肾衰养真颗粒改善CKD4、5期营养不良的临床研究
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摘要
研究背景
1 999年,美国肾脏病基金会(NKF)提出慢性肾脏病(chronic kidney disease,CKD)的概念。2002年,NKF-Kidney Disease Outcomes Quality Initiative(NKF-K/DOQI指南)公布了CKD的定义为:(1)肾脏损害(肾脏的结构或功能异常)≥3个月。可伴或不伴肾小球滤过率(glomerular filtration rate,GFR)下降,表现为下述之一:病理异常;血液或尿液成分检查异常,或者影像学检查异常;(2)GFR＜60ml/min/1.73m~2≥3个月,有或无肾脏损害。CKD是严重危害人类健康的重大疾病,其发病率在全球范围内呈持续增长趋势。在我国南方的大城市中,人群CKD的患病率为10.1%;北京40岁以上人群中,11.3%至少有一项肾脏损伤指标。而CKD最终进展为终末期肾病(end stage renal disease,ESRD),在《慢性肾脏病及透析的临床实践指南》(以下简称为K/DOQI指南)中根据临床表现的严重程度和是否存在并发症以及对预后的影响将CKD的病程划分为5期。当29ml/min≥GFR＞15ml/min时,为CKD 4期:当GFR＜15ml/min时,为CKD5期。慢性肾衰竭(chronic renal failure,CRF)是常见的临床综合征,主要表现为毒性代谢产物潴留,水、电解质、酸碱平衡紊乱,以及全身多系统的损害。假设肾功能正常时,GFR为100%,按肾功能损害的程度可分为4期。当CRF进展至肾衰竭期和尿毒症期时,约棚当于K/DOQI指南的第4、5期。此两期GFR明显下降,血肌酐(Scr)显著升高(约为450μmol/L以上)。研究表明,GFR低于35 ml/min的CKD患者中有45%～64%发生不同程度的营养不良,而ESRD患者中有9.6%死于严重营养不良。营养不良可以导致患者免疫功能低下、贫血、频发感染及心血管事件,甚至导致多脏器衰竭,其发生不仅直接影响患者的生活质量和生存率,而且也是合并症发生率和死亡率增加的危险因素。随着透析技术的日益改进和完善,维持性透析病人增加,CKD4、5期营养不良的发生率进一步提高。因此,临床上迫切需要可以改善患者营养不良,延缓CKD病情进展,降低CKD4、5期发病率和病死率的治疗药物与方法。
目前,对于CKD4、5期营养不良的治疗,主要集中在促进蛋白质合成,降低血清瘦素(Leptin)水平,提高胰岛素样生长因子-Ⅰ(IGF-Ⅰ)含量,改善氮质代谢等。其常用的治疗方法:蛋白质制剂、复方α-酮酸制剂(开同,德国研制)、氨基酸制剂以及重组人类促红细胞生成素(rhuEPO)等来改善CKD4、5期患者蛋白质营养不良,其疗效不尽满意,并不能从本质上改善CKD4、5期患者的蛋白质合成,而且价格昂贵,使用受限。传统的中药复方汤剂虽有不同程度的改善CKD4、5期营养不良的作用,但是其多为经验治疗,方案多种多样,并且服用不方便,疗效不统一,质量难以控制。迄今为止,国内尚无治疗CKD4、5期营养不良的中药新药问世。因此,研制有效的防治CKD4、5期营养不良的药物,具有十分重要的社会意义和价值,并且其潜在的市场和经济效益也相当可观。肾衰养真颗粒是珠江医院中医科魏连波教授根据多年的临床经验总结出来的改善CKD 4、5期营养不良的中药复方,山黄芪、当归、大黄、人参等六味中药组成。现代药理学研究证实黄芪可提高血浆白蛋白(Alb)水平、调节脂质代谢、改善高凝状态、促进水钠排泄、调整机体免疫力及减轻。肾组织损伤。前期的临床试验和药效学试验均已证实肾衰养真颗粒可通过促进蛋白质的合成,提高血浆Alb、前白蛋白(PA)、转铁蛋白(Tf)、IGF-Ⅰ的水平,改善蛋白质营养不良。肾衰养真颗粒不仅具有开同补充氨基酸的作用,还能改善病人的食欲,纠正肾性贫血等综合效用,且为纯中约制剂,价格低廉,可减轻痫人的经济负担。本课题拟采用单中心、随机对照的临床试验方案研究肾衰养真颗粒改善CKD4、5期营养不良的临床疗效和安全性,旨在为CKD4、5期营养不良的药物治疗方面提供新的安全有效的方法。
研究目的及意义
目的:
1初步评价肾衰养真颗粒改善CKD4、5期患者营养不良,延缓病情进展的作用。
2初步评价CKD4、5期患者使用。肾衰养真颗粒的安全性。
意义:
国内尚无治疗CKD4、5期营养不良的中药新药,有望为其药物治疗方面提供新的安全有效的中药新药。从而为改善CKD4、5期营养不良找到具有中医药特色和优势的中医临床治疗方法。
方法
1试验设计采用单中心、随机对照的临床试验方案。
2临床资料观察病例均为2007年11月到2009年02月南方医科大学珠江医院中西医结合肾病中心住院及门诊患者,同时结合计量资料最小样本量的要求以及临床收集病例的实际,共收集90例有完整资料的病例。采用区组随机化方法,规定区组大小为6,即每6名患者按就诊先后顺序进入同一区组,其中2名接受颗粒治疗,2名接受开同治疗,2名接受汤剂治疗。随机排列治疗顺序的组合,构成15个区组的随机化方案。将就诊患者随机分为颗粒治疗组30例、开同对照组30例、汤剂对照组30例。
3治疗方法所有患者均采用优质低蛋白饮食,根据病情结合利尿,控制血压,纠正酸中毒,纠正钙磷代谢紊乱等对症处理。在上述治疗基础上,治疗组给予肾衰养真颗粒(三九医药集团提供),主要药物:黄芪1.5g(批号:0710081),当归1.5g(批号:0709031),人参1.5g(批号:0708021),白术1g(批号:0708021),大黄1g(批号:0707021),砂仁1g(批号:0708021)。相当于汤剂的剂量,温水冲服,每日2次。开同对照组用开同片(北京费森尤斯卡比医药有限公司生产,批号:国药准字H20041442),每日3次,每次4片。汤剂对照组,给予肾衰养真方(药物购自广东省药材公司,经本校中药制剂室鉴定),主要药物:黄芪30g,当归10g,人参10g,白术12g,大黄6g,砂仁6g,水煎服150ml,每日一剂,分2次口服。8周为一个疗程。
4观察指标
4.1症状观察及不良反应记录所有病人治疗前和用药后计算主症积分,主观综合营养评估(SGA)评分以及丙氨酸氨基转移酶(ALT),同时记录不良反应。
4.2评价指标(1)肾功能指标24小时尿蛋白定量(24h Upr)、Scr、血尿素氮(BUN)、估计肾小球滤过率(eGFR)。(2)营养指标①体格营养状况检查指标体重、肱三头肌皮褶厚度(TSF)、上臂中段肌肉周径(MAMC);②蛋白营养指标血清Alb、PA、Tf以及IGF-Ⅰ。(3)造血功能指标血红蛋白(Hb)、红细胞(RBC)计数、网织红细胞绝对值(RET#)。比较各组治疗前后对肾功能、营养不良状态以及造血功能的影响。
5疗效评价临床痊愈:临床症状、体征消失或基本消失,主要理化指标正常;显效:临床症状、体征明显改善,主要理化指标改善50%;有效:临床症状、体征均有好转,主要理化指标改善30%;无效:临床症状、体征及理化指标均无明显改善,甚或加重。
6统计学处理使用SPSS13.0统计软件进行统计学分析,所有计量数据采用((?)±s)表示;并先进行方差齐性分析,证实方差齐后,组内比较应用配对t检验。治疗前组间比较采用完全随机设计资料的方差分析,治疗后组间及其差值比较用协方差分析(analysis of covariance,ANCOVA),协变量为治疗前。等级资料采用Kruskal-Wallis检验,P<0.05显示差异有统计学意义。
结果
1各组综合疗效比较颗粒治疗组显效15例,有效10例,无效5例;开同对照组显效14例,有效9例,无效7例;汤剂对照组显效16例,有效9例,无效5例。各组间比较差异无显著性(P>0.05)。
2各组治疗前后体格营养状况检查各项指标的比较各组内治疗前后体重、TSF和MAMC相比,均无显著性差异(P＞0.05);各组间治疗后各检查指标相比亦无统计学意义(P＞0.05)
