablets(group C).The main efficacy indicators were the change of 24-hour urine protein and the efficiency of treatment after 12 weeks,and the safety indicators were the adverse event rates.Result:1.Retrospective observation:There was no difference between the RAS inhibitor group and the combined treatment group in the baseline period in demographic data,routine biochemical indexes and 24-hour urine protein quantification.After 6 months of treatment,the 24 h urinary protein in both groups decreased compared with the baseline(P<0.05),and the RAS inhibitor group decreased by 0.55±0.79 g/24h,with an effective rate of 54.17%.In the RAS inhibitor combined with sinomenine hydrochloride group,the decrease was 1.19±0.78 g/24h,and the effective rate was90.91%.The latter’s decline and effective rate were greater than the former(P<0.05).2.Multi-center RCT study:There were no differences between groups in demographic data,routine biochemical indexes and 24-hour urine protein quantification.According to the Per-Protocol Set(PPS),after 12weeks of treatment,the 24 h urinary protein in the sinomenine hydrochloride group,the losartan potassium group,and the combined treatment group decreased by-0.19±1.09 g/24h,0.35±0.65 g/24h,0.51±0.46 g/24h respectively,the decrease of urine protein in losartan potassium group and combined treatment group was greater than that in sinomenine hydrochloride group(P<0.05),and the effective rates were37.50%,59.38%,and 88.46%respectively,the effective rate of the combined treatment group was higher than that of the sinomenine hydrochloride group and the losartan potassium group(P<0.05).In the Safety-Analysis Set(SS),there were 12 cases of adverse events and 1 case of serious adverse events,of which 7 cases were withdrawn from the trial due to allergic reactions.The incidences of adverse events in the sinomenine hydrochloride group,the losartan potassium group,and the combination therapy group were 15.79%,2.78%,and 11.11%,respectively,and the incidences of allergic reactions were 10.53%,2.78%,and 11.11%,respectively,with no statistics among the groups.Conclusion:1.In the optimal treatment of IgA nephropathy patients with 24-hour urine protein 0.5-2.0 g,the curative effect of RAS inhibitor combined with sinomenine hydrochloride is better than that of RAS inhibitor alone;2.Sinomenine hydrochloride has good safety except endogenous allergic reaction.