济生肾气丸治疗肾气不足型肾结石的临床疗效与机制研究

发布时间：2018-01-02 02:13

  本文关键词：济生肾气丸治疗肾气不足型肾结石的临床疗效与机制研究　出处：《广州中医药大学》2017年博士论文　论文类型：学位论文

  更多相关文章： 济生肾气丸 肾气不足 肾结石 氧化损伤OS 炎症反应NF-KB通路

【摘要】：背景肾结石是我国也是世界最常见的泌尿外科疾病之一,世界范围内的发病率为1%～20%。在我国,一般人群中发病率达1%～10%,其中25%的患者需住院治疗。改革开放后,随着生活水平的提高,肾结石的发病率在我国大幅度增长,业已成为世界上三大结石高发地区之一[4],在我国南方诸省中,以肾结石为主的肾结石患者几乎均占泌尿外科住院患者的首位。这种不良的增长趋势不得不引起我们泌尿外科医生的重视。肾结石治疗后存在结石残留和远期高复发率(15至20年内复发率60%-80%)的特点,所以,"清除残留结石和防石"对肾结石的防治、预后意义重大。笔者在临床工作中发现,因肾结石住院治疗的老年患者(年纪≥55岁)大多数具备肾气不足症状,辨证论治予以济生肾气丸治疗后疗效明显改善,结石也有减少,该中药得到了许多患者的认可。欣喜之余,我们设想,济生肾气丸是否可以解决上述的难题(排石、防石)呢,我们查阅文献,未发现有过肾气不足肾结石的相关"防、治"研究。由于中医治疗"淋证"先以清热通淋排石等治标为先,后以补肾固本善后。中医理论认为,排石乃属"治标",石净后,当图根本,否则肾气仍虚,机体仍然处于不平衡状态,日后复有重新结石之虞,此观点在老年肾结石患者尤为适用。现代医学中肾结石术后结石复发率很高,术后结石虽除,但对肾气是否充足应进一步辨治,如若忽略此项,对于肾气不足型肾结石的治疗与预后是非常不利的。目的所以,本着"治病救人,发扬中医"的职责,笔者认为有必要通过临床和实验研究两方面验证济生肾气丸治疗肾气不足型肾结石的临床疗效(排石、防石、改善症状)、安全性、不良反应,及其作用机制。以期进一步探索经方防治肾结石的特色疗效及安全性与可能的作用机制。方法1、临床研究:通过2015年6月至2017年2月这段时间内,在广中医第一附属医院,因肾结石而在外科行PCNL术后的住院患者,年纪≥55岁,中医辨证归属于"肾气不足"型,符合诊断、纳入标准的患者纳入本研究,共65人(男39人,女26人,平均年龄60岁)。按随机原则分为治疗组(济生肾气丸组34例)及对照组(枸橼酸钾颗粒组31例)。治疗组与对照组均从PCNL术后第7天开始服用指定药物,疗程7个月。两组病人分别于用药前及服药后1个月、第4个月、第7个月(即取1/4左肾,运用Western-blotting检测技术测大鼠肾脏组织中IKB、IKK、NF-KB、P65的表达情况;运用ELISA酶联免疫检测法测大鼠肾脏组织中1L-1 β的表达。结果1、临床结果:治疗前,两组纳入病例在性别、年龄、PCNL术后残余结石数量、结石直径、血清肌酐Cr、尿素氮BUN、肝功能ALT、AST、TBIL、肾气不足中医证候总分、腰腹疼痛、尿中带血、小便不利、腰膝酸软无力、倦怠乏力、畏寒肢冷、颜面或肢体水肿、痰饮咳喘等中西医各项指标基线相同(p0.05)。两组在治疗后第1个月、第4个月、第7月观察时,治疗组除了在结石直径上与对照组无统计差异(p0.05),其他指标如:残余结石数量、血清肌酐Cr、尿素氮BUN、肾气不足中医证候总分、腰腹疼痛、尿中带血、小便不利、腰膝酸软无力、倦怠乏力、畏寒肢冷、颜面或肢体水肿、痰饮咳喘等的疗效均明显优于对照组,统计学有差异(p0.05);在治疗过程中,治疗组不良反应明显少于对照组(p0.05);7个月的药费,治疗组花费不到西药组费用的3/10,可节约成本7/10以上(p0.05)。2、动物实验结果:2.1从各组大鼠肾脏病理切片中,草酸钙结晶沉积程度与肾组织病理改变情况的比较来讨论:模型组与空白组比较,有明显结晶沉积(P0.05),镜下见:大量不规则形态的结晶,肾小管扩张明显,肾小球呈不规则形态,周围炎性细胞浸润明显,皮质肾髓质排列紊乱。说明了该造模方法是成功的,且成石率较高。济生肾气丸3个剂量组结晶沉积度与病理情况与模型组、空白组、西药组比较均有不同。中药中等剂量组、高剂量组比模型组结晶减少(P0.05),且高剂量组统计有显著性差异(P0.01),说明高、中剂量中药均能抑制肾结石的形成,且高剂量疗效显著。低剂量组与模型组相比较(P0.05),抑制肾结石的形成无明显疗效。西药组与模型组相比较(P0.05),能抑制肾结石的形成。中药高剂量组与西药组抑制肾结石形成的疗效相似(P0.05)。2.2从各组大鼠血清S0D活力、MDA含量、肾组织S0D活力、MDA含量、血肌酐(Cr)、血尿素氮(BUN)、血清Ca2+离子的含量来比较讨论:肾组织总SOD活力与血清SOD活力的变化趋势与肾组织总MDA含量与血清MDA含量水平的变化趋势是一致的。说明局部与整体的关系是一致的,共同提示清除氧自由基的能力,提示机体抗氧化能力与氧化损伤程度。模型组与空白组比较:肾组织SOD活力、血清SOD活力有降低(P0.05),肾组织MDA含量、血清MDA含量升高(P0.05),血Cr与血BUN均有升高趋势(P0.05),说明模型组抗氧化损伤能力下降、肾组织细胞氧化损伤加重,肾功能受损严重。低剂量组与模型组比较:肾组织总S0D活力、血清S0D活力、肾MDA含量、血清MDA含量、血肌酐Cr与血尿素氮BUN、血钙Ca2+均无明显改善(P0.05),说明中药低剂量组在提升大鼠肾脏组织细胞抗氧化损伤能力、保护肾功能、降低肾结石形成危险因素中血钙等方面,疗效不明显。中等剂量组与模型组比较:肾组织总SOD活力、血清SOD活力、肾MDA含量、血清MDA含量、血肌酐Cr与血尿素氮BUN、血钙Ca2+有改善(P0.05),说明中等剂量组在提升大鼠肾组织细胞抗氧化损伤能力、保护肾功能方面有一定的疗效,但在降低肾结石形成危险因素中血Ca2+这一方面无明显疗效。高剂量组与模型组比较:肾组织总S0D活力、血清SOD活力、肾MDA含量、血清MDA含量、血肌酐Cr与血尿素氮BUN均有明显改善趋势(P0.01),说明高等剂量组在提升肾脏组织细胞抗氧化损伤能力、保护肾功能方面有显著的疗效;在降低血Ca2+这一方面疗效不明显。西药组与模型组比较:肾组织总SOD活力、血清S0D活力、肾总MDA含量、血清MDA含量、血钙Ca2+方面均有改善(0.05),说明西药组在在提升肾组织细胞抗氧化损伤能力、降低血Ca2+方面有明显的疗效;但血Cr与血BUN均无明显差异(P=0.0810.05),说明西药组在保护肾功能方面的无明显疗效。中等剂量组与西药组比较:在提高肾脏组织细胞抗氧化损伤能力方面无明显差异(P0.05),在保护肾功能方面的疗效优于西药组(P0.05);两组在降低血钙方面疗效无统计差异(P0.05)。高剂量组与西药组比较:在提高肾脏组织细胞抗氧化损伤能力方面有明显的疗效(P0.05),在保护肾功能方面的疗效优于西药组(P0.01);两组在降低血钙方面疗效无统计差异(P0.05)。2.3从各组大鼠肾组织中的IKB、IKK、NF-KB、P65的Western-blotting检测表达情况,和肾脏组织中1L-1β的ELISA检测的表达情况讨论:模型组与空白组比较:NF-KB通路中的因子IKB表达有下调,IKK和NF-KB/P65表达有上调,炎性因子1L-1β的表达有上调,统计均有意义(P0.05),说明造模方法是成功的,已经造成了肾组织的炎性损伤,发生了炎症反应。