| Objective:There is a close clinical relationship between urolithiasis and metabolic syndrome.The number of urolithiasis complicated with metabolic syndrome is increasing.However,there is no relevant research on the TCM syndrome and treatment of urolithiasis combined with metabolic syndrome.It is of great clinical value to explore the characteristics of TCM syndromes of urolithiasis combined with metabolic syndrome and to seek prevention and treatment methods.Current studies suggest that activation of RAAS induces ROS production through NADPH oxidase,promotes oxidative stress injury and inflammation,and participates in the formation of urolithiasis and metabolic syndrome,which may be the pathological mechanism of clinical correlation between of them.This study explored the TCM syndrome characteristics of urolithiasis combined with metabolic syndrome through clinical syndrome investigation,and then found out the potential classic formulas for urolithiasis combined with metabolic syndrome through literature research and data mining.Finally,a rat model of renal calcium oxalate stone was established to observe the effects of the formula on calcium oxalate stone,as well as the effects on oxidative stress,inflammation and RAAS,so as to provide evidence for clinical application.Methods:Part 1:Adopt the research method of clinical syndrome investigation,develop the syndrome questionnaire,and collect the TCM syndrome information of urolithiasis patients.The frequency statistics,factor analysis and cluster analysis of the four diagnostic information were used to explore the overall syndrome characteristics of urolithiasis complicated with metabolic syndrome.Through matching case-control study design,the related syndromes of urolithiasis with metabolic syndrome were analyzed.Part 2:Using the research methods of literature research and data mining,the clinical research literatures on the treatment of urolithiasis and metabolic syndrome with TCM formulas were collected from CNKI and Wanfang database,and compound ingredients and applicable syndrome types were extracted.Firstly,the application of classical formulas in treatment of urolithiasis and metabolic syndrome was analyzed statistically,and the classical compounds coused in urolithiasis and metabolic syndrome were screened out.Secondly,a statistical analysis was made about formulas used for dampness syndromes of urolithiasis and metabolic syndrome,and the prescription rules of both dampness syndromes were obtained through frequency statistics and cluster analysis.Finally,through comprehensive investigation and analysis,it is concluded that the classic formula has the potential to prevent and cure urolithiasis combined with metabolic syndrome.Part 3:Establishing a ethylene glycol(EG)-induced renal calcium oxalate stone model of rats.Five weeks of intervention with Wulingsan and thiazide diuretic hydrochlorothiazide as the control were used to record the changes of body weight and water intake,collect urine for 24 hours,and collect serum and kidney samples.The effects of Wulingsan on body weight,water intake and urine volume were observed.The effects on urinary calcium,serum ion and renal function of rats were observed by biochemical analysis.HE staining and Von kossa staining were used to observe the effects on renal tissue morphology and calcium oxalate crystal deposition.The levels of oxidative stress indexes such as superoxide anion,MDA,SOD,GPX,CAT and NO were detected by biochemical method.The expressions of inflammatory cytokines IL-1β and IL-18 in renal tissue and the contents of serum RAAS related indexes such as renin,Ang II and ALD were detected by Elisa.Results:Part 1:(1)Analysis of overall syndromes,168 patients with urolithiasis combined with metabolic syndrome were included.The most common tongue manifestation are white,thick,greasy,red,yellow and dark tongue.The most common pulse manifestation are smooth pulse,chord pulse,fine pulse,sinking pulse and so on.Common symptoms and signs are lumbago,abdominal pain,hyperhidrosis,loose stool,obesity,yellow urine,lumbago,abdominal distension,dry mouth,etc.Through factor analysis and cluster analysis,the main syndrome types were spleen-kidney Yang deficiency syndrome,damp-heat with stasis syndrome,spleen deficiency and damp-heat syndrome and kidney deficiency and damp-heat syndrome.