Application of X-linked inhibitor of apoptosis protein in the diagnosis of chronic kidney disease

Abstract

This application relates to the field of disease diagnosis technology, and specifically relates to the application of X-linked inhibitor of apoptosis protein in the diagnosis of chronic kidney disease.

Description

Technical Field

[0001] This application relates to the technical field of disease diagnosis, and particularly to the application of XIAP in the diagnosis of chronic kidney disease and the preparation of diagnostic products. Background Art

[0002] With the acceleration of the global population aging process, the incidence of hypertension, diabetes and metabolic diseases has increased significantly, and the incidence of chronic kidney disease (CKD) has also been increasing year by year globally. CKD can progress to the ESRD stage, and is often accompanied by the occurrence of complications such as cardiovascular diseases, resulting in poor prognosis and high medical costs for CKD patients, imposing a huge economic burden on patients' families, society and the country.

[0003] Progression to end-stage renal failure is the main clinical severe consequence of CKD patients and the most important factor affecting the death and long-term prognosis of CKD patients. CKD has an insidious onset and often has no obvious symptoms in the early stage. Therefore, CKD patients should be diagnosed as early as possible and timely intervention measures should be carried out to reduce the progressive damage of the kidneys and improve the prognosis of patients. How to intervene in the early stage of CKD onset and avoid expensive renal replacement therapy (dialysis or kidney transplantation) is one of the key issues in the current research in the field of nephrology.

[0004] Although there are currently some diagnostic methods for kidney diseases, such as serum creatinine (SCr), blood urea nitrogen (BUN), proteinuria, kidney tissue biopsy, etc., these methods are still difficult to meet the clinical needs and have limitations such as invasive examinations, low sensitivity and specificity. Screening potential renal injury molecular markers and finding biomarkers that can early and efficiently predict the occurrence and development risks of chronic kidney disease are difficult problems that urgently need to be solved in current clinical work.

[0005] Urine is a "window" that directly reflects kidney lesions. Signals of kidney injury can often be detected by measuring specific biomarkers in urine. The non-invasive method of "one-drop urine test" will help clinicians conduct large-scale screening, effectively identify high-risk patients, and thus achieve the goals of precise monitoring and precise prevention and treatment. With the in-depth study of the pathogenesis of various kidney injuries and the progress of high-throughput transcriptomics and proteomics technologies, several biomarkers that can predict the risk of CKD progression have been discovered in recent years, such as Kidney Injury Molecule-1 (KIM-1), Tissue Inhibitor of Metalloproteinase-2 (TIMP-2), Insulin-like Growth Factor-Binding Protein-7 (IGFBP-7), Matrix Metalloproteinase-7 (MMP-7), Epidermal Growth Factor (EGF), etc. However, their sensitivity, specificity, and reproducibility for predicting CKD progression are insufficient. Clinically, it is not only necessary to detect kidney injury at an early stage, but also to predict the risk of CKD progressing to renal failure to prevent and reduce the occurrence of end-stage kidney disease.

[0006] X-linked inhibitor of apoptosis (XIAP) is one of the important members of the inhibitor of apoptosis protein family (IAPs). IAPs are a class of highly conserved multifunctional proteins that participate in a series of cellular activities, and their functions include but are not limited to apoptosis regulation. Clinically, since XIAP in serum or urine can be obtained non-invasively or with low invasiveness, has stable expression, and is convenient for storage, it is often used as a novel biomarker for the diagnosis and prognosis judgment of various diseases such as tumors and cardiovascular diseases. In the existing technology, although it has been mentioned that XIAP can be used as a diagnostic indicator for renal clear cell carcinoma, its diagnostic or therapeutic value for CKD has not been disclosed.

[0007] In view of this, the present application is proposed. Summary of the Invention

[0008] To solve the above technical problems, the present application surprisingly discovers through a series of bioinformatics methods that XIAP can be used as a diagnostic indicator for chronic kidney disease. Therefore, it is proposed that XIAP nucleic acid or XIAP protein can be used as a biomarker for the diagnosis and judgment of chronic kidney disease, making up for the deficiencies of existing chronic kidney disease-related indicators and having significant clinical value.

[0009] Therefore, the present application has at least the following objectives:

[0010] The first objective of this application is to seek a new use for the diagnosis of chronic kidney disease;

[0011] The second objective of this application is to seek a new product suitable for the diagnosis of chronic kidney disease;

[0012] The third objective of this application is to seek a new method for the diagnosis of chronic kidney disease;

[0013] The fourth objective of this application is to seek an application in the treatment of chronic kidney disease, especially in delaying the progression of renal fibrosis.

[0014] To achieve the above objectives, the present application proposes the following specific technical solutions:

[0015] This application first provides the use of XIAP as a biomarker in the diagnosis of chronic kidney disease, or the use of a detection agent or component for obtaining the XIAP level in a sample in the preparation of a product for diagnosing chronic kidney disease.

[0016] In some aspects, the product includes but is not limited to the form of a kit, a system device, a computer-readable medium, or a computer system.

[0017] In some aspects, the XIAP serves as an independent indicator for the diagnosis of chronic kidney disease.

[0018] In some aspects, the level includes the nucleic acid level or the protein level.

[0019] In some aspects, the nucleic acid level includes the DNA level or the RNA level.

[0020] In some aspects, the nucleic acid level or the protein level includes but is not limited to the abundance or concentration of nucleic acid or protein; in some aspects, it may also include, for example, the mutant abundance or concentration of nucleic acid or protein.

[0021] Furthermore, the nucleic acid level is obtained by sequencing technology, nucleic acid amplification technology, nucleic acid hybridization technology, electrophoresis technology, biomass spectrometry technology, or chromatography technology.

[0022] Furthermore, the method for obtaining the nucleic acid level includes but is not limited to any one of the following methods: gene sequencing method, polymerase chain reaction method, isothermal amplification reaction method, gene chip method, probe hybridization method, gel electrophoresis method, RNA blotting method, nucleic acid mass spectrometry method, or liquid chromatography method.

[0023] Furthermore, the protein level is obtained by sequencing technology, immunological technology, electrophoresis technology, biomass spectrometry technology, or chromatography technology.

[0024] Furthermore, the method for obtaining the protein level includes, but is not limited to, any of the following methods: amino acid sequencing, enzyme-linked immunosorbent assay, chemiluminescence assay, immunochromatography, radioimmunoassay, immunohistochemistry, immunoblotting, flow cytometry, gel electrophoresis, protein mass spectrometry, or liquid chromatography.

