CN114755313B - Acute kidney injury marker comprising urine nad+ metabolite - Google Patents
Acute kidney injury marker comprising urine nad+ metabolite Download PDFInfo
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/724—Nebulising, aerosol formation or ionisation
- G01N30/7266—Nebulising, aerosol formation or ionisation by electric field, e.g. electrospray
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Abstract
The invention belongs to the field of biological detection, and particularly relates to application of a urine NAD+ metabolite as an acute kidney injury marker, a kit and a use 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, has simple and clear use aspect, and provides a new way for 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 a urine NAD+ metabolite as an acute kidney injury marker, a kit and a use method thereof.
Background
Diabetes is a group of metabolic diseases characterized by hyperglycemia, and its symptoms can be divided into two major categories: one general category is the manifestations associated with metabolic disorders, especially "how much three are" associated with hyperglycemia, most commonly seen in type 1 diabetes, which is often not very pronounced or only partially manifested, and another general category is the manifestations of various acute, chronic complications. According to the medium of france, report 4/6/2016, world health organization report shows that the number of people with diabetes worldwide has increased by a factor of 4 compared with 1980. About 11% of adults in China, which is the most serious world with diabetes mellitus, are reported by 28 days of 6.2017.
Diabetes is an aging-related metabolic disease, and is also one of the risk factors for the occurrence of AKI. Studies have found that liver, white adipose tissue, blood vessels, and other organs in the diabetic model have reduced nad+. Although there is currently no direct evidence of reduced nad+ in diabetic kidneys, reduced Sirt1 expression with nad+ as a substrate leads to proteinuria by upregulating Claudin, involved in the development of DKD. It is not clear whether AKI susceptibility is caused by diabetes by affecting nad+ content.
Effectively preventing the occurrence of AKI (acute kidney injury), not only requires defining high-risk susceptibility factors, but also requires efficient biomarker prediction of AKI susceptibility. Currently SCr is a universal AKI biomarker, as a functional marker rather than an damaging marker, with hysteresis and lower sensitivity and specificity, resulting in omission and delay of AKI diagnosis.
In recent years, a great deal of research has been devoted to the search for novel AKI biomarkers, including pro-inflammatory mediators IL-18, NGAL (neutrophil gelatinase-associated lipocalin), structural upregulation protein KIM-1 (kidney injury molecule-1), L-FABP (liver-TYPE FATTY ACID-binding protein), cell cycle regulatory factor TIMP-2 (tissue inhibitor of metalloproteinases-2), IGFBP7 (IGF-binding protein-7), etc., most of which are difficult to achieve the desired clinical diagnostic effect, and research has found that TIMP-2 and IGFBP-7 have a higher early diagnostic efficacy of AKI in combination than other markers, but have not yet been widely used, and none of the current AKI biomarkers have the ability to predict the occurrence of AKI before the occurrence of an injury predisposition.
Disclosure of Invention
The invention aims 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 marker 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 the urine before QA/3-OH AA chemotherapy.
The study was a prospective cohort study, and found that patients who were scheduled to undergo high-dose MTX chemotherapy in the hematology department of the Huashan hospital were queued, and patients who were scheduled to undergo general surgery in situ liver transplantation were validated. Urine is collected from the queue within 72 hours before and 0-12 hours after the start of MTX treatment of patients, the content of NAD+ metabolites in the urine is detected by a liquid chromatography-mass spectrometry (liquid chromatograph mass spectrometer, LC-MS) method, whether AKI occurs within 72 hours after MTX chemotherapy is taken as a follow-up endpoint, concentration differences of the NAD+ metabolites in urine of a diabetes group and a non-diabetes group and the AKI group and the non-AKI group are compared, and the analysis of urine metabolites with obvious screening differences predicts the efficacy of AKI. The urine of the patient is collected from the verification queue within 72 hours before liver transplantation operation and within 0-12 hours after operation, whether AKI occurs within 5 days after operation is taken as a follow-up end point, and the effect of predicting AKI of the NAD+ metabolite of the urine is verified according to the result of the discovery queue. AKI is defined as serum creatinine ≡1.5 fold baseline value or 26.5 μmol/L higher than baseline value after chemotherapy/post-operative or receiving renal replacement therapy.
