Prediction and early diagnosis of acute kidney injury

Abstract

The present invention relates to the prediction and early diagnosis of acute kidney injury (AKI). The methods provide biomarkers that correlate with a patient's risk of developing AKI, or the presence of early AKI. The invention also provides devices and kits for predicting the risk of development of AKI and for diagnosing AKI.SOLUTION: A method for predicting the risk of occurrence of acute kidney injury (AKI) or for early diagnosis of AKI in a subject, the method comprising: a. determining in a sample obtained from the subject the amount of at least one biomarker selected from the group consisting of complement factor D and insulin-like growth factor binding protein 1 and combinations, isoforms, fragments and variants thereof.SELECTED DRAWING: None

Description

Summary of the Invention

[0001] The present invention relates to the field of organ failure prediction and early diagnosis. To predict the risk of acute kidney injury (AKI) and / or diagnose AKI at an early stage This relates to methods for

[0002] The present invention relates to a method for detecting a leukemia virus by using at least one biomarker selected from the biomarkers shown in Table 1. determining the amount of said at least one biomarker in said at least one sample; and comparing the amount of the biomarker to a control amount for at least one biomarker, whereby The risk of developing AKI is predicted and / or AKI is diagnosed in a timely manner. The authors identified a different set of biomarkers.

[0003] In one aspect, the present invention provides a method for predicting the risk of AKI at an early time point during medical intervention; and and / or a method for diagnosing AKI. More preferably, the present invention relates to a method for diagnosing AKI after surgical intervention. Methods for predicting risk of AKI and / or diagnosing AKI, sometimes at an early stage More preferably, the present invention relates to solid organ transplantation (sTx) and / or cardiac transplantation. Methods for predicting the risk of AKI and / or diagnosing AKI early at the time of surgery More preferably, the present invention relates to a method for the treatment of lung transplantation (LuTx), kidney transplantation, and heart valve repair. During repair or replacement, coronary artery bypass graft (CABG), transmyocardial laser revascularization Predict the risk of AKI early at the time of cardiac transplantation and / or A It relates to a method for diagnosing KI.

[0004] The present invention also stratifies subjects for changes in treatment regimens to improve patient outcomes. The method also contemplates a method for stratifying additional drugs to stabilize kidney function. In one embodiment, the present invention may include a method for determining its applicability to a particular person. We are developing diagnostic tests (companion diagnostic tests) that are useful as companion diagnostics for therapeutic drugs. Additionally, diagnostic devices and methods for carrying out the methods disclosed herein may be used. and kits are included. [Background technology]

[0005] Kidney / AKI The kidneys are responsible for the excretion of water and solutes from the body. Their functions include maintaining acid-base balance. These include maintaining blood flow, regulating electrolyte levels, controlling blood volume, and regulating blood pressure. Loss of kidney function due to kidney disease and / or kidney disease results in significant morbidity and mortality. Diseases and / or disorders can be acute and / or chronic. Acute kidney injury (AKI) is a condition that affects the filtration A rapid decline in kidney function with loss of renal capacity (typically detected within about 48 hours to 1 week) This is a decrease in the amount of nitrogenous and non-nitrogenous waste products normally excreted by the kidneys. This in turn leads to increased blood pressure, which leads to acid-base and electrolyte imbalances, which in turn reduces urine output. changes in fluid overload and serum renal retention parameters such as creatinine and urea This results in an increase in non-nitrogenous and nitrogenous metabolic waste products. The symptoms associated with AKI are highly variable. , decreased urine production, nausea and vomiting, high blood pressure, abdominal and chest pain, edema, shortness of breath, and mental confusion However, AKI may be particularly severe in the early stages. In the early stages, symptoms may be absent. AKI is a diagnosis code according to ICD-10 (2019). Includes N17.0, N17.1, N17.2, N17.8 and N17.9.

[0006] Etiological group Clinically, AKI can be divided into three etiological groups: Prerenal - severe renal blood flow reduction due to massive bleeding, hypotension, and ischemia-reperfusion injury adaptive response to Nephrogenic or intrinsic - a response to cytotoxic, ischemic, or inflammatory insults of the kidney; or autoimmune diseases affecting the kidneys (i.e., glomerular damage) with structural and functional damage nephritis, interstitial nephritis, etc.), and Postrenal - As a result of mechanical obstruction of the urinary tract (i.e., prostatic hyperplasia, obstructive uropathy, stones) Fruit.

[0007] Prerenal AKI can occur as a result of conditions such as hemorrhage; hypovolemia can occur as a result of congestive heart failure; Decreased cardiac output; resulting from conditions such as sepsis or renal vasoconstriction from vasoconstrictors Prerenal AKI can be a result of decreased vascular resistance due to intrinsic vasculitis if not treated properly. It often leads to AKI.

[0008] The renal pathogenesis of AKI is highly variable and can affect all four kidney structures. This means that the injury can be ductal, glomerular, interstitial, or vascular. The main causes of renal pathogenesis are ischemia, e.g., as a result of surgery; Nephrotoxicity resulting from certain types of antibiotics; acute glomerulonephritis; acute interstitial nephritis or other For example, renal vascular damage caused by malignant hypertension.

[0009] Causes of postrenal AKI include, for example, prostate or gynecological cancer, fibrosis, or ureteral valve disease. It is characterized by an obstruction to the flow of urine, which may be due to kidney disease or kidney stones.

[0010] Prevalence of AKI In the Western Hemisphere, AKI has become a predominantly hospital-acquired disease in critically ill patients. AKI is a very common clinical condition in hospitalized patients, especially in children and after major surgery. 7% of patients (Basile et al., 2012). Furthermore, the incidence of AKI is 5-7.5% of all intensive care unit (ICU) admissions, up to 52.6% of all patients % of AKI cases (Fuhrman et al., 2018). Surgical intervention is a major risk factor for AKI. 50% of patients experience AKI during their perioperative hospital stay (Hobson et al., 2016). After organ transplantation (tx = transplant), the incidence in the perioperative period ranges from 25% (after kidney transplantation) to 65% (after kidney transplantation). % (after liver transfusion) (Kalisvaart et al., 2018). After lung transfusion (LuTx) , the incidence of AKI is 50-65% (Wehbe et al., 2013; Wehbe et al., 2012) Furthermore, the incidence of AKI after hematopoietic cell transplantation is up to 70% (Kogon & Hingoran i, 2010). The incidence of AKI in men is 1.6 times higher than that in women (Brown et al., 2010). (T al., 2016). AKI also increases patient morbidity and length of hospital stay. Furthermore, the long-term consequences of AKI, such as chronic kidney disease (CKD), may be related to dialysis, renal replacement therapy (RRT), or other treatment options. AKI can lead to severe kidney failure or the need for a kidney transplant. Therefore, AKI is associated with significant medical costs. .

[0011] Classification of AKI The first classification system for defining and detecting AKI emerged in 2002 and In 2004, RIFLE (Risk, Impairment, Failure, Loss of Kidney Function, and ESKD - End-Stage Kidney Disease) The RIFLE classification was published as a classification of three clinical patterns (Bellomo et al., 2004). parameters (SCreat: serum creatinine or GFR: glomerular filtration rate and UO: The severity of urinary excretion is based on three severity classes (risk, disability and failure) and two outcome classes (loss of kidney function and end-stage renal disease, ESKD). R: "Risk": 1.5x increase in SCreat or more than 25% decrease in GFR within 6 hours small and UO<0.5 ml / kg / h; "Failure": 2.0-fold increase in SCreat or more than 50% decrease in GFR within 12 hours small and UO<0.5 ml / kg / h; "Insufficient": 3.0-fold increase in SCreat or SCr of 4 mg / dl or more in 24 hours Eat and GFR decreased by more than 75% and UO<0.3 ml / kg / h or anuria for at least 12 hours; "Loss": persistent need for renal replacement therapy for more than 4 weeks; "ESKD": The need for dialysis for more than three months.

[0012] For example, UO > 0.5 ml / kg / h for 6 hours and SCreat > 2 times Patients showing increased risk of stroke will be classified into disability classes. high sensitivity and low specificity for renal failure (risk and disorder), i.e., Patients who do not have end-stage renal disease will be erroneously included in the risk class. It has high specificity and low sensitivity, so it will miss some patients. .

[0013] The RIFLE classification has a significant impact on the diagnosis and prognosis of AKI in various clinical settings. Although it has been well justified (Lopes & Jorge, 2013), it has some important limitations. These limitations include the requirement for a baseline SCreat value, the limited precision of urine output measurements, and The role of several confounding factors in urine output measurements, such as blood pressure and diabetes, diuretic use, or in a hydrated state.

[0014] In an attempt to further improve outcomes for AKI patients, the AKI Network In 2007, a new classification was proposed (Mehta et al., 2007). This classification has two outcome classes: and the risk, disability and impairment classes were divided into categories AKIN1, AKIN2 and It was replaced by AKIN3. Furthermore, some modifications were made compared to the RIFLE classification. Before diagnosing AKI, adequate hydration should be achieved and urinary obstruction should be excluded. AKIN1 class is when it does not reach 1.5 times the baseline. including an increase in SCreat of more than or equal to 0.3 mg / dl Therefore, it is wider than the RISK class. The use of R was discarded because it added additional complexity to the classification system.

[0015] The AKIN classification of AKI proposed by Mehta et al., 2007

[0016] [Table 1]

[0017] The present invention divides patients into two groups: AKI corresponding to AKI stages 1, 2 and 3; and controls corresponding to patients without signs of AKI according to the AKIN classification. It is based on the AKIN classification system.

[0018] One of the main drawbacks of the AKIN classification system is the elevated clinical parameters (SCreat). Or, AKI can be diagnosed only if the decline in blood pressure (UO) occurs within 48 hours. Therefore, patients with AKI that develops over a longer period of time should be monitored closely. The AKIN classification is slightly different from the RIFLE classification. It is a modified version of the RIFLE classification, and some of its limitations are very similar to those of the RIFLE classification. The main general limitation of both classification systems is the clinical patterns used to stage patients. parameters are affected by various confounding factors such as sex, age, or volume status. Furthermore, these classification systems are subject to the does not allow for early detection of AKI, and today, individual risk assessment of AKI before surgery or ICU admission is limited. There are no available assays that allow prediction of risk.

[0019] Biomarkers in the field of AKI To date, no biomarkers have been described to assess individual risk of AKI. Regarding the diagnosis of AKI, the current diagnostic method for AKI is mainly based on blood Based on monitoring for elevated serum creatinine and decreased glomerular filtration rate or urine output. These parameters are influenced by gender, age, and volume status. Therefore, they are inadequate for early detection.

[0020] Currently, the biomarkers under discussion for the prediction and diagnosis of AKI are NGAL, Kim-1, IL18, L-FABP, AGT, TIMP-2, and IGFBP7 and the latter are both U.S. Food and Drug Administration (FDA)-approved NephroChe ck® (Astute Medical, Inc.) test NephroCheck® has limited reliability (sensitivity 76%, false positives Other biomarkers were detected only transiently (NGAL) or at later stages. It has the disadvantage of being regulated by KIM1.

[0021] Thus, more reliable biomarkers for the prediction and early diagnosis of AKI are needed. Furthermore, there is still a great need for diagnostic and further personalized medical treatment of subjects with AKI. Treatment would be beneficial for improved patient outcomes and cost-effectiveness for the healthcare system.

[0022] Proteins, as the end products or action products of gene expression, are essential for all cellular activities. It plays a vital role in the regulation of the immune system through many body fluids, including plasma, urine, and tissue extracts. The readily available proteins offer an immediate option for clinical analysis. Biochemical technologies are important for the discovery of clinically relevant biomarkers in various indications. It is essential. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention is a method for predicting AKI and diagnosing early stage AKI.

[0024] method The methods of the present invention can be used to predict the risk of developing acute kidney injury (AKI) in a subject or to assess the risk of developing AKI. and a sample obtained from the subject is suitable for the early diagnosis of I, determining the amount of biomarkers and determining the amount of biomarkers and the amount of biomarkers; Preferably, the biomarkers of the present invention are human proteins. It is of human origin, containing proteins and human carbohydrates.

[0025] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, CD9 antigen, prostaglandin G / H synthase 2, CD15, CD99 antigen, CD9 9R antigen, high-affinity immunoglobulin epsilon receptor subunit alpha, tumor necrosis factor Tumor necrosis factor receptor superfamily members, including lymphotoxin-alpha and lymphotoxin-alpha Ligand for β-cell receptor 1B, tumor necrosis factor receptor superfamily member 6, interferon alpha-1 / 13, basigin, CC motif, chemokine 7, Dickkopf protein Link protein 2, hyaluronan-mediated motility receptor, interleukin-18, interleukin-18 Leukin-7, major prion protein, receptor tyrosine protein phosphatase C , P-selectin glycoprotein ligand 1, tumor necrosis factor ligand superfamily member Bar-14, DNA topoisomerase 2-alpha, brain-derived neurotrophic factor, caspase-8 , eotaxin, CC motif chemokine 3, CC motif chemokine 5, monocyte differentiation Antigen CD14, cytokine receptor-like factor 2, lamin-B1, cell tumor antigen p53, parsley Serine / threonine protein kinase PAK1, caspase-9, transforming Growth factor-beta inducible protein ig-h3, leukocyte surface antigen CD47, T cell surface glycoprotein Protein CD8 alpha chain, Dickkopf-related protein 3, growth arrest-specific protein Protein 6, interleukin-15, cytokine receptor common subunit beta, keratinocytes Type II cytoskeleton 8, leukosialin, MAP / microtubule affinity-regulating kinase 4, melanofibrillar collagen, interstitial collagenase, matrilysin, prostaglandin G / H synthase 1, Myeloblastin, RNA-binding protein 3, serum amyloid P component, tetraspanin 16, urokinase-type plasminogen activator, CTP synthase 1, CD139 , Max dimerization protein 4, transmembrane protein 54, actin cytoplasmic 1, caspase -3, complement decay-accelerating factor, high mobility group protein B2, homeobox protein, Ho x-C11, intercellular adhesion molecule 1, interleukin-12 subunit alpha, Kru Eppel-like factor 8, galectin-4, regulatory complex protein LAMTOR1, L- Selectins, mitogen-activated protein kinase 3, mucin-5B, activated T cells Nuclear factor, transforming growth factor beta-1 proprotein, serine / threonine Protein kinase VRK1, cyclin-dependent kinase inhibitor 3, tissue factor pathway inhibitor 2, microtubule-associated protein 1A / 1B light chain 3B, phosphatidylinositol 3,4,5-triphosphate 3-phosphatase and dual specificity protein phosphatase PTEN, interleukin-8, Rho guanine nucleotide exchange factor 2, CASP8 and FADD-like apoptosis regulator, CUE domain-containing protein 2, cell death-associated Protein kinase 1, endothelin-1 receptor, eukaryotic translation initiation factor 3 subunit B, DNA-binding protein inhibitor ID-2, prelamin-A / C, CAD protein Protein, zinc finger protein 593, mitogen-activated protein kinase 12, cytochrome P450 1B1, angiotensinogen, adenomatous polyposis coli protein , POU domain class 2 transcription factor 1, somatostatin receptor type 4, tumor necrosis factor-alpha α-inducible protein 3, E3 ubiquitin protein ligase TRIM22, complement factor D, Neurotrophin-4, insulin-like growth factor binding protein 1, cystatin-B, insulin Interleukin-18 binding protein, WAP4 disulfide core domain protein 2 , haptoglobin, uteroglobin, chitinase-3-like protein 1, elafin, cartilage Oligomeric matrix proteins, interleukin-16 and inter-alpha trypsin Inhibitor heavy chain H1, and combinations thereof and their isoforms, fragments and and variants (this list includes SEQ ID NOS: 1-304 and CD15 and CD139) (Respond) determining the amount of at least one biomarker selected from the group consisting of: b. comparing the amount of the biomarker with a control amount of the biomarker; The present invention relates to a method comprising:

[0026] The present inventors identified 92 biomarkers (shown in Table 1). Of these, 79 have proven particularly useful in predicting the risk of developing AKI. (shown in Table 2), 26 of which have been shown to be particularly useful for the early diagnosis of AKI. The 12 biomarkers were associated with the risk of AKI development (Table 3). These findings have proven particularly useful for both the prediction and early diagnosis of AKI (Table 4). Thirty-five biomarkers showed higher abundance in association with AKI (Table 5), 68 biomarkers showed lower abundance in association with AKI. (shown in Table 6).

[0027] In one embodiment, the method comprises administering to a subject having or at risk of developing AKI. In some embodiments, determining the amount of a biomarker that is downregulated in the subject. In one embodiment, the biomarker has a logFC of less than -0.7. , is upregulated in subjects with or at risk of developing AKI In some embodiments, the biomarker is at least It has a logFC of at least 0.7.

[0028] "logFC" is defined as the logarithmic fold change calculated to the base 2 and is used to compare AKI patients with The difference in protein abundance / abundance between patients with and without AKI is shown in the Examples section. The amount can be determined using the antibody microarrays disclosed herein, such as those disclosed in logFC=1 means that patients with AKI have a higher FC rate than patients without AKI. On average, 2 1 = 2-fold higher abundance of the biomarker. c=-1 indicates the presence or absence of biomarkers in patients with AKI compared to patients without AKI The quantity is 2 -1 =1 / 2.

[0029] All of the methods disclosed herein involve determining an amount of a biomarker, a control amount of the biomarker, and The method may include predicting the subject's risk of developing AKI based on a comparison of the above. Biomarkers that are upregulated in subjects with AKI compared to control levels are An increase in the amount of the biomarker may indicate that the subject has AKI. For biomarkers that are upregulated in subjects at risk, the levels are compared to control levels. An increased amount of the selected biomarker may indicate that the subject is at risk for developing AKI. Biomarkers that are downregulated in subjects with AKI compared to control levels A decrease in the amount of the biomarker may indicate that the subject has AKI. For biomarkers that are down-regulated in subjects at risk, the levels are compared to control levels. A decrease in the amount of the selected biomarker can indicate that the subject is at risk for developing AKI.

[0030] Determining the amount of a biomarker in a sample may include biomarker detection. The biomarker detection may include binding the biomarker to a binding agent. The protein can be selected from proteins that specifically bind to the biomarker. An example of a protein is an antibody. Another example is a protein that binds to a receptor. A binding agent can be immobilized on a substrate, e.g., a receptor, where the binding agent is a ligand. Many of the biomarkers of the present invention can be detected using immobilized antibodies.

[0031] Some of the biomarkers described herein are members of the tumor necrosis factor receptor superfamily. These markers were identified using immobilized Fc-tumor necrosis factor receptor 1B. The use of a soluble receptor superfamily member 1B-fusion protein as an alternative to the use of antibodies This can be used as a means to capture the ligand of this receptor. tumor necrosis factor and lymphotoxin-alpha (SEQ ID NOs: 251-252). Examples of such ligands are marker number 5 in Table 1, marker number 4 in Table 2, and and / or marker number 5 in Table 6. The usefulness of all these biomarkers Evidence regarding the sex is provided in the Examples section. In general, these biomarkers All of these are useful for predicting and diagnosing AKI.

