CN114755313A - Acute kidney injury markers comprising urine NAD + metabolites - Google Patents
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Abstract
The invention belongs to the field of biological detection, and particularly relates to application of urine NAD + metabolite as an acute kidney injury marker, a kit and an application method thereof. The invention provides a marker for detecting acute kidney injury, which is QA/3-OH AA. The invention also discloses a detection method and application of the marker. The invention provides an early diagnosis marker for acute kidney injury, the use aspect of the marker is simple and clear, and a new way is provided for the diagnosis and treatment of acute kidney injury.
Description
Technical Field
The invention belongs to the field of biological detection, and particularly relates to application of urine NAD + metabolite as an acute kidney injury marker, a kit and an application method thereof.
Background
Diabetes is a group of metabolic diseases characterized by hyperglycemia, and its symptoms can be divided into two major categories: one large group is the manifestations associated with metabolic disorders, especially "three more or one less" associated with hyperglycemia, most commonly seen in type 1 diabetes, type 2 diabetes often is not very obvious or only partially manifested, and the other large group is the manifestations of various acute and chronic complications. The world health organization reports reported in french media 2016, 4 and 6, show that the number of people with diabetes worldwide has increased 4-fold compared to 1980. The report of 6 months and 28 days in 2017 indicates that China is the most serious country with diabetes worldwide, and about 11 percent of adults suffer from diabetes.
Diabetes is an aging-related metabolic disease and is also one of the risk factors for AKI development. It has been found that liver, white adipose tissue and vascular tissues and organs in diabetes model have decreased NAD +. Although there is currently no direct evidence of a decrease in NAD + in diabetic kidneys, a decrease in Sirt1 expression on NAD + substrate leads to proteinuria by upregulation of Claudin, which is involved in the development of DKD. Whether diabetes causes susceptibility to AKI by affecting NAD + content is not clear.
Effective prevention of AKI (acute kidney injury) requires not only the definition of high-risk susceptibility factors, but also the prediction of susceptibility to AKI by highly effective biomarkers. Currently, SCr is a general AKI biomarker as a functional rather than a damaging marker, and SCr has hysteresis and low sensitivity and specificity, thereby resulting in omission and delay of AKI diagnosis.
In recent years, a great deal of research is devoted to search for novel AKI biomarkers, including proinflammatory mediators IL-18, NGAL (neutrophile enzyme-associated lipocalin), structural up-regulation proteins KIM-1(kidney in polypeptide molecule-1), L-FABP (lift-type fatty acid-binding protein), cell cycle regulator TIMP-2(tissue inhibitor of metalloproteinases-2), IGFBP7(IGF-binding protein-7) and the like, most of which are difficult to achieve ideal clinical diagnosis effects, and research finds that the combination of TIMP-2 and IGFBP-7 has higher AKI early diagnosis efficiency than other markers, but is still not widely used, and none of the current AKI biomarkers has the capability of predicting the occurrence of AKI before the occurrence of injury inducers.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel marker for acute kidney injury.
Another technical problem to be solved by the present invention is to provide the use of the above-mentioned markers for acute kidney injury.
The invention provides a marker for detecting acute kidney injury, which is QA/3-OH AA.
The ratio of quinolinic acid to 3-hydroxy anthranilic acid in urine before QA/3-OH AA chemotherapy.
The study is a prospective cohort study, and the cohort is found to select patients to be treated by high-dose MTX chemotherapy in the department of hematology in Huashan Hospital, and the validation cohort is to select patients to be subjected to general surgery in-situ liver transplantation. The discovery queue collects urine of patients within 72 hours before MTX treatment and 0-12 hours after the MTX treatment, detects the content of urine NAD + metabolites by a liquid chromatography-mass spectrometer (LC-MS) method, determines whether AKI occurs within 72 hours after MTX chemotherapy as a follow-up endpoint, compares the concentration difference of the urine NAD + metabolites of a diabetic group and a non-diabetic group as well as the concentration difference of the urine NAD + metabolites of the AKI group and the non-AKI group, screens urine metabolites with obvious difference, and analyzes and predicts the efficacy of the AKI. The validation cohort collects urine from patients within 72 hours before liver transplantation and 0-12 hours after the liver transplantation, and verifies the effectiveness of urine NAD + metabolite prediction AKI according to the results of the validation cohort by taking whether AKI occurs within 5 days after the operation as a follow-up endpoint. AKI is defined as a post-chemotherapy/post-operative increase of serum creatinine of > 1.5 fold baseline value or 26.5 μmol/L over baseline value or receiving renal replacement therapy.
