CN115389773A - Application of glycocalyx shedding marker in diagnosis and prevention of early-stage renal injury of type 2 diabetic nephropathy - Google Patents
Application of glycocalyx shedding marker in diagnosis and prevention of early-stage renal injury of type 2 diabetic nephropathy Download PDFInfo
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Abstract
The invention discloses an application of a glycocalyx shedding marker in diagnosing and preventing early-stage renal injury of type 2 diabetic nephropathy, belonging to the field of biomarkers. A marker for diagnosing and preventing early stage renal injury comprising any one of: (1) syndecan-1 (Sdc-1); (2) Hyaluronic Acid (HA); (3) Sdc-1 and HA. According to the invention, by analyzing the relation between the glycocalyx falling condition of the incipient T2DM patient and the renal function index and researching the diagnostic value of the patient on early renal injury, the result shows that the endothelial glycocalyx falling of the incipient T2DM patient with trace albuminuria is serious, the glycocalyx falling is related to the early renal injury, sdc-1 is a main influence factor of the ratio (UACR) of urine trace albumin and urine creatinine, the occurrence risk of trace albuminuria is increased by the glycocalyx falling, and the combination detection of Sdc-1 and HA is beneficial to the diagnosis and prevention of the early renal injury of the incipient T2DM patient.
Description
Technical Field
The invention relates to the field of biomarkers, in particular to application of a marker for shedding glycocalyx in diagnosing and preventing early-stage renal injury of type 2 diabetic nephropathy.
Background
The prevalence rate and the daily rise of type 2diabetes mellitis (T2DM), an initial T2DM patient can be accompanied by kidney damage of different degrees caused by hyperglycemia, and early diagnosis and timely treatment of the initial T2DM kidney damage have great clinical significance and value for effectively preventing and controlling the development of diabetic complications. The pathophysiology of early renal injury in Diabetes Mellitus (DM) is characterized by impairment of the glomerular filtration barrier, the glycocalyx is a polysaccharide-protein complex structure located on the endothelial cell membrane and is an important structure in the components of the glomerular filtration barrier, and the major components of the glycocalyx include Heparin Sulfate (HS), hyaluronic Acid (HA) and syndecan-1 (sdc-1). High sugars can destroy the integrity of the glycocalyx structure, leading to its shedding leading to increased filtration membrane porosity, and filtered macromolecular substances further aggravate the high sugar induced structural and functional damage to the kidney. Studies have found elevated plasma Sdc-1 levels in patients with type 1diabetes mellitus (t 1 dm) combined with Diabetic Kidney Disease (DKD) with microalbuminuria. The Glycocalyx Shedding (GS) is closely related to the generation and development of DKD, and the GS can participate in the DKD process and accelerate the generation of urinary albumin. At present, the correlation research of the GS marker and the kidney function of the patient with the incipient T2DM is lacked, so that the search of a new marker for diagnosing and preventing early kidney injury for the patient with the incipient T2DM has important significance.
Disclosure of Invention
The invention aims to provide application of a glycocalyx shedding marker in diagnosis and prevention of early renal injury of type 2 diabetic nephropathy, so as to solve the problems in the prior art, and the markers of syndecan-1 and hyaluronic acid are obtained by screening, so that the early renal injury of T2DM can be detected with high sensitivity and specificity, and a new marker is provided for clinical medicine.
In order to achieve the purpose, the invention provides the following scheme:
the present invention provides a marker for diagnosing and preventing early kidney injury, the marker comprising any one of:
(1) Syndecan-1;
(2) Hyaluronic acid;
(3) Syndecan-1 and hyaluronic acid.
Preferably, the early stage renal injury is an initial early stage renal injury of T2 DM.
The invention also provides application of a detection reagent for detecting the expression level of the marker in preparation of products for diagnosing and preventing early kidney injury.
Preferably, the detection of the expression level of the marker is specifically:
detecting the expression level of syndecan-1 and hyaluronic acid in a biological sample of a subject to be detected;
comparing the detected expression levels of syndecan-1 and hyaluronic acid with those of a control, indicating whether the test subject suffers from early renal injury based on the result of the comparison; wherein the control is a type 2 diabetic without albuminuria.
