Discussion
The pathological changes of DKD are complex, many diseases are hidden, showing chronic progressive development, and eventually progress to End-stage renal disease (ESRD), which seriously affects the quality of life and life safety of patients. At present, DKD is the main cause of chronic kidney disease and ESRD in the world [
11]. timely prevention and diagnosis of DKD is an important part of the treatment of diabetic patients. Up to now, a large number of researchers have explored the early predictive markers of DKD, including proteomics and genomics. However, these new biomarkers are still lack of stability, and the detection cost is high, which is difficult to promote in clinical practice [
12]. Therefore, this study relies on the pathological diagnosis of renal biopsy as the gold standard, and explores the convenient and sensitive non-invasive indicators that can predict the diagnosis of DKD.
In this review, we retrospectively reviewed the recent diagnosis of type 2 diabetes mellitus complicated with proteinuria in our city. According to the diagnostic criteria of renal biopsy, 25 cases were diagnosed as DKD and 34 cases diagnosed as NDKD. There are many pathological types in NDKD group, among which membranous nephropathy is the most common pathological type in NDKD group, which is similar to the results reported in other Asian Studies [
3,
13].
By reviewing and comparing the clinical indexes of the two groups, it was found that the TG/Cys-C ratio was significantly different in DKD and NDKD patients. TG/Cys-C also considered the status of dyslipidemia and indicators of renal dysfunction in T2DM patients with renal impairment. At present, there is no definite conclusion about the role of TG/Cys-C in differentiating DKD and NDKD. Studies have shown that hyperlipidemia is an independent risk factor for the progression of DKD [
14]. In vivo and in vitro experiments have shown that hyperlipidemia can cause glomerulosclerosis and tubulointerstitial sclerosis by stimulating resident renal cells to produce fibrotic cytokines and chemokines, leading to infiltration of monocytes or macrophages into glomerular tissue to promote extracellular matrix deposition in tubulointerstitial and mesangial cells [
15]. Animal experiments have shown that lipid accumulation, lipid toxicity and lipid metabolism disorders are related to diabetic kidney damage [
16]. In addition, T2DM patients with other kidney diseases, especially primary nephrotic syndrome, are closely associated with hyperlipidemia. Studies [
17] have found that dyslipidemia not only promotes glomerulosclerosis and tubulointerstitial damage, but also induces or aggravates renal and external vascular lesions, leading to thromboembolism and other serious complications. Serum Cys-C, a low molecular weight protein, is an endogenous cysteine protease inhibitor and is not affected by inflammation, muscle content, gender, age and other factors [
18]. Serum cystatin C is an ideal indicator of glomerular filtration rate [
19]. Previous studies [
7] have shown that serum Cys-C is an early sensitive biomarker in DKD patients. Therefore, this study intends to explore the clinical significance of TG/ Cys-C in the differential diagnosis of DKD and NDKD.
Previous meta-analysis [
20] showed that TG levels were higher in NDKD patients than in DKD patients, and the specific mechanism remains to be further studied. In the univariate regression analysis, the TG level in the DKD group was lower than that in the NDKD group, and the Cys-C level in the DKD group was higher than that in the NDKD group. Here, we used the ratio of these two indexes for analysis. When the TG/Cys-C ratio was included in the regression, the results showed that the TG/Cys-C ratio was significantly better than the two indexes alone in distinguishing DKD and NDKD. The multivariate regression analysis showed that the TG/Cys-C ratio was an independent protective factor for DKD in T2DM patients with proteinuria.
This retrospective study shows that in patients with type 2 diabetes and proteinuria, DKD patients have higher blood pressure and creatinine levels, lower glomerular filtration rate and hemoglobin level. This indicates that the level of renal function in patients with DKD is relatively poor in the course of diabetes mellitus. Besides the combined effect of renal hemodynamic disorder, the sensitivity of insulin receptor is reduced, the function of islet is reduced, and the time of exposure to high glucose environment is prolonged. This leads to the increased risk of DKD in patients [
21]. All the above confounding factors were included in the multivariate logistic regression analysis. The results showed that TG/Cys-C ratio was a protective factor for DKD in patients with type 2 diabetes and proteinuria, that is, the TG/Cys-C ratio increased by one unit, and the risk of DKD decreased by 0.571 times. Diabetic retinopathy and systolic blood pressure are independent risk factors for DKD in patients with type 2 diabetes and proteinuria. The risk of DKD in patients with diabetic retinopathy is 6.054 times higher than that in patients without diabetic retinopathy. When systolic blood pressure increased by one unit, the risk of DKD increased by 0.041 times. The results of this retrospective study show that the lower the TG/Cys-C ratio is, the greater the likelihood of diagnosing DKD in type 2 diabetic patients with proteinuria. Conversely, it is possible to alert NDKD lesions to renal biopsy indications.
