JP7471581B2 - Pathological biomarkers for kidney disease - Google Patents
Pathological biomarkers for kidney disease Download PDFInfo
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- JP7471581B2 JP7471581B2 JP2019106257A JP2019106257A JP7471581B2 JP 7471581 B2 JP7471581 B2 JP 7471581B2 JP 2019106257 A JP2019106257 A JP 2019106257A JP 2019106257 A JP2019106257 A JP 2019106257A JP 7471581 B2 JP7471581 B2 JP 7471581B2
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- kidney disease
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- lysine
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Images
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Description
本発明は、唾液中のアミノ酸のD体及び/又はL体に基づき腎臓病の病態指標値を算出する工程を含む分析方法、腎臓病の検査方法、並びに腎臓病についての病態情報を出力する試料分析システムに関する。 The present invention relates to an analytical method that includes a step of calculating a pathological index value for kidney disease based on the D- and/or L-isomers of amino acids in saliva, a kidney disease testing method, and a sample analysis system that outputs pathological information about kidney disease.
腎臓は、血液中の老廃物や余分な水分を濾過し、尿として排出することで、体液の恒常性を維持することを主な役割とする臓器である。腎臓は、免疫系の異常や薬剤、高血圧、糖尿病、出血や急激な血圧低下、感染症、熱傷に伴う脱水等の要因により障害を受け、腎機能が低下する。腎障害により腎機能が約60%以下に低下した場合に腎不全と呼び、腎機能低下の進行速度の違いにより、急性腎障害(Acute Kidney Injury:AKI)と慢性腎臓病(Chronic Kidney Disease:CKD)に大別される。特に糖尿病を原因とするものは糖尿病性腎臓病(Diabetic Kidney Disease:DKD)という。 The kidneys are organs whose main role is to maintain homeostasis of bodily fluids by filtering waste products and excess water from the blood and excreting them as urine. Kidneys can be damaged and lose renal function due to factors such as immune system abnormalities, drugs, high blood pressure, diabetes, bleeding, sudden drop in blood pressure, infections, and dehydration due to burns. Renal failure occurs when renal function falls to about 60% or less due to renal damage, and is broadly divided into acute kidney injury (AKI) and chronic kidney disease (CKD) depending on the rate at which renal function declines. Diabetes-related kidney disease is called diabetic kidney disease (DKD).
急性腎障害(AKI)は、発症までの期間として数時間から数週間である腎障害をいう。急性腎障害は、虚血、薬剤、エンドトキシンショック等の原因によって腎機能が急激に低下した状態であり、体内代謝産物である尿素窒素やクレアチニンの血中濃度上昇、電解質代謝の異常及びアシドーシス等の症状が認められ、一般に血中クレアチニンの値の急上昇により急性腎障害と診断される。急性腎障害は、治療により回復が期待されるため、より早期の急性腎障害を判別できる診断マーカーの開発が望まれている。しかしながら、一般に用いられている血中クレアチニンの値は、年齢、性別、筋肉量及び服用する薬剤等の条件により変動するので、特異的な診断マーカーとはいえない(非特許文献1)。また好中球ゼラチナーゼ関連リポカリン(NGAL)、インターロイキン-18(IL-18)、腎障害分子(KIM-1)、肝脂肪酸結合タンパク質(FABPs)、シスタチンC等のタンパク質と、ホモバニリン酸硫酸、トリメチルアミン-N-オキシド等の代謝低分子化合物等が、急性腎障害のマーカーとして報告されているが、これらのマーカーよりも、より早くより正確に病態を検出できる診断マーカーの開発が期待されている。 Acute kidney injury (AKI) refers to kidney damage that lasts from a few hours to a few weeks. Acute kidney injury is a state in which kidney function is suddenly reduced due to ischemia, drugs, endotoxin shock, etc., and symptoms such as increased blood levels of urea nitrogen and creatinine, which are metabolic products in the body, electrolyte metabolism abnormalities, and acidosis are observed. Acute kidney injury is generally diagnosed when the blood creatinine level rises. Since acute kidney injury is expected to recover with treatment, there is a need to develop a diagnostic marker that can identify acute kidney injury at an earlier stage. However, the commonly used blood creatinine level varies depending on conditions such as age, sex, muscle mass, and medication taken, so it cannot be said to be a specific diagnostic marker (Non-Patent Document 1). In addition, proteins such as neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver fatty acid-binding proteins (FABPs), cystatin C, and metabolic low molecular weight compounds such as homovanillic acid sulfate and trimethylamine-N-oxide have been reported as markers of acute kidney injury, but there is hope for the development of diagnostic markers that can detect the pathology more quickly and accurately than these markers.
慢性腎臓病(CKD)は、各種腎障害により、糸球体濾過量で表される腎機能の低下があるか、もしくは腎臓の障害を示唆する所見が慢性的(3カ月以上)に持続する状態をいう。慢性腎臓病は、日本国の成人人口の約13%に相当する1,330万人が罹患する疾患で、末期腎不全(ESKD)に至るリスクが高く、国民の健康を脅かしている。慢性腎臓病に有効な治療法はなく、慢性腎臓病が進行して腎機能低下が進むと尿毒症の危険があり、人工透析や腎移植が必要となることから、医療経済上も大きな負担となっている(非特許文献2)。慢性腎臓病は、自覚症状がないまま病状が進行するため、慢性腎臓病の早期発見及び進行抑制のためには、腎障害の早期診断マーカーによる診断が必要である。しかし、現在臨床現場で汎用されているクレアチニンや尿素窒素(BUN)の値は腎障害の発生と進行を正確に反映する診断マーカーとして満足できるものではない。 Chronic kidney disease (CKD) refers to a state in which renal function, as measured by glomerular filtration rate, is reduced due to various renal disorders, or symptoms suggesting renal disorders persist chronically (for more than three months). Chronic kidney disease affects 13.3 million people, which is equivalent to approximately 13% of the adult population of Japan, and is a threat to the health of the nation due to its high risk of developing end-stage renal disease (ESKD). There is no effective treatment for chronic kidney disease, and as chronic kidney disease progresses and renal function declines, there is a risk of uremia, which requires artificial dialysis or kidney transplantation, which places a heavy burden on the medical economy (Non-Patent Document 2). Since chronic kidney disease progresses without any subjective symptoms, early detection and inhibition of the progression of chronic kidney disease require diagnosis using early diagnostic markers for renal disorders. However, the values of creatinine and blood urea nitrogen (BUN), which are currently widely used in clinical practice, are not satisfactory diagnostic markers that accurately reflect the occurrence and progression of renal disorders.
近年、哺乳類の生体には存在しないと考えられていたD-アミノ酸が、様々な組織において見出されており、何らかの生理機能を担うことが予測されている。そして、血中のD-アミノ酸のうち、D-セリン、D-アラニン、D-プロリン、D-グルタミン酸、D-アスパラギン酸の量が、腎臓病のバイオマーカーとなり得ることが示されている(非特許文献3、非特許文献4、非特許文献5、非特許文献6)。さらに、D-セリン、D-スレオニン、D-アラニン、D-アスパラギン、D-アロ-スレオニン、D-グルタミン、D-プロリン及びD-フェニルアラニンからなるグループから選択される1種類又は2種類以上のD-アミノ酸が、腎臓病の病態指標値とすることができることが開示されており(特許文献1)、この文献では、試料に用いられる生物学的材料として、血液、血漿、血清、腹水、羊水、リンパ液、唾液、精液、尿等の体液と、糞便、汗、鼻汁等の排泄物、体毛、爪、皮膚組織、内臓組織等の体組織を挙げているが、実際には血清と尿のみが試験されており、唾液中のD体のアミノ酸を診断マーカーとして用いたことについては、何ら示されていない。
In recent years, D-amino acids, which were thought to be absent in mammalian organisms, have been found in various tissues and are predicted to play some physiological role. It has also been shown that the amounts of D-serine, D-alanine, D-proline, D-glutamic acid, and D-aspartic acid in the blood may serve as biomarkers for kidney disease (
クレアチニンやBUNの値等の既存の腎臓病マーカーは、臨床において感度及び/又は特異度が十分でない場合があるため、異なる原理の腎臓病障害マーカーを同定する分析・解析技術、並びにそれにより、腎臓病を正確に判定、検査又は診断する技術の開発が望まれている。 Existing kidney disease markers, such as creatinine and BUN values, may not have sufficient sensitivity and/or specificity in clinical practice, so there is a need to develop analytical techniques to identify kidney disease markers based on different principles, and techniques to accurately determine, test, or diagnose kidney disease.
本発明者らは、唾液を試料として用い、唾液中のアミノ酸のD体及び/又はL体に基づく値が、推算糸球体濾過量(eGFR)や血中クレアチニンの値と相関することを見出し本発明に至った。 The inventors used saliva as a sample and discovered that values based on the D- and/or L-forms of amino acids in saliva correlate with estimated glomerular filtration rate (eGFR) and blood creatinine levels, leading to the present invention.
したがって、本発明は被検体の唾液の分析方法であって、
該被検体の唾液中のアミノ酸のD体及び/又はL体を測定する工程、及び
前記少なくとも1のアミノ酸のD体及び/又はL体に基づき腎臓病の病態指標値として算出する工程
を含む、分析方法に関する。
Accordingly, the present invention provides a method for analyzing saliva of a subject, comprising the steps of:
and calculating a pathological condition index value for kidney disease based on the D- and/or L-isomer of at least one amino acid.