Preferably, in the test subject, syndecan-1. Gtoreq.16.64 ng/mL or hyaluronic acid. Gtoreq.78.31 ng/mL indicates early renal injury. If the serum Sdc-1 level in the test object (T2 DM patient) is more than 16.64ng/ml, the sensitivity and specificity for diagnosing early-stage renal injury are respectively 89.5 percent and 68.1 percent, and if the serum HA level in the test object (T2 DM patient) is more than 78.31ng/ml, the sensitivity and specificity for diagnosing early-stage renal injury are respectively 79.0 percent and 62.8 percent.
Preferably, the biological sample is a blood sample.
Preferably, the products include reagents and kits.
The invention also provides a reagent or a kit, which comprises a reagent for detecting the expression level of the marker.
The invention discloses the following technical effects:
the invention screens out the multi-ligand proteoglycan-1 and hyaluronic acid which can be used for diagnosing and preventing early T2DM early kidney injury by analyzing the relation between the shedding condition of the glycocalyx of a patient with early type 2diabetes mellitus (T2 DM) and renal function indexes and researching the diagnostic value of the early T2DM early kidney injury, and experiments verify that the detection threshold of the serum Sdc-1 level is 16.64ng/ml, the sensitivity and the specificity of the diagnosis are 89.5 percent and 68.1 percent respectively, the detection threshold of the serum HA level is 78.31ng/ml, the sensitivity and the specificity of the diagnosis are 79.0 percent and 62.8 percent respectively, and the sensitivity and the specificity of the combined detection and diagnosis are 84.6 percent and 86.7 percent respectively, thereby showing that the two markers can be used independently and also can be used together, and providing a new marker for clinical medical diagnosis and prevention of early T2DM early kidney injury.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without creative efforts.
FIG. 1 is a subject's working characteristic curve for glycocalyx shedding marker diagnosis of early renal injury; sdc-1: syndecan-1; HA: hyaluronic acid; sdc-1&HS: detecting syndecan-1 and hyaluronic acid jointly; ROC: subject work characteristics; AUC: area under the curve.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but rather as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
Example 1 screening and identification of early T2DM diagnostic markers for early renal injury
1. Sample source
Collecting initial T2DM patients managed by national standardized metabolic disease management center of second people hospital in Wuxi city from 10 to 2022 in 2018, wherein the collected T2DM patients meet the diagnosis standard of T2DM in Chinese type 2diabetes prevention and treatment guidelines (2020 edition), the urine microalbumin/creatinine ratio (UACR) measured by the patients is less than or equal to 300mg/g, and the collected initial T2DM patients are temporarily administered with metformin, acarbose or long-acting insulin for reducing blood sugar by single or combined scheme. The clinical guidelines for renal disease control of diabetes in 2019 in China propose that 3UACR are determined for patients in the group within 3 months, wherein at least two UACR < 30mg/g are defined as urine protein negative (no albuminuria), and at least two UACR < 30mg/g and 300mg/g are defined as trace albuminuria. Accordingly, patients were classified into a albuminuria-free group (n =113 cases) and a microalbuminuria group (n =105 cases) according to UACR measured 3 times in a row at the time of admission.
Elimination of patients in this studyAnd (3) standard: (1) suffering from malignant tumors and autoimmune diseases; (2) recent surgery, severe trauma and combined severe infection; (3) Suffering from severe liver and kidney dysfunction [ alanine aminotransferase or aspartate aminotransferase>100U/L or glomerular filtration rate (eGFR)<60mL·min -1 ·(1.73m 2 ) -1 Or UACR > 300mg/g or positive for urine protein](ii) a (4) Combining diabetes acute complications or coronary heart disease, cerebral infarction, pulmonary embolism and other diseases; (5) Patients with hypertension for more than or equal to 10 years or refractory hypertension with poor control of taking various medicines; (6) HbA1c > 10 as measured in the patient; (7) severe psychiatric disease was associated or could not be matched by this study. The experimental study is a cross-sectional study, meets the ethical standard of human body experiments, is approved by the ethical committee of the second people hospital in the Wuxi city (the approval of the ethical examination No. (2022) ethical examination No. (Y-125)), and signs an informed consent for all the study subjects.
