| Background:Chronic kidney disease(CKD)is a worldwide medical and public health issues, The data of U.S.Renal Data System(USRDS)prompted that the incidence of end-stage renal failure caused by the CKD rised year by year.Chronic kidney disease is a clinical syndrome which can be caused by various diseases,but in China mainly caused by chronic glomerulonephritis.In recent years,chronic kidney disease caused by diabetes,hypertension and other kidney disease also showed an upward trend,which is a new an important new epidemic threat to human health and longevity in today' s society which lead to cardiovascular disease that is a threat to human health and an important reason 1 to death. Therefore,actively exploring and studying the prevention and effective treatment of the disease has very important and practical significance.Chronic kidney disease belongs to the TCM medicine edema,back pain and other disease areas in the latter part of which can be evolve into Xulao,guange and other related diseases.According to the theory of knowledge of Chinese and Western Medicine with many years of clinical investigation and syndrome study Mentor Professor Yang Nizhi considers that the chronic kidney disease is a disease of deficiency in origin and excess in superficiality,in which qi deficiency and blood stasis is one of the critical machines.Professor Yang carried out a variety of clinical research related to chronic kidney disease with the treatment of supplementing Qi and activating blood circulation method and achieved good effect.On this basis,"Tongmai oral solution" had been developed which has the efficacy of supplementing Qi and activating blood circulation.Through more than 10 years of clinical research,"Tongmai oral solution" could interfere with the progress of chronic kidney disease and improve their prognosis through various mechanisms.To further adopt various science funding,and in the in vivo/in vitro studies,we found that Tongmai oral solution through a variety of mechanisms could inhibit mesangial cell proliferation which indicated that Tongmai oral solution can improve the prognosis of chronic kidney disease through control glomerulosclerosis.All along,for the primary diseases of CKD such as chronic glomerulonephritis, diabetes,kidney disease,and other diseases,the related research main focus on glomerular damage,glomerulosclerosis.The previous view considered that tubulointerstitial lesions(TIL)was not so important because it was only in the results of glomerular lesions.But in recent years,with the In-depth study of kidney pathological changes of human and animal model of kidney damage,the new view prompted that the development of chronic glomerular diseases and the prognosis was not only with the glomerular damage on its own, but also with the existence and extent Of the severity of the tubulointerstitial lesions.The latest point of view considered that tubulointerstitial damage is a most important factor which determined the the kidney survival rate in 10 years.The mechanism of TIL is very complicated,in the early stage the kidney mesenchymal became local inflammatory,subsequently cytokines secreted,Then the tubular epithelial cells and other forms transformed, the cell apoptosised or excessive proliferated,extracellular matrix (ECM)synthesis increased,and degradation reduced,resulted in excessive sedimentation of ECM,eventually led to renal fibrosis(RIF),the latter was the pathological features which performanced by almost all chronic kidney disease in the end stage.Therefore,early prevention TIL to stop the progress of RIF could improve the prognosis of CKD that was of great significance.Objective:Therefore,under the guidance of Professor Yang Nizhi,to further conduct the investigation of TCM Clinical Syndrome of IgA nephropathy-the most common chronic kidney disease in china,and investigate the TCM Syndrome characteristic of the tubulointerstitial lesions in order to illustrate the chinese medical pathogenesis of the tubulointerstitial lesions to guide clinical research and treatment,and to further conduct the the study of Tongmai oral solution intervention on experimental Qi blood stasis tubulointerstitial damage of animal,to discuss the possible treatment target and the mechanism of the Tongmai oral solution to chronic kidney disease for further development of chinese medicine to the prevention and treatment of chronic kidney disease.Method:The first part clinical researchThe patients confirmed IgA nephropathy by renal biopsy in Chinese medicine hospitals of Guangdong Province from 2002.9 to 2007.12 who had tubulointerstitial damage,urine protein <3.5 g/d,without hypertension,renal function was normal,ther toatle numbe of the patients were 87.Through investigations of Chinese medicine and pathology Syndrome,blood pressure,serum creatinine,a 24-hour urine protein quantitative information etc we explored the relationship