【作者】 程军；

【导师】 陈江华；

【作者基本信息】 浙江大学 ， 临床医学， 2010， 博士

【摘要】 背景原发性IgA肾病(IgA nephropathy, IgAN)是以出现镜下血尿或肉眼血尿或蛋白尿、常见血清IgA水平升高、肾脏病理显示肾小球系膜区IgA免疫复合物沉积为特征的一类肾小球肾炎。大约有15—20%的IgAN患者在10年后进展至肾功能衰竭；20年后这个数字将上升到30——40%；IgAN已经成为原发性肾病发展为终末期肾功能衰竭中需要肾替代治疗的主要病因之一。原发性IgAN病因至今尚不清楚,在成人与儿童中,高血压、高的肾小球组织病理积分、持续性镜下血尿、和24小时尿蛋白定量大于1克、早期存在肾功能损害,均强烈提示该患者有较差的预后。对大多数患者而言,依靠单一指标,预测预后的作用可能并不大；由于病因未明,发病机制与多种因素有关,因此迄今为止,对于IgAN尚无肯定有效的治疗方法。近年来国内外期刊发表了较多关于非免疫抑制剂如血管紧张素转换酶抑制剂、他汀类降脂药和n-3型多聚不饱和脂肪酸等与免疫抑制剂如糖皮质激素,骁悉和环磷酰胺等治疗IgAN的随机对照研究(Randomized Control Trial, RCT),这些RCT大多评价了药物对蛋白尿以及肾功能的影响,但是大多数RCT样本量少,观察时间较短,有的试验结果也是相互矛盾,对临床决策实践的指导作用有限。本研究通过检索近年来发表在国际期刊上药物治疗IgAN的RCT,并根据治疗干预药物不同,分为单用免疫抑制剂组,单用非免疫抑制剂组,以及两药以上的联合治疗组,对以上RCT研究进行了系统评价,以帮助我们临床决策。第一部分非免疫抑制剂治疗IgA肾病的系统评价目的：循证评价单用一种非免疫抑制剂肾素-血管紧张素系统阻断剂(renin-angiotensin system inhibitors, RASI)、鱼油、他汀类降脂药物对IgAN患者的蛋白尿、肾功能的影响以及治疗的安全性,为非免疫抑制剂治疗IgAN提供临床治疗的决策依据。方法：通过MEDLINE, EMBASE, the Cochrane Library数据库检索文献,两名评价员独立选择研究,进行文献筛选。文献纳入RASI,鱼油,他汀类降脂药物治疗IgAN的RCT,运用Jade评分评价纳入文献的质量。并提取评价肾功能以及蛋白尿的数据；统计软件采用Cochrane协作网提供的RevMan4.2.7进行meta分析。计数资料采用相对危险度(relative risk, RR,相对危险度)及其95%可信区间(confidence interval, CI)表示疗效分析效应量；计量资料采用加权均数差(WMD)或标准化均数差(SMD)作为分析效应量,各效应量均以95%CI表示。各亚组间有统计学同质性者采用固定效应模型计算总结果,若存在统计学异质性时采用随机效应模型计算总结果,并评价纳入文献的偏倚性。结果1一共有19篇RCT被纳入本次系统综述。其中关于RASI治疗IgAN的RCT有11篇；关于鱼油治疗IgAN的RCT有5篇；关于他汀类降脂药治疗IgAN的RCT的有3篇；语种均为英文。2 RASI与安慰剂或其他其他降压药比较共纳入11项RCT研究,meta分析显示：与对照组比较,RASI能更有效减少终末期肾功能衰竭的发生,延长肾存活率(P＜0.05),并降低IgA肾病患者的蛋白尿(P＜0.05)；RASI具有良好的安全性。3鱼油与安慰剂或玉米油、橄榄油比较共纳入5项RCT研究,meta分析显示：与对照组比较,鱼油并不能有效保护肾功能,不能减少终末期肾功能衰竭的发生以及降低IgA肾病患者的蛋白尿(P＞0.05)。4他汀类调血脂药物与安慰剂或双嘧达莫比较共纳入3项小样本RCT研究,meta分析显示：与对照组比较,他汀类调血脂药物能延缓eGFR的下降(P＜0.05),并降低IgA肾病患者的蛋白尿(P＜0.05)。结论本研究显示单用非免疫抑制剂在IgAN的治疗上具有相当的前景。RASI对IgA肾病具有明显的肾保护作用,可以有效延缓肾功能的进展以及降低蛋白尿,而且具有良好的安全性；鱼油的肾保护作用尚需进一步RCT证实；他汀类具有降蛋白尿作用,由于纳入RCT少,且未用肾功能衰竭作为研究终点,而且为小样本,对于肾功能的保护,还需要近一步研究证实。根据本次meta分析结果,RASI目前是治疗IgAN最具希望的药物,在临床上应给予推荐；对于合并有高脂血症的IgAN患者,可推荐使用他汀类调脂药。第二部分免疫抑制剂治疗IgA肾病的系统评价目的：循证评价单用一种免疫抑制剂对IgAN的蛋白尿、肾功能的影响以及治疗的安全性,为免疫抑制剂治疗IgAN提供临床决策依据。方法：通过MEDLINE, EMBASE, the Cochrane Library数据库检索文献,两名评价员独立选择研究,进行文献筛选。本研究文献纳入单用免疫抑制药物治疗IgAN的RCT,运用Jade评分评价纳入文献质量。并提取评价肾功能以及蛋白尿的数据；统计软件采用Cochrane协作网提供的RevMan 4.2.7进行meta分析。计数资料采用相对危险度(relative risk, RR,相对危险度)及其95%(confidence intervalCI,可信区间)表示疗效分析效应量；计量资料采用加权均数差(WMD)或标准化均数差(SMD)作为疗效分析效应量,各效应量均以95%CI表示。如纳入RCT均用K-M曲线评价肾生存率,则选用HR作为荟萃分析统计效应指标。各亚组间有统计学同质性采用固定效应模型计算总结果,若存在统计学异质性时采用随机效应模型计算总结果。结果1关于单用激素治疗IgAN的RCT,一共有6个临床试验被纳入研究；关于霉酚酸酯(Mycophenolate Moretil, MMF),由于MMF治疗IgAN的最新系统评价已经于2009年发表,目前尚无新的RCT发表,故本研究只引用其结论,而不再重新进行评价；关于环磷酰胺(cyclophosphamide, CTX)与硫唑嘌呤(AZAazathioprine),单用于治疗IgAN的RCT没有报道,所以关于CTX与AZA治疗IgAN的RCT均未纳入本研究。语种均为英文。2糖皮质激素与安慰剂或双嘧达莫比较共纳入6项RCT,meta分析显示：与对照组比较,激素能有效保护肾功能,延长肾存活率(P＜0.05),并降低IgA肾病患者的蛋白尿(P＜0.05)；激素不会增加2型糖尿病,高血压的发病率；但是激素的运用能增加患者消化道疾病的发病的风险(P＜0.05)。3关于骁悉一项已经发表的meta分析显示,与对照组比较, MMF并不能有效保护肾功能,延长肾存活率以及降低IgA肾病患者的蛋白尿(P＞0.05)。3 4关于来氟米特一项RCT研究显示其具有肾保护作用,但并不优于对照组。结论IgAN的病因比较复杂,各种免疫抑制剂治疗被广泛用于IgAN的治疗；本次meta分析主要纳入了激素治疗IgAN的RCT,结果显示对于中等量蛋白尿患者以及肾功能损害轻到中度的IgAN患者,激素能有效保护肾功能,延长肾生存率以及降低蛋白尿的作用,是临床治疗IgAN具有前景的药物,应给予临床推荐,激素具有较好的临床耐受性,但我们应关注其消化道副反应；骁悉的肾脏保护作用尚不明确。