The results indicated that 191 cases of treatment with high dose MTX chemotherapy were found to be queued, 38 cases of diabetes (19.90%), and 35 cases of AKI (18.32%) were found to occur within 72 hours after chemotherapy. 191 urine samples were collected 72 hours before chemotherapy and 91 urine samples were collected 12 hours after chemotherapy. Compared with the non-diabetic group, the urine kynurenine (kynurenine, KYN) and the 3-hydroxy anthranilic acid (3-hydroxyanthranilic acid,3-OH AA) before the diabetes group is treated have higher concentration, the quinolinic acid (quinolinic acid, QA) has lower concentration, and the other metabolites have no obvious difference; the concentration of 3-OH AA is higher after chemotherapy, and the other metabolites have no obvious difference. Compared with the non-AKI group, the concentration of urine 3-OH AA before AKI group chemotherapy is higher, the concentration of quinolinic acid QA is lower, the change trend of the two metabolites is the same as that of the diabetes group, and the other metabolites have no obvious difference; the concentration of each metabolite in urine after chemotherapy is not obviously different. The risk of AKI occurrence is predicted by taking pre-chemotherapy urine QA/3-OH AA as a biomarker, the risk of AKI occurrence in a binary low-value group is 4.37 times that of a high-value group, the area under the curve (AUC) of a receiver operating characteristic (receiver operating characteristic, ROC) is 0.748, the approximate dengue index is maximum at a critical value of 4.62, and the sensitivity and the specificity are 77.1% and 69.9% respectively. Clinical model (age, sex, diabetes) predicts an AKI risk of developing AUC of 0.672, and the combined AUC of pre-chemotherapy urine QA/3-OH AA and clinical model is 0.772.
The validation cohort was 49 in group in situ liver transplant patients, 16 AKI occurred post-operatively (32.65%). 49 cases of urine were collected within 72 hours prior to surgery, with patients with AKI having a higher concentration of 3-OH AA and significantly lower QA/3-OH AA than those without AKI. Urine QA/3-OH AA predicts that AKI occurs with an AUC of 0.729, with a maximum about dengue index at a threshold of 6.04, and sensitivity and specificity of 87.5% and 66.7%, respectively.
The invention also provides a method for detecting QA/3-OH AA, which comprises the following steps:
Acquiring a urine sample to be detected;
detecting the quinolinic acid content of the obtained urine sample;
detecting the content of 3-hydroxy anthranilic acid in the obtained urine sample;
QA/3-OH AA was calculated.
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 content of quinolinic acid and 3-hydroxy-anthranilic acid is completed by using liquid chromatography-mass spectrometry.
The pre-operation urine QA/3-OH AA predicts that AKI occurs with AUC of 0.729 and the about dengue index is maximum at a critical value of 6.04.
Pre-chemotherapy urine QA/3-OH AA is used as a biomarker to predict the risk of AKI, the risk of AKI occurrence in a binary low-value group is 4.37 times that in a high-value group, the area under a receiver operation characteristic curve is 0.748, and the about dengue index is maximum when the critical value is 4.62.
The invention also provides application of the marker in preparing medicines for diagnosing or treating acute kidney injury.
The marker is a target or positive control in a medicament for diagnosing acute kidney injury.
Or the marker is a screening standard of a drug for treating acute kidney injury; substances that raise QA/3-OH AA are candidates for drugs for treating acute kidney injury.
The invention provides an early diagnosis marker for acute kidney injury, has simple and clear use aspect, and provides a new way for diagnosis and treatment of acute kidney injury.
Drawings
FIG. 1 schematic of the NAD+ synthesis pathway.
The NAD+ synthesis pathway mainly comprises three pathways, namely, the De novo pathway, the compensation pathway (SALVAGE PATHWAY) and Preiss-HANDLER PATHWAY, and TRP (Tryptophan ), NAM (Nicotinamide) and NA (Nicotinic acid ) are respectively used as initial substrates.
