TW202028748A - Method for assaying validity of renal function test result based on cystatin c content in blood - Google Patents

Method for assaying validity of renal function test result based on cystatin c content in blood Download PDF

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TW202028748A
TW202028748A TW108137531A TW108137531A TW202028748A TW 202028748 A TW202028748 A TW 202028748A TW 108137531 A TW108137531 A TW 108137531A TW 108137531 A TW108137531 A TW 108137531A TW 202028748 A TW202028748 A TW 202028748A
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renal function
cystin
serine
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三田真史
池田達彦
木村友則
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日商資生堂股份有限公司
國立研究開發法人醫藥基盤 健康 營養研究所
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Abstract

The present invention provides: a method for assaying the validity of a renal function test result based on the cystatin c content in blood, the method comprising a step for measuring the D-serine content in the blood of a subject who has had a renal function test performed based on the cystatin C content in blood, a step for comparing the D-serine content with a prescribed threshold; and a step for determining the validity of the renal function test result based on the cystatin C content in blood; and a sample analysis system and program for implementing said method.

Description

檢定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性之方法Method to verify the validity of renal function test results based on the content of cystin C in the blood

本發明係關於一種檢定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性之方法、實施該方法之試樣分析系統、及程式。The present invention relates to a method for determining the validity of a renal function test result based on the content of cystin C in the blood, a sample analysis system for implementing the method, and a program.

作為表示腎功能之指標，使用腎絲球濾過率(GFR)。腎絲球濾過率表示由腎絲球自血液中1分鐘過濾之液量，其國際標準測定法係菊糖清除試驗。然而，菊糖清除試驗需要歷時2小時之菊糖之持續點滴、複數次采尿及採血、及準確之測定，受驗者及實施者之負擔較大。基於此種情況，雖然被確立為國際標準測定法，但由於各國醫療之各種情況，亦存在未導入實地診療而是利用代替標記物確定腎絲球濾過率之情況。在日本雖然已於2006年將藉由菊糖清除試驗進行之GFR之測定作為檢查應用於保險，但僅限於在限定之情況下進行，於日常臨床現場使用利用其他腎功能標記物之推算式。如此，作為未使用作為腎絲球濾過率之黃金標準之菊糖清除率的弊端，存在腎功能之準確判定、或伴隨其之腎臟病之早期發現變困難之問題。As an indicator of renal function, glomerular filtration rate (GFR) is used. The glomerular filtration rate indicates the amount of fluid filtered from the blood by the glomerulus in 1 minute, and its international standard measurement method is the inulin clearance test. However, the inulin removal test requires continuous infusion of inulin that lasts 2 hours, multiple urine and blood sampling, and accurate measurement, and the burden on the subject and the implementer is relatively large. Based on this situation, although it has been established as an international standard measurement method, due to various medical conditions in various countries, there are also cases where the glomerular filtration rate is determined by substitute markers without introducing on-site diagnosis and treatment. Although the measurement of GFR by the inulin clearance test was applied to insurance in Japan in 2006, it is limited to limited circumstances, and the calculation formula using other renal function markers is used in daily clinical scenes. In this way, as a disadvantage of not using the inulin clearance rate as the gold standard of glomerular filtration rate, there is a problem that it is difficult to accurately determine the renal function, or the early detection of kidney disease that accompanies it.

作為代替菊糖清除試驗之腎絲球濾過率之確定方法，開發有根據菊糖以外之物質之清除率之方法、以及根據血液中之腎功能標記物值之方法。藉由調查該等對作為國際標準測定法之菊糖清除試驗之關聯性而將該等用於GFR之確定。作為現在通用之腎功能標記物之胱蛋白C於無需投予來自體外之物質之方面優異，藉由將年齡與性別資訊進行組合之公式確定推算腎絲球濾過率(eGFR)。As a method for determining the glomerular filtration rate instead of the inulin clearance test, a method based on the clearance rate of substances other than inulin and a method based on the value of renal function markers in the blood have been developed. These were used for the determination of GFR by investigating the relevance of these to the inulin clearance test as an international standard assay. Cystatin C, a commonly used marker of renal function, is excellent in that it does not require the administration of substances from outside the body. The estimated glomerular filtration rate (eGFR) is determined by a formula combining age and gender information.

以此方式確定之eGFR被廣泛用於健康診斷或醫療現場。然而，eGFR係以用於對腎功能惡化之篩查、或如將多個對象者進行比較之流行病學研究中之簡便且客觀之評價為主要目的所製作之指標，對於個別患者之腎功能評價，日本腎臟學會依然推薦使用利用菊糖之菊糖清除試驗。The eGFR determined in this way is widely used in health diagnosis or medical field. However, eGFR is an index produced for the main purpose of screening for deterioration in renal function, or simple and objective evaluation in epidemiological studies such as comparing multiple subjects. It is an indicator for the renal function of individual patients. Evaluation, the Japanese Society of Nephrology still recommends the use of inulin elimination test.

作為其理由，說起來可列舉胱蛋白C之測定範圍之狹窄性。於腎功能高度降低之情況時(例如GFR為30以下)，血液中之胱蛋白C含量之上升停滯，與原本之GFR之偏離變大，故而對末期腎臟病難以進行準確之腎功能評價。又，已知會由於體格或類固醇、環孢素等免疫系統之藥劑之使用、或糖尿病、甲狀腺功能亢進症、炎症、高膽紅素血症、高三酸甘油酯血症等患者之狀態而造成精度降低。如此，若根據胱蛋白含量或eGFR對腎功能進行篩查，則有做出偽陽性與偽陰性之判定之虞。The reason for this is the narrowness of the measurement range of cystin C. When the renal function is highly reduced (for example, the GFR is below 30), the increase of the cystatin C content in the blood stagnates, and the deviation from the original GFR becomes larger. Therefore, it is difficult to accurately evaluate the renal function of end-stage renal disease. In addition, it is known that the accuracy will be caused by the use of physique, steroids, cyclosporine and other immune system drugs, or the condition of patients with diabetes, hyperthyroidism, inflammation, hyperbilirubinemia, and hypertriglyceridemia. reduce. As such, if the kidney function is screened based on the cystin content or eGFR, there is a risk of making false positive and false negative judgments.

已查明先前認為不存在於哺乳類活體中之D-胺基酸存在於各種組織中並承擔生理功能。又，揭示有血液中之D-胺基酸中之D-絲胺酸、D-丙胺酸、D-脯胺酸、D-麩胺酸、D-天冬胺酸之濃度於腎功能衰竭患者體內發生變動並與胱蛋白C相關，故而可成為腎功能衰竭之診斷標記物(非專利文獻1、非專利文獻2、非專利文獻3、非專利文獻4)。進而，關於將選自由D-絲胺酸、D-蘇胺酸、D-丙胺酸、D-天冬醯胺、D-別蘇胺酸、D-麩醯胺、D-脯胺酸及D-***酸所組成之群中之胺基酸作為腎臟病之病狀指標值已有揭示(專利文獻1)。於該等文獻中揭示了如下主旨：與健康者相比，患腎臟病之患者之血液中之D-胺基酸發生變動，故而可將該等變動作為指標進行腎臟病之診斷。 另一方面，關於可根據血液中之D-胺基酸含量確定以菊糖清除率為基準之腎絲球濾過能力，無任何記載或暗示。再者，近年來，作為腎臟病之標記物，開發有尿中L-FABP(Liver-type Fatty Acid Binding Protein，肝型脂肪酸結合蛋白)、血液中NGAL(Neutrophil Gelatinase-associated Lipocalin，中性粒細胞明膠酶相關脂質運載蛋白)、尿中KIM-1(Kidney Injury Molecule-1，腎損傷分子1)等，但即便為腎臟病之標記物，亦未必可確定、推定腎絲球濾過能力。 [先前技術文獻] [專利文獻]It has been ascertained that D-amino acids, which were previously thought not to be present in living mammals, exist in various tissues and perform physiological functions. In addition, it is revealed that the concentration of D-serine, D-alanine, D-proline, D-glutamic acid, and D-aspartic acid in the D-amino acid in the blood is in patients with renal failure It changes in the body and is related to cystin C, so it can be a diagnostic marker for renal failure (Non-Patent Document 1, Non-Patent Document 2, Non-Patent Document 3, Non-Patent Document 4). Furthermore, regarding the selection of D-serine, D-threonine, D-alanine, D-asparagine, D-allothreonine, D-glutamine, D-proline and D -Amino acids in the group consisting of phenylalanine have been disclosed as a pathological index value of kidney disease (Patent Document 1). These documents revealed the following theme: Compared with healthy people, the D-amino acid in the blood of patients with kidney disease changes, so these changes can be used as indicators for the diagnosis of kidney disease. On the other hand, there is no record or suggestion about the glomerular filtration capacity based on the inulin clearance rate that can be determined based on the D-amino acid content in the blood. Furthermore, in recent years, L-FABP (Liver-type Fatty Acid Binding Protein) in urine and NGAL (Neutrophil Gelatinase-associated Lipocalin) in blood have been developed as markers of kidney disease. Gelatinase-related lipocalin), urine KIM-1 (Kidney Injury Molecule-1, kidney injury molecule 1), etc., but even if it is a marker of kidney disease, it may not be possible to determine or estimate the glomerular filtration capacity. [Prior Technical Literature] [Patent Literature]