3各组治疗前后主症积分与SGA评分比较各组内治疗前后主症积分与SGA评分相比,均有显著性差异(P＜0.01);各组间治疗后各指标相比较无统计学意义(P＞0.05)。
4各组治疗前后肾功能指标的比较各组内治疗前后24h Upr、BUN、Scr、eGFR的比较,均有统计学意义(P＜0.01或P＜0.05);各组间治疗后各指标比较无显著性差异(P＞0.05)。
5各组治疗前后营养指标的比较各组内治疗前后Alb、PA、Tf、IGF-Ⅰ的比较,均有显著性差异(P＜0.01或P＜0.05);各组间治疗后各指标比较无统计学意义(P＞0.05)。
6各组治疗前后造血功能指标的比较各组内治疗前Hb、RBC计数、RET#的比较,均有统计学意义(P＜0.001);各组间治疗后各指标比较,颗粒治疗组与汤剂对照组比较无统计学意义(P＞0.05),而颗粒治疗组、汤剂对照组与开同对照组比较均有显著性差异(P＜0.001)。
7不良反应观察期内颗粒治疗组与汤剂对照组有部分病例服药后有轻微的胃部不适、大便次数增多等反应,适当减少剂量或饭后服药后大多消除,可继续进行观察;开同对照组,偶有高钙血症发生,适当减少维生素D的摄入量后,可消除症状,继续进行观察。其差别无统计学意义(P＞0.05)。各组患者ALT的检测值虽有波动,但都在正常值范围内(5～40 IU/L),其差别无显著性(P＞0.05)。
结论
肾衰养真颗粒可以改善CKD4、5期患者的营养不良状况,与开同、汤剂具有相同的疗效;但在改善患者贫血时,其疗效等同于汤剂,而优于开同;并且不良反应轻。因此,其可以作为改善CKD4、5期患者营养不良的安全有效的选择之一。
Background
In the year 1999,National Kidney Foundation(NKF) brought forth the concept of chronic kidney disease(CKD).In 2002,the guide of National Kidney Foundation-Kidney Disease Outcome Quality Initiative(NKF-K/DOQI) published the definition of CKD.(1) kidney damage(structural or functional kidney abnormalities) lasted at least for 3 months,with or without decreased glomerular filtration rate,and the performance was as anyone of the following:pathological abnormalities,blood or urine to check abnormal composition,imaging abnormalities; (2) GFR<60ml/min/1.73m~2 lasted at least for 3 months,with or without kidney damage.CKD was one of the major diseases which could seriously endanger human health,and its incidence sustainedly grew in the whole world.At our country's major cities in the South,prevalence rate of CKD population was 10.1%;population aged above 40 in Beijing,11.3%had at least one indicator of kidney damage.But CKD eventually progressed to end-stage renal disease(ESRD),in the "chronic kidney disease and dialysis of the Clinical Practice Guidelines"(hereinafter referred to K/DOQI guidelines),according to the severity of clinical manifestations and the presence of complications,as well as the impact on the prognosis,CKD is divided into five stages.When 29ml/min≥GFR≥15ml/min,it is CKD stage 4;then GFR＜ 15ml/min,it is stage 5.Chronic renal failure(CRF) was a common clinical syndrome. The main performances are retention of toxic metabolites,balance disorders of water, electrolyte,acid-base,as well as multisystem damage.Assuming normal renal function,the GFR was 100%.According to the degree of renal dysfunction,it could be divided into four stages.When CRF progressed to renal failure and uremia period, it approximately equivalent to CKD4 or 5period.In the two periods,GFR decreased to 25%or less of normal lever,Serum creatinine was significantly higher(about 450μmol/L and above).Studies showed that 45%～64%CKD patients with GFR≥35ml/min appeared varying degrees of malnutrition.While 9.6%ESRD patients died of severe malnutrition.Malnutrition could cause immunosuppression,anemia, frequent infections,ardiovascular events,and even led multiple organ failure.They not only directly affect the patient's quality of life and survival rate,but they were also the risk factors that increased the incidence of complications and mortality With the increasing improvements and perfection in dialysis technology,maintenance dialysis patients increased.Then the incidence of CKD4 or 5period of malnutrition was further improved.Therefore,in clinical treatment there were urgently need treatment methods to improve malnutrition,retard the process of CKD and reduce CKD4 or 5 morbidity and mortality.