Intermediate from the first synthetic pathway: N-FORMYLKYN (N-Formylkynurenine ); KYN (Kynurenine kynurenine); 3-OHKYN,3-Hydroxykynurenine, 3-hydroxykynurenine); 3-OH AA, (3-Hydroxyanthranilic acid ); ACMS (Aminocarboxymuconic semialdehyde, aminocarboxylic acid semialdehyde); QA (Quinolinic acid ); NAMN (Nicotinic acid mononucleotide ).
The de novo synthesis pathway involves enzymes: TDO (tryptophan 2,3-dioxygenase, tryptophan 2, 3-dioxygenase); IDO (indoleamine 2,3-dioxygenase, indoleamine 2, 3-dioxygenase); AFMID (formamidase, kynureninase); KMO (kynurenine monooxygenase );
KYNU (kynureninase ); HAAO (3-hydroxyanthranilic acid dioxygenase ); QPRT (Quinolinic acid phosphoribosyltransferase ); ACMSD (ACMS decarboxylase, aminocarboxylic acid semialdehyde decarboxylase).
Compensating for the synthetic pathway intermediates: NMN (nicotinamide mononucleotide ). The compensatory synthetic pathway is involved in enzymes: NAMPT (nicotinamide phosphoribosyltransferase, nicotinamide riboside transferase); NMNAT (nicotinamide mononucleotide adenylyltransferase ).
Preiss-HANDLER PATHWAY involved in the enzyme: NART (nicotinic acid phosphoribosyltransferase ).
Figure 2 finds a baseline urine nad+ metabolite comparison of cohort AKI and non-AKI groups.
Figure 3 finds the risk of AKI onset in the queue baseline urine QA/3-OH AA bipartite grouping. Wherein, annotate: model 1 did not incorporate correction factors, model 2 incorporated correction factors including age, gender, and diabetes.
FIG. 4 shows a cohort baseline urine QA/3-OH AA and a clinical model predictive AKI risk ROC curve. Wherein, the area under the curve (AUC) of the baseline urine QA/3-OH AA ROC is 0.748, the clinical model AUC consisting of age, gender and diabetes is 0.672, and the combined clinical model AUC of the baseline urine QA/3-OH AA is 0.772.
Figure 5 verifies baseline urine nad+ metabolite comparisons for cohort AKI and non-AKI groups.
Figure 6 verifies that cohort baseline urine QA/3-OH AA and clinical model predict AKI risk ROC curves. The area under the curve (AUC) of the baseline urine QA/3-OH AA ROC was 0.729.
Detailed Description
The present invention will be described in detail below with reference to examples and drawings, but the practice of the invention is not limited thereto. The raw materials of the kit used in the invention are commercially available or can be prepared according to a literature method. The experimental procedure, which does not specify specific conditions in the following examples, can generally be followed by conventional conditions such as "molecular cloning: the conditions described in the laboratory guidelines (NewYork: cold Spring Harbor Laboratory Press, 1989) are either conventional or recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
The experimental steps are as follows:
1. study object
(1) MTX chemotherapy patients
Primary central nervous system lymphoma patients receiving large-dose MTX chemotherapy in hematological department of China university of double denier affiliated China mountain Hospital in 1 month 2019 to 1 month are primary central nervous system lymphoma with definite pathological diagnosis, and MTX administration mode is intravenous drip, and the dose is more than 500mg/m 2.
1) Inclusion criteria:
a. age is more than or equal to 18 years old, and sex is unlimited;
b. The pathological diagnosis is definitely primary central nervous system lymphoma, and the treatment scheme is large-dose MTX intravenous drip.
2) Exclusion criteria:
a. the diagnosis is CKD3-5 phase before treatment;
b. AKI occurs prior to chemotherapy;
c. tumor infiltrating the kidney;
d. congenital renal malformations such as kidney deficiency, ectopic kidneys, horseshoe kidneys, etc. exist;
e. Receiving a kidney transplant or a kidney resection;
f. refusal or inability to match the study.