2. Screening method of early T2DM early kidney injury diagnosis marker
2.1 general data and clinical indices
Subjects who had not had a diabetic intervention were left with 10mL of fasting blood sample and 10mL of morning urine, while general clinical data was collected on the patients. The fasting C-peptide (FCP) level (C-peptide kit, roche), glycated hemoglobin (HbA 1C) level (glycated hemoglobin assay kit, berle), urine microalbumin (urine microalbumin assay kit, langerhans), serum creatinine (Scr) (blood creatinine assay kit, beckman), blood Urea Nitrogen (BUN) (blood urea nitrogen assay kit, beckman), urinary creatinine (urinary creatinine assay kit, beckman), and Fasting Plasma Glucose (FPG) level (blood glucose assay kit, beckman) were measured for the subjects. According to the formula (BMI = weight/height) 2 ) Calculating Body Mass Index (BMI), calculating UACR according to a calculation formula (UACR = urine microalbumin/urine creatinine), and calculating CKD-EPI according to the Chronic Kidney epidemic disease (the epidemic disease) cooperation working group through Scr WaterThe eGFR was evaluated flat (ref. "Schwand A, denking M, fastening P, et al. Comparison of MDRD, CKD-EPI, and Cockcroft-Gault equalisation in relation to the measured macromolecular amplification a large particle costs with two reagents [ J].Journal of Diabetes and Its Complications,2017,31(9):1376-1383.”)。
2.2 blood sample Collection and detection
Taking 10ml of fasting venous blood and 10ml of morning urine sample of patients, centrifuging for 10min at 3000r/min by using a centrifuge, taking supernatant after centrifugation, placing in a new EP tube, and storing at-20 ℃. The serum Sdc-1 and HA levels of the patients were measured by enzyme linked immunosorbent assay (ELISA), and the urine alpha 1-microglobulin (alpha 1-MG) levels (NOVUS, germany), the urine Retinol Binding Protein (RBP) levels (ICL, USA) and the neutrophil gelatinase-associated lipocalin (NGAL) levels (Lifespan, USA) were all <15% both in-kit and inter-kit variability.
2.3 statistical analysis
Statistical analysis and data processing were performed using SPSS 25.0 and GraphPad Prism 8 software. Variable adoption of normal distribution
In the way, the variable of the skewed distribution is expressed in an M (Q1, Q3) way. In the two groups of measurement data, the variable which accords with normal distribution is subjected to t test of independent samples, and the variable which accords with skewed distribution is subjected to Mann-Whitney nonparametric test. Spearman correlation analyses the correlation of UCAR, serum Sdc-1 and HA levels with renal function indices. And (3) analyzing the influence factors of the UACR by multiple stepwise regression. Binary logistic regression analyzed the risk factors for development of microalbuminuria. The area under the curve (AUC) calculated by a Receiver Operating Characteristic (ROC) curve is used for analyzing the diagnostic efficacy of serum Sdc-1 and HA levels on screening early-stage renal injury, and the more the AUC is close to 1, the stronger the efficacy is. P<A difference of 0.05 is statistically significant.
2.4 results and analysis
2.4.1 comparison of baseline data between albuminuria-free and microalbuminuria patients
218 patients with T2DM were enrolled in the study and divided into 113 albuminuria-free groups and 105 microalbuminuria groups according to UACR levels. The study data showed that there was no statistical significance (P > 0.05) in the differences in gender, age, BMI, scr, BUN, eGFR, FPG, FCP and HbA1c between the two groups of patients, and there was a statistical significance in the differences in UACR, α 1-MG, RBP, NGAL, sdc-1 and HA between the two groups of patients (P < 0.05). Serum Sdc-1 and HA levels in the microalbuminuria group were significantly higher than those in the albuminuria-free group (P <0.01, see Table 1).