(2)Syndrome related analysis:A total of 139 patients with urolithiasis combined with metabolic syndrome and 139 patients without combined metabolic syndrome were included according to age ±5 years and gender 1:1 matching.The proportion of syndrme factors dampness,heat,spleen deficiency and phlegm in urolithiasis patients was higher than those in patients with nonmetabolic syndrome.Multivariate regression analysis showed that dampness(OR=5.031,P<0.05)and spleen deficiency(OR=4.56,P<0.05)were independently correlated with urolithiasis and metabolic syndrome.Part 2:(1)30 classic formulas of urolithiasis were obtained,Shiweisan,Bazhengsan,Wulingsan,Zhulingtang were widely used;31 classic compounds of metabolic syndrome were obtained,most of which were dampness-removing agents and expectorant agents.Huanglianwendantang,Lingguizhugantang and Wulingsan were widely used.(2)Six classical formulas both used in urolithiosis and metabolic syndrome were Wulingsan,Lingguizhugantang,Xuefuzhuyutang,Shenqiwan,Liuweidihuangwan and zhulingtang.(3)Four cluster prescriptions were obtained by clustering analysis of high-frequency herbs of dampness syndrome of urolithiasis.The first category was mainly diuretic herbs.The second type is mainly for diuretic,activating blood and qi and tonifying kidney qi.The third compound is mainly for transforming qi and draining water,which belongs to Wulingsan.The fourth type is mainly for tonifying kidney and activating blood.Four cluster compounds were obtained from high frequency drugs for dampness syndrome of metabolic syndrome.The first type was mainly to remove phlegm and dampness,regulate qi and remove blood stasis,which belonged to Erchentang formula.The second type,mainly clearing heat and removing dampness,belongs to Gegenqinliantang.The third type is mainly transforming qi and draining dampness,which belongs to Wulingsan.The fourth type is mainly for the benefit qi and clear dampness.(4)By comprehensive analysis,Wulingsan is a potential classic formula suitable for urolithiasis combined with metabolic syndrome wet syndrome.Part 3:(1)EG intervention resulted in significant weight reduction in rats.Wulingsan administration had no significant effect on weight loss caused by EG(P>0.05).Hydrochlorothiazide increased weight loss(P<0.05).(2)EG intervention significantly increased the water intake and urine volume of rats.Compared with model group,water intake of Wulingsan group had no significant difference(P>0.05);The urine volume of the high-dose group increased at 4 h after administration(P<0.05),but there was no significant difference in total urine volume at 2 h,8 h and 24 h(P>0.05).The water intake of hydrochlorothiazide group was significantly increased,and the urine volume was significantly increased at 4h and 8h after administration(P<0.05),while the total urine volume at 24 h had no statistical difference(P<0.05).(3)Compared with model group,the kidney index and calcium oxalate crystals in Wulingsan group were significantly decreased;There was no significant difference in hydrochlorothiazide group.(4)Compared with model group,serum BUN,SCr,serum Na,serum K,serum Ca and urine Ca in Wulingsan group were significantly decreased(P<0.05),and serum K and urine Ca in hydrochlorothiazide group were significantly decreased(P<0.05).(5)Compared with model group,superoxide anion,MDA,CAT,NO and IL-1 β in kidney tissue of Wulingsan group were significantly decreased(P<0.05),while SOD,GPX and IL-18 were not significantly different(P>0.05).There were no significant differences in renal oxidative stress and inflammation in hydrochlorothiazide group.(6)Compared with model group,serum REN and Ang Ⅱ in Wulingsan group were significantly decreased(P<0.05),while REN in hydrochlorothiazide group was significantly increased(P<0.05),and ALD had no statistical difference in all groups(P>0.05).Conclusion:(1)The main syndrome types of urolithiasis combined with metabolic syndrome can be divided into spleen-kidney Yang deficiency,damp-heat and stasis,spleen deficiency and damp-heat and kidney deficiency damp-heat syndrome based on a preliminary small sample exploratory study.(2)Compared with urolithiasis without metabolic syndrome,the proportion of syndrome factors dampness,heat,phlegm and spleen deficiency in urolithiasis combined with metabolic syndrome are higher.Dampness and spleen deficiency are independent syndromes related to urolithiasis combined with metabolic syndrome,and urolithiasis patients with dampness and spleen deficiency are at increased risk of combined metabolic syndrome.(3)Wulingsan is a classic formula with potential prevention and treatment for urolithiasis combined with metabolic syndrome of dampness syndrome.(4)Wulingsan can reduce calcium oxalate crystal deposition in renal calcium and improve renal function,which may be related to inhibiting RAAS activation,reducing oxidative stress damage and inflammatory response.(5)Although the diuretic hydrochlorothiazide had more obvious diuretic effect and reduced urinary Ca excretion,it did not show the prevention and treatment effect on calcium oxalate stones,which may be related to its effect on RAAS. |
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