与模型组比较,中药中等剂量组、高剂量组均能使NF-KB通路中的因子IKB表达有上调,IKK和NF-KB/P65表达有下调,炎性因子1L-1β的表达有下调,统计均有差异(P0.05),反应中等剂量组对于抑制肾脏炎症损伤有一定的疗效,而高剂量组疗效更显著(P0.01)。与模型组比较,中药低剂量组因子IKB、IKK和NF-KB/P65、1L-1β表达无统计学差异(P0.05),说明低剂量组对于抑制肾脏炎症损伤无明显疗效。西药组与模型组相比较:以上因子有改变(P0.05),反应西药组抑制肾脏炎症损伤有一定疗效。与西药组相比较:中药高剂量组NF-KB通路中的因子IKB表达、IKK和NF-KB/P65表达有所改善,炎性因子1L-1β的表达较为相近(P0.05),说明高剂量组抑制肾脏炎症损伤的疗效优于西药组。结论1、临床结论济生肾气丸治疗肾气不足型肾结石患者,可明显减少残余结石数量,保护肾功能(Cr ↓、BUN↓),同时对肾气不足中医证候总分、腰腹疼痛、尿中带血、小便不利、腰膝酸软无力、倦怠乏力、畏寒肢冷、颜面或肢体水肿、痰饮咳喘等症状有明显改善。在为期7个月的疗程中,不良反应发生率较低;未出现毒副作用。且经济费用不到西药组的3/10。2、实验结论济生肾气丸有抗氧化损伤(SOD ↑、MDA↓)、抗炎性反应(IKB ↑、IKK↓、NF-KB ↓、P65 ↓、1L-1 β ↓)、保护肾功能(Cr ↓、BUN↓,肾病理切片结晶沉积↓、肾组织破坏↓)的作用,且有防石作用。济生肾气丸可能通过抗氧化损伤(0S)与抗炎症反应(NF-KB通路)来保护肾小管上皮细胞与肾功能的。所以,济生肾气丸治疗肾气不足型肾结石具有一定的可行性及优越性,值得临床进一步研究与应用。
[Abstract]:The background of kidney stones is one of the most common diseases in the Department of Urology of the world in the world, the incidence rate of 1% ~ 20%. in our country, the general population incidence rate of 1% to 10%, of which 25% of the patients required hospitalization. After the reform and opening up, with the improvement of living standards, the incidence of nephrolithiasis in growth our country greatly, has become one of the world's three largest stone regions with a high incidence of [4], in the southern provinces of China, in patients with kidney stones of kidney stones mainly are almost accounted for inpatients in the Department of Urology in the first place. This negative growth trend have caused us urologists attention. Residual stones and long-term Gao Fufa rate of renal stones after the treatment (60%-80% recurrence rate of 15 to 20 years) of the characteristics, so, "to remove the residual stones and the prevention and control of anti stone" on renal calculi, prognosis of great significance. The author found that in clinical work, hospital treatment for kidney stones The treatment of elderly patients (aged over 55 years old) with most kidney qi deficiency symptoms, syndrome differentiation and treatment to economic effect Shenqi Pill was improved after treatment, stone also decreased, the traditional Chinese medicine has been recognized by many patients. Meanwhile, we assume that the economy whether can solve the problem of Shenqi Pill (a row of stone yet, we, anti stone) literature, there have been no kidney qi deficiency of kidney stones "prevention, treatment related research. Because TCM treatment with stranguria with Qingre Tonglin Paishi such symptoms as the first, then to tonifying kidney rehabilitation. The TCM theory argues that the row of stone is temporary after the net, stone, when the fundamental diagram, or kidney is still empty, the body is still in a state of imbalance, days after the complex re stone removal, this view is particularly applicable in elderly patients with kidney stones. Modern medicine in renal calculi postoperative recurrence rate is very high, although in addition to calculus of kidney Qi is sufficient, but should a If you ignore this step of treatment, treatment and prognosis for kidney qi deficiency of kidney stones is very harmful. Therefore, the spirit of "saving lives, the development of traditional Chinese" duties, the author thinks that it is necessary by the two aspects of clinical and experimental