To Explore The Clinical Efficacy Of Treating Diabetic Nephropathy By Heat Stage Based On The Theory Of "latent Heat Causing Disease

With the continuous increase in the number of diabetes,diabetic kidney disease has gradually become the first cause of chronic kidney disease.It is not only an important cause of end-stage renal disease,but also significantly increases the incidence and mortality of cardiovascular and cerebrovascular disease,leaving a heavy burden on society and individuals.However,there still less effective treatments to DKD.In view of the complex etiology and occult onset of the disease,and stubborn and poor efficacy of conventional treatment,we believe that inbubated pathogenic factor plays an important role in the development of the disease.Professor Yaoxian Wang put forward the view of "incubated heat generate zhenjia" based on the theory of "er yang jie" in Yellow Emperor combined with his clinical experience.It is considered that incubated heat is the fundamental cause of DKD,and"incubated heat generate zhenjia" is the core pathogenesis of the development of DKD,and in different stages of DKD,the characteristics and performance of heat are different,and the treatment in different stages should also be different.From the two aspects of "rationalism" and "law",this study intend to analyze the theoretical connotation of "incubated heat generate zhenjia" through clinical observational research,and to explore the effectiveness and safety of treating DKD from heat through randomized controlled trials.Objective:1.From the two aspects of macroscopic clinical manifestation and microscopic material basis,the law of incubated heat in the development process of DKD was analyzed,and the theoretical connotation of "incubated heat generate zhenjia "was explored.2.To evaluate the clinical efficacy and safety of treating DKD from heat.Methods:1.Based on the cross-sectional clinical data of 414 patients with DKD,the source incubated heat,the distribution of heat syndrome,its clinical symptoms,and the relationship between heat and the general condition of patients,and other complications of diabetes were described and analyzed.Then the HOMA2-IR,serum TNF-α,sTNFR1,sTNFR2,IL-6,and IL-8 levels in certain patients were measured and calculated,and the correlation between heat syndromes and clinical indicators,and these micro-inflammation markers were also analyzed.2.The study is designed as a multicenter randomized controlled trial.Participants with DKD of each stage will be randomly allocated at a 1:1 ratio to either the control group,which will receive basic treatment only,or the experimental group,which will receive Xiaozhen therapy and basic treatment.The study duration will be 24 weeks.The primary outcome will be UAER for early-stage DKD,24-hour urinary protein for middle-stage DKD,and eGFR for advanced-stage DKD,Secondary efficacy indicators were renal function,TCM syndromes sore,and quality of life and micro-inflammation indicators.Safety indicators include the incidence of adverse reactions,blood routine,liver function,electrocardiogram.Data for all outcome indicators will be collected at baseline and week 4,12,and 24.Results:Part one:1.Multivariate logistic regression analysis showed that high stable food intake(≥500 g/d)in the stage of diabetes was an independent risk factor for the development of heat syndrome in DKD patients(P=0.033).2.89.61%of DKD patients have at least one kind of heat syndrome.The main type in the early stage was heat accumulation syndrome,accounting for 73.83%,and the main type in the advanced stage was dirt heat syndrome,accounting for 61.76%,which were all significantly different from the other two stages(P<0.05).The distribution of heat syndrome types in middle stage was relatively balanced.Heat syndrome was often accompanied by qi deficiency,yang deficiency and yin deficiency syndrome.3.Heat-related symptoms in the top 10 were dry mouth and throat,lips purpura,irritable irritability,skin itching,head stuck limbs,afraid of heat sweating,dry stool,sticky mouth,cardiothoracic Fanre,cardiothoracic full.4.BMI of patients with phlegm-heat syndrome was significantly higher than those of patients without heat(P=0.007).BMI of patients with heat twisting syndrome and phlegm heat syndrome were significantly higher than those with other heat syndromes(P<0.001).There was a significant positive correlation between phlegm-heat scores and BMI in patients with phlegm-heat syndrome(r=0.294).5.The prevalence of coronary heart disease and cerebrovascular disease in patients with phlegm heat syndrome was not only significantly higher than that in patients without heat(P=0.015,P=0.045),but also higher than that in patients with other heat syndromes(P=0.002;P=0.004).The prevalence of peripheral neuropathy in patients with blood stasis heat syndrome was significantly higher than that in patients without heat or with other heat syndromes(P=0.002;P=0.005).The prevalence of diabetic retinopathy in patients with heat accumulation syndrome or blood stasis-heat syndrome were only significantly higher than that in patients without heat syndrome(P=0.043,P=0.025).6.Patients with heat accumulation syndrome had a significantly higher percentage having renal hyperfiltration than patients without heat syndrome or with other heat syndromes when eGFR≥90 ml/min/1.73m2(P=0.044);Regardless of renal function,eGFR levels in patients with dirt heat syndrome were significantly lower than those in patients with other heat syndromes(P<0.05).7.HOMA2-IR levels in patients with phlegm heat syndrome were significantly higher than those without heat syndrome or with other heat syndromes(P=0.047;P=0.004),but their heat scores had no significant