At present,the ways to improve CKD4 or 5 period of malnutrition focused on promoting protein synthesis,reducing the level of serum Leptin,enhancing the content of IGF-Ⅰand improving the quality of nitrogen metabolism,and so on.Its common treatment to improve in CKD4 or 5 patients with protein-energy malnutrition were as follows:Protein preparations,Compoundα-keto acid formulations(ketosteril,the German development),Amino acid formulations,as well as recombinant human erythropoietin(rhuEPO).Not only their efficacy was not satisfied,for the reason that they could not improve protein synthesis of CKD4 or 5 patients.But also they were expensive and their use was limited.Although Traditional Chinese herbal compound decoction could improve malnutrition of varying degrees in CKD4 or 5 period,they were various treatments from experience, which led to inconvenience for use,ununified efficacy,and difficulties in quality control.As so far,there was no new Chinese medicine preparation to treat CKD4 or 5 period of malnutrition.So,it was very important and significant to develop effective drugs to prevent and cure CKD4 or 5 period of malnutrition,and there were potential market and considerable economic benefits.Shenshuai Yangzhen granule was a new Chinese herbal preparation,summarized by pros.Wei Lianbo based on his clinical experience for treating CKD4 or 5 period of malnutrition.It consisted of six herbs: Astragalus,Chinese angelic,Rhubarb,Ginseng,and so on.Modern pharmacological research had shown that Astragalus could improve the level of plasma albumin, regulate lipid metabolism,improve the hypercoagulable state,promote water and sodium excretion,adjust body immunity,and reduce the renal tissue injury. Pre-clinical trials and pharmacodynamic experiments had proved that Shenshuai Yangzhen granule could improve the level of plasma albumin(Alb),prealbumin(PA), transferrin(Tf) and insulin-like growth factor-Ⅰ(IGF-Ⅰ) by the way of promoting protein synthesis.Then it would improve protein-energy malnutrition.Not only did Shenshuai Yangzhen granule has the role of supplementing amino acids as ketosteril, but also it could improve appetite,correct renal anemia,and so on.Shenshuai Yangzhen granule as pure Traditional Chinese Medicine with low price,could also alleviate the financial burden of sick.The present study was to investigate the effects and safety of Shenshuai Yangzhen granule in improving CKD4 or 5 period of malnutrition by adopting Single-center,prospective,randomized controlled clinical trials,with the purpose of providing a new,safe and effective method to improve CKD4 or 5 period of malnutrition.
Objective and significance
Objective:
1.To preliminarily evaluate the effects of Shenshuai Yangzhen granule improving malnutrition of patients with CKD4 or 5period(that is kidney failure period or uremia period) and the effects on retarding the progress of the illness.
2.To preliminarily evaluate the security of Shenshuai Yangzhen granule for CKD patients.
Significance:
There is no new Chinese medicine to treat malnutrition during CKD4 or 5 period. We hope we would provide a new safe and effective method in drug treatments to treat the illness.A new clinical treatment with charateristic and preponderant Traditional Chinese medicine(TCM) and is found to improve malnutrition during CKD4 or 5 period.
Method
1 Experimental design:Adopting one single-center,randomized controlled clinical trials program.
2 Clinical resources:From November 2007 to February 2009,all the observed cases were collected from hospitalized patients or outpatients in the Center of Integrated Traditional and Western Nephrology,Zhujiang Hospital,which was one affiliated hospital of Southern Medical University.At the same time,combining measurement data requirements for the smallest samples size and actual collection of the clinical cases,90 cases who met the requirements for this study were collected. Using the block randomization method,the block size was 6.In other words,every six patients entered in the same block according to the order in which they were treated.In every block,there were three groups:particles group,ketosteril group and decoction group,in which ketosteril group and decoction group were control group. So two patients were treated with particles,two with ketosteril,while two with decoction.Random arranging treating sequence brought about 15 of the randomized blocks.By the order in which they were treated,90 patients were randomly distributed to the three groups with 30 cases in each group.