TABLE 1 comparison of clinical data for T2DM patients in albuminuria-free and microalbuminuria groups
Note: BMI: body mass index; UACR: urinary microalbumin to urinary creatinine ratio; and (2) Scr: (ii) blood creatinine; BUN: blood urea nitrogen; eGFR: glomerular filtration rate; α 1-MG: α 1 microglobulin; RBP: retinol binding protein; NGAL: neutrophil gelatinase-associated lipocalin; FPG (field-programmable gate array): fasting blood glucose; FCP: fasting C-peptide; hbA1c: glycated hemoglobin; SBP: contracting pressure; DBP: diastolic blood pressure; sdc-1: syndecan-1; HA: hyaluronic acid; 1mmhg =0.133kpa; compared with the albuminuria-free group, a P＜0.01。
2.4.2 correlation of UACR, sdc-1 and HA with clinical indices in two groups of patients
The correlation analysis of UACR, sdc-1 and HA with clinical index was performed by Spearman correlation, and the analysis results are shown in Table 2. The research result shows that UACR is positively correlated with BUN, alpha 1-MG, NGAL, sdc-1 and HA (P < 0.05), negatively correlated with eGFR (P < 0.01) and HAs no significant correlation with Scr, RBP, FCP and HbA1c (P > 0.05); serum Sdc-1 is positively correlated with UACR, alpha 1-MG, NGAL and HA (P < 0.01), and negatively correlated with HbA1c (P < 0.05), and serum HA is positively correlated with UACR, alpha 1-MG, NGAL and Sdc-1 (P < 0.01), and serum Sdc-1 and HA are not significantly correlated with eGFR, scr, BUN, FPG and FCP (P > 0.05).
TABLE 2 correlation analysis results of UACR, sdc-1 and HA with clinical index variables
Note: UACR: urinary microalbumin to urinary creatinine ratio; and (2) Scr: (ii) blood creatinine; BUN: blood urea nitrogen; eGFR: glomerular filtration rate; α 1-MG: α 1 microglobulin; RBP: retinol binding protein; NGAL: neutrophil gelatinase-associated lipocalin; FPG (field-programmable gate array): fasting blood glucose; FCP: fasting C-peptide; hbA1c: glycated hemoglobin; sdc-1: syndecan-1; HA: hyaluronic acid; r is s : a regression coefficient; and (2) preparing: no data; * P＜0.05， ** P＜0.01。
2.4.3 multiple stepwise Linear regression of UACR and related factors
The detection parameters of the invention have the characteristics of linearity, independence and homogeneity of variance, factors BUN, alpha 1-MG, NGAL, sdc-1, HA and eGFR related to UCAR are included in the detection for multi-element stepwise linear regression analysis, and the result shows that NGAL, sdc-1, alpha 1-MG and RBP are main influence factors of UACR (see table 3).
TABLE 3 results of multiple stepwise linear regression analysis of UACR influencing factors
Note: UACR: urinary microalbumin to urinary creatinine ratio; NGAL: neutrophil gelatinase-associated lipocalin; sdc-1: syndecan-1; α 1-MG: α 1 microglobulin; RBP: retinol binding protein; b value: a regression coefficient; beta value: a standard regression coefficient; and (3) t value: t test statistic; VIF: a variable expansion factor; and (2) preparing: there is no data.
2.4.5 assessment of the Risk of development of microalbuminuria in T2DM patients
After the normality test, the median of the variables Sdc-1 and HA which accord with the deviation distribution is respectively 18.53 and 79.92, the variable which is more than or equal to the median is defined as a high level, the variable which is less than the median is defined as a low level, after the mixed factors of sex (classification variable), age and BMI are controlled, the high and low levels of Sdc-1 and HA are used as covariates, whether the microalbuminuria occurs is used as a dependent variable, and binary Logistic regression analysis is carried out, so that the results show that the risks of the microalbuminuria of the high level Sdc-1 and the HA are 8.90 times and 5.76 times (P is less than 0.01, see Table 4).
TABLE 4 binary logistic regression analysis of risk of microalbuminuria in T2DM patients
Note: b value: a regression coefficient; wald: wald test statistics; exp (B): relative risk; BMI: body mass index; sdc-1: syndecan-1; HA: hyaluronic acid; and (2) preparing: there is no data.