(2) In situ liver transplantation patient
Patients with cadaveric liver donor in-situ liver transplantation were accepted in general surgery at the department of Huashan Hospital affiliated with the university of double denier from 8 months 2019 to 1 month 2020.
1) Inclusion criteria:
a. age is more than or equal to 18 years old, and sex is unlimited;
b. Patients who receive liver transplantation due to the causes of end-stage liver disease, acute or subacute liver failure and the like are supplied with liver from cadavers, and the operation formula is in-situ liver transplantation.
2) Exclusion criteria:
a. The preoperative diagnosis is CKD3-5 phase;
b. Preoperatively liver and kidney syndrome or other types of AKI occur;
c. congenital renal malformations such as kidney deficiency, ectopic kidneys, horseshoe kidneys, etc. exist;
d. Receiving a kidney transplant or a kidney resection;
e. The operation is liver and kidney combined transplantation;
f. Repeating liver transplantation;
g. Refusal or inability to match the study.
2. Clinical data acquisition
The patient data acquisition is from the electronic medical record and the inspection system of the affiliated Huashan hospital of the complex denier university.
(1) MTX chemotherapy patients
Clinical data of the patient were collected as follows:
1) Basic information: age, gender, race, BMI, BSA;
2) Combining the history of basal disease: 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, evfr, urine PH;
5) MTX treatment related information: dosage, hydration and alkalization scheme, and calcium folinate use;
6) post-MTX treatment correlation test results: 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) In situ liver transplantation patient
Clinical data of the patient were collected as follows:
1) Basic information: age, sex, race, BMI;
2) Etiology of liver transplantation: viral, alcoholic, autoimmune, tumor, etc.;
3) Combining the history of basal disease: history of diabetes, hypertension, CKD;
4) Test results within 72 hours prior to 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) Operation related information: type of liver source, surgical procedure, blood loss during the procedure;
6) Post-operative correlation test results: postoperative SCr on day 1, day 2, day 3, day 4, day 5.
Note that: the eGFR uses a 2009 CKD-EPI formula to calculate according to the race, sex, age and SCr value of a patient; BMI calculation formula: BMI = weight (kg)/height 2(m2); BSA calculation formula: 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×etiology score (biliary or alcoholic 0, others 1).
AKI diagnosis
MTX chemotherapy patients follow-up to discharge or 7 days after MTX chemotherapy is finished, in-situ liver transplantation patients follow-up to discharge on 7 days, SCr increase of more than or equal to 26.5umol/l within 48 hours or increase to more than or equal to 1.5 times of baseline value within 7 days according to KDIGOSCr diagnosis standard, or kidney substitution treatment is carried out.
4. Specimen collection and preservation
(1) Specimen collection
1) MTX chemotherapy patients
The patient was collected 10ml of urine 72 hours prior to MTX chemotherapy and 10ml of urine 0-12 hours after MTX chemotherapy.
2) In situ liver transplantation patient
10Ml of urine was collected from the patient 72 hours before surgery and 10ml of urine was collected from 0-12 hours after surgery.
(2) Specimen preservation
1) Centrifuging a urine sample: 3000 rpm for 10 minutes;
2) The pipette sucks 1ml of urine supernatant into a clean EP tube, and the EP tube marks the hospitalization number, name and sampling date of the patient;
3) And (5) placing the treated sample in a refrigerator at the temperature of-80 ℃ for preservation.
NAD+ metabolite detection
(1) Main instrument
LC30 ultra-high performance liquid chromatography system Shimadzu, japan
Triple quaternary rod 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 mu L
(3) Mass spectrometry conditions
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 gas: 35psi
5) Spraying gas: 40psi
6) Auxiliary heating gas: 55psi
7) Interface heater: opening the valve
8) Collision gas: in (a)
(4) Ion pair parameters
Positive ions:
Negative ions:
(5) Analysis software
Data acquisition and processing used software analysis 1.6.3 (AB Sciex, usa).