[專利文獻1]國際公開第2013/140785號 [非專利文獻][Patent Document 1] International Publication No. 2013/140785 [Non-Patent Literature]

[非專利文獻1]Fukushima, T.等人、Biol. Pharm. Bull. 18: 1130 (1995) [非專利文獻2]Nagata. Y Viva Origino Vol. 18 (No.2) (1990)第15次學術報告會報告摘要 [非專利文獻3]Ishida等人、北里醫學 23: 51～62 (1993) [非專利文獻4]Yong Huang等人、Biol. Pharm. Bull. 21: (2) 156-162 (1998)[Non-Patent Document 1] Fukushima, T. et al., Biol. Pharm. Bull. 18: 1130 (1995) [Non-Patent Document 2] Nagata. Y Viva Origino Vol. 18 (No. 2) (1990) Summary of the 15th Academic Conference Report [Non-Patent Document 3] Ishida et al. Kitasato Medical Science 23: 51～62 (1993) [Non-Patent Document 4] Yong Huang et al., Biol. Pharm. Bull. 21: (2) 156-162 (1998)

[發明所欲解決之問題][The problem to be solved by the invention]

雖然於健康診斷中以腎功能檢查為目的算出血液中之胱蛋白C含量、或基於血液中之胱蛋白C含量之推算腎絲球濾過率，但於根據血液中之胱蛋白C含量之腎功能檢查中會因體格之影響、或測定範圍之狹窄性而導致精度降低，因此於結果之判定中可能包含偽陽性及偽陰性。本發明之目的在於對此種偽陽性及偽陰性進行檢定。 [解決問題之技術手段]Although the cystatin C content in the blood is calculated for the purpose of renal function examination in the health diagnosis, or the glomerular filtration rate is estimated based on the cystatin C content in the blood, the renal function is based on the cystatin C content in the blood During the examination, the accuracy will be reduced due to the influence of the physique or the narrowness of the measurement range. Therefore, the result judgment may include false positives and false negatives. The purpose of the present invention is to detect such false positives and false negatives. [Technical means to solve the problem]

本發明者等人著眼於血液中之D-絲胺酸而對其與GFR(菊糖清除率)之關聯性進行了調查，結果令人吃驚地發現血液中之D-絲胺酸含量較現在通用之血液中之胱蛋白C含量對GFR(菊糖清除率)之關聯性更高，從而完成本發明。The inventors of the present invention focused on D-serine in the blood and investigated the relationship between it and GFR (inulin clearance rate). As a result, it was surprisingly found that the content of D-serine in the blood was higher than the current one. The general blood cystatin C content has a higher correlation with GFR (inulin clearance rate), thus completing the present invention.