[0025] In some aspects, the product further includes a detection agent or component for obtaining the level of other markers.

[0026] Furthermore, the other markers include, but are not limited to, one or more of SCr, BUN, KIM-1, TIMP-2, IGFBP-7, MMP-7, or EGF.

[0027] In some aspects, the product further includes a sample processing reagent, and the sample processing reagent includes at least one of a sample lysis reagent, a sample purification reagent, and a sample extraction reagent.

[0028] In some aspects, the product further includes at least one of a standard, a calibrator, a control, and a buffer.

[0029] In some aspects, the sample includes tissue, cells, body fluid, serum, plasma, whole blood (peripheral blood), urine, semen, saliva, pleural effusion, ascites, cerebrospinal fluid, feces, or synovial fluid; preferably serum or urine.

[0030] In some aspects, the diagnosis includes, but is not limited to, screening for chronic kidney disease, early diagnosis, auxiliary confirmation of diagnosis, confirmation of diagnosis, prediction / judgment of disease severity, assessment of disease activity, monitoring of treatment, etc.; preferably for early diagnosis.

[0031] The present application also provides a product for diagnosing chronic kidney disease, including a detection agent or component for obtaining the XIAP level in a sample.

[0032] In some aspects, the product includes, but is not limited to, products in the form of a kit, a system device, a computer-readable medium, or a computer system.

[0033] In some aspects, the XIAP can be independently used as an indicator for diagnosing chronic kidney disease.

[0034] In some aspects, the level includes a nucleic acid level or a protein level.

[0035] In some aspects, the nucleic acid level or protein level includes, but is not limited to, the abundance or concentration of nucleic acid or protein; in some aspects, it may also include, for example, the mutant abundance or concentration of nucleic acid or protein.

[0036] Furthermore, the nucleic acid level is obtained by sequencing technology, nucleic acid amplification technology, nucleic acid hybridization technology, electrophoresis technology, biomass spectrometry technology, or chromatography technology.

[0037] Further, the nucleic acid level acquisition methods include, but are not limited to, any one of the following methods: gene sequencing method, polymerase chain reaction method, isothermal amplification reaction method, gene chip method, probe hybridization method, gel electrophoresis method, RNA blotting method, nucleic acid mass spectrometry method, or liquid chromatography method.

[0038] Further, the protein level is obtained by sequencing technology, immunological technology, electrophoresis technology, biomass spectrometry technology, or chromatography technology.

[0039] Preferably, the protein level acquisition methods include, but are not limited to, any one of the following methods: amino acid sequencing method, enzyme-linked immunosorbent assay, chemiluminescence method, immunochromatography method, radioimmunoassay, immunohistochemistry method, immunoblotting method, flow cytometry, gel electrophoresis method, protein mass spectrometry method, or liquid chromatography method.

[0040] In some aspects, the product further includes a detection agent or component for obtaining the levels of other markers.

[0041] Further, the other markers include, but are not limited to, one or more of SCr, BUN, KIM-1, TIMP-2, IGFBP-7, MMP-7, or EGF.

[0042] In some aspects, the product further includes a sample processing reagent, and the sample processing reagent includes at least one of a sample lysis reagent, a sample purification reagent, and a sample extraction reagent.

[0043] In some aspects, the product further includes at least one of a standard, a calibrator, and a control.

[0044] In some aspects, the sample includes tissue, cells, body fluid, serum, plasma, whole blood (peripheral blood), urine, semen, saliva, pleural effusion, ascites, cerebrospinal fluid, feces, or synovial fluid; preferably serum or urine.

[0045] In some aspects, the diagnosis includes, but is not limited to, screening for chronic kidney disease, early diagnosis, auxiliary confirmation of diagnosis, confirmation of diagnosis, prediction / judgment of disease severity, assessment of disease activity, and monitoring of treatment; preferably for early diagnosis.

[0046] This application also provides a method for diagnosing chronic kidney disease in vivo or in vitro, including the step of obtaining the level of XIAP in a subject sample.

[0047] In some aspects, the method includes the following steps:

[0048] (i) Obtaining the level of XIAP in the subject sample;

[0049] (ii) Compare the XIAP level with a control sample; wherein, a significant difference in the XIAP level between the subject sample and the control sample is an indication that the subject has chronic kidney disease; or,

[0050] (ii) Compare with a set threshold absolute amount; wherein, the subject sample level being higher than the threshold absolute amount is an indication that the subject has chronic kidney disease.

[0051] In some aspects, the XIAP can be independently used as an indication for the diagnosis of chronic kidney disease.

[0052] In some aspects, the level includes nucleic acid level or protein level.

[0053] In some aspects, the nucleic acid level or protein level includes, but is not limited to, the abundance or concentration of nucleic acid or protein; in some aspects, it can also include, such as, the mutant abundance or concentration of nucleic acid or protein.

[0054] Furthermore, the nucleic acid level is obtained by sequencing technology, nucleic acid amplification technology, nucleic acid hybridization technology, electrophoresis technology, bio-mass spectrometry technology or chromatography technology.

[0055] Furthermore, the methods for obtaining the nucleic acid level include, but are not limited to, any of the following methods: gene sequencing method, polymerase chain reaction method, isothermal amplification reaction method, gene chip method, probe hybridization method, gel electrophoresis method, RNA blotting method, nucleic acid mass spectrometry method or liquid chromatography method.

[0056] Furthermore, the protein level is obtained by sequencing technology, immunological technology, electrophoresis technology, bio-mass spectrometry technology or chromatography technology.

[0057] Furthermore, the methods for obtaining the protein level include, but are not limited to, any of the following methods: amino acid sequencing method, enzyme-linked immunosorbent assay method, chemiluminescence method, immunochromatography method, radioimmunoassay method, immunohistochemistry method, immunoblotting method, flow cytometry, gel electrophoresis method, protein mass spectrometry method or liquid chromatography method.

[0058] In some aspects, the method further includes the step of obtaining the levels of other markers in the subject sample.

[0059] Furthermore, the other markers include, but are not limited to, one or more of SCr, BUN, KIM-1, TIMP-2, IGFBP-7, MMP-7 or EGF.

[0060] In some aspects, the sample includes tissue, cell, body fluid, serum, plasma, whole blood (peripheral blood), urine, semen, saliva, pleural effusion, ascites, cerebrospinal fluid, feces or synovial fluid; preferably serum or urine.

[0061] In some aspects, the diagnosis includes but is not limited to screening for chronic kidney disease, early diagnosis, auxiliary confirmation of diagnosis, confirmation of diagnosis, prediction / judgment of disease severity, assessment of disease activity, and monitoring of treatment; preferably for early diagnosis.