6. Statistical method
Statistical analysis was performed using SPSS25.0 software. The distribution type of the metering data is detected by adopting a single sample Kolmogorov-Smirnov test, the average number which accords with the normal distribution is expressed by +/-standard deviation of the average number, the median (25 percentile-75 percentile) which does not accord with the normal distribution is expressed, and the counting data is expressed by frequency and percentage. The comparison between the groups of the metering data in normal distribution adopts independent sample t test, the comparison between the groups of the metering data in non-normal distribution and uneven variance and the grade data adopts Mann-WhitneyU test in non-parameter test, the comparison between the counting data groups adopts a list method, if the minimum expectation of each cell in the list is more than 5 and the sample content is more than 40, the test of Pearson's square is adopted; if the list table is a four-grid table, the sample content is more than 40, the expected frequency of all the cells is more than 1, and when the expected frequency of only 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 lattice is less than 1, or more than 1 and less than 5, a Fisher precise probability method is adopted. OR values were calculated using a Logistic regression model. The area under the subject operating profile (receiver operating characteristic curve, ROC) curve (Area Under the Curve, AUC) is used to represent the ability of biomarkers and clinical models to distinguish AKI from non-AKI. All tests in this section were double-sided tests, with P < 0.05 being statistically significant differences.
Example 1 discovery queue
(1) Basic information
The study in this section found that the total treatment course of the large dose MTX treatment was 191 times, 38 times of diabetes, the proportion of which was 19.89 times, 35 times of AKI occurrence, and the occurrence rate was 18.32%, wherein 18 times of AKI occurred within 24 hours, 8 times of AKI occurred within 24-48 hours, and 9 times of AKI occurred within 48-72 hours. The median age (quartile) for all courses was 59.0 (51.00-65.00) years of age with a male proportion of 66.49%. The median (quartile) of baseline EGFR was 94.70 (79.90-104.28) ml/min/1.73m 2 for the AKI group and no significant difference (98.58 (89.33-105.59) ml/min/1.73m 2) for the non-AKI group. The proportion of courses with diabetic background in the AKI group was 42.85%, significantly higher than in the non-AKI group (14.74%). The median MTX treatment doses for the AKI group and the non-AKI group were 5.08g/m 2 and 4.22g/m 2, respectively, and there was no significant difference, the MTX excretion delay ratio for the AKI group was 34.28%, which was higher than that for the non-AKI group (14.74%). The ratio of pH of urine at 0 and 24 hours after treatment to 7.5 was 37.14% for the AKI group, which was lower than for the non-AKI group (58.33%). (Table 1)
Table 1 find out the basic information of the queue treatment course
Note that: MTX excretion delay: the blood concentration of 48 hours is more than 1 mu mol/L and the blood concentration of 72 hours is more than 0.1 mu mol/L.
(2) Differences in urine nad+ metabolites in AKI and non-AKI groups
Among 191 baseline urine, 35 parts are AKI, the relative concentrations of the baseline urine TRP, N-formacyl KYN and KYN before MTX chemotherapy are not obviously different between the AKI group and the non-AKI group, the relative concentration of the AKI group baseline urine 3-OH AA is higher and the relative concentration of QA is lower. The ratio of baseline urine QA and 3-OH AA concentration was used as the biomarker to be analyzed, and the ratio was significantly lower in the AKI group than in the non-AKI group. (FIG. 2) the maximum value of SCr change within 72 hours after chemotherapy correlated inversely with baseline urine QA and QA/3-OH AA. (Table 2)
TABLE 2 baseline urine 3-OH AA, QA and QA/3-OH AA and SCr elevation correlation coefficients
(3) Baseline urine QA/3-OH AA predicts the efficacy of AKI
The baseline urine QA/3-OH AA median is divided into a high group and a low group, the model 1 is not added with correction factors, the risk of AKI occurrence in the low group is 4.67 times that in the high group, the model 2 is added with correction factors comprising age, sex, eGFR before treatment and diabetes, and the risk of AKI occurrence in the low group is 3.15 times that in the high group. (FIG. 3)
The AUC of the baseline urine QA/3-OH AA to predict the risk of AKI onset is 0.748; clinical models consisting of age, sex and diabetes predict an AUC of 0.672 for the risk of AKI onset; the AUC of the baseline urine QA/3-OH AA in combination with the clinical model predicted the risk of AKI onset was 0.772. (FIG. 4)
The about log index was maximum when the baseline urine QA/3-OH AA value was 4.62, the sensitivity was 77.1%, the specificity was 69.9%, the positive likelihood ratio was 2.56, and the negative likelihood ratio was 0.33.