本発明の別の態様では、唾液を試料とする腎臓病の検査方法であって、
唾液中の少なくとも1のアミノ酸のD体及び/又はL体を測定する工程、
前記少なくとも1種類のアミノ酸のD体及び/又はL体に基づき腎臓病の病態指標値として算出する工程、
腎臓病の病態指標値と、腎臓病の病態とを関連づける工程
をさらに含む、前記検査方法に関する。かかる検査方法は、病態指標値を、予め決められた病態指標値の基準値と比較することで、病態指標値と腎臓病の病態とを関連づけることができる。
In another aspect of the present invention, there is provided a method for testing for kidney disease using saliva as a sample, comprising the steps of:
Measuring the D- and/or L-forms of at least one amino acid in saliva;
A step of calculating a pathological index value for kidney disease based on the D-isomer and/or L-isomer of the at least one type of amino acid;
The present invention relates to the testing method, further comprising the step of: correlating the pathology index value of kidney disease with the pathology of kidney disease. The testing method can correlate the pathology index value with the pathology of kidney disease by comparing the pathology index value with a predetermined reference value for the pathology index value.
さらに別の態様では、本発明の分析方法又は検査方法を実施することができる試料分析システムに関する。このような試料分析システムは、記憶部と、入力部と、分析測定部と、データ処理部と、病態情報出力部とを含んでおり、唾液試料を分析し、病態情報を出力することができる。 In yet another aspect, the present invention relates to a sample analysis system capable of carrying out the analysis method or testing method. Such a sample analysis system includes a memory unit, an input unit, an analysis and measurement unit, a data processing unit, and a pathological condition information output unit, and is capable of analyzing a saliva sample and outputting pathological condition information.
さらに別の態様では、本発明の試料分析システムにインストールされうるプログラム及び当該プログラムを格納する記憶媒体にも関する。 In yet another aspect, the present invention also relates to a program that can be installed in the sample analysis system and a storage medium that stores the program.
唾液中のアミノ酸のD体とL体の比に基づき算出された値は、推算糸球体濾過量や、血中クレアチニンの値と相関した。また、唾液試料中のアミノ酸のD体の量、L体の量、及びそれらの合計量からなる群から選ばれる1以上に基づき算出された値は、健常者群と、腎臓病患者群との間で有意な差を示した。これにより、腎臓病の診断が可能となる。 The value calculated based on the ratio of D- to L-amino acids in saliva correlated with the estimated glomerular filtration rate and blood creatinine value. In addition, the value calculated based on one or more selected from the group consisting of the amount of D-amino acids, the amount of L-amino acids, and their total amount in the saliva sample showed a significant difference between the healthy subject group and the kidney disease patient group. This makes it possible to diagnose kidney disease.
本発明に係る唾液の分析方法は、以下の:
被検体の唾液中の少なくとも1のアミノ酸のD体及び/又はL体を測定する工程、及び
前記少なくとも1のアミノ酸のD体及び/又はL体に基づく腎臓病の病態指標値として算出する工程、
を含む。当該分析方法は、医師が診断を行うためのデータの提供を行うことができ、診断の予備的方法又は診断補助方法ということもできる。この分析方法は、腎臓病の病態指標値と、腎臓病の病態とを関連づける工程をさらに含んでいてもよい。このような分析方法は、分析会社や分析技術者により行われて、腎臓病の病態と関連づけられた結果が提供されてもよい。
The method for analyzing saliva according to the present invention comprises the steps of:
measuring the D- and/or L-form of at least one amino acid in the saliva of a subject; and calculating a pathological index value for kidney disease based on the D- and/or L-form of the at least one amino acid.
The analysis method can provide data for a doctor to make a diagnosis, and can be called a preliminary diagnosis method or a diagnostic assistance method. The analysis method may further include a step of correlating the pathological index value of kidney disease with the pathology of kidney disease. Such an analysis method may be performed by an analysis company or an analysis technician, and a result associated with the pathology of kidney disease may be provided.
本発明において分析される試料は、唾液である。唾液は、唾液腺より口腔内に分泌される液体であり、任意の方法で採取することができる。採取された試料は、常温下、冷蔵下又は冷凍下で保管されてもよいし、分析用の誘導体化等の前処理を実施してもよい。 The sample analyzed in the present invention is saliva. Saliva is a liquid secreted into the oral cavity from the salivary glands and can be collected by any method. The collected sample may be stored at room temperature, refrigerated, or frozen, and may be subjected to pretreatment such as derivatization for analysis.
本発明において、腎臓病の病態指標値を算出するために用いられるアミノ酸は、好ましくはタンパク質構成アミノ酸及びその光学異性体である。タンパク質構成アミノ酸として、グリシン、アラニン、システイン、アスパラギン酸、グルタミン酸、フェニルアラニン、ヒスチジン、イソロイシン、リジン、ロイシン、メチオニン、アスパラギン、プロリン、グルタミン、アルギニン、セリン、スレオニン、バリン、トリプトファン、チロシンが挙げられる。ここで、グリシン以外のアミノ酸は不斉炭素を有し、光学異性体が存在し、イソロイシンとスレオニンは不斉炭素を二つ有するため、アロ体が存在する。例えばイソロイシンとアロ-イソロイシンはL-イソロイシンのα位が反転したD-アロ-イソロイシン、β位が反転したL-アロ-イソロイシン、α位とβ位が反転したD-イソロイシンという関係にある。これらのアミノ酸のうちの少なくとも1のアミノ酸について、D体及び/又はL体の量を測定し、アミノ酸のD体及び/又はL体に基づき腎臓病の病態指標値を算出することができる。アミノ酸は1であってもよいし、複数、例えば2~19のアミノ酸の組合せであってもよい。 In the present invention, the amino acids used to calculate the pathological index value of kidney disease are preferably proteinogenic amino acids and their optical isomers. Examples of proteinogenic amino acids include glycine, alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine. Here, amino acids other than glycine have asymmetric carbons and exist as optical isomers, and isoleucine and threonine have two asymmetric carbons and therefore exist as allo-isomers. For example, isoleucine and allo-isoleucine are related to D-allo-isoleucine, which is an inversion of the α position of L-isoleucine, L-allo-isoleucine, which is an inversion of the β position, and D-isoleucine, which is an inversion of the α position and the β position. The amount of D- and/or L-isomers of at least one of these amino acids can be measured, and a pathological index value for kidney disease can be calculated based on the D- and/or L-isomers of the amino acid. The amino acid may be one or a combination of multiple amino acids, for example, 2 to 19 amino acids.
腎臓病の病態指標値とは、腎臓病の病態を指し示すことができる数値であり、バイオマーカーということもできる。予め健常者群及び腎臓病の患者群において測定された病態指標値に基づいて決定された病態指標基準値と比較をすることで、被験者の病態指標値を腎臓病の病態と関連づけることができる。このような病態指標基準値は、閾値として決定することができる。当業者であれば、健常者群や腎臓病患者群の病態指標値から、病態指標基準値となる閾値を適宜設定することができる。閾値としては、例えば健常者群又は腎臓病患者群の平均値、中央値、Xパーセンタイル値を使用することができるがこれらに限定されるものではない。ここでXは任意の数値を選択することができ、3、5、10、15、20、30、40、60、70、80、85、90、95、97を適宜使用することができる。閾値は1つであってもよいし、腎臓病の病態や原因(例えば、薬剤性腎症、糖尿病性腎症、IgA腎症、膜性腎症、腎硬化症等)、状態(早期、中期、後期)、並びに使用するアミノ酸若しくはその組合せに応じて複数設定することもでき、重篤度に応じて病態を分類することもできる。予め設定された基準値と、被験者の病態指標値とを比較することにより、被験者の腎臓病の病態を判定、決定又は診断することが可能になる。さらに別の態様では、健常者群と各ステージの解析を行うことで、基準値(カットオフ値)を決定することもできる。 The pathological index value of kidney disease is a numerical value that can indicate the pathological condition of kidney disease, and can also be called a biomarker. By comparing the pathological index value of the subject with a pathological index reference value determined based on pathological index values measured in advance in a healthy subject group and a kidney disease patient group, the pathological index value of the subject can be associated with the pathological condition of kidney disease. Such a pathological index reference value can be determined as a threshold value. A person skilled in the art can appropriately set a threshold value that is the pathological index reference value from the pathological index values of the healthy subject group and the kidney disease patient group. As the threshold value, for example, the mean value, median value, and X percentile value of the healthy subject group or the kidney disease patient group can be used, but are not limited to these. Here, X can be selected from any numerical value, and 3, 5, 10, 15, 20, 30, 40, 60, 70, 80, 85, 90, 95, and 97 can be appropriately used. There may be one threshold value, or multiple threshold values may be set depending on the pathology or cause of kidney disease (e.g., drug-induced nephropathy, diabetic nephropathy, IgA nephropathy, membranous nephropathy, nephrosclerosis, etc.), state (early, middle, late), and the amino acid or combination thereof used, and the pathology may be classified according to severity. By comparing the pathology index value of the subject with a preset reference value, it is possible to determine, determine, or diagnose the pathology of the kidney disease of the subject. In yet another embodiment, the reference value (cutoff value) can also be determined by analyzing each stage with a group of healthy subjects.