studies to verify the clinical effect and Jisheng Shenqi pills in the treatment of renal insufficiency type of kidney stones (gas discharge stone, stone prevention, improve the symptoms of adverse reactions), safety, and its mechanism of action. In order to further explore the prevention and treatment of renal stone characteristics of efficacy and safety and the possible mechanism. Methods 1 clinical research: from June 2015 to February 2017 this period of time, in the First Affiliated Hospital of Guangzhou traditional Chinese medicine for kidney stones in patients undergoing PCNL surgery, older than 55 years old, TCM belongs to "kidney deficiency", consistent with the diagnosis, inclusion criteria were included in this study, a total of 65 people (39 male, 26 female, mean age 60 years). In accordance with the The machine is divided into treatment group (Jisheng Shenqi pills group 34 cases) and control group (Potassium Citrate Granules group 31 cases). The treatment group and the control group from the seventh day after PCNL take prescribed medicine, treatment for 7 months. Two patients were in use before and after treatment for 1 months, fourth months, seventh months (i.e. 1/4 left kidney, using Western-blotting detection technology of rats were measured in kidney tissue of IKB, IKK, NF-KB, P65 expression by ELISA; enzyme linked immunosorbent assay measuring rat kidney tissues. Results the expression of 1L-1 beta 1, clinical results: before treatment, two cases in group gender, age, PCNL number of postoperative residual stones, stone diameter Cr, serum creatinine, urea nitrogen BUN, liver function ALT, AST, TBIL, kidney qi deficiency of TCM syndrome score, abdominal pain, hematuria, dysuria, Yaoxisuanruan weakness, lassitude, aversion to cold, face or limb edema the traditional Chinese medicine and Western medicine such as cough, phlegm The same baseline indicators (P0.05). The two groups first months after treatment, fourth months, seventh months of observation, the treatment group in addition to the diameter of the stones and the control group had no statistical difference (P0.05), other indicators such as the number of residual stones, serum creatinine Cr blood urea nitrogen BUN, kidney qi deficiency syndrome of traditional Chinese medicine the total score, abdominal pain, hematuria, dysuria, Yaoxisuanruan weakness, lassitude, aversion to cold, face or limb edema, phlegm cough and asthma curative effect was significantly better than the control group, a statistically significant difference (P0.05); in the course of treatment, adverse reactions in the treatment group was significantly less than the control group (P0.05) 7 months; the drugs, the treatment group takes less than the cost of Western medicine group 3/10, can save the cost of more than 7/10 (P0.05).2, the results of animal experiment: 2.1 from the kidney of rats, calcium oxalate deposition and the degree of renal tissue pathological changes compared to the model group and the blank discussion: Groups have obvious crystal deposition (P0.05), microscope: a large number of irregular shape crystals, dilatation of tubules and glomeruli showed irregular morphology, infiltration of