3 Treatment methods:During treatment and observation,high-quality low-protein diet was permitted.And alsosymptomatic treatments were given,such asdiuresis, controlling blood pressure,retrieving acidosis,retrieving calcium and phosphorus metabolism disorders,and so on.On the basis of the above mentioned treatments, the treatment group was given Shenshuai Yangzhen granule(provided by SanjiuMedical and Pharmaceutical Group),which consisted of Astragalus 1.5g (Batch number:0710081),Angelica 1.5g(Batch number:0709031),Gin-seng 1.5g (Batch number:0708021),Atractylodes 1g(Batch number:0708021),Rhubab 1g (Batch number:0707021) and Villosum 1g(Batch number:0708021).It was taken with warm water,twice a day.The control group of ketosteril took ketosteril (provided by Beijing Fresenius Pharmaceutical Co.,Ltd.Batch number:国药准字H20041442).It was taken 3 times a day,4 tablets for each time.The control group of decoction caplendused Shenshuai Yangzhen decoction(bought from medicine companies in GuangdongProvince,by our identification of Traditional Chinese Medicine Room),and it consisted of Astragalus 30g,Angelica 10g,Ginseng10g, Atractylodes 12g,Rhubarb 6g and Villosum 6g.They were decoctd to syrup 150ml one dosis a day,with taking orally in twice and8 weeks for a course.
4 Examination contents:
4.1 Symptoms observed and record of adverse reaction:The main symptoms scores, subjective global nutritional assessment(SGA) score and ALT were monitored and recorded before and during the treatment of medicine.In the period of treatment,the adverse reaction were recorded.
4.2 Indicators of evaluation:(1) Indicators of Renal function:24-hour Urinary protein(24h Upr),Serum creatinine(Scr),Blood Urea Nitrogen(BUN),estimated Glomerular Filtration Rate(eGFR).(2) Indicators of Nutrition:①Indicators the nutritional status of physical examination:Weight,Triceps SkinFold thickness(TSF), Mid-upper Arm Muscle Circumference(MAMC).②Indicators of protein nutrition: Albumin(Alb),Transferrin(Tf),Prealbumin(PA),Insulin-like Growth Factor-Ⅰ(IGF-Ⅰ).(3)Indicators of hematopoietic function:Hemoglobin(Hb),Red Blood Cell count(RBC),absolute Reticulocyte(RET#).Compare the impact with each group on renal function,protein nutrition,as well as hematopoietic function after treatment.
5 Evaluation criteria of therapy effects:
Clinical recovery:Clinical symptoms and body signs disappeared or basic disappeared,and the main physical and chemical indicators are normal;
Markedly effective:Clinical symptoms and signs improved significantly,and the main physical and chemical indicators are basic normal;
Effective:Clinical symptoms and signs have improved,and the main physical and chemical indicators are basic normal;
No effect:Clinical symptoms and signs had no significant improvement,or even increased.
6 Statistic analyses:All data were processed statistically using software SPSS13.0. Before analysis all measurement data were for homogeneity of variance,then they were shown in the format of((?)±s).Inter-group comparisons were conducted by Paired-Sameples T Test(referred to as paired t test).Before treatment,comparison among the three groups usesd completely randomized design analysis of variance data;after treatment,comparison of the numerical between prior-treatment minus post-treament among the three groups with analysis of covariance,concomitant variable is treatment Prior treatment.Level test data used Kruskal-Wallis Test,and the difference was considered to be significant in statistics if(P<0.05).
Results
1 Comparison of general effects of each group:The treatment group of granule, markedly effective:15 cases;effective:10 cases;no effect:5 cases.The control group of ketosteril,markedly effective:14 cases;effective:9 cases;no effect:7 cases.The control group of decoction,markedly effective:16 cases;effective: 9 cases;no effect:5 cases.There was no significant difference between the three groups(P＞0.05).
2 Comparison of the physical indicators of the nutritional status of inspection of each group before and after treatment:There were no significant difference in body weight,TSF and MAMC within each group before and after treatment(P>0.05). Also no significant difference(P>0.05) among the three groups after treatment.
3 Comparison of main symptoms score and the SGA scores of each group before and after treatment:There were significant difference in the main symptoms score and the SGA scores within each group before and after treatment(P＜0.01). But the comparison among the three groups after treatment were no statistically significant(P>0.05).
4 Comparison of renal function indicators of each group befbre and after treatment: There were significant difference in 24h Upr,BUN,Scr,eGFR within each group before and after treatment(P<0.01 or P<0.05).But no significance(P>0.05) among the three groups after treatment.
5 Comparison of nutrition indicators of each group before and after treatment:There were significant difference in Alb,PA,Tf,IGF-Ⅰwithin each group before and after treatment(P<0.01or P<0.05).But no statistical significance(P>0.05) existed in the three groups after treatment.
6 Comparison of hematopoietic function indicators of each group before and after treatment:There were significant difference in Hb,RET#,RBC count,within each group before and after treatment(P<0.01).There was no statistical significance of the treatment group of granule and the control group of decoction(P>0.05).when compared to the comparison the control group of ketosteril,significant difference existed(P<0.05).
7 Adverse effects:After administration,some cases in the treatment group of granule and the control group of decoction appeared adverse reactions such as minor stomach discomfort,increased frequency of stool,and so on.And most adverse reactions could eliminate when appropriately reducing dose or takeing medicine after a meal.So observation continued.Some cases in the control group of ketosteril happened Hypercalcemia sometimes,but it would disappear after appropriate reducing the intake of vitamin D.Then could continue to observe.There were no significant difference among them(P>0.05).Although the detected value of ALT fluctuated in each group,they are within normal range(5～40 IU/L).And there was no significant difference before and after treatment compared to.
Conclusions
Shenshuai Yangzhen granule can improve malnutrition in CKD4 or 5 patients, and has the same effect with the ketosteril and decoction group.Meanwhile,it is better than ketosteril group in improving patients with anemia,which has equivalent efficacy to decoction group.And the adverse reactions are less.Thus,it can be used as a safe and effective method in improving malnutrition in CKD4 or 5 patients.