[0062] In some aspects, the subject is preferably a human.

[0063] The present application also provides a method for detecting a biomarker in a subject with or suspected of having chronic kidney disease in vivo or in vitro, the method comprising determining or detecting the level of XIAP in a sample from the subject.

[0064] Further, the method also comprises determining or detecting the level of one or more of SCr, BUN, KIM-1, TIMP-2, IGFBP-7, MMP-7 or EGF in a sample from the subject.

[0065] In some aspects, the method can be for disease diagnosis purposes or for non-disease diagnosis purposes.

[0066] The present application can also provide a method for evaluating or screening a diagnostic biomarker for chronic kidney disease, comprising the step of performing a correlation or consistency analysis of a potential biomarker with XIAP, and verifying the diagnostic value of the potential biomarker based on the conclusion of the correlation or consistency.

[0067] The present application also provides a method for screening a therapeutic agent for chronic kidney disease in vivo or in vitro, the method comprising the step of evaluating the level of XIAP in a sample treated with the therapeutic agent.

[0068] The present application also provides a biomarker for diagnosing chronic kidney disease, comprising XIAP nucleic acid or protein.

[0069] The present application also provides the use of an XIAP inhibitor in the treatment of chronic kidney disease, especially in delaying the progression of renal fibrosis, and the corresponding use of the XIAP inhibitor in the preparation of a drug for treating chronic kidney disease, especially in delaying the progression of renal fibrosis.

[0070] The beneficial technical effects of the present application:

[0071] By screening for genes or their proteins with differential expression between chronic kidney disease patients and healthy control groups, the present application first proposes that XIAP may be highly correlated with the occurrence and progression of CKD, and further confirms that XIAP nucleic acid or protein can be used as a biomarker for the diagnosis and judgment of chronic kidney disease, making up for the deficiencies in the diagnosis of existing chronic kidney disease and having significant clinical value.

[0072] Compared with the prior art, detecting apoptosis inhibitor protein XIAP in human urine in the present invention not only has a simple measurement method, but also can evaluate the incidence of chronic kidney disease with good accuracy. Therefore, it can be used as a risk factor for evaluating chronic kidney disease patients who can detect primary chronic kidney disease events at an early stage. In addition, it can predict and prevent the occurrence of renal failure, and can effectively intervene in the irreversible damage of the kidney at an early stage. Specifically:

[0073] 1. Renal biopsy pathological examination is of great significance for the clinical diagnosis, treatment guidance, and prognosis judgment of kidney diseases, and is often used as the gold standard for kidney disease diagnosis. However, there is currently no unified standard for the renal biopsy pathological diagnosis process in China, and there are risks such as the need for hospitalization for renal puncture biopsy, long waiting time, bleeding, and infection, as well as limitations such as more contraindications, large sampling errors, and subjective judgment biases. By collecting urine from clinical patients and detecting XIAP using enzyme-linked immunosorbent assay, it has the advantages of fast detection speed, low cost, simple and portable instrument, high sensitivity, and strong selectivity. It can be used for on-site inspection and can dynamically, objectively, highly sensitively, and non-invasively evaluate CKD patients at an early stage.

[0074] 2. Serum creatinine (SCr), blood urea nitrogen (BUN), and proteinuria are important indicators for evaluating renal function in current clinical work, and are widely used in the clinical diagnosis of CKD due to their simple detection and low cost. ① However, SCr and BUN are easily affected by various factors such as race, gender, age, diet, and muscle mass. Moreover, in the early stage of kidney damage, due to the strong compensatory function of the kidney, the serum creatinine content often does not change in a timely manner. Therefore, it is difficult to make an early, sensitive, and reliable diagnosis, and it also lacks effective prognostic value. ② The proteinuria level is a biomarker that can predict the prognosis of patients and reflect the effectiveness of intervention methods, but it varies greatly daily, up to 40%, and is easily affected by urine concentration, with low reliability. ③ Glomerular filtration rate (e-GFR) is the main indicator for evaluating renal function and the main basis for the diagnosis and staging of chronic kidney disease. However, the e-GFR calculated by different formulas varies greatly, with complex calculations and no unified standard. XIAP can indicate early kidney damage, and its expression is stable. That is, during the process of tubular epithelial cell to mesenchymal transformation, the expression of XIAP is significantly up-regulated, and kidney damage can be detected earlier.

[0075] 3. A newly developed CKD prediction model published in JAMA in 2019, based on traditional risk factors such as age, gender, race, estimated glomerular filtration rate (eGFR), history of cardiovascular disease, smoking, hypertension, body mass index (BMI), and urinary microalbumin creatinine ratio (ACR), had a prediction accuracy of only 76% for the 5-year progression risk in the Chinese CKD population (n = 5,291 cases). Currently, the full picture of the practice of CKD risk prediction models in the academic community is still unknown, and there are still many problems that are not suitable for local conditions and need to be solved. Therefore, establishing a risk prediction system that suits Chinese CKD patients remains the common goal of clinical and research workers. As an emerging CKD biomarker, XIAP may also contribute a certain proportion to the risk prediction model.

[0076] In summary, the apoptosis inhibitor protein XIAP as a biomarker in this application has the effects of early diagnosis, early intervention, improving quality of life, and reducing medical costs for patients with primary chronic kidney disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0078] Figure 1 Heatmap of differentially expressed genes in the dataset;

[0079] Figure 2 Expression levels of IAP family members in CKD;

[0080] Figure 3 Correlation analysis of XIAP levels with serum creatinine and urea nitrogen;

[0081] Figure 4 ROC curve of XIAP concentration for diagnosing CKD. DETAILED DESCRIPTION OF THE INVENTION

[0082] The present application discloses the use of XIAP in the diagnosis of chronic kidney disease. Those skilled in the art can implement its application with reference to the content of this article. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are all considered to be included in the present application. The methods and applications of the present application have been described through preferred embodiments. Relevant personnel can obviously make changes or appropriate changes and combinations to the preparation methods and applications herein without departing from the content, spirit and scope of the present application to implement and apply the technology of the present application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this application belongs.

[0083] The following basic terms or definitions are provided only to assist in understanding the present application. These definitions should not be construed as having a scope less than that understood by those skilled in the art. Unless otherwise defined below, the meanings of all technical terms and scientific terms used in the specific embodiments of the present application are intended to be the same as commonly understood by those of ordinary skill in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are still set forth to better explain the present application.