本発明において腎臓病の病態指標値は、アミノ酸のD体及び/又はL体に基づいて算出される。より具体的に、D体の量、L体の量、及びそれらの合計量、又はD体とL体の比に基づいて算出される。本発明でいうアミノ酸のD体とL体の比とは、アミノ酸のD体及びL体の和に対するD体の比、D体及びL体の和に対するL体の比、D体に対するL体の比、又はL体に対するD体の比であってもよい。病態指標値の算出には、腎臓病マーカーとして用いられる限りにおいて、加算、減算、積算、及び/又は除算によって補正してもよく、その場合、年齢、体重、性別、BMI、GFR等、任意の変数を用いてもよい。 In the present invention, the pathological index value for kidney disease is calculated based on the D- and/or L-forms of amino acids. More specifically, it is calculated based on the amount of D-forms, the amount of L-forms, and the total amount thereof, or the ratio of D-forms to L-forms. The ratio of D-forms to L-forms of amino acids in the present invention may be the ratio of D-forms to the sum of D-forms and L-forms of amino acids, the ratio of L-forms to the sum of D-forms and L-forms, the ratio of L-forms to D-forms, or the ratio of D-forms to L-forms. The pathological index value may be calculated by correction by addition, subtraction, integration, and/or division, so long as it is used as a kidney disease marker, and in that case, any variable such as age, weight, sex, BMI, GFR, etc. may be used.
アミノ酸のD体の量を指標とする場合、推算糸球体濾過量(eGFR)との相関から(|r|>0.2)、グルタミン酸、アラニン、リジン、ヒスチジン、アスパラギン酸、プロリン、及びセリンからなる群から選ばれるアミノ酸のD体の量を使用して、病態指標値を算出することが好ましい。eGFRとの相関がより高い(|r|>0.4)という観点から、グルタミン酸、アラニン、リジン、ヒスチジン、アスパラギン酸、及びプロリンからなる群から選ばれるアミノ酸のD体の量を使用して、病態指標値を算出することがより好ましい。eGFRとの相関がより高い(|r|>0.6)という観点から、グルタミン酸、アラニン、リジン及びプロリンからなる群から選ばれるアミノ酸のD体の量を使用して、病態指標値を算出することがさらにより好ましい。 When the amount of D-form of an amino acid is used as an index, it is preferable to calculate the pathological index value using the amount of D-form of an amino acid selected from the group consisting of glutamic acid, alanine, lysine, histidine, aspartic acid, proline, and serine, based on the correlation with estimated glomerular filtration rate (eGFR) (|r|>0.2). From the viewpoint of a higher correlation with eGFR (|r|>0.4), it is more preferable to calculate the pathological index value using the amount of D-form of an amino acid selected from the group consisting of glutamic acid, alanine, lysine, histidine, aspartic acid, and proline. From the viewpoint of a higher correlation with eGFR (|r|>0.6), it is even more preferable to calculate the pathological index value using the amount of D-form of an amino acid selected from the group consisting of glutamic acid, alanine, lysine, and proline.
アミノ酸のL体の量を指標とする場合、推算糸球体濾過量(eGFR)との相関から(|r|>0.2)、グルタミン酸、スレオニン、プロリン、リジン、ヒスチジン、セリン、グルタミン、アスパラギン酸、グリシン、アラニン、バリン、ロイシン、及びチロシンからなる群から選ばれるアミノ酸のL体の量を使用して、病態指標値を算出することが好ましい。eGFRとの相関がより高い(|r|>0.4)という観点から、グルタミン酸、スレオニン、プロリン、及びリジンからなる群から選ばれるアミノ酸のL体の量を使用して、病態指標値を算出することがより好ましい。 When the amount of L-form of an amino acid is used as an index, it is preferable to calculate the pathological index value using the amount of L-form of an amino acid selected from the group consisting of glutamic acid, threonine, proline, lysine, histidine, serine, glutamine, aspartic acid, glycine, alanine, valine, leucine, and tyrosine, based on the correlation with estimated glomerular filtration rate (eGFR) (|r|>0.2). It is more preferable to calculate the pathological index value using the amount of L-form of an amino acid selected from the group consisting of glutamic acid, threonine, proline, and lysine, based on the higher correlation with eGFR (|r|>0.4).
アミノ酸のD体の量及びL体の量の合計量を指標とする場合、推算糸球体濾過量(eGFR)との相関から(|r|>0.2)、グルタミン酸、スレオニン、プロリン、リジン、ヒスチジン、セリン、グルタミン、アスパラギン酸、グリシン、アラニン、バリン、ロイシン、及びチロシンからなる群から選ばれるアミノ酸のD体及びL体の合計量を使用して、病態指標値を算出することが好ましい。eGFRとの相関がより高い(|r|>0.4)という観点から、グルタミン酸、スレオニン、プロリン、リジン、及びアラニンからなる群から選ばれるアミノ酸のD体及びL体の合計量を使用して、病態指標値を算出することがより好ましい。 When the total amount of D- and L-amino acids is used as an index, it is preferable to calculate the pathological index value using the total amount of D- and L-amino acids selected from the group consisting of glutamic acid, threonine, proline, lysine, histidine, serine, glutamine, aspartic acid, glycine, alanine, valine, leucine, and tyrosine, based on the correlation with estimated glomerular filtration rate (eGFR) (|r|>0.2). It is more preferable to calculate the pathological index value using the total amount of D- and L-amino acids selected from the group consisting of glutamic acid, threonine, proline, lysine, and alanine, based on the higher correlation with eGFR (|r|>0.4).
D体とL体の比を指標とする場合、推算糸球体濾過量(eGFR)との相関から(|r|>0.2)、アミノ酸は、ヒスチジン、リジン、アスパラギン酸、グルタミン酸、アラニン、及びプロリンからなる群から選ばれる少なくとも1のアミノ酸を使用して、病態指標値を算出することが好ましい。eGFRとの相関がより高い(|r|>0.4)という観点から、アミノ酸は、ヒスチジン、リジン、アスパラギン酸、アラニン、及びプロリンからなる群から選ばれる少なくとも1のアミノ酸を使用して、病態指標値を算出することがより好ましい。eGFRとの相関がより高い(|r|>0.6)という観点から、ヒスチジン、リジン、プロリン、及びアラニンからなる群から選ばれる少なくとも1のアミノ酸を用いることがより好ましい。ヒスチジン、リジン、プロリン、及びアラニンからなる群から選ばれる2以上の組合せ、すなわち、ヒスチジンとリジン、ヒスチジンとプロリン、ヒスチジンとアラニン、リジンとプロリン、リジンとアラニン、プロリンとアラニン、又はヒスチジンとリジンとプロリンとアラニンの組合せを用いることもできる。 When the ratio of D-form to L-form is used as an index, it is preferable to calculate the pathological index value using at least one amino acid selected from the group consisting of histidine, lysine, aspartic acid, glutamic acid, alanine, and proline, based on the correlation with estimated glomerular filtration rate (eGFR) (|r|>0.2). From the viewpoint of a higher correlation with eGFR (|r|>0.4), it is more preferable to calculate the pathological index value using at least one amino acid selected from the group consisting of histidine, lysine, aspartic acid, alanine, and proline. From the viewpoint of a higher correlation with eGFR (|r|>0.6), it is more preferable to use at least one amino acid selected from the group consisting of histidine, lysine, proline, and alanine. It is also possible to use combinations of two or more selected from the group consisting of histidine, lysine, proline, and alanine, i.e., combinations of histidine and lysine, histidine and proline, histidine and alanine, lysine and proline, lysine and alanine, proline and alanine, or histidine, lysine, proline, and alanine.
一方、健常者と慢性腎臓病患者との間で有意差を有する観点では、D-アスパラギン酸、D-グルタミン酸、D-アラニン、D-プロリンの量、及びL-ヒスチジン、L-セリン、L-グルタミン、L-アスパラギン酸、グリシン、L-グルタミン酸、L-スレオニン、L-アラニン、L-プロリン、L-バリン、L-イソロイシン、L-ロイシン、L-チロシンの量、及び(D+L)-ヒスチジン、(D+L)-セリン、(D+L)-グルタミン、(D+L)-アスパラギン酸、(D+L)-グルタミン酸、(D+L)-スレオニン、(D+L)-アラニン、(D+L)-プロリン、(D+L)-バリン、(D+L)-イソロイシン、(D+L)-ロイシン、(D+L)-チロシンの量、及びスレオニン、イソロイシンについてはアロ体が存在することからD-スレオニン+L-アロ-スレオニン、D-アロ-スレオニン+L-スレオニン、D-イソロイシン+L-アロ-イソロイシン、D-アロ-イソロイシン+L-イソロイシンの量を病態指標値として算出することが好ましい。 On the other hand, in terms of significant differences between healthy individuals and patients with chronic kidney disease, the amounts of D-aspartic acid, D-glutamic acid, D-alanine, and D-proline, as well as the amounts of L-histidine, L-serine, L-glutamine, L-aspartic acid, glycine, L-glutamic acid, L-threonine, L-alanine, L-proline, L-valine, L-isoleucine, L-leucine, and L-tyrosine, as well as the amounts of (D+L)-histidine, (D+L)-serine, (D+L)-glutamine, (D+L)-aspartic acid, (D+L)- It is preferable to calculate the amounts of glutamic acid, (D+L)-threonine, (D+L)-alanine, (D+L)-proline, (D+L)-valine, (D+L)-isoleucine, (D+L)-leucine, (D+L)-tyrosine, and, since alloforms of threonine and isoleucine exist, the amounts of D-threonine + L-allo-threonine, D-allo-threonine + L-threonine, D-isoleucine + L-allo-isoleucine, and D-allo-isoleucine + L-isoleucine are used as pathological index values.