The results indicated that 191 courses of high dose MTX chemotherapy, 38 courses of diabetes (19.90%), and 35 courses of AKI (18.32%) occurred within 72 hours after chemotherapy were found to be queued. 191 urine samples were collected within 72 hours before chemotherapy and 91 urine samples within 12 hours after chemotherapy. Compared with a non-diabetic group, the urine Kynurenine (KYN) and 3-hydroxyanthranilic acid (3-OH AA) in the diabetic group before chemotherapy have higher concentration, the Quinolinic Acid (QA) has lower concentration, and other metabolites have no obvious difference; after chemotherapy, the 3-OH AA concentration is higher, and other metabolites have no obvious difference. Compared with a non-AKI group, the concentration of 3-OH AA in urine before chemotherapy of the AKI group is higher, the concentration of quinolinic acid QA is lower, the change trend of the two metabolites is the same as that of a diabetes group, and the other metabolites have no obvious difference; the concentrations of all metabolites in urine after chemotherapy have no obvious difference. Urine QA/3-OH AA before chemotherapy is used as a biomarker to predict the risk of AKI, the risk of AKI generation in a binary low group is 4.37 times of that in a high group, the Area (AUC) under a curve of Receiver Operating Characteristics (ROC) is 0.748, and the critical value is the maximum about exponential value at 4.62, wherein the sensitivity and specificity are 77.1% and 69.9% respectively. Clinical models (age, sex, diabetes) predicted the onset risk AUC of AKI to be 0.672, and pre-chemotherapy urine QA/3-OH AA and clinical model combined AUC to be 0.772.
Validation cohort 49 orthotopic liver transplant patients with post-operative AKI16 (32.65%). 49 urine samples within 72 hours before collection, compared with the sample without AKI, the urine 3-OH AA concentration of the AKI patient is higher, and the QA/3-OH AA concentration is obviously lower. The AUC for predicting AKI occurrence by the urine QA/3-OH AA is 0.729, the john index is maximum when the critical value is 6.04, and the sensitivity and specificity are 87.5% and 66.7% respectively.
The present invention also provides a method for detecting QA/3-OH AA, said method comprising the steps of:
obtaining a urine sample to be detected;
detecting the content of quinolinic acid in the obtained urine sample;
detecting the content of the 3-hydroxy anthranilic acid in the obtained urine sample;
calculate QA/3-OH AA.
The urine sample is urine within 72 hours before treatment and/or 0-12 hours after treatment, and is pretreated before detection.
The detection of the contents of the quinolinic acid and the 3-hydroxy anthranilic acid is completed by using liquid chromatography-mass spectrometry.
The AUC of AKI occurrence predicted by urine QA/3-OH AA at 72 hours before the operation is 0.729, and the Yotan index is maximum when the critical value is 6.04.
Urine QA/3-OH AA before chemotherapy is used as a biomarker for predicting AKI occurrence risk, the AKI occurrence risk of a binary low group is 4.37 times that of a high group, the area under an operation characteristic curve of a receiver is 0.748, and the Yotanden index is the maximum when a critical value is 4.62.
The invention also provides application of the marker in preparing a medicine for diagnosing or treating acute kidney injury.
The marker is a target or a positive control in the medicament for diagnosing acute kidney injury.
Or the marker is a screening standard of the medicine for treating acute kidney injury; substances that elevate QA/3-OH AA are candidates for drugs to treat acute kidney injury.
