The Study Of Cystatin C In Predicting Diabetic Retinopathy In Patients With Type 2 Diabetes Mellitus

BackgroundDiabetic retinopathy (DR) is the main micro vascular complication of diatetes and the leading cause of visual loss or blindness. Primary prevention and secondary prevention are the crucial measures to improve the prevention and control level of DR. Currently, three aspects of difficulties contribute to the poor control level of DR. First, the epidemiological data about DR is absent in many local regions, For example, there is no epidemiological data about DR at present in our region (Dezhou), and this is very adverse to formulate the targeted control strategy of DR; Second, traditional risk factors, such as the duration of diabetes, poor glucose control, hypertension and lipids disorder, could not fully interpret the risk that a diabetic patient has DR, and other important risk factors are not determined. This is adverse to primary prevention of DR; Third, many realistic reasons, such as the huge number of DM, disproportion of medical resources, low cognition of DR, low financial investment of DR and so on, resulted in a great gap between screening of DR and China guideline for type 2 diabetes. Three problems need to be solved:First, to establish the epidemiological data of DR; Second, to explore the risk factors that independent of traditional risk factors of DR; Third, to confirm the valuable predictive factors or effective discrimination model of DR. Cystatin C (CysC) is a 13-kDa, non-glycosylated basic protein belonging to the cystatin super-family of cysteine proteinase inhibitors. Recently, several studies implied that CysC was the independent risk factor and a worthwhile predictive marker of DR. However, the existed epidemiological evidences could not fully interpret the association between CysC and DR. On the base of theoretical studies and exsited epidemiological investigations, the study hopes to disclose those problems in patients with type 2 diabetes as follows:(1) to investigate the prevalence and cognition level of DR in inpatients with type 2 diabetes; (2) to further confirm whether CysC is an independent risk factor of DR and explore the possible physiopathologic mechanism; (3) to evaluate the value of CysC in predicting DR and establish a effective model in predicting DR. Those expected outcomes could provide the basal epidemiological data of DR, and the establishment of new risk factor and predictive model should provide basis of primary prevention and secondary prevention for DR.Part one:The investigation of prevalence and cognition level of DR in inpatients with type 2 diabetes mellitusObjective:The basal epidemiological data of DR is lacking in our region, and this is disadvantageous to the prevention of DR. The study aims to investigate the prevalence and cognition level of DR in inpatients with type 2 diabetes. The expected results should provide a helpful basis for primary and secondary prevention of DR.Methods:A cross-sectional hospital-based survey that including 450 type 2 diabetes mellitus was analysed in the study. Those patients came form endocrinology department of dezhou people’s hospital since January 2012 to December 2013. The cognition level of DR and other related information were acquired by means of a special epidemiological questionnaire that designed for the study. DR was assessed by fundus fluorescein angiography (FFA) and certificated into NDR, mild NPDR, moderate NPDR, severe NPDR and PDR. The comparison of discrete variables was performed by the Chi-square test (2x2 tables).Results:Of the 450 patients,60 (13.33%) had mild NPDR,51 (11.33%) had moderate NPDR,39 (8.67%) had severe NPDR, and 21 (4.67%) had PDR. The prevalence of DR was 38.00%.6 (9.52%) patients had DR in 63 patients who were new diagnosed.47(12.14%) patients had ever been conducted eye examination among non-newly-diagnosed diabetic patients. Of the 387 inpatients with history of DM, 156(40.31%) patients knew that DM could result in visual loss,98(25.32%) patients knew that DM could result in DR,63(16.28) patients knew that diabetic patient should regularly examine eye, and 36(9.30%) patients knew that panretinal photocoagulation is the effective treatment of DR. Compared with patients came from city, the