本発明における試料中のD-アミノ酸及びL-アミノ酸の測定は、当業者に周知ないかなる方法を用いて実施しても構わない。例えば、酵素法(Y. Nagata et al., Clinical Science, 73 (1987), 105. Analytical Biochemistry, 150 (1985), 238., A. D'Aniello et al., Comparative Biochemistry and Physiology Part B, 66 (1980), 319. Journal of Neurochemistry, 29 (1977), 1053., A. Berneman et al., Journal of Microbial & Biochemical Technology, 2 (2010), 139., W. G. Gutheil et al., Analytical Biochemistry, 287 (2000), 196., G. Molla et al., Methods in Molecular Biology, 794 (2012), 273., T. Ito et al., Analytical Biochemistry, 371 (2007), 167. 等)、抗体法(T. Ohgusu et al., Analytical Biochemistry, 357 (2006), 15.,等 )、ガスクロマトグラフィー(GC)(H. Hasegawa et al., Journal of Mass Spectrometry, 46 (2011), 502., M. C. Waldhier et al., Analytical and Bioanalytical Chemistry, 394 (2009), 695., A. Hashimoto, T. Nishikawa et al., FEBS Letters, 296 (1992), 33., H. Bruckner and A. Schieber, Biomedical Chromatography, 15 (2001), 166. , M. Junge et al., Chirality, 19 (2007), 228., M. C. Waldhier et al., Journal of Chromatography A, 1218 (2011), 4537. 等)、キャピラリー電気泳動法(CE)(H. Miao et al., Analytical Chemistry, 77 (2005), 7190., D. L. Kirschner et al., Analytical Chemistry, 79 (2007), 736., F. Kitagawa, K. Otsuka, Journal of Chromatography B, 879 (2011), 3078., G. Thorsen and J. Bergquist, Journal of Chromatography B, 745 (2000), 389. 等)、高速液体クロマトグラフィー(HPLC)(N. Nimura and T. Kinoshita, Journal of Chromatography, 352 (1986), 169., A. Hashimoto et al., Journal of Chromatography, 582 (1992), 41., H. Bruckner et al., Journal of Chromatography A, 666 (1994), 259., N. Nimura et al., Analytical Biochemistry, 315 (2003), 262., C. Muller et al., Journal of Chromatography A, 1324 (2014), 109., S. Einarsson et al., Analytical Chemistry, 59 (1987), 1191., E. Okuma and H. Abe, Journal of Chromatography B, 660 (1994), 243., Y. Gogami et al., Journal of Chromatography B, 879 (2011), 3259., Y. Nagata et al., Journal of Chromatography, 575 (1992), 147., S. A. Fuchs et al., Clinical Chemistry, 54 (2008), 1443., D. Gordes et al., Amino Acids, 40 (2011), 553., D. Jin et al., Analytical Biochemistry, 269 (1999), 124., J. Z. Min et al., Journal of Chromatography B, 879 (2011), 3220., T. Sakamoto et al., Analytical and Bioanalytical Chemistry, 408 (2016), 517., W. F. Visser et al., Journal of Chromatography A, 1218 (2011), 7130., Y. Xing et al., Analytical and Bioanalytical Chemistry, 408 (2016), 141., K. Imai et al., Biomedical Chromatography, 9 (1995), 106., T. Fukushima et al., Biomedical Chromatography, 9 (1995), 10., R. J. Reischl et al., Journal of Chromatography A, 1218 (2011), 8379., R. J. Reischl and W. Lindner, Journal of Chromatography A, 1269 (2012), 262., S. Karakawa et al., Journal of Pharmaceutical and Biomedical Analysis, 115 (2015), 123., 等)がある。 In the present invention, the measurement of D-amino acids and L-amino acids in a sample may be carried out using any method known to those skilled in the art. For example, enzyme methods (Y. Nagata et al., Clinical Science, 73 (1987), 105. Analytical Biochemistry, 150 (1985), 238., A. D'Aniello et al., Comparative Biochemistry and Physiology Part B, 66 (1980), 319. Journal of Neurochemistry, 29 (1977), 1053., A. Berneman et al., Journal of Microbial & Biochemical Technology, 2 (2010), 139., W. G. Gutheil et al., Analytical Biochemistry, 287 (2000), 196., G. Molla et al., Methods in Molecular Biology, 794 (2012), 273., T. Ito et al., Analytical Biochemistry, 371 (2007), 167., etc.), antibody methods (T. Ohgusu et al., al., Analytical Biochemistry, 357 (2006), 15., etc.), gas chromatography (GC) (H. Hasegawa et al., Journal of Mass Spectrometry, 46 (2011), 502., M. C. Waldhier et al., Analytical and Bioanalytical Chemistry, 394 (2009), 695., A. Hashimoto, T. Nishikawa et al., FEBS Letters, 296 (1992), 33., H. Bruckner and A. Schieber, Biomedical Chromatography, 15 (2001), 166. , M. Junge et al., Chirality, 19 (2007), 228., M. C. Waldhier et al., Journal of Chromatography A, 1218 (2011), 4537. etc.), capillary electrophoresis (CE) (H. Miao et al., Analytical Chemistry, 77 (2005), 7190., D. L. Kirschner et al., Analytical Chemistry, 79 (2007), 736., F. Kitagawa, K. Otsuka, Journal of Chromatography B, 879 (2011), 3078., G. Thorsen and J. Bergquist, Journal of Chromatography B, 745 (2000), 389. etc.), high performance liquid chromatography (HPLC) (N. Nimura and T. Kinoshita, Journal of Chromatography, 352 (1986), 169., A. Hashimoto et al., Journal of Chromatography, 582 (1992), 41., H. Bruckner et al., Journal of Chromatography A, 666 (1994), 259., N. Nimura et al., Analytical Biochemistry, 315 (2003), 262., C. Muller et al., Journal of Chromatography A, 1324 (2014), 109., S. Einarsson et al., Analytical Chemistry, 59 (1987), 1191., E. Okuma and H. Abe, Journal of Chromatography B, 660 (1994), 243., Y. Gogami et al., Journal of Chromatography B, 879 (2011), 3259., Y. Nagata et al., Journal of Chromatography, 575 (1992), 147., S. A. Fuchs et al., Clinical Chemistry, 54 (2008), 1443., D. Gordes et al., Amino Acids, 40 (2011), 553., D. Jin et al., Analytical Biochemistry, 269 (1999), 124., J. Z. Min et al., Journal of Chromatography B, 879 (2011), 3220., T. Sakamoto et al., Analytical and Bioanalytical Chemistry, 408 (2016), 517., W. F. Visser et al., Journal of Chromatography A, 1218 (2011), 7130., Y. Xing et al., Analytical and Bioanalytical Chemistry, 408 (2016), 141., K. Imai et al., Biomedical Chromatography, 9 (1995), 106., T. Fukushima et al., Biomedical Chromatography, 9 (1995), 10., R. J. Reischl et al., Journal of Chromatography A, 1218 (2011), 8379., R. J. Reischl and W. Lindner, Journal of Chromatography A, 1269 (2012), 262., S. Karakawa et al., Journal of Pharmaceutical and Biomedical Analysis, 115 (2015), 123., etc.
本明細書における光学異性体の分離分析系は、複数の分離分析を組み合わせる場合がある。より具体的に、光学異性体を有する成分を含む試料を、移動相としての第一の液体と共に、固定相としての第一のカラム充填剤に通じて、前記試料の前記成分を分離するステップ、前記試料の前記成分の各々をマルチループユニットにおいて個別に保持するステップ、前記マルチループユニットにおいて個別に保持された前記試料の前記成分の各々を、移動相としての第二の液体と共に、固定相としての光学活性中心を有する第二のカラム充填剤に流路を通じて供給し、前記試料の成分の各々に含まれる前記光学異性体を分割するステップ、及び前記試料の成分の各々に含まれる前記光学異性体を検出するステップを含むことを特徴とする光学異性体の分析方法を用いることにより、試料中のD-/L-アミノ酸濃度を測定することができる(特許第4291628号)。代替的には、アミノ酸の光学異性体を識別するモノクローナル抗体、例えばD-ロイシン、D-アスパラギン酸等に特異的に結合するモノクローナル抗体を用いる免疫学的手法によってD-アミノ酸を測定することができる(特願2008-27650明細書)。また、D体及びL体の合計量を指標とする場合、D体及びL体を分離して分析する必要はなく、D体及びL体を区別せずにアミノ酸を分析することもできる。その場合も酵素法、抗体法、GC、CE、HPLCで分離及び定量することができる。 In the present specification, the optical isomer separation and analysis system may combine a plurality of separation and analysis steps. More specifically, the optical isomer analysis method includes the steps of passing a sample containing components having optical isomers through a first column packing material as a stationary phase together with a first liquid as a mobile phase to separate the components of the sample, individually retaining each of the components of the sample in a multi-loop unit, supplying each of the components of the sample individually retained in the multi-loop unit through a flow path to a second column packing material having an optically active center as a stationary phase together with a second liquid as a mobile phase to separate the optical isomers contained in each of the components of the sample, and detecting the optical isomers contained in each of the components of the sample, thereby measuring the concentration of D-/L-amino acids in a sample (Patent No. 4291628). Alternatively, D-amino acids can be measured by an immunological method using a monoclonal antibody that identifies optical isomers of amino acids, for example, a monoclonal antibody that specifically binds to D-leucine, D-aspartic acid, etc. (Patent Application No. 2008-27650). Furthermore, when the total amount of D- and L-isomers is used as an index, there is no need to separate and analyze D- and L-isomers, and amino acids can be analyzed without distinguishing between D- and L-isomers. In this case, too, separation and quantification can be performed using enzyme methods, antibody methods, GC, CE, and HPLC.
