Studies On The Biological Markers,genetic And Environmental Pathogenesis Of Membranous Nephropathy

Membranous nephropathy is immune diseases,which is non-inflammation induced and is characterized by the deposition of immune complex in glomerular basement membrane.About 75% of the patients are Idiopathic Membranous Nephropathy(IMN),the remaining are secondary to infection,cancer,autoimmune disease,drugs and other factors which is called the secondary MN.The incidence of MN in our country is on the rise,which accounts for 22.7% of primary glomerular diseases and was only 6.48% ten years ago.The reason for the sharp rise in incidence is unknown.MN is one of the most common pathological types of adult nephrotic syndrome.Foreign reports showed MN accounted for 30% to 40% of NS which was 40% in our hospital.1/3 ~ 1/2 patients came into end-stage renal disease(ESRD),so many nephrologists committed to IMN pathogenesis and translational medical research.In 2009,they confirmed M-type phospholipase A2 receptor(PLA2R)exists in podocytes of the IMN patients while there are PLA2 R antibody in their circulation.In 2014,Thrombospondin Type-1 Domain-Containing 7A(THSD7A),similar to PLA2 R in structure,was found.In half a century,many scholars in this field are constantly working to make the molecular pathogenesis of IMN improve.However,the genetic mechanism of familial MN(FMN)were merely reported.The first part of this study is to explore the application value of MN blood,kidney tissue and urine biomarkers in order to establish a new biomarker for MN,which can be applied to clinical application.The results showed that the serum anti-PLA2 R antibody was 100% in the diagnosis of MN,and the sensitivity was 42.59%-69.5% in MN patients.PLA2 R in lupus nephritis were negative,but in other secondary factors such as hepatitis B,tumors were lack of evidence.Serum anti PLA2 R antibody are specific indicators of disease progression or remission of MN,but the baseline antibody level can not be used as a reliable indicator to predict the prognosis of the disease,and the prognosis of PLA2 R related MN is not worse than that of non PLA2R-related MN.The incidence of THSD7A-related MN was 1.5%,and the incidence of non PLA-related MN was 11.11%.The clinical manifestations of THSD7A-related MN were similar to that of PLA2R-related MN.Urinary retinol binding protein(RBP)/ urinary creatinine can be used to predict the remission of proteinuria,and the increasing level of lysosome membrane protein 2(LIMP-2)was associated with MN.In the second part,with comparison to the literature reported FMN patients and our FMN patients,the proportion of men and women in the FMN group is lower than the foreign literature group,but there is no difference between the domestic reports FMN group.There was no significant difference between the two groups in the age of onset,clinical manifestation and prognosis.Comparing the clinical,pathological and prognostic characteristics of FMN patients with spontaneous MN(SMN),our data shows that FMN onset age is earlier than SMN,21.43%FMN patients came into the ESRD and the prognosis of renal function is far worse than SMN.We performed further exploratory research on the particularity genetic background of FMN.By all exon sequencing analysis of the probands of FMN and the healthy people,analyzing sequencing results,we selected possible pathogenic genes,verified in 100 healthy people and found 2 new genes mutation.The genetic background of FMN was analyzed from the perspective of PLA2R1 and THSD7 A gene polymorphism.The results showed that there were differences in PLA2R1 and THSD7 A gene polymorphisms between FMN patients and East Asian populations.The allleic frequencies for rs3828323 T allele,rs35771982 C allele,rs3749117 C allele in FMN was lower than in normal population,however,the T allele at rs33985939 was higher(P=0.005).Although the PLA2 R test was positive in FMN patients,the genetic background of the disease may be different from IMN.The frequency of THSD7 A allele at rs47 C allele was lower than that of healthy population(P=0.013),suggesting that the THSD7 A gene polymorphism was less affected in the pathogenesis of FMN.In the third part of the study,heavy metals such as lead,manganese,mercury,cadmium,chromium,nickel,arsenic,phenol,were tested in MN patients.Combined with heavy metal detection results,we explored the environmental factors affecting the incidence of MN.The results showed that the average value of mercury,lead,cadmium and other heavy metals in MN patients was much higher than the average value of non occupational exposure population at home and abroad(P<0.001).The mean value of blood Hg in MN patients is 2.96 times of the average population,and the average value of the urine Hg is 5.65 times of the average population.The mean value of blood lead was 4.12 times that of the population,and the average value of lead in urine was 25.56 times that of the population.The average value of blood cadmium is 8.78 times the average of the population,the average value of the urine cadmium is 10.32 times of the population average.Reference to the diagnostic criteria for heavy metals in occupational exposure groups,in MN patients,the excessive incidence rate is 21%,but the actual rate is far higher than 21%.Therefore,MN combined with excessive concentration of heavy metals should be paid high attention.Comparing the clinical characteristics,pathological and prognosis for non heavy metals exceeded MN patients,heavy metals exceeded MN patients have lower serum albumin and serum immune globulin IgG.In summary,PLA2 R can be used for the diagnosis of the severity of proteinuria in MN patients and THSD7 A has diagnostic value in the non PLA2R-related MN.In addition to the new mutation genes,lower vatiation rate of PLA2R1 gene polymorphism than normal people,suggested that there was special genetic background for FMN.Furthermore,heavy metals may be an important environmental factor in the pathogenesis process.