The Study On Prognosis Of Diabetic Nephropathy Underlying Renal Pathologic Lesions

Background:About 10%of medical and health expenditures in the world are used to support diabetes(DM).Diabetic nephropathy(DN),as a serious and dangerous microvascular complication of DM,has become the main cause of end stage renal disease(ESRD)in all over the world.In China,the number of patients with DN has increased rapidly and has become a common cause of hospitalization in the nephrology department.It is also the second cause of hemodialysis replacement therapy for ESRD.Angiotensin-converting enzyme inhibitor(ACEI)or angiotensin receptor blocker(ARB),as one of the current conservative treatment,can inhibit the excessive activation of the renin-angiotensin system(renin-angiotensin system,RAS)and delay the development of DN.Among them,angiotensin angiotensin ? type 1 receptor(AT1R),angiotensin II type 2 receptor(AT2R),Mas receptor(MasR)are the three most common receptors.In recent years,a MAS-related G-protein coupled receptor member D(MrgD)receptor,has gradually attracted attention in recent years.As a new member of the RAS,we know little about its expression in DN and its effect on prognosis.In addition,the sodium-glucose cotransporter 2(SGLT2)inhibitor is a new type of hypoglycemic drugs,and it is also a current research hotspot.By inhibiting the above-mentioned transporters,it can inhibit the reabsorption of most of glucose and sodium in urine.Thereby,the purpose of controlling hyperglycemia is accomplished.Will this process affect the intrarenal RAS system of DN patients?These are questions that need to be answered urgently in clinical practice.Objective:(1)To explore the relationship between glomerular basement membrane(GBM)thickness and diabetic nephropathy.(2)To explore the relationship between pathological changes,angiotensin receptor expression and prognosis of stage 4 CKD of DN.(3)To explore the effects of SGLT2 inhibitors on the expression of AT1R,AT2R,MasR and MrgD receptors in the renal.Preliminary exploration of the effects of SGLT2 inhibitors on renal fibrosis.Methods:The subjects of the study were patients who were treated at China-Japan Friendship hospital from January 1,2017 to December 30,2020 and undergo renal biopsy.They were divided into four groups based on clinical history and pathological diagnosis,and the thickness of the GBM of each group was measured by transmission electron microscope.At the same time,the relationship between GBM thickness and renal pathology and prognosis of 61 patients with pure DN was analyzed.(2)From January 1,2006 to May 30,2020.46 patients who were pathologically diagnosed as simple DN by renal biopsy at China-Japan Friendship hospital and 15 mL/(min·1.73m2)<eGFR<30 mL/(min·1.73m2).We collected clinical and pathological data,medication treatment,etc.,and detect the expression of AT1R,AT2R,MasR and MrgD through immunohistochemical methods,and then compare the difference expression levels between two groups.(3)Use spontaneous diabetic model db/db mice to determine the age of establishment of the DN model,and divide the db/db mice into model control group(n=15)and dapagliflozin group(n=15).There are three groups including the m/m mice(n=15)group.At the age of 12 weeks,16 weeks,and 20 weeks of age,5 animals were sacrificed,blood and urine samples were collected for test.and immunohistochemical methods were used to detect renal RAS system receptors:AT1R,AT2R,MasR and MrgD.The expression of each receptor,and the expression of fibronectin,laminin,Collagen ? and ?-SMA were detected at the same time.Results:(1)Among the 122 patients,23 were in the control group,18 in the hypertension group,20 in the diabetes group,and 61 in the DN group.The average thickness of GBM at baseline was 367.9±46.2nm,458.1 ±82.1 nm,427.7±50.2nm,684.5± 158.1 nm.There were 8 cases in the hypertension group and 7 cases in the diabetes group that the thickness of GBM exceeded the normal range.Among 61 patients with simple DN,the GBM thickness of glomerular pathological type ?+? group was higher than that of type ?+?a group,and there was a significant statistical difference.The overall median follow-up period was 16.7 months(5-43 months).There were no correlation between clinical parameters such as urine protein quantification,diabetes duration and GBM thickness.(2)There were 17 cases in the stable group and 29 cases in the progress group.The median survival time of the ARB group was 25.3 months,and the ARB group was 12.7 months.The overall renal median survival time was 17.3 months,and 29 cases happened the primary endpoint events.The expression levels of AT1 R,AT2R,MasR and MrgD receptors in glomeruli,renal tubules and renal blood vessels of diabetic nephropathy patients during stage 4 CKD were not significantly different between the stable group and the progressive group.(3)At 12 weeks of age,the model group showed hyperglycemia,increased urinary microalbumin,and GBM thickening,which confirmed the appearance of diabetic kidney injury.After SGLT2 inhibitor intervention for 12 weeks(20 weeks of age),it can not only lower blood sugar,lower blood pressure and urinary microalbumin,but also reduce the expression of AT1R in kidney tissues,stimulate the increase of MasR expression,and attenuate glomerular laminin and Collagen? cells Decrease in the expression of the outer matrix.Conclusions:(1)Thickening of glomerular basement membrane under transmission electron microscope is not a specific pathological manifestation of early stage in DN.Hypertension and diabetes can also cause thickening of the glomerular basement membrane.The thickness of glomerular basement membrane in patients with DN nephropathy is closely related to the severity of renal pathological changes.(2)Among patients with CKD stage 4 of diabetic nephropathy,63.0%of the population developed ESRD or died within 17.3 months of median survival time.DN.There is no significant difference in ESRD time among patients with different pathological types of renal biopsy.Adding ARB drugs and CPM-Rheum,or a reasonable HbA1c concentration and targeting BP could barely delay the progression of advanced DN to ESRD.It is no close relationship between pathological classification of renal biopsy and therapeutic effect.The focus of treatment is to reduce the incidence of cardiovascular complications and reduce mortality.(3)Early pathological changes of diabetic nephropathy appear in db/db mice at 12 weeks of age.After 12 weeks of treatment of db/db mice with SGLT2 inhibitors,it can effectively lower blood sugar,lower systolic blood pressure,lower urine microalbumin,and reduce the production of extracellular matrix such as laminin and collagen ? in glomeruli.This effectively delays the progression of mesangial disease damage in the early stage of DN.It reduces the expression of AT1R in glomeruli,tubulointerstitial and arterioles,up-regulates the expression of MasR.