of distribution of TCM syndrome with tubuloin- terstitial pathological changes.The second part experimental studyExperiment 1:Lotensin for the use of as control medicine,the election of SD 60,into the control group,model,Lotensin group,Tongmai Solution high,medium and low-dose group.The models were blood stasis Qi Syndrome combining tubulointerstitial fibrosis model caused by swimming fatigue +aging + unilateral ureteral ligation.The rats in the control group were treated with sham treatment.After the model successed drug was treated for four weeks. To Observe the general body weight;Chinese Qi Deficiency Syndrome,blood stasis score;serum BUN,Scr,t-PA,PAI,and other indicators;Obstruction side kidney HE,Masson stain,light microscope to stromal cells infiltration score(CIS)and chronic tubulointerstitial change(including tubular atrophy and fibrosis)score(AFS),and other indicators on the base of which Evaluate the effect of Tongmai oral solution.Experiment 2:On the basis of experiment one proving that high-dose oral solution Tongmai was effective,Applicating immunohistochemistry to detected HGF,TGF-β1, MMP-9,TIMP-1 and other targets by ELISA serum PAI,t-PA,and other indicators, and to explore its possible mechanism. Result:The first part clinical research1.Study found that Qi deficiency of Fei and Shen accounted for 39.1%,Qi deficiency of Fei and pi accounted for 35.6%,Qi and Yin deficiency accounted for 19.5%,Yin deficiency of Gan and Shen accounted for 5.7%,Yang deficiency of Pi and Shen accounted for about capital syndroms in selected patients. This shows that Qi deficiency accounted for 94.3%in capital syndromes. Among biao syndrom,blood stasis syndrome accounted for 55.2%,damp-heat syndrome accounted for 50.1%,damp-zhuo syndrome accounted for 17.2%.There is no significant difference about distribution of biao syndrom of no significant difference among every capital syndrom.2.There was no significant difference about urine protein,blood pressure, serum creatinine among TCM syndrome types.3.The sorting of tubulointerstitial damage average points of every TCM syndrome type:blood stasis> damp-heat> damp-zhuo> Yin deficiency of Gan and Shen> Qi deficiency of Fei and pi> Qi and Yin deficiency> Qi deficiency of Fei and Shen> Yang deficiency of Pi and Shen.The second part empirical studyExperiment 1:1.Post-treatment,compared with the control group,body weight decreased significantly in other groups(P＜0.001).Compared with the model group,high, medium-dose Tongmai Oral Solution treatment group rats can be signif- icantly improved in weight(P＜0.05).Before treatment,each made-modle group Qi deficiency and blood stasis syndrome' s score increased significantly compared with the control group(P＜0.001).Post-treatment,Qi deficiency and blood stasis syndrome' s score of high,medium,medium and low-dose Tongmai oral solution treatment group significantly decrease compared with the model group and lotensin treatment group(P＜0.01),there are no significant differentce between the model group and lotensin treatment group,no significant difference among high,medium,medium and low-dose Tongmai oral solution treatment group too.3.Post-treatment,compared with the control group,serum t-PA content decreease and serum PAl content increase with varying degrees in other groups. Compared with the model group,serum t-PA content increased and serum PAI content decrease slightly in treatment groups.But there was no significant difference.Post-treatment,compared with the control group,the BUN and Scr have tended to increase in model group and low-dose Tongmai oral soluteion treatment groups without statistical significance.4.We can see through the light microscope:the model group kidney HE and Masson staining:Most particles tubular-epithelial cells appear granularor vacuolar degeneration.Some tubular epithelial cells necrosis and desquamate,present bare basement membrane.nephric tubule lumen expand,there are some granular cast and cellular cast formed necrotic tissue and cell.Focal tubular atrophy can be seen.Renal interstitial are a widened significantly,inflammatory cell infiltrate,fibrous tissue hyperplasia,appear cable-like,patchy fibrosis. In addition to a part of glomerular renal capsule light-oderate expansion, there are noobvious lesions in glomerulus.All rongmai oral solution treatment group and Lotensin group have analogous changes,But there are different levels of improvement about pathological changes,compared with the model.5.Post-treatment,CIS increased significantly in other made-modle groups (P＜0.001),compared with the control group.Compared with the model group, CIS decrease with varying degrees in treatment groups,among the total, high dose of Chinese medicine and Lotensin treatment group decreased significantly(P＜0.05).Compared with the lotensin treatment group,Chinese high-dose group has no significant difference(P＞0.05).Compared with the control