The invention provides an early diagnostic marker for acute kidney injury, the use aspect of the marker is simple and clear, and a new way is provided for the diagnosis and treatment of acute kidney injury.
Drawings
FIG. 1 is a schematic diagram of the NAD + synthesis pathway.
The NAD + synthesis pathway mainly comprises three pathways, namely a De novo pathway, a compensatory pathway (Salvage pathway) and a Preiss-Handler pathway, and TRP (Tryptophan ), NAM (Nicotinamide, Nicotinamide) and NA (Nicotinaic acid, Nicotinic acid) are respectively used as initial substrates.
De novo synthesis pathway intermediates: N-FORMYLKYN (N-Formyllkynurenine, N-Formylkynurenine); KYN (Kynurenine); 3-OHKYN, 3-Hydroxykynurenine); 3-OH AA, (3-hydroxyanthranic acid, 3-Hydroxyanthranilic acid); ACMS (aminocarbaxymomonic semialdehyde, Aminocarboxymuconic acid semialdehyde); QA (quininic acid, Quinolinic acid); NAMN (Nicotinic acid mononucleotide).
The de novo synthetic pathway is involved in enzymes: TDO (tryptophan 2,3-dioxygenase, tryptophan 2, 3-dioxygenase); IDO (indoleamine 2,3-dioxygenase, indoleamine 2, 3-dioxygenase); AFMID (formamidase, kynurenine carboxamide enzyme); KMO (kynurenine monooxygenase);
kynur (kynureninase ); HAAO (3-hydroxyanthranilic acid dioxygenase ); QPRT (Quinolinic acid phosphoribosyltransferase, quinolinate phosphoribosyltransferase); ACMSD (ACMS decarbonylase, aminocarboxymuconate semialdehyde decarboxylase).
Offset synthetic pathway intermediates: NMN (nicotinamide mononucleotide). Compensatory synthetic pathways involving enzymes: NAMPT (nicotinamide phosphoribosyltransferase); NMNAT (nicotinamide mononucleotide adenylyltransferase).
Preiss-Handler pathway is involved in the enzyme: NAPRT (nicotinic acid phosphoribosyltransferase ).
Figure 2 found a comparison of baseline urine NAD + metabolites between cohort AKI and non-AKI groups.
FIG. 3 finds the risk of onset of AKI in a cohort baseline urine QA/3-OH AA binary group. Wherein, note: model 1 had no correction factors added, and model 2 had correction factors added including age, gender and diabetes.
FIG. 4 discovers cohort baseline urine QA/3-OH AA and clinical model predictive AKI Risk ROC curves. Wherein, the area under the ROC curve (AUC) of the baseline urine QA/3-OH AA is 0.748, the clinical model AUC composed of age, sex and diabetes is 0.672, and the AUC of the baseline urine QA/3-OH AA combined clinical model is 0.772.
Figure 5 demonstrates a baseline urine NAD + metabolite comparison between cohort AKI group and non-AKI group.
FIG. 6 verifies cohort baseline urine QA/3-OH AA and clinical model predictive AKI Risk ROC curve. The area under the baseline urine QA/3-OH AA ROC curve (AUC) was 0.729.
Detailed Description
The present invention will be described in detail below with reference to examples and drawings, but the present invention is not limited to the examples. The kit materials used in the present invention are commercially available or can be prepared according to literature procedures. The experimental methods without specifying the specific conditions in the following examples can be generally performed according to conventional conditions such as molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), either according to the usual conditions or according to the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight.
The experimental steps are as follows:
1. study object
(1) MTX chemotherapy patients
Affiliated Huashan medical doctor at Fudan university between 1 month in 2019 and 1 month in 2020Hospital hematology patients with primary central nervous system lymphoma receiving large-dose MTX chemotherapy, all patients are primary central nervous system lymphoma with definite pathological diagnosis, the MTX administration mode is intravenous drip, and the dose is more than 500mg/m2。
1) And (3) inclusion standard:
a. the age is more than or equal to 18 years, and the nature is not limited;
b. the pathological diagnosis is definitely primary central nervous system lymphoma, and the treatment scheme is high-dose MTX intravenous drip.