[0032] In one embodiment, the method comprises administering to a subject a therapeutically effective amount of at least one compound that is upregulated in association with AKI. In this embodiment, the present invention provides a method for determining the amount of a biomarker in a subject. To predict the risk of developing acute kidney injury (AKI) or for the early diagnosis of AKI 1. A method comprising: a. In a sample obtained from a subject, Interferon alpha-1 / 13, cell tumor antigen p53, caspase-9, interferon Leukin-7, interleukin-18, serum amyloid P component, urokinase-type plasma Activator of keratinocytes, keratin type II cytoskeleton 8, eotaxin, Max dimerization protein Protein 4, interleukin-15, CTP synthase 1, cytokine receptor-like factor 2 , RNA-binding protein 3, transmembrane protein 54, CC motif chemokine 7, homeostasis factor receptor 1 (F1), Hox-C11, a regulatory complex protein LAMTOR1, and Transforming growth factor beta-1 proprotein, high mobility group protein B2, cells Intercellular adhesion molecule 1, complement decay-accelerating factor, microtubule-associated protein 1A / 1B light chain 3B, phosphatase Tidylinositol 3,4,5-trisphosphate 3-phosphatase and dual specificity protein stromal phosphatase PTEN, caspase-8, growth arrest specific protein 6, interstitial collagen enzyme, eukaryotic translation initiation factor 3 subunit B, zinc finger protein 593, Indocerin-1 receptor, CASP8 and FADD-like apoptosis regulators, DNA binding Protein inhibitor ID-2, mitogen-activated protein kinase 12, POU Domain class 2 transcription factor 1, E3 ubiquitin protein ligase TRIM22, Gale tin-4, major prion protein, complement factor D, insulin-like growth factor binding protein 1, cystatin B, WAP4 disulfide core domain protein 2, uteroglobin , chitinase-3-like protein 1, elafin and cartilage oligomeric matrix protein, etc. and combinations thereof and their isoforms, fragments and variants. At least one biomarker that is upregulated in association with AKI selected from the group consisting of determining the amount of o-marker; b. comparing the amount of the biomarker with a control amount of the biomarker; The present invention relates to a method comprising:

[0033] These biomarkers showed higher abundance in association with AKI. The upregulated biomarkers identified are SEQ ID NOs: 13, 69-77, 80-8, and 90-97, respectively. 3, 27-29, 25-26, 122, 127-128, 102-103, 61, 131 , 98-99, 129-130, 65-67, 121, 132-134, 18, 145, 153, 184, 144, 146, 137-143, 190, 191-193, 52-6 0, 93~97, 112, 223~224, 233, 218~222, 198~212, 225, 234-235, 241-246, 249-250, 30, 152, 253-2 55, 259-265, 271-276, and 282-294.

[0034] As used herein, upregulated or downregulated "in the context of AKI" Biomarkers that may be useful for identifying patients at risk for developing AKI or for detecting (e.g., early) AKI This means that the biomarkers are up- or down-regulated, respectively, in subjects with do.

[0035] In one embodiment, the method comprises administering to a subject at least one gene that is downregulated in association with AKI. In this embodiment, the present invention provides a method for determining the amount of a biomarker in a subject. To predict the risk of developing acute kidney injury (AKI) or for the early diagnosis of AKI 1. A method comprising: a. In a sample obtained from a subject, Prostaglandin G / H synthase 2, CD15, CD99 antigen, CD99R antigen, tumor Tumor necrosis factor receptor superfamily member 6, tumor necrosis factor and lymphotoxin High-affinity ligand for tumor necrosis factor receptor superfamily member 1B, including alpha Immunoglobulin epsilon receptor subunit alpha, CD9 antigen, Dickkop f-related protein 2, CC motif chemokine 7, DNA topoisomerase 2-alf α, receptor tyrosine protein phosphatase C, major prion protein, P-selectin tin glycoprotein ligand 1, interleukin-7, basigin, hyaluronic acid-mediated transport Mobile receptor, interleukin-18, tumor necrosis factor ligand superfamily member -14, serine / threonine protein kinase PAK1, lamin-B1, monocyte differentiation antigen CD14, eotaxin, caspase-8, CC motif chemokine 3, brain-derived neurotrophic factor trophic factor, CC motif chemokine 5, cytokine receptor-like factor 2, leukocyte surface antigen C D47, leukosialin, interstitial collagenase, melanophilin, myeloblastin, Di ckkopf-related protein 3, MAP / microtubule affinity-regulating kinase 4, transforming Ig-H3, cytokine receptor common subunit Tobeta, prostaglandin G / H synthase 1, growth arrest-specific protein 6, RN A-binding protein 3, T-cell surface glycoprotein CD8 alpha chain, interleukin-1 5, tetraspanin-16, matrilysin, interferon alpha-1 / 13, C D139, nuclear factor of activated T cells, L-selectin, actin cytoplasmic 1, Krueppe I-like factor 8, interleukin-12 subunit alpha, interleukin-8, Cleavage promoter-activated protein kinase 3, caspase-3, galectin-4, mucin-5 B, serine / threonine protein kinase VRK1, cyclin-dependent kinase inhibitor Bitar 3, tissue factor pathway inhibitor 2, Rho guanine nucleotide exchange factor 2, pre Lamin-A / C, CAD protein, cell death-associated protein kinase 1, CUE domain containing protein 2, cytochrome P450 1B1, somatostatin receptor type 4, angiotensin Tensinogen, adenomatous polyposis coli protein, tumor necrosis factor alpha-inducible protein Protein 3, neurotrophin-4, interleukin-18 binding protein, haptoglobin bin, interleukin-16 and inter-alpha trypsin inhibitor heavy chain H1 and combinations thereof and their isoforms, fragments and variants. At least one valproate that is downregulated in association with AKI is selected from the group consisting of: determining the amount of biomarker; b. comparing the amount of the biomarker with a control amount of the biomarker; The present invention relates to a method comprising:

[0036] These biomarkers showed lower abundance in AKI. The biomarkers to be regulated are SEQ ID NOs: 1, 2-4, 6-12, 5, 19, 2 0, 18, 43-46, 31-38, 30, 39-40, 27-29, 14-17, 21 ~24, 25~26, 41~42, 78~79, 68, 64, 61, 52~60, 62, 47-51, 63, 65-67, 85-88, 104, 112, 107-111, 120 , 92, 105-106, 84, 100-101, 114-119, 93-97, 121 , 89-91, 98, 123-126, 113, 13, 160-183, 154-155 , 135, 148–151, 147, 194, 156–158, 136, 152, 159 , 185, 186, 188-189, 195-197, 226-231, 232, 214 ~217, 213, 236, 247, 237, 238~240, 248, 251~252 , 256-258, 266-270, 277-281, and 295-304, and Corresponds to CD15 and CD139.

[0037] The following methods are preferred methods: Biomarkers used in the preferred methods This set is particularly useful for predicting the risk of AKI occurrence and / or for early diagnosis of AKI. It has been shown to be useful. In the following progression, only step a. is shown. Preferably, the method also comprises, after step a., the following step: b. Comparing the amount of the biomarker with a control amount of the biomarker.

[0038] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, CD15 and interferon alpha-1 / 13, and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one biomarker selected from the group consisting of: These biomarkers show an excellent quality score of 6.

[0039] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. detecting in a sample obtained from a subject nuclear factor of activated T cells, complement factor D, insulin -like growth factor binding protein 1, haptoglobin, and combinations thereof and their At least one biotin selected from the group consisting of isoforms, fragments and variants Determining the amount of opiate marker These biomarkers show an excellent quality score of 6.

[0040] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, CD9 antigen, Dickkopf-related protein 2 and hyaluronan-mediated motility receptors, and combinations thereof and their isomers at least one biomer selected from the group consisting of forms, fragments and variants; Steps for determining the amount of car These biomarkers show an excellent quality score of 5.

[0041] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. Cytokine receptor-like factor 2 and lamin-B1 in a sample obtained from a subject and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one biomarker selected from the group These biomarkers show a very high quality score of 4. do.

[0042] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, the major prion protein, interleukin-1 8-binding protein, elafin, cartilage oligomeric matrix protein, and their combinations and isoforms, fragments and variants thereof. determining the amount of at least one biomarker These biomarkers show a very high quality score of 4. do.

[0043] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. The presence of cytokine receptor common subunit beta, rhodopsin, or rhodopsin in a sample obtained from the subject. Icosialin, MAP / microtubule affinity-regulating kinase 4, melanophilin, myeloblastic , RNA-binding protein 3, serum amyloid P component and tetraspanin-16, and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one biomarker selected from These biomarkers show a high quality score of 3.

[0044] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, CD99 antigen, CD99R antigen, and interalfa Trypsin inhibitor heavy chain H1, and combinations thereof and their isoforms at least one biomarker selected from the group consisting of a genome, a fragment, and a variant determining the amount of These biomarkers show a high quality score of 3.

[0045] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. Dickkopf-related protein 2 and interleukin-1 (IL-1) are detected in a sample obtained from a subject. -feron alfa-1 / 13, and combinations thereof and their isoforms , fragments, and variants of at least one biomarker selected from the group consisting of Steps to determine These biomarkers show excellent quality scores of 5-6. They are secreted proteins that make them particularly good candidates for detection in urine, blood, plasma or serum. It is also a type biomarker.

[0046] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. Neurotrophin-4 and complement factor D in a sample obtained from a subject, and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one biomarker selected from These biomarkers show excellent quality scores of 5-6. They are secreted proteins that make them particularly good candidates for detection in urine, blood, plasma or serum. It is also a type biomarker.

[0047] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, Dickkopf-related protein 2, cytokine Serum amyloid receptor-like factor 2 and serum amyloid P component, and their combinations and their At least one biotin selected from the group consisting of isoforms, fragments and variants Determining the amount of opiate marker These biomarkers are classified into 3-6 very high to excellent quality classes. They are particularly suitable for detection in urine, blood, plasma or serum. It is also a candidate secreted biomarker.

[0048] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, CD9 antigen, CD15, and hyaluronic acid-mediated Motility receptors, and combinations thereof and their isoforms, fragments and variants determining the amount of at least one biomarker selected from the group consisting of P These biomarkers show excellent quality scores of 5-6. They are membrane-type antibodies that are particularly good candidates for detection in urine, blood, plasma or serum. It is also a biomarker.

[0049] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. Complement factor D and insulin-like growth factor binding protein (IGF-binding protein) are detected in a sample obtained from the subject. Protein 1 and combinations thereof and their isoforms, fragments and variants determining the amount of at least one biomarker selected from the group consisting of These biomarkers show excellent quality scores of 5-7. They are membrane-type antibodies that are particularly good candidates for detection in urine, blood, plasma or serum. It is also a biomarker.

[0050] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, CD9 antigen, CD15, and hyaluronic acid-mediated motility receptors, myeloblastin and tetraspanin-16, and combinations thereof and isoforms, fragments and variants thereof. Determining the amount of one biomarker These biomarkers are classified into 3-6 very high to excellent quality classes. They are particularly suitable for detection in urine, blood, plasma or serum. It is also a candidate membrane-type biomarker.

[0051] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. CD99 antigen, and CD99R antigen in a sample obtained from a subject, and and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one biomarker selected These biomarkers are classified into 3-6 very high to excellent quality classes. They are particularly suitable for detection in urine, blood, plasma or serum. It is also a candidate membrane-type biomarker.

[0052] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. Identification of CD9 antigen, CD15, cytokine receptor-like factors in a sample obtained from a subject Child 2, lamin-B1, melanophilin, myeloblastin, serum amyloid P component, Kr Ueppel-like factor 8, nuclear factor of activated T cells, Rho guanine nucleotide exchange factor 2 , CASP8 and FADD-like apoptosis regulator, CUE domain-containing protein 2 , cell death-associated protein kinase 1, prelamin-A / C, cytochrome P450 1B1 , adenomatous polyposis coli protein and POU domain, class 2, transcription factor 1, etc. and combinations thereof and isoforms, fragments and variants thereof. determining the amount of at least one biomarker selected from These biomarkers exhibit differential kidney expression. Renal expression refers to the relative abundance within the kidney substructure observed by the inventors. The relative renal function of the markers is shown, making them particularly suitable as biomarkers for renal damage. To do.

[0053] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. CD9 antigen, CD15, and myeloblastin in a sample obtained from a subject; and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one biomarker selected from the group These biomarkers have a high to excellent quality score of 3 to 6. They also show differential kidney expression. This refers to the specific abundance in the renal substructure observed by

[14] . These findings make them particularly suitable as biomarkers for kidney damage. These three proteins are expressed by leukocytes; more specifically, they It is located on the vacuolar membrane or in the granules of polymorphonuclear leukocytes. The immune response to kidney injury during AKI is Leukocytes are an important contributor to the long-term loss of kidney function and the progression of kidney damage. This is particularly important since it is known to be involved in the pathogenesis of chronic kidney disease (Kinsey & O kusa, 2012).

[0054] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, the nuclear factor of activated T cells, interferon alfa, α-1 / 13 and myeloblastin, and combinations thereof and their isoforms at least one biomarker selected from the group consisting of forms, fragments and variants Step 1: Determine the amount of These biomarkers have a high to excellent quality score of 3 to 6. It shows.

[0055] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, CD15, lamin-B1, MAP / microtubule affinity Regulatory kinase 4, Dickkopf-related protein 2, Krueppel-like factor 8, Rh o Guanine nucleotide exchange factor 2, CUE domain-containing protein 2, cell death-associated protein Protein kinase 1, DNA-binding protein inhibitor ID-2, prelamin A / C, Adenomatous polyposis coli protein, POU domain class 2 transcription factor 1, somatostatin receptor type 4 and major necrosis factor alpha-inducible protein 3, and their combinations and isoforms, fragments and variants thereof. determining the amount of one biomarker at a time These biomarkers are differentially abundant in male patients. However, it was found to be particularly useful for predicting and / or diagnosing AKI in male patients. It is useful.

[0056] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, CD15, lamin-B1, and MAP / microtubule progenitor and combinations thereof and their isoforms, fragments and and a variant thereof. Steps These biomarkers have a high to excellent quality score of 3 to 6. They were also detected as differentially abundant in male patients, It is particularly useful for predicting and / or diagnosing AKI in male patients.

[0057] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, the CD9 antigen, tetraspanin-16, and and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one biomarker These biomarkers are integral membrane markers of the tetraspanin family. They interact with various proteins and other tetraspanins. is necessary for the normal development and function of several organs, including the eyes, kidneys, and immune system. (Charrin et al., 2014).

[0058] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. A sample obtained from a subject is tested for serum amyloid P component, L-selectin, and gastrointestinal Lectin-4, and combinations thereof and their isoforms, fragments and variants determining the amount of at least one biomarker selected from the group consisting of P These biomarkers belong to the lectin family. Proteins are specific carbohydrate-binding proteins whose main function is to facilitate cell-cell contact. For example, selectins mediate leukocyte adhesion and signal transduction in the blood vessel wall. , which is a key step during inflammation and immune responses (McEver, 2015).

[0059] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. A sample obtained from a subject is tested for the presence of MAP / microtubule affinity-regulating kinase 4, microtubule-associated kinase 5 (MAP / microtubule affinity-regulating kinase 4), or Link protein 1A / 1B light chain 3B, Rho guanine nucleotide exchange factor 2, adenomatous colorectal cancer Polyposis proteins, and combinations thereof and their isoforms and fragments and determining the amount of at least one biomarker selected from the group consisting of: Steps to take These biomarkers belong to the microtubule-associated proteins. In renal tubular epithelial cells, the microtubule cytoskeleton plays an important role in maintaining cell polarity, This in turn affects kidney function (Drubin & Nelson, 1996).

[0060] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. MAP / microtubule affinity-regulating kinase 4, mitogenic kinase in a sample obtained from a subject Factor-activated protein kinase 3, serine / threonine protein kinase VRK1, cell Cell death-associated protein kinase 1, mitogen-activated protein kinase 12, and and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one biomarker selected These biomarkers include protein serine / threonine kinase Serine / threonine kinases play a variety of roles, including regulating renal tubular transport. It is a key mediator in signal transduction pathways ( Satoh et al., 2015 ).

[0061] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. detecting a cyclin-dependent kinase inhibitor 3 (PKI-3), phosphodiesterase 4 (PDR-4), or phosphodiesterase 5 (PDR-4) in a sample obtained from the subject; Phatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual specificity protein Protein phosphatase PTEN, and combinations thereof and their isoforms , fragments, and variants of at least one biomarker selected from the group consisting of Steps to determine These biomarkers include protein tyrosine phosphatase activity. Protein tyrosine phosphorylation and dephosphorylation signaling are essential for podocytes. It is important for vacuolar function and repair ( Nezvitsky et al., 2014 ; Hsu et al., 2017 ). .

[0062] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. In a sample obtained from a subject, CTP synthase 1 and CAD protein, and combinations thereof and isoforms, fragments and variants thereof. determining the amount of at least one biomarker selected from These biomarkers are involved in pyrimidine biosynthesis. Glycoproteins are fundamental for DNA repair, gene transcription, protein synthesis, and cellular metabolism .

[0063] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. Identification of cytokine receptor common subunit beta, ibuprofen, ibuprofen, ibuprofen-1, ibuprofen-2, ibuprofen-3, ibuprofen-4, ibuprofen-5, ibuprofen-6, ibuprofen-7, ibuprofen-8, ibuprofen-9, ibuprofen-10, ibuprofen-11, ibuprofen-12, ibuprofen-13, ibuprofen-14, Interferon alfa-1 / 13 and cytokine receptor-like factor 2, and their and combinations thereof, and isoforms, fragments and variants thereof. determining the amount of at least one biomarker These biomarkers are involved in the Jak-STAT signaling pathway. Janus kinase / signal transducer and activator of transcription ( The JAK / STAT pathway, particularly STAT1 and STAT3, is a key regulator of renal fibrosis and diabetes It has been shown to be activated in renal and non-renal cells in kidney diseases such as nephropathy. (Chuang & He, 2010;Pang et al., 2010).

[0064] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. The presence of complement factor D, neurotrophin-4, insulin in a sample obtained from a subject Cystin-like growth factor binding protein 1, cystatin B, interleukin-18 binding protein Protein, WAP4 disulfide core domain protein 2, haptoglobin, uteroglobin , chitinase-3-like protein 1, elafin, cartilage oligomeric matrix protein, interleukin-1 -leukin-16, and inter-alpha trypsin inhibitor heavy chain H1, and and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one biomarker selected The present invention relates to a method comprising:

[0065] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. or for the early diagnosis of AKI, comprising: a. Identification of nuclear factor of activated T cells, CD99R antigen, galectin, and galactosidase in a sample obtained from a subject. tin 4, prostaglandin G / H synthase 2, insulin-like growth factor binding protein 1. Haptoglobin, uteroglobin, and combinations thereof and their isoforms at least one biomarker selected from the group consisting of a genome, a fragment, and a variant determining the amount of These biomarkers are useful in determining whether a patient is at increased risk of developing AKI or not. A ratio of at least 0.5, preferably at least 1.0, associated with a diagnosis of early AKI; Shows large absolute delta logFC between the predicted and diagnostic states of subjects.

[0066] In embodiments of the diagnostic methods, in addition to the biomarkers listed herein, additional biomarkers may be used. Biomarkers are determined in the sample. Further biomarkers include protein biomarkers. Car, male patient biomarker, predictive biomarker, diagnostic biomarker, or combination One, two, or more of the combined predictive and diagnostic biomarkers It may also be a biomarker.

[0067] Forecasting Method The following methods are preferred predictive methods, i.e., for determining a subject's risk of developing AKI. The set of biomarkers used in the preferred method is The following has been shown to be particularly useful for predicting the risk of developing AKI. In the transition, only step a. is shown. Preferably, the method after step a. also includes the following steps: b. Comparing the amount of the biomarker with a control amount of the biomarker.

