Development Of A Novel Model For Clinical Diagnosis And Evaluation Of ACEI/ARB Therapy In Diabetic Nephropathy

Background:Diabetic nephropathy(DN)is the leading cause of end-stage renal disease(ESRD)worldwide.It is the second cause of ESRD in China,but its number is still increasing,which will seriously affect the national health.Chronic kidney disease in patients with diabetes is not necessarily DN.How to make a rapid and accurate diagnosis is of fundamental importance in the treatment of DN.Renin-angiotensin-aldosterone system(RAAS)inhibitors(ACEI/ARB)are by far the most widely used drugs for patients with DN.However,whether the use of ACEI or ARB has different beneficial effects on mortality and renal outcomes in patients with DN is still uncertain.In addition,the use of sodium-glucose cotransporter-2(SGLT2)inhibitor in the treatment of diabetes is a current hot topic of discussion.Whether inhibition of SGLT2 will induce an effect on the intrarenal RAAS or not is an urgent question to be answered in clinical practice.The aims of our study were:(1)to evaluate the role of microscopic hematuria and diabetic retinopathy(DR)for differential diagnosis of DN and to establish a probabilistic diagnostic model;(2)to compare the relative effects of ACEI and ARB on renal outcomes and mortality in DN;and(3)to investigate the effect of SGLT2 inhibition on the expression of angiotensin ?type 1 receptor(AT1R)and aldosterone receptor in an animal model of DN.Methods:(1)PubMed,EMBASE and Cochrane library were systematically searched for diagnostic trials,which evaluated the role of microscopic hematuria and DR in the differential diagnosis of DN and non-diabetic renal disease(NDRD).The pathological examination of renal tissues was used as the reference standard.(2)The subjects were patients with type 2 diabetes(T2D)who underwent renal biopsy at China-Japan Friendship Hospital between January 2014 and June 201 9.Both clinical and laboratory data of patients were collected.The data were randomly split into two datasets.One was used to develop the model,and the other was used for its external validation.(3)A systematic research of PubMed,EMBASE,and the Cochrane Library was conducted for randomized controlled trials(RCTs)with at least one year of follow-up.They were the trials in which ACEI or ARB was compared with each other,or with placebo,no treatment,or other antihypertensive drugs.Trials should report renal outcomes,and/or cardiovascular death,and/or all-cause deaths.(4)We evaluated the effect of dapagliflozin,an SGLT2 inhibitor,in the period of glomerular hyperfiltration,using an animal model of T2D,db/db mice,and their littermate m/m mice(normal control group,n=15).The mice in the model group were randomly divided into two groups:model control group(n=15)and dapagliflozin group(n=15).Dapagliflozin was added to the drinking water at a concentration of lmg/kg/d for eight weeks.At the end of the study period,all mice were killed and the kidney tissue was removed and weighed.Immunohistochemical analysis was used to evaluate the expression of AT1 R and aldosterone receptor in formalin-fixed and paraffin-embedded renal tissues.Results:(1)Thirty-eight studies(4,353 patients with T2D)investigated the role of hematuria and glomerular hematuria for diagnosis of NDRD.For hematuria,the pooled sensitivity and specificity was 0.42 and 0.72,respectively.The area under the summary receiver operating characteristic curve(AUC)was 0.59.For glomerular hematuria,the sensitivity was 0.27 while the specificity was 0.94.The AUC was 0.79.(2)Forty-five studies(4,561 patients with T2D)investigated the role of DR and proliferative DR(PDR)for diagnosis of DN.For DR,the sensitivity was 0.67,and the specificity was 0.78.The specificity of DR for the detection of DN was 0.99,but the sensitivity was 0.34,and the AUC was 0.58.(3)A total of 302 patients pathologically diagnosed with DN and NDRD were finally included.A model that incorporated gender,diabetes duration,DR,hematuria,hemoglobin A1c,anemia,blood pressure,urinary protein excretion,and estimated glomerular filtration rate was represented as the nomogram.The C-index value was 0.91 for internal validation and 0.88 for external validation.(4)61 trials(16,929 patients),with a total of 4 different treatments,were pooled using a Bayesian network meta-analysis.Compared with ARB,ACEI was associated with consistently higher probabilities of reducing the risk of kidney failure events,cardiovascular mortality and all-cause mortality.(5)The drug was given to db/db mice at the age of 16 weeks.Treatment with dapagliflozin for 8 weeks revealed that the beneficial effects were not only confined to its glucose-lowering actions,but its ability to downregulate the expression of AT1 and aldosterone receptors in renal tissue,especially in the tubular region.Conclusion:Either hematuria or DR is helpful in predicting DN in T2D,and the severity of DR may not parallel the presence of DN.The novel model helps to determine the probability of DN in T2D.ACEI may be possibly superior to ARB for kidney failure,cardiovascular death and all-cause mortality in DN.Long-term use of SGLT2 inhibitor can inhibit the activation of intrarenal RAAS,and therefore further delay the progression of DN.