Example 2 diagnostic value of serum Sdc-1 and HS levels for early stage renal injury in T2DM
According to the invention, UACR is used as a state variable (the state variable meeting UACR < 30mg/g is set as 0, and the state variable meeting UACR < 30mg/g and 300mg/g is set as 1), and an ROC curve is adopted to test the diagnostic efficacy of serum glycocalyx shedding markers Sdc-1 and HA on early kidney injury.
As shown in FIG. 1, the areas under the ROC curve (AUC) of the serum Sdc-1 level, the serum HA level and the combined detection diagnosis T2DM with early stage renal injury are 0.857 (95% confidence interval of 0.81-0.91), 0.812 (95% confidence interval of 0.76-0.87) and 0.931 (95% confidence interval of 0.90-0.96). The detection threshold of the serum Sdc-1 level is 16.64ng/ml, the sensitivity and specificity of diagnosis are 89.5% and 68.1% respectively, the detection threshold of the serum HA level is 78.31ng/ml, the sensitivity and specificity of diagnosis are 79.0% and 62.8% respectively, and the sensitivity and specificity of combined detection and diagnosis are 84.6% and 86.7% respectively. The sensitivity and specificity of the serum Sdc-1 level on early diagnosis of the kidney injury of T2DM are higher than the serum HA level, and the combined detection and diagnosis of the kidney injury of early stage in a T2DM patient HAs higher sensitivity and specificity.
From the results of the above examples, it can be seen that GS was significantly increased in the initial T2DM patient who combined microalbuminuria, and that GS was positively correlated with urinary microalbumin production, where Sdc-1 was the major contributor to UACR. As GS increases, the risk of developing microalbuminuria increases. The combined detection of the plasma Sdc-1 and HA levels of the initial T2DM patient HAs better diagnosis efficiency on early renal injury. It is speculated that under DM microenvironment, development of GS by glomerular endothelial cells leads to production of microalbuminuria and thus contributes to development of DKD. Sdc-1 and HA are expected to become novel markers for early diagnosis of T2DM and prevention of kidney injury, and early kidney injury can be diagnosed and prevented by preparing products for detecting Sdc-1 and HA, such as reagents, kits and the like, by measuring the expression levels of the two, so that the method is simple and easy to implement.
The above embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solution of the present invention by those skilled in the art without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.
Claims (8)
1. Marker for the diagnosis and prevention of early stage renal injury, wherein the marker comprises any one of the following:
(1) Syndecan-1;
(2) Hyaluronic acid;
(3) Syndecan-1 and hyaluronic acid.
2. The marker of claim 1, wherein the early stage renal injury is an initial early stage renal injury of T2 DM.
3. Use of a test agent for detecting the expression level of a marker as defined in claim 1 or 2 in the manufacture of a product for diagnosing and preventing early stage renal injury.
4. The use according to claim 3, wherein the detection of the expression level of the marker is in particular:
detecting the expression level of syndecan-1 and hyaluronic acid in a biological sample of a subject to be detected;
comparing the detected expression levels of syndecan-1 and hyaluronic acid with those of a control, indicating whether the test subject suffers from early renal injury based on the result of the comparison; wherein the control is a type 2 diabetic without albuminuria.
5. The use of claim 4, wherein syndecan-1.16 ng/mL or hyaluronan 78.31ng/mL or more in the test subject is indicative of early renal injury.
6. The use of claim 4, wherein the biological sample is a blood sample.
7. The use of claim 3, wherein the products comprise reagents and kits.
8. A reagent or kit comprising a reagent for detecting the expression level of the marker of claim 1 or 2.
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| CN116179687A (en) * | 2023-04-17 | 2023-05-30 | 郑州大学第一附属医院 | PiRNA biomarker for early diagnosis of diabetic nephropathy and application thereof |
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| CN116179687A (en) * | 2023-04-17 | 2023-05-30 | 郑州大学第一附属医院 | PiRNA biomarker for early diagnosis of diabetic nephropathy and application thereof |
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