Clinical And Basic Studies On Risk Factors Of Chronic Kidney Disease

Part Ⅰ:Association of H.pylori infection with chronic kidney disease among Chinese adults.Background:Chronic kidney disease(CKD)is caused by various causes of kidney damage,including primary kidney disease such as chronic nephritic syndrome,primary nephritic syndrome,or secondary kidney disease such as diabetes,hypertension,autoimmune diseases,etc.At present,the incidence of CKD has been increasing year by year.It has become a public health problem of concern all over the world,and it seriously endangers global human health,and has epidemiological characteristics of high morbidity,high morbidity,high medical cost,and low awareness rate.Most patients with CKD have hidden disease,especially in China’s economically underdeveloped areas.Due to imperfect primary health and prevention and health care measures,CKD screening and early prevention and treatment are not done.When many patients with CKD have symptoms,the renal function often enters to the stage of end stage renal disease(ESRD),need hemodialysis,peritoneal dialysis or kidney transplantation.No matter what type of renal replacement therapy is adopted by patients with ESRD,the cost of treatment is very high,which greatly increases the country’s medical expenses and the burden of medical insurance.It is also a huge challenge for the development of medical services.In short,ESRD is for the entire society,families and individuals bring a heavy burden.The global prevalence rate of CKD is currently high.In the US Registry of Nephrology in 2014,the prevalence of CKD in the United States was 13.6%,of which nearly 637,000 people were dialysis patients,and annual medical expenditure was 87 billion US dollars(excluding pharmaceuticals cost).The 2017 USRDS shows that the prevalence of earlier stages of CKD is relatively stable at 14.8%,implies that an estimated 30 million American adults have CKD.In 2012,the prevalence of adult CKD in our country was 10.8%,of which the prevalence of renal impairment was 1.7%and the awareness rate of CKD was only 10.1%.The prevalence in other Asian countries or regions is also high,with 11.9%in Taiwan,12.9%in Japan,13.7%in Korea,and 13.9%in Mongolia.Helicobacter pylori(Hp)is a Gram-negative strain of Helicobacter that adheres to the gastric mucosa.It is reported that nearly 50%of people in the world are infected with Hp.In our country,Hp infection rate is high,there are reports up to 40%to 90%.Hp infection is associated with various diseases,such as various peptic ulcers,functional dyspepsia,chronic atrophic gastritis,and gastric cancer.It has also been reported that Hp infection can cause unexplained iron-deficiency anemia,colorectal cancer,and Alzheimer’s disease,and it is also a risk factor for hypertension and hypertensive heart disease.Meta-analysis of more than 4,000 patients by Wang ZW found that chronic Hp infection is closely related to the risk of ischemic stroke caused by atherosclerosis and arteriolar disease,but not to cardiogenic embolism and ischemic stroke.The meta-analysis showed that chronic Hp infection is significantly associated with increased risk of ischemic stroke,especially non-cardiogenic stroke.There are also reports that the eradication of Hp treatment can reduce the severity of autoimmune encephalomyelitis and multiple sclerosis.It can also improve the symptoms of dyspnea in COPD patients,prolong the interval of acute attacks,and increase exercise tolerance and quality of life.Ando T,et al found that the eradication treatment of Hp increased circulating adiponectin levels in Japanese and could be beneficial in preventing the metabolic syndrome.Hp infection has been shown to cause atherosclerosis and cardiovascular disease.In the African population,there is also evidence that Hp infection is associated with an increase in the number of cardiovascular disease and metabolic syndrome components and that Hp infection itself may occur in some people with low triglyceride levels.Atherosclerosis or metabolic syndrome,especially in Hp seropositive men.Gunji T examined the relationship between Hp infection and insulin resistance in a large Japanese population and found that Hp infection significantly and independently promoted insulin resistance in a large number of asymptomatic populations.In a large number of Japanese populations,Hp infection is significantly associated with metabolic syndrome,and Hp infection is considered a contributing factor.Metabolic syndrome includes a set of metabolic abnormalities leading to insulin resistance and atherosclerosis,the pathophysiology of which is currently considered mostly insulin resistance.Insulin resistance seems to be associated with increased oxidative stress in Hp infection and further study is needed To