correlation with HOMA2-IR levels(P>0.05).8.The levels of inflammatory factors in patients with heat syndrome were generally lower than those without heat syndrome.Besides patients with dirt heat syndrome,the levels of sTNFR1 in patients with heat syndrome were significantly lower than those in patients without heat syndrome(P<0.05).The levels of sTNFR2 in patients with dampness heat syndrome was significantly higher than that in patients with other heat syndromes(P=0.046),and there was a significant positive correlation between the dampness heat scores and serum sTNFR2 levels(P=0.034).Part two:1.In the early stage of DKD,UAER at week 4 was significantly lower than that at baseline in the experimental group(P=0.004),and the reduction of UAER from baseline in the experimental group.was significantly higher than that in the control group at week 4 and 24(P=0.005,P=0.044).According to general linear model analysis,the effect of experimental treatment on UAER of patients was not significant,but the change of systolic blood pressure had a certain influence on UAER(P=0.051).The eGFR at week 12 was significantly lower than that at the baseline in the experimental group(P=0.031),and the reduction of eGFR was significantly higher than that in the control group(P=0.011).The increase of PCS and MCS from baseline in the experimental group was significantly higher than that of the control group at week 24(P=0.016,P=0.013).There was no significant difference in the change of heat syndrome score and microinflammatory factors between the two groups.2.In the middle stage of DKD,the 24UTP at week 4 and 12 were significantly lower than those at baseline in the experimental group(P=0.001;P=0.039),and the reduction of 24UTP from the baseline were significantly higher than that in the control group at week 4,12 and 24(P=0.009;P=0.005;P=0.005).The general linear model analysis showed that the experimental treatment can significantly reduce 24UTP(P=0.043).The heat syndrome score at week 24 was significantly lower than that at baseline in the experimental group(P=0.017),and the reduction of the heat score was significantly higher than that in the control group(P=0.023).In the experimental group,PCS and MCS at week 24 were significantly higher than those at baseline(P=0.0046;P=0.0045),and the increase of PCS and MCS from baseline in the experimental group was significantly higher than that of the control group(P=0.009,P=0.006).Serum sTNFR1 at week 24 increased significantly compared with that at baseline in the control group(P=0.005),while there was no significant difference in the experimental group,and there was no significant difference in the change of renal function index and other microinflammatory factors between the two groups.3.In the advanced stage of DKD,there was no significant difference in eGFR between baseline and week 12 in the experimental group.The eGFR levels at week 12 and 24 were significantly lower than those at the baseline in the control group(P=0.041;P=0.031).According to the analysis of the general linear model,the impact of experimental treatment on eGFR was not significant,but the effect of time was significant(P=0.045).PCS at week 24 was significantly higher than that at baseline in the experimental group(P=0.016),and the increase of PCS at week 24 from baseline in the experimental group was significantly higher than that of the control group(P=0.019).Serum TNF-α level at week 24was significantly lower than that at the baseline in the experimental group,and serum IL-6 level of the experimental group at weeks 24 were significantly lower than that of the control group(P=0.048).there was no significant difference in the change of heat syndrome score between the two groups.4.Cardiovascular events were the most common adverse events during the follow-up of DKD patients.However,the occurrence of various events was not related to the use of experimental drugs.The occurrence rate of blood routines,liver function,and electrocardiogram abnormalities in the experimental and control groups showed no statistically significant difference.Conclusion:1.The source of incubated heat in DKD has a significant correlation with the high intake of staples during the diabetes stage,and it reflects the pathogenesis of incubated heat of latent onset.The clinical manifestations of heat are diverse.In different stages of DKD,there are certain patterns of syndrome manifestation,from the invisible heat,gradually combined with the visible pathogenic factors,which participating in the formation of dampness heat,phlegm heat and blood stasis heat,and then generate zhenjia.To some extent,different patterns of heat syndrome can reflect the severity of the disease.2.Heat accumulation can reflect renal hyperfiltration in the early stage of DKD,and dampness heat syndrome may reflect renal functional decline in DKD.Phlegm-heat syndrome has close relationship with insulin resistance,and serum sTNFR2 maybe one of the material basis of dampness heat syndrome,suggesting that incubated heat may be an important factor in the occurrence and progression of DKD,especially in the early stage.3.Compared with tourexiaozheng therapy,systolic blood pressure has a more important impact on UAER of DKD patients in the early stage,but tourexiaozheng therapy may improve renal hyperfiltration.By using basic treatment combined with qingrexiaozhen therapy,it can significantly reduce 24UTP of DKD patients in the middle stage,which may through inhibiting the effects of tumor necrosis factor related pathways.Basic treatment combined with xierexiaozhen therapy has the tendency to delay the progression of renal function in advanced DKD patients.Treatment of DKD from heat has good clinical safety.