本文關(guān)鍵詞：濟(jì)生腎氣丸治療腎氣不足型腎結(jié)石的臨床療效與機(jī)制研究　出處：《廣州中醫(yī)藥大學(xué)》2017年博士論文　論文類型：學(xué)位論文

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【摘要】：背景腎結(jié)石是我國(guó)也是世界最常見的泌尿外科疾病之一,世界范圍內(nèi)的發(fā)病率為1%～20%。在我國(guó),一般人群中發(fā)病率達(dá)1%～10%,其中25%的患者需住院治療。改革開放后,隨著生活水平的提高,腎結(jié)石的發(fā)病率在我國(guó)大幅度增長(zhǎng),業(yè)已成為世界上三大結(jié)石高發(fā)地區(qū)之一[4],在我國(guó)南方諸省中,以腎結(jié)石為主的腎結(jié)石患者幾乎均占泌尿外科住院患者的首位。這種不良的增長(zhǎng)趨勢(shì)不得不引起我們泌尿外科醫(yī)生的重視。腎結(jié)石治療后存在結(jié)石殘留和遠(yuǎn)期高復(fù)發(fā)率(15至20年內(nèi)復(fù)發(fā)率60%-80%)的特點(diǎn),所以,"清除殘留結(jié)石和防石"對(duì)腎結(jié)石的防治、預(yù)后意義重大。筆者在臨床工作中發(fā)現(xiàn),因腎結(jié)石住院治療的老年患者(年紀(jì)≥55歲)大多數(shù)具備腎氣不足癥狀,辨證論治予以濟(jì)生腎氣丸治療后療效明顯改善,結(jié)石也有減少,該中藥得到了許多患者的認(rèn)可。欣喜之余,我們?cè)O(shè)想,濟(jì)生腎氣丸是否可以解決上述的難題(排石、防石)呢,我們查閱文獻(xiàn),未發(fā)現(xiàn)有過腎氣不足腎結(jié)石的相關(guān)"防、治"研究。由于中醫(yī)治療"淋證"先以清熱通淋排石等治標(biāo)為先,后以補(bǔ)腎固本善后。中醫(yī)理論認(rèn)為,排石乃屬"治標(biāo)",石凈后,當(dāng)圖根本,否則腎氣仍虛,機(jī)體仍然處于不平衡狀態(tài),日后復(fù)有重新結(jié)石之虞,此觀點(diǎn)在老年腎結(jié)石患者尤為適用�，F(xiàn)代醫(yī)學(xué)中腎結(jié)石術(shù)后結(jié)石復(fù)發(fā)率很高,術(shù)后結(jié)石雖除,但對(duì)腎氣是否充足應(yīng)進(jìn)一步辨治,如若忽略此項(xiàng),對(duì)于腎氣不足型腎結(jié)石的治療與預(yù)后是非常不利的。目的所以,本著"治病救人,發(fā)揚(yáng)中醫(yī)"的職責(zé),筆者認(rèn)為有必要通過臨床和實(shí)驗(yàn)研究?jī)煞矫骝?yàn)證濟(jì)生腎氣丸治療腎氣不足型腎結(jié)石的臨床療效(排石、防石、改善癥狀)、安全性、不良反應(yīng),及其作用機(jī)制。以期進(jìn)一步探索經(jīng)方防治腎結(jié)石的特色療效及安全性與可能的作用機(jī)制。方法1、臨床研究:通過2015年6月至2017年2月這段時(shí)間內(nèi),在廣中醫(yī)第一附屬醫(yī)院,因腎結(jié)石而在外科行PCNL術(shù)后的住院患者,年紀(jì)≥55歲,中醫(yī)辨證歸屬于"腎氣不足"型,符合診斷、納入標(biāo)準(zhǔn)的患者納入本研究,共65人(男39人,女26人,平均年齡60歲)。按隨機(jī)原則分為治療組(濟(jì)生腎氣丸組34例)及對(duì)照組(枸櫞酸鉀顆粒組31例)。治療組與對(duì)照組均從PCNL術(shù)后第7天開始服用指定藥物,療程7個(gè)月。兩組病人分別于用藥前及服藥后1個(gè)月、第4個(gè)月、第7個(gè)月(即取1/4左腎,運(yùn)用Western-blotting檢測(cè)技術(shù)測(cè)大鼠腎臟組織中IKB、IKK、NF-KB、P65的表達(dá)情況;運(yùn)用ELISA酶聯(lián)免疫檢測(cè)法測(cè)大鼠腎臟組織中1L-1 β的表達(dá)。