Example 2 validation queue
(1) Basic information
The study in this section verifies that cohorts of 49 in situ liver-transplanted patients, with an age median (quartile) of 52.00 (46.00-55.50) years old, 81.63% in men, with 16 AKIs occurring, accounting for 32.65%. Compared with non-AKI patients, the AKI patients have larger blood loss during operation, and the other indexes have no obvious difference. 6 of the AKI patients were diagnosed with diabetes (37.50%), 5 of the non-AKI patients were diagnosed with diabetes (15.15%), and there was no statistical difference between the two. (Table 3)
Table 3 validates the patient base information of the cohort
(2) Risk relationship of urine NAD+ metabolite and AKI
49 Parts of urine were collected over 72 hours prior to surgery, with 16 parts of patients with AKI. The relative concentrations of baseline urine TPR, N-formacyl KYN, QA were not significantly different for the two groups of patients. Baseline urine 3-OH AA was higher in patients with AKI and lower in QA/3-OH AA than in non-AKI patients. (FIG. 5)
(3) Baseline urine QA/3-OH AA predicts the efficacy of AKI
The AUC of baseline urine QA/3-OH AA predicted the risk of AKI onset was 0.729. (FIG. 6) the about step index was maximum when the critical value was 6.04, 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+ is expressed from the head synthase in the proximal tubule of the human kidney and not in other structures of the kidney. Higher concentrations of baseline urine 3-OH AA and lower concentrations of QA before the predisposition to injury are correlated with the occurrence of AKI, and baseline urine QA/3-OH AA can be used as a biomarker for predicting the occurrence of AKI. The baseline urine 3-OH AA concentration and QA concentration of diabetics are consistent with the trend of AKI patients and are related to AKI susceptibility of diabetes.
Comparative example
In recent years, proteomics and metabolomics have gradually been applied to diagnosis of kidney diseases including AKI, and dynamic changes in proteins and metabolites reflect kidney disease states in more real time, wherein blood and urine histology analysis can non-invasively obtain samples, greatly increasing the feasibility of clinical applications. In the present invention, the relative concentration of 3-OH AA/Cre (after urinary creatinine correction) in urine is higher in AKI patients before AKI occurs compared with AKI-free patients, and QA/Cre is lower, which suggests that the AKI susceptibility of different patients is different due to the difference of HAAO expression or activity, the relative concentration difference of products upstream and downstream of the enzyme in urine is shown, the area under the ROC curve of QA/3-OH AA serving as a biomarker for predicting the risk of AKI occurrence is 0.748, and the AUC is increased to 0.769 when the biological marker is used in combination with a diabetes clinical model. The concentration of urine 3-OH AA increases and the concentration of QA decreases after the injury causing effect, regardless of whether AKI occurs, and the QA/3-OH AA ratio decreases, suggesting that HAAO may be expressed or active to decrease after injury striking. Pariah et al found that a decrease in expression of QPRT, another enzyme of the nad+ de novo synthetic pathway, mediated the occurrence of AKI, accumulation of QPRT substrate QA in the kidney of AKI mice, elevated urine QA concentrations, and consistent results in cardiac surgery patients and ICU patient cohorts, with significantly higher urine QA concentrations in AKI patients after cardiac surgery and 72 hours into ICU ward than in non-AKI patients, unlike this study. Firstly, we are different from patient queues selected by Pariah and the like, the study excludes CKD3-5 patients, primary diseases of patients in a development queue are primary central nervous system lymphomas, 191 cases of treatment courses receive large-dose MTX intravenous drip, the cause of AKI is mainly the nephrotoxic effect of MTX and metabolites thereof, the verification queue is a patient who receives liver transplantation due to acute liver failure or end-stage liver disease, the liver supply mode is consistent with the operation mode, AKI is mainly related to the liver transplantation, and the homogeneity of the patients in the two queue groups is higher; pariah and the like select cardiac surgery as development queues, the number of samples is small, AKI and non-AKI are respectively 6, and 215 ICU patients in the verification queues have high heterogeneity in disease background and AKI etiology. Second, we focused on study of baseline urine nad+ metabolite levels of patients before receiving medical intervention as biomarkers to predict whether AKI will occur after MTX chemotherapy or after liver transplantation, whereas in Pariah et al study, there was no significant difference in baseline urine QA concentration in cardiac surgery patients, post-operative AKI patients were QA concentration rising, urine collected in ICU cohorts before AKI occurred, but the time point relationship between urine collection and AKI predisposition was not clear, unlike the baseline urine metabolite levels of this study to predict the risk of AKI occurrence.