本発明において、腎臓病とは、腎臓に障害が生じた状態の全てを指す。腎機能が低下する原因としては、免疫系の異常や薬剤、高血圧、糖尿病や、出血や急激な血圧低下、感染症、熱傷に伴う脱水等複数の因子が挙げられる。急性腎障害(AKI)は、RIFLE分類、AKIN分類、KDIGO分類といった病期の分類が提唱されており、急性腎障害を、Risk(ステージ1)、Injury(ステージ2)、Failure(ステージ3)、さらには持続期間に応じてLossとEnd stage kidney diseaseに分類した。これらの分類は、どれも血中クレアチニンの量と尿量とを指標としており、例えばRisk(ステージ1)では、血中クレアチニンがベースラインから1.5~2.0倍に上昇すること又は0.5ml/kg/時未満の尿量が6時間以上であること、Injury(ステージ2)では、血中クレアチニンがベースラインから2.0~3.0倍に上昇すること又は0.5ml/kg/時未満の尿量が12時間以上であること、Failure(ステージ3)では、血中クレアチニンがベースラインから3.0倍以上に上昇すること又は0.3ml/kg/時未満の尿量が24時間以上であることを判断基準としている。一方で、これらの分類は、他の指標、例えばGFRの変化量を併用することでより正確に急性腎障害の分類を可能にする。慢性腎臓病(CKD)は、日本腎臓学会のガイドライン(2013改訂)で病期ステージ1(腎機能は正常、eGFR≧90)~ステージ5(腎不全、eGFR<15)の診断基準が示されている。ここで指標となっている推算糸球体濾過量(eGFR)は血中クレアチニンの値と年齢、性別より算出されるもので、腎臓病の進行度を表すことができる。本発明の分析・検査方法では、これまでの腎臓病マーカーとは異なる原理で腎臓病を検出しているため、従来とは異なるリスク評価ができる可能性がある。また、血中クレアチニンやGFR等と組み合わせて使用することで、より詳細に腎臓病を区別して診断することが可能になる。 In the present invention, kidney disease refers to any condition in which the kidney is damaged. Causes of decreased kidney function include immune system abnormalities, drugs, high blood pressure, diabetes, bleeding, sudden drop in blood pressure, infections, dehydration due to burns, and other factors. Classification of disease stages such as the RIFLE, AKIN, and KDIGO classifications have been proposed for acute kidney injury (AKI), and acute kidney injury is classified into Risk (Stage 1), Injury (Stage 2), Failure (Stage 3), and further into Loss and End stage kidney disease depending on the duration. All of these classifications use the amount of blood creatinine and the amount of urine as indicators. For example, in Risk (Stage 1), blood creatinine rises 1.5-2.0 times from baseline or urine volume less than 0.5 ml/kg/hour for 6 hours or more; in Injury (Stage 2), blood creatinine rises 2.0-3.0 times from baseline or urine volume less than 0.5 ml/kg/hour for 12 hours or more; and in Failure (Stage 3), blood creatinine rises 3.0 times or more from baseline or urine volume less than 0.3 ml/kg/hour for 24 hours or more. On the other hand, these classifications enable more accurate classification of acute kidney injury by using other indicators, such as the change in GFR. The Japanese Society of Nephrology guidelines (revised in 2013) show diagnostic criteria for chronic kidney disease (CKD) from stage 1 (normal renal function, eGFR≧90) to stage 5 (renal failure, eGFR<15). The index here, estimated glomerular filtration rate (eGFR), is calculated from blood creatinine levels, age, and gender, and can indicate the progression of kidney disease. The analysis and testing method of the present invention detects kidney disease using a different principle than previous kidney disease markers, which may allow for risk assessments that are different from conventional methods. In addition, by using it in combination with blood creatinine, GFR, etc., it becomes possible to distinguish and diagnose kidney disease in more detail.
本発明の別の態様では、本発明は、唾液を試料とする腎臓病の検査方法に関する。この検査方法は、以下の工程を含む:
唾液中の少なくとも1のアミノ酸のD体及び/又はL体を測定する工程、
前記少なくとも1種類のアミノ酸のD体及び/又はL体に基づく腎臓病の病態指標値として算出する工程、
腎臓病の病態指標値と、腎臓病の病態とを関連づける工程
をさらに含む。関連付ける工程は、病態指標値を、予め決められた病態指標値の基準値と比較することで、病態指標値と腎臓病の病態とを関連づけることができる。本発明の検査方法は、分析会社や分析技術者により行われて、腎臓病の病態と関連づけられた結果が提供されてもよい。検査方法において用いられる試料、関連づけられる腎臓病の病態、行われる各工程は、分析方法において定義されたものと同じであってよい。
In another aspect, the present invention relates to a method for testing for kidney disease using saliva as a sample, the method comprising the steps of:
Measuring the D- and/or L-forms of at least one amino acid in saliva;
A step of calculating a pathological index value for kidney disease based on the D-isomer and/or L-isomer of the at least one type of amino acid;
The method further includes a step of associating the pathology index value of kidney disease with the pathology of kidney disease. The associating step can associate the pathology index value with the pathology of kidney disease by comparing the pathology index value with a predetermined reference value of the pathology index value. The testing method of the present invention may be performed by an analysis company or an analysis technician to provide a result associated with the pathology of kidney disease. The sample used in the testing method, the pathology of kidney disease to be associated, and each step performed may be the same as those defined in the analysis method.
図8は、本発明の試料分析システムの構成図である。図8に示す本発明の試料分析システム10は、本発明の分析方法及び検査方法を実施することができるように構成される。このような試料分析システム10は、記憶部11と、入力部12、分析測定部13と、データ処理部14と、出力部15とを含んでおり、唾液試料を分析し、病態情報を出力することができる。より具体的に、本発明の試料分析システム10において、
記憶部11は、入力部12から入力された腎臓病を判別するための病態指標値の基準値を記憶し、
分析測定部13は、前記被検体の唾液試料中のアミノ酸のうちの少なくとも1のアミノ酸の光学異性体を分離し測定し、
データ処理部14は、前記少なくとも1のアミノ酸のD体及び/又はL体に基づき腎臓病の病態指標値を算出し、
データ処理部14は、記憶部11に記憶された基準値と比較することにより、腎臓病の病態情報を判別し、
出力部15が被検体の腎臓病についての病態情報を出力することができる。
Fig. 8 is a configuration diagram of the sample analysis system of the present invention. The
The
The analysis and
the
The
The
記憶部11は、RAM、ROM、フラッシュメモリ等のメモリ装置、ハードディスクドライブ等の固定ディスク装置、又はフレキシブルディスク、光ディスク等の可搬用の記憶装置等を有する。記憶部は、分析測定部で測定したデータ、入力部から入力されたデータ及び指示、データ処理部で行った演算処理結果等の他、情報処理装置の各種処理に用いられるコンピュータプログラム、データベース等を記憶する。コンピュータプログラムは、例えばCD-ROM、DVD-ROM等のコンピュータ読み取り可能な記録媒体や、インターネットを介してインストールされてもよい。コンピュータプログラムは、公知のセットアッププログラム等を用いて記憶部にインストールされる。
The
入力部12は、インターフェイス等であり、キーボード、マウス等の操作部も含む。これにより、入力部は、分析測定部13で測定したデータ、データ処理部14で行う演算処理の指示等を入力することができる。また、入力部12は、例えば分析測定部13が外部にある場合は、操作部とは別に、測定したデータ等をネットワークや記憶媒体を介して入力することができるインターフェイス部を含んでもよい。
The
分析測定部13は、唾液試料におけるアミノ酸のD体及び/又はL体の量の測定工程を行う。したがって、分析測定部13は、アミノ酸のD体及びL体の分離及び測定を可能にする構成を有することが好ましいが、合計量のみを測定する場合には、D体とL体を分離せずにまとめて測定することもできる。アミノ酸は、1ずつ分析されてもよいが、一部又は全ての種類のアミノ酸についてまとめて分析することもできる。分析測定部13は、以下のものに限定されることを意図するものではないが、例えば試料導入部、光学分割カラム、検出部を備えた高速液体クロマトグラフィーシステムであってもよい。分析測定部13は、試料分析システムとは別に構成されていてもよく、測定したデータ等をネットワークや記憶媒体を用いて入力部12を介して入力してもよい。
The analysis and
データ処理部14は、測定された各アミノ酸のD体及びL体の測定値から、D体の量、L体の量、D体及びL体の合計量、又はD体とL体の比に基づく腎臓病の病態指標値を算出し、そして記憶部11に記憶された基準値と比較することにより、腎臓病を判別するように構成される。データ処理部14は、記憶部に記憶しているプログラムに従って、分析測定部13で測定され記憶部11に記憶されたデータに対して、各種の演算処理を実行する。演算処理は、データ処理部に含まれるCPUによりおこなわれる。このCPUは、分析測定部13、入力部12、記憶部11、及び出力部15を制御する機能モジュールを含み、各種の制御を行うことができる。これらの各部は、それぞれ独立した集積回路、マイクロプロセッサ、ファームウェア等で構成されてもよい。
The
出力部15は、データ処理部で演算処理を行った結果である病態指標値及び/又は病態情報を出力するように構成さる。出力部15は、演算処理の結果を直接表示する液晶ディスプレイ等の表示装置、プリンタ等の出力手段であってもよいし、外部記憶装置への出力又はネットワークを介して出力するためのインターフェイス部であってもよい。
The
図8Aは、本発明のプログラムによる病態指標値を決定するための手続きの例を示すフローチャートであり、図8Bは、本発明のプログラムによる病態指標値及び又は病態情報を決定するための動作の例を示すフローチャートである。
具体的に、本発明のプログラムは、入力部、出力部、データ処理部、記憶部とを含む情報処理装置に病態指標値及び/又は病態情報を決定させるプログラムである。本発明のプログラムは、以下の:
入力部から入力された少なくとも1のアミノ酸のD体及び/又はL体の測定値を記憶部に記憶させ、
記憶部に記憶された値に基づきデータ処理部に病態指標値を算出させ、
算出された病態指標値を記憶部に記憶させ、そして
記憶された病態指標値を出力部に出力させる
ことを前記情報処理装置に実行させるための指令を含む。本発明のプログラムは、記憶媒体に格納されてもよいし、インターネット又はLAN等の電気通信回線を介して提供されてもよい。
FIG. 8A is a flowchart showing an example of a procedure for determining a pathology index value using the program of the present invention, and FIG. 8B is a flowchart showing an example of an operation for determining a pathology index value and/or pathology information using the program of the present invention.