結(jié)果1、臨床結(jié)果:治療前,兩組納入病例在性別、年齡、PCNL術(shù)后殘余結(jié)石數(shù)量、結(jié)石直徑、血清肌酐Cr、尿素氮BUN、肝功能ALT、AST、TBIL、腎氣不足中醫(yī)證候總分、腰腹疼痛、尿中帶血、小便不利、腰膝酸軟無力、倦怠乏力、畏寒肢冷、顏面或肢體水腫、痰飲咳喘等中西醫(yī)各項(xiàng)指標(biāo)基線相同(p0.05)。兩組在治療后第1個(gè)月、第4個(gè)月、第7月觀察時(shí),治療組除了在結(jié)石直徑上與對(duì)照組無統(tǒng)計(jì)差異(p0.05),其他指標(biāo)如:殘余結(jié)石數(shù)量、血清肌酐Cr、尿素氮BUN、腎氣不足中醫(yī)證候總分、腰腹疼痛、尿中帶血、小便不利、腰膝酸軟無力、倦怠乏力、畏寒肢冷、顏面或肢體水腫、痰飲咳喘等的療效均明顯優(yōu)于對(duì)照組,統(tǒng)計(jì)學(xué)有差異(p0.05);在治療過程中,治療組不良反應(yīng)明顯少于對(duì)照組(p0.05);7個(gè)月的藥費(fèi),治療組花費(fèi)不到西藥組費(fèi)用的3/10,可節(jié)約成本7/10以上(p0.05)。2、動(dòng)物實(shí)驗(yàn)結(jié)果:2.1從各組大鼠腎臟病理切片中,草酸鈣結(jié)晶沉積程度與腎組織病理改變情況的比較來討論:模型組與空白組比較,有明顯結(jié)晶沉積(P0.05),鏡下見:大量不規(guī)則形態(tài)的結(jié)晶,腎小管擴(kuò)張明顯,腎小球呈不規(guī)則形態(tài),周圍炎性細(xì)胞浸潤(rùn)明顯,皮質(zhì)腎髓質(zhì)排列紊亂。說明了該造模方法是成功的,且成石率較高。濟(jì)生腎氣丸3個(gè)劑量組結(jié)晶沉積度與病理情況與模型組、空白組、西藥組比較均有不同。中藥中等劑量組、高劑量組比模型組結(jié)晶減少(P0.05),且高劑量組統(tǒng)計(jì)有顯著性差異(P0.01),說明高、中劑量中藥均能抑制腎結(jié)石的形成,且高劑量療效顯著。低劑量組與模型組相比較(P0.05),抑制腎結(jié)石的形成無明顯療效。西藥組與模型組相比較(P0.05),能抑制腎結(jié)石的形成。中藥高劑量組與西藥組抑制腎結(jié)石形成的療效相似(P0.05)。2.2從各組大鼠血清S0D活力、MDA含量、腎組織S0D活力、MDA含量、血肌酐(Cr)、血尿素氮(BUN)、血清Ca2+離子的含量來比較討論:腎組織總SOD活力與血清SOD活力的變化趨勢(shì)與腎組織總MDA含量與血清MDA含量水平的變化趨勢(shì)是一致的。說明局部與整體的關(guān)系是一致的,共同提示清除氧自由基的能力,提示機(jī)體抗氧化能力與氧化損傷程度。模型組與空白組比較:腎組織SOD活力、血清SOD活力有降低(P0.05),腎組織MDA含量、血清MDA含量升高(P0.05),血Cr與血BUN均有升高趨勢(shì)(P0.05),說明模型組抗氧化損傷能力下降、腎組織細(xì)胞氧化損傷加重,腎功能受損嚴(yán)重。低劑量組與模型組比較:腎組織總S0D活力、血清S0D活力、腎MDA含量、血清MDA含量、血肌酐Cr與血尿素氮BUN、血鈣Ca2+均無明顯改善(P0.05),說明中藥低劑量組在提升大鼠腎臟組織細(xì)胞抗氧化損傷能力、保護(hù)腎功能、降低腎結(jié)石形成危險(xiǎn)因素中血鈣等方面,療效不明顯。中等劑量組與模型組比較:腎組織總SOD活力、血清SOD活力、腎MDA含量、血清MDA含量、血肌酐Cr與血尿素氮BUN、血鈣Ca2+有改善(P0.05),說明中等劑量組在提升大鼠腎組織細(xì)胞抗氧化損傷能力、保護(hù)腎功能方面有一定的療效,但在降低腎結(jié)石形成危險(xiǎn)因素中血Ca2+這一方面無明顯療效。高劑量組與模型組比較:腎組織總S0D活力、血清SOD活力、腎MDA含量、血清MDA含量、血肌酐Cr與血尿素氮BUN均有明顯改善趨勢(shì)(P0.01),說明高等劑量組在提升腎臟組織細(xì)胞抗氧化損傷能力、保護(hù)腎功能方面有顯著的療效;在降低血Ca2+這一方面療效不明顯。