[0068] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. Upregulated in a sample obtained from a subject in association with impending AKI determining the amount of at least one biomarker and the upregulated predictive biomarkers include: Cellular tumor antigen p53, serum amyloid P component, urokinase-type plasminogen activator keratin type II cytoskeleton 8, homeobox protein Hox-C11, regulatory factors LAMTOR1, a transforming growth factor beta-1 protein complex protein Protein, high mobility group protein B2, intercellular adhesion molecule 1, complement decay-accelerating factor, eukaryotic translation Translation initiation factor 3 subunit B, zinc finger protein 593, endothelin-1 receptor CASP8 and FADD-like apoptosis regulators, DNA-binding protein inhibitors terID-2, POU domain class 2 transcription factor 1, and combinations thereof and Isoforms, fragments and variants of The present invention relates to a method for producing a pharmaceutical composition comprising the steps of:

[0069] The listed upregulated predictive biomarkers are useful for predicting the risk of AKI development. These biomarkers have proven particularly useful in the treatment of rhesus macular degeneration. ~77, 122, 127~128, 102~103, 145, 153, 184, 144, 146, 137-143, 223-224, 233, 218-222, 198-212, Corresponds to 225 and 241-246.

[0070] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. Downregulated in a sample obtained from a subject in association with impending AKI determining the amount of at least one biomarker and the predictive biomarkers that are downregulated include: CD15, CD99 antigen, CD99R antigen, tumor necrosis factor receptor superfamily member Tumor necrosis factor receptor serogroups, including member 6, tumor necrosis factor, and lymphotoxin-alpha Ligand for Parr family member 1B, the high-affinity immunoglobulin epsilon receptor subunit Unit alpha, CD9 antigen, Dickkopf-related protein 2, CC motif Ke Mokine 7, DNA topoisomerase 2-alpha, receptor tyrosine-linked protein phosphatase adenosine triphosphate (ATP), major prion protein, P-selectin glycoprotein ligand 1, interleukin (IL-1), leukin-7, basigin, hyaluronan-mediated motility receptor, interleukin-18, Tumor necrosis factor ligand superfamily member 14, serine / threonine protein Kinase PAK1, lamin-B1, monocyte differentiation antigen CD14, eotaxin, caspase- 8, CC motif chemokine 3, brain-derived neurotrophic factor, CC motif chemokine 5, Cytokine receptor-like factor 2, leukocyte surface antigen CD47, leukosialin, interstitial collagen enzymes, melanophilin, myeloblastin, Dickkopf-related protein 3, MAP / Microtubule affinity-regulating kinase 4, transforming growth factor beta-inducible, protein Ig-H3, cytokine receptor common subunit beta, prostaglandin G / H synthase 1, growth arrest-specific protein 6, RNA-binding protein 3, T cell surface glycoprotein Protein CD8 alpha chain, interleukin-15, tetraspanin-16, matrila Isin, interferon alpha-1 / 13, nuclear factor of activated T cells, L-selectin , actin cytoplasmic 1, Krueppel-like factor 8, interleukin-12 subunit alpha, interleukin-8, mitogen-activated protein kinase 3, caspar Ze-3, galectin-4, mucin-5B, serine / threonine protein kinase VRK 1, Rho guanine nucleotide exchange factor 2, prelamin-A / C, CAD protein, Death-associated protein kinase 1, CUE domain-containing protein 2, somatostatin receptor Type 4, angiotensinogen, adenomatous polyposis coli protein, tumor necrosis factor Lupus-inducible protein 3, neurotrophin-4, interleukin-18 binding protein Protein, interleukin-16 and inter-alpha trypsin inhibitor heavy chain H 1, and combinations thereof and their isoforms, fragments and variants The present invention relates to a method for producing a pharmaceutical composition comprising the steps of:

[0071] The listed down-regulated predictive biomarkers are useful for predicting the risk of AKI development. These biomarkers have proven particularly useful in the treatment of rhesus macular degeneration. 4, 6-12, 5, 19, 20, 18, 43-46, 31-38, 30, 39-40, 2 7-29, 14-17, 21-24, 25-26, 41-42, 78-79, 68, 64 , 61, 52-60, 62, 47-51, 63, 65-67, 85-88, 104, 11 2, 107-111, 120, 92, 105-106, 84, 100-101, 114- 119, 93-97, 121, 89-91, 98, 123-126, 113, 13, 16 0~183, 154~155, 135, 148~151, 147, 194, 156~15 8, 136, 152, 159, 185, 195-197, 226-231, 232, 21 4-217, 213, 247, 237, 238-240, 248, 251-252, 25 6–258, 266–270, 277–281, and 295–304, and CD1 Corresponds to 5.

[0072] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, CD15 and interferon alpha-1 / 13, and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one predictive biomarker selected from the group consisting of: These biomarkers show an excellent quality score of 6.

[0073] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. Identifying nuclear factor of activated T cells and interferon-α in a sample obtained from a subject Lufa-1 / 13, and combinations thereof and their isoforms, fragments and determining the amount of at least one predictive biomarker selected from the group consisting of variants Steps to take These biomarkers show excellent quality scores of 5-6. do.

[0074] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, CD9 antigen, Dickkopf-related protein 2 , hyaluronan-mediated motility receptors, and their combinations and isoforms at least one predicted biomarker selected from the group consisting of a genome, a fragment, and a variant; Steps for determining the amount of car These biomarkers show an excellent quality score of 5.

[0075] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. The presence of interferon alpha-1 / 13 and neutrophils in a sample obtained from a subject and a polypeptide selected from the group consisting of adenosine triphosphate-4, its isoforms, fragments and variants. determining the amount of at least one predictive biomarker selected These biomarkers show an excellent quality score of 5. In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for: a. Cytokine receptor-like factor 2 and lamin-B1 in a sample obtained from a subject and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one predictive biomarker selected from the group These biomarkers show a very high quality score of 4. do.

[0076] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. Identification of interleukin-18 binding proteins, at least one protease selected from the group consisting of isoforms, fragments and variants of Determining the amount of the measured biomarker These biomarkers show a very high quality score of 4. In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for a. A sample obtained from a subject is found to contain cytokine receptor common subunit beta, rhodopsin, and / or rhodopsin. Icosialin, MAP / microtubule affinity-regulating kinase 4, melanophilin, myeloblastic , RNA-binding protein 3, serum amyloid P component and tetraspanin-16, and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one predictive biomarker selected from These biomarkers show a high quality score of 3.

[0077] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, CD99 antigen, CD99R antigen, CUE domain Contains protein 2, interleukin-16, inter-alpha trypsin inhibitor Heavy chain H1, and combinations thereof and their isoforms, fragments and variants determining the amount of at least one predictive biomarker selected from the group consisting of These biomarkers show a high quality score of 3.

[0078] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. Dickkopf-related protein 2 and interleukin-1 (IL-1) are detected in a sample obtained from a subject. -feron alfa-1 / 13, and combinations thereof and their isoforms at least one predictive biomarker selected from the group consisting of: a fragment and a variant determining the amount of These biomarkers show excellent quality scores of 5-6. They are secreted proteins that make them particularly good candidates for detection in urine, blood, plasma or serum. It is also a type biomarker.

[0079] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. Neurotrophin-4 and interferon in a sample obtained from a subject Alpha-1 / 13, and combinations thereof and their isoforms, fragments and and determining the amount of at least one predictive biomarker selected from the group consisting of: Steps to take These biomarkers show excellent quality scores of 5-6. They are secreted proteins that make them particularly good candidates for detection in urine, blood, plasma or serum. It is also a type biomarker.

[0080] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, Dickkopf-related protein 2, cytokine Serum amyloid receptor-like factor 2, and serum amyloid P component, and combinations thereof and at least one protease selected from the group consisting of isoforms, fragments and variants of Determining the amount of the measured biomarker These biomarkers have a high to excellent quality score of 3 to 6. They are particularly suitable candidates for detection in urine, blood, plasma or serum. It is also a secreted biomarker.

[0081] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, CD9 antigen, CD15, and hyaluronic acid-mediated motility Sex receptors, and combinations thereof and their isoforms, fragments and variants determining the amount of at least one predictive biomarker selected from the group consisting of P These biomarkers show excellent quality scores of 5-6. They are membrane-type antibodies that are particularly good candidates for detection in urine, blood, plasma or serum. It is also a biomarker.

[0082] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, CD9 antigen, CD15, and hyaluronic acid-mediated motility Sex receptor, myeloblastin, tetraspanin-16, CD99 antigen, and CD99R antigens, and combinations thereof and their isoforms, fragments and variants determining the amount of at least one predictive biomarker selected from the group consisting of: These biomarkers have a high to excellent quality score of 3 to 6. They are particularly suitable candidates for detection in urine, blood, plasma or serum. It is also a membrane-type biomarker.

[0083] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. Identification of CD9 antigen, CD15, cytokine receptor-like factors in a sample obtained from a subject Child 2, lamin-B1, melanophilin, myeloblastin, Krueppel-like factor 8, Nuclear factor of activated T cells, Rho guanine nucleotide exchange factor 2, CUE domain-containing protein Protein 2, death-associated protein kinase 1, prelamin-A / C, adenomatous polyposis coli sis proteins, and combinations thereof and their isoforms, fragments and determining the amount of at least one predictive biomarker selected from the group consisting of variants Steps to take These biomarkers exhibit differential kidney expression. Renal expression refers to the relative abundance within the kidney substructure observed by the inventors. The relative renal function of the markers is shown, making them particularly suitable as biomarkers for renal damage. To do.

[0084] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, CD9 antigen, CD15, and hyaluronic acid-mediated motility Sex receptors, and combinations thereof and their isoforms, fragments and variants determining the amount of at least one predictive biomarker selected from the group consisting of P These biomarkers have a high to excellent quality score of 3 to 6. They also show differential kidney expression. This refers to the specific abundance in the renal substructure observed by

[14] . These findings make them particularly suitable as biomarkers for kidney damage.

[0085] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, CD15, lamin-B1, MAP / microtubule affinity Regulatory kinase 4, Dickkopf-related protein 2, Krueppel-like factor 8, Rh Guanine nucleotide exchange factor 2, prelamin A / C, cell death-related protein kinase Ze1, CUE domain-containing protein 2, somatostatin receptor type 4, adenomatous polyposis coli sis protein, DNA-binding protein inhibitor ID-2, POU domain class 2 transcription factor 1, tumor necrosis factor alpha-inducible protein 3, and combinations thereof and isoforms, fragments and variants thereof. Determining the amount of one predictive biomarker These biomarkers are differentially abundant in male patients. These findings are particularly useful for predicting AKI in male patients.

[0086] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, CD15, lamin-B1, MAP / microtubule affinity Regulatory kinase 4, and combinations thereof and their isoforms, fragments and variants thereof and determining the amount of at least one biomarker selected from the group consisting of: Top These biomarkers have a high to excellent quality score of 3 to 6. They were also detected as differentially abundant in male patients, It is particularly useful for predicting AKI in male patients.

[0087] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. In a sample obtained from a subject, the CD9 antigen, tetraspanin-16, and and combinations thereof and their isoforms, fragments and variants. determining the amount of at least one predictive biomarker These biomarkers are integral membrane markers of the tetraspanin family. They interact with various proteins and other tetraspanins. It is necessary for the normal development and function of several organs, including the eyes and immune system ( Charrin et al., 2014 ).

[0088] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. A sample obtained from a subject is tested for serum amyloid P component, L-selectin, and gastrointestinal Lectin-4, and combinations thereof and their isoforms, fragments and variants A method for determining the amount of at least one predictive biomarker selected from the group consisting of: Tep These biomarkers belong to the lectin family. Proteins are specific carbohydrate-binding proteins whose main function is to facilitate cell-cell contact. For example, selectins mediate leukocyte adhesion and signal transduction in the blood vessel wall. , which is a key step during inflammation and immune responses (McEver, 2015).

[0089] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. The presence of MAP / microtubule affinity-regulating kinase 4, Rho kinase, or anion nucleotide exchange factor 2, adenomatous polyposis coli protein, and their combinations thereof and their isoforms, fragments and variants. Determining the amount of at least one predictive biomarker These biomarkers belong to the microtubule-associated proteins. In renal tubular epithelial cells, the microtubule cytoskeleton plays an important role in maintaining cell polarity, This in turn affects kidney function (Drubin & Nelson, 1996).

[0090] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. MAP / microtubule affinity-regulating kinase 4, mitogenic kinase in a sample obtained from a subject Factor-activated protein kinase 3, serine / threonine protein kinase VRK1, cell Cell death-associated protein kinase 1, and combinations thereof and their isoforms at least one predictive biomarker selected from the group consisting of: a fragment and a variant determining the amount of These biomarkers include protein serine / threonine kinase Serine / threonine kinases play a variety of roles, including regulating renal tubular transport. It is a key mediator in signal transduction pathways ( Satoh et al., 2015 ).

[0091] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. Detecting CAD proteins and their isoforms in a sample obtained from a subject determining the amount of one predictive biomarker selected from the group of a sequence, a fragment, and a variant; Steps to take These biomarkers are involved in pyrimidine biosynthesis. Glycoproteins are fundamental for DNA repair, gene transcription, protein synthesis, and cellular metabolism .

[0092] In one aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. 1. A method for producing a medicament for use in a medical device, comprising: a. Identification of cytokine receptor common subunit beta, ibuprofen, ibuprofen, ibuprofen-1, ibuprofen-2, ibuprofen-3, ibuprofen-4, ibuprofen-5, ibuprofen-6, ibuprofen-7, ibuprofen-8, ibuprofen-9, ibuprofen-10, ibuprofen-11, ibuprofen-12, ibuprofen-13, ibuprofen-14, Interferon alfa-1 / 13, cytokine receptor-like factor 2, and their combinations and isoforms, fragments and variants thereof. determining the amount of at least one predictive biomarker These biomarkers are involved in the Jak-STAT signaling pathway. Janus kinase / signal transducer and activator of transcription ( The JAK / STAT pathway is involved in the renal response to injury and the progression of several renal diseases. This is important (Chuang & He, 2010; Pang et al., 2010).

[0093] In embodiments of the prediction methods, in addition to the biomarkers listed herein, additional biomarkers may be used. Biomarkers are determined in the sample. Additional biomarkers include protein biomarkers. markers, male patient biomarkers, predictive biomarkers, diagnostic biomarkers, or One, two, or more biomarkers selected from predictive and diagnostic biomarkers It may also be a car.

[0094] Diagnostic methods The following methods are preferred diagnostic methods, and these methods are used to determine whether a subject has (early) AKI. The biomarkers used in the preferred method are used to determine whether or not to Carr's set has been shown to be particularly useful for the early diagnosis of AKI. In the transition, only step a. is shown. Preferably, the method after step a. also includes the following steps: b. Comparing the amount of the biomarker with a control amount of the biomarker.

[0095] In one aspect, the present invention provides a method for diagnosing acute kidney injury (AKI) in a subject. There was, a. Upregulated in a sample obtained from a subject in association with the presence of early AKI determining the amount of at least one biomarker present in the sample; and the diagnostic biomarker that is upregulated comprises: Interferon alpha-1 / 13, caspase-9, interleukin-7, Interleukin-18, eotaxin, Max dimerization protein 4, interleukin- 15, CTP synthase 1, cytokine receptor-like factor 2, RNA-binding protein 3, membrane Transmembrane protein 54, CC motif chemokine 7, microtubule-associated protein 1A / 1B light Chain 3B, phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and Dual specificity protein phosphatase PTEN, caspase-8, growth arrest specific protein Interstitial collagenase 6, interstitial collagenase, mitogen-activated protein kinase 12, E3 ubiquitin Protein ligase TRIM22, galectin-4, major prion protein, complement factors D, insulin-like growth factor binding protein 1, cystatin B, WAP4 disulfide copolymer Adomain protein 2, uteroglobin, chitinase-3-like protein 1, elafin and cartilage oligomeric matrix proteins, and combinations thereof and isoforms thereof Forms, Fragments and Variants The present invention relates to a method selected from the group consisting of:

[0096] The listed upregulated diagnostic biomarkers are particularly useful for early diagnosis of AKI. These biomarkers were identified as SEQ ID NOs: 13, 80, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 4 83, 27-29, 25-26, 61, 131, 98-99, 129-130, 65-6 7, 121, 132-134, 18, 190, 191-193, 52-60, 93-97 , 112, 234-235, and 249-250, 253-255, 259-265, 266-270, 271-294).

[0097] In one aspect, the present invention provides a method for diagnosing acute kidney injury (AKI) in a subject. There was, a. Downregulated in a sample obtained from a subject in association with the presence of early AKI determining the amount of at least one biomarker present in the sample; and the diagnostic biomarker that is downregulated comprises: Prostaglandin G / H synthase 2, CD139, cyclin-dependent kinase inhibitor 3, tissue factor pathway inhibitor 2, Krueppel-like factor 8, and cytochrome c P450 1B1, and combinations thereof and their isoforms, fragments and and variants The present invention relates to a method selected from the group consisting of:

[0098] The listed down-regulated diagnostic biomarkers are particularly useful for early diagnosis of AKI These biomarkers were identified as SEQ ID NOs: 1, 148-149, respectively. 51, 186, 188-189, and 236, as well as CD139.

[0099] In one aspect, the present invention provides a method for diagnosing acute kidney injury (AKI) in a subject. There was, a. Downregulated in a sample obtained from a subject in association with the presence of early AKI determining the amount of at least one biomarker present in the sample; and the downregulated diagnostic biomarkers include complement factor D, insulin-like growth factor binding, Protein 1, interleukin-18 binding protein and haptoglobin and and combinations thereof and their isoforms, fragments and variants. This relates to the method used.

[0100] The listed down-regulated diagnostic biomarkers are particularly useful for early diagnosis of AKI These biomarkers are SEQ ID NOs: 253 to 255, respectively. , 259–262, 266–270, 277–281, and CD139.

[0101] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. In a sample obtained from a subject, interferon alpha-1 / 13, one diagnostic biomarker selected from the group of isoforms, fragments and / or variants Step 1: Determine the amount of These biomarkers show an excellent quality score of 6.

[0102] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. In a sample obtained from a subject, complement factor D, insulin-like growth factor binding protein of haptoglobin 1 and haptoglobin, their isoforms, fragments and / or variants determining the amount of one diagnostic biomarker selected from the group These biomarkers show a good quality score of 6 or more. do.

[0103] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. Cytokine receptor-like factor 2, its isoforms, or and measuring an amount of one diagnostic biomarker selected from the group consisting of a marker, a fragment and / or a variant thereof. Decision Steps These biomarkers show a very high quality score of 4. do.

[0104] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. In a sample obtained from a subject, interferon alpha-1 / 13, cystatin Interleukin-B, interleukin-18 binding protein, WAP4 disulfide core domain protein Protein 2, uteroglobin, chitinase-3-like protein 1, elafin, cartilage oligonucleotides from the group of mer substrate proteins, their isoforms, fragments and / or variants Determining the amount of one selected diagnostic biomarker These biomarkers have very high quality scores of 4 or 5. In one aspect, the present invention provides a method for the early diagnosis of AKI in a subject. So, a. RNA binding protein 3, its isoforms, in a sample obtained from a subject Determining the amount of one diagnostic biomarker selected from the group of fragments and / or variants Steps to take These biomarkers show a high quality score of 3.