clarify the mechanism of this association.Clinical risk factors for chronic kidney disease include diabetes,hypertension,autoimmune diseases,systemic infections,urinary tract infections,urolithiasis,lower urinary tract obstruction,tumors,family history of chronic kidney disease,convalescence of acute renal failure,decreased kidney mass,Drug exposure,low birth weight,and socio-demographic factors include the elderly,ethnic minorities in the United States(African American,Native American,Hispanic,Asian American or Pacific Islander),chemical and environmental exposures,low income or education level.Among them,hypertension,diabetes and many more are associated with insulin resistance or metabolic syndrome.At present,there is no obvious evidence of the relationship between Hp infection and chronic kidney disease.Therefore,we designed this study to investigate the relationship between bacterial infection and chronic kidney disease。Objective:Hp infection is associated with metabolic syndrome and insulin resistance,and is also one of risk factors for hypertension and hypertensive heart disease.Hypertension,metabolic syndrome and atherosclerosis are related to the progress of chronic kidney disease and the risk factors for kidney disease,however,whether Hp infection is related to the development of CKD.Therefore,this study will explore the relationship between Hp infection and chronic kidney disease,found that new risk factors for the progression of chronic kidney disease,provide the basis for the prevention and control of chronic kidney disease.Methods:From January 2013 to May 2014,we selected 22044 adults from the Qianfoshan Hospital Health Examination Center in Shandong Province as the subjects of the study.These participants were from various places in Jinan and were subjected to health examinations.Venous blood is taken at least 10 hours after fasting.Blood glucose,hemoglobin,serum albumin,blood uric acid,total cholesterol,low density lipoprotein,high density lipoprotein and triglyceride were determined by automatic biochemical analyzer.Glomerular filtration rate(eGFR)was estimated using the CKD-EPI formula.Urine routine urine samples were collected routinely for routine urine tests.Proteinuria grade was negative,(+-),1+,2+,3+,or 4+in urinalysis.Proteinuria ≥1+was urinary protein positive.CKD was defined as the presence of kidney damage persisting for 3 months or more(eGFR<60 ml/min/1.73m2 or urinary protein positive).Diabetes is defined as an increase in fasting blood glucose≥ 7.0 mmol/L or HbA1c>6.5%or is undergoing hypoglycemic agents or previous diagnosis of diabetes.Clinical data such as age,gender,lifestyle,smoking,hypertension,diabetes,etc.were obtained through questionnaire surveys.BMI is calculated by measuring the patient’s height and weight squared.Determination of blood pressure is 3 times,then take the average.If the difference between the two blood pressure readings exceeds 10 mmHg,then the average of the two results with the blood pressure values close to each other is used.Hypertension was defined as systolic blood pressure>140 mmHg and/or diastolic blood pressure>90 mmHg,or both,or the patient was on antihypertensive medication.We measured Hp immunoglobulin G antibody titers by serum enzyme-linked immunosorbent assay(ELISA),with a positive value of>20 U/ml.ELISA tests were repeated within 1 week at 15-20 U/ml.If the titer is still within 15-20 U/ml,Hp infection is evaluated by 13 C-urea breath test or rapid urease test.When at least one of the surrogate tests was positive,we judged the patient to be Hp positive.Patients previously treated for Hp infection should not be enrolled.The research design was approved by the Ethics Committee of Qianfoshan Hospital of Shandong Province and informed consent was obtained from all participants.Results:Of the 22,044 participants we studied,the average age was 48.6 ± 14.3 years(range 18-92 years),of which approximately 71.1%were men.Among all participants in this study,the prevalence of Hp infection was 20.6%(4541/22,044).Subjects with Hp infection were more likely to have the following complications than Hp-infected subjects according to stratification of Hp infection:hypertension(35.3 vs.28.9%,P<0.001),diabetes(14.3 compared with 11.7%,P<0.001)and lower eGFR(100.0 ± 15.4 vs.103.6± 15.8 ml/min/1.73 m 2,P<0.001).Hp positive patients were older(51.9±14.0 vs.47.7±14.3 years,P<0.001)and had a higher proportion of men than those with negative Hp(74.8%vs 70.2%,P<0.001),The body mass index was higher(25.8 ± 3.5 vs.25.3 ± 3.6 kg/m 2,P<0.001),and serum uric acid was higher(345.3± 81.4 vs.341.2±84.4 μmol/L,P<0.001).There were no significant differences in the biochemical and clinical characteristics of smoking,habitual drinking,hemoglobin,serum albumin,total cholesterol,triglyceride,and