Specifically, the program of the present invention is a program for causing an information processing device including an input unit, an output unit, a data processing unit, and a storage unit to determine a pathological condition index value and/or pathological condition information.
storing the measured value of the D-form and/or L-form of at least one amino acid inputted from the input unit in the memory unit;
Calculating a pathological index value in the data processing unit based on the value stored in the storage unit;
The program includes instructions for causing the information processing device to store the calculated pathological condition index value in a storage unit and to output the stored pathological condition index value to an output unit. The program of the present invention may be stored in a storage medium or provided via a telecommunication line such as the Internet or a LAN.
情報処理装置が、分析測定部を備える場合、入力部から少なくとも1のアミノ酸のD体及びL体の測定値を入力させる代わりに、分析測定部が、唾液試料から測定値を測定し記憶部に記憶させることを情報処理装置に実行させるための指令を含んでもよい。 When the information processing device includes an analysis and measurement unit, instead of inputting the measurement values of at least one D- and L-isomer of an amino acid from the input unit, the analysis and measurement unit may include instructions for causing the information processing device to measure the measurement value from a saliva sample and store the measurement value in the memory unit.
病態情報の決定には、さらに、
記憶された病態指標値と、予め記憶部に記憶された基準値とをデータ処理部に比較させることで、腎臓病の病態を判別させ、
判別された病態情報を記憶部に記憶させ、そして
記憶された病態情報を出力部に出力させる
ことを情報処理装置に実行させるための指令を含んでもよい。
The determination of pathological information further includes:
The data processing unit compares the stored pathological condition index value with a reference value previously stored in the storage unit, thereby determining the pathological condition of the kidney disease;
The method may include instructions for causing the information processing device to store the determined pathological condition information in the storage unit, and to output the stored pathological condition information to the output unit.
本発明において、被検体は、ヒトに限定されず、実験動物、例えばマウス、ラット、ウサギ、イヌ、サル等を包含しうる。最も好適な態様では、本発明の分析方法及び検査方法は、腎臓病について自覚症状を有する被験者や、腎臓病が疑われる被験者に対して、確定診断のために実施することができるし、腎臓病について自覚症状を有しない被験者に対しても、健康診断として実施することができる。 In the present invention, the subject is not limited to humans, but may include laboratory animals such as mice, rats, rabbits, dogs, and monkeys. In the most preferred embodiment, the analysis method and testing method of the present invention can be performed for a definitive diagnosis on subjects who have subjective symptoms of kidney disease or subjects suspected of having kidney disease, and can also be performed as a health check on subjects who do not have subjective symptoms of kidney disease.
本発明の分析方法は、慢性腎臓病及び/又は急性腎障害の診断方法のための予備的なデータを収集するために使用することができる。このような予備的データを用いて医師が慢性腎臓病及び/又は急性腎障害を診断することができるが、かかる分析方法は、医師ではない医療補助者等により行われてもよいし、分析機関等が行うこともできる。したがって、本発明の分析方法は、診断の予備的方法又は補助方法と言うこともできる。より好ましい態様では、本発明の分析方法は、健康診断において採取された唾液試料に対して行われる。 The analytical method of the present invention can be used to collect preliminary data for a method of diagnosing chronic kidney disease and/or acute kidney injury. A doctor can diagnose chronic kidney disease and/or acute kidney injury using such preliminary data, but such an analytical method may also be performed by a medical assistant who is not a doctor, or by an analytical institution. Therefore, the analytical method of the present invention can also be said to be a preliminary or auxiliary method of diagnosis. In a more preferred embodiment, the analytical method of the present invention is performed on a saliva sample collected during a health checkup.
本発明の分析法による検査の結果を参照することによって、腎臓病の重症度の分類が可能になる。一例として、慢性腎臓病患者の分類であるG1、G2、G3a、G3b、G4、及びG5の6つの重症度に則して分類することができる。G2~G5に対応する分類に分類された対象に対して、治療介入がされる。各分類に応じて治療介入は適宜選択することができる。治療介入は、生活習慣改善、食事指導、血圧管理、貧血管理、電解質管理、尿毒素管理、血糖値管理、免疫管理、及び脂質管理等が、独立に又は組み合わせて指導される。生活習慣改善としては、禁煙及びBMI値の25未満への減量等が推奨される。食事指導としては、減塩及びタンパク質制限が行われる。この中でも特に、血圧管理、貧血管理、電解質管理、尿毒素管理、血糖値管理、免疫管理、脂質管理については、投薬による治療が行われうる。血圧管理としては、130/80mmHg以下となるように、管理され、場合により高血圧治療薬が投与されうる。高血圧治療薬としては、利尿薬(サイアザイド系利尿薬、例えばトリクロルメチアジド、ベンチルヒドロクロロチアジド、ヒドロクロロチアジド、サイアザイド系類似利尿薬、例えばメチクラン、インダバミド、トリバミド、メフルシド、ループ利尿薬、例えばフロセミド、カリウム保持性利尿薬・アルドステロン拮抗薬、例えばトリアムテレン、スピロノラクトン、エプレレノン等)、カルシウム拮抗薬(ジヒドロピリジン系、例えばニフェジピン、アムロジピン、エホニジピン、シルニジピン、ニカルジピン、ニソルジピン、ニトレンジピン、ニルバジピン、バルニジピン、フェロジピン、ベニジピン、マニジピン、アゼルニジピン、アラニジピン、ベンゾチアゼピン系、ジルチアゼム等)、アンジオテンシン変換酵素阻害薬(カプトプリル、エナラプリル、アセラプリル、デラプリル、シラザプリル、リシノプリル、ベナゼプリル、イミダプリル、テモカプリル、キナプリル、トランドラプリル、ベリンドプリルエルブミン等)、アンジオテンシン受容体拮抗薬(アンジオテンシンII受容体拮抗薬、例えばロサルタン、カンデサルタン、バルサルタン、テルミサルタン、オルメサルタン、イルベサルタン、アジルサルタン等)、交感神経遮断薬(β遮断薬、例えばアテノロール、ビソプロロール、ベタキソロール、メトプロロール、アセプトロール、セリプロロール、プロプラノロール、ナドロール、カルテオロール、ピンドロール、ニプラジロール、アモスラロール、アロチノロール、カルベジロール、ラベタロール、ベバントロール、ウラピジル、テラゾシン、ブラゾシン、ドキサゾシン、ブナゾシン等)等が用いられうる。貧血治療薬としてはエリスロポエチン製剤、鉄剤、HIF-1阻害剤等が用いられる。電解質調整薬としてカルシウム受容体作動薬(シナカルセト、エテルカルセチド等)、リン吸着剤が用いられる。尿毒素吸着剤として活性炭等が用いられる。血糖値は、Hba1c6.9%未満になるように管理され、場合により血糖降下薬が投与される。血糖降下薬として、SGLT2阻害薬(イプラグリフロジン、ダパグリフロジン、ルセオグリフロジン、トホグリフロジン、カナグリフロジン、エンパグリフロジン等)、DPP4阻害薬(シタグリプチンリン酸、ビルダグリプチン、サキサグリプチン、アログリプチン、リナグリプチン、テネリグリプチン、トレラグリプチン、アナグリプチン、オマリグリプチン等)、スルホニル尿素薬(トルブタミド、アセトヘキサミド、クロルプロパミド、グリクロピラミド、グリベンクラミド、グリクラジド、グリメピリド等)、チアゾリジン薬(ピオグリタゾン等)、ビグアナイド薬(メトホルミン、ブホルミン等)、α―グルコシダーゼ阻害薬(アカルボース、ボグリボース、ミグリトール等)、グリニド薬(ナテグリニド、ミチグリニド、レパグリニド等)インスリン製剤、NRF2活性化剤(バルドキソロンメチル等)等が用いられる。免疫管理としては、免疫抑制剤(ステロイド類、タクロリムス、抗CD20抗体、シクロヘキサミド、ミコフェノール酸モフェチル(MMF)等)が用いられる。脂質管理では、LDL-C120mg/dL未満となるよう管理され、場合により脂質異常症治療薬、例えばスタチン系薬剤(ロスバスタチン、ピタバスタチン、アトルバスタチン、セリバスタチン、フルバスタチン、シンバスタチン、プラバスタチン、ロバスタチン、メバスタチン等)、フィブラート系薬剤(クロフィブラート、ベザフィブラート、フェノフィブラート、クリノフィブラート等)、ニコチン酸誘導体(ニコチン酸トコレロール、ニコモール、ニセリトロール等)、コレステロールトランスポーター阻害剤(エゼチミブ等)、PCSK9阻害剤(エボロクマブ等)EPA製剤等が用いられる。いずれの薬剤も剤形は単剤でも合剤でもよい。腎機能の低下の度合いによっては、腹膜透析、血液透析、持続的血液濾過透析、血液アフェレーシス(血漿交換、血漿吸着等)や腎移植のような腎代替療法が施されてもよい。 