[0105] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. In a sample obtained from a subject, interferon alpha-1 / 13, and and combinations thereof and their isoforms, fragments and variants. determining the amount of one selected diagnostic biomarker; These biomarkers show excellent quality scores of 5-6. They are secreted proteins that make them particularly good candidates for detection in urine, blood, plasma or serum. It is also a type biomarker.

[0106] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. detecting cytokine receptor-like factor 2, and its receptors in a sample obtained from the subject; at least one diagnostic biomarker selected from the group consisting of isoforms, fragments and variants; Determining the amount of opiate marker These biomarkers have a high to excellent quality score of 5-6. They are particularly suitable candidates for detection in urine, blood, plasma or serum. It is also a secreted biomarker.

[0107] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. Cytokine receptor-like factor 2, Krueppel -like factor 8, cytochrome P450 1B1, and combinations thereof and their isoforms at least one diagnostic biomarker selected from the group consisting of forms, fragments and variants; Determining the amount of marker These biomarkers exhibit differential kidney expression. Renal expression refers to the relative abundance within the kidney substructure observed by the inventors. The relative renal function of the markers is shown, making them particularly suitable as biomarkers for renal damage. To do.

[0108] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. Krueppel-like factor 8 and galectin-4 in a sample obtained from a subject and isoforms, fragments and variants thereof. determining the amount of at least one diagnostic biomarker These biomarkers are differentially abundant in male patients. These findings are particularly useful for diagnosing AKI in male patients.

[0109] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. Microtubule-associated protein 1A / 1B light chain 3B in a sample obtained from a subject, and at least one selected from the group consisting of: combinations thereof and fragments and variants thereof. determining the amount of each diagnostic biomarker These biomarkers belong to the microtubule-associated proteins. In renal tubular epithelial cells, the microtubule cytoskeleton plays an important role in maintaining cell polarity, This in turn affects kidney function (Drubin & Nelson, 1996).

[0110] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. In a sample obtained from a subject, mitogen-activated protein kinase 12, and at least one diagnostic biomarker selected from the group consisting of: Determining the amount of marker These biomarkers include protein serine / threonine kinase Serine / threonine kinases play a variety of roles, including regulating renal tubular transport. It is a key mediator in signal transduction pathways ( Satoh et al., 2015 ).

[0111] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. detecting a cyclin-dependent kinase inhibitor 3 (PKI-3), phosphodiesterase 4 (PDR-4), or phosphodiesterase 5 (PDR-4) in a sample obtained from the subject; Phatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual specificity protein Protein phosphatase PTEN, and combinations thereof and their isoforms at least one diagnostic biomarker selected from the group consisting of: a fragment and a variant determining the amount of These biomarkers include protein tyrosine phosphatase activity. Protein tyrosine phosphorylation and dephosphorylation signaling are essential for podocytes. It is important for vacuolar function and repair ( Nezvitsky et al., 2014 ; Hsu et al., 2017 ). .

[0112] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. detecting CTP synthase 1, and fragments and variants thereof, in a sample obtained from a subject; and determining the amount of at least one diagnostic biomarker selected from the group consisting of: Steps These biomarkers are involved in pyrimidine biosynthesis. Glycoproteins are fundamental for DNA repair, gene transcription, protein synthesis, and cellular metabolism .

[0113] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. Identification of cytokine receptor common subunit beta, ibuprofen, ibuprofen, ibuprofen-1, ibuprofen-2, ibuprofen-3, ibuprofen-4, ibuprofen-5, ibuprofen-6, ibuprofen-7, ibuprofen-8, ibuprofen-9, ibuprofen-10, ibuprofen-11, ibuprofen-12, ibuprofen-13, ibuprofen-14, Interferon alfa-1 / 13, cytokine receptor-like factor 2, and their combinations and isoforms, fragments and variants thereof. determining the amount of at least one diagnostic biomarker These biomarkers are involved in the Jak-STAT signaling pathway. Janus kinase / signal transducer and activator of transcription ( The JAK / STAT pathway is involved in the renal response to injury and the progression of several renal diseases. This is important (Chuang & He, 2010; Pang et al., 2010).

[0114] In embodiments of the diagnostic methods, in addition to the biomarkers listed herein, additional biomarkers may be used. Biomarkers are determined in the sample. Additional biomarkers include protein biomarkers. markers, male patient biomarkers, predictive biomarkers, diagnostic biomarkers, or One, two, three or more combinations of predictive and diagnostic biomarkers The above biomarkers may also be used.

[0115] Preferred biomarkers As used herein, biomarkers refer to the polypeptides set forth in SEQ ID NOs: 1-304 or or fragments or variants of such polypeptides, The terms "polypeptide" and "protein" are used herein to refer to proteins that are involved in the development of AKI or AKI. All protein biomarkers in the table are listed by their Uniprot registration names. , Uniprot accession numbers as well as the Each protein is uniquely described by its gene name and official protein name. For more information on quality, see the UniProt Database, especially See UniProt release 2019_02 of February 13, 2019. Also see Un See also iProt Consortium (2017). The sequences of the protein biomarkers are listed in the sequence listing under SEQ ID NOs: 1-304.

[0116] Variants and / or isoforms of the biomarkers disclosed herein include: For example, polypeptides that differ in their amino acid sequence due to the presence of conservative amino acid substitutions. Preferably, such variants and / or isoforms include those of the sequence listed in the Sequence Listing. The amino acid sequences of the above specific polypeptides given in At least 70%, at least 80%, at least 90%, at least 95%, at least 98% %, or at least 99% identical amino acid sequence. variants, splice variants or any other species-specific homologs, paralogs, or orthologues. Preferably, the percent identity is calculated using the Needlema n and Wunsch or Smith and Waterman algorithms Programs and algorithms for performing sequence alignments The algorithm is well known to those skilled in the art. To perform sequence alignment, GCG software is used. Software Packet (Genetics Computer Group, 575 Science Drive, Madison, Wisconsin, US A 53711, Version 1991), part of the PileUp program (Feng & Doolittle, 1 987; Higgins & Sharp, 1989) or the Gap and BestFit program (Needlema (N & Wunsch, 1970; Smith & Waterman, 1981) can be used. Sequence identity values, reported in percent (%), were calculated using the following settings: gap weight: 50; Throwing weight: 3, Average match: 10,000, and Average mismatch: 0.000 (always used as the default setting for sequence alignments unless otherwise specified) (assumed to be a sequence of a sequence of a nucleotide sequence) and can be determined using the GAP program across the entire sequence region. In certain embodiments, the variants of the biomarkers can be any of the variants of each biomarker. Contains isoforms.

[0117] The biomarkers of the present invention include protein biomarkers and non-protein biomarkers. Thus, all of the 92 biomarkers of the present invention are proteins. The present invention also relates to the use of non-protein biomarkers, i.e., CD15 and CD Including 139.

[0118] In one aspect, the present invention provides a method for early diagnosis of AKI in a subject, comprising: a. In a sample obtained from a subject, at least one protein biomarker, Patient biomarkers, predictive biomarkers, diagnostic biomarkers, or predictive biomarkers Combinations of markers and diagnostic biomarkers, as well as combinations thereof and fragments thereof and determining the amount of the variant; b. comparing the amount of the biomarker with a control amount of the biomarker; The present invention relates to a method comprising:

[0119] The "protein biomarkers" of the present invention include CD9 antigen, prostaglandin G / H syndrome, and Intase 2, CD99 antigen, CD99R antigen, high-affinity immunoglobulin epsilon receptor Tumor necrosis factor, including subunit alpha, tumor necrosis factor, and lymphotoxin-alpha The ligand for tumor necrosis factor receptor superfamily member 1B Milli member 6, interferon alpha-1 / 13, basigin, CC motif, Chemokine 7, Dickkopf-related protein 2, hyaluronan-mediated motility receptor, Interleukin-18, interleukin-7, major prion protein, receptor-type thrombin Lysine protein phosphatase C, P-selectin glycoprotein ligand 1, tumor necrosis factor Drosophila ligand superfamily member 14, DNA topoisomerase 2-alpha, brain derived neurotrophic factor, caspase-8, eotaxin, CC motif chemokine 3, C- C-motif chemokine 5, monocyte differentiation antigen CD14, cytokine receptor-like factor 2, lamin -B1, cellular tumor antigen p53, serine / threonine protein kinase PAK1, caspase lyase-9, transforming growth factor-beta-inducible protein IG-H3, leukocytes Surface antigen CD47, T cell surface glycoprotein CD8 alpha chain, Dickkopf-related Protein 3, growth arrest-specific protein 6, interleukin-15, cytokine receptor Common subunit beta, keratin type II cytoskeleton 8, leukosialin, MAP / microglobulin Tubulotropy-regulating kinase 4, melanophilin, interstitial collagenase, matrilysin, prostaglandin Taglandin G / H synthase 1, myeloblastin, RNA-binding protein 3, serum albumin Myloid P component, tetraspanin-16, urokinase-type plasminogen activator , CTP synthase 1, Max dimerization protein 4, transmembrane protein 54, actin , cytoplasmic 1, caspase-3, complement decay-accelerating factor, high mobility group protein B2, homeobox Hox protein, Hox-C11, intercellular adhesion molecule 1, interleukin-12 subunit Nit alpha, Krueppel-like factor 8, galectin-4, regulatory factor complex protein LAMTOR1, L-selectin, mitogen-activated protein kinase 3, mucin -5B, nuclear factor of activated T cells, transforming growth factor beta-1 proprotein protein, serine / threonine protein kinase VRK1, cyclin-dependent kinase inhibitor Bitter 3, tissue factor pathway inhibitor 2, microtubule-associated protein 1A / 1B light chain 3B, Sphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual specificity Protein phosphatase PTEN, interleukin-8, Rho guanine nucleotides Exchange factor 2, CASP8 and FADD-like apoptosis regulator, CUE domain-containing Protein 2, death-associated protein kinase 1, endothelin-1 receptor, eukaryotic translation Initiation factor 3 subunit B, DNA-binding protein inhibitor ID-2, prelamin A / C, CAD protein, zinc finger protein 593, mitogen-activating protein Protein kinase 12, cytochrome P450 1B1, angiotensinogen, adenomatous colon Polyposis protein, POU domain class 2 transcription factor 1, somatostatin receptor 4 type, tumor necrosis factor alpha-inducible protein 3, E3 ubiquitin protein ligase TR IM22, complement factor D, neurotrophin-4, insulin-like growth factor binding protein 1, cystatin-B, interleukin-18 binding protein, WAP4 disulfide copolymer Adomain protein 2, haptoglobin, uteroglobin, chitinase-3-like protein Protein 1, elafin, cartilage oligomeric matrix protein, interleukin-16 and interleukin tha-alpha trypsin inhibitor heavy chain H1, and its isoforms .

[0120] The "male patient biomarkers" of the present invention are CD15, tumor necrosis factor, and lymphotoxin. Ligands for tumor necrosis factor receptor superfamily member 1B, including lanthanide-alpha, Min-B1, MAP / microtubule affinity-regulating kinase 4, Dickkopf-related protein 2 , Krueppel-like factor 8, Rho guanine nucleotide exchange factor 2, CUE domain containing protein 2, cell death-associated protein kinase 1, DNA-binding protein inhibitor -ID-2, prelamin-A / C, adenomatous polyposis coli protein, POU domain Class 2 transcription factor 1, somatostatin receptor type 4, tumor necrosis factor alpha-inducible protein Protein 3, CD99R antigen, and galectin-4 and their isoforms. The sex-related biomarkers were useful for predicting and predicting the risk of developing AKI in male subjects, respectively. This method is particularly useful for the early diagnosis of AKI and AKI. SEQ ID NOs: 68, 105, 106, 20, 148, 149, 150, 151, 152, 195, 196, 197, 213, 214, 215, 216, 217, 225, 226, 227, 228, 229, 230, 231, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, and at least one selected from CD15, or a fragment or variant thereof determining the amount of at least one biomarker; and comparing the amount to a control amount of said at least one biomarker. The dose should preferably be determined in male subjects.

[0121] The "female patient biomarker" of the present invention is the major prion protein (SEQ ID NO: 30). Female patient biomarkers are associated with the risk of AKI in female subjects. This is particularly useful for predicting AKI and for early diagnosis of AKI. In one embodiment, the method comprises detecting SEQ ID NO: 30 or a fragment or fragments thereof in a sample from a female subject. determining the amount of a biomarker that is a variant; comparing the amount of the biomarker with a control amount of said at least one biomarker. The control amount should preferably be determined in female subjects.

[0122] The "predictive biomarkers" of the present invention include CD15, CD99 antigen, CD99R antigen, and high affinity markers. Sympathetic immunoglobulin epsilon receptor subunit alpha, tumor necrosis factor, and lymphocytes Ligand for tumor necrosis factor receptor superfamily member 1B containing toxin-alpha Tumor necrosis factor receptor superfamily member 6, basigin, CC motif chemokine Kine 7, CD9 antigen, Dickkopf-related protein 2, hyaluronan-mediated motility receptor, interleukin-18, interleukin-7, major prion protein, receptor receptor-type tyrosine protein phosphatase C, P-selectin glycoprotein ligand 1, Tumor necrosis factor ligand superfamily member 14, DNA topoisomerase 2-α Lufa, brain-derived neurotrophic factor, caspase-8, eotaxin, CC motif chemokine chemokine 3, CC motif chemokine 5, monocyte differentiation antigen CD14, cytokine receptor-like factor 2, lamin-B1, cellular tumor antigen p53, serine / threonine protein kinase PAK 1. Transforming growth factor beta-inducible protein IG-H3, leukocyte surface antigen CD47, T cell surface glycoprotein CD8 alpha chain, Dickkopf-related protein 3, growth arrest specific protein 6, interferon alpha-1 / 13, interleukin-1 Kin-15, cytokine receptor common subunit beta, keratin type II cytoskeleton 8, Leukosialin, MAP / microtubule affinity-regulating kinase 4, melanophilin, interstitial collagen -ase, matrilysin, prostaglandin G / H synthase 1, myeloblastin, R NA-binding protein 3, serum amyloid P component, tetraspanin-16, urokinase type Plasminogen activator, actin cytoplasmic 1, caspase-3, complement decay-accelerating factor , high mobility group protein B2, homeobox protein Hox-C11, cell-cell junction Child 1, Interleukin-12 subunit alpha, Interleukin-8, Krue ppel-like factor 8, galectin-4, regulatory factor complex protein, LAMTOR1, L- Selectins, mitogen-activated protein kinase 3, mucin-5B, activated T cells Nuclear factor cytoplasmic 4, transforming growth factor beta-1 proprotein, serine / triphosphate leonine protein kinase VRK1, Rho guanine nucleotide exchange factor, CASP 8 and FADD-like apoptosis regulator, CUE domain-containing protein 2, cell death-related Associated protein kinase 1, endothelin-1 receptor, eukaryotic translation initiation factor 3 subunit DNA binding protein inhibitor ID-2, prelamin A / C, CAD protein Protein, zinc finger protein 593, angiotensinogen, adenomatous polyposis coli protein, POU domain, class 2, transcription factor 1, somatostatin receptor type 4, tumor Necrosis factor alpha-inducible protein 3 and its isoforms, neurotrophic factors interleukin-4, interleukin-18 binding protein, interleukin-16 and interleukin-18 binding protein ter-alpha trypsin inhibitor heavy chain H1 (SEQ ID NOs: 2-79, 84-97, 98- 128, 135-185, 194-233, 237-248, 251-252, 256- These correspond to 258, 266-270, 295-304, and CD15. These biomarkers have been found to be particularly useful for predicting AKI in subjects. The sample may be taken prior to the planned surgical intervention. Even more preferably, the sample may be taken prior to the planned surgical intervention. Biomarkers may include CD9 antigen, CD15, myeloblastin, or fragments thereof. or variants thereof. More preferably, the biomarker is selected from the group consisting of SEQ ID NO: The CD9 antigen has the sequence of No. 19.

[0123] The "diagnostic biomarker" of the present invention is a cytokine receptor-like factor 2 (CRF2), a prostaglandin E receptor (PGR), a cytokine receptor-like factor 2 (CRF2), a cytokine receptor-like factor 2 (PGR ... Interferon G / H synthase 2, interferon alpha-1 / 13, caspase-9, interferon -leukin-18, interleukin-7, CTP synthase 1, CC motif chemokine Insulin 7, CD139, Eotaxin, Max dimerization protein 4, Interleukin- 15, RNA-binding protein 3, transmembrane protein 54, Krueppel-like factor 8, collagenase, cyclin-dependent kinase inhibitor 3, tissue factor pathway inhibitor 2, growth arrest specific protein 6, microtubule-associated protein 1A / 1B light chain 3B, caspase ze-8, phosphatidylinositol 3,4,5-triphosphate 3-phosphatase and diphosphatase Dual specificity protein phosphatase PTEN, mitogen-activated protein kinase 1 2, cytochrome P450 1B1, E3 ubiquitin protein ligase TRIM22, Ga Lectin-4, major prion protein, complement factor D, insulin-like growth factor binding protein Protein 1, cystatin B, interleukin-18 binding protein, WAP4 disulfide Dodecore domain protein 2, haptoglobin, uteroglobin, chitinase-3-like protein Protein 1, elafin, and cartilage oligomeric matrix protein and their isoforms (SEQ ID NOs: 1, 13, 30, 80-83, 25-29, 129, 130, 18, 61 ~67, 131, 98, 99, 121, 132~134, 148~15, 112, 152 , 186-189, 93-97, 190, 52-60, 191-193, 234-250 , 253–255, 259–265, 266–270, 271–294, and CD1 These biomarkers are useful for the early diagnosis of AKI in subjects. Samples were collected at 24, 36, or 48 hours after surgical intervention. may be collected within 48 hours.

[0124] The "combined predictive and diagnostic biomarkers" of the present invention are receptor-like factor 2, caspase-8, eotaxin, CC motif chemokine 7, proliferation Arrest-specific protein 6, interferon alpha-1 / 13, interleukin-1 5, interleukin-18, interleukin-7, Krueppel-like factor 8, interstitial Collagenase, RNA-binding protein 3, and interleukin-18 binding protein , and their isoforms (SEQ ID NOs: 52-61, 18, 65-67, 93-9 7, 13, 98, 99, 25-29, 148-151, 112, 121, 267-269 These biomarkers are useful for predicting the risk of developing AKI in subjects. It has been found to be particularly useful for both the prognosis and early diagnosis of AKI.

[0125] Furthermore, in the context of the present invention, for example, to predict the risk of developing AKI or to It is particularly envisioned to determine the amount of more than one biomarker for the early diagnosis of KI. For example, when predicting the risk of AKI occurrence or diagnosing AKI in a timely manner, Combinatorial determination of biomarkers is advantageous as it allows for higher specificity and sensitivity is.