[0084] As used in the present application, the terms "comprising", "including", "having", "containing" or "involving" are inclusive or open-ended and do not exclude other unenumerated elements or method steps. The term "consisting of" is considered a preferred embodiment of the term "comprising". If a group is defined below as including at least a certain number of embodiments, this should also be understood as disclosing a group preferably consisting only of these embodiments.

[0085] The indefinite or definite article used when referring to a singular form noun, such as "a" or "an", "the", includes the plural form of that noun.

[0086] The terms "about" and "substantially" in the present application indicate an accuracy range that those skilled in the art can understand and still ensure the technical effects of the features in question. This term generally means a deviation of ±10% from the indicated value, preferably ±5%.

[0087] In addition, the terms first, second, third, (a), (b), (c), and the like in the specification and claims are used to distinguish similar elements and are not necessarily descriptive of an order or time sequence. It should be understood that the terms so applied can be interchanged in appropriate circumstances, and the embodiments described in the present application can be implemented in an order different from that described or illustrated in the present application.

[0088] Reference will now be made in detail to embodiments of the present application, one or more examples of which are described below. Each example is provided by way of explanation and not limitation of the present application. It will be apparent to those skilled in the art that various modifications and variations can be made to the present application without departing from the scope or spirit of the present application. For example, features illustrated or described as part of one embodiment can be used in another embodiment to yield a still further embodiment. Accordingly, it is intended that the present application cover such modifications and variations that fall within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present application are disclosed in or are apparent from the following detailed description. Those of ordinary skill in the art will understand that this discussion is only a description of exemplary embodiments and is not intended to limit the broader aspects of the present application.

[0089] Diagnostic use

[0090] In the present application, differentially expressed protein XIAP between patients with chronic kidney disease and healthy control group was screened out through differential expression genes of the data set. Pearson correlation analysis showed that there was a significant positive correlation between the level of XIAP in the urine of patients and the level of serum creatinine (r = 0.3762, P < 0.0001), and there was a significant strong positive correlation between the level of XIAP in the urine and the level of blood urea nitrogen (r = 0.4225, P < 0.0001); by plotting the Receiver Operating Characteristic Curve (ROC) of XIAP, it was found that the sensitivity of XIAP for the detection of chronic kidney disease was as high as 94.59%, and the specificity was 82.5%, indicating that XIAP had good discrimination performance between patients with chronic kidney disease and normal population.

[0091] Therefore, in various aspects of the present disclosure, there is provided a diagnostic use of XIAP as a biomarker for chronic kidney disease (CKD), and a use of a detection agent for detecting XIAP in a sample in the preparation of a product for diagnosing chronic kidney disease.

[0092] As used herein, the terms "chronic kidney disease" and "CKD" are interchangeable and generally refer to kidney damage and / or a decrease in GFR [< 60 ml / (min·1.73m 2 )] for more than 3 months. Clinically, the clinical manifestations of different stages of CKD are different. In stages 1 and 2 of CKD, patients may have no symptoms, or only have mild fatigue, low back pain, and increased nocturia, etc.; a small number of patients have loss of appetite, mild anemia, etc. After stage 3 of CKD, the above symptoms may worsen, and hypertension, heart failure, acid-base balance disorder, electrolyte disorder, digestive tract symptoms, anemia, mineral-bone metabolism disorder, central nervous system disorder, etc. may occur.

[0093] As used herein, the term "XIAP" or "X-linked inhibitor of apoptosis" is used interchangeably and is one of the important members of the inhibitor of apoptosis protein family (IAPs). IAPs are a class of highly conserved multifunctional proteins that participate in a series of cellular activities, and their functions include, but are not limited to, apoptosis regulation. Clinically, since the acquisition of XIAP in serum or urine is non-invasive or minimally invasive, with stable expression and convenient storage, it is often used as a novel biomarker for the diagnosis and prognosis judgment of various diseases such as tumors and cardiovascular diseases.

[0094] As used herein, the term "diagnosis" refers to the process of identifying a medical disorder or disease (such as CKD) through its signs, symptoms, and especially the results of various diagnostic procedures (including detecting the level of XIAP in a biological sample (such as serum or urine) obtained from an individual). Moreover, as used herein, the term "diagnosis" includes disease screening, early diagnosis, auxiliary confirmation of diagnosis, confirmation of diagnosis (judging the presence or absence of a disease), prediction or judgment of the severity of a disease, assessment of disease activity, monitoring of treatment, such as monitoring disease exacerbation or recurrence during treatment, evaluation of the therapeutic efficacy of a disease, and selection of a given treatment regimen, etc. Without limitation, in some specific embodiments, the present application has fully demonstrated that the level of XIAP can be used to judge the presence or absence of CKD in a subject, and thus can be used for screening, early diagnosis, auxiliary confirmation of diagnosis or confirmation of diagnosis, etc.

[0095] As used herein, the terms "sample", "specimen", "test sample", "subject sample", etc. include various sample types obtained from a patient, individual or subject and useful for diagnostic or monitoring assays. Patient samples can be obtained from healthy subjects, diseased patients or patients with CKD-related symptoms. In addition, a sample obtained from a patient can be divided into portions, and only a portion can be used for diagnosis. Further, a sample or a portion thereof can be stored under conditions that maintain the sample for subsequent analysis. This definition specifically includes blood and other liquid samples of biological origin (including but not limited to tissues, cells, body fluids, serum, plasma, whole blood, urine, semen, saliva, pleural effusion, ascites, cerebrospinal fluid, feces and synovial fluid, etc.). In one specific embodiment, the sample includes a urine sample. In one specific embodiment, the sample includes a blood sample. In another embodiment, serum samples are used. This definition also includes samples that have been manipulated in any way after sample acquisition, such as by centrifugation, filtration, precipitation, dialysis, chromatography, treatment with reagents, washing or enrichment of certain cell populations. These terms also include clinical samples, and also include cells in culture, cell supernatants, tissue samples, organs, etc. Samples can also include fresh frozen and / or formalin-fixed, paraffin-embedded tissue blocks, such as blocks prepared from clinical or pathological biopsies, prepared for pathological analysis or study by immunohistochemistry. Samples can be tested immediately after collection, stored at RT, 4 degrees Celsius, -20 degrees Celsius or -80 degrees Celsius and tested after storage for 24 hours, 1 week, 1 month, 1 year, 10 years or up to 30 years.

[0096] The terms "individual", "subject", "patient" and "person" are used interchangeably herein and refer to any mammalian subject in need of diagnosis, treatment or therapy, particularly a human.