因此，本發明係關於下述內容。 [1]一種檢定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性之方法，其包括如下步驟： 對接受了根據血液中之胱蛋白C含量之腎功能檢查之對象的血液中之D-絲胺酸含量進行測定之步驟、 將D-絲胺酸含量與特定之閾值進行比較之步驟、及 確定根據血液中之胱蛋白C含量之腎功能檢查之結果之妥當性之步驟。 [2]如項目1記載之方法，其中檢定腎功能檢查結果之妥當性之方法係對根據血液中之胱蛋白C含量之腎功能檢查結果之偽陽性及/或偽陰性進行判定。 [3]如項目2記載之方法，其中上述確定步驟係於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，但D-絲胺酸含量超過上述閾值之情形時，確定為偽陽性。 [4]如項目2記載之方法，其中上述確定步驟係於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為正常，但D-絲胺酸含量低於上述閾值之情形時，確定為偽陰性。 [5]如項目1至4中任一項記載之方法，其中於同一樣品中測定D-絲胺酸含量及血液中之胱蛋白C含量。 [6]如項目1至5中任一項記載之方法，其中上述對象係被投予了免疫系統之藥劑(類固醇類、他克莫司、抗CD20抗體、放線菌酮、MMF(mycophenolate mofetil，麥考酚酸酯)、環孢素等)之對象。 [7]如項目1至6中任一項記載之方法，其中對被判定為偽陰性或真陰性之對象進行治療介入。 [8]如項目7記載之方法，其中上述治療介入係選自由生活習慣改善、飲食指導、血壓管理、貧血管理、電解質管理、尿毒素管理、血糖值管理、免疫管理及脂質管理所組成之群。 [9]如項目7或8之方法，其中作為上述治療介入，包括對上述對象投予選自由利尿劑、鈣拮抗劑、血管緊張素轉化酶抑制劑、血管緊張素受體拮抗劑、交感神經阻斷劑、SGLT2(sodium-dependent glucose transporters 2，鈉-葡萄糖協同轉運蛋白2)抑制劑、磺醯脲劑、噻唑啶劑、雙胍劑、α-葡萄糖苷酶抑制劑、格列奈劑、胰島素製劑、NRF2(Nuclear factor erythroid 2-related factor 2，核因子E2相關因子2)活化劑、免疫抑制劑、他汀系藥劑、貝特系藥劑、貧血治療劑、紅血球生成素製劑、HIF-1(hypoxia-inducible factor 1，缺氧誘導因子1)抑制劑、鐵劑、電解質調整劑、鈣受體促效劑、磷吸附劑、尿毒素吸附劑、DPP4 (Dipeptidyl peptidase 4，二肽基肽酶4)抑制劑、EPA(Eicosapentaenoic Acid，二十碳五烯酸)製劑、菸鹼酸衍生物、膽固醇轉運蛋白抑制劑、及PCSK9 (Proprotein convertase subtilisin/kexin type 9，前蛋白轉化酶枯草溶菌素9)抑制劑所組成之群中之至少1種藥劑。 [10]一種試樣分析系統，其係包含記憶部、輸入部、分析測定部、資料處理部、及輸出部，對根據胱蛋白C含量之腎功能檢查結果之妥當性進行檢定者，且包含： 記憶部記憶自輸入部所輸入之D-絲胺酸含量之閾值， 記憶部記憶自輸入部所輸入之根據血液中之胱蛋白C含量之腎功能檢查結果， 分析測定部對血液試樣中之D-絲胺酸進行分離定量， 資料處理部將D-絲胺酸含量與記憶部中所記憶之D-絲胺酸含量之閾值進行比較而對記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性進行判定， 輸出部輸出根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性。 [11]一種試樣分析系統，其係包含記憶部、輸入部、分析測定部、資料處理部、及輸出部，對根據胱蛋白C含量之腎功能檢查結果之妥當性進行檢定者，且包含： 記憶部記憶自輸入部所輸入之D-絲胺酸含量之閾值， 記憶部記憶自輸入部所輸入之根據血液中之胱蛋白C含量之腎功能檢查結果， 分析測定部對血液試樣中之D-絲胺酸進行分離定量， 資料處理部將D-絲胺酸含量與記憶部中所記憶之D-絲胺酸含量之閾值進行比較而對記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性進行判定， 輸出部輸出根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性。 [12]如項目11記載之試樣分析系統，其中腎功能檢查結果之妥當性之判定係對根據血液中之胱蛋白C含量之腎功能檢查結果之偽陽性及/或偽陰性進行判定。 [13]如項目12記載之試樣分析系統，其中上述判定係於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，但D-絲胺酸含量低於上述閾值之情形時，判定為偽陽性。 [14]如項目12記載之試樣分析系統，其中上述判定係於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為正常，但D-絲胺酸含量高於上述閾值之情形時，確定為偽陰性。 [15]如項目10至14中任一項之試樣分析系統，其中於同一樣品中測定D-絲胺酸含量及血液中之胱蛋白C含量。 [16]一種程式，其係使包含輸入部、輸出部、資料處理部、及記憶部之資訊處理裝置確定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性者，且包含用以使上述資訊處理裝置執行以下內容之指令： 使記憶部記憶自輸入部所輸入之D-絲胺酸含量之閾值， 使記憶部記憶自輸入部所輸入之根據血液中之胱蛋白C含量之腎功能檢查結果， 使記憶自輸入部所輸入之血液試樣中之D-絲胺酸含量， 讀出記憶部中所記憶之D-絲胺酸含量及D-絲胺酸含量之閾值，利用資料處理部進行比較並使記憶部記憶關於高於閾值還是低於閾值之比較結果， 讀出記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果及比較之結果，判定腎功能檢查之結果之妥當性並使記憶部記憶， 使輸出部輸出所記憶之妥當性。 [17]一種程式，其係使包含輸入部、輸出部、資料處理部、及記憶部之資訊處理裝置確定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性者，且包含用以使上述資訊處理裝置執行以下內容之指令： 使記憶部記憶自輸入部所輸入之血液中之胱蛋白C含量之閾值， 使記憶自輸入部所輸入之血液試樣中之胱蛋白C含量， 使記憶部記憶自輸入部所輸入之D-絲胺酸含量之閾值， 使記憶自輸入部所輸入之血液試樣中之D-絲胺酸含量， 讀出記憶部中所記憶之血液中之胱蛋白C含量及血液中之胱蛋白C含量之閾值，利用資料處理部進行比較並使記憶部記憶根據胱蛋白C含量之腎功能檢查結果， 讀出記憶部中所記憶之D-絲胺酸含量及D-絲胺酸含量之閾值，利用資料處理部進行比較並使記憶部記憶比較之結果， 讀出記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果及比較之結果，判定腎功能檢查之結果之妥當性並使記憶部記憶， 使輸出部輸出所記憶之妥當性。 [發明之效果]Therefore, the present invention relates to the following. [1] A method for determining the validity of the results of renal function tests based on the content of cystin C in the blood, which includes the following steps: Steps for measuring the D-serine content in the blood of subjects who have undergone a renal function test based on the content of cystin C in the blood, Steps to compare the content of D-serine with a specific threshold, and Steps to determine the validity of the results of renal function tests based on the content of cystin C in the blood. [2] The method described in item 1, wherein the method for determining the validity of the renal function test result is to determine the false positive and/or false negative of the renal function test result based on the content of cystin C in the blood. [3] The method according to item 2, wherein the above-mentioned determining step is determined by the renal function test based on the content of cystin C in the blood as a decrease in renal function, but the content of D-serine exceeds the above-mentioned threshold, Determined as a false positive. [4] The method according to item 2, wherein the above determination step is determined when the renal function test based on the blood cystatin C content is determined to be normal, but the D-serine content is lower than the above threshold It is false negative. [5] The method according to any one of items 1 to 4, wherein the content of D-serine and the content of cystin C in blood are measured in the same sample. [6] The method according to any one of items 1 to 5, wherein the above-mentioned subject is administered an agent of the immune system (steroids, tacrolimus, anti-CD20 antibodies, cycloheximide, MMF (mycophenolate mofetil, Mycophenolate mofetil), cyclosporine, etc.). [7] The method according to any one of items 1 to 6, wherein the subject judged to be false negative or true negative is treated with intervention. [8] The method as described in item 7, wherein the above-mentioned therapeutic intervention is selected from the group consisting of lifestyle improvement, diet guidance, blood pressure management, anemia management, electrolyte management, urinary toxin management, blood glucose management, immune management, and lipid management . [9] The method according to item 7 or 8, wherein as the above-mentioned therapeutic intervention, it comprises administering to the above-mentioned subject selected from diuretics, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, sympathetic nerve block Breaking agents, SGLT2 (sodium-dependent glucose transporters 2, sodium-glucose cotransporter 2) inhibitors, sulfonylureas, thiazolidine agents, biguanides, α-glucosidase inhibitors, glinide agents, insulin preparations , NRF2 (Nuclear factor erythroid 2-related factor 2, nuclear factor E2 related factor 2) activator, immunosuppressant, statin-based drugs, fibrate-based drugs, anemia treatment agents, erythropoietin preparations, HIF-1 (hypoxia- Inducible factor 1, hypoxia inducible factor 1) inhibitors, iron agents, electrolyte regulators, calcium receptor agonists, phosphorus adsorbents, urotoxin adsorbents, DPP4 (Dipeptidyl peptidase 4, dipeptidyl peptidase 4) inhibition Agents, EPA (Eicosapentaenoic Acid) preparations, nicotinic acid derivatives, cholesterol transporter inhibitors, and PCSK9 (Proprotein convertase subtilisin/kexin type 9, proprotein convertase subtilisin/kexin type 9) inhibitors At least one medicine in the group. [10] A sample analysis system that includes a memory unit, an input unit, an analysis and measurement unit, a data processing unit, and an output unit, which verifies the validity of the renal function test results based on the content of cystin C, and includes : The memory part memorizes the threshold value of D-serine content input from the input part, The memory part remembers the renal function test results based on the cystatin C content in the blood input from the input part, The analysis and measurement department separates and quantifies D-serine in the blood sample, The data processing unit compares the D-serine content with the threshold value of the D-serine content memorized in the memory unit to determine the appropriateness of the renal function test results stored in the memory unit based on the blood cystin C content Judgement, The output unit outputs the validity of the renal function test result based on the content of cystin C in the blood. [11] A sample analysis system that includes a memory unit, an input unit, an analysis and measurement unit, a data processing unit, and an output unit, which verifies the validity of the renal function test results based on the content of cystin C, and includes : The memory part memorizes the threshold value of D-serine content input from the input part, The memory part remembers the renal function test results based on the cystatin C content in the blood input from the input part, The analysis and measurement department separates and quantifies D-serine in the blood sample, The data processing unit compares the D-serine content with the threshold value of the D-serine content memorized in the memory unit to determine the appropriateness of the renal function test results stored in the memory unit based on the blood cystin C content Judgement, The output unit outputs the validity of the renal function test result based on the content of cystin C in the blood. [12] The sample analysis system described in item 11, wherein the validity of the renal function test result is judged by the false positive and/or false negative of the renal function test result based on the content of cystin C in the blood. [13] The sample analysis system according to item 12, wherein the above-mentioned determination is based on the determination of decreased renal function by renal function test based on the content of cystin C in the blood, but the content of D-serine is lower than the above-mentioned threshold In the case, it is judged as false positive. [14] The sample analysis system according to item 12, wherein the above determination is when it is determined to be normal by renal function test based on the content of cystin C in the blood, but the content of D-serine is higher than the above threshold , Identified as false negative. [15] The sample analysis system according to any one of items 10 to 14, wherein the content of D-serine and the content of cystin C in blood are measured in the same sample. [16] A program that enables an information processing device including an input unit, an output unit, a data processing unit, and a memory unit to determine the validity of a renal function test result based on the content of cystin C in the blood, and includes Make the above information processing device execute the following commands: Make the memory part memorize the threshold value of D-serine content input from the input part, Make the memory part memorize the renal function test results based on the content of cystin C in the blood input from the input part, To memorize the D-serine content in the blood sample input from the input unit, Read out the D-serine content and the threshold value of D-serine content memorized in the memory unit, use the data processing unit to compare and make the memory unit memorize the comparison result of whether it is above the threshold or below the threshold, Read the renal function test results based on the content of cystin C in the blood and the results of the comparison stored in the memory unit to determine the validity of the renal function test results and make the memory unit memorize it. Make the output unit output the validity of the memory. [17] A program that enables an information processing device including an input unit, an output unit, a data processing unit, and a memory unit to determine the validity of a renal function test result based on the content of cystin C in the blood, and includes Make the above information processing device execute the following commands: Make the memory part remember the threshold value of the cystin C content in the blood input from the input part, To memorize the cystatin C content in the blood sample input from the input unit, Make the memory part memorize the threshold value of D-serine content input from the input part, To memorize the D-serine content in the blood sample input from the input unit, Read the blood cystatin C content and the blood cystatin C content threshold value memorized in the memory part, compare it with the data processing part, and make the memory part memorize the renal function test results based on the cystin C content, Read the D-serine content and the threshold value of D-serine content memorized in the memory unit, compare the results with the data processing unit, and make the memory unit memorize the comparison result. Read the renal function test results based on the content of cystin C in the blood and the results of the comparison stored in the memory unit to determine the validity of the renal function test results and make the memory unit memorize it. Make the output unit output the validity of the memory. [Effects of Invention]

本發明藉由對根據血液中之胱蛋白C含量之腎功能判定配合使用對GFR(菊糖清除率)關聯性更高之D-絲胺酸含量，可判定根據血液中之胱蛋白C含量之腎功能判定之妥當性。In the present invention, the determination of renal function based on the content of cystin C in the blood and the use of D-serine content, which has a higher correlation with GFR (inulin clearance rate), can be determined based on the content of cystin C in the blood. The adequacy of renal function determination.

本發明係關於一種檢定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性之方法。更具體而言，本發明之檢定方法包括以下步驟： 對接受了根據血液中之胱蛋白C含量之腎功能檢查之對象的血液中之D-絲胺酸含量進行測定之步驟、 將D-絲胺酸含量與特定之閾值進行比較之步驟、 確定根據血液中之胱蛋白C含量之腎功能檢查之結果之妥當性之步驟。The present invention relates to a method for determining the validity of the results of renal function tests based on the content of cystatin C in the blood. More specifically, the verification method of the present invention includes the following steps: Steps for measuring the D-serine content in the blood of subjects who have undergone a renal function test based on the content of cystin C in the blood, Steps to compare the content of D-serine with a specific threshold, Steps to determine the validity of the results of renal function tests based on the content of cystin C in the blood.

於一態樣中，檢定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性之方法係關於一種確定根據血液中之胱蛋白C含量之腎功能檢查結果之偽陰性或偽陽性之方法。確定偽陰性或偽陽性之步驟如下：於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，但D-絲胺酸含量低於上述閾值之情形時，可確定為偽陽性，或者，於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為正常，但D-絲胺酸含量高於上述閾值之情形時，可確定為偽陰性。In one aspect, the method for determining the validity of a renal function test result based on the content of cystin C in the blood relates to a method for determining the false negative or false positive result of the renal function test based on the content of cystatin C in the blood . The steps for determining false negatives or false positives are as follows: when the renal function is determined to be decreased by the renal function test based on the blood cystatin C content, but the D-serine content is lower than the above threshold, it can be determined as false Positive, or, when the renal function test based on the cystin C content in the blood is determined to be normal, but the D-serine content is higher than the above threshold, it can be determined to be false negative.