[0126] The following biomarker combinations are used in accordance with the methods, kits, devices and uses of the present invention: Therefore, in a preferred embodiment, the present invention provides a method for detecting a leukemia virus in a subject. In terms of fees, A) CD9 and CD15; B) CD9 antigen, CD15 and myeloblastin C) CD9 antigen, CD15 and Dickkopf-related protein 2; D) CD15 and Dickkopf-related protein 2; E) CD15 and interstitial collagenase; F) CD15 and cytokine receptor-like factor 2; G) CD15, Dickkopf-related protein 2, and CD99 antigens (alternatively, CD 99R antigen), H) CD15, Dickkopf-related protein 2, and Dickkopf-related protein quality 3, I) cytokine receptor-like factor 2 and Dickkopf-related protein 2; J) Dickkopf-related protein 2 and interstitial collagenase; K) CD15, Dickkopf-related protein 2, and cytokine receptor-like factor 2; or L) CD99 antigen, CD15, myeloblastin, Dickkopf-related protein 2, and and cytokine receptor-like factor 2, M) Nuclear factor of activated T cells, interferon alpha-1 / 13 and myeloblastoma hmm, N) Nuclear factor of activated T cells and interferon alpha-1 / 13; O) Interferon alpha-1 / 13, CD99R antigen, myeloblastin and activity nuclear factor of sexualized T cells, P) myeloblastin and nuclear factor of activated T cells; Q) Complement factor D, neurotrophin-4, insulin-like growth factor binding protein 1, Statin-B, interleukin-18 binding protein and WAP4 disulfide core Domain Protein 2 at least a minimum amount of (and, if desired, fragments, variants and / or isoforms thereof) The method includes determining a system.

[0127] Combinations of the above markers will increase the sensitivity and specificity of the method.

[0128] In some embodiments, in addition to the combinations given under A) to Q) above, further bio Markers are determined in the sample. Additional biomarkers include protein biomarkers. Car, male patient biomarker, predictive biomarker, diagnostic biomarker, or combination One or more biomarkers selected from the combined predictive and diagnostic biomarkers It may also be an ion marker.

[0129] Method Steps The method of the present invention comprises the steps: a. in a sample obtained from a subject, at least one biomarker of the present invention, and determining the amounts of their combinations and their fragments, isoforms, and variants. and b. comparing the amount of the biomarker with a control amount of the biomarker; It may consist essentially of

[0130] The method may include further steps. In a preferred embodiment, the method comprises ex v The method is carried out in ivo, i.e., not performed on the human or animal body. This can be supported by

[0131] According to the methods of the present invention, the risk of developing AKI in a subject is predicted, or AKI is diagnosed early. Preferably, AKI is predicted or diagnosed in the context of a medical intervention. In the case of surgical interventions, the term "perioperative" refers to the period in which the procedure is performed. "Operative setting" refers to the admission of a subject in the hospital or ICU and the complete regeneration of the subject at the time of surgery, e.g. For example, the period between a subject's release from the hospital and the time of discharge. Within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 10 days, or 2 weeks after intervention , or within any intermittent time range.

[0132] The term "medical intervention" includes "surgical intervention" and other interventions. Other interventions may include the use of contrast agents or Other interventions may also include the administration of medications such as nephrotoxic substances. This may include avoiding the administration of drugs.

[0133] definition As used herein, the term "solid organ" refers to an organ having a firm tissue consistency and which is neither hollow nor liquid. The heart, kidneys, liver, lungs, ovaries, spleen, and pancreas are by definition organs that are not part of the body. For example, it is a solid organ.

[0134] As used herein, the term "solid organ transplant" refers to the transplantation of a missing or damaged organ. A solid organ is removed from a subject's body and placed in a recipient subject's body to replace the organ. Refers to surgical intervention during entry into the

[0135] As used herein, the term "hematopoietic cells" refers to blood cells. Hematopoietic cells include hematopoietic stem cells. These include cells, progenitor cells and different blood cell types.

[0136] As used herein, the term "hematopoietic cell transplantation" refers to the transplantation of hematopoietic cells, usually from bone marrow, peripheral blood, or umbilical cord blood. Refers to surgical intervention during transplantation of derived hematopoietic cells.

[0137] "Prediction of the risk of AKI occurrence" refers to the risk of AKI occurring in a subject within a period after a medical intervention. This may include assessing the probability of a medical intervention according to what is likely to happen. Preferably, the risk / probability of developing AKI within a maximum of 2 weeks after completion of the medical intervention is predicted. In a preferred embodiment, the prediction window is at least at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least at least 6 days, at least 1 week, at least 10 days, or at least 2 weeks, or any In a particularly preferred embodiment of the present invention, the prediction window is Preferably, at most 10 days, or more preferably at most 4 weeks. The window ranges from completion of medical intervention to approximately 2 years or until further medical intervention. Preferably, the prediction window is calculated from the completion of the medical intervention.

[0138] As used herein, the term "completion of a medical intervention" refers to the point in time when a medical intervention has ended, e.g. For example, a medical intervention refers to the time a subject is released from a hospital. If the period of release is longer than the time of release of the subject from the hospital, the period of release will not end with the subject's release from the hospital. Alternatively, the prediction window is calculated from the time the sample to be tested is obtained. .

[0139] As one skilled in the art will appreciate, such predictions may not be accurate for 100% of subjects. However, the term should be used to describe the statistical significance of the subject in an appropriate and precise manner. It is necessary to be able to make predictions about the parts. The statistical significance of a result can be assessed using various well-known statistical evaluation methods, such as determining confidence intervals and p Determine the value, using Student's t-test, Mann-Whitney test, etc. For more information, see Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983. Preferred confidence intervals are at least 90% The probability of a variance is 95%, at least 97%, at least 98%, or at least 99%. The value is preferably less than 0.1, less than 0.05, less than 0.01, less than 0.005, or Preferably, the probability estimated by the present invention is less than 0.0001. , prediction of normal risk or reduced risk is based on a low percentage of subjects in a given cohort or population. At least 60%, at least 70%, at least 80%, or at least 90% correct The term preferably refers to the incidence of AKI in a population of subjects. Determine whether a subject's risk is elevated or decreased compared to the raw average risk. It relates to predicting what will happen.

[0140] As used herein, the prediction of the risk of developing AKI is determined by the method of the present invention. The subjects to be analyzed were divided into a group of subjects at risk for developing AKI, or This may involve assigning subjects to either a group of subjects not in the group. The risk of developing KI is increased (within the prediction window) by 20%. In particular, the risk is the average risk in a cohort of subjects undergoing a medical intervention. It may be elevated compared to the average risk. Within the measurement window, the subject is considered not at risk for developing AKI. The risk is reduced compared with the average risk in a cohort of subjects receiving medical intervention. Subjects at risk for developing AKI should be monitored for 9 weeks, especially within the 4-week predictive window. The risk of developing AKI may be 0% or greater, or 75% or greater. Risk-free subjects are particularly likely to have a risk of less than 50% or less than 10% within a 4-week prediction window. There may be a risk of developing AKI.

[0141] In one embodiment, the "prediction of the risk of developing AKI" is carried out by detecting a small amount of AKI in a sample derived from a subject. and comparing the amount of at least one upregulated biomarker with a control amount. If the exposure exceeds that in the sample, the subject is considered at risk for developing AKI. In one embodiment, the "prediction of the risk of developing AKI" is carried out by detecting a small amount of AKI in a sample derived from a subject. comparing the amount of at least one downregulated biomarker with a control amount; If the amount in the sample is less than the control amount, the subject is considered to be at risk for developing AKI. .

[0142] As used herein, the term "early diagnosis" refers to the timely diagnosis of AKI after intervention. More preferably, AKI should be diagnosed within 24 hours after the intervention.

[0143] As used herein, the term "subject" refers to an animal, preferably a mammal, more preferably a human. In one embodiment, the subject is a male subject. Preferably, the method comprises the steps of: In some embodiments, the subject is known to receive the intervention in the future. Will undergo surgical intervention or are undergoing surgical intervention at the time the sample is taken. For example, the subject may have undergone a medical intervention 48 hours, 24 hours or less prior to the sample being obtained. In another embodiment, the sample is collected within, for example, 48 or 24 hours of receiving medical intervention. It is collected from subjects who are likely to be affected.

[0144] Preferred Method In the method according to the present invention, the above biomarker group, preferably SEQ ID NOs: 1 to 304 at least one biomarker of a protein shown in However, more preferably, the panel of biomarkers is a specific Such groups will preferably be determined to enhance accuracy and / or sensitivity. At least two, at least three, at least four, at least five, at least six species, at least 7 species, at least 8 species, at least 9 species, at least 10 species or up to In addition to the specific biomarkers described herein, Preferably, other biomarkers can be similarly determined in the methods of the present invention. do.

[0145] In a preferred embodiment of the method of the present invention, said at least one biomarker is Biomarker group Nos. 1 to 304 and CD15 and CD139, or It is selected from a fragment or a variant.

[0146] In a preferred embodiment of the method of the present invention, said at least one biomarker is Numbers 68, 105, 106, 20, 148, 149, 150, 151, 195, 196, 197, 213, 214, 215, 216, 217, 225, 226, 227, 228, 229, 230, 231, 238, 239, 240, 241, 242, 243, 244, Biomarkers listed in 245, 246, 247, and 248, as well as CD15, is selected from fragments or variants thereof. Changes in such biomarkers in the diet indicate risk for the development of AKI.

[0147] In a preferred embodiment of the method of the present invention, said at least one biomarker is Numbers 68, 105, 106, 20, 148, 149, 150, 151, 195, 196, 197, 213, 214, 215, 216, 217, 225, 226, 227, 228, 229, 230, 231, 238, 239, 240, 241, 242, 243, 244, Biomarkers listed in 245, 246, 247, and 248, as well as CD15, is selected from fragments or variants thereof. Changes in such biomarkers in the specimens indicate the development of AKI at an early time point.

[0148] As used herein, the term "medical intervention" refers to the treatment of a condition in a subject potentially suffering from a medical disorder. In the context of the present invention, intervention refers to medical action taken to analyze or improve a condition. It may be the administration of a drug, the avoidance of a drug, the injection of a contrast medium or surgical intervention.

[0149] As used herein, the term "change in therapeutic regimen" refers to a change in a therapeutic regimen in response to a prognosis or diagnosis of AKI. Adaptation of patient care refers to the adaptation of patient care to the patient's specific needs. Adaptation of patient care includes renal dialysis, elimination of nephrotoxic compounds, etc. avoidance of pulmonary embolism, administration of renal stabilizers, avoidance of allogeneic blood transfusion, optimization of surgical strategies, and earlier intervention Patients may be kept under close observation.

[0150] The sample may be a body fluid sample, a sample of separated cells, or a sample derived from a tissue or organ. The body fluid sample can be obtained by well-known techniques, and preferably is urine. The sample may be a blood, plasma, or serum sample, or more preferably a tissue or organ sample. The material can be obtained from any tissue. Separation techniques such as centrifugation or cell sorting can be used. By this method, the separated cells can be obtained from the body fluid or tissue or organ. Preferably, the cell, tissue or organ sample is prepared using the biomarkers described herein. The antibody is obtained from cells, tissues or organs which express or produce the marker.

[0151] For the present invention, it is particularly preferred that the sample is plasma or serum obtained from a patient. More preferably, the sample is collected prior to surgical intervention to predict the risk of AKI. or up to 48 hours after medical intervention for early diagnosis of AKI, or up to 24 hours The plasma obtained is:

[0152] As used herein, the term "blood product" refers to any therapeutic substance prepared from human blood. This refers to blood components and plasma derivatives. For the purposes of this invention, red blood cells and fresh blood Only frozen plasma was considered for analysis.

[0153] Analysis of samples In one embodiment, the subject may be evaluated for a medical intervention and / or for AKI. Certain measures must be taken before or during intervention to reduce the risk of Predictive methods are used to determine whether a disease is present or absent prior to medical intervention. To this end, samples can be taken up to six months before the planned medical intervention.

[0154] The samples analyzed in the context of the method of the present invention can be analyzed before or after a medical intervention, in particular by the method described herein. The samples may be obtained before or after the surgical intervention described in the literature. The sample is preferably obtained immediately prior to the intervention. It may also be obtained within 6 months, 3 months or more prior to the medical intervention. Within, within 6 weeks, within 2 weeks, or within 1 week, or within 2 hours, 6 hours, or 12 hours before medical intervention Samples were collected at any time before medical intervention, such as within 1 h, 24 h, 36 h, 48 h, or within 7 days. It is also contemplated that samples obtained after a medical intervention are preferably obtained after the completion of the medical intervention. You can get it within 2 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours or within 7 days after the order. do.

[0155] The determination of the amount of the biomarkers described herein is preferably semi-quantitative or quantitative. Measurement can be made directly or indirectly. Direct measurement is the measurement of a biomarker based on the signal obtained from the biomarker itself. Correlates directly or indirectly with the amount or concentration and number of molecules of the polypeptide present in the sample This is sometimes referred to as an intensity signal. Such signals can be converted into, for example, intensity values ​​of specific physical or chemical properties of the polypeptide. Indirect measurements can be obtained by measuring secondary components (i.e., bio a component that is not a marker itself) or a biological readout system, e.g., a measurable cellular response This includes measuring signals obtained from the response, ligand, label, or enzymatic reaction product.

[0156] According to the present invention, determining the amount of a biomarker is performed by determining the amount of a biomarker in a sample. This can be achieved by different means for preparing the food, such as various sandwiches, Immunoassays that can use labeled molecules in competitive or other assay formats Preferably, the immunoassay device is an antibody array, particularly , planar antibody microarrays or bead-based antibody microarrays. The assay is preferably a stripe test. The resulting signal will indicate the presence or absence of the tide biomarker.

[0157] Furthermore, preferably, the signal intensity is proportional to the amount of biomarker present in the sample. They can be directly or indirectly correlated (e.g., proportionally or inversely proportional). A suitable method is to identify specific biomarkers, such as their exact molecular mass or NMR spectrum. The method preferably comprises measuring a biochemical or physical property of the sample. sensors, optical devices coupled with immunoassays, biochips, mass spectrometers , NMR analyzers, or chromatographic devices. Methods include microplate ELISA-based methods, fully automated or robotic methods, and Cobalt-binding assay (CBA), or latex agglutination assay The determination of the amount of the biomarker can be performed in a clinical laboratory or may comprise a point-of-care test.

[0158] Also preferably, the determination of the amount of the biomarker is obtained from the biomarker in the sample. The step of measuring a specific intensity signal may also be included. As noted above, such a signal may be Nulls are observed in mass or NMR spectra specific to the biomarker. The signal intensity observed at the mass-to-charge (m / z) variable specific to the biomarker being studied. It's okay to have it.

[0159] The determination of the amount of the biomarker preferably comprises: aa) contacting a biomarker with a specific ligand; ab) optionally removing unbound ligand; and ac) measuring the amount of bound ligand may include:

[0160] Bound ligands will generate an intense signal. Binding can be covalent or non-covalent. A ligand is any chemical that binds to a biomarker described herein. The compound may be, for example, a peptide, polypeptide, nucleic acid, or small molecule. Ligands include receptors or binding partners for biomarkers and peptides and fragments thereof containing the binding domain for the Examples include antibodies, nucleic acids, peptides or polypeptides, such as aptamers. Methods for preparing suitable ligands are well known in the art. Identification and production of peptides is also offered by commercial suppliers. and methods for developing derivatives of such ligands with higher affinity or specificity. For example, random mutations can be introduced into nucleic acids, peptides, or polypeptides. These derivatives can then be screened using screening techniques known in the art. The antibodies can be tested for binding according to, for example, phage display. The antibodies described herein include both polyclonal and monoclonal antibodies, as well as antibodies against antigens. or Fv, Fab, scFv and F(ab)2 fragments capable of binding to haptens The present invention also encompasses single chain antibodies and fragments thereof, such as non-human antibodies exhibiting the desired antigen specificity. Humanized hybrids are created in which the amino acid sequence of a donor antibody is combined with the sequence of a human acceptor antibody. Alternatively, chimeric mouse antibodies with rabbit Fc can be used. The donor sequence will usually include at least the antigen-binding amino acid residues of the donor, but may also include other amino acid residues. may contain other structurally and / or functionally relevant amino acid residues of the donor antibody. Such hybrids can be prepared by several methods well known in the art. Preferably, the ligand or agent specifically binds to the biomarker.

[0161] "Specific binding" according to the present invention means that the ligand or agent binds to the target molecule present in the sample to be analyzed. substantially binds ("cross-reacts") to another biomarker, polypeptide or substance present in the Preferably, the biomarker that specifically binds to at least three times higher than any other substance, biomarker or polypeptide in the sample , more preferably at least 10 times higher, and even more preferably at least 50 times higher. Non-specific binding is the binding of a specific antibody to a specific target protein, e.g., a specific antibody on a Western blot. It can be clearly distinguished according to its size or by its relatively high abundance in the sample. If it can be identified and measured, it is acceptable.

[0162] Binding of the ligand can be measured by any method known in the art. Alternatively, the method may be semi-quantitative or quantitative. Suitable methods are described below. 1. Ligand binding can be assessed by, for example, mass spectrometry, NMR, or surface plasmon resonance. Second, the ligand can directly measure the enzymatic activity of the biomarker of interest. If it also serves as a substrate, the enzymatic reaction product can be measured (e.g., proteases The amount of cleaved substrate is measured, for example, by measuring the amount of cleaved substrate on a Western blot. Alternatively, the ligand may exhibit enzymatic properties itself, respectively The biomarker-bound "ligand / biomarker" complex or ligand is then strongly The antibody can be contacted with a suitable substrate that allows detection by generation of a specific signal.

[0163] For measurement of enzymatic reaction products, the amount of substrate is preferably saturating. Preferably, the substrate is allowed to react for a sufficient period of time. A sufficient period of time is sufficient to produce a detectable, preferably measurable amount of It refers to the time required for a product to be produced. Instead of measuring the amount of product, it is used to measure a given (e.g. For example, the time required for the appearance of a detectable amount of product can be measured. The ligand is covalently or non-covalently linked to a label that allows for detection and measurement of the ligand. It can be coupled.

[0164] Labeling can be done by direct or indirect methods. Direct labeling involves the attachment of a ligand to a target molecule. Indirect labeling involves the direct (covalent or non-covalent) coupling of a label to a molecule. The binding (covalent or non-covalent) of a second ligand to one ligand. The second ligand should bind specifically to the first ligand. a third ligand that can be coupled to the second ligand and / or binds to the second ligand; It may be the target (receptor) of a ligand. Secondary, tertiary or even higher order ligands The use of a second, more preferred, Higher order ligands include antibodies, secondary antibodies, and the well-known streptavidin-biotin system. The system may include a system (Vector Laboratories, Inc.).

[0165] The ligand or substrate may also be "tagged" with one or more tags. Such tags may then be targets for higher order ligands. These include biotin, digoxigenin, His-Tag, and glutathione-S-transferase. enzyme, FLAG, GFP, myc tag, influenza A virus hemagglutinin (H A), maltose-binding protein, etc. In the case of peptides or polypeptides The tag is preferably at the N-terminus and / or C-terminus. Suitable labels are suitable for suitable detection The label is any label that can be detected by the method. Typical labels include gold particles, latex Beads, acridan ester, luminol, ruthenium, enzyme activity label, radioactive label, magnetic Magnetic labels (e.g., "magnetic beads," including paramagnetic and superparamagnetic labels), and fluorescent labels Examples of enzyme-active labels include horseradish peroxidase, alkaline phosphatase, and the like. Examples include isoforms of phosphodiesterase, beta-galactosidase, luciferase, and their derivatives. Suitable substrates for detection include diaminobenzidine (DAB), 3, 3'-5,5'-tetramethylbenzidine, NBT-BCIP (4-nitro blue tetrahydrofuran) Zolium chloride and 5-bromo-4-chloro-3-indolyl-phosphate, Ro Available as a ready-made stock solution from che Diagnostics), CDP-S tar (trademark) (Amersham Biosciences), ECF (trademark) (Am Suitable enzyme-substrate combinations include: Measurements can be made according to methods known in the art (e.g., by using a photosensitive film or suitable camera system), which can result in a colored reaction product, fluorescence, or chemiluminescence. For the measurement of enzymatic reactions, the criteria given above apply analogously.