[0097] As used herein, the term "ROC" or "ROC curve" can refer to a receiver operating characteristic curve. An ROC curve can be a graphical representation of the performance of a binary classifier system. For any given method, an ROC curve can be generated by plotting sensitivity against specificity at multiple threshold settings. Further, as long as at least one of three parameters (such as sensitivity, specificity and threshold setting) is provided, and the ROC curve can determine the value or expected value of any unknown parameter. The unknown parameter can be determined using a curve fitted to the ROC curve.

[0098] As used herein, the terms "AUC" or "ROC-AUC" generally refer to the area under the receiver operating characteristic curve. This metric takes into account the sensitivity and specificity of a method and can provide a measure of the diagnostic utility of the method. Generally, ROC-AUC ranges from 0.5 to 1.0, where values closer to 0.5 indicate limited diagnostic utility of the method (e.g., lower sensitivity and / or specificity), and values closer to 1.0 indicate greater diagnostic utility of the method (e.g., higher sensitivity and / or specificity). See, e.g., Pepe et al., "Limitations of the Odds Ratio in Gauging the Performance of a Diagnostic, Prognostic, or Screening Marker", Am. J. Epidemiol 2004, 159(9):882-890, which is incorporated herein by reference in its entirety. Other methods of characterizing diagnostic utility using likelihood functions, odds ratios, information theory, predictive values, calibration (including goodness of fit), and reclassification measures are outlined in Cook, "Use and Misuse of the Receiver Operating Characteristic Curve in Risk Prediction)", Circulation 2007, 115:928-935, which is incorporated herein by reference in its entirety.

[0099] An agent or component for obtaining the level of XIAP in a sample can understandably include a detection reagent that directly obtains the level of XIAP in the sample, or a component that indirectly obtains the level of XIAP in the sample (such as a computer program directly obtaining the index of the level of XIAP in a sample that has already been tested).

[0100] According to some embodiments of the present application, an index of the level of a biomarker can be obtained in any one of ways such as at the nucleic acid level, protein level, etc. The detection method is not limited, but any method that can be used to directly or indirectly evaluate the level of XIAP nucleic acid or protein is suitable for the present application. It can be understood that the nucleic acid level can include the DNA level or the RNA level. There are various methods for detecting the DNA or RNA level in the art, including but not limited to sequencing techniques, nucleic acid amplification techniques, nucleic acid hybridization techniques, electrophoresis techniques, bio-mass spectrometry techniques, or chromatography techniques, and these techniques can all be used in the present application. In some specific embodiments of the present application, it includes but is not limited to any one of the following specific methods: gene sequencing method, polymerase chain reaction method, isothermal amplification reaction method, gene chip method, probe hybridization method, gel electrophoresis method, RNA blotting method, nucleic acid mass spectrometry method, or liquid chromatography method.

[0101] For example, in some specific embodiments, the polymerase chain reaction method includes primers for XIAP amplification. Among them, the primers refer to primers that can specifically amplify the XIAP gene, such as polynucleotides of a certain length, such as primers of about 35 nucleotides or longer, which can hybridize with at least part of the template sequence and serve as the starting site for synthesizing primer extension products. In some specific embodiments, the probe hybridization method includes a probe for XIAP. Among them, the probe refers to a probe that can specifically recognize the XIAP gene or the transcript of this gene, which is a molecule that can bind to a specific sequence or subsequence or other part of another molecule, usually referring to a nucleic acid probe that binds to another nucleic acid (i.e., the specific sequence of XIAP as the target nucleotide) through complementary base pairing. In some specific embodiments, the gene chip refers to a composite structure formed by an array of the aforementioned probes fixed on a substrate material (specifically including but not limited to polymers such as nylon membranes, nitrocellulose membranes, and glass, etc.). In some embodiments, when detecting RNA, reverse transcription is required to obtain cDNA, and then detection is carried out through the primers for XIAP amplification.

[0102] It can be understood that there are various protein detection methods in the art, including but not limited to sequencing techniques, immunological techniques, electrophoresis techniques, bio-mass spectrometry techniques, or chromatography techniques, and these techniques can all be used in this application; in some specific embodiments of this application, it includes but is not limited to any of the following specific methods: amino acid sequencing method, enzyme-linked immunosorbent assay, chemiluminescence method, immunochromatography method, radioimmunoassay, immunohistochemistry method, immunoblotting method, flow cytometry, gel electrophoresis method, protein mass spectrometry method, or liquid chromatography method.

[0103] For example, in some embodiments, specific antibodies are included in the method for quantitatively detecting XIAP at the protein level. Among them, the specific antibody refers to an antibody that can specifically recognize the protein encoded by XIAP, specifically including but not limited to monoclonal antibodies (such as full-length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multispecific antibodies (such as bispecific antibodies with expected biological activities), nanobodies, or at least one of certain antibody fragments. It can be understood that the antibody can be a human, humanized, and / or affinity-matured antibody.

[0104] According to the experimental data of this application, the XIAP can be used as an independent indicator for the diagnosis of chronic kidney disease, and the effective diagnosis of chronic kidney disease can be achieved only based on XIAP.

[0105] It is understandable that, in order to further enhance the diagnostic effect for chronic kidney disease, the biomarkers detected by the reagent can also be other biomaterials such as nucleic acid fragments, proteins, metabolites, etc. that are well-known to those skilled in the art and have a diagnostic effect and can be used as biomarkers. By this way, the combined use of multiple biomarkers can be achieved, and they cooperate with each other to achieve a better diagnostic effect on chronic kidney disease patients, so as to achieve a more effective diagnostic evaluation. Therefore, in addition to being an independent indicator for the diagnosis of chronic kidney disease, the XIAP can also be jointly detected with other existing known diagnostic markers to improve the diagnostic efficiency.

[0106] For example, in some specific embodiments, the diagnosis also includes diagnostic reagents for detecting other genes or proteins, such as SCr, BUN, KIM-1, TIMP-2, IGFBP-7, MMP-7 or EGF mentioned in this application. The joint detection can be the combination of any one or more of them.

[0107] In some embodiments of the present application, the test samples described in the present application can be selected from tissues, cells, body fluids (serum, plasma, whole blood (peripheral blood), urine, semen, saliva, pleural effusion, ascites, cerebrospinal fluid, feces and synovial fluid); in a preferred embodiment, the test sample is selected from any one of serum, plasma, whole blood or urine.

[0108] Therapeutic use

[0109] The present application also finds through research that inhibiting XIAP can inhibit the epithelial-mesenchymal transition of renal tubular epithelial cells and thus delay the progression of renal fibrosis. Therefore, the present application also includes the application of XIAP in the treatment of chronic kidney disease patients, especially in delaying the progression of renal fibrosis.