Many large clinical studies have found that part of the novel AKI biomarkers have the ability to recognize AKI more timely and efficiently than SCr. At 36h after the onset of the predisposition for injury, urinary IL-18 and CYSTATINC concentrations were able to predict the risk of AKI development within 48 hours of ICU patients, with AUC of 0.75 and 0.73, respectively. The urine L-FABP and KIM-1 of patients suffering from AKI after cardiac surgery reach peaks at 6 hours and 2 days after surgery, the risk of occurrence of the postoperative urine KIM-1 concentration is more than 1.18ng/mlAKI and reaches 4.7 times, when the urine KIM-1 concentration is combined with a clinical model containing AKI related risk factors, 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 efficacy than urine NAGL, and AUC for assessing risk of AKI occurrence by integration of blood NAGL concentrations and clinical models is 0.75. Urine TIMP-2 and IGFBP have higher early-stage AKI discovery efficiency than other biomarkers, especially for more serious AKI (stage 2 and stage 3 AKI defined by KDIGO), AUC is 0,79 and 0.76 respectively, and TIMP-2 and IGFBP combined application can improve the efficiency, and AUC can reach 0.8. None of these biomarkers was found to have the ability to predict AKI occurrence prior to injury. Unlike the above-mentioned injury-related biomarkers, nad+ metabolites are metabolites of normal vital activities of cells, and our team earlier study found that decrease in kidney nad+ leads to high susceptibility to AKI in aged mice, so this section is based on the assumption that baseline urine nad+ metabolites can reflect nad+ content in kidneys to distinguish between high and low susceptibility to AKI, focusing on analysis of baseline urine nad+ metabolites before injury, found that patients with low urine QA/3-OH AA have increased susceptibility to AKI, with the effect of predicting AKI occurrence before injury causation.
Claims (6)
1. A marker for detecting acute kidney injury, which is characterized in that the marker is the ratio QA/3-OH AA of the concentration of quinolinic acid QA and 3-hydroxy anthranilic acid 3-OH AA.
2. The marker of claim 1, wherein the ratio QA/3-OH AA of the concentration is a ratio of the concentration of quinolinic acid to the concentration of 3-hydroxy anthranilic acid in an isolated urine sample collected 72 hours before and 0 to 12 hours after the treatment.
3. The marker of claim 2, wherein detecting the content of quinolinic acid and 3-hydroxy anthranilic acid is accomplished using a liquid chromatography-mass spectrometry combination.
4. Use of the marker of claim 1 in the manufacture of a product for detecting acute kidney injury.
5. The use of claim 4, wherein the marker is used as a target or positive control in a preparation for diagnosing acute kidney injury.
6. The use of the marker of claim 1 in the manufacture of a medicament for diagnosing or treating acute kidney injury, said marker being used as a screening criterion for medicaments for treating acute kidney injury; substances that raise the ratio QA/3-OH AA of the compound concentrations are candidates for drugs for treating acute kidney injury.
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