第三部分IgA肾病的联合治疗模式的系统评价目的：循证评价2种药物(包含2种药物)以上的联合治疗对IgAN的蛋白尿、肾功能的影响以及治疗的安全性,为联合治疗IgAN提供决策依据。方法：通过MEDLINE, EMBASE, the Cochrane Library数据库检索文献,两名评价员独立选择研究,进行文献筛选。本研究文献纳入RASI与其他非免疫抑制剂联合的RCT；激素与RASI联合的RCT；CTX与华法林以及双嘧达莫联合的RCT；CTX联合激素与AZA的RCT；激素联合AZA以及华法林与双嘧达莫的RCT。运用Jade评分评价纳入文献质量,并提取评价肾功能以及蛋白尿的数据；统计软件采用Cochrane协作网提供的RevMan 4.2.7进行meta分析。计数资料采用相对危险度(relative risk, RR,相对危险度)及其95%(confidence interval, CI,可信区间)表示疗效分析效应量；计量资料采用加权均数差(WMD)或标准化均数差(SMD)作为疗效分析效应量,各效应量均以95%CI表示。各亚组间有统计学同质性采用固定效应模型计算总结果,若存在统计学异质性时采用随机效应模型计算总结果。结果1RASI与其他非免疫抑制剂的联合的RCT有8篇；关于激素与RASI联合的RCT有3篇；关于CTX与华法林以及双嘧达莫联合的RCT有2篇；CTX联合激素与AZA的研究1篇；激素联合AZA以及华法林与双嘧达莫的RCT有2篇；2 RASI与其他非免疫抑制剂的联合与单用RASI比较由于明显的临床异质性,亚组meta分析显示：与单用ACEI/ARB比较,ACEI与ARB联合治疗更能减少患者的蛋白尿,但不能延缓GFR下降；ACEI/ARB与鱼油以及尿激酶联用在减少蛋白尿以及延缓GFR下降方面优于单用ACEI/ARB,未见明显的副作用。3激素与RASI联合与单用RASI或激素比较meta分析显示：与对照组比较,联合治疗可以有效保护肾功能,减少终点事件肾功能衰竭的发生(P＜0.05),并降低IgA肾病患者的蛋白尿(P<0.05),未见明显的副作用。4 CTX与华法林以及双嘧达莫联合与未治疗组比较meta分析显示：联合治疗可以降低IgA肾病患者的蛋白尿(P＜0.05),但在保护肾功能,减少终点事件肾功能衰竭方面作用不明显(P＞0.05)未见严重的明显的副作用。5 CTX联合激素、AZA与非免疫抑制剂比较只有一项研究,研究表明联用在肾功能的保护以及降蛋白尿作用方面均优于非免疫抑制剂,未见明显的副作用。6激素联合AZA以及华法林、双嘧达莫与激素或华法林与双嘧达莫联用进行比较激素联合AZA与华法林以及双嘧达莫较对照组具有更加明显的降蛋白尿作用(P＜0.05),但在保护肾功能方面作用不明显(P＞0.05),但重复肾活检显示联合治疗组能有效延缓患者肾小球的硬化率,未见严重的副作用。结论根据本系统评价,目前所有联合治疗降低蛋白作用均明显强于对照组。但与对照组比较,只有激素联合RASI与激素联合CTX与AZA对降低蛋白尿以及延缓肾功能进展(以ESRD为硬终点)有明显帮助,并具有较少的严重的副反应报道。激素联合CTX与AZA对降低蛋白尿以及延缓肾功能进展有明显疗效；但目前该研究只有一项单中心,小样本研究,因此该治疗方案还需进一步观察研究,更需要一些大型,多中心大样本的研究进行证实。激素与AZA、双嘧达莫、华法林联合可以减少蛋白尿,虽然在延缓肾功能进展方面不能明显获益,但研究进行了重复肾活检,从病理上显示联合治疗可以延缓肾小球硬化率。合理的联合治疗可以使IgAN患者更大获益。但仍应注意毒副作用。第四部分基于循证依据的IgA肾病的治疗建议(全文总结)根据本次荟萃分析结果以及我们中心已经发表的meta分析研究结果,我们研究小组对IgAN的治疗提出如下的基于循证医学的治疗建议。1免疫抑制剂激素与非免疫抑制RASI均能使IgAN患者获益,对于合并有高血脂的患者,可选用他汀类调制药物。2对于IgA肾病的治疗,ACEI与ARB联用对减少尿蛋白的作用优于单用,但对肾功能的保护方面与单用比较无明显优势。3对于蛋白尿大于1g/d, eGFR大于30ml/min,能耐受RASI的患者,我们推荐运用RASI与激素作为联合治疗模式。4对于重度的IgAN,我们可以运用“鸡尾酒疗法”治疗,并根据肾病理积分,高血压,镜下血尿,蛋白尿水平,和肾功能情况调整药物剂量和种类。总之,目前由于IgAN的机理不明,对因治疗无从说起,难以获得。最佳治疗IgAN的方法尚未发现。我们的研究结果推荐对于IgAN尤其临床较重的IgAN(24h蛋白尿＞1g, eGFR＞30ml/min)应给予联合治疗模式；这种联合治疗模式应以RASI加激素作为联合的基础。该疗法主要来源于小样本的RCT研究的荟萃结果,临床运用还需要大样本,多中心,设计良好的RCT来进一步证实。更多还原

【Abstract】 IntroductionIgAN was first reported in 1968 by Dr J.Berger. It is now generally known to be the most common type of primary glomerulonephritis throughout the world. IgAN was initially thought to be a rare and benign cause of recurrent hematuria, however, it is neither rare nor benign. It has been demonstrated that IgAN is a worldwide disease that causes ESRD in up to 15-20%of affected patients within 10 years from the apparent onset of disease and in up to 30-40% of individuals within 20 years from diagnosis.Clinical observations of IgA nephropathy patients show over 35 percent of patients who have undergone renal transplantation have recurrent IgA nephropathy. This Clinical manifestations provided strong support for the idea that IgA nephropathy is a systemic disease. The mechanisms involved