It is generally believed that the duration of diabetes, the absence of diabetic retinopathy, hematuria or unexplained acute kidney injury may be a useful indicator of renal biopsy in patients with type 2 diabetes combined with dominant proteinuria [
22]. Previous studies have found that duration of diabetes was the strongest predictor of whether NDKD or DKD was identified on biopsy [
23]. However, other studies confirm that NDKD can not be completely excluded in patients with type 2 diabetes mellitus with longer duration of diabetes and diabetic retinopathy [
24]. In addition, some studies have suggested that the presence of microhaematuria is an independent risk factor for NDKD [
25]. However, the comparative analysis of DKD and NDKD patients in this retrospective study showed no significant difference in microhaematuria, which may be related to the small sample size of this study.
In order to evaluate the diagnostic value of TG/Cys-C ratio for DKD in patients with type 2 diabetes mellitus and dominant proteinuria, the ROC curve was constructed in this retrospective study. The results showed that the area under the DKD curve predicted by the TG/Cys-C ratio was 0.816, corresponding sensitivity and specificity were 84% and 67.6%, respectively, and the cut-off point value was 2.43. The results of this study showed that when the TG/Cys-C ratio was lower than 2.43 in patients with type 2 diabetes and proteinuria, it was suggested that the possibility of diagnosing DKD was too large. When the TG/Cys-C ratio was higher than 2.43, we should be alert to the possibility of combining NDKD. Further renal biopsy was recommended to make clear diagnosis and guide treatment.
In order to further verify the predictive value of TG/Cys-C ratio for the diagnosis of DKD, based on the results of previous retrospective studies, a prospective study was carried out in newly enrolled type 2 diabetic patients with proteinuria by taking the cut-off point value TG/Cys-C of the ratio as the defined value. The results showed that among the 37 patients with type 2 diabetes mellitus combined with proteinuria, TG/ Cys-C < 2.43 in 29 patients and TG/ Cys-C ≥ 2.43 in the other 8 patients. We analyzed the clinical characteristics of patients in the two groups, and the renal function level of patients in the TG/ Cys-C < 2.43 group was worse. We analyzed the pathological characteristics of renal biopsy in patients with type 2 diabetes. (a) DKD, defined by the presence of suggestive glomerular lesions like nodular sclerosis, diffuse mesangial sclerosis, mesangial expansion, basement membrane thickening, arteriolar hyalinosis, micro aneurysms and exudative lesions [
26]. (b) NDKD, defined by any histological alteration different from the above-mentioned and suggestive of other renal diseases. There were 11 cases of membranous nephropathy and 2 cases of mesangial proliferative nephropathy. Among the 29 patients, 22 were diagnosed as DKD by renal pathology, and 6 of the 8 patients were diagnosed as NDKD by renal pathology. The sensitivity was 91.67%, the specificity was 46.15%, the positive predictive value was 75.80%, and the negative predictive value was 75.00%. In the population with TG/Cys-C ratio < 2.43, the proportion of pathological diagnosis of DKD by fine needle renal biopsy was significantly higher, which confirmed that TG / Cys-C ratio had a certain predictive value for the diagnosis of DKD.
In summary, the low level of TG/Cys-C is a protective factor for DKD in type 2 diabetic patients with proteinuria. TG/Cys-C ratio has important clinical guiding significance for the prediction and diagnosis of DKD.
This study has some limitations. Firstly, information bias cannot be avoided in this retrospective study. All patients' medical history data are from the internal electronic medical record system of the hospital, and there may be poor accuracy of medical history records. In addition, blood pressure measurement is greatly affected by emotion or activity, which is easy to cause blood pressure fluctuation and data deviation. Secondly, due to the limitation of clinical sample size, the cases collected in this study are only within the scope of this city and can not represent the population in all regions of the country, which limits the universal applicability of the research results to other groups. Finally, the occurrence and development process of DKD and NDKD diseases is extremely complex. There may be other influencing factors that have not been explored in the research, and more in-depth exploration is needed in the future.
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