1 999年,美国肾脏病基金会(NKF)提出慢性肾脏病(chronic kidney disease,CKD)的概念。2002年,NKF-Kidney Disease Outcomes Quality Initiative(NKF-K/DOQI指南)公布了CKD的定义为:(1)肾脏损害(肾脏的结构或功能异常)≥3个月。可伴或不伴肾小球滤过率(glomerular filtration rate,GFR)下降,表现为下述之一:病理异常;血液或尿液成分检查异常,或者影像学检查异常;(2)GFR＜60ml/min/1.73m~2≥3个月,有或无肾脏损害。CKD是严重危害人类健康的重大疾病,其发病率在全球范围内呈持续增长趋势。在我国南方的大城市中,人群CKD的患病率为10.1%;北京40岁以上人群中,11.3%至少有一项肾脏损伤指标。而CKD最终进展为终末期肾病(end stage renal disease,ESRD),在《慢性肾脏病及透析的临床实践指南》(以下简称为K/DOQI指南)中根据临床表现的严重程度和是否存在并发症以及对预后的影响将CKD的病程划分为5期。当29ml/min≥GFR＞15ml/min时,为CKD 4期:当GFR＜15ml/min时,为CKD5期。慢性肾衰竭(chronic renal failure,CRF)是常见的临床综合征,主要表现为毒性代谢产物潴留,水、电解质、酸碱平衡紊乱,以及全身多系统的损害。假设肾功能正常时,GFR为100%,按肾功能损害的程度可分为4期。当CRF进展至肾衰竭期和尿毒症期时,约棚当于K/DOQI指南的第4、5期。此两期GFR明显下降,血肌酐(Scr)显著升高(约为450μmol/L以上)。研究表明,GFR低于35 ml/min的CKD患者中有45%～64%发生不同程度的营养不良,而ESRD患者中有9.6%死于严重营养不良。营养不良可以导致患者免疫功能低下、贫血、频发感染及心血管事件,甚至导致多脏器衰竭,其发生不仅直接影响患者的生活质量和生存率,而且也是合并症发生率和死亡率增加的危险因素。随着透析技术的日益改进和完善,维持性透析病人增加,CKD4、5期营养不良的发生率进一步提高。因此,临床上迫切需要可以改善患者营养不良,延缓CKD病情进展,降低CKD4、5期发病率和病死率的治疗药物与方法。
目前,对于CKD4、5期营养不良的治疗,主要集中在促进蛋白质合成,降低血清瘦素(Leptin)水平,提高胰岛素样生长因子-Ⅰ(IGF-Ⅰ)含量,改善氮质代谢等。其常用的治疗方法:蛋白质制剂、复方α-酮酸制剂(开同,德国研制)、氨基酸制剂以及重组人类促红细胞生成素(rhuEPO)等来改善CKD4、5期患者蛋白质营养不良,其疗效不尽满意,并不能从本质上改善CKD4、5期患者的蛋白质合成,而且价格昂贵,使用受限。传统的中药复方汤剂虽有不同程度的改善CKD4、5期营养不良的作用,但是其多为经验治疗,方案多种多样,并且服用不方便,疗效不统一,质量难以控制。迄今为止,国内尚无治疗CKD4、5期营养不良的中药新药问世。因此,研制有效的防治CKD4、5期营养不良的药物,具有十分重要的社会意义和价值,并且其潜在的市场和经济效益也相当可观。肾衰养真颗粒是珠江医院中医科魏连波教授根据多年的临床经验总结出来的改善CKD 4、5期营养不良的中药复方,山黄芪、当归、大黄、人参等六味中药组成。现代药理学研究证实黄芪可提高血浆白蛋白(Alb)水平、调节脂质代谢、改善高凝状态、促进水钠排泄、调整机体免疫力及减轻。肾组织损伤。前期的临床试验和药效学试验均已证实肾衰养真颗粒可通过促进蛋白质的合成,提高血浆Alb、前白蛋白(PA)、转铁蛋白(Tf)、IGF-Ⅰ的水平,改善蛋白质营养不良。肾衰养真颗粒不仅具有开同补充氨基酸的作用,还能改善病人的食欲,纠正肾性贫血等综合效用,且为纯中约制剂,价格低廉,可减轻痫人的经济负担。本课题拟采用单中心、随机对照的临床试验方案研究肾衰养真颗粒改善CKD4、5期营养不良的临床疗效和安全性,旨在为CKD4、5期营养不良的药物治疗方面提供新的安全有效的方法。
研究目的及意义
目的:
1初步评价肾衰养真颗粒改善CKD4、5期患者营养不良,延缓病情进展的作用。
2初步评价CKD4、5期患者使用。肾衰养真颗粒的安全性。
意义:
国内尚无治疗CKD4、5期营养不良的中药新药,有望为其药物治疗方面提供新的安全有效的中药新药。从而为改善CKD4、5期营养不良找到具有中医药特色和优势的中医临床治疗方法。
方法
1试验设计采用单中心、随机对照的临床试验方案。
2临床资料观察病例均为2007年11月到2009年02月南方医科大学珠江医院中西医结合肾病中心住院及门诊患者,同时结合计量资料最小样本量的要求以及临床收集病例的实际,共收集90例有完整资料的病例。采用区组随机化方法,规定区组大小为6,即每6名患者按就诊先后顺序进入同一区组,其中2名接受颗粒治疗,2名接受开同治疗,2名接受汤剂治疗。随机排列治疗顺序的组合,构成15个区组的随机化方案。将就诊患者随机分为颗粒治疗组30例、开同对照组30例、汤剂对照组30例。
3治疗方法所有患者均采用优质低蛋白饮食,根据病情结合利尿,控制血压,纠正酸中毒,纠正钙磷代谢紊乱等对症处理。在上述治疗基础上,治疗组给予肾衰养真颗粒(三九医药集团提供),主要药物:黄芪1.5g(批号:0710081),当归1.5g(批号:0709031),人参1.5g(批号:0708021),白术1g(批号:0708021),大黄1g(批号:0707021),砂仁1g(批号:0708021)。相当于汤剂的剂量,温水冲服,每日2次。开同对照组用开同片(北京费森尤斯卡比医药有限公司生产,批号:国药准字H20041442),每日3次,每次4片。汤剂对照组,给予肾衰养真方(药物购自广东省药材公司,经本校中药制剂室鉴定),主要药物:黄芪30g,当归10g,人参10g,白术12g,大黄6g,砂仁6g,水煎服150ml,每日一剂,分2次口服。8周为一个疗程。
4观察指标
4.1症状观察及不良反应记录所有病人治疗前和用药后计算主症积分,主观综合营养评估(SGA)评分以及丙氨酸氨基转移酶(ALT),同时记录不良反应。
4.2评价指标(1)肾功能指标24小时尿蛋白定量(24h Upr)、Scr、血尿素氮(BUN)、估计肾小球滤过率(eGFR)。(2)营养指标①体格营养状况检查指标体重、肱三头肌皮褶厚度(TSF)、上臂中段肌肉周径(MAMC);②蛋白营养指标血清Alb、PA、Tf以及IGF-Ⅰ。(3)造血功能指标血红蛋白(Hb)、红细胞(RBC)计数、网织红细胞绝对值(RET#)。比较各组治疗前后对肾功能、营养不良状态以及造血功能的影响。
5疗效评价临床痊愈:临床症状、体征消失或基本消失,主要理化指标正常;显效:临床症状、体征明显改善,主要理化指标改善50%;有效:临床症状、体征均有好转,主要理化指标改善30%;无效:临床症状、体征及理化指标均无明显改善,甚或加重。
6统计学处理使用SPSS13.0统计软件进行统计学分析,所有计量数据采用((?)±s)表示;并先进行方差齐性分析,证实方差齐后,组内比较应用配对t检验。治疗前组间比较采用完全随机设计资料的方差分析,治疗后组间及其差值比较用协方差分析(analysis of covariance,ANCOVA),协变量为治疗前。等级资料采用Kruskal-Wallis检验,P<0.05显示差异有统计学意义。
结果
1各组综合疗效比较颗粒治疗组显效15例,有效10例,无效5例;开同对照组显效14例,有效9例,无效7例;汤剂对照组显效16例,有效9例,无效5例。各组间比较差异无显著性(P>0.05)。
2各组治疗前后体格营养状况检查各项指标的比较各组内治疗前后体重、TSF和MAMC相比,均无显著性差异(P＞0.05);各组间治疗后各检查指标相比亦无统计学意义(P＞0.05)
3各组治疗前后主症积分与SGA评分比较各组内治疗前后主症积分与SGA评分相比,均有显著性差异(P＜0.01);各组间治疗后各指标相比较无统计学意义(P＞0.05)。