in the pathogenesis of this disease have remained unclear. Therefore many treatments approaches have been attempted in the past 2 decades, however, no specific treatment has been established, there are wide variations in current practice.The most commonly used regimens include immunosuppressive agents such as glucocorticoids, cyclosporin A or cyclophosphamide, and nonimmunosuppressive medications including fish oils, anticoagulants, antihypertensive agents and surgical tonsillectomy,which have been tested in a variety of studies including RCTs.The mechanisms of this disease have remained unclear. Our published meta-analysis show ACEI or steroids alone have statistically significant effects on protecting renal function and reduction of proteinuria in IgA nephropathy patients. Over the past decade or so, many studies from around the world, involving large cohorts of patients,have reported combination therapy RCTs studies for IgAN.Maybe combination therapy of nonimmunosuppressive treatment and/or immunosuppressive agents would have shown a benefit for slowing the deterioration of renal function, as well as a reduction in daily proteinuria, however, published reports examining the efficacy for preserving renal function and reduction proteinuria in IgAN have yielded conflicting results.Therefore, we present results of a systematic review summarizing currently available evidence from RCTs pertaining to the effect of combination treatment for IgA nephropathy.PartⅠ:Systematic review to evaluate nonimmunosuppressive agents for IgA nephropathyObjective:Published reports examining the efficacy of nonimmunosuppressive agents:RAS blockers, fish oils and statins agents for preserving renal function in IgA nephropathy (IgAN) have yielded conflicting results. To evaluate systematically the effects of nonimmunosuppressive agents on IgAN,we conducted a meta analysis of published randomised controlled trials (RCTs). Methods:MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that compared nonimmunosuppressive agents with placebo and any other antihypertensive agents or non-immunosuppressive agents for treating IgAN. The quality of the studies was evaluated with the method of intention to treat analysis and allocation concealment, as well as with the Jadad method. Meta analyses were performed on the outcomes of proteinuria and renal function in patients with IgAN. Results:1 nineteen RCTs were included in the review.eleven RCTS about RASI vs other nonimmunosuppressive agents;five RCTS about fish oils;three RCTs about statins. 