Receptor Expression,Gene Polymorphism In Renin-angiotensin System(RAS) And The Efficacy Evaluation Of RAS Inhibitor(ACEI/ARB) In IgA Nephropathy

BackgroundIgA nephropathy(IgAN)accounts for about 24.3%of primary glomerular diseases in China.IgAN is the most common primary glomerular disease in China and the main cause of the end-stage renal disease(ESRD).Numerous animal experiments and clinical studies have shown that the renin-angiotensin system(RAS)plays an important role in the occurrence and progression of IgAN,but evidence from the human renal biopsy is lack.Renin-angiotensin inhibitor(RASI)has long been the basic drug in the treatment of IgAN.RASI is often combined with immunosuppressive agents in IgAN patients with urinary protein>1g/d and without severe renal impairment.However,the efficacy and safety of combined immunosuppressive agents have been controversial in recent years.This study examined the expression of RAS receptors and gene polymorphisms in renal biopsy tissues of IgAN patients and analyzed their correlation with clinical and pathological injury in IgAN.A meta-analyzed was performed on the efficacy and side effects of RASI(ACEI/ARB)and immunosuppressive agents in the treatment of IgAN.The purpose of this study is to explore the correlation between RAS and IgAN and the appropriate treatment of IgAN.Methods1.506 cases of patients with IgAN who underwent renal biopsy in the nephrology department of China-Japanese Friendship Hospital were selected.Age,sex,body Mass index,admission blood pressure,mean arterial pressure,hemoglobin,urinary erythrocyte,24-hour urinary protein quantification,plasma albumin,serum creatinine,uric acid,cholesterol,triglyceride,serum IgA,C3 and so on were collected at the time of renal biopsy.The 2016 updated version of IgAN Oxford classification,MEST-C,was used to classify the pathological results of the renal biopsy of patients with IgAN.The expressions of angiotensin receptor type 1(AT1R),angiotensin receptor type 2(AT2R)and MAS receptor(MASR)protein in renal biopsy tissues of IgAN patients were detected by immunohistochemical method.The correlation between these three receptors expressions and the Oxford classification were analyzed.To study the effects of angiotensin-converting enzyme inhibitors(ACEI)and angiotensin receptor blockers(ARB)on proteinuria and the effects of ARB on AT1R and AT2R protein expression.2.From January 2018 to December 2018,111 patients with IgAN who underwent renal biopsy in the nephrology department of China-Japanese Friendship Hospital were selected.DNA was extracted from 5 pieces of 2 μ m paraffin sections of renal biopsy.Three gene loci,M235T,A1166C,and A1675G,were detected by generation one sequencing method.To analyze the differences in clinical indicators and pathological typing among patients with IgAN with different genotypes.3.Search MEDLINE,EMBASE and Cochrane Library databases to screen Randomized Control Trial(RCT)for comparing RASI(ACEI/ARB)with immunosuppressive therapy for IgAN.ESRD,estimated Glomerular Filtration Rate(eGFR),serum creatinine levels and urinary protein quantification were selected as observational indicators for meta-analysis.Results1.In 506 IgAN patients who underwent renal biopsy,the protein expression of AT1R,AT2R and MASR protein in Ml group(mesangial score>0.5)was significantly higher than that in MO group(mesangial score<0.5).The expression of ATI R protein in the S1 group(segmental glomerulosclerosis)was significantly higher than that in the SO group(non-segmental glomerulosclerosis);The expression of AT1R protein in the C2 group(crescent body>25%)was significantly higher than that in the CO group(crescent body=0)and C1 group(crescent body<25%).The level of urinary protein in patients treated with ARB for less than 6 months was significantly lower than that for more than 6 months,suggesting that ARB treatment of IgAN patients for the first six months has a significant effect on reducing urinary protein.2.Among 111 IgAN patients who were selected into gene polymorphism study,62 were males and 49 were females,40.0+14.4 years old.There were 4 MM,34 MT and 62 TT genotypes of M235T(Angiotensinogen gene).There were no significant differences in clinical and pathological types among the three groups of IgAN patients.The levels of diastolic blood pressure,24-hour urinary protein quantification,serum creatinine,uric acid and triglyceride of 89 patients with A1166C(AT1R gene)genotype AA,16 patients with A/C genotype and 0 patients with CC genotype AA IgAN were significantly higher than those of A/C genotype.The area of tubular atrophy/interstitial fibrosis and the proportion of crescent body were also significantly higher than those of A/C genotype.In addition,it was found that the AA type of IgAN patients had the highest uric acid and GG type of IgAN patients had the highest hemoglobin levels among A1675G(AT2R gene)patients.But the clinical significance and mechanism of the results still need further research.3.10 RCT studies(1027 patients)were enrolled.The combined immunosuppressive group could significantly reduce the urinary protein level(WMD-0.9,95%CI-1.88 to 0.08)and the risk of ESRD(RR 0.48,95%CI 0.28 to 0.83).There was no significant difference between RASI group and RASI group in improving eGFR(WMD 2.52,95%CI-0.51 to 5.55)and reducing serum creatinine level(WMD-0.08,95%CI-0.2 to 0.04)in IgAN patients.The risk of infection increased significantly in the combined immunosuppressive group.While hyperkalemia was more common in the RASI group(RR 0.19,95%CI 0.05-0.64).Conclusion1.Overexpression of AT1R protein in mesangial cells of IgAN patients may promote mesangial cell proliferation,segmental glomerulosclerosis,and crescent formation,thus accelerating renal injury.RASI treatment of IgAN patients within 6 months have significantly reduced proteinuria.2.The clinical and pathological impairment is severe in AA type of A1166C gene,while that of C allele is relatively mild in IgAN patients.However,due to the limited number of samples,the clinical significance of C allele remains to be further studied.Whether A1675G gene polymorphism is associated with uric acid and hemoglobin levels remains to be further researched.3.Compared with RASI,combined immunosuppressive therapy can significantly reduce proteinuria and reduce the risk of ESRD in IgAN patients.There was no significant difference between the RASI group and immunosuppressive agent group in improving eGFR and reducing serum creatinine level.It shows RASI can also protect the renal function of IgAN patients.But immunosuppressive therapy significantly increases the risk of infection.Therefore,immunosuppressive agents should be used cautiously in the treatment of IgAN.