於本發明之另一態樣中，檢定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性之方法亦可為確定根據血液中之胱蛋白C含量之腎功能檢查結果之真陰性或真陽性之方法。確定真陰性或真陽性之步驟如下：於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，而D-絲胺酸含量高於上述閾值之情形時，可確定為真陽性，或者，於根據血液中之胱蛋白C含量之腎功能檢查判定為正常，而D-絲胺酸含量低於上述閾值之情形時，可確定為真陰性。In another aspect of the present invention, the method for determining the validity of the renal function test result based on the cystin C content in the blood can also be to determine whether the renal function test result based on the cystin C content in the blood is true negative or The method of true masculine. The steps to determine true negative or true positive are as follows: when the renal function is determined to be decreased by the renal function test based on the blood cystatin C content, and the D-serine content is higher than the above threshold, it can be determined as true Positive, or, when the renal function test based on the cystin C content in the blood is determined to be normal, and the D-serine content is below the above threshold, it can be determined as true negative.

於本發明中，被用作指標之D-絲胺酸係作為構成蛋白質之胺基酸之L-絲胺酸之光學異構物。D-絲胺酸含量主要藉由絲胺酸消旋酶或D-胺基酸氧化酶等代謝酶於各組織或血液中被嚴格控制，但於產生腎損傷之情形時，血液中之D-絲胺酸含量發生變動。In the present invention, D-serine used as an indicator is an optical isomer of L-serine, which is an amino acid constituting a protein. The content of D-serine is strictly controlled in various tissues or blood by metabolic enzymes such as serine racemase or D-amino acid oxidase. However, in the case of kidney injury, D- in the blood The serine content changes.

於本發明中，「血液中之D-絲胺酸含量」可指特定之血液量中之D-絲胺酸含量，亦可以濃度表示。血液中之D-絲胺酸含量係作為於所採集之血液中進行過離心分離、沈澱分離、或用以進行分析之預處理後之試樣中之量而測定者。因此，血液中之D-絲胺酸含量可作為所採集之全血、血清、血漿等來自血液之血液試樣中之量而測定。作為一例，於使用HPLC(High Performance Liquid Chromatography，高效液相層析法)進行分析之情形時，特定量之血液中所包含之D-絲胺酸含量係以層析圖表示，可藉由關於波峰之高度、面積、形狀與標準品進行之比較或藉由校準進行之分析進行定量。D-絲胺酸濃度係可藉由與已知樣品之比較而測定血液中之D-絲胺酸含量，可使用血液中之D-絲胺酸濃度作為血液中之D-絲胺酸含量。又，酵素法可藉由使用標準品之校準曲線的定量分析而算出胺基酸濃度。In the present invention, "the content of D-serine in blood" can refer to the content of D-serine in a specific blood volume, or it can be expressed by concentration. The content of D-serine in blood is measured as the amount in the sample after centrifugation, precipitation separation, or pretreatment for analysis in the collected blood. Therefore, the content of D-serine in blood can be measured as the amount of collected blood, serum, plasma, and other blood samples. As an example, when using HPLC (High Performance Liquid Chromatography, high performance liquid chromatography) for analysis, the content of D-serine contained in a specific amount of blood is represented by a chromatogram. The height, area, and shape of the wave peak are compared with standard products or quantified by analysis by calibration. The concentration of D-serine can be determined by comparing with known samples. The concentration of D-serine in blood can be used as the content of D-serine in blood. In addition, the enzyme method can calculate the amino acid concentration by quantitative analysis using the calibration curve of the standard.

關於用以進行修正之公式，作為一例，可根據對GFR(菊糖清除率)之關聯性而確定。可藉由將受驗者之D-絲胺酸含量代入根據菊糖清除率與血液中之D-絲胺酸含量之關聯性所算出之公式或圖表而進行確定。菊糖清除率可為經體表面積修正之菊糖清除率，亦可為體表面積修正前之菊糖清除率。可視需要選擇體表面積修正前與修正後之腎絲球濾過能力之任一者。Regarding the formula for correction, as an example, it can be determined based on the correlation to GFR (inulin clearance rate). It can be determined by substituting the subject's D-serine content into a formula or graph calculated based on the correlation between the inulin clearance rate and the blood D-serine content. The inulin clearance rate can be the inulin clearance rate after body surface area correction, or the inulin clearance rate before body surface area correction. Optionally, select one of the glomerular filtration capacity before and after correction of the body surface area.

D-絲胺酸含量可藉由任意方法進行測定，例如可藉由使用手性管柱層析法之測定、或使用酵素法之測定、以及使用識別胺基酸之光學異構物之單株抗體之免疫學方法進行定量。本發明中之試樣中之D-絲胺酸含量之測定可使用業者熟知之任何方法實施。例如有層析法或酵素法(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)、抗體法(T. Ohgusu et al., Analytical Biochemistry, 357 (2006), 15.,等)、氣相層析法(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)、毛細管電泳法(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)、高效液相層析法(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)。The content of D-serine can be measured by any method, for example, it can be measured by using chiral column chromatography, or by enzyme method, and by using individual plants that recognize optical isomers of amino acids Quantification of antibodies by immunological methods. The measurement of the D-serine content in the sample in the present invention can be carried out by any method well known to the industry. For example, there are chromatography or enzyme method (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., WG 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 method (T. Ohgusu et al., Analytical Biochemistry, 357 (2006), 15., etc.), gas chromatography (GC) (H. Hasegawa et al., Journal of Mass Spectrometry, 46 (2011) , 502., MC 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., MC Waldhier et al., Journal of Chromatography A, 1218 (2011), 4537. etc. ), capillary electrophoresis (CE) ( H. Miao et al., Analytical Chemistry, 77 (2005), 7190., DL 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., SA Fuchs et al., Clinical Chemistry, 54 (2008), 1443., D. Gordes et al., Amino Acids, 40 (2011), 553., D . Jin et al., Analyti cal Biochemistry, 269 (1999), 124., JZ Min et al., Journal of Chromatography B, 879 (2011), 3220., T. Sakamoto et al., Analytical and Bioanalytical Chemistry, 408 (2016), 517., WF 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., RJ Reischl et al., Journal of Chromatography A, 1218 (2011), 8379., RJ 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.).

本發明中之光學異構物之分離分析系統亦可將複數種分離分析加以組合。更具體而言，可藉由使用光學異構物之分析方法測定試樣中之D-/L-胺基酸含量(專利第4291628號)，該光學異構物之分析方法之特徵在於包含如下步驟：將包含具有光學異構物之成分之試樣與作為流動相之第一液體一併通入作為固定相之第一管柱填充劑中，而將上述試樣之上述成分分離之步驟；將上述試樣之上述成分各者個別地保持於多環單元中之步驟；將上述多環單元中個別地保持之上述試樣之上述成分各者與作為流動相之第二液體一併通過流路供給至作為固定相之具有光學活性中心之第二管柱填充劑中，而將上述試樣之成分各者中所包含之上述光學異構物分離之步驟；及檢測出上述試樣之成分各者中所包含之上述光學異構物之步驟。HPLC分析中存在預先利用鄰苯二甲醛(OPA)或4-氟-7-硝基-2,1,3-苯并㗁二唑(NBD-F)之類的螢光試劑使D-及L-胺基酸衍生物化，或使用N-第三丁氧基羰基-L-半胱胺酸(Boc-L-Cys)等進行非鏡像異構物化之情形(濱瀨健司及財津潔、分析化學、第53卷、677-690(2004))。作為替代，可藉由免疫學方法測定D-胺基酸，該免疫學方法使用識別胺基酸之光學異構物之單株抗體，例如特異地鍵結於D-絲胺酸、L-絲胺酸等之單株抗體。又，於將D體及L體之合計量作為指標之情形時，無需將D體及L體分離而進行分析，亦可不區別D體及L體而對胺基酸進行分析。於該情形時，亦可藉由酵素法、抗體法、GC、CE、HPLC進行分離及定量。The separation and analysis system for optical isomers in the present invention can also combine a plurality of kinds of separation analysis. More specifically, the D-/L-amino acid content in a sample can be determined by using an analysis method of optical isomers (Patent No. 4,291,628). The analysis method of optical isomers is characterized by including the following Step: pass the sample containing the components with optical isomers and the first liquid as the mobile phase into the first column filler as the stationary phase together to separate the above components of the sample; The step of individually holding each of the above-mentioned components of the above-mentioned sample in a multi-ring unit; passing each of the above-mentioned components of the above-mentioned sample separately held in the above-mentioned multi-ring unit together with the second liquid as the mobile phase The process of supplying the second column filler with optically active center as a stationary phase to separate the optical isomers contained in each of the components of the sample; and detecting the components of the sample The steps of the above-mentioned optical isomers included in each. In the HPLC analysis, there is a fluorescent reagent such as o-phthalaldehyde (OPA) or 4-fluoro-7-nitro-2,1,3-benzodiazole (NBD-F) to make D- and L -Amino acid derivation, or diastereoisomerization using N-tert-butoxycarbonyl-L-cysteine (Boc-L-Cys), etc. (Hamase Kenji and Zaizuki, Analytical Chemistry , Volume 53, 677-690 (2004)). As an alternative, D-amino acids can be determined by immunological methods, which use monoclonal antibodies that recognize optical isomers of amino acids, such as specifically bound to D-serine, L-siline Monoclonal antibodies such as amino acids. In addition, when the total amount of the D body and the L body is used as an index, it is not necessary to separate the D body and the L body for analysis, and it is also possible to analyze the amino acid without distinguishing the D body and the L body. In this case, separation and quantification can also be performed by enzyme method, antibody method, GC, CE, and HPLC.