[0166] Suitable fluorescent labels include fluorescent proteins (such as GFP and its derivatives), Cy3, Cy5, or scioDye1, scioDye2, scioDye3, scioDy e4 (Sciomics, Germany) or Texas Red, Fluorescein, and and Alexa dyes (e.g., Alexa 568). Additional fluorescent labels include , e.g., Molecular Probes (Oregon) or Dyomics ( Furthermore, the use of quantum dots as fluorescent labels has been proposed. Suitable radiolabels include: <35> S, <125> I, <32> Radioactive labels can be attached by any known and suitable method, for example, by using a photosensitive film. The detection can be performed by a microscope or a phosphor imager. Precipitation (especially immunoprecipitation), electrochemiluminescence (electrically generated chemiluminescence), RIA (radioimmunoassay) ELISA (enzyme-linked immunosorbent assay), sandwich enzyme immunoassay, electrochemical Chemiluminescence sandwich immunoassay (ECLIA), dissociation-enhanced lanthanide fluoroimmunoassay DELFIA, Scintillation Proximity Assay (SPA), FRET-based The fusion proximity assay (Pulli et al., 2005) or the ligation proximity assay (Fredriksso et al., 2005) n et al., 2002), turbidimetry, nephelometry, latex-enhanced turbidimetry or nephelometry, or Solid-phase immunoassays include gel electrophoresis, 2D gel electrophoresis, and SDS polyacrylamide gel electrophoresis. SDS-PAGE, Western blotting, and mass spectrometry. These additional methods may be used alone or in combination with the labeling or other detection methods described above. It is possible.

[0167] Preferably, the amount of the biomarker can also be determined as follows: a1) A solid support containing a ligand for the biomarker identified above, and contacting the sample containing the probe with a sample containing the probe; a2) optionally removing unbound biomarkers; and a3) Measuring the amount of biomarker bound to the support.

[0168] Preferably, the nucleic acid is selected from the group consisting of a nucleic acid, a peptide, a polypeptide, an antibody, and an aptamer. The selected ligand is preferably present in immobilized form on a solid support.

[0169] Materials for preparing solid supports are well known in the art, and in particular commercially available Column materials, polystyrene beads, latex beads, magnetic beads, colloidal metal particles, Glass and / or silicon chips and surfaces, nitrocellulose strips, membranes, sheets, devices duracite, the wells and walls of a reaction tray, plastic tubing, or Combinations of these are also possible.

[0170] Ligands or drugs can be bound to many different carriers. Examples of well-known carriers are: Examples include glass, polystyrene, polyvinyl chloride, polypropylene, polyethylene, Polycarbonate, dextran, nylon, amylose, natural and modified cellulose, poly Examples of suitable carriers include acrylamide, agarose, and magnetite. It may be soluble or insoluble for the purposes of the invention.

[0171] Suitable methods for fixing / immobilizing the ligand include, but are not limited to: However, examples of the interaction include ionic, hydrophobic, and covalent interactions. It is also contemplated to use "suspension arrays" for such purposes (Nolan & Sklar, 2002). In suspension arrays, the carrier, e.g., microbeads or microspheres, is present in suspension. The array is made up of different, possibly labeled, microbeads carrying different ligands. For example, based on solid-phase chemistry and photolabile protecting groups, , and methods for producing such arrays are as if fully described herein. Disclosed in US Pat. No. 5,744,305, which is incorporated by reference.

[0172] The term "amount" as used herein refers to the absolute amount of a biomarker, the amount of said biomarker Relative amounts or concentrations and any other parameters that correlate therewith or can be derived therefrom Such values ​​or parameters may be determined by direct measurement. Therefore, all the specific physical or chemical properties derived from the biomarkers are The intensity signal values, for example, mass spectra or NMR spectra or surface plasmon In addition, the indirect values ​​specified elsewhere in this specification may be used to Any value or parameter obtained by measurement, e.g., biological response to a peptide The response level determined from a quantitative readout system or obtained from specifically bound ligand The values ​​that correlate with the above quantities or parameters are included in any standard. It should be understood that the above values ​​may also be obtained by simple mathematical manipulations.

[0173] As used herein, the term "comparing" refers to comparing the amount of variance contained in the sample to be analyzed. The amount of biomarker is compared to the amount of a suitable control source identified elsewhere herein. As used herein, "comparing" includes comparing corresponding parameters. It should be understood that the term refers to a comparison of a parameter or value, e.g., an absolute amount compared to an absolute control amount. The concentrations are compared to a control concentration or to the intensity signal obtained from the test sample. The signal is compared to the intensity signal of the same type in a control sample. Preferably, the control amount is a healthy control. The amount of the biomarker in the elephant, e.g., 10 or more, 30 or more, 50 or more, or 100 These are the average amounts of each biomarker in the above group of healthy subjects.

[0174] The comparison of the method of the present invention can be performed manually or with computer assistance. For computer-assisted comparison, the values ​​of the determined quantities are calculated using a computer program. The values ​​are compared with those corresponding to suitable controls stored in a database by program. The computer program can further evaluate the results of the comparison, i.e., The desired evaluation can be automatically provided in a suitable output format. Based on the dose administered and the control dose, the risk of AKI occurrence in subjects after medical intervention was estimated. The present invention can predict risk and / or diagnose AKI.

[0175] As used herein, the term "control" refers to a group of subjects who are at risk for developing AKI or not. The amount of biomarkers that can predict AKI or diagnose it at an early stage is specified. Therefore, the control is (i) Patients who are known to be at risk for developing AKI or have been diagnosed with AKI a subject (or group of subjects) or (ii) Patients who are known not to be at risk for developing AKI or who have been diagnosed with AKI Subjects who have not been screened (or the above subject group) Preferably, said control is derived from a sample of a healthy subject as described above.

[0176] More preferably, the sequences of SEQ ID NOs: 2 to 79, 84 to 97, 98 to 128, 1 Biomarkers described in 35 to 185, 194 to 233, 237 to 248, and 251 to 252 and CD15 (Table 2). The change indicates that the subject is or is not at risk for developing AKI, but is not related to the control. SEQ ID NOs: 1, 13, 80-83, 25-29, 129, 130, 18, 61 compared to ~67, 131, 98, 99, 121, 132~134, 148~15, 112, 186 -189, 93-97, 190, 52-60, 191-193, 234-250 and the at least one biomarker selected from CD139 (Table 3). Changes in the amount of the markers indicate whether a subject has AKI or not at an early time point. Indicates that.

[0177] Preferably, the changes described herein are statistically significant.

[0178] In the context of the methods of the present invention, the amount of more than one biomarker can be determined. In theory, the determined amounts are compared with various control amounts, i.e., the amounts of each biomarker tested. A control amount can be compared.

[0179] Furthermore, the control preferably defines a threshold amount or threshold. Suitable control amounts or thresholds The amount of a control sample to be analyzed together with, i.e., simultaneously with, or subsequently to, the test sample. A preferred control amount to serve as a threshold is Upper limit of normal (ULN), i.e., the upper limit of normal (ULN) in a population of subjects (e.g., patients enrolled in a clinical trial). The ULN for a given subject population may be derived from the upper limit of physiological levels found in The method of the present invention can be used to determine the amount of the hydroxyl group. The objective of the present invention may be to determine the median value of the population for the amount of biomarker present in the sample. The overlap between the two distributions can be determined by plotting 1-specificity against sensitivity for a range of A suitable threshold amount can also be identified by a ROC plot depicting: Sensitivity, or as (number of true-positive test results) / (number of true-positive + number of false-negative test results) The true positive rate is defined as the rate at which a given disease is detected. On the x-axis, the ratio is calculated as (number of false positive results) / (number of true negative results). The false positive rate, defined as the number of positive results + the number of false positive results), or 1 minus the specificity. , a measure of specificity, calculated from the completely unaffected subgroup. The positivity rate was completely independent by using test results from two different subgroups. The ROC plot is independent of the prevalence of disease in the sample because it is calculated as Each point on the plot represents a sensitivity / 1-specificity pair corresponding to a particular discrimination threshold. A test showing perfect discrimination (no overlap in the two distributions of results) passes through the upper left corner It has an ROC plot, where the true positive rate is 1.0, or 100% (perfect sensitivity). The false positive rate is 0 (perfect specificity). The theoretical plot for the same distribution of Most plots fall between these two extremes.

[0180] diagnosis Even more preferred is the following diagnostic algorithm: i) at least one biomarker is selected from the biomarkers shown in Table 5 and the control dose is known to be at risk for the development of AKI or When derived from a subject diagnosed with AKI, at least one biomarker is increased compared to a control amount. Essentially the same or increased amounts of carbohydrate may be administered to determine whether a subject is at risk for developing AKI or not. or AKI diagnosis and / or at least one biomarker When the biomarker is selected from the biomarkers shown in Table 5, and the control amount is Subjects who are known to be at no risk of developing AKI or who have been diagnosed as not developing AKI essentially the same amount of at least one biomarker compared to a control amount when derived from Alternatively, the decreased amount may indicate that the subject is not at risk of developing AKI or is at increased risk of developing AKI. Indicates that the condition is diagnosed as not present. ii) at least one biomarker is selected from the biomarkers shown in Table 6; and the control dose is administered to patients known to be at risk for the development of AKI or If derived from a subject diagnosed with AKI, at least one biomarker is increased compared to the control amount. Essentially the same or reduced amount of the marker is used to determine whether a subject is at risk for developing AKI. or indicates a diagnosis of AKI, and / or at least one biomarker When the biomarker is selected from the biomarkers shown in Table 6, and the control amount is Patients who are known to be at no risk of AKI or who have been diagnosed as not having AKI essentially identical levels of at least one biomarker compared to a control level when derived from an elephant The amount or increased amount is used to determine whether the subject is at risk for developing AKI or whether the subject is at risk for developing AKI. Indicates that the diagnosis is that the patient does not have the condition.

[0181] Advantageously, the biomarkers according to SEQ ID NOs: 1 to 304 and CD15 and CD1 39 to predict the occurrence of AKI in subjects undergoing medical intervention and / or The research underlying the present invention has demonstrated that IFN-γ is a reliable marker for the early diagnosis of AKI. The above prediction and early diagnosis of AKI are particularly important in the perioperative setting. AKI is of great importance due to its high incidence in the elderly. with consequences such as chronic kidney disease (CKD), which requires extensive testing and treatment and results in high healthcare costs. The findings underlying the above methods also support the therapeutic approach. Identifying targets for plan modification, enabling improved clinical management of AKI do.

[0182] Changes in therapy Subjects at risk for developing AKI or who are diagnosed with AKI at an early time point are It is understood that modifications to the treatment regimen may be necessary compared to subjects not at risk for developing KI. It should be.

[0183] Therefore, the above method preferably further comprises the step of modifying the therapeutic regimen. Modifications to the treatment plan, as discussed above, include renal dialysis, avoidance of nephrotoxic drugs, and administration of renal stabilizers. administration of drugs to prevent AKI, or drugs or The current study focuses on the best strategies for preventing AKI from further progressing to CKD, including drugs, avoidance of anemia, and surgical intervention. This includes close monitoring of patients, which may result in optimization and earlier intervention.

[0184] definition As used herein, the term "dialysis" refers to a condition in which a subject undergoes end-stage renal disease corresponding to less than 15% kidney function. This refers to the procedures required when kidney failure develops. Renal failure can occur suddenly, as in AKI. It may be due to the nature of the condition or may be the result of slowly deteriorating kidney function, as in CKD. Dialysis relies on the principle of permeation of solutes across a semi-permeable membrane and ultrafiltration of fluids. The primary goal is to remove excess water, solutes, and toxins from the subject's blood, thereby promoting healthy kidney function. If AKI is diagnosed within 24 hours of medical intervention, In this case, dialysis can be performed at an earlier stage.

[0185] As used herein, the phrase "avoidance of nephrotoxic drugs" refers to the avoidance of nephrotoxic drugs when a subject is at risk for AKI. or avoidance of substances that damage kidney function if AKI has already been diagnosed. These substances may be chemicals or drugs, for example, painkillers, antibiotics, immunosuppressants, etc. Immunosuppressive agents and contrast media, particularly radiocontrast media, are included.

[0186] As used herein, the phrase "avoidance of anemia" refers to the reduction of red blood cells (RBCs) or hemoglobin in the blood. This refers to avoiding a decrease in total amount of ATP, or the blood's ability to carry oxygen. .

[0187] As used herein, the phrase "administration of a renal stabilizer" refers to administering a renal stabilizer to a subject at risk for AKI. Presumptive drugs to support the physiological function of the kidneys in cases where AKI is already diagnosed Refers to the administration of a substance.

[0188] As used herein, the phrase "administration of a drug to prevent AKI" refers to administering a drug to a subject at risk of AKI. This refers to the administration of a drug that is presumed to prevent the onset of AKI when a risk is present.

[0189] As used herein, the phrase "a drug that reduces or reverses the effects of AKI" refers to: Refers to the administration of drugs that are presumed to reduce the severity of symptoms and disease associated with AKI.

[0190] As used herein, the phrase "a drug that prevents the further development of AKI into CKD" means This refers to the administration of drugs that are thought to prevent AKI from developing into the chronic disease CKD.

[0191] As used herein, the phrase "optimizing the strategy of surgical intervention" refers to optimizing the overall strategy of surgical intervention. to reduce the duration and thereby the time the patient is dependent on a heart-lung machine Refers to the use of a surgical method. A heart-lung machine is a device that keeps the heart and lungs functioning during a surgical intervention. It is a mechanical device consisting of a pump, an oxygenator, and a heat exchanger for receiving oxygen. .

[0192] As used herein, the phrase "close observation of patients which may result in earlier intervention" refers to " refers to decreasing the monitoring interval if the subject is at risk for AKI.

[0193] The definitions and explanations given herein above apply to the embodiments described herein below. are applied mutatis mutandis (except as otherwise stated).

[0194] Changes in therapy (details) In one embodiment, the method comprises determining whether the subject is suffering from AKI or at a high risk of developing AKI. If the patient is at increased risk, the method may include modifying the subject's treatment regimen. A change in the treatment regimen may be understood to be at least beneficial to such a subject. As discussed above, the methods of the present invention may be used to identify subjects at risk for AKI. Therefore, such subjects can be evaluated based on their clinical symptoms. It is not necessary for the item to be clearly identifiable.

[0195] In one embodiment, the change in the therapeutic regimen is indicative of a condition that is associated with AKI or is at a high risk of developing AKI. subjects at high risk of developing glaucoma, preferably with a combination of D-glucose and L-carnitine. More preferably, about 1.5% (weight / volume) of D-glucose and / or Peritoneal dialysis therapy performed with approximately 0.1% (weight / volume) L-carnitine This may include:

[0196] Alterations to the therapeutic regimen, if necessary, are described herein above.

[0197] Preferably, the control is a subject or group known to require a change in therapeutic regimen. from a group of elephants, or a subject or group of subjects for whom it is known that no change in the treatment plan is required do.

[0198] Preferably, the sample tested is obtained after a medical intervention. Preferably, the sample is obtained after a medical intervention, in particular after a surgical intervention. The samples may be collected after surgical intervention, in particular after solid organ transplantation, cardiac surgery, or artificial knee or hip replacement. More preferably, the sample is obtained after solid organ transplantation, in particular lung transplantation. , obtained after liver, heart or kidney transplantation. Even more preferably The samples were obtained after lung transplantation, specifically after lung transplantation in male subjects.

[0199] Devices for predicting AKI or for early diagnosis of AKI The present invention also provides a method for predicting the occurrence of AKI or for the early diagnosis of AKI in a subject's sample. 1. A device for detecting a blood vessel, comprising: - at least one biomarker of the invention, or a variant or fragment thereof the detection agent for detecting the amount of the at least one biomarker in the sample, an analytical unit for said sample of subject, which allows the determination of - an evaluation unit including a data processing unit and a database, said database The data processing unit determines the control data by the analysis unit. performing a comparison of the amount of at least one biomarker determined with a stored control; By this, predictions can be established,evaluation units The present invention also relates to a device comprising:

[0200] Biomarkers were classified into protein biomarkers, male patient biomarkers, and predictive biomarkers. markers, diagnostic biomarkers, or a combination of predictive and diagnostic biomarkers The present invention relates to the use of markers, as well as combinations thereof and fragments and variants thereof. The biomarkers can be selected from any of the groups of biomarkers disclosed in the literature.

[0201] Biomarkers were CD9 antigen, prostaglandin G / H synthase 2, CD15, CD99 antigen, CD99R antigen, high-affinity immunoglobulin epsilon receptor subunit Tumor necrosis factor receptor serogroups, including tumor necrosis factor alpha, tumor necrosis factor receptor serogroups, and lymphotoxin-alpha Ligand for Parr family member 1B, a tumor necrosis factor receptor superfamily member -6, interferon alpha-1 / 13, basigin, CC motif, chemokine 7 , Dickkopf-related protein 2, hyaluronan-mediated motility receptor, interleukin-1 Kin-18, interleukin-7, major prion protein, receptor tyrosine protein Protein phosphatase C, P-selectin glycoprotein ligand 1, tumor necrosis factor ligand s PAR family member 14, DNA topoisomerase 2-alpha, brain-derived neurotrophin factor, caspase-8, eotaxin, CC motif chemokine 3, CC motif Ke Mokine 5, monocyte differentiation antigen CD14, cytokine receptor-like factor 2, lamin-B1, cell Tumor antigen p53, serine / threonine protein kinase PAK1, caspase-9, Transforming growth factor-beta-inducible protein IG-H3, leukocyte surface antigen CD 47, T cell surface glycoprotein CD8 alpha chain, Dickkopf-related protein 3, Growth arrest-specific protein 6, interleukin-15, cytokine receptor common subunit Nit beta, keratin type II cytoskeleton 8, leukosialin, MAP / microtubule affinity regulation Kinase 4, melanophilin, interstitial collagenase, matrilysin, prostaglandin G / H synthase 1, myeloblastin, RNA-binding protein 3, serum amyloid P formation Minutes, tetraspanin-16, urokinase-type plasminogen activator, CTP synthase Tase 1, CD139, Max dimerization protein 4, transmembrane protein 54, actin Cytoplasmic 1, caspase-3, complement decay-accelerating factor, high mobility group protein B2, homeobox Hox protein, Hox-C11, intercellular adhesion molecule 1, interleukin-12 subunit ct alpha, Krueppel-like factor 8, galectin-4, regulatory factor complex protein LAMTOR1, L-selectin, mitogen-activated protein kinase 3, mucin- 5B, nuclear factor of activated T cells, transforming growth factor beta-1 proprotein , serine / threonine protein kinase VRK1, cyclin-dependent kinase inhibitor tether 3, tissue factor pathway inhibitor 2, microtubule-associated protein 1A / 1B light chain 3B, phosphatase inhibitor 3B, and Phatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual specificity protein Protein phosphatase PTEN, interleukin-8, and Rho guanine nucleotide interactors Recombination factor 2, CASP8 and FADD-like apoptosis regulator, CUE domain-containing protein Protein 2, death-associated protein kinase 1, endothelin-1 receptor, eukaryotic translational reactivity Cofactor 3 subunit B, DNA-binding protein inhibitor ID-2, prelamin A / C, CAD protein, zinc finger protein 593, mitogen-activating protein Protein kinase 12, cytochrome P450 1B1, angiotensinogen, colon adenomatous polyposis Lipoprotein, POU domain class 2 transcription factor 1, somatostatin receptor type 4 , tumor necrosis factor alpha-inducible protein 3, E3 ubiquitin protein ligase TRI M22, complement factor D, neurotrophin-4, insulin-like growth factor binding protein 1 , cystatin-B, interleukin-18 binding protein, WAP4 disulfide core Domain protein 2, haptoglobin, uteroglobin, chitinase-3-like protein 1, elafin, cartilage oligomeric matrix protein, interleukin-16 and interleukin-17 Alpha trypsin inhibitor heavy chain H1 (SEQ ID NOs: 1-304 and CD15 and and CD139), and their isoforms, fragments, and variants. You can choose from:

[0202] The biomarker CD99R is expressed on myeloid cells, NK cells, and T lymphocytes. by the antibody MEM-131, which reacts with an epitope restricted to a subset of D99 molecules. Be recognized.