inflammatory cells around the renal medulla cortex obviously disordered. The modeling method is successful, and the stone Jisheng rate is higher. Shenqi Pill 3 dose groups of crystal deposition and pathological conditions with the model group, blank group, western medicine group. Traditional Chinese medicine has different medium dose group, high dose group lower than model group (P0.05), the crystallization and the high dose group there was significant statistical difference (P0.01), said that high dose of traditional Chinese medicine were formed in can inhibit renal calculi, and significant effect. High dose low dose group compared with model group (P0.05), inhibit the formation of kidney stones had no obvious effect. The western medicine group compared with model group (P0.05), can inhibit the formation of kidney stones. High dose of Chinese medicine group and Western medicine group inhibited the formation of kidney stones The effect is similar to (P0.05).2.2 from serum S0D activity, MDA content, S0D activity, MDA content of renal tissue, serum creatinine (Cr), blood urea nitrogen (BUN), the serum content of Ca2+ ion to compare discussion: renal tissue total SOD activity and serum SOD activity with the change of renal tissue total the content of MDA and serum MDA level of the trend is the same. Explain the relationship between local and overall is consistent, suggested that the capacity of scavenging oxygen free radicals, suggesting that the antioxidant ability and the degree of oxidative damage. The model group compared with the control group, SOD activity in renal tissue, serum SOD activity decreased (P0.05, MDA) the content of renal tissue, the content of serum MDA (P0.05), serum Cr and serum BUN were increased (P0.05), indicating a decline in model group, antioxidant capacity, oxidative damage of renal tissue increased, renal function is severely damaged. The low dose group compared with model group: the total S0D activity in renal tissue, The activity of serum S0D, renal MDA content, serum MDA content, serum creatinine and blood urea nitrogen Cr BUN, serum Ca2+ had no significant improvement (P0.05), low dose of Chinese medicine group that enhance the ability of anti oxidative damage in kidney tissue of rats and protect renal function, reduce the risk factors in the formation of kidney stones, calcium, curative effect is not obvious. The medium dose group compared with the model group: the total SOD activity in renal tissue, serum SOD activity, MDA content in kidney, serum MDA content, serum creatinine and blood urea nitrogen Cr BUN, serum calcium can improve Ca2+ (P0.05), medium dose group that enhance the ability of anti oxidative damage in renal tissue of rats, there are certain effect of the protection of renal function, but the decrease in the formation of kidney stones in the risk factors of blood Ca2+ on the one hand, no obvious curative effect. The high dose group compared with model group: the total S0D activity in renal tissue, serum SOD activity, MDA content in kidney, serum MDA content, serum creatinine and blood urea nitrogen BUN Cr The trend was significantly improved (P0.01), high dose group in improving renal cell