於本發明中，作為檢定對象之胱蛋白C係自全身之有核細胞以一定比率產生之分子量為13 kDa之蛋白質，全部經腎絲球過濾後經過腎小管之再吸收而於腎臟中被分解。由於與濾過率相應地自血液中去除，故而使用血液中之胱蛋白C含量、或根據血液中之胱蛋白C含量推算之腎絲球濾過率作為腎功能之指標。在日本開發有以菊糖清除率為標準之推算式。然而，已知血液中之胱蛋白C含量會因體格之影響、或有無疾患或藥劑投予而發生變動。又，亦已知於腎功能高度降低之情形時，血液中之胱蛋白C含量會停止上升，即便為標準之對象，若為30 mL/分鐘/1.73m2 以下之值，則亦無法進行正確之評價。In the present invention, cystin C, which is the test object, is a protein with a molecular weight of 13 kDa produced at a certain ratio from nucleated cells of the whole body. After filtration by the glomerulus, it is reabsorbed in the renal tubules and then decomposed in the kidney. . Since it is removed from the blood corresponding to the filtration rate, the cystin C content in the blood or the glomerular filtration rate calculated from the cystin C content in the blood is used as an indicator of renal function. A calculation formula based on the inulin clearance rate has been developed in Japan. However, it is known that the content of cystin C in the blood may change due to the influence of physical fitness, the presence or absence of disease or the administration of drugs. In addition, it is also known that when the kidney function is highly reduced, the cystatin C content in the blood will stop rising. Even if it is a standard object, if the value is less than 30 mL/min/1.73m 2 , it will not be correct. The evaluation.

如上所述，雖然關於根據血液中之胱蛋白C含量之腎功能檢查報告有問題，但根據迄今為止通用之實績，於健康診斷中，腎功能檢查多採用血液中之胱蛋白C含量及/或基於血液中之胱蛋白C含量之推算腎絲球濾過率。例如於使用血液中之胱蛋白C含量之情形時，若為男性，則將0.95 mg/L設為閾值，若為女性，則將0.87 mg/L設為閾值，若高於閾值，則判定為腎功能降低，若低於閾值，則判定為正常。又，於使用推算腎絲球濾過率之情形時，在日本根據以菊糖清除率為標準之推算式計算推算腎絲球濾過率，閾值使用60.0 mL/分鐘/1.73 m2 ，若低於該閾值，則判定為腎功能降低，若高於該閾值，則判定為正常。血液中之胱蛋白C含量及推算腎絲球濾過率中表示腎功能降低之閾值有時會因學會主導之調查等而發生變更，並不意欲侷限於上述數值。直接受體格之影響之血液中之胱蛋白C含量自不必說，即便為根據年齡與性別進行了修正之推算腎絲球濾過率之情形時，若為罹患疾病或被投予了藥劑之特殊受驗者，則亦會產生偽陽性之問題及偽陰性之問題。存在由於健康診斷等一次篩查之結果中包含偽陰性之結果而漏診初期之腎臟病之實際情況。由於腎功能基本一旦喪失便無望恢復，故而對於初期之腎臟病，較佳為不漏過偽陰性地判定腎功能。又，於包含偽陽性之情形時，對象通常接受二次檢查，故而將根據其他症狀或標記物等之值綜合性地對腎臟病進行判斷，但對於個別腎功能之確定推薦測定菊糖清除率，不僅對象之負擔大，醫療相關者之負擔亦較大。如上所述，胱蛋白C之測定範圍較窄，故而於顯示腎功能降低之對象中，判定為陰性之可能性較高。另一方面，血液中之D-絲胺酸含量即便於腎功能降低時亦於輕度～高度之較廣範圍內對菊糖清除率之關聯性較高，可判定胱蛋白C檢查之偽陰性。又，胱蛋白C含量受體格之影響較大亦是導致偽陰性、偽陽性之原因，另一方面，血液中之D-絲胺酸未顯示出對體表面積(BSA)之關聯性，無論於何種體格之對象中，導致偽陰性、偽陽性之可能性均較低。As mentioned above, although there are problems with the report of the renal function test based on the content of cystin C in the blood, according to the general results so far, in the health diagnosis, the renal function test mostly uses the content of cystin C in the blood and/or Calculate the glomerular filtration rate based on the content of cystin C in the blood. For example, when using the cystin C content in the blood, if it is a male, set 0.95 mg/L as the threshold; if it is a female, set 0.87 mg/L as the threshold; if it is higher than the threshold, it is judged as Decreased renal function, if it is lower than the threshold, it is judged as normal. In addition, when the estimated glomerular filtration rate is used, in Japan, the estimated glomerular filtration rate is calculated based on the calculation formula based on the inulin clearance rate. The threshold is 60.0 mL/min/1.73 m 2 , if it is lower than this If the threshold value is lower, it is judged that the renal function is decreased, and if it is higher than the threshold value, it is judged as normal. The blood cystatin C content and the estimated glomerular filtration rate, which indicate reduced renal function, may sometimes change due to investigations led by the society, and it is not intended to be limited to the above values. Needless to say, the content of cystin C in the blood that is directly affected by the receptors, even when the glomerular filtration rate is estimated based on age and gender, if it is a disease or a drug that has been administered If tested, there will also be false positives and false negatives. There are actual cases of missed initial kidney disease due to false negative results in a screening result such as health diagnosis. Since renal function is basically lost, there is no hope of recovery. Therefore, for early kidney disease, it is better to judge renal function without missing false negatives. In addition, when false positives are included, subjects usually undergo a second examination. Therefore, kidney disease will be comprehensively judged based on the values of other symptoms or markers. However, it is recommended to measure the inulin clearance rate for the determination of individual renal function. , Not only the burden of the subject is large, but also the burden of the medical related parties. As mentioned above, the measurement range of cystin C is relatively narrow, so in subjects showing decreased renal function, the possibility of being judged as negative is higher. On the other hand, the D-serine content in the blood has a high correlation with the inulin clearance rate in a wide range from mild to high even when the renal function is reduced, and it can be judged that the cystin C test is false negative . In addition, the greater influence of the cystatin C content receptor grid is also the cause of false negatives and false positives. On the other hand, D-serine in the blood shows no correlation with body surface area (BSA), regardless of In any physique, the possibility of false negative and false positive is low.

於本發明中，根據血液中之胱蛋白C含量之腎功能檢查可為使用血液中之胱蛋白C含量之檢查，亦可為利用根據血液中之胱蛋白C含量推導之數值之檢查。作為根據血液中之胱蛋白C含量推導之數值，其一例為推算腎絲球濾過率，但並不意欲限定於此。所謂接受了根據血液中之胱蛋白C含量之腎功能檢查之對象，可預先接受根據血液中之胱蛋白C含量之腎功能檢查，亦可同時接受。所謂同時接受腎功能檢查，可使用同一天採集之同一血液試樣或不同之血液試樣進行檢查，亦可使用另一天採集之血液試樣進行檢查。In the present invention, the renal function test based on the content of cystin C in the blood can be a test using the content of cystin C in the blood, or an examination using a value derived from the content of cystin C in the blood. As a value derived from the content of cystin C in the blood, one example is to estimate the glomerular filtration rate, but it is not intended to be limited to this. The so-called subjects who have undergone a renal function test based on the content of cystin C in the blood may undergo a renal function test based on the content of cystin C in the blood in advance, or at the same time. The so-called simultaneous renal function test can be performed with the same blood sample or different blood samples collected on the same day, or a blood sample collected on another day.

雖不意欲進行理論限定，但血液中之D-絲胺酸含量之優點在於：與血液中之胱蛋白C含量不同而受體格之影響較少，而且與血液中之胱蛋白C含量相比，對菊糖清除率之關聯性較高。因此，血液中之D-絲胺酸含量可解決先前之藉由健康診斷等所測得之血液中之胱蛋白C含量、或基於血液中之胱蛋白C含量之推算腎絲球濾過率所伴有之偽陽性或偽陰性之問題。Although it is not intended to be theoretically limited, the advantage of the content of D-serine in blood is that it is different from the content of cystin C in the blood and has less influence on the receptor, and compared with the content of cystin C in the blood, The correlation to inulin clearance rate is relatively high. Therefore, the D-serine content in the blood can solve the previous cystin C content in the blood measured by health diagnosis, or the estimated glomerular filtration rate based on the cystin C content in the blood. There are false positives or false negatives.