2) Exclusion criteria:
a. the diagnosis before treatment is CKD3-5 stage;
b. AKI before chemotherapy;
c. tumor infiltration into the kidney;
d. congenital renal malformations such as kidney deficiency, ectopic kidney, horseshoe kidney, etc.;
e. receiving a kidney transplant or kidney resection;
f. the study was rejected or not allowed to fit.
(2) Orthotopic liver transplant patient
Patients who had been subjected to cadaveric liver donor liver orthotopic liver transplantation in the general surgery department of Huashan Hospital affiliated to the university of Compound Dan from 8 months in 2019 to 1 month in 2020.
1) And (3) inclusion standard:
a. the age is more than or equal to 18 years old, and the nature is not limited;
b. patients who accept liver transplantation due to end-stage liver diseases, acute or subacute liver failure and other causes have the liver from a corpse, and the operation is orthotopic liver transplantation.
2) Exclusion criteria:
a. the preoperative confirmed diagnosis is CKD3-5 stage;
b. hepatorenal syndrome or other types of AKI occurring preoperatively;
c. congenital kidney malformations such as kidney deficiency, ectopic kidney, horseshoe kidney, etc. exist;
d. receiving a kidney transplant or kidney resection;
e. the operation formula is combined transplantation of liver and kidney;
f. repeating the liver transplantation;
g. the study was rejected or not allowed to fit.
2. Clinical data acquisition
Patient data acquisition was derived from the electronic medical record and testing system of the Huashan Hospital affiliated with the university of Compound Dan.
(1) MTX chemotherapy patients
Clinical data were collected for the patients as follows:
1) basic information: age, gender, race, BMI, BSA;
2) merging the history of basic diseases: diabetes, hypertension, CKD;
3) imaging results before chemotherapy: renal ultrasound or CT or PET-CT;
4) laboratory test results within 72 hours prior to MTX treatment: hb. WBC, N%, PLT, HbA1c, AST, ALT, TB, albumin, SCr, eGFR, urine PH;
5) MTX treatment-related information: dosage, hydration and alkalization scheme, calcium folinate use;
6) relevant test results after MTX treatment: MTX blood concentration, urine PH and SCr at 0 hours, 24 hours, 48 hours, 72 hours;
7) the combined medication condition in the treatment process: PPI, mannitol, ACEI/ARB.
(2) Orthotopic liver transplantation patients
Clinical data were collected for the patients as follows:
1) basic information: age, sex, race, BMI;
2) causes of liver transplantation: viral, alcoholic, autoimmune, tumor, etc.;
3) merging the history of basic diseases: diabetes, history of hypertension, CKD;
4) test results within 72 hours before surgery: hb. WBC, N%, PLT, HbA1c, AST, ALT, TB, albumin, blood ammonia, PT, INR, blood lipids (cholesterol, triglycerides), NT-proBNP, SCR, eGFR, MELD scores;
5) surgery-related information: for liver origin type, operation type, intraoperative blood loss;
6) and (3) postoperative related test results: day 1, day 2, day 3, day 4, day 5 SCr after surgery.
Note: calculating eGFR according to the race, sex, age and SCR value of the patient by using a 2009 CKD-EPI formula; BMI calculation formula: BMI-weight (kg)/height2(m2) (ii) a BSA calculation: male: BSA 0.00607 × height (cm) +0.0127 × weight (kg) -0.0698, female: BSA 0.00586 × height (cm) +0.0126 × weight (kg) -0.0461; MELD score calculation formula: MELD score 3.78 × ln (TB (mg/dL)) +11.2 × ln (inr)) +9.57 × ln (SCr (mg/dL)) +6.43 × cause score (0 for biliary or alcoholic, others 1).