[0110] Diagnostic method

[0111] The applicant finds that the level of XIAP in chronic kidney disease patients is higher than that in healthy people. Therefore, a relatively accurate prediction of the diagnosis of chronic kidney disease (especially early diagnosis) can be made according to the level of XIAP (such as the expression level).

[0112] The core of the diagnostic method includes the step of detecting or determining XIAP in the sample of the subject;

[0113] In some specific embodiments, the method includes the following steps:

[0114] (i) Detect or determine the level of XIAP in the test sample;

[0115] (ii) Compare the level of XIAP with a control sample; wherein, a significant difference in the level of XIAP between the test sample and the control sample is an indication that the subject has chronic kidney disease;

[0116] Or,

[0117] (ii) Compare with a set absolute threshold value; wherein, the level of the subject sample being higher than the absolute threshold value is an indication that the subject has chronic kidney disease.

[0118] In some embodiments, the "level of XIAP" or "XIAP level" in the text includes, but is not limited to, the abundance or concentration of XIAP nucleic acid or protein. For example, in some specific embodiments, it is the expression abundance or concentration of the corresponding protein.

[0119] It can be understood that the control sample can be selected according to actual needs. For example, in disease diagnosis, the control sample is a sample from the normal population, while in prognostic evaluation, it can be control samples with different prognostic situations.

[0120] In some specific embodiments, a set value of the XIAP expression level can be given. This set value can be determined based on the XIAP expression levels of normal samples of normal people and / or non-chronic kidney disease patients. For example, the average value of the XIAP expression levels of a suitable number of normal samples is selected, or a reasonable multiple is set based on this average value, such as 0.9 times, 0.8 times, 0.7 times, 0.6 times, 0.5 times, etc. When the XIAP expression level of the subject is higher than this set value, it is judged as chronic kidney disease. It can be understood that the set value determined based on the average value or a multiple of the average value needs to have good classification significance. It can be tested by using common statistical test methods on known samples based on the classification of this set value. When the result is statistically significant, it indicates that this set value can be used as a judgment criterion. Among them, the level of XIAP refers to a value directly measured for this biomarker of the subject or further indirectly derived based on the direct measurement. It usually at least partially originates from the abundance or concentration of the biomarker in the sample of the subject. Among them, the way of indirectly deriving the value includes being derived by applying a function to the measured value of this biomarker. The direct measurement values include, but are not limited to, the values of biomarkers determined by at least one of sequencing, hybridization, mass spectrometry, immunoassay, immunofluorescence, flow cytometry, etc.

[0121] Product

[0122] According to the core diagnostic use of the present application, the process for detecting the XIAP level can be configured into a corresponding product form for the diagnosis or prediction of chronic kidney disease. Such a product includes reagents or components for detecting the XIAP biomarker. It can be understood that such product forms are diverse and include, but are not limited to, the form of a kit, a system device, a computer-readable medium, or a computer system.

[0123] The form of a kit

[0124] In some embodiments of the present application, a kit for detecting or analyzing the XIAP level to predict CKD disease is also disclosed herein. Such a kit may include reagents for detecting the level of one or more biomarkers and instructions for predicting CKD disease based on the detected levels.

[0125] The kit may include a set of reagents for generating a data set through at least one determination. This set of reagents is capable of detecting the quantitative XIAP level. This set of reagents may further detect the level of one or more other biomarkers. In some aspects, the reagents detect at the nucleic acid or protein level.

[0126] When the detection reagent detects at the nucleic acid level, it can be understood that there are various nucleic acid detection methods in the art, including but not limited to sequencing techniques, nucleic acid amplification techniques, nucleic acid hybridization techniques, electrophoresis techniques, biomass spectrometry techniques, or chromatography techniques, and these techniques can all be used in the present application. In some specific embodiments of the present application, it includes but is not limited to any of the following specific methods: gene sequencing method, polymerase chain reaction method, isothermal amplification reaction method, gene chip method, probe hybridization method, gel electrophoresis method, RNA blotting method, nucleic acid mass spectrometry method, or liquid chromatography method.

[0127] Therefore, for example, in some specific embodiments, the reagent may be a sequencing reagent, such as first-generation Sanger sequencing reagent, second-generation sequencing (“NGS”) reagent, third-generation sequencing reagent, etc. In some other specific embodiments, the reagent is a PCR primer reagent, where the primer refers to a primer that can specifically amplify the XIAP gene, for example, a polynucleotide of a certain length, such as a primer of about 35 nucleotides or longer, which can hybridize with at least part of the template sequence and serve as the starting site for synthesizing the primer extension product. In some other specific embodiments, the reagent is a probe reagent, where the probe refers to a probe that can specifically recognize the XIAP gene or its gene transcript, and it is a molecule that can bind to a specific sequence or subsequence or other part of another molecule, usually referring to a nucleic acid probe that binds to another nucleic acid (i.e., the specific sequence of XIAP as the target nucleotide) through complementary base pairing.

[0128] When the detection agent is detected at the protein level, it can be understood that there are various protein detection methods in the art, including but not limited to sequencing technology, immunological technology, electrophoresis technology, bio-mass spectrometry technology or chromatography technology, and all these technologies can be used in this application; in some specific embodiments of this application, it includes but is not limited to any of the following specific methods: amino acid sequencing method, enzyme-linked immunosorbent assay, radioimmunoassay, immunohistochemistry, immunoblotting, flow cytometry, gel electrophoresis, protein mass spectrometry or liquid chromatography.

[0129] Thus, for example, in some specific embodiments, the reagent is a specific antibody, wherein the specific antibody refers to an antibody that can specifically recognize the protein encoded by XIAP, and specifically includes but is not limited to monoclonal antibodies (such as full-length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multispecific antibodies (such as bispecific antibodies with expected biological activities) or at least one of certain antibody fragments. It can be understood that the antibody can be a human, humanized and / or affinity matured antibody.

[0130] In some embodiments, such a kit may include a carrier, a package or a container, and the package or container is compartmentalized to receive one or more containers, such as vials, tubes, etc., and each container contains one of the independent elements to be used in the method. The kit of the present application may include the containers as described above and one or more other containers containing substances required from the perspective of commercial end-users, and the substances include buffers, diluents, filters and package inserts with instructions for use.

[0131] In some embodiments, the kit further includes a sample processing reagent, and the sample processing reagent may include at least one of a sample lysis reagent, a sample purification reagent and a sample extraction reagent.