於本發明中，偽陽性係指第一種過失。具體而言指如下情況：於根據血液中之胱蛋白C含量及/或基於血液中之胱蛋白C含量之推算腎絲球濾過率的檢查中被判定為陽性(即腎功能降低)，但實際上未患腎功能降低。偽陰性係指第二種過失。具體而言指如下情況：於根據血液中之胱蛋白C含量及/或基於血液中之胱蛋白C含量之推算腎絲球濾過率的檢查中被判定為陰性(即腎功能正常)，但實際上患有腎功能降低。雖不意欲限定於理論，但被投予了如類固醇或環孢素之作用於免疫之藥劑之對象於根據血液中之胱蛋白C含量及/或基於血液中之胱蛋白C含量之推算腎絲球濾過率的檢查中偽陽性之可能性增加。關於偽陽性及偽陰性、以及真陽性及真陰性，可藉由參照下述表格而容易地理解。 [表1]    實際狀態(腎功能降低) 有 無 檢查結果 陽性 真陽性 偽陽性(第一種過失) 陰性 偽陰性(第二種過失) 真陰性 In the present invention, false positive refers to the first type of negligence. Specifically, it refers to the following situation: it is judged to be positive in the examination based on the cystatin C content in the blood and/or the estimated glomerular filtration rate based on the cystatin C content in the blood (ie, the renal function is reduced), but the actual She did not suffer from decreased renal function. False negative refers to the second type of negligence. Specifically, it refers to the following conditions: in the examination based on the cystatin C content in the blood and/or the estimated glomerular filtration rate based on the cystatin C content in the blood, it is judged to be negative (that is, the renal function is normal), but the actual Suffering from decreased renal function. Although not intended to be limited to theory, subjects who have been administered immune-acting agents such as steroids or cyclosporine are estimated to be based on the blood cystatin C content and/or based on the blood cystatin C content. The possibility of false positives in the examination of the ball filtration rate increases. Regarding false positives and false negatives, and true positives and true negatives, it can be easily understood by referring to the following table. [Table 1] Actual status (decreased kidney function) Have no test result Positive True positive False positive (first type of negligence) Negative False negative (second negligence) True negative

偽陽性之確定係藉由如下方式進行：於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，但D-絲胺酸含量低於上述閾值之情形時，確定為偽陽性。偽陰性之確定係藉由如下方式進行：於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為正常，但D-絲胺酸含量高於上述閾值之情形時，確定為偽陰性。該等閾值可不因對象之要素，例如性別、年齡、體重等之區別而使用1個值，亦可根據區別分別確定。The determination of false positive is performed by the following method: when the renal function is determined to be decreased by renal function test based on the content of cystin C in the blood, but the content of D-serine is lower than the above threshold, it is determined as false Positive. The determination of the false negative is carried out by the following method: when the renal function test based on the cystin C content in the blood is determined to be normal, but the D-serine content is higher than the above threshold, it is determined to be a false negative. These thresholds may not be based on differences in the elements of the object, such as gender, age, weight, etc., using one value, and may also be determined separately based on differences.

於本發明中，檢定偽陽性或偽陰性之方法亦可換稱作檢定真陽性或真陰性之方法。具體而言藉由如下方式進行：於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，而D-絲胺酸含量超過上述閾值之情形時，確定為真陽性。真陰性之確定係藉由如下方式進行：於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為正常，而D-絲胺酸含量高於上述閾值之情形時，確定為真陰性。In the present invention, the method of detecting false positive or false negative can also be changed to the method of detecting true positive or true negative. Specifically, it is performed by the following method: when the renal function is determined to be decreased by the renal function test based on the cystin C content in the blood, and the D-serine content exceeds the above threshold, it is determined as a true positive. The determination of the true negative is performed by the following method: when the renal function test based on the cystin C content in the blood is determined to be normal, and the D-serine content is higher than the above threshold, it is determined to be a true negative.

本發明之檢定方法係針對接受了根據血液中之胱蛋白C含量之腎功能檢查之對象的血液試樣而進行，該血液試樣可為與為了測定血液中之胱蛋白C含量所使用之血液試樣相同之試樣，亦可為於與為了測定血液中之胱蛋白C含量所使用之血液試樣不同之時間點所採集之試樣。The assay method of the present invention is performed on a blood sample of a subject who has undergone a renal function test based on the content of cystin C in the blood. The blood sample may be the same as the blood used to determine the content of cystin C in the blood. The same sample may also be a sample collected at a time point different from the blood sample used for measuring the cystatin C content in the blood.

本發明之妥當性之檢定方法係藉由與閾值之比較進行，故而不包含醫師之判斷。藉由根據本發明之檢定方法之結果，醫師可更加準確地對腎臟病進行診斷。因此，本發明之檢定方法係診斷之預備方法或診斷之輔助方法。本發明之方法可由醫師以外者、例如血液之分析業者、健康診斷業者、資料處理公司、分析系統、及分析程式等實施。於本發明之進而另一態樣中，亦可關於一種利用本發明之妥當性之研究方法對腎功能或腎臟病進行診斷之方法。The validity verification method of the present invention is performed by comparison with a threshold value, so it does not include the judgment of the physician. With the result of the verification method according to the present invention, the doctor can diagnose kidney disease more accurately. Therefore, the test method of the present invention is a preliminary method for diagnosis or an auxiliary method for diagnosis. The method of the present invention can be implemented by persons other than physicians, such as blood analysis companies, health diagnosis companies, data processing companies, analysis systems, and analysis programs. In yet another aspect of the present invention, it can also be related to a method for diagnosing renal function or kidney disease using the appropriate research method of the present invention.

於藉由本發明之偽陽性及偽陰性之檢定判定為腎功能降低之情形時，為了防止腎功能進一步惡化，早期治療或保健指導尤為有效。保健指導主要是對生活習慣改善、飲食指導、血壓管理、血糖值管理、及脂質管理等獨立地或組合地進行指導。作為飲食指導，進行減鹽及蛋白質限制。作為血壓管理，可以成為130/80 mmHg以下之方式進行管理。關於血糖值，進行管理直至Hba1c未達6.9%。脂質管理係以成為LDL-C未達120 mg/dL之方式進行管理。作為生活習慣改善，推薦禁煙及減輕體重至BMI(Body Mass Index，身體質量指數)值未達25等。When it is determined by the false positive and false negative tests of the present invention that the renal function is reduced, in order to prevent further deterioration of the renal function, early treatment or health care guidance is particularly effective. Health guidance is mainly to provide guidance on lifestyle improvement, diet guidance, blood pressure management, blood sugar level management, and lipid management, independently or in combination. As a dietary guide, carry out salt reduction and protein restriction. As blood pressure management, it can be managed in a way below 130/80 mmHg. Regarding the blood glucose level, management was performed until Hba1c did not reach 6.9%. Lipid management is managed so that LDL-C does not reach 120 mg/dL. As a lifestyle improvement, it is recommended to ban smoking and reduce weight until the BMI (Body Mass Index) value does not reach 25.