2 about RASI vs other nonimmunosuppressive agents:Eleven RCTs involving 585 patients were included in the review.Seven trials used placebo/no treatment as controls. Four trials used other antihypertensive agents as controls. Overall, ACEI/ARB agents had statistically significant effects on protecting renal function(p＜0.00001) and reduction of proteinuria (p＜0.00001) when compared with control group. Tests for heterogeneity showed no difference in effect among the studies. Systolic and diastolic blood pressure,glomerular filtration rate and age did not influence treatment response.ACEI/ARB agents were well tolerated.3 about fish oils:Five RCTs involving 266 patients were included in the review. Overall, fish oils agents had not statistically significant effects on protecting renal function(p＞0.05) and reduction of proteinuria (p＞0.05) when compared with control group.4 about statins:Three RCTs involving 66 patients were included in the review. Overall, fish oils agents had statistically significant effects on protecting renal function(p＜0.05) and reduction of proteinuria (p＜0.05) when compared with control group. Conclusions:The current cumulative evidence suggests that ACEI/ARB agents had statistically significant effects on protecting renal function and reduction of proteinuria in patients with IgAN when compared with control groups. But for fish oil, The current cumulative evidence suggests patients with IgAN cannot get benfit from it;For statins, we need more RCTs for its effects on protecting renal function and reduction of proteinuria in patients with IgAN. So we conclude ACEI/ARB agents are a promising medication and evidence-based recommendations for IgAN.PartⅡ:Systematic review to evaluate immunosuppressive agents for IgA nephropathyObjective:Published reports have examined the efficacy of immunosuppressive agents. To evaluate systematically the effects of immunosuppressive agents on IgAN,we conducted a meta analysis of published randomised controlled trials (RCTs).Methods:MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that compared immunosuppressive agents with placebo and any other antihypertensive agents or non-immunosuppressive agents for treating IgAN. RCTs for two or more immunosuppressive agents were excluded.The quality of the studies was evaluated with the method of intention to treat analysis and allocation concealment, as well as with the Jadad method. Meta analyses were performed on the outcomes of proteinuria and renal function in patients with IgAN.Results:1 six RCTs about Glucocorticoids were included in the review.Because a meta analysis about MMF have be published in 2009,so we do not evaluate it for IgAN again.2 about Glucocorticoids vs other nonimmunosuppressive agents:six RCTs involving 585 patients were included in the review. glucocorticoid agents had statistically significant effects on improved renal survival (HR 0.20,95%CI 0.20 to 0.39) and reduction of proteinuria when compared with the con trol group. Tests for heterogeneity showed no difference in effect among the studies. In general, glucocorticoid agents were well tolerated. Patients receiving glucocorticoids therapy did not have an increased risk of development of type 2 diabetes mellitus, hypertension or Cushingoid adverse effects, while glucocorticoids were