[0203] As used herein, the term "device" refers to a set of devices operable together to enable diagnosis. a system of means including at least the above-mentioned analysis unit and an evaluation unit coupled to Preferred detection agents for use in the devices of the present invention are those in connection with the methods of the present invention. Preferably, the detection agent is an antibody or an aptamer. The manner in which the units of the device are linked together depends on the types of units contained in the device. For example, if a unit for automatically determining the amount of a biomarker is suitable, When used, the data obtained by the automatically operating unit may be used, for example, The data can be processed by a computer program to achieve the desired results. , the unit is in such a case contained by a single device. The kit preferably includes a database containing stored controls as well as biomarker determinations. a computer to perform a comparison of the measured amount with stored controls in a database; As used herein, "computer-implemented" includes computer-implemented algorithms. "Computer-readable program code tangibly contained in a computer unit" means a computer-readable program code tangibly contained in a computer unit. The results can be given as raw data output that requires interpretation by a physician. Preferably, however, the output of the device is processed, i.e. evaluated. It is raw data and does not require a physician to interpret it.

[0204] In a preferred device of the present invention, the detection agent, preferably an antibody, is immobilized in an array format. The device according to the present invention can measure the amount of more than one biomarker. It will be appreciated that the detection agent may be determined simultaneously. Immobilized on a solid support and arranged in an array format, e.g., a so-called "microarray." It is possible.

[0205] kit The present invention also provides a method for detecting at least one biomarker of the present invention, or a variant thereof, and a detection agent for determining the amount of erythropoietin or its fragments, and a method for establishing a prediction or early diagnosis of AKI. The present invention also relates to a kit containing instructions for evaluation of the

[0206] Biomarkers were classified into protein biomarkers, male patient biomarkers, and predictive biomarkers. markers, diagnostic biomarkers, or a combination of predictive and diagnostic biomarkers The present invention relates to the use of markers, as well as combinations thereof and fragments and variants thereof. The biomarkers can be selected from any of the groups of biomarkers disclosed in the literature.

[0207] In one embodiment, the biomarkers are CD9 antigen, prostaglandin G / H synthase, and the like. ase 2, CD15, CD99 antigen, CD99R antigen, high-affinity immunoglobulin epsilon Tumors containing receptor subunit alpha, tumor necrosis factor, and lymphotoxin-alpha Tumor necrosis factor receptor superfamily member 1B, a ligand for necrosis factor receptor superfamily member 1B -family member 6, interferon alpha-1 / 13, basigin, CC mochi chemokine 7, Dickkopf-related protein 2, hyaluronan-mediated motility receptor condition, interleukin-18, interleukin-7, major prion protein, receptor Body tyrosine protein phosphatase C, P-selectin glycoprotein ligand 1, tumor Necrosis factor ligand superfamily member 14, DNA topoisomerase 2-alpha A, brain-derived neurotrophic factor, caspase-8, eotaxin, CC motif chemokine 3 , CC motif chemokine 5, monocyte differentiation antigen CD14, cytokine receptor-like factor 2, Lamin-B1, cellular tumor antigen p53, serine / threonine protein kinase PAK1, Caspase-9, transforming growth factor-beta-inducible protein IG-H3, Leukocyte surface antigen CD47, T cell surface glycoprotein CD8 alpha chain, Dickkopf related protein 3, growth arrest specific protein 6, interleukin-15, cytokine Serum receptor common subunit beta, keratin type II cytoskeleton 8, leukosialin, MAP / microtubule affinity-regulating kinase 4, melanophilin, interstitial collagenase, matrilysin, Prostaglandin G / H synthase 1, myeloblastin, RNA-binding protein 3, Serum amyloid P component, tetraspanin-16, urokinase-type plasminogen activator activator, CTP synthase 1, CD139, Max dimerization protein 4, transmembrane protein Protein 54, actin cytoplasmic 1, caspase-3, complement decay-accelerating factor, high mobility group protein Protein B2, homeobox protein, Hox-C11, intercellular adhesion molecule 1, interleukin-1 Kin-12 subunit alpha, Krueppel-like factor 8, galectin-4, regulatory factor The mitogen-activated protein kinase C (MITK), the mitogen-activated protein kinase C (LMK), and the mitogen-activated protein kinase C (L-selectin) are involved in the mitochondrial endothelial cell death. Enzyme kinase 3, mucin-5B, nuclear factor of activated T cells, transforming growth factor beta -1 proprotein, serine / threonine protein kinase VRK1, cyclin-dependent receptor agonist kinase inhibitor 3, tissue factor pathway inhibitor 2, microtubule-associated protein 1A / 1B light chain 3B, phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and and dual specificity protein phosphatases PTEN, interleukin-8, and Rho-guanine N-nucleotide exchange factor 2, CASP8 and FADD-like apoptosis regulator, CU E domain-containing protein 2, cell death-associated protein kinase 1, endothelin-1 receptor Eukaryotic translation initiation factor 3 subunit B, DNA-binding protein inhibitor ID- 2. Prelamin A / C, CAD protein, zinc finger protein 593, mitogenic Factor-activated protein kinase 12, cytochrome P450 1B1, angiotensin II Gen, adenomatous polyposis coli protein, POU domain class 2 transcription factor 1, somato Statin receptor type 4, tumor necrosis factor alpha-inducible protein 3, E3 ubiquitin protein Protein ligase TRIM22, tumor necrosis factor- and lymphotoxin-alpha-containing Ligand for death factor receptor superfamily member 1B, complement factor D, neurotrophin Insulin-like growth factor binding protein 1, cystatin B, interleukin -18 binding protein, WAP4 disulfide core domain protein 2, haptoglobin uteroglobin, chitinase-3-like protein 1, elafin, cartilage oligomeric matrix Proteins, interleukin-16 and inter-alpha trypsin inhibitor heavy Chain H1 (SEQ ID NOs: 1 to 304 and CD15, CD139), and their isoforms forms, fragments and variants.

[0208] As used herein, the term "kit" refers to a kit for determining the amount of a biomarker in a sample. refers to a collection of said medications and instructions for use provided in a ready-to-use format. The instructions are preferably provided in a single container. Preferably, the kit also includes a bio It also contains additional components that are necessary to carry out the determination of the amount of the marker. Such components include: It may also be an auxiliary agent required for the detection of a biomarker or a calibration standard. Additionally, the kit preferably includes reagents for the detection of more than one biomarker. good.

[0209] In one embodiment, the kit comprises a beta-casomorphin, alpha calcitonin gene related Calcitonin gene-related peptide (alpha-CGRP), beta-calcitonin gene-related peptide (beta-CG RP) Lampalizumab, recombinant human C1 esterase inhibitor, Ruconest, Slamin agonists, bone morphogenetic protein-7 agonists (e.g., THR-184), α-melanocyte stimulators Intensive hormone analogues (e.g., ABT-719), hepatocyte growth factor (HGF) mimics ( e.g., ANG-3777), deferoxamine, and / or any combination thereof The present invention may further comprise a pharmaceutical composition comprising a compound selected from the group consisting of: or further, the compound is QPI-1002 (teprasiran, I5NP) and / or A SP1128 (selective peroxisome proliferator-activated receptor delta modulator) It's okay to have it.

[0210] In one embodiment, such a kit is a theranostic concept (i.e. For this purpose, the subject may first be screened for biomarkers and then the dosage and treatment concept are adjusted accordingly, preferably as described above. The compound and / or pharmaceutical composition of the present invention is compatible with one of the compounds and / or pharmaceutical compositions of the present invention.

[0211] Several groups from which the biomarkers of the present invention may be preferably selected are described above. These groups are described specifically with respect to the methods of the present invention. This group not only relates to the method of the invention, but also to the kit, device and use of the invention. It should be understood that the above is also relevant.

[0212] A detection agent, preferably an antibody or fragment thereof, included by the above kit or composition It is specifically envisaged that the strips be immobilised on a solid support in an array format. , immobilized on a solid support and arranged in an array format, e.g., a so-called "microarray" Therefore, the present invention also contemplates a microarray comprising the above detection agent. did.

[0213] Preferably, the kits, compositions and microarrays are used to assess the incidence of AKI in a subject's sample. It is used to predict the risk of AKI and to diagnose AKI.

[0214] All references cited herein are incorporated by reference in their entirety and as specifically incorporated herein. The disclosures specifically mentioned are hereby incorporated by reference.

[0215] Embodiment Below is a list of embodiments within the scope of the present invention.

[0216] The present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject, or A method for early diagnosis of AKI, comprising: a. A sample obtained from the subject has a logFC of less than -0.7 and is D9 antigen and myeloblastin, and their isoforms, fragments and barriers determining the amount of at least one biomarker selected from the group consisting of and, b. The amount of said at least one biomarker and the amount of said at least one biomarker comparing the amount of the antibody to a control amount of the antibody; Including, The control dose is administered to subjects who are not at risk of developing AKI and / or do not have AKI. and the amount of each biomarker in a healthy subject.

[0217] In a further aspect, the present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject. A method for measuring AKI or for early diagnosis of AKI, comprising: a. A sample obtained from a subject has a logFC of less than -0.7 and is a measure of activated T cells nuclear factor, interferon alpha-1 / 13 and myeloblastin, and At least one selected from the group consisting of isoforms, fragments and variants thereof determining the amount of a biomarker; b. The amount of said at least one biomarker and the amount of said at least one biomarker comparing the amount of the antibody to a control amount of the antibody; Including, The control dose is administered to subjects who are not at risk of developing AKI and / or do not have AKI. The method includes a method in which the amount of each biomarker in a healthy subject is a control amount, A decrease in the amount of at least one of the biomarkers compared indicates that the subject has AKI or includes embodiments in which the patient is at risk for developing AKI.

[0218] The method includes determining whether a subject is at risk of developing AKI and / or has AKI. The present invention includes an embodiment that includes predicting whether the

[0219] The method comprises detecting in the sample at least CD15 and Dickkopf-related protein 2 or an isoform, fragment or variant thereof. This includes embodiments including:

[0220] The method comprises detecting in the sample at least the CD9 antigen and myeloblastin, or determining the amount of an isoform, fragment, or variant of nothing.

[0221] The method comprises detecting in the sample at least Dickkopf related protein 2 and interleukin 1 (IL-1). Feron alfa-1 / 13 or an isoform, fragment or variant thereof

[0033] In some embodiments, the method includes determining the amount of

[0222] The method comprises detecting Dickkopf-related protein 2 and hyaluronic acid-mediated Determining the amount of a motility receptor, or an isoform, fragment, or variant thereof The present invention includes embodiments including steps.

[0223] The method comprises detecting in the sample at least nuclear factor of activated T cells and myeloblastin, or or an isoform, fragment, or variant thereof. Including embodiments.

[0224] The method comprises detecting in the sample at least interferon alpha-1 / 13 and myeloproliferative agents. A method for determining the amount of blastin, or an isoform, fragment, or variant thereof. The present invention includes embodiments that include steps.

[0225] The method comprises detecting in the sample at least nuclear factor of activated T cells and interferon alfa. Determining the amount of Fa-1 / 13, or their isoforms, fragments, or variants The present invention also includes embodiments comprising the step of:

[0226] The method includes detecting in a sample nuclear factor of activated T cells and hyaluronan-mediated motility receptor. or an isoform, fragment or variant thereof. This includes embodiments including:

[0227] The methods include embodiments in which the sample is a urine, blood, plasma or serum sample.

[0228] The method may involve the sample being subjected to a variety of procedures, such as administration of a drug, avoidance of drug administration, injection of a contrast medium, or surgical intervention. This includes embodiments in which the sample is taken prior to a planned medical intervention.

[0229] The method may further comprise determining one, two, three or more additional biomarkers in the sample and The biomarkers that are used include protein biomarkers, male patient biomarkers, and predictive biomarkers. marker, diagnostic biomarker, or a combination of predictive and diagnostic biomarkers The present invention includes embodiments selected from one or more of the following:

[0230] The method further comprises the step of: At least 70%, at least 80%, at least 9% of the total length of the biomarkers 0%, at least 95%, at least 98%, or at least 99% sequence identity. This includes embodiments in which:

[0231] The method may further comprise determining the amount of said at least one biomarker by ELISA (enzyme-linked immunosorbent assay). immunosorbent assays) or antibody arrays, in particular planar antibody microarrays or bead-based This includes embodiments that involve using immunoassay devices such as antibody microarrays. nothing.

[0232] The present invention provides a method for predicting the risk of developing acute kidney injury (AKI) in a subject, or A device for early diagnosis of AKI, - Testing for at least one biomarker, or a variant or fragment thereof a detection agent, said detection agent being adapted to determine the amount of said at least one biomarker in a sample. an analytical unit for said sample of interest, - an evaluation unit including a data processing unit and a database, said database The data processing unit determines the control data by the analysis unit. performing a comparison of the amount of at least one biomarker determined with a stored control; By this, predictions can be established,evaluation units Including, - in one embodiment, wherein the biomarkers are CD15, CD9 antigen, and myeloblastin; Nuclear factor of activated T cells, interferon alpha-1 / 13, and myeloblastin In another embodiment, the present invention relates to a compound of formula (I), a compound of formula (II ... At least one of the devices is selected.

[0233] The present invention provides a detection agent for determining the amount of at least one biomarker, and an AK and instructions for evaluation to establish a prognosis or early diagnosis of I, wherein the biomarker is CD1 5, CD9 antigen and myeloblastin and their isoforms, fragments and variants The kit comprises at least one selected from the group consisting of:

[0234] The present invention includes a kit wherein the detection agent is selected from the group consisting of an antibody and an aptamer. [Example]

[0235] method In the study underlying the present invention, plasma samples from subjects before and after LuTx (lung transplantation) were collected. , an antibody microarray containing 1130 antibodies against 930 different potential biomarkers. The analysis was performed using the AKIN classification. To assess whether differences exist between subjects who were not diagnosed with AKI using the classification Differences in marker abundance between subjects that were found to be statistically significant are shown in Table 1 below. These markers can be used to predict the risk of developing AKI and for the early diagnosis of AKI. It can be used as a biomarker for diagnosis.

[0236] Patients with and without increased risk of developing AKI and those with AKI To identify biomarkers that are differentially abundant in patients with and without the compound A study using antibody microarrays was carried out. In this study, the protein fraction of the sample was analyzed. , directly labeled with a fluorescent dye. By pooling all samples included in the study, A control was established and labeled with a second fluorescent dye. The sample was mixed with a control sample and incubated on the antibody microarray in a competitive two-color procedure. I did.

[0237] The antibody microarray applied in this study was directed against 900 different proteins. The assay contained 1130 antibodies. All antibodies were immobilized in at least two replicates. The study included a total of 135 samples with or without AKI. They were classified as none (AKIN0) or AKI (AKIN1, 2, 3).

[0238] After measuring the concentration from plasma samples by BCA assay, the samples were analyzed using scioDye-1 (Sc The cells were labeled with the adjusted protein concentration for 1 hour in a PBS (Fujimi Biomics, Germany). After pooling the samples, the samples were analyzed with scioDye-2 (Sciomics, Germany). A common control was prepared by labeling the cells with hydroxylamine after 1 hour. After 30 min, excess dye was removed and the buffer was replaced with PBS. All labeled protein samples were used immediately.

[0239] All samples were analyzed using scioDiscover antibody arrays (Sciomics, Heide The arrays were incubated on scioBlock (Berlin, Germany). (Sciomics, Germany) and then the samples were analyzed using a two-color technique. After 3 hours of incubation, the slurries were diluted with 1x PBSTT. The plates were washed thoroughly and rinsed with 0.1x PBS and water, followed by drying with nitrogen. .

[0240] Using the same instrument laser power and PMT, a Powerscanner (Tec Slides were scanned using GenePix Pro 6 (Schwarzschild, Germany). 0 (Molecular Devices, Union City, USA) Spot segmentation was performed. Mean signal intensity and median background intensity After uploading the values, use the LIMMA package in R-Bioconductor The data obtained were analyzed using the invariant Lowess normalization method. For differential analysis, linear models were used based on moderated statistics. The results were fitted with LIMMA obtained in two-tailed t-tests or F-tests. By controlling for the false discovery rate (false discovery rate) and Hochberg's false discovery rate (false discovery rate), all presented p Values ​​were adjusted for multiple testing. Proteins were classified as having |logFC|>0.3 and adjusted A p-value <0.05 was defined as differential.

[0241] Using LIMMA analysis, 92 proteins were identified as differential, as defined above. The differential abundance between AKI and non-AKI samples was used to identify the markers. The differences in protein abundance between the two sample groups are summarized in the table below. The significance level is given by the logarithmic fold change (logFC) calculated to the base 2. The significance is indicated by the p-value adjusted for multiple testing as described above.

[0242] To assess the quality of the markers, use logFC values, adjusted p-values, etc. and stripchart (graphical representation of the distribution of abundance differences and discriminatory power) A quality score (QS) was calculated for each marker: QS = QS[logFC] + QS[adjusted p-value] + QS[stripchart].

[0243] QS[logFC] is defined as "3" for |logFC|>1.0.

[0244] QS[logFC] is defined as "2" for |logFC|>0.7.

[0245] QS[logFC] is defined as '1' for |logFC|>0.5.

[0246] QS [adjusted p-value] is defined as '3' for adjusted p-values ​​< 0.0001. can be.

[0247] QS [adjusted p-value] is defined as '2' for adjusted p-values ​​< 0.001. do.

[0248] QS [adjusted p-value] is defined as "1" for adjusted p-values ​​< 0.01 .

[0249] Regarding the QS[stripchart] definition, the distinctiveness of the stripchart is After evaluation by academic scientists, the score is rated as "excellent" = 2.0 within the range of 0.5 to 2.0, The classification was "very good" = 1.0 and "good" = 0.5.

[0250] QS[stripchart] has excellent or very good discrimination. It is defined as "1" for od.

[0251] A maximum quality score of 7 can be achieved with one marker.

[0252] A quality score above 5 is defined as "excellent" A quality score of 4 is defined as "very high" A quality score of 3 is defined as "high."

[0253] "logFC" is defined as the logarithmic fold change calculated to the base 2 and is used to compare AKI patients with The difference in protein abundance between patients with and without AKI is shown in Figure 1. For prediction methods, "AK" is used. "AKI patients" refers to subjects who have developed AKI. logFC=1 means that AKI patients have On average, 2 1 = means having a 2-fold higher signal. logFc=-1 indicates a 2-fold increase in the signal in patients with AKI compared to patients without AKI. -1 =1 / 2.

