Expression Of Serum Hypoxia Inducible Pathway Related Indicators And Its Significance In Patients With Chronic Kidney Disease

Objective:A cross-sectional study was conducted to study the expression of proteins related to serum hypoxia-induced pathway and its correlation with clinical data in patients with chronic kidney disease(CKD)in the second Hospital of Jilin University,and to analyze its correlation with disease progression,renal anemia and low response to erythropoietin,so as to provide theoretical basis for clinical prediction and treatment.Method:This study recruited patients who were diagnosed as chronic kidney disease in the Department of Nephrology of the second Hospital of Jilin University from January2019 to January 2020 and who underwent long-term regular hemodialysis in the Blood purification Center of the second Hospital of Jilin University.According to whether they had received hemodialysis or not the whole subjects were divided into non-dialysis group and dialysis group.The patients in the dialysis group were divided into four groups according to the level of hemoglobin(Hb)and whether or not to use erythropoietin stimulant(ESA): EPO response group,EPO low response group,anemia untreated group and non-anemia group.The clinical records of all subjects were collected,and the expression levels of serum hypoxia inducible factor-1α(HIF-1α),serum hypoxia-inducible factor-2α(HIF-2α),serum prolyl hydroxylase 2(PHD2)and serum hepcidin in patients with CKD were measured by double antibody sandwich enzyme-linked immunosorbent assay(Elisa).Then analyze the relationship between the indexes of serum hypoxia-induced pathway and the progression,treatment and prognosis of chronic kidney disease.Results:一、 Overall population1.General informationA total of 160 patients were included,and divided into dialysis group(n=129)and non-dialysis group(n=31).There was no significant difference in sex,age,BMI and other indexes between these two groups(P > 0.05).2.Laboratory indexesIn blood routine,the red blood cell count and platelet count in the dialysis group were lower than those in the non-dialysis group;Among the biochemical indexes,the expression levels of serum phosphorus,potassium,blood urea nitrogen,serum creatinine and parathyroid hormone in the dialysis group were higher than those in the non-dialysis group;In iron metabolism,the expression levels of serum iron concentration and transferrin saturation in dialysis group were higher than those in non-dialysis group;Among the related indexes of serum hypoxia-induced pathway,the expression levels of serum HIF-1α and PHD2 in the dialysis group were higher than those in the non-dialysis group,While the expression of serum HIF-2α in the dialysis group were lower than those in the non-dialysis group.The above indexes were all statistically different(P<0.05).There was no statistical significance in other indexes(P > 0.05).3.Logistic regression analysisLow red blood cell count,low platelet count,high blood phosphorus,high potassium,high parathyroid hormone,high blood urea nitrogen,high serum creatinine,low serum iron concentration and high serum PHD2 concentration are closely related to the progression of the disease to HD stage(P<0.05).Among them,low platelet count and high serum PHD2 expression level are independent risk factors for CKD patients progressing to hemodialysis stage(P<0.05).4.ROC curve analysisUsing serum PHD2 683.82 pg/ml as the cut-off value,the sensitivity and specificity of judging whether or not to enter the dialysis stage was 59.7% and 87.1%,respectively.And the AUC was 0.755(95% CI:0.679-0.831,P<0.001).二、 MHD population1.General informationA total of 129 patients were included,including EPO response group(n=47),EPO low response group(n=52),anemia untreated group(n=7)and non-anemia group(n=23).There were significant differences in male proportion,BMI,pre-osmotic systolic blood pressure and ESA dosage among the four groups(P<0.05).There was no significant difference in age,dialysis age and pre-dialysis diastolic blood pressure(P > 0.05).2.Laboratory indexesThere were significant differences in Hb、red blood cell count and hematocrit of blood routine,serum creatinine and plasma albumin of biochemical indexes,serum ferritin of iron metabolism,serum HIF-1α levels,serum HIF-2α levels,serum Hepcidin and serum PHD2 of detected indexes(P<0.05).With the aggravation of anemia,the expression levels of serum HIF-1α,Hepcidin and PHD2 gradually increased,while the expression of serum HIF-2α decreased.There was no statistical significance in other indexes(P > 0.05).3.Correlation analysisThe level of serum Hepcidin in patients with MHD was positively correlated with serum HIF-1α levels,serum ferritin and age,but negatively correlated with Hb,red blood cell count,hematocrit and BMI,and the expression level of serum PHD2 was positively correlated with serum HIF-1α levels,BMI,ESA dosage and iron dosage.The expression level of serum HIF-1α goat was positively correlated with serum Hepcidin,serum PHD2,serum ferritin and ESA dosage,and negatively correlated with serum HIF-2α serum,plasma albumin,serum creatinine and BMI,while the expression level of serum HIF-2α goat was negatively correlated with serum HIF-1α hormone,ESA dosage and iron dosage.4.Logistic regression analysisIt showed that advanced age,low BMI,high pre-osmotic systolic blood pressure,low plasma albumin and high serum Hepcidin were the influencing factors of anemia in patients with MHD(P<0.05).Low BMI and high serum Hepcidin are independent risk factors for anemia in patients with MHD(P<0.05).5.ROC curve analysisUsing serum ferritin 198.50 ug/L as the cut-off value,the sensitivity was 83.3%,the specificity was 62.5%,and the AUC was 0.718(95% CI:0.593-0.843,P=0.002);Using serum Hepcidin 281.44 pg/ml as the cut-off value to judge low ESA response,the sensitivity was 75%,the specificity was 25%,and the specificity was 0.613(95%CI:0.513-0.714,P= 0.033).Taking the age of 57.5 years as the cut-off value,the sensitivity of judging EPO low response in MHD patients was 56%,the specificity was 68.1%,and the AUC was 0.611(95% CI:0.508-0.715,P=0.037).Conclusions:1.Serum HIF-1α levels and serum PHD2 expression levels are important biomarkers of disease progression to dialysis stage in patients with chronic renal disease.Serum PHD2 may be a predictor of disease progression to dialysis in patients with chronic kidney disease.2.Age,nutritional status,inflammatory state and serum Hepcidin expression level of maintenance hemodialysis patients may affect the occurrence and development of renal anemia,and may also be part of the reason for the low response to erythropoiesis stimulants.Serum ferritin and serum Hepcidin may be predictive indexes for detection of low response to erythropoietin.3.The expression level of serum HIF-2α hormone is closely related to renal anemia in patients with maintenance hemodialysis,which may be the key factor to improve renal anemia in patients with chronic renal disease.The research on the related drugs acting on the target gene of HIF-2α may bring a new treatment scheme for the treatment of inflammatory anemia and reduction of toxicity and side effects.