於判定為腎功能降低之情形時，亦可進行治療介入。作為治療介入，獨立地或組合地進行血壓管理、血糖值管理、貧血管理、電解質管理、尿毒素管理、免疫管理及脂質管理等。其中，尤其關於血壓管理、血糖值管理、貧血管理、電解質管理、尿毒素管理、免疫管理、脂質管理，可藉由給藥進行治療。作為血壓管理，以成為130/80 mmHg以下之方式進行管理，可視情況投予高血壓治療劑。作為高血壓治療劑，可使用利尿劑(噻嗪系利尿劑，例如三***、苯甲基氫***、氫***；類噻嗪系利尿劑，例如美替克侖、吲達帕胺、曲帕胺、美夫西特；亨氏環利尿劑，例如利尿磺胺；留鉀利尿劑-醛固酮拮抗劑，例如胺苯喋啶、螺內酯、依普利酮)、鈣拮抗劑(二氫吡啶系，例如硝苯地平、胺氯地平、依福地平、西尼地平、尼卡地平、尼索地平、尼群地平、尼伐地平、巴尼地平、非洛地平、貝尼地平、馬尼地平、阿折地平、阿雷地平、苯并噻氮呯系、地爾硫卓)、血管緊張素轉化酶抑制劑(卡托普利、依那普利、阿拉普利、地拉普利、西拉普利、賴諾普利、貝那普利、咪達普利、替莫普利、喹那普利、群多普利、培哚普利)、血管緊張素受體拮抗劑(血管緊張素II受體拮抗劑，例如洛沙坦、坎地沙坦、纈沙坦、替米沙坦、奧美沙坦、厄貝沙坦、阿齊沙坦)、交感神經阻斷劑(β阻斷劑，例如阿替洛爾、比索洛爾、倍他洛爾、美托洛爾、醋丁洛爾、塞利洛爾、普萘洛爾、納多洛爾、卡替洛爾、品多洛爾、尼普地洛、氨磺洛爾、阿羅洛爾、卡維地洛、拉貝洛爾、貝凡洛爾、烏拉地爾、特拉唑嗪、哌唑嗪、多沙唑嗪、布那唑嗪)等。作為貧血治療劑，可使用紅血球生成素製劑、鐵劑、HIF-1抑制劑等。作為電解質調整劑，可使用鈣受體促效劑(西那卡塞、依他卡西肽等)、磷吸附劑。作為尿毒素吸附劑，可使用活性碳等。關於血糖值，以成為Hba1c未達6.9%之方式進行管理，視情況投予降血糖劑。作為降血糖劑，可使用SGLT2抑制劑(依普列淨、達格列淨、魯格列淨、托格列淨、坎格列淨、恩格列淨等)、DPP4抑制劑(磷酸西格列汀、維格列汀、沙格列汀、阿格列汀、利拉列汀、特力列汀、曲格列汀、阿拉格列汀、奧格列汀)、磺醯脲劑(甲苯磺丁脲、乙醯苯磺醯環己脲、氯磺丙脲、格列吡脲、格列本脲、格列齊特、格列美脲等)、噻唑啶劑(皮利酮等)、雙胍劑(二甲雙胍、丁雙胍等)、α-葡萄糖苷酶抑制劑(阿卡波糖、伏格列波糖、米格列醇等)、格列奈劑(那格列奈、米格列奈、瑞格列奈)胰島素製劑、NRF2活化劑(甲基巴多索隆等)等。作為免疫管理，可使用免疫抑制劑(類固醇類、他克莫司、抗CD20抗體、放線菌酮、麥考酚酸酯(MMF)等)。脂質管理係以成為LDL-C未達120 mg/dL之方式進行管理，視情況可使用脂質異常症治療劑、例如他汀系藥劑(瑞舒伐他汀、匹伐他汀、阿托伐他汀、西立伐他汀、氟伐他汀、辛伐他汀、普伐他汀、洛伐他汀、美伐他汀等)、貝特系藥劑(安妥明、苯紮貝特、非諾貝特、克利貝特)、菸鹼酸衍生物(生育酚菸鹼酸酯、尼可莫耳、菸鹼酸戊四醇酯)、膽固醇轉運蛋白抑制劑(依折麥布)、PCSK9抑制劑(依洛尤單抗(Evolocumab)等)、EPA製劑等。所有藥劑之劑型均既可為單劑，亦可為合劑。於腎功能嚴重降低而危及生命預後之情形時，實施腹膜透析、血液透析、持續性血液過濾透析、血液離析(血漿更換、血漿吸附等)或如腎移植般之腎替代療法。When it is determined that the renal function is reduced, therapeutic intervention can also be performed. As a therapeutic intervention, blood pressure management, blood glucose level management, anemia management, electrolyte management, urinary toxin management, immune management, lipid management, etc. are performed independently or in combination. Among them, in particular, blood pressure management, blood sugar level management, anemia management, electrolyte management, urinary toxin management, immune management, and lipid management can be treated by administration. As blood pressure management, management is performed so that it becomes 130/80 mmHg or less, and hypertension treatment agents are administered as appropriate. As the therapeutic agent for hypertension, diuretics (thiazide diuretics, such as trichlorothiazide, benzyl hydrochlorothiazide, and hydrochlorothiazide; thiazide-like diuretics, such as meteclan, indapamide, tripa Amine, Mefuxide; Heinz's ring diuretics, such as diuretic sulfonamide; potassium-saving diuretics-aldosterone antagonists, such as triamterene, spironolactone, eplerenone), calcium antagonists (dihydropyridine series, such as nitrate Bendipine, Amlodipine, Ifodipine, Cinidipine, Nicardipine, Nisoldipine, Nitrendipine, Nilvadipine, Barnidipine, Felodipine, Benidipine, Manidipine, Azeldipine , Aredipine, benzothiazepine, diltiazem), angiotensin converting enzyme inhibitors (captopril, enalapril, alapril, delapril, cilazapril, lisinopril) Li, benazepril, imidapril, temopril, quinapril, trandolapril, perindopril), angiotensin receptor antagonists (angiotensin II receptor antagonists, Such as Losartan, Candesartan, Valsartan, Telmisartan, Olmesartan, Irbesartan, Azilsartan), sympathetic nerve blockers (beta blockers, such as atenolol , Bisoprolol, betaxolol, metoprolol, acebutolol, celilolol, propranolol, nadolol, carteolol, pindolol, nipradiol, Amisulol, arolol, carvedilol, labetalol, bevanolol, urapidil, terazosin, prazosin, doxazosin, bunazosin) and the like. As therapeutic agents for anemia, erythropoietin preparations, iron agents, HIF-1 inhibitors, etc. can be used. As the electrolyte regulator, calcium receptor agonists (cinacalcet, eptakacitide, etc.) and phosphorus adsorbents can be used. As the urotoxin adsorbent, activated carbon or the like can be used. Regarding the blood glucose level, it is managed so that Hba1c is less than 6.9%, and hypoglycemic agents are administered as appropriate. As a hypoglycemic agent, SGLT2 inhibitors (Eprilegliflozin, Dapagliflozin, Lupagliflozin, Togliflozin, Canagliflozin, Enpagliflozin, etc.), DPP4 inhibitors (sieggliflozin phosphate, etc.) can be used Lietagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, triagliptin, troxagliptin, alatagliptin, ologliptin), sulfonylurea (toluene Butyuramide, acetophenone, cyclohexyl urea, chlorpropamide, glipizide, glibenclamide, gliclazide, glimepiride, etc.), thiazolidine (Pelridone, etc.), biguanide Agents (metformin, buformin, etc.), α-glucosidase inhibitors (acarbose, voglibose, miglitol, etc.), glinide agents (nateglinide, mitiglinide, etc.) Repaglinide) insulin preparations, NRF2 activators (bardoxolone methyl, etc.), etc. As immune management, immunosuppressive agents (steroids, tacrolimus, anti-CD20 antibodies, cycloheximide, mycophenolate mofetil (MMF), etc.) can be used. Lipid management is managed in such a way that LDL-C does not reach 120 mg/dL. Depending on the situation, treatment agents for dyslipidemia, such as statin drugs (rosuvastatin, pitavastatin, atorvastatin, ceriva Vastatin, fluvastatin, simvastatin, pravastatin, lovastatin, mevastatin, etc.), fibrate-based drugs (antuomin, bezafibrate, fenofibrate, clefibrate), nicotine Acid derivatives (tocopherol nicotinate, nicomol, pentaerythritol nicotinate), cholesterol transporter inhibitor (ezetimibe), PCSK9 inhibitor (Evolocumab), etc. ), EPA preparations, etc. The dosage forms of all medicines can be single or mixture. When the kidney function is severely reduced and the prognosis of life is threatened, peritoneal dialysis, hemodialysis, continuous hemofiltration dialysis, hemodialysis (plasma exchange, plasma adsorption, etc.) or renal replacement therapy like kidney transplantation is performed.

於本發明之另一態樣中，亦可關於一種執行檢定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性之方法的試樣分析系統或程式。圖4係本發明之試樣分析系統之構成圖。圖4所示之試樣分析系統10係以可實施本發明之檢定根據血液中之胱蛋白C含量之腎功能檢查結果之偽陰性及偽陽性之方法的方式構成。此種試樣分析系統10包含記憶部11、輸入部12、分析測定部13、資料處理部14、及輸出部15，可對血液試樣進行分析，並針對根據血液中之胱蛋白C含量之腎功能檢查結果輸出妥當性、即真陰性、真陽性、偽陰性、或偽陽性。In another aspect of the present invention, it can also be related to a sample analysis system or program for performing a method for determining the validity of a renal function test result based on the content of cystatin C in the blood. Figure 4 is a structural diagram of the sample analysis system of the present invention. The sample analysis system 10 shown in FIG. 4 is constructed in such a manner that the method of the present invention can be implemented to determine the false negative and false positive results of the renal function test based on the content of cystatin C in the blood. Such a sample analysis system 10 includes a memory unit 11, an input unit 12, an analysis and measurement unit 13, a data processing unit 14, and an output unit 15, which can analyze blood samples, and target the results according to the content of cystin C in the blood. The output validity of the renal function test result is true negative, true positive, false negative, or false positive.

更具體而言，於本發明之試樣分析系統10中， 記憶部11可記憶自輸入部12所輸入之D-絲胺酸含量之閾值， 記憶部11可記憶自輸入部12所輸入之根據血液中之胱蛋白C含量之腎功能檢查結果， 分析測定部13可對血液試樣中之D-絲胺酸進行分離定量， 資料處理部14可將D-絲胺酸含量與記憶部中所記憶之D-絲胺酸含量之閾值進行比較而對記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性進行判定， 輸出部15可輸出根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性。More specifically, in the sample analysis system 10 of the present invention, The memory part 11 can memorize the threshold value of the D-serine content input from the input part 12, The memory unit 11 can memorize the renal function test results based on the content of cystin C in the blood input from the input unit 12, The analysis and measurement unit 13 can separate and quantify D-serine in the blood sample, The data processing unit 14 can compare the D-serine content with the threshold value of the D-serine content memorized in the memory unit to compare the renal function test results stored in the memory unit based on the blood cystin C content To determine the appropriateness of The output unit 15 can output the validity of the renal function test result based on the cystatin C content in the blood.