AKI diagnosis
The MTX chemotherapy patients follow-up visit to discharge or 7 days after the MTX chemotherapy, the orthotopic liver transplantation patients follow-up visit to 7 days after discharge, and the SCr is increased to be more than or equal to 26.5umol/l within AKI48 hours or increased to be more than or equal to 1.5 times of the baseline value within 7 days or renal replacement therapy is carried out according to KDIGOSCr diagnostic standard.
4. Specimen collection and preservation
(1) Specimen collection
1) MTX chemotherapy patients
10ml of urine was collected from patients within 72 hours before MTX chemotherapy and 10ml of urine was collected from patients 0-12 hours after MTX chemotherapy.
2) Orthotopic liver transplant patient
10ml of urine within 72 hours before operation and 10ml of urine within 0-12 hours after operation of the patient are collected.
(2) Specimen preservation
1) Centrifuging the urine sample: rotating for 10 minutes at 3000;
2) a pipette sucks 1ml of urine supernatant into a clean EP tube, and the EP tube marks the hospitalization number, the name and the sampling date of the patient;
3) the treated sample was stored in a-80 ℃ freezer.
NAD + metabolite detection
(1) Main instrument
LC30 ultra high Performance liquid chromatography System Shimadzu, Japan
Triple quadrupole 5500 mass spectrometer AB Sciex, usa.
(2) Conditions of liquid chromatography
1) Column: ACQUITY UPLC HSS T3 (100X 2.1mm,1.7 μm, Waters), temperature: 40 deg.C
2) Mobile phase: a: water and 0.1% formic acid B: acetonitrile and 0.1% formic acid
3) Gradient: 1-6.5-7.5-8-8.5 min, 1% B-15% B-30% B-70% B
4) Flow rate: 0.4ml/min
5) Injection amount: 1 μ L
(3) Conditions of Mass Spectrometry
1) Scanning mode: MRM mode
2) Ionization voltage: 5.5kV (positive ion mode); 4.5kV (anion mode)
3) Temperature: 500 deg.C
4) Air curtain air: 35psi
5) Spraying mist: 40psi
6) Auxiliary heating gas: 55psi
7) Interface heater: is opened
8) Collision gas: in
(4) Ion pair parameter
Positive ion:
negative ions:
(5) analysis software
Data acquisition and processing used the software Analyst 1.6.3(AB Sciex, usa).
6. Statistical method
Statistical analysis was performed using SPSS25.0 software. The distribution type of the measurement data is detected by adopting a single-sample Kolmogorov-Smirnov test, the distribution conforming to the normal distribution is expressed by mean +/-standard deviation, the distribution not conforming to the normal distribution is expressed by median (25 percentile-75 percentile), and the counting data is expressed by frequency and percentage. The method comprises the following steps that (1) independent sample t test is adopted for inter-group comparison of normally distributed metering data, Mann-WhitneyU test in nonparametric test is adopted for inter-group comparison of non-normally distributed metering data and grade data, a list and connection table method is adopted for inter-group comparison of the counting data, and if the minimum expectation of each unit cell in the list and connection table is greater than 5 and the sample content is greater than 40, Pearson chi-square test is adopted; if the list is a four-grid table, the sample content is more than 40, the expected frequency of all cells is more than 1, and only if the expected frequency of less than 1/5 cells is less than 5 and more than 1, the chi-square test of continuity correction is used; if the sample content is less than 40, or the expected frequency of the lattices is less than 1, or more than 1 and less than 5, a Fisher exact probability method is adopted. OR values were calculated using Logistic regression model. The Area Under the receiver operating characteristic Curve (ROC) Curve (Area Under the Curve, AUC) is used to represent the ability of biomarkers and clinical models to distinguish between AKI and non-AKI. All tests in this study were bilateral tests, with differences of less than 0.05 being statistically significant.