By referring to the results of the test using the analytical method of the present invention, it is possible to classify the severity of kidney disease. As an example, it is possible to classify according to six severity levels, G1, G2, G3a, G3b, G4, and G5, which are classifications of chronic kidney disease patients. Treatment intervention is performed for subjects classified into classifications corresponding to G2 to G5. Treatment intervention can be appropriately selected according to each classification. Treatment intervention includes lifestyle improvement, dietary guidance, blood pressure management, anemia management, electrolyte management, uremic toxin management, blood glucose management, immune management, and lipid management, which are independently or in combination. As for lifestyle improvement, smoking cessation and weight loss to a BMI value of less than 25 are recommended. As for dietary guidance, salt reduction and protein restriction are performed. Among these, blood pressure management, anemia management, electrolyte management, uremic toxin management, blood glucose management, immune management, and lipid management can be treated with medication. As for blood pressure management, blood pressure is managed to be 130/80 mmHg or less, and hypertension medication can be administered in some cases. Examples of antihypertensive drugs include diuretics (thiazide diuretics, e.g., trichlormethiazide, benzylhydrochlorothiazide, hydrochlorothiazide, thiazide-like diuretics, e.g., meticrane, indabamide, tribamide, mefruside, loop diuretics, e.g., furosemide, potassium-sparing diuretics/aldosterone antagonists, e.g., triamterene, spironolactone, eplerenone, etc.), calcium antagonists (dihydropyridine-based, e.g., nifedipine, amlodipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nilvadipine, barnidipine, felodipine, benidipine, manidipine, azelnidipine, aranidipine, benzothiazepine-based, diltiazem, etc.), angiotensin-converting enzyme inhibitors (captopril, enalapril, Acela Pril, delapril, cilazapril, lisinopril, benazepril, imidapril, temocapril, quinapril, trandolapril, belindopril erbumine, etc.), angiotensin receptor antagonists (angiotensin II receptor antagonists, e.g., losartan, candesartan, valsartan, telmisartan, olmesartan, irbesartan, azilsartan, etc.), sympatholytic agents (β-blockers, e.g., atenolol, bisoprolol, betaxolol, metoprolol, aceptolol, celiprolol, propranolol, nadolol, carteolol, pindolol, nipradilol, amosulalol, arotinolol, carvedilol, labetalol, bevantolol, urapidil, terazosin, brazosin, doxazosin, bunazosin, etc.), etc. may be used. As anemia treatment drugs, erythropoietin preparations, iron preparations, HIF-1 inhibitors, etc. are used. As electrolyte regulators, calcium receptor agonists (cinacalcet, etelcalcetide, etc.) and phosphorus adsorbents are used. As a uremic toxin adsorbent, activated charcoal, etc. is used. Blood glucose levels are controlled to Hba1c less than 6.9%, and hypoglycemic drugs are administered in some cases. As hypoglycemic drugs, SGLT2 inhibitors (ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin, canagliflozin, empagliflozin, etc.), DPP4 inhibitors (sitagliptin phosphate, vildagliptin, saxagliptin, alogliptin, linagliptin, teneligliptin, trelagliptin, anagliptin, omarigliptin, etc.), sulfonylureas (tolbutamide, acetohexaglycine, etc.), For immune management, immunosuppressants (steroids, tacrolimus, anti-CD20 antibodies, cyclohexamide, mycophenolate mofetil (MMF), etc.) are used. In lipid management, LDL-C is controlled to be less than 120 mg/dL, and in some cases, dyslipidemia treatment drugs such as statin drugs (rosuvastatin, pitavastatin, atorvastatin, cerivastatin, fluvastatin, simvastatin, pravastatin, lovastatin, mevastatin, etc.), fibrate drugs (clofibrate, bezafibrate, fenofibrate, clinofibrate, etc.), nicotinic acid derivatives (tocorrel nicotinate, nicomol, niceritrol, etc.), cholesterol transporter inhibitors (ezetimibe, etc.), PCSK9 inhibitors (evolocumab, etc.), EPA preparations, etc. are used. Each drug may be in the form of a single drug or a combination drug. Depending on the degree of decline in renal function, renal replacement therapy such as peritoneal dialysis, hemodialysis, continuous hemofiltration dialysis, hemoapheresis (plasma exchange, plasma adsorption, etc.) or kidney transplantation may be performed.
本明細書において言及される全ての文献はその全体が引用により本明細書に取り込まれる。 All documents referred to herein are incorporated herein by reference in their entirety.
以下に説明する本発明の実施例は例示のみを目的とし、本発明の技術的範囲を限定するものではない。本発明の技術的範囲は特許請求の範囲の記載によってのみ限定される。本発明の趣旨を逸脱しないことを条件として、本発明の変更、例えば、本発明の構成要件の追加、削除及び置換を行うことができる。 The examples of the present invention described below are for illustrative purposes only and are not intended to limit the technical scope of the present invention. The technical scope of the present invention is limited only by the claims. Modifications of the present invention, such as additions, deletions, and substitutions of constituent elements of the present invention, may be made without departing from the spirit of the present invention.
材料及び方法
研究倫理
全ての実験は「ヘルシンキ宣言(2013年10月 WMAフォルタレザ総会で修正)」及び「人を対象とする医学系研究に関する倫理指針(2014年12月22日公布)」のガイドラインに従って実施された。
Materials and Methods
Research ethics All experiments were conducted in accordance with the guidelines of the Declaration of Helsinki (amended at the WMA Fortaleza General Assembly in October 2013) and the Ethical Guidelines for Medical Research Involving Human Subjects (promulgated on December 22, 2014).
材料
アミノ酸のエナンチオマー及びHPLC級のアセトニトリルはナカライテスク(京都)から購入された。HPLC級のメタノール、トリフルオロ酢酸、ホウ酸等は和光純薬(大阪)から購入された。水はMill-QグラジエントA10システムを用いて精製された。
Materials: Amino acid enantiomers and HPLC-grade acetonitrile were purchased from Nacalai Tesque (Kyoto). HPLC-grade methanol, trifluoroacetic acid, boric acid, etc. were purchased from Wako Pure Chemical Industries (Osaka). Water was purified using a Mill-Q gradient A10 system.
試料
唾液試料は、朝食摂取後、歯磨きを行った被験者から、歯磨きの2時間後に5mlの唾液を採取した。唾液は、口腔全体からでた全唾液を採取した。採取された唾液は、嫌気条件下で4℃又は-80℃で実験まで保存した。また同じ被験者から血液試料を採取した。
Saliva samples were collected from subjects who had eaten breakfast and brushed their teeth, and 5 ml of saliva was collected 2 hours after brushing their teeth. Whole saliva from the entire oral cavity was collected. The collected saliva was stored under anaerobic conditions at 4°C or -80°C until the experiment. Blood samples were also collected from the same subjects.