4各组治疗前后肾功能指标的比较各组内治疗前后24h Upr、BUN、Scr、eGFR的比较,均有统计学意义(P＜0.01或P＜0.05);各组间治疗后各指标比较无显著性差异(P＞0.05)。
5各组治疗前后营养指标的比较各组内治疗前后Alb、PA、Tf、IGF-Ⅰ的比较,均有显著性差异(P＜0.01或P＜0.05);各组间治疗后各指标比较无统计学意义(P＞0.05)。
6各组治疗前后造血功能指标的比较各组内治疗前Hb、RBC计数、RET#的比较,均有统计学意义(P＜0.001);各组间治疗后各指标比较,颗粒治疗组与汤剂对照组比较无统计学意义(P＞0.05),而颗粒治疗组、汤剂对照组与开同对照组比较均有显著性差异(P＜0.001)。
7不良反应观察期内颗粒治疗组与汤剂对照组有部分病例服药后有轻微的胃部不适、大便次数增多等反应,适当减少剂量或饭后服药后大多消除,可继续进行观察;开同对照组,偶有高钙血症发生,适当减少维生素D的摄入量后,可消除症状,继续进行观察。其差别无统计学意义(P＞0.05)。各组患者ALT的检测值虽有波动,但都在正常值范围内(5～40 IU/L),其差别无显著性(P＞0.05)。
结论
肾衰养真颗粒可以改善CKD4、5期患者的营养不良状况,与开同、汤剂具有相同的疗效;但在改善患者贫血时,其疗效等同于汤剂,而优于开同;并且不良反应轻。因此,其可以作为改善CKD4、5期患者营养不良的安全有效的选择之一。
Background
In the year 1999,National Kidney Foundation(NKF) brought forth the concept of chronic kidney disease(CKD).In 2002,the guide of National Kidney Foundation-Kidney Disease Outcome Quality Initiative(NKF-K/DOQI) published the definition of CKD.(1) kidney damage(structural or functional kidney abnormalities) lasted at least for 3 months,with or without decreased glomerular filtration rate,and the performance was as anyone of the following:pathological abnormalities,blood or urine to check abnormal composition,imaging abnormalities; (2) GFR<60ml/min/1.73m~2 lasted at least for 3 months,with or without kidney damage.CKD was one of the major diseases which could seriously endanger human health,and its incidence sustainedly grew in the whole world.At our country's major cities in the South,prevalence rate of CKD population was 10.1%;population aged above 40 in Beijing,11.3%had at least one indicator of kidney damage.But CKD eventually progressed to end-stage renal disease(ESRD),in the "chronic kidney disease and dialysis of the Clinical Practice Guidelines"(hereinafter referred to K/DOQI guidelines),according to the severity of clinical manifestations and the presence of complications,as well as the impact on the prognosis,CKD is divided into five stages.When 29ml/min≥GFR≥15ml/min,it is CKD stage 4;then GFR＜ 15ml/min,it is stage 5.Chronic renal failure(CRF) was a common clinical syndrome. The main performances are retention of toxic metabolites,balance disorders of water, electrolyte,acid-base,as well as multisystem damage.Assuming normal renal function,the GFR was 100%.According to the degree of renal dysfunction,it could be divided into four stages.When CRF progressed to renal failure and uremia period, it approximately equivalent to CKD4 or 5period.In the two periods,GFR decreased to 25%or less of normal lever,Serum creatinine was significantly higher(about 450μmol/L and above).Studies showed that 45%～64%CKD patients with GFR≥35ml/min appeared varying degrees of malnutrition.While 9.6%ESRD patients died of severe malnutrition.Malnutrition could cause immunosuppression,anemia, frequent infections,ardiovascular events,and even led multiple organ failure.They not only directly affect the patient's quality of life and survival rate,but they were also the risk factors that increased the incidence of complications and mortality With the increasing improvements and perfection in dialysis technology,maintenance dialysis patients increased.Then the incidence of CKD4 or 5period of malnutrition was further improved.Therefore,in clinical treatment there were urgently need treatment methods to improve malnutrition,retard the process of CKD and reduce CKD4 or 5 morbidity and mortality.
