摘要
研究背景和目的以往研究显示血管紧张素受体拮抗剂(ARB)和抗氧化治疗均能减少IgA肾病患者的蛋白尿排泄率,延缓疾病进展。本研究拟通过多中心、随机、开放标签、平行对照研究,探讨联合应用抗氧化剂普罗布考(Probucol)和血管紧张素受体拮抗剂缬沙坦对高危IgA肾病患者疾病进展的影响。探讨联合应用2种药物对IgA肾病患者24小时蛋白尿的影响及用药安全性。
方法本研究在5个中心75例经肾活检确诊IgA肾病而且24小时尿蛋白)1.0g/24小时的患者进入筛选,经筛选后69例入组,随机进入治疗组(Probucol750mg/d+缬沙坦160mg/d)或对照组(缬沙坦160mg/d)；其中1人退出研究,测定患者的血、尿的氧化应激指标,收集患者的临床病理资料并随访3年。
统计分析方法：利用SPSS18.0软件进行统计学分析,数据均采用均数±标准差(x±s)来描述。治疗组与对照组基线情况采用独立样本t检验进行分析；采用配对t检验比较后续治疗时期与基线时期的相关指标的差异,根据比较次数校正检验水准,P<0.007被定义为有统计学差异。治疗组和对照组随访基线主要观察终点和次要观察终点的比较采用重复测量的方差分析。P<0.05被定义为有统计学差异。
结果共68例患者完成研究,其中治疗组33人,对照组35人。入组时两组患者的基础血压、血肌酐水平、24小时蛋白尿排泄水平、肝功能、血钾、血胆固醇及诊断时体内的氧化应激指标及抗氧化指标水平(血、尿丙二醛,超氧化物歧化酶SOD,总抗氧化能力T-AOC)均相当(P>0.05),基线病理评分没有统计学差异。治疗组和对照两组分别有23和20例患者达到主要观察终点。其中治疗组患者24小时尿蛋白下降50%所需时间较对照组短。两组的中位终点时间分别为8.13和19.63个月(χ2=5.476,P=-0.019)。两组患者第一年24小时蛋白尿排泄率明显降低,分别从基线的1391.21±534.91mg/24h和1466.54±638.81mg/24h降至1010.04±421.20mg/24h和1048.39±639.55mg/24h(与基线比较F=11.74,P<0.001)。随访2年时,治疗组24小时尿蛋白排泄率定量为968.98±338.98mg/24h(与基线比较F=11.74,P<0.001)。而对照组24小时尿蛋白排泄率为1237.13±720.41mg/24h(与基线比较F=4.411,P=0.009)。但随访3年后治疗组和对照两组24小时蛋白尿排泄率分别为1365.68±395.31mg/24h和1357.20±427.19mg//24h(与基线比较F=1.101,P=-0.298)。治疗组和对照组eGFR分别从基线的54.83±13.11ml/min和57.75±10.36ml/min升高至56.70±9.92和58.61±8.47ml/min(F=0.225,P=0.862)。随访1年时,治疗组血清胆固醇水平显著比对照组低,分别为4.37±0.94mmol/L和4.87±0.80mmol/L(t=02.376,p=0.020)。随访3年过程中均未见AST和ALT升高。没有一例患者进入终末期肾病。
结论probucol联合缬沙坦治疗高危的IgA肾病患者安全,能在短期内更快降低24小时尿蛋白水平,但经长期随访(3年)并不能持续降低这类患者24小时尿蛋白排泄率,但患者肾功能保持稳定。这一疗法能否改善高危IgA肾病的远期预后还有待于进一步的观察。
Background Angiotensin receptor antagonists (ARBs) and anti-oxidants reduce urinary protein excretion and delay progression of IgA nephropathy. We investigated the efficacy and safety of probucol (an anti-oxidant) combined with valsartan (an ARB) on the progression of IgA nephropathy.
Methods Patients with IgA nephropathy (n=69) were recruited from5centers and randomly assigned to a treatment group (750mg/day probucol plus160mg/day valsartan) or a control group (160mg/day valsartan) and were followed for3years.
Results At baseline, the two groups in any measured clinical information were comparable. The primary endpoint (doubling serum creatinine) showed no significant difference between the two groups during3year follow-up. The secondary endpoint (50%reduction in24-h urinary protein) occurred in23patients in the treatment group and20patients in the control group. The time to the secondary end-point was shorter in the treatment group than the control group (8.13months vs.19.63months,%=5.476, p0.019). However, at the3year follow-up, the24-h urinary protein levels were not significantly different from the baseline levels (1365.68±395.31mg/24h vs.1357.20±427.19mg/24h, respectively, F=1.101, P=0.298). At the1year follow-up, plasma cholesterol in the treatment group was markedly lower than in the control group (4.37±0.94mmol/L vs.4.87±0.80mmol/L,p=0.020).
Conclusion Kidney function remained stable and no significant difference in two group patients. Probucol combined with valsartan led to a more rapid decrease of24-h urinary protein excretion than valsartan alone. However, the long-term effect needs further investigation.
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