associated with a significant increase in the risk of gastrointestinal tract adverse events.Conclusions:The current cumulative evidence suggests that glucocorticoids have statistically significant effects on protecting renal function and reduction of proteinuria in patients with IgAN, but we should be careful for its gastrointestinal tract reaction.In general, glucocorticoids agents are a promising medication and should be investigated further.PartⅢ:Systematic review to evaluate combined treatment modality for IgA nephropathy Objective:To evaluate systematically the effects of combined treatment modality on IgAN,we conducted a meta analysis of published randomised controlled trials (RCTs).Methods:MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that Studies with a combination therapy with nonimmunosuppressive medications and/or immunosuppressive agents, in only one arm, were included.The quality of the studies was evaluated with the method of intention to treat analysis and allocation concealment, as well as with the Jadad method. Meta analyses were performed on the outcomes of proteinuria and renal function in patients with IgAN.Results:1 sixteen RCTs were included in the review. RCTs were divided into five sub-groups according to the administered therapy. The first group includes 8 studies evaluating the effect of RASI plus nonimmunosuppressive agents therapy on renal function and daily proteinuria in patients with IgA nephropathy. The second group includes three studies on the effect of steroids plus RASB agents, and the third group includes two studies relating to the effect of CTX+W+D; the fourth group includes one studies relating to the effect of Steroids plus CTX plus AZA;the fifth group includes two studies relating to the effect of STEROIDS+ARC+W+D on these same outcomes.2 RASB plus non-immunosuppressive agents for IgA nephropathy:according to our meta-analysis, in which the weight of individual studies has been taken into account, combined treatment with ACEI plus ARB and RASB and fish oil or UK was more effective than with RASB alone for a reduction in daily proteinuria; The GFR at the end of treatment was significantly higher in patients receiving combined with non-immunosuppressive agents therapy compared to patients in the control groups receiving RASI alone.There was no significant heterogeneity between these trials3 steroids and RASB agents for IgA nephropathyour meta-analysis indicates that combined treatment with steroids and RASB agents had significant effects on protecting renal function when compared with control group,as well as a reduction in daily proteinuria.4 Trials of combined cyclophosphamide and dipyridamole and warfarin treatmentaccording to our meta-analysis,The results indicate that combined treatment with cyclophosphamide and dipyridamole and warfarin agents seem not to be beneficial for stabilizing kidney function in patients with IgA nephropathy, as