Example 1 discovery queue
(1) Basic information
The study found that the cohort counted 191 doses of MTX treatment sessions and 38 diabetes treatments, accounting for 19.89%, experienced 35 cases of AKI and 18.32% incidence, with 18 cases of AKI occurring within 24 hours, 8 cases of AKI occurring over 24-48 hours and 9 cases of AKI occurring over 48-72 hours. The median (quartile) age for all treatment periods was 59.0(51.00-65.00) years with 66.49% male proportion. The median eGFR (quartile) of the baseline eGFR of the AKI group is 94.70(79.90-104.28) ml/min/1.73m2And no obvious difference with the non-AKI group (98.58(89.33-105.59) ml/min/1.73 m)2). In the AKI group, the proportion of the treatment course with the diabetic background was 42.85%, which was significantly higher than that in the non-AKI group (14.74%). The median MTX treatment dose was 5.08g/m for the AKI group and the non-AKI group, respectively2And 4.22g/m2Without significant difference, the MTX excretion delay rate was 34.28% higher in the AKI group than in the non-AKI group (14.74%). AKIThe proportion of urine pH 7.5 at 0 and 24 hours post treatment in group was 37.14%, lower than that in the non-AKI group (58.33%). (Table 1)
Table 1 discovery queue course basic information
Note: delay of MTX excretion: blood concentration > 1. mu. mol/L at 48 hours and > 0.1. mu. mol/L at 72 hours.
(2) Urinary NAD + metabolite differences between AKI and non-AKI groups
And 35 parts of 191 parts of baseline urine are AKI, the relative concentrations of TRP, N-FORMYL KYN and KYN in the baseline urine before MTX chemotherapy have no obvious difference between an AKI group and a non-AKI group, and the relative concentration of 3-OH AA in the baseline urine of the AKI group is higher while the relative concentration of QA is lower. The ratio of the concentrations of QA and 3-OH AA in the baseline urine was used as the biomarker to be analyzed, and the ratio in the AKI group was significantly lower than that in the non-AKI group. (FIG. 2) the maximum change in SCR within 72 hours post-chemotherapy correlated negatively with baseline urinary QA and QA/3-OH AA. (Table 2)
TABLE 2 correlation coefficients for baseline urine 3-OH AA, QA and QA/3-OH AA and SCr elevation
(3) Effect of baseline urine QA/3-OH AA in predicting AKI
The median of baseline urine QA/3-OH AA is used as a boundary to be divided into two groups of high and low groups, the model 1 is not added with correction factors, the AKI risk of the low group is 4.67 times that of the high group, the model 2 is added with correction factors including age, gender, eGFR before treatment and diabetes, and the AKI risk of the low group is 3.15 times that of the high group. (FIG. 3)
The AUC of the baseline urine QA/3-OH AA for predicting the onset risk of AKI is 0.748; the AUC for predicting the risk of AKI onset by clinical models consisting of age, gender, and diabetes was 0.672; the baseline urinary QA/3-OH AA combined with the clinical model predicted an AUC of 0.772 at risk of AKI onset. (FIG. 4)
The jotan index was maximal at a baseline urine QA/3-OH AA value of 4.62, at which the sensitivity was 77.1%, specificity was 69.9%, positive likelihood ratio was 2.56, and negative likelihood ratio was 0.33.
Example 2 validation queue
(1) Basic information
This section of the study demonstrated that the cohort was cohort with 49 orthotopic liver transplant patients, with a median age (quartile) of 52.00(46.00-55.50) years and 81.63% of males, in which AKI16 occurred, accounting for 32.65%. Compared with non-AKI patients, the blood loss of the AKI patients in the operation is larger, and other indexes have no obvious difference. There were 6 of the AKI patients diagnosed with diabetes (37.50%), 5 of the non-AKI patients diagnosed with diabetes (15.15%), and there were no statistical differences between the two. (Table 3)
Table 3 validation cohort patient basis information
(2) Risk relationship between urine NAD + metabolite and AKI
Total 49 urine samples were collected over 72 hours prior to surgery, with 16 samples of AKI patients. There was no significant difference in the relative concentrations of the baseline urine TPR, N-FORMYL KYN, QA in the two groups of patients. Patients with AKI have higher relative concentrations of 3-OH AA and lower QA/3-OH AA in their baseline urine compared to non-AKI patients. (FIG. 5)
(3) Effect of baseline urine QA/3-OH AA in predicting AKI
The baseline urinary QA/3-OH AA predicted an AUC of 0.729 for the risk of onset of AKI. (FIG. 6) the cutoff value was 6.04, the Yotanden index was the maximum, and the sensitivity was 87.5%, the specificity was 66.7%, the positive likelihood ratio was 2.63, and the negative likelihood ratio was 0.19.