西藥組與模型組比較:腎組織總SOD活力、血清S0D活力、腎總MDA含量、血清MDA含量、血鈣Ca2+方面均有改善(0.05),說明西藥組在在提升腎組織細(xì)胞抗氧化損傷能力、降低血Ca2+方面有明顯的療效;但血Cr與血BUN均無明顯差異(P=0.0810.05),說明西藥組在保護(hù)腎功能方面的無明顯療效。中等劑量組與西藥組比較:在提高腎臟組織細(xì)胞抗氧化損傷能力方面無明顯差異(P0.05),在保護(hù)腎功能方面的療效優(yōu)于西藥組(P0.05);兩組在降低血鈣方面療效無統(tǒng)計(jì)差異(P0.05)。高劑量組與西藥組比較:在提高腎臟組織細(xì)胞抗氧化損傷能力方面有明顯的療效(P0.05),在保護(hù)腎功能方面的療效優(yōu)于西藥組(P0.01);兩組在降低血鈣方面療效無統(tǒng)計(jì)差異(P0.05)。2.3從各組大鼠腎組織中的IKB、IKK、NF-KB、P65的Western-blotting檢測(cè)表達(dá)情況,和腎臟組織中1L-1β的ELISA檢測(cè)的表達(dá)情況討論:模型組與空白組比較:NF-KB通路中的因子IKB表達(dá)有下調(diào),IKK和NF-KB/P65表達(dá)有上調(diào),炎性因子1L-1β的表達(dá)有上調(diào),統(tǒng)計(jì)均有意義(P0.05),說明造模方法是成功的,已經(jīng)造成了腎組織的炎性損傷,發(fā)生了炎癥反應(yīng)。與模型組比較,中藥中等劑量組、高劑量組均能使NF-KB通路中的因子IKB表達(dá)有上調(diào),IKK和NF-KB/P65表達(dá)有下調(diào),炎性因子1L-1β的表達(dá)有下調(diào),統(tǒng)計(jì)均有差異(P0.05),反應(yīng)中等劑量組對(duì)于抑制腎臟炎癥損傷有一定的療效,而高劑量組療效更顯著(P0.01)。與模型組比較,中藥低劑量組因子IKB、IKK和NF-KB/P65、1L-1β表達(dá)無統(tǒng)計(jì)學(xué)差異(P0.05),說明低劑量組對(duì)于抑制腎臟炎癥損傷無明顯療效。西藥組與模型組相比較:以上因子有改變(P0.05),反應(yīng)西藥組抑制腎臟炎癥損傷有一定療效。與西藥組相比較:中藥高劑量組NF-KB通路中的因子IKB表達(dá)、IKK和NF-KB/P65表達(dá)有所改善,炎性因子1L-1β的表達(dá)較為相近(P0.05),說明高劑量組抑制腎臟炎癥損傷的療效優(yōu)于西藥組。結(jié)論1、臨床結(jié)論濟(jì)生腎氣丸治療腎氣不足型腎結(jié)石患者,可明顯減少殘余結(jié)石數(shù)量,保護(hù)腎功能(Cr ↓、BUN↓),同時(shí)對(duì)腎氣不足中醫(yī)證候總分、腰腹疼痛、尿中帶血、小便不利、腰膝酸軟無力、倦怠乏力、畏寒肢冷、顏面或肢體水腫、痰飲咳喘等癥狀有明顯改善。在為期7個(gè)月的療程中,不良反應(yīng)發(fā)生率較低;未出現(xiàn)毒副作用。且經(jīng)濟(jì)費(fèi)用不到西藥組的3/10。2、實(shí)驗(yàn)結(jié)論濟(jì)生腎氣丸有抗氧化損傷(SOD ↑、MDA↓)、抗炎性反應(yīng)(IKB ↑、IKK↓、NF-KB ↓、P65 ↓、1L-1 β ↓)、保護(hù)腎功能(Cr ↓、BUN↓,腎病理切片結(jié)晶沉積↓、腎組織破壞↓)的作用,且有防石作用。濟(jì)生腎氣丸可能通過抗氧化損傷(0S)與抗炎癥反應(yīng)(NF-KB通路)來保護(hù)腎小管上皮細(xì)胞與腎功能的。所以,濟(jì)生腎氣丸治療腎氣不足型腎結(jié)石具有一定的可行性及優(yōu)越性,值得臨床進(jìn)一步研究與應(yīng)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 緇撶煶鎮(zhèn)ｈ，

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