[0132] In some embodiments, the product further includes at least one of a standard, a calibrator, a control and a buffer. Among them, the control is a control product for testing the validity of the experiment and serves as a control for judging the results. The buffer can be any solution well-known in the art that can provide appropriate buffer conditions during the detection process.

[0133] The kit may include instructions for using a set of reagents. For example, the kit may include instructions for performing at least one assay, such as an immunoassay, a protein binding assay, an antibody-based assay, an antigen-binding protein-based assay, a protein-based array, an enzyme-linked immunosorbent assay (ELISA), flow cytometry, a protein array, a blot, a Western blot, nephelometry, turbidimetry, chromatography, mass spectrometry, enzyme activity, and immunoassays, and the immunoassays are selected from RIA, immunofluorescence, immunochemiluminescence, immuno-electrochemiluminescence, immunoelectrophoresis, competitive immunoassays, and immunoprecipitation.

[0134] In addition to the above components, the kit will further include instructions for practicing the subject method. These instructions may exist in a variety of forms in the subject kit, and one or more of these forms may be present in the kit. One form in which these instructions may exist is that they are printed information on a suitable medium or substrate, for example, one or more sheets of paper on which the information is printed, and the paper is in the packaging of the kit in the form of a package insert, and so on.

[0135] System device

[0136] In some embodiments of the present application, a system for detecting or analyzing XIAP levels to predict CKD disease is also disclosed herein. Such a system may include a set of reagents for detecting the levels of one or more markers; a device configured to receive a mixture of one or more reagents and a test sample obtained from a subject to measure the XIAP level; and a computer system communicatively coupled to the device to obtain the measured level and determine a score for predicting the likelihood of CKD disease in a CKD patient.

[0137] The device is configured to detect the XIAP level in a mixture of the reagent and the test sample. For example, the device may determine the XIAP level by an immunoassay or an assay for nucleic acid detection. The mixture of the reagent and the test sample may be provided to the device through various containers, and examples of these containers include wells of a microtiter plate (e.g., a 96-well plate), vials, or tubes. Because of this, the device may have an opening (e.g., a slot, a cavity, an opening, a sliding tray) that can receive the container containing the reagent test sample mixture and read it to generate a quantitative expression value of the soluble medium. Examples of the device include a microplate reader (e.g., a luminescence microplate reader, an absorbance microplate reader, a fluorescence microplate reader), a spectrometer, and a spectrophotometer.

[0138] The computer system communicates with the device to receive the quantitative expression value of the soluble medium. The computer system analyzes the quantitative expression value by applying a prediction model and determines the likelihood of a CKD disease event in the subject.

[0139] in the form of a computer system or a computer-readable medium

[0140] In some embodiments of the present application, the methods or uses of the present application can be implemented on a computer, including detecting or analyzing the XIAP level by a computer to predict CKD disease.

[0141] For example, the construction and execution of a predictive model for generating a score (e.g., LFPI score) can be implemented in hardware or software or a combination of both. In one embodiment, a readable storage medium is provided. For example, the medium includes data storage material encoded with machine-readable data, which is capable of displaying any data set of the predictive model of the present application and performing and presenting results when used with a machine programmed with instructions to utilize the data. Such data can be used for various purposes, such as CKD patient monitoring, diagnosis, treatment considerations, etc. Embodiments of the above methods can be implemented in a computer program executable on a programmable computer, which includes a processor, a data storage system, a graphics adapter, a network adapter, at least one input device, and at least one output device, etc. A display is coupled to the graphics adapter. Program code is applied to the input data to perform the above functions and generate output information. The output information is applied to one or more output devices in a known manner. The computer can be, for example, a personal computer, a microcomputer, or a traditionally designed workstation.

[0142] Each program can be implemented in a high-level or object-oriented programming language to communicate with the computer system. However, if desired, the program can be implemented in assembly or machine language. In any case, the language can be a compiled or interpreted language. Each such computer program is preferably stored on a general-purpose or special-purpose programmable computer-readable storage medium or device (e.g., ROM or disk) for configuring and operating the computer to execute the program described herein when the computer reads the storage medium or device. The system can also be considered to be implemented in the form of a computer-readable storage medium configured with a computer program, where the storage medium so configured causes the computer to operate in a specific and predefined manner to perform the functions described herein.

[0143] Feature patterns and their databases can be provided in various media to facilitate their use. "Media" refers to a manufactured article containing the feature pattern information of this application. The database of this application can be recorded on a computer-readable medium, such as any medium that can be directly read and accessed by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy disks, hard disk storage media, and magnetic tapes; optical storage media, such as CD-ROMs; electronic storage media such as RAM and ROM; and mixtures of these categories, such as magnetic / optical storage media. Those skilled in the art can easily understand how any currently known computer-readable medium can be used to produce a manufactured article containing a record of the current database information. "Recording" refers to the process of storing information on a computer-readable medium using any such method known in the art. Any convenient data storage structure can be selected based on the manner used to access the stored information. Multiple data processor programs and formats can be used for storage, such as word processing text files, database formats, etc.

[0144] Other aspects

[0145] It can be understood that on the basis of being convinced that XIAP can be used as a diagnostic marker for chronic kidney disease, those skilled in the art can evaluate or screen other potential diagnostic markers for chronic kidney disease accordingly. Generally, potential biomarkers are evaluated for correlation with XIAP. Based on a positive correlation conclusion, it helps to illustrate the value of the potential diagnostic marker.

[0146] This application may also relate to a method for detecting a biomarker in a subject with or suspected of having chronic kidney disease in vivo or in vitro. The method includes determining or detecting the level of XIAP in a biological sample from the subject. The method may include non-diagnostic uses for diseases.

[0147] In addition, this application may also relate to a method for screening therapeutic agents for chronic kidney disease in vivo or in vitro. The method includes the step of evaluating the level of XIAP in a sample treated with a therapeutic agent, and evaluating the therapeutic effect of the therapeutic agent based on the XIAP level evaluation. For example, when the expression level of XIAP decreases, the therapeutic effect of the therapeutic agent can be determined.

[0148] The embodiments of this application will be described in detail below in conjunction with the examples.

[0149] Example 1

[0150] 1. Clinical samples:

[0151] A healthy control group and a CKD group were established. The healthy control group consisted of healthy individuals without clinical chronic kidney disease. The CKD group consisted of patients with primary chronic kidney disease who met the following criteria according to the CKD clinical practice guidelines developed by the Kidney Disease: Improving Global Outcomes (KDIGO) in clinical practice, i.e., patients with primary chronic kidney disease stages 4 - 5 met the following conditions: diagnosed with primary chronic kidney disease stages 4 - 5, where primary chronic kidney disease stages 4 - 5 refer to: the measured individual had an eGFR < 30 mL / min·1.73m 2 , for a duration of ≥ 3 months, without the need for immediate dialysis replacement therapy, without concurrent acute infectious diseases or tumors, and secondary kidney diseases were excluded. The secondary kidney diseases included lupus nephritis, diabetic nephropathy, allergic purpura nephritis, ANCA nephritis, or obstructive nephropathy.