At present,the ways to improve CKD4 or 5 period of malnutrition focused on promoting protein synthesis,reducing the level of serum Leptin,enhancing the content of IGF-Ⅰand improving the quality of nitrogen metabolism,and so on.Its common treatment to improve in CKD4 or 5 patients with protein-energy malnutrition were as follows:Protein preparations,Compoundα-keto acid formulations(ketosteril,the German development),Amino acid formulations,as well as recombinant human erythropoietin(rhuEPO).Not only their efficacy was not satisfied,for the reason that they could not improve protein synthesis of CKD4 or 5 patients.But also they were expensive and their use was limited.Although Traditional Chinese herbal compound decoction could improve malnutrition of varying degrees in CKD4 or 5 period,they were various treatments from experience, which led to inconvenience for use,ununified efficacy,and difficulties in quality control.As so far,there was no new Chinese medicine preparation to treat CKD4 or 5 period of malnutrition.So,it was very important and significant to develop effective drugs to prevent and cure CKD4 or 5 period of malnutrition,and there were potential market and considerable economic benefits.Shenshuai Yangzhen granule was a new Chinese herbal preparation,summarized by pros.Wei Lianbo based on his clinical experience for treating CKD4 or 5 period of malnutrition.It consisted of six herbs: Astragalus,Chinese angelic,Rhubarb,Ginseng,and so on.Modern pharmacological research had shown that Astragalus could improve the level of plasma albumin, regulate lipid metabolism,improve the hypercoagulable state,promote water and sodium excretion,adjust body immunity,and reduce the renal tissue injury. Pre-clinical trials and pharmacodynamic experiments had proved that Shenshuai Yangzhen granule could improve the level of plasma albumin(Alb),prealbumin(PA), transferrin(Tf) and insulin-like growth factor-Ⅰ(IGF-Ⅰ) by the way of promoting protein synthesis.Then it would improve protein-energy malnutrition.Not only did Shenshuai Yangzhen granule has the role of supplementing amino acids as ketosteril, but also it could improve appetite,correct renal anemia,and so on.Shenshuai Yangzhen granule as pure Traditional Chinese Medicine with low price,could also alleviate the financial burden of sick.The present study was to investigate the effects and safety of Shenshuai Yangzhen granule in improving CKD4 or 5 period of malnutrition by adopting Single-center,prospective,randomized controlled clinical trials,with the purpose of providing a new,safe and effective method to improve CKD4 or 5 period of malnutrition.
Objective and significance
Objective:
1.To preliminarily evaluate the effects of Shenshuai Yangzhen granule improving malnutrition of patients with CKD4 or 5period(that is kidney failure period or uremia period) and the effects on retarding the progress of the illness.
2.To preliminarily evaluate the security of Shenshuai Yangzhen granule for CKD patients.
Significance:
There is no new Chinese medicine to treat malnutrition during CKD4 or 5 period. We hope we would provide a new safe and effective method in drug treatments to treat the illness.A new clinical treatment with charateristic and preponderant Traditional Chinese medicine(TCM) and is found to improve malnutrition during CKD4 or 5 period.
Method
1 Experimental design:Adopting one single-center,randomized controlled clinical trials program.
2 Clinical resources:From November 2007 to February 2009,all the observed cases were collected from hospitalized patients or outpatients in the Center of Integrated Traditional and Western Nephrology,Zhujiang Hospital,which was one affiliated hospital of Southern Medical University.At the same time,combining measurement data requirements for the smallest samples size and actual collection of the clinical cases,90 cases who met the requirements for this study were collected. Using the block randomization method,the block size was 6.In other words,every six patients entered in the same block according to the order in which they were treated.In every block,there were three groups:particles group,ketosteril group and decoction group,in which ketosteril group and decoction group were control group. So two patients were treated with particles,two with ketosteril,while two with decoction.Random arranging treating sequence brought about 15 of the randomized blocks.By the order in which they were treated,90 patients were randomly distributed to the three groups with 30 cases in each group.
3 Treatment methods:During treatment and observation,high-quality low-protein diet was permitted.And alsosymptomatic treatments were given,such asdiuresis, controlling blood pressure,retrieving acidosis,retrieving calcium and phosphorus metabolism disorders,and so on.On the basis of the above mentioned treatments, the treatment group was given Shenshuai Yangzhen granule(provided by SanjiuMedical and Pharmaceutical Group),which consisted of Astragalus 1.5g (Batch number:0710081),Angelica 1.5g(Batch number:0709031),Gin-seng 1.5g (Batch number:0708021),Atractylodes 1g(Batch number:0708021),Rhubab 1g (Batch number:0707021) and Villosum 1g(Batch number:0708021).It was taken with warm water,twice a day.The control group of ketosteril took ketosteril (provided by Beijing Fresenius Pharmaceutical Co.,Ltd.Batch number:国药准字H20041442).It was taken 3 times a day,4 tablets for each time.The control group of decoction caplendused Shenshuai Yangzhen decoction(bought from medicine companies in GuangdongProvince,by our identification of Traditional Chinese Medicine Room),and it consisted of Astragalus 30g,Angelica 10g,Ginseng10g, Atractylodes 12g,Rhubarb 6g and Villosum 6g.They were decoctd to syrup 150ml one dosis a day,with taking orally in twice and8 weeks for a course.