antioxidant ability, have a significant effect on protecting renal function; reduce blood Ca2+ the effect is not obvious. The western medicine group compared with the model group: the total SOD activity in renal tissue, serum S0D activity, kidney total MDA content the content of serum MDA, serum Ca2+ were improved (0.05), that in the western medicine group in improving renal cell antioxidant ability has obvious curative effect on reducing blood Ca2+; but there were no significant difference between the serum Cr and serum BUN (P=0.0810.05), indicating no obvious curative effect of Western medicine group in the protection of renal function at moderate dose group and Western medicine group: there was no significant difference in improving renal cell antioxidant capacity (P0.05), the curative effect is better than western medicine group in the protection of renal function (P0.05); the two group in reducing the blood calcium effect had no statistical difference (P0.05 ). High dose group and Western medicine group: there is obvious effect in improving renal cell antioxidant capacity (P0.05), the curative effect is better than western medicine group in the protection of renal function (P0.01); the two group in reducing the blood calcium effect had no statistical difference (P0.05).2.3 from renal tissue in rats of each group IKB, IKK, NF-KB, Western-blotting to detect the expression of P65, discuss the expression of ELISA in kidney tissue and detection of 1L-1 beta: the model group compared with the control group: factor IKB in NF-KB pathway expression down regulated IKK and NF-KB/P65 expression was up-regulated, the expression of inflammatory factor 1L-1 beta increased, statistical significant (P0.05), indicating that the model is successful, has caused the inflammatory injury of renal tissue, inflammation reaction. Compared with the model group, Chinese medicine middle dose group, high dose group were able to make the factor IKB in NF-KB pathway and NF-KB/P65 IKK expression was up-regulated. The expression down regulated the expression of inflammatory factor 1L-1 beta down, statistical difference (P0.05), the reaction medium dose group has certain curative effect on the inhibition of renal inflammatory injury, and the curative effect of high dose group was more significant (P0.01). Compared with the model group, low dose of Chinese medicine group factor IKB, IKK and NF-KB/P65,1L-1 beta expression statistical difference (P0.05), low dose group for the inhibition of renal inflammatory injury had no obvious effect. The western medicine group compared with model group: a change in the above factor (P0.05), western medicine group reaction inhibition of renal inflammatory injury has certain curative effect. Compared with the Western medicine group, Chinese medicine high dose group factor IKB expression in NF-KB pathway the expression of NF-KB/P65, IKK and improved the expression of inflammatory factor 1L-1 beta is similar (P0.05), that is more effective than western medicine group in high dose group decreased renal inflammatory injury. Conclusion 1. Conclusion clinical Jisheng Shenqi Pill in the treatment of kidney qi deficiency of kidney 缁撶煶鎮ｈ，

本文编号：1367224