group,AFS is significantly in other made-modle groups (P＜0.001).Compared with the model group,AFS decrease markedly in treatment groups(P＜0.01).among the total,high dose of Chinese medicine treatment group decreased significantly.Compared with Lotensin and medium and low-dose Tongmai oral solution treatment group,there is significant difference too (P＜0.05).Experiment 2:1.No significant expression of TGF-β1 in nephridial tissue of control group. Post-treatment,the expression of TGF-β1 increased significantly in mademodle groups(P＜0.001),compared with the control group.Compared with the model group,the expression of TGF-β1 decrease with varying degrees in treatment groups,among the total,Lotensin treatment group decreased significantly(P＜0.01).High dose of Chinese medicine treatment group decreased obviously(p＜0.05),but worse than treatment group treatment group(p＜0.05); No significant expression of HGF in nephridial tissue of control group, Post-treatmen,the expression of HGF increased significantly in made-modle groups(P＜0.001);Compared with the model group,high-dose of chinese medicine treatment group decreased significantly(P＜0.05).Compared with the model group,the expression of HGF increased significantly in high-dose Tongmai oral solution treatment group(P＜0.05).2.Post-treatment,compared with the control group,the expression of MMP-9,TIMP-1 increased significantly in made-modle groups(P＜0.001),MMP-9/TIMP-1 decreased significantly.Compared with the model group,MMP-9 and MMP-9/TIMP-1 increase with varying degrees in treatment groups,TIMP-1 decrease signifycantly with varying degrees in treatment groups(P＜0.001),high-dose Tongmai oral solution treatment group is better than Benazepri treatment group (P＜0.001).3.Post-treatment,compared with the control group,the content of t-PA within obstruction-side kidney of made-modle groups decrease with varying degrees, among the total,the modle group decreased significantly(P＜0.05),the content of PAI within obstruction-side kidney of made-modle groups increase with varying degrees,among the total,the modle group decreased significantly (P＜0.05).Compared with the model group,the content of t-PA within obstructtion-side kidney of made-modle groups increase with varying degrees,but no significant difference(P＞0.05),the content of PAl within obstruction side kidney of made-modle groups decrease with varying degrees,but only high-dose Tongmai oral solution treatment group decrease significantly(P＜0.05).Conclusion:1.To IgA nephropathy(with TIL,24-hour urine protein <3.5 g/d,without hypertension,renal function was normal)patiens,Qi deficiency of Fei and Shen,Qi deficiency of Fei and pi,Qi and Yin deficiency are common to capital syndromes,Yin deficiency of Gan and Shen and Yang deficiency of Pi relatively rare.Blood stasis syndrome and damp-heat syndrome are common to Biao syndrome. Capital syndrome included Qi deficiency syndrome accounted for 94.3%,blood stasis syndrome,blood stasis syndrome accounted for 55.2%among biao syndrome. Qi deficiency syndrome and blood stasis syndrome are common syndromes to the disease.Therefore,it could be inferred that yiqihuoxue herbs have a wider applicability in such diseases。The existence of biao syndromes such as blood stasis,damp-heat and damp-zhuo prompt tubulointerstitial damage to some extent,especially the blood stasis syndrome.The patiens with Yin deficiency of Gan and Shen as capital syndrome cound have more serious tubulo interstitial damage than as capital syndrome.2.TO made-model group rats,weight and other general condition decreased significantly. Qi deficiency and blood stasis syndrome score increased significantly, the content of t-PA of Serum decreased in varying degrees,the content of t-PA of Serum decreased in varying degrees with typical tubulointerstitial damage pathological changes.YiqihuoxueL compound-Tongmai oral solution have a certain degree of improvement to above-mentioned appearances.This shows that the modle of ombination of disease and syndrome made by aging and swimming fatigue and UUO is relatively successful,It is expected for a similar study of reference.3.Research shows that:Tongmai oral solution can improve made-modle rats overall performance such as weight,other general condition,Qi deficiency and blood stasis syndrome.At the same time,it can significantly reduce the local micro-pathological changes of tubulointerstitial damage,Improvements about CIS score are similar to benazepril.On the other hand,improvements abo AFS score are better than the benazepril,the results are dose-dependent.4.The mechanism of Tongmai oral solution to TIL may be related to the following: increasing HGF expression,decreasing TGF-β1 expression;increasing MMP-9 expression,decreasing TIMP-1 expression,increasing MMP-9/ TIMP-1 ratio, Reducing the content of the PAI of kidney mechanisms and so on.
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