分析
唾液試料は、財津らが開発したD、L-アミノ酸一斉高感度分析システム(特許第4291628号)によるアミノ酸光学異性体分析系に供した。各アミノ酸の分析条件の詳細は、MiyoshiY.、ら、J.Chromatogr.B, 879:3184(2011)及びSasabe,J.ら、Proc.Natl.Acad.Sci.U.S.A.、109:627(2012)に説明される。簡潔には、唾液試料に対し、NBD-F(4-フルオロ-7-ニトロ-2,1,3-ベンゾオキサジアゾール、東京化成工業株式会社)の無水シアン化メチル溶液5μlを添加し、60℃で2分間加熱した。反応後75μlの2%(v/v)トリフルオロ酢酸水溶液を添加した。この混合液の2μLをHPLCシステム(NANOSPACE SI-2、株式会社資生堂)に供した。簡潔には、逆相分離用分析カラムは、40℃に保温された自社製のモノリシックODSカラム(内径0.53mm×500mm)が用いられた。移動相はシアン化メチル-トリフルオロ酢酸-水(容積比5:0.05:95)が用いられた。流速は毎分35μLであった。蛍光検出は、励起波長470nm、検出波長530nmで実行された。逆相分離の後、光学異性体分離系に供された。光学異性体分離には、キラルセレクターとして(S)-ナフチルグリシンを用いるスミキラルOA-2500Sカラム(250mm×1.5mm、自家充填、材料は株式会社住化分析センター製)が使用された。本実施例で説明された2次元HPLCシステムは、例えば生体試料中のセリンの光学異性体を区別して1fmolから100pmolの範囲で定量的に測定できる。これは、健常者と腎臓病患者とにおけるヒスチジンやリジンのD体及びL体の濃度変化を識別するのに十分な感度であった。得られたD体のアミノ酸及びL体のアミノ酸の測定値から、D体の-アミノ酸濃度、L体のアミノ酸濃度、D体及びL体の合計濃度、及びD/L比を算出した。健常者と慢性腎臓病患者におけるアミノ酸のD体の濃度、L体の濃度、及びD体及びL体の合計の濃度を、それぞれ図4~6に示す。なお、グリシンは不斉炭素を有さないために光学異性体が存在しないが、ここでは便宜的にグリシンをL-アミノ酸の区分として表記している。
The saliva samples were subjected to an amino acid optical isomer analysis system using the D, L-amino acid simultaneous high sensitivity analysis system (Patent No. 4291628) developed by Zaitsu et al. Details of the analysis conditions for each amino acid are described in Miyoshi Y., et al., J. Chromatogr. B, 879:3184 (2011) and Sasabe, J. et al., Proc. Natl. Acad. Sci. U.S.A., 109:627 (2012). Briefly, 5 μl of anhydrous methyl cyanide solution of NBD-F (4-fluoro-7-nitro-2,1,3-benzoxadiazole, Tokyo Chemical Industry Co., Ltd.) was added to the saliva sample and heated at 60° C. for 2 minutes. After the reaction, 75 μl of 2% (v/v) trifluoroacetic acid aqueous solution was added. 2 μL of this mixture was subjected to an HPLC system (NANOSPACE SI-2, Shiseido Co., Ltd.). Briefly, a monolithic ODS column (inner diameter 0.53 mm x 500 mm) made in-house and kept at 40°C was used as the analytical column for reversed-phase separation. The mobile phase used was methyl cyanide-trifluoroacetic acid-water (volume ratio 5:0.05:95). The flow rate was 35 μL per minute. Fluorescence detection was performed at an excitation wavelength of 470 nm and a detection wavelength of 530 nm. After reversed-phase separation, the mixture was subjected to an optical isomer separation system. For optical isomer separation, a SumiChiral OA-2500S column (250 mm x 1.5 mm, self-packed, material from Sumika Chemical Analysis Center Co., Ltd.) using (S)-naphthylglycine as a chiral selector was used. The two-dimensional HPLC system described in this embodiment can quantitatively measure the optical isomers of serine in a biological sample in a range of 1 fmol to 100 pmol, for example, by distinguishing between them. This was a sufficient sensitivity to distinguish between the changes in the concentrations of D- and L-isomers of histidine and lysine in healthy subjects and patients with kidney disease. From the measured values of D- and L-amino acids obtained, the D-amino acid concentration, L-amino acid concentration, total concentration of D- and L-isomers, and D/L ratio were calculated. The concentrations of D- and L-isomers of amino acids in healthy subjects and patients with chronic kidney disease are shown in Figures 4 to 6, respectively. Note that glycine does not have an optical isomer because it does not have an asymmetric carbon, but for convenience, glycine is shown here as a category of L-amino acids.
取得された血液試料について、血清クレアチニンを酵素法により計測した。計測された血清クレアチニンの値と年齢に基づいて推算糸球体濾過量(eGFR)を決定した。eGFRの決定式は以下の通りである:
女性患者には、数式の計算値に補正係数0.739をかけた。
被験者のeGFR値と、22種類の各アミノ酸についてD体のアミノ酸の量、L体のアミノ酸の量、それらの合計量、及びD体とL体の比との関係をピアソンの積率相関係数(Pearson’s product-moment correlation coefficient)を用い、相関を解析した。その結果を図3に示す。
The serum creatinine of the collected blood samples was measured by an enzymatic method. The estimated glomerular filtration rate (eGFR) was determined based on the measured serum creatinine value and age. The formula for determining eGFR is as follows:
For female patients, the formula calculations were multiplied by a correction factor of 0.739.
The correlation between the eGFR value of the subject and the amount of D-amino acid, the amount of L-amino acid, the total amount of these, and the ratio of D-amino acid to L-amino acid for each of the 22 types of amino acids was analyzed using Pearson's product-moment correlation coefficient. The results are shown in Figure 3.
得られた血清クレアチニンの値と、D/L-リジン比及びD/L-ヒスチジン比との関係を解析したところ、高い相関がみられた(r=0.762、p=0.046及びr=0.762、p=0.046)。得られた推算糸球体濾過量と、D/L-リジン比及びD/L-ヒスチジン比との関係を解析したところ、高い負の相関がみられた(r=-0.926、p=0.003及びr=-0.749、p=0.053)。血清クレアチニンの値と、D/L-リジン比及びD/L-ヒスチジン比との相関を示すグラフを図1A及びBに示す。推算糸球体濾過量と、D/L-リジン比及びD/L-ヒスチジン比との相関を示すグラフを図2A及びBに示す。2群間の比較には対応のないt検定(Student’s t-test)をおこない、統計的有意差を測定した。 Analysis of the relationship between the obtained serum creatinine value and the D/L-lysine ratio and the D/L-histidine ratio showed a high correlation (r = 0.762, p = 0.046 and r = 0.762, p = 0.046). Analysis of the relationship between the obtained estimated glomerular filtration rate and the D/L-lysine ratio and the D/L-histidine ratio showed a high negative correlation (r = -0.926, p = 0.003 and r = -0.749, p = 0.053). Graphs showing the correlation between serum creatinine value and the D/L-lysine ratio and the D/L-histidine ratio are shown in Figures 1A and B. Graphs showing the correlation between the estimated glomerular filtration rate and the D/L-lysine ratio and the D/L-histidine ratio are shown in Figures 2A and B. An unpaired t-test (Student's t-test) was used to compare the two groups and determine statistical significance.
Claims (12)
唾液中の少なくとも1のアミノ酸のD体、又はD体及びL体を測定する工程、及び
前記少なくとも1のアミノ酸のD体、又はD体及びL体に基づき腎臓病の病態指標値として算出する工程
を含む、分析方法であって、
前記アミノ酸が、リジン、プロリン、ヒスチジン、アラニン、アスパラギン酸、及びグルタミン酸からなる群から選ばれる、分析方法。 A method for analyzing saliva, comprising:
1. An analysis method comprising: a step of measuring the D-form or the D-form and the L-form of at least one amino acid in saliva; and a step of calculating a pathological condition index value for kidney disease based on the D-form or the D-form and the L-form of the at least one amino acid,
The method of claim 1, wherein the amino acid is selected from the group consisting of lysine, proline, histidine, alanine, aspartic acid, and glutamic acid.
前記記憶部は、入力部から入力された腎臓病の病態指標値の基準値を記憶し、
前記分析測定部は、前記唾液中の少なくとも1のアミノ酸のD体、又はD体及びL体を分離して測定し、
前記データ処理部は、前記少なくとも1のアミノ酸のD体、又はD体及びL体に基づき腎臓病の病態指標値を算出し、
前記データ処理部は、記憶部に記憶された病態指標値の基準値と比較することにより、腎臓病を判別し、
前記出力部が被検体の腎臓病についての病態情報を出力する、前記分析システムであって、
前記アミノ酸が、リジン、プロリン、ヒスチジン、アラニン、アスパラギン酸、及びグルタミン酸からなる群から選ばれる、前記分析システム。 A saliva analysis system including a memory unit, an input unit, an analysis measurement unit, a data processing unit, and an output unit,
The storage unit stores a reference value of a pathological condition index value of a kidney disease inputted from an input unit,
The analysis and measurement unit separates and measures the D-form or the D-form and the L-form of at least one amino acid in the saliva,
the data processing unit calculates a pathology index value for kidney disease based on the D-isomer or the D-isomer and the L-isomer of the at least one amino acid;
The data processing unit compares the pathological condition index value with a reference value stored in a storage unit to determine whether or not there is a kidney disease;
The analysis system, wherein the output unit outputs pathological information regarding a renal disease of a subject,
The above analytical system, wherein the amino acid is selected from the group consisting of lysine, proline, histidine, alanine, aspartic acid, and glutamic acid.
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