well as a reduction in daily proteinuria.5 Trials of combined cyclophosphamide and steroids and azathioprine treatmentThis therapy has an acceptably low risk of side effects and seem to be beneficial for both reducing proteinuria and protecting kidney function in patients with IgA nephropathy.6 Trials of combined steroids and azathioprine and warfarin,and dipyridamole treatmentAccording to this analysis, combined treatment induced a stronger reduction in proteinuria when compared with control group, but not give benefit to the outcome of renal functionin.Conclusions:In conclusion, At present, The pathogenesis of IgAN is still unknown. causal therapy is not available. The best treatment for IgAN remains poorly defined. our analysis provides recommendations for IgAN treatment especially for Severe IgA Nephropathy that "A cocktail therapy" about combination Therapy with RASB and steroids as fundamental combination would have shown a benefit for renoprotective effect; Of course, this treatment still need a large sample, multi-center, well-designed RCT to confirm.Part IV Evidence-based recommendations for IgANEvidence-based recommendations for the management of IgAN were published since 1999. Most of the evidence-based recommendations are about immunosuppressive treatments for IgAN. However, the results are paradoxical, and these recommendations should be partly criticized for methodology. The main criticism of meta-analysis by Samuels was that they were based on a variety of sources, including non-randomized controlled trial data and quasi-randomized controlled trials. More importantly, no recommendations or meta-analysis commented on combintion treatment for IgAN in protecting renal function and reducing proteinuria.1 recommendationsnonimmunosuppressive agents and immunosuppressive agents can get benefit for IgA nephropathy.we pay attention to RASI for nonimmunosuppressive agents and steroids for immunosuppressive agents.2 recommendationscombination therapy of nonimmunosuppressive treatment and/or immunosuppressive agents for IgAN would have shown benefits.3 recommendationswe can recommended combination therapy with RASB and steroids as fundamental combination.4 recommendationswe can use such a"cocktail therapy" for severe IgAN patientst and adjust dose or species by glomerular histopathological scores,hypertension,persistent microscopic hematuria and proteinuria, and impaired renal function.In conclusion, At present, The pathogenesis of IgAN is still unknown. causal therapy is not available. The best treatment for IgAN remains poorly defined. our analysis provides recommendations for IgAN treatment especially for Severe IgA Nephropathy that“A cocktail therapy”about combination Therapy with RASB and steroids as fundamental combination would have shown a benefit for renoprotective effect; Of course, this treatment still need a large sample, multi-center, well-designed RCT to confirm.更多还原