Disscussion On "Turbid Poisonous Veins" In IgA Nephropathy Based On Vascular Injury Induced By Uremic Toxin

Background:IgA nephropathy(IgAN)is the most common primary glomerulonephritis(GN)and a leadi.ng cause of end-stage renal disease(ESRD)worldwide.Based on the "multi-hit" hypothesis and the gut-kidney axis theory,galactose deficient IgA l(Gd-IgAl)can be generated at mucosal surfaces and its elevated serum levels trigger B-cell activation and mucosal immune response in IgAN.Currently,the Oxford MEST-C score and two validated prediction models can be used for predicting the progression of IgAN,Besides,and maximal glomerular diameter(Max GD)was found to be a long-term prognostic factor for IgAN.Despite abounding studies for IgAN biomarkers,such as glomerular C4d deposition and uremic toxins,no biomarker is ready for clinical application.The onset and initial immune activity of IgAN are usually relatively insidious.Most patients have their course of disease beginning and lasting for several years before clinical manifestations.However,in the early stages of IgA nephropathy,severe vascular disease may appear pathologically.IgAN vascular endothelial injury were studied earlier in traditional Chinese medicine.The understanding of intestinal-derived uremic toxins was limited,but a consensus has been reached.It is believed that the toxins are related to the "turbid toxin" in traditional Chinese medicine.The turbid stubbornly cements it,and it accumulates toxins over time,damage the blood veins,and to the vein stagnation.Then the blood flow is not smooth,which affects the conveyance of qi,blood,and body fluid by the veins.According to this study,the mechanism of intestinal-derived uremic toxins on the vascular damage of IgA nephropathy is explored,and then the theory of"turbidity poisonous veins" provided by Chinese medicine.Purpose:First,we established the LC-MS/MS method for detecting the serum IS and pCS concentration of patients:1.To explore the correlation between serum endotoxin IS,pCS and IgAN glomerular pathology;2.To explore the correlation between serum enterotoxin IS,pCS and IgAN Oxford grade MEST-C;3.To explore the correlation between serum enterotoxin IS,pCS and TCM damp turbidity and blood stasis syndrome"turbid poisonous veins".Method:A cross-sectional study was conducted to collect blood from 65 IgAN patients and 10 healthy volunteers who met the inclusion criteria.Serum intestinal uremic toxin levels were detected by LC-MS/MS,and glomerular ischemic lesions were compared with serum.The correlation between enterotoxin IS and pCS;compare the correlation between Oxford pathological classification MEST-C score and serum enterotoxin IS,pCS;compare the correlation between mean arterial pressure and serum enterotoxin IS,pCS;compare traditional Chinese medicine blood stasis and turbidity The correlation between poison syndrome and serum enterotoxin IS,pCS;at the same time,based on the above correlation analysis results,further analysis of the differences between groups of each index.Results:1.General analysis.75 subjects were enrolled in the study,which includes 10 cases in healthy group and 65 cases in IgAN group.Based on the intrarenal vascular disease of IgAN patients,they are divided into three groups,which are 0,1 and 2 of intrarenal vascular disease score.The analysis shows that the more severe the renal vascular disease,the lower the glomerular filtration rate,the higher the serum IS concentration,the higher the proportion of glomerular ischemic sclerosis,the higher the score of blood stasis syndrome,the turbid toxin syndrome,and the turbidity stasis mutual resistance syndrome.2.Correlation analysis of intrarenal vascular disease and glomerular fracture sclerosis.Both of two clinical characteristics are not related to age;Cr,UA,serum IS(p<0.001),immunohistochemistry C1q,FRA,Cd4,blood stasis syndrome score,damp turbidity syndrome score,turbidity toxin syndrome score and turbidity stasis mutual resistance syndrome score and intrarenal vascular disease scores were positively correlated,eGFR,immunohistochemical IgA and renal vascular disease scores were negatively correlated;Oxford type T score(p<0.001)was negatively correlated with glomerular contractile sclerosis.3.The difference of eGFR among intrarenal vascular disease groups.The eGFR of the IgAN intrarenal vascular disease group was lower than that of the IgAN non-renal vascular disease group and the healthy group,and the difference was statistically significant.There was no statistically significant difference between the eGFR of the IgAN group without intrarenal vascular disease and the healthy group.With a further analysis among subgroups,the results shows that IgAN intrarenal vascular disease group 1 and group 2 have lower eGFR than the healthy group,and the difference is statistically significant.IgAN