[0254] "Adjusted p-value" is the p-value adjusted for multiple testing and indicates the level of significance. vinegar.

[0255] A "stripchart" is a graphical representation of differential abundance distribution as well as discriminatory power.

[0256] result The following table identifies the biomarkers identified by the inventors.

[0257] The present invention includes 92 biomarkers as shown in Table 1. Table 1 shows the predictive biomarkers and diagnostic biomarkers.

[0258] [Table 2-1]

[0259] [Table 2-2]

[0260] Table 2-3

[0261] Table 2-4

[0262] Table 2-5

[0263] Table 2-6

[0264] Table 2-7

[0265] Table 2-8

[0266] Table 2-9

[0267] Table 2-10

[0268] Table 2-11

[0269] Table 2-12

[0270] [Table 2-13]

[0271] [Table 2-14]

[0272] Tumor necrosis factor receptor superfamily member 1B (marker number 5 in Table 1, Table 2 The ligands of the biomarkers of the present invention are markers numbered 4 in Table 1 and 5 in Table 6. The markers were identified by binding to immobilized antibodies. Fc-tumor necrosis factor receptor superfamily member 1B fusion protein was administered to tumor necrosis factor receptor superfamily member 1B. Used to capture ligands for this receptor, including factor and lymphotoxin-alpha did.

[0273] "Qual Score" is a logFC value, adjusted p-value and stripchart A quality score that takes into account the differential abundance distribution as well as a graphical representation of the discriminatory power is shown.

[0274] The logFC values ​​and adjusted p-values ​​are also shown in Table 1. Positive logFC values ​​are Each biomarker was upregulated in patients with AKI compared to patients without AKI. Negative logFC values ​​indicate that each biomarker is associated with a higher risk of AKI in patients without AKI. , and is downregulated in AKI patients compared with

[0275] Where applicable, the Uniprot registration name and Uniprot accession number are given. The biomarkers of the invention are, although not all, proteins, and not all biomarkers has a UniProt registration.

[0276] Tables 1, 5 and 6 show the combined predictive and diagnostic biomarkers. Table 4 includes biomarkers identified as predictive as well as diagnostic. In this case, biomarkers identified in predictive assays are indicated by "pre" and diagnostic Biomarkers identified in the diagnostic assay are indicated by "diag."

[0277] Table 2 shows the 78 predictive biomarkers of the present invention.

[0278] [Table 3-1]

[0279] [Table 3-2]

[0280] [Table 3-3]

[0281] [Table 3-4]

[0282] [Table 3-5]

[0283] [Table 3-6]

[0284] [Table 3-7]

[0285] [Table 3-8]

[0286] [Table 3-9]

[0287] [Table 3-10]

[0288] [Table 3-11]

[0289] Table 3 shows 26 diagnostic biomarkers of the present invention.

[0290] [Table 4-1]

[0291] [Table 4-2]

[0292] [Table 4-3]

[0293] Twelve biomarkers were found to be both predictive and diagnostic biomarkers. Twelve biomarkers were found to be both predictive and diagnostic biomarkers. The markers are shown in Table 4.

[0294] [Table 5-1]

[0295] [Table 5-2]

[0296] The 35 biomarkers showing higher abundance in AKI patients are shown in Table 5.

[0297] [Table 6-1]

[0298] [Table 6-2]

[0299] The 68 biomarkers showing lower abundance in AKI patients are shown in Table 6.

[0300] [Table 7-1]

[0301] [Table 7-2]

[0302] [Table 7-3]

[0303] [Table 7-4]

[0304] Further testing included 597 samples with or without AKI (230 preoperative; Another larger cohort of samples, including 368 post-surgery patients, was analyzed using a novel antibody microarray. Sample preparation, incubation and raw data acquisition were performed according to the method described above. For differential analysis, a linear model was used as described in section The results obtained in two-tailed t-tests or F-tests based on rated statistics Proteins were selected based on |logFC| > 0.25 and fit with LIMMA using standard M estimation. and an adjusted p-value <0.001 was defined as differential.

[0305] Significantly down- or up-regulated biomarkers are depicted in Table 7.

[0306] [Table 8]

[0307] During large-scale trials, the presence of significantly higher or lower Several additional biomarkers that indicate the amount of HIV were also identified. These markers are listed in Table 8. is depicted in.

[0308] [Table 9-1]

[0309] [Table 9-2]

[0310] [Table 9-3]

[0311] In some cases, the change in logFC from the predicted state to the diagnostic state (i.e., delta logF C) indicates meaningful biomarkers of special interest. Such markers are listed in Table 9. Depicted.

[0312] [Table 10]

[0313] clinical case AKI is a major complication in critically ill patients and after major surgery, especially cardiac surgery. In this setting, patients are typically elderly and may have pre-existing conditions such as high blood pressure and diabetes. Both are risk factors for kidney failure. These patients are particularly at increased risk of acute kidney injury (AKI). There is a risk of developing glaucoma, with a prevalence of up to 40%. In many cases, the decline in kidney function is , is recognized later.

[0314] A concrete example from daily clinical practice is the treatment of patients with mitral and tricuspid valve disease with long-term underlying hypertension. The patient was a 72-year-old female with renal failure. Before surgery, the patient's renal function had decreased by 45%. The surgery had to be performed using a heart-lung machine and required the administration of blood products. After surgery, the patient was hypervolemic with approximately 5 L of intravascular fluid administration. Increased creatinine as a common clinical parameter is not recognized, and thus, the risk of AKI is low. This means that early diagnosis is extremely difficult. Predictive tests, e.g., 5-10 Using an immune-based point-of-care device containing a biomarker combination of markers Pre-determine risk profiles by analyzing patients' plasma before surgery using Alternative procedures for valve replacement can be discussed to prevent the development of AKI. Furthermore, when blood products are administered, small amounts of free heme are released as a hemoglobin breakdown product that can damage the kidneys. Short-term stored packed red blood cells may be considered if indicated. Creatinine was then reassessed as a renal parameter in this patient, and AKI was diagnosed. It took 7 days for dehydration to occur. After OP, the diagnostic barometer was used immediately after surgery in the 6-24 hour time frame. A biomarker combination is used to detect the onset and severity of AKI early and to assess the efficacy and safety of drugs. The amount of steroids administered can be adjusted for renal status. Those skilled in the art will appreciate that renal stabilizing drugs may be considered. and / or by avoiding or adjusting the dosage of nephrotoxic substances such as antibiotics. This can improve patient outcomes and prevent secondary conditions such as chronic kidney disease.

[0315] References

[0316] [Table 11-1]

[0317] [Table 11-2]

[0318] [Table 11-3]

Claims

1. To predict the risk of developing acute kidney injury (AKI) in a subject or to predict the early onset of AKI. A method for early diagnosis, comprising: a. In a sample obtained from said subject, a biomarker having a logFC of less than -0.7 The antibodies include nuclear factor of activated T cells, interferon alpha-1 / 13, and mycobacterium globulin. From the group consisting of eloblastin and its isoforms, fragments and variants determining the amount of at least one biomarker selected from the group consisting of: b. The amount of said at least one biomarker and the amount of said at least one biomarker comparing the amount of the antibody to a control amount of the antibody; Including, The control amount is not at risk of developing AKI and / or is free of AKI. The method of claim 1, wherein the amount of each biomarker in a healthy subject, such as a subject.

2. A decrease in the amount of the at least one biomarker compared to the control amount indicates that the subject 10. The method of claim 1, which indicates that the patient has AKI or is at risk of developing AKI. method.

3. determining whether the subject is at risk of developing and / or has AKI; The method of claim 1 or 2, comprising a predicting step.

4. in said sample at least nuclear factor of activated T cells and myeloblastin, or determining the amount of an isoform, fragment, or variant thereof. Item 4. The method according to any one of items 1 to 3.

5. In said sample, at least interferon alpha-1 / 13 and myelobacter determining the amount of a protein, or an isoform, fragment, or variant thereof; The method of claim 1 , further comprising:

6. In said sample, at least nuclear factor of activated T cells and interferon alpha -1 / 13, or an isoform, fragment, or variant thereof. The method of any one of claims 1 to 5, comprising the steps of:

7. In said sample, nuclear factor of activated T cells and hyaluronan-mediated motility receptor, or or an isoform, fragment or variant thereof, 7. The method according to any one of claims 1 to 6.

8. 8. The method according to claim 1, wherein the sample is a urine, blood, plasma or serum sample. How to post.

9. The sample may be a result of a procedure such as administration of a drug, withdrawal of a drug, injection of a contrast medium or surgical intervention.

9. The method according to claim 1, wherein the sample is taken before a planned medical intervention. The method described.

10. One, two, three or more additional biomarkers are determined in the sample, and the additional biomarkers are Biomarkers include protein biomarkers, male patient biomarkers, and predictive biomarkers. predictive biomarkers, diagnostic biomarkers, or a combination of predictive and diagnostic biomarkers Select one or more of the following: - the protein biomarker is selected from the group consisting of CD9 antigen, prostaglandin G / H synthase, ase 2, CD15, CD99 antigen, CD99R antigen, high-affinity immunoglobulin epsilon Tumors containing receptor subunit alpha, tumor necrosis factor and lymphotoxin-alpha Ligand for necrosis factor receptor superfamily member 1B, tumor necrosis factor receptor superfamily member 1B - Family member 6, interferon alpha-1 / 13, basigin, C-C motif chemokine 7, Dickkopf-related protein 2, hyaluronan-mediated motility receptor condition, interleukin-18, interleukin-7, major prion protein, receptor Body tyrosine protein phosphatase C, P-selectin glycoprotein ligand 1, tumor Necrosis factor ligand superfamily member 14, DNA topoisomerase 2-alpha Brain-derived neurotrophic factor, caspase-8, eotaxin, C-C motif chemokine 3 , C-C motif chemokine 5, monocyte differentiation antigen CD14, cytokine receptor-like factor 2, Lamin-B1, cellular tumor antigen p53, serine / threonine protein kinase PAK1, Caspase-9, transforming growth factor-beta-inducible protein ig-h3, Leukocyte surface antigen CD47, T cell surface glycoprotein CD8 alpha chain, Dickkopf related protein 3, growth arrest specific protein 6, interleukin-15, cytokine Serum receptor common subunit beta, keratin, type II cytoskeleton 8, leukosialin, MA P / microtubule affinity-regulating kinase 4, melanophilin, interstitial collagenase, matrilysin , prostaglandin G / H synthase 1, myeloblastin, RNA-binding protein 3 , serum amyloid P component, tetraspanin-16, urokinase-type plasminogen activator beta, CTP synthase 1, CD139, Max dimerization protein 4, transmembrane protein Protein 54, actin, cytoplasmic 1, caspase-3, complement decay-accelerating factor, high mobility group protein Protein B2, homeobox protein, Hox-C11, intercellular adhesion molecule 1, intercellular adhesion molecule 2 Leukin-12 subunit alpha, Krueppel-like factor 8, galectin-4, Nodal factor complex protein LAMTOR1, L-selectin, mitogen-activating protein Protein kinase 3, mucin-5B, nuclear factor of activated T cells, transforming growth factor-β VRK1, a serine / threonine protein kinase, and a cyclin -dependent kinase inhibitor 3, tissue factor pathway inhibitor 2, microtubule-associated protein 1 A / 1B light chain 3B, phosphatidylinositol 3,4,5-triphosphate 3-phosphatase and dual specificity protein phosphatases PTEN, interleukin-8, and Rho Guanine nucleotide exchange factor 2, CASP8 and FADD-like apoptosis regulator, CUE domain-containing protein 2, cell death-associated protein kinase 1, endothelin-1 Receptor, eukaryotic translation initiation factor 3 subunit B, DNA-binding protein inhibitor I D-2, prelamin-A / C, CAD protein, zinc finger protein 593, min Cleavage promoter-activated protein kinase 12, cytochrome P450 1B1, angiotensin II Synogen, adenomatous polyposis coli protein, POU domain class 2 transcription factor 1, So Tomatostatin receptor type 4, tumor necrosis factor alpha-inducible protein 3, E3 ubiquitin Protein ligase TRIM22, complement factor D, neurotrophin-4, insulin-like protein Growth factor binding protein 1, cystatin B, interleukin-18 binding protein, W AP4 disulfide core domain protein 2, haptoglobin, uteroglobin, chitin Nase-3-like protein 1, elafin, cartilage oligomeric matrix protein, interleukin Kin-16 and inter-alpha trypsin inhibitor heavy chain H1 (SEQ ID NOs: 1-30) 4 and CD15, CD139), and their isoforms, fragments and variants selected from one or more of the following: The male patient biomarkers are CD15, tumor necrosis factor, and lymphotoxin. Lamin, a ligand for tumor necrosis factor receptor superfamily member 1B, including alpha -B1, MAP / microtubule affinity-regulating kinase 4, Dickkopf-related protein 2, K Rueppel-like factor 8, Rho guanine nucleotide exchange factor 2, CUE domain-containing Protein 2, cell death-associated protein kinase 1, DNA-binding protein inhibitor I D-2, prelamin-A / C, adenomatous polyposis coli protein, POU domain class serotype 2 transcription factor 1, somatostatin receptor type 4, and tumor necrosis factor alpha-inducible protein Protein 3, and one or more of their isoforms, fragments and variants. Selected; - the predictive biomarkers are CD15, CD99 antigen, CD99R antigen, high affinity Immunoglobulin epsilon receptor subunit alpha, tumor necrosis factor, and lymphokine Ligands for tumor necrosis factor receptor superfamily member 1B, including syn-alpha; Tumor necrosis factor receptor superfamily member 6, basigin, C-C motif chemokine 7, CD9 antigen, Dickkopf-related protein 2, hyaluronan-mediated motility receptor Body, Interleukin-18, Interleukin-7, Major Prion Protein, Receptor Type tyrosine protein phosphatase C, P-selectin glycoprotein ligand 1, tumor Necrosis factor ligand superfamily member 14, DNA topoisomerase 2-alpha Brain-derived neurotrophic factor, caspase-8, eotaxin, C-C motif chemokine 3 , C-C motif chemokine 5, monocyte differentiation antigen CD14, cytokine receptor-like factor 2, Lamin-B1, cellular tumor antigen p53, serine / threonine protein kinase PAK1, Transforming growth factor beta-inducible protein ig-h3, leukocyte surface antigen CD 47, T cell surface glycoprotein CD8 alpha chain, Dickkopf-related protein 3, Growth arrest-specific protein 6, interferon alpha-1 / 13, interleukin -15, cytokine receptor common subunit beta, keratin type II cytoskeleton 8, Roy Cosialin, MAP / microtubule affinity-regulating kinase 4, melanophilin, interstitial collagenase , matrilysin, prostaglandin G / H synthase 1, myeloblastin, RNA binding protein 3, serum amyloid P component, tetraspanin-16, urokinase-type protein Suminogen activator, actin cytoplasmic 1, caspase-3, complement decay-accelerating factor, high Mobility group protein B2, homeobox protein Hox-C11, intercellular adhesion molecule 1 , interleukin-12 subunit alpha, interleukin-8, Kruepp el-like factor 8, galectin-4, regulatory complex protein, LAMTOR1, L-selenium Cutin, mitogen-activated protein kinase 3, mucin-5B, nuclear factor of activated T cells Cytoplasmic 4, transforming growth factor beta-1 proprotein, serine / threonine VRK1, Rho guanine nucleotide exchange factor, CASP8, and and FADD-like apoptosis regulator, CUE domain-containing protein 2, cell death-associated protein Protein kinase 1, endothelin-1 receptor, eukaryotic translation initiation factor 3 subunit, DNA binding protein inhibitor ID-2, prelamin-A / C, CAD protein, Zinc finger protein 593, angiotensinogen, adenomatous polyposis coli Protein, POU domain, class 2, transcription factor 1, somatostatin receptor type 4, tumor necrosis Factor alpha-inducible protein 3, neurotrophin-4, interleukin-18 binding Synthetic protein, interleukin-16 and inter-alpha trypsin inhibitor heavy chain H1, and one or more of their isoforms, fragments and variants. Selected from; - the diagnostic biomarker is selected from the group consisting of cytokine receptor-like factor 2, prostaglandin G / H synthase 2, interferon alpha-1 / 13, caspase-9, interro Ikin-18, interleukin-7, CTP synthase 1, CC motif chemokine 7, CD139, eotaxin, Max dimerization protein 4, interleukin-15 , RNA-binding protein 3, transmembrane protein 54, Krueppel-like factor 8, stromal cyclin-dependent kinase inhibitor 3, tissue factor pathway inhibitor 2, Growth arrest-specific protein 6, microtubule-associated protein 1A / 1B light chain 3B, caspase 8. Phosphatidylinositol 3,4,5-triphosphate 3-phosphatase and dual specific isomeric protein phosphatase PTEN, mitogen-activated protein kinase 12; cytochrome P450 1B1, and the E3 ubiquitin protein ligase TRIM22; Complement factor D, insulin-like growth factor binding protein 1, cystatin B, WAP4 disulfide fidcore domain protein 2, haptoglobin, uteroglobin, chitinase-3-like Protein 1, elafin and cartilage oligomeric matrix protein, and their selected from one or more of isoforms, fragments, and variants; - the combined predictive and diagnostic biomarkers are associated with cytokine reception receptor-like factor 2, caspase-8, eotaxin, C-C motif chemokine 7, growth arrest specific protein 6, interferon alpha-1 / 13, interleukin-15, Interleukin-18, interleukin-7, Krueppel-like factor 8, interstitial collagen Genase, and RNA-binding protein 3 and their isoforms, fragments and The method of any one of claims 1 to 9, wherein the method is selected from one or more of the following variants: Law.

11. The fragments, isoforms and / or variants of the biomarkers are of the sequence At least 70%, at least 80%, at least at least 90%, at least 95%, at least 98%, or at least 99% sequence identity 11. The method of claim 1, wherein the

12. Determining the amount of said at least one biomarker may be performed by ELISA (enzyme-linked immunosorbent assay). antibody arrays, particularly planar antibody microarrays or bead-based antibody microarrays.

12. The method of claim 1, comprising using an immunoassay device such as a microarray.

10. The method according to any one of claims 1 to 9.

13. To predict the risk of developing acute kidney injury (AKI) in a subject or to predict the early onset of AKI. A device for early diagnosis, comprising: - detection for at least one biomarker or a variant or fragment thereof an agent for detecting the amount of said at least one biomarker in a sample, an analysis unit for said sample of said subject, which enables an evaluation unit comprising a data processing unit and a database, said database The data processing unit may be configured to process the stored control data by the analysis unit. comparing the determined amount of at least one biomarker with the stored control. an evaluation unit by which said prediction can be established; Including, - the biomarker is nuclear factor of activated T cells, interferon alpha-1 / 13 and myeloblastin and their isoforms, fragments and variants The device is at least one selected from the group consisting of:

14. A detection agent for determining the amount of at least one biomarker and a method for predicting or predicting AKI. and instructions for evaluation to establish an early diagnosis of a disease, wherein the biomarker is activated T cells. nuclear factor, interferon alpha-1 / 13 and myeloblastin and their at least one selected from the group consisting of isoforms, fragments and variants of Ru, kit.

15. 15. The method of claim 14, wherein the detection agent is selected from the group consisting of an antibody and an aptamer. kit.

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