recognition levels of DR is significantly lower (P<0.05) in rural patients.295 (76.23%) patients didn’t acquire effective information that DR is a serious complication of DM from their doctors among 387 patients with history of DM.Conclusion:The prevalence of DR in inpatients with type 2 diabetes is higher in our region, and there is also a relatively higher prevalence of DR in new diagnosed diabetic patients. Among inpatients with history of DM, the percentage of patients who had ever been conducted screening of DR is very low. The cognition level of DR in inpatients is very low, especially in rural inpatients. Doctors should be responsible for the lower cognition of DR.Part two:Cystatin C is the independent risk factor and predictive factor of diabetic retinopathy in patients with type 2 diabetesObjective:The prevalence of DR (38.00%) in our region is higher in part one, and severe DR accounted for about 1/3 in all DR. In the control of DR, primary prevention and secondary prevention are the basal means, and the confirmation of risk factors or predictive factors of DR is crucial for primary and secondary prevention. Many studies disclosed that traditional risk factors, such as the duration of diabetes, poor glucose control, hypertension and lipids disorder, couldn’t fully interpret the risk that a diabetic patient has DR. On the base of current theoretical researches and epidemiological data, the study aims to further confirm whether CysC is an independent risk factor of DR and explore the possible physiopathologic mechanism. The studies between CysC and DR were very lacking, and our study would further disclose the association between them. This must be helpful to improving the control level of DR.Methods:A cross-sectional hospital-based survey that including 450 type 2 diabetes mellitus was analysed in the study. Those patients came from endocrinology department of dezhou people’s hospital since January 2012 to December 2013 and complied with strict selective critetion. Gender, age, duration of DM, therapeutic regimen of hyperglycemia, family history of DM, history of smoking, history of hypertension, history of Cardiovascular or cerebrovascular diseases and other related imformations were acquired by means of a special epidemiological questionnaire that designed for the study. Diagnosis and certification of DR was same as part one. Blood pressure, CysC, HbA1c, TC, TG, HDL-C, LDL-C, ApoA1, ApoB, BUN, Scr, UA and UAE were measured. The ratio of AopAl/ApoB was calculated. Estimated GFR (eGFR) was acquired by Chineses modified MDRD equation [eGFR (ml/min/1.72m2) =186×Scr (mg/dl)-1.154×age(year)-0.203(female×0.742)×1.233]. BMI was calculated by equation. Binary logistic regression was performed to evaluate the risk factors of DR. In order to further definite the significance of parameters, variable assignment were used in continuous variables by certain standard. Related variables were compared between groups of NDR and DR. Those variables that there were significant difference between patients with NDR and DR were taken as independent variables into binary regression model. Ordinal regression analysis was used to evaluate the association between related factors and severity grades of DR.Results:Gender, age, duration, hypertension, history of diabetes, history of smoking, history of CVD, therapeutic regimen of hyperglycemia, BMI, SBP, DBP, HbA1c, BUN, Scr, hyperuricemia, eGFR, CysC, UAE, TC, TG, LDL-C, HDL-C, ApoA1, ApoB and ApoA1/ApoB were compared by univariate analysis between groups of NDR and DR. There were significant differences in age, duration of diabetes, hypertension, history of CVD, therapeutic regimen of hyperglycemia, BMI, SBP, HbA1c, BUN, Cr, CysC, hyperuricemia, eGFR, UAE, TC, TG, LDL-C, ApoA1, ApoB, ApoA1/ApoB. Those variables that proved to be significant differences were taken as independent variables into binary logistic regression. At last, duration of diabetes(OR:2.483; 95%CI:1.405-4.388;P=0.002), HbA1c (OR:2.408; 95%CI: 1.371-4.228; P=0.002), hypertension (OR:3.901; 95%CI:1.257-12.105;P=0.018), CysC(OR:2.364; 95%CI:1.300-4.298; P=0.005), eGFR (OR:2.587; 95%CI:1.336 -5.009; P=0.005) and ApoAl/ApoB (OR:0.452; 95%CI:0.244-0.837;P=0.012) retained their significant associations with the presence of DR. Of