[0152] 2. Inclusion criteria:

[0153] Ages 18 - 65 years; clinically diagnosed with chronic kidney disease stages 1 - 5; infections, acidosis, electrolyte disorders, hypertension, etc. were effectively controlled. Exclusion criteria: ages < 18 years or > 65 years; pregnant and lactating women; those with severe primary diseases in other systems; those who were unable to cooperate. The inclusion and exclusion criteria for the healthy control group were the same as those for the CKD group, and they had no kidney diseases.

[0154] 3. Experimental design and results

[0155] ① The expression profile GSE29677 dataset containing glomerular components of CKD patients was downloaded from the Gene Expression Omnibus (GEO). The R software package was used for data processing, and genes with log2FC > 1 or log2FC < -1 and P Value < 0.05 were selected as differentially expressed genes (DEGs). The ggplot package in R language was used to draw the DEG heatmap, and it was found that the members of the inhibitor of apoptosis protein (IAP) family (c-IAP1, c-IAP2, ML-IAP, Survivin, XIAP) were significantly upregulated in chronic kidney disease compared with the control group ( Figure 1 ).

[0156] To further verify the relationship between the IAP family and chronic kidney disease, this application used the Nephroseq online database and found that the expressions of c-IAP1, c-IAP2, ML-IAP, Survivin, XIAP, and TS-IAP in the IAP family were all significantly upregulated in patients with chronic kidney disease ( Figure 2) Among them, XIAP is a key member of the inhibitor of apoptosis protein family, which can directly inhibit apoptosis by binding to promoter caspases - 9, 3, and 7, and is involved in the mesenchymal transformation of malignant cells. Studies have found that inhibiting the XIAP signaling pathway can reduce kidney injury in rats with diabetic nephropathy. Preliminary experimental studies of this application have shown that the α7nAChR selective receptor antagonist MLA can inhibit the epithelial - mesenchymal transition of renal tubular epithelial cells by inhibiting the apoptosis inhibitor protein XIAP, thereby delaying the progression of renal fibrosis. Therefore, XIAP plays a certain role in the occurrence and development of renal fibrosis and chronic kidney disease.

[0157] ② From August 2021 to October 2022, 128 CKD patients (CKD group) and 40 healthy control subjects (healthy control group) were collected in the Department of Nephrology, People's Hospital Affiliated to Shanxi Medical University. CKD patients were diagnosed as primary glomerulonephritis by pathology or clinically. Information such as age, gender, body mass index (BMI), primary disease, serum creatinine, urea nitrogen, eGFR, etc. of the selected subjects was collected. This study was approved by the Ethics Committee of People's Hospital Affiliated to Shanxi Medical University, and the participants in the study signed an informed consent form. Collection of urine XIAP detection specimens: Subjects collected 5 ml of clean mid - stream urine in the early morning, centrifuged at a speed of 3000 r / min at 4°C for 15 minutes, and the urine supernatant was collected and stored in a - 80°C refrigerator. Urine from in - patients and the control group was collected, and the content of XIAP protein in urine was quantitatively detected by enzyme - linked immunosorbent assay (ELISA). IBM SPSS Statistics 20 software was used for statistical analysis. Normality tests were performed on continuous variables. Measurement data that conformed to a normal distribution were expressed as mean ± standard deviation (x ± s), and Pearson correlation analysis was used to analyze the correlation between the concentration of XIAP in urine and the concentrations of serum creatinine and urea nitrogen. When P < 0.05, there was a significant correlation between the two. The data of the concentration of XIAP in the urine of patients and the concentrations of serum creatinine and urea nitrogen are shown in the following table.

[0158] Table. Data of the concentration of XIAP in patients' urine and the concentrations of serum creatinine and urea nitrogen

[0159]

[0160]

[0161]

[0162]

[0163]

[0164] 4. Statistical analysis of the concentration of serum creatinine and the concentration of XIAP

[0165] Pearson correlation analysis: Pearson correlation analysis showed that there was a significant positive correlation between the level of XIAP in the urine of patients and the level of serum creatinine (r = 0.3762, P < 0.0001), and there was a significant strong positive correlation between the level of XIAP in the urine and the level of blood urea nitrogen (r = 0.4225, P < 0.0001). The specific visualization results are as Figure 3 shown.

[0166]

[0167]

[0168] Example 2

[0169] Furthermore, in this example, the sensitivity and specificity of XIAP in diagnosis were evaluated. Experimentally, another 80 CKD patients (CKD group) and 40 healthy control subjects (healthy control group) were selected as the experimental data set. Taking eGFR as the gold standard for diagnosing CKD in clinical work, the receiver operating characteristic curve (ROC Curve) was drawn using Graphpad Prism software. The area under the curve (AUC) value was used to evaluate whether the screened XIAP could be used as an early biological marker for diagnosis. The specificity and sensitivity of XIAP in diagnosing chronic kidney disease were calculated, and a suitable cut-off value was screened to be used as the upper limit of the reference value for XIAP in diagnosing chronic kidney disease and progression risk in clinical work.

[0170] The results are as Figure 4 shown. When the cut-off value of XIAP was 724.9 ng / L, the AUC was 0.9610, the sensitivity was as high as 94.59%, and the specificity was 82.5%. Therefore, XIAP has extremely excellent sensitivity and specificity for the occurrence and progression of CKD.

[0171] The study found that XIAP was significantly elevated in the early stage of CKD, and was positively correlated with the indicators reflecting renal function (serum creatinine and blood urea nitrogen), and showed a gradually increasing trend with the deterioration of renal function. XIAP is highly correlated with the occurrence and progression of CKD, and can be used as a new biological marker for the early diagnosis and progression evaluation of CKD, with significant clinical value.

[0172] Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present application, and are not intended to limit them; although the present application has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. Use of an agent for detecting the XIAP level in a sample in the preparation of a product for diagnosing chronic kidney disease, wherein the level is a protein level and the sample is urine.

2. The application according to claim 1, wherein The protein level is obtained by sequencing technology, immunoassay technology, electrophoresis technology, biomass spectrometry technology or chromatography technology.

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