intrarenal vasculopathy group 1 and group 2 eGFR are both the eGFR difference between IgAN intrarenal vascular disease.4.The difference of traditional Chinese medical syndrome scores among renal vascular disease groups.The score of IgAN intrarenal vascular disease in 2 groups with blood stasis syndrome exceeded 1 group,and the difference was statistically significant.IgAN intrarenal vascular disease is classified as 1 and 0.The scores of blood stasis syndrome are not statistically significant.The scores of IgAN intrarenal vascular disease in group 2 were higher than group 1 and group 0,and the difference was statistically significant.The score of damp turbidity syndrome between group 1 and group 0 of IgAN intrarenal vascular disease was not statistically significant.The scores of IgAN intrarenal vascular disease in group 2 turbidity and blood stasis mutual obstruction syndrome were higher than group 1 and group 0,and the difference was statistically significant.The scores of the turbidity stasis mutual resistance syndrome between group 1 and group 0 of IgAN intrarenal vascular disease were not statistically significant.5.The correlation between Oxford classification and various clinical indicators.Serum IgM,serum C3,Cr,BUN,Oxford T score are positively correlated with Oxford M score,and immunohistochemical FRA is negatively correlated with Oxford M score;URBP(p<0.001),Cr(p<0.001),UA,glomerular ischemic sclerosis ratio(p<0.001),Oxford classification M,immunohistochemistry C1q,serum IS level(p<0.05),turbidity syndrome scores are positively correlated with Oxford T-score,eGFR(p<0.0001),immunohistochemical IgA are negatively correlated with Oxford T-score;It can be seen that in the included IgA nephropathy patients,eGFR,serum intestinal uremic toxin IS level,glomerular ischemic sclerosis ratio and Oxford pathological type T score(i.e.renal tubular atrophy/interstitial fiber Chemistry)are closely related.6.With mean arterial pressure as the dependent variable,only the TCM Qi and Yin Deficiency Syndrome score is positively correlated with it.Other indicators,such as intrarenal vascular disease,serum intestinal-derived uremic toxin levels,intrarenal vascular disease,Oxford pathological classification scores were not correlated with mean arterial pressure.In the patients enrolled in this study,hypertension is not a confounding factor of intrarenal vascular disease and glomerular ischemic sclerosis in IgA nephropathy.7.The correlation between serum endogenous uremic toxins and clinical indicators.Serum endogenous uremic toxin IS and pCS were positively correlated with Cr,and both were negatively correlated with eGFR(IS:p<0.0001,pCS:p<0.01)and HGB.It further confirmed that IS and pCS are closely related to renal function.In addition,serum Pcs,BUN,UA,K,intrarenal arteriole score,Oxford pathological type T score,blood stasis syndrome score,turbidity syndrome score,damp turbidity syndrome score,and turbidity stasis mutual resistance score are all related to the serum IS level Positive correlation;serum IS,P,immunohistochemical κ and serum Pcs are positive correlation.This further confirms that the serum endogenous uremic toxin IS is closely related to the score of renal vascular disease and the blood stasis syndrome and damp turbid syndrome in traditional Chinese medicine.8.Differences in serum IS and pCS between intrarenal vascular disease groups.The serum IS level of IgAN intrarenal vasculopathy group 2 was higher than that of IgAN intrarenal vascular disease group 1,group 0,and the healthy group,and the difference was statistically significant;the IS level of IgAN intrarenal vascular disease group 1 was higher than that of IgAN intrarenal vascular disease 0 group,the difference is statistically significant;IgAN intrarenal vascular disease 0 group serum IS levels and the healthy group are not statistically significant.The serum pCS level of IgAN intrarenal vascular disease group was higher than that of healthy group,but the difference of pCS level between each group was not statistically significant.Conclusions:With the progression of renal vascular disease in IgAN patients,the level of intestinal-derived uremic toxin IS increased significantly,and renal function decreased progressively.At the same time,the syndromes of blood stasis,turbid toxin,and the turbidity stasis mutual resistance syndrome are becoming more and more obvious.Endogenous uremic toxin IS is also closely related to renal tubular atrophy or interstitial fibrosis(T)in Oxford pathological classification.This study based on intestinal uremic toxins further confirmed the correlation between IgAN vascular disease and the traditional Chinese medicine "turbid poisonous veins",and provided a theoretical basis for the study of IgAN vascular disease and the pathogenesis of traditional Chinese medicine "turbid poisonous veins".