NAD + de novo synthase is expressed in the proximal tubule of the human kidney and not in other structures of the kidney. The baseline urine QA/3-OH AA can be used as a biomarker for predicting the occurrence of AKI, and the baseline urine QA/3-OH AA has higher concentration and lower concentration of QA and is related to the occurrence of AKI before the injury inducement effect. The baseline urine 3-OH AA concentration and QA concentration of the diabetic patients are consistent with the trend of the AKI patients and are related to the AKI susceptibility of the diabetes.
Comparative example
In recent years, proteomics and metabolomics are gradually applied to diagnosis of renal diseases including AKI, and dynamic changes of proteins and metabolites reflect renal disease states in real time, wherein the feasibility of clinical application is greatly increased by noninvasive sample acquisition of blood and urine omics analysis. In the invention, compared with a patient without AKI, the relative concentration of 3-OH AA/Cre (after urinary creatinine correction) of urine 3-OH AA of the patient with AKI before the occurrence of AKI is higher, QA/Cre is lower, which indicates that different patients have different AKI susceptibility due to NAD + synthesis difference caused by HAAO expression or activity difference, and the relative concentration difference of upstream and downstream products of the enzyme in urine is shown, the area under the ROC curve of QA/3-OH AA as a biomarker for predicting the occurrence risk of AKI is 0.748, and when the area is used in combination with a diabetes clinical model, the AUC is increased to 0.769. After the injury-causing effect, the urine 3-OH AA concentration is increased, QA concentration is decreased, and the QA/3-OH AA ratio is decreased no matter whether AKI occurs or not, suggesting that HAAO may express or have activity decreased after the injury hit. Pariah et al found that expression of another enzyme QPRT from the de novo pathway of NAD + synthesis mediated the development of AKI, that renal QPRT substrate QA was accumulated in AKI mice, that urinary QA concentrations were elevated and consistent results were obtained in the cohort of cardiac surgery patients and ICU patients, and that urinary QA concentrations in AKI patients after cardiac surgery and within 72 hours of entry into the ICU ward were significantly higher than in non-AKI patients, unlike this study. Firstly, different from patient cohorts selected by Pariah and the like, patients in CKD3-5 stage are excluded from the research, the original diseases of patients in development cohort are primary central nervous system lymphoma, 191 treatment courses all receive large dose of MTX intravenous drip, AKI causes are mainly the nephrotoxic action of MTX and metabolites thereof, the verification cohort is patients who receive liver transplantation due to acute liver failure or terminal liver diseases, the liver supply mode and the operation formula are consistent, AKI is mainly related to the liver transplantation, and the homogeneity of the patients in the two cohort groups is higher; pariah et al chose cardiac surgery as the development cohort with a small number of samples, 6 cases of AKI and non-AKI, respectively, and verified that there was high heterogeneity in disease background and AKI etiology among 215 ICU patients in the cohort. Secondly, we focused on the baseline urine NAD + metabolite level of patients before receiving medical intervention as a biomarker for predicting the occurrence of AKI after MTX chemotherapy or after liver transplantation, whereas in the study of Pariah et al, there was no significant difference in the baseline urine QA concentration of cardiac surgery patients, the QA concentration of post-operative AKI patients increased, the urine in ICU cohort was collected before the occurrence of AKI, but the time point relationship between urine collection and the occurrence of AKI predisposition could not be determined, which is different from the study using the baseline urine metabolite level to predict the occurrence risk of AKI.