age, duration of diabetes, BMI, SBP, DBP, HbA1c, BUN, Scr, UA, eGFR, CysC, UAE, TC, TG, LDL-C, HDL-C, ApoAl, ApoB, ApoA1/ApoB, gender, hypertension, history of diabetes, history of C VD, treatment of insulin and history of smoking, there were significant differences in age, duration of DM, HbAlc, BMI, SBP, BUN, Cr, CysC, eGFR, UAE, family history of DM and treatment of insuline (P<0.05) among groups of mild NPDR, moderate NPDR, severe NPDR and PDR. Those variables that proved to be significant differences were taken as independent variables into logistic regression of ordered categorical variables. At last, duration of DM (P=0.026), HbA1c (P<0.001), Cys C (P=0.023) and eGFR (P=0.043) retained their significant association with the severity grade of DR.Conclusion:CysC is the independent risk factor for DR and could predict the occurrence and progression of DR. Two aspects of reason should be contributed to the close association between CysC and DR. The closed association between DN and DR should be the first reason. In addition, CysC should play an important role in the microvascular impairment. ApoAl/ApoB should play an important protective role in the occurrence of DR.Part three:The study of the predictive value for Cystatin C in predicting diabetic retinopathy in patients with type 2 diabetes mellitusObjective:On the base of the part one, the prevalence of any DR or severe DR is higher but the cognition level of DR is lower in our region. There were only 12.14% patients had ever been conducted screening of DR among inpatients with history of DM. This indicates that it’s urgent, realistic and important to explore a practical program for screening of DR. The part two disclosed that Cys C is an independent risk factor and a helpful predictive marker for DR. On the base of results of part one and part two, the aims of study are to further evaluate the predictive value for Cys C in predicting DR and to establish an effective model for the prediction of DR. This will be helpful to overall evaluate the association between Cys C and DR, and must be helpful to the secondary prevention of DR.Methods:The selection of subjects and the main methods was same as that of part two. The ability of cystain C in predicting DR or severe DR (severe NPDR or PDR) was evaluated using a receiver operating characteristic (ROC) curve. Used discriminant analysis, the predictive model of DR was established on the base of training sample (382 subjects). Those varialbes (duration of DM, HbAlc, hypertentsion, CysC, eGFR and ApoA1/ApoB) were proved be significant in the binary logistic regression model of part two were taken as independent variables, and NDR/DR were taken as grouping variables. On the base of verification sample (68 subjects),χ2-test and κ-Coefficient test of paired count data were used to confirm the effect of the predictive model in predicting DR.Results:Cystatin C had significant value (AUC:0.763, P<0.001) in predicting DR. The optimal cut-off value of cystatin C in predicting DR was 1.11 mg/L (sensitivity:56.00%, specificity:83.90%). Cystatin C was significant (AUC:0.821, P<0.001) for predicting the presence of severe DR (severe NPDR or PDR), and the optimal cut-off value was 1.23 mg/L (sensitivity:73.60%; specificity:88.70%). On the base of training sample [duration of DM(X1), HbA1c(X2)、hypertension(X3)、Cys C (X4)、eGFR(X5)、ApoAl/ApoB(X6)were taken as independent variables], Fisher discriminant functions were as follows:Primary classification (NDR)=-18.365+0.461X1+2.670X2+6.505X3+1.990X4+2.331X5+3.527X6; Primary classification(DR)=-29.628+1.553X1+3.600X2+8.481X3+3.185X4+3.249X5+2.716 X6. The correct discriminant rate, sensitivity, specificity or Yoden index is 87.7%, 80.14%,92.12% and 0.7231 respectively. On the base of Verification sample, the coincidence rate, sensitivity, specificity or Yoden index is 91.07%,86.67%,94.74% and 0.8140 respectively. P value of McNemar test is 0.687, and the Coefficient of fit (Discriminant model and FFA) is 0.820。Conclusion:There is a moderate value for Cystatin C in predicting any DR or severe DR, and the ability in predicting severe DR is superior to that in predicting any DR. The discriminant model including duration of DM, HbAlc, hypertension, CysC, eGFR and ApoA1/ApoB has better effect in predicting DR.