low-density lipoprotein cholesterol between positive and negative Hp infection.The incidence of decreased eGFR in Hp infection was significantly higher than in the noninfected(1.6%vs 1.2%,P=0.04),but the prevalence of proteinuria and overall CKD were not significantly different between the two groups(1.7 vs.1.6%P=0.65,3.0 vs.2.7%,P=0.2).In a multivariate logistic regression analysis,after adjustment for age,gender,hypertension,diabetes,BMI,uric acid,smoking,alcohol consumption,total cholesterol,triglycerides,LDL cholesterol,and HDL cholesterol,there was no statistics for Hp infection rate and CKD.OR was 0.92(95%CI 0.75-1.12).Among 13,844 participants without hypertension and without diabetes,we further analyzed that after correction for age,sex,BMI,uric acid,smoking,alcohol consumption,total cholesterol,triglycerides,LDL cholesterol and HDL cholesterol,Hp There was no significant difference in the ratio of decreased eGFR and proteinuria between positive and negative patients.Conclusions:1.The study found that the prevalence of Hp infection was 20.6%,Hp infection in patients with higher incidence of hypertension,diabetes,and lower eGFR.2.Hp positive patients were older,had a higher proportion of men,had a higher body mass index,and had higher serum uric acid than Hp negative patients.3.There was no significant correlation between Hp infection and CKD after adjusting for age,gender,hypertension,diabetes,BMI,uric acid,smoking,drinking,total cholesterol,triglycerides,LDL cholesterol and HDL cholesterol。Part Ⅱ:Mechanism of MBTPS2 aggravating proteinuria in streptozotocin induced type Ⅰ DNBackground:Diabetic nephropathy is a common microvascular complication of diabetes and has gradually become the main cause of end-stage renal disease(ESRD)worldwide.Previous studies have shown that the high levels of blood sugar,proteinuria,glycosylation end products(which)and free fatty acid(FFA)which were happened in diabetic nephropathy can induce unfolded protein reaction(unfolded protein response,UPR)in the kidney cells,at the same time,accumulating evidences suggested that the endoplasmic reticulum stress(endoplasmic reticulum stress and the ER stress)plays an important role in the occurrence and development of diabetic nephropathy,therefore,it is of great significance to deeply explore the important factors affecting the occurrence and development of diabetic nephropathy and the role of endoplasmic reticulum stress in it for the research and develop a more optimal treatment strategy for DN.Research Method and Result:Firstly,the expression changes of MBTPS2 in THE STZ-induced DN mouse model were detected,and it was found that compared with the normal control group,the expression of MBTPS2 in the STZ-induced DN mouse model was significantly increased regardless of mRNA or protein levels.Further,the body expression experiments have shown that once MBTPS2 expression can raise STZ induced DN mouse model to the level of proteinuria,reply function experiments confirmed that inhibit MBTPS2 expression can reduce the levels of proteinuria STZ induced DN mice model,prompting MBTPS2 on the development of diabetic nephropathy and proteinuria in the level control is of important clinical significance.Further analysis the possible reasons for MBTPS2 participate in regulating the occurrence and development of DN,we found that overexpression of MBTPS2 expression can promote the endoplasmic reticulum stress response of STZ induced DN mice model,along with the glomerular filtration barrier damage and the increase of renal cell apoptosis,reply function experiments confirmed that inhibit MBTPS2 expression after STZ induced DN mice model of endoplasmic reticulum stress response is abate,at the same time the glomerular filtration barrier damage and renal cell apoptosis,effectively relieve MBTPS2 may by promoting the endoplasmic reticulum stress response mediated glomerular filtration barrier damage and the increase of renal cell apoptosis,And then participate in the regulation of the occurrence and development of diabetic nephropathy and proteinuria level.This indicates that MBTPS2 is dependent on promoting endoplasmic reticulum stress response to regulate the occurrence and development of DN disease.Conclusion:1.Patients with positive Hp infection have statistically significant differences in hypertension compared to patients without Hp infection.The patients in the Hp(+)group were older,had a higher proportion of men,had a higher body mass index(BMI),and had higher serum uric acid.2.In kidney pathology,IgA nephropathy and membranous nephropathy are more common.In pathological changes,the incidence of sclerosis,basement membrane thickening,and arteriolar intimal thickening was significantly higher in the Hp(+)group than in the Hp(-)group.