Many large clinical studies have found that some of the novel biomarkers of AKI have the ability to recognize AKI more promptly and efficiently than SCr. At 36h after the induction of the injury, the urine IL-18 and cystatinC concentrations can predict the risk of AKI in ICU patients within 48 hours, and the AUC is 0.75 and 0.73 respectively. Urine L-FABP and KIM-1 of a patient suffering from AKI after a cardiac surgery respectively reach peak values in 6 hours and 2 days after the surgery, the occurrence risk of the urine KIM-1 concentration after the surgery is more than 1.18ng/ml AKI reaches 4.7 times, when the urine KIM-1 concentration is combined with a clinical model containing relevant risk factors of AKI, the AUC can reach 0.73, and the urine L-FABP has no good distinguishing effectiveness. Blood and urine NGAL concentrations rise during cardiac surgery-related AKI, blood NGAL has a higher AKI detection potency than urine NAGL, and blood NAGL concentrations and clinical model integration assess risk for AKI development AUC is 0.75. Urine TIMP-2 and IGFBP have a higher potency for early detection of AKI than other biomarkers, especially for more severe AKI (stage 2 and stage 3 AKI defined by KDIGO), the AUC is 0,79 and 0.76, respectively, and the combined use of TIMP-2 and IGFBP can improve the potency to an AUC of 0.8. None of these biomarkers were found to have the ability to predict the onset of AKI prior to injury. Different from the injury-related biomarker, the NAD + metabolite is a metabolite of normal life activity of cells, and the pre-team research finds that the reduction of renal NAD + causes high susceptibility of AKI of aged mice, so that the method is mainly based on the hypothesis that the NAD + metabolite in baseline urine can reflect the NAD + content in the kidney so as to distinguish the high susceptibility of AKI, focuses on the analysis of the NAD + metabolite in baseline urine before injury, finds that the AKI susceptibility of patients with low urine QA/3-OH AA is increased, and has the effect of predicting the occurrence of AKI before the injury inducement effect.
Claims (10)
1. A marker for detecting acute kidney injury, wherein said marker is QA/3-OH AA.
2. The marker of claim 1 wherein the ratio of quinolinic acid to 3-hydroxyanthranilic acid in urine is 72 hours prior to QA/3-OH AA chemotherapy or 1-12 hours post-surgery.
3. A method of detecting the QA/3-OH AA of claim 1, comprising the steps of:
obtaining a urine sample to be detected;
detecting the content of quinolinic acid in the obtained urine sample;
detecting the content of the 3-hydroxy anthranilic acid in the obtained urine sample;
calculate QA/3-OH AA.
4. The method of claim 3, wherein the urine sample is urine within 72 hours before treatment initiation and/or 0-12 hours after treatment initiation, and is pretreated prior to detection.
5. The method of claim 3, wherein the detecting the quinolinic acid and 3-hydroxyanthranilic acid content is performed using a combination of liquid chromatography-mass spectrometry.
6. The method of claim 3, wherein the QA/3-OH AA urine samples 72 hours prior to surgery predicted an AUC for AKI to occur of 0.729 with a cutoff value of 6.04 at the highest Yoden index.
7. The method of claim 3, wherein urine QA/3-OHAA before chemotherapy predicts a risk of developing AKI for the biomarker, the risk of developing AKI in the dichotomized low is 4.37 times higher, the area under the receiver operating profile is 0.748, and the Yotanden index is maximal at cutoff 4.62.
8. Use of the marker of claim 1, wherein the marker is used in the manufacture of a medicament for the diagnosis or treatment of acute kidney injury.
9. The use of claim 8, wherein the marker is a target or positive control in an agent for diagnosing acute kidney injury.
10. The use of claim 8, wherein the marker is a screening criteria for a drug for the treatment of acute kidney injury;
substances that elevate QA/3-OH AA are candidates for drugs to treat acute kidney injury.
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