4 Examination contents:
4.1 Symptoms observed and record of adverse reaction:The main symptoms scores, subjective global nutritional assessment(SGA) score and ALT were monitored and recorded before and during the treatment of medicine.In the period of treatment,the adverse reaction were recorded.
4.2 Indicators of evaluation:(1) Indicators of Renal function:24-hour Urinary protein(24h Upr),Serum creatinine(Scr),Blood Urea Nitrogen(BUN),estimated Glomerular Filtration Rate(eGFR).(2) Indicators of Nutrition:①Indicators the nutritional status of physical examination:Weight,Triceps SkinFold thickness(TSF), Mid-upper Arm Muscle Circumference(MAMC).②Indicators of protein nutrition: Albumin(Alb),Transferrin(Tf),Prealbumin(PA),Insulin-like Growth Factor-Ⅰ(IGF-Ⅰ).(3)Indicators of hematopoietic function:Hemoglobin(Hb),Red Blood Cell count(RBC),absolute Reticulocyte(RET#).Compare the impact with each group on renal function,protein nutrition,as well as hematopoietic function after treatment.
5 Evaluation criteria of therapy effects:
Clinical recovery:Clinical symptoms and body signs disappeared or basic disappeared,and the main physical and chemical indicators are normal;
Markedly effective:Clinical symptoms and signs improved significantly,and the main physical and chemical indicators are basic normal;
Effective:Clinical symptoms and signs have improved,and the main physical and chemical indicators are basic normal;
No effect:Clinical symptoms and signs had no significant improvement,or even increased.
6 Statistic analyses:All data were processed statistically using software SPSS13.0. Before analysis all measurement data were for homogeneity of variance,then they were shown in the format of((?)±s).Inter-group comparisons were conducted by Paired-Sameples T Test(referred to as paired t test).Before treatment,comparison among the three groups usesd completely randomized design analysis of variance data;after treatment,comparison of the numerical between prior-treatment minus post-treament among the three groups with analysis of covariance,concomitant variable is treatment Prior treatment.Level test data used Kruskal-Wallis Test,and the difference was considered to be significant in statistics if(P<0.05).
Results
1 Comparison of general effects of each group:The treatment group of granule, markedly effective:15 cases;effective:10 cases;no effect:5 cases.The control group of ketosteril,markedly effective:14 cases;effective:9 cases;no effect:7 cases.The control group of decoction,markedly effective:16 cases;effective: 9 cases;no effect:5 cases.There was no significant difference between the three groups(P＞0.05).
2 Comparison of the physical indicators of the nutritional status of inspection of each group before and after treatment:There were no significant difference in body weight,TSF and MAMC within each group before and after treatment(P>0.05). Also no significant difference(P>0.05) among the three groups after treatment.
3 Comparison of main symptoms score and the SGA scores of each group before and after treatment:There were significant difference in the main symptoms score and the SGA scores within each group before and after treatment(P＜0.01). But the comparison among the three groups after treatment were no statistically significant(P>0.05).
4 Comparison of renal function indicators of each group befbre and after treatment: There were significant difference in 24h Upr,BUN,Scr,eGFR within each group before and after treatment(P<0.01 or P<0.05).But no significance(P>0.05) among the three groups after treatment.
5 Comparison of nutrition indicators of each group before and after treatment:There were significant difference in Alb,PA,Tf,IGF-Ⅰwithin each group before and after treatment(P<0.01or P<0.05).But no statistical significance(P>0.05) existed in the three groups after treatment.
6 Comparison of hematopoietic function indicators of each group before and after treatment:There were significant difference in Hb,RET#,RBC count,within each group before and after treatment(P<0.01).There was no statistical significance of the treatment group of granule and the control group of decoction(P>0.05).when compared to the comparison the control group of ketosteril,significant difference existed(P<0.05).
7 Adverse effects:After administration,some cases in the treatment group of granule and the control group of decoction appeared adverse reactions such as minor stomach discomfort,increased frequency of stool,and so on.And most adverse reactions could eliminate when appropriately reducing dose or takeing medicine after a meal.So observation continued.Some cases in the control group of ketosteril happened Hypercalcemia sometimes,but it would disappear after appropriate reducing the intake of vitamin D.Then could continue to observe.There were no significant difference among them(P>0.05).Although the detected value of ALT fluctuated in each group,they are within normal range(5～40 IU/L).And there was no significant difference before and after treatment compared to.
Conclusions
Shenshuai Yangzhen granule can improve malnutrition in CKD4 or 5 patients, and has the same effect with the ketosteril and decoction group.Meanwhile,it is better than ketosteril group in improving patients with anemia,which has equivalent efficacy to decoction group.And the adverse reactions are less.Thus,it can be used as a safe and effective method in improving malnutrition in CKD4 or 5 patients.
引文
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[13]倪玲,朱汉威.慢性肾功能衰竭的微炎症状态[J].上海交通大学学报(医学版),2006,26(1):100-104.
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[25]于俊生,杜雅静,庄文清,等.补肾排毒合剂治疗慢性肾衰竭营养不良60例临床观察[J].中国中西医结合肾病杂志,2006,7(7):395-397.
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[36]刘必成.慢性肾脏病新理论与实践[M].南京:东南大学出版社,2008:1-2.
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