於進而較佳之態樣中，本發明之試樣分析系統亦可包含分析測定部13確定血液試樣中之胱蛋白C含量之步驟代替記憶部11記憶自輸入部12所輸入之根據血液中之胱蛋白C含量之腎功能檢查結果之步驟。於該情形時，亦可進而包含資料處理部14根據血液試樣中之胱蛋白C含量對腎功能檢查之結果進行判定，記憶部記憶判定之結果之步驟。於該情形時，記憶部11預先記憶自輸入部12所輸入之關於血液中之胱蛋白C含量之閾值，資料處理部14將血液中之胱蛋白C含量與所記憶之關於血液中之胱蛋白C含量之閾值進行比較，藉此對腎功能檢查之結果進行判定。In a further preferred aspect, the sample analysis system of the present invention may also include the step of determining the cystatin C content in the blood sample by the analysis and measurement unit 13 instead of the memory unit 11 memorizing the input from the input unit 12 according to the blood Steps of renal function test results of cystatin C content. In this case, the data processing unit 14 may further determine the result of the renal function test based on the cystatin C content in the blood sample, and the memory unit may memorize the result of the determination. In this case, the memory unit 11 previously memorizes the threshold value of the cystin C content in the blood input from the input unit 12, and the data processing unit 14 compares the cystin C content in the blood with the stored cystin C content in the blood. The threshold of C content is compared to judge the result of renal function test.

更具體而言，於某一態樣之本發明之試樣分析系統10中， 記憶部11可記憶自輸入部12所輸入之血液中之胱蛋白C含量之閾值， 記憶部11可記憶自輸入部12所輸入之D-絲胺酸含量之閾值， 分析測定部13可測定血液試樣中之胱蛋白C含量， 資料處理部14可將記憶部中所記憶之血液中之胱蛋白C含量之閾值與血液試樣中之胱蛋白C含量進行比較而對根據血液中之胱蛋白C含量之腎功能檢查結果進行判定， 分析測定部13可對血液試樣中之D-絲胺酸進行分離定量， 資料處理部14可將血液中之D-絲胺酸含量與記憶部中所記憶之D-絲胺酸含量之閾值進行比較而對根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性進行判定， 輸出部15可輸出根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性。More specifically, in a certain aspect of the sample analysis system 10 of the present invention, The memory unit 11 can memorize the threshold value of the cystatin C content in the blood input from the input unit 12, The memory part 11 can memorize the threshold value of the D-serine content input from the input part 12, The analysis measurement unit 13 can measure the cystatin C content in the blood sample, The data processing unit 14 can compare the threshold value of the cystin C content in the blood stored in the memory unit with the cystin C content in the blood sample to determine the result of the renal function test based on the cystin C content in the blood , The analysis and measurement unit 13 can separate and quantify D-serine in the blood sample, The data processing unit 14 can compare the D-serine content in the blood with the threshold value of the D-serine content memorized in the memory unit to determine the validity of the renal function test result based on the cystin C content in the blood Make judgments, The output unit 15 can output the validity of the renal function test result based on the cystatin C content in the blood.

作為血液中之胱蛋白C含量，亦可使用根據血液中之胱蛋白C含量推導之數值(例如推算腎絲球濾過率)。作為一例，於使用根據血液中之胱蛋白C含量推導之數值之情形時，亦可包含如下步驟：記憶部11記憶自輸入部12所輸入之對象之年齡及性別等其他要素，進而記憶算出根據血液中之胱蛋白C含量推導之數值之公式或圖表，資料處理部14根據如下者算出數值：所測得之血液中之胱蛋白C含量、記憶部11中所記憶之對象之年齡及性別等其他要素、及算出根據血液中之胱蛋白C含量推導之數值的公式或圖表。作為推算腎絲球濾過率之閾值，可使用60 mL/min/1.73 m2 作為一例。As the content of cystin C in the blood, a value derived from the content of cystin C in the blood can also be used (for example, the estimated glomerular filtration rate). As an example, when a value derived from the content of cystatin C in the blood is used, the following steps may also be included: the memory unit 11 memorizes the age and gender of the object input from the input unit 12, and then memorizes the calculation based on Formula or graph of the value derived from the content of cystin C in the blood, the data processing unit 14 calculates the value based on the following: the measured content of cystin C in the blood, the age and gender of the object memorized in the memory unit 11, etc. Other factors, and formulas or graphs to calculate values derived from the content of cystatin C in the blood. As a threshold for estimating the glomerular filtration rate, 60 mL/min/1.73 m 2 can be used as an example.

更具體而言，於使用推算腎絲球濾過率之情形時，於本發明之試樣分析系統10中， 記憶部11可記憶自輸入部12所輸入之基於血液中之胱蛋白C含量之推算腎絲球濾過率之算出式， 記憶部11可記憶自輸入部12所輸入之受驗者之年齡及性別， 記憶部11可記憶自輸入部12所輸入之基於血液中之胱蛋白C含量之推算腎絲球濾過率之閾值， 記憶部11可記憶自輸入部12所輸入之D-絲胺酸含量之閾值， 分析測定部13可測定血液試樣中之胱蛋白C含量， 資料處理部14可根據血液中之胱蛋白C含量、記憶部中所記憶之受驗者之年齡、性別、及推算腎絲球濾過率之算出式算出推算腎絲球濾過率， 資料處理部14可將記憶部中所記憶之推算腎絲球濾過率之閾值與所算出之推算腎絲球濾過率進行比較而對根據血液中之胱蛋白C含量之腎功能檢查結果進行判定， 分析測定部13可對血液試樣中之D-絲胺酸進行分離定量， 資料處理部14可將血液中之D-絲胺酸含量與記憶部中所記憶之D-絲胺酸含量之閾值進行比較而對根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性進行判定， 輸出部15可輸出根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性。More specifically, when the estimated glomerular filtration rate is used, in the sample analysis system 10 of the present invention, The memory unit 11 can memorize the calculation formula of the estimated glomerular filtration rate based on the cystatin C content in the blood input from the input unit 12, The memory unit 11 can memorize the age and gender of the subject input from the input unit 12, The memory unit 11 can memorize the threshold value of the estimated glomerular filtration rate based on the cystatin C content in the blood input from the input unit 12, The memory part 11 can memorize the threshold value of the D-serine content input from the input part 12, The analysis measurement unit 13 can measure the cystatin C content in the blood sample, The data processing unit 14 can calculate the estimated glomerular filtration rate based on the cystatin C content in the blood, the age and sex of the subject memorized in the memory unit, and the calculation formula for the estimated glomerular filtration rate, The data processing unit 14 can compare the threshold value of the estimated glomerular filtration rate stored in the memory unit with the calculated estimated glomerular filtration rate to determine the result of the renal function test based on the content of cystin C in the blood, The analysis and measurement unit 13 can separate and quantify D-serine in the blood sample, The data processing unit 14 can compare the D-serine content in the blood with the threshold value of the D-serine content memorized in the memory unit to determine the validity of the renal function test result based on the cystin C content in the blood Make judgments, The output unit 15 can output the validity of the renal function test result based on the cystatin C content in the blood.

於資料處理部14中，腎功能檢查之結果之妥當性係藉由D-絲胺酸含量與其閾值之比較確定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性。具體而言，於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，但D-絲胺酸含量低於上述閾值之情形時，可確定為偽陽性，於D-絲胺酸含量高於上述閾值之情形時，可確定為真陽性。另一方面，於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為正常，但D-絲胺酸含量高於上述閾值之情形時，可確定為偽陰性，於D-絲胺酸含量低於上述閾值之情形時，可確定為真陰性。In the data processing unit 14, the validity of the result of the renal function test is determined by comparing the D-serine content with its threshold value to determine the validity of the result of the renal function test based on the cystin C content in the blood. Specifically, when the renal function is determined to be decreased by the renal function test based on the blood cystatin C content, but the D-serine content is lower than the above threshold, it can be determined as a false positive. When the amino acid content is higher than the above threshold, it can be determined as a true positive. On the other hand, when the renal function test based on the cystin C content in the blood is judged to be normal, but the D-serine content is higher than the above threshold, it can be determined as a false negative. When the content is lower than the above threshold, it can be determined as true negative.

記憶部11具有RAM(Random Access Memory，隨機存取記憶體)、ROM(Read Only Memory，唯讀記憶體)、快閃記憶體等記憶體裝置，硬碟驅動機等固定磁碟裝置，或軟碟、光碟等可搬用之記憶裝置等。記憶部記憶藉由分析測定部所測得之資料、自輸入部所輸入之資料及指示、藉由資料處理部進行之運算處理結果等，此外，還記憶用於資訊處理裝置之各種處理的電腦程式、資料庫等。電腦程式亦可經由例如CD-ROM(Compact Disc-Read Only Memory，唯讀光碟)、DVD-ROM(Digital Versatile Disc-Read Only Memory，唯讀數位多功能光碟)等電腦可讀取之記錄媒體、或網際網路進行安裝。電腦程式係使用公知之設置程式等安裝於記憶部。記憶部可記憶預先自輸入部12所輸入之D-絲胺酸含量之閾值、根據血液中之胱蛋白C含量之腎功能檢查結果。進而，可記憶用於腎功能檢查之血液中之胱蛋白C含量之閾值。又，於使用推算腎絲球濾過率代替血液中之胱蛋白C含量之情形時，亦可記憶推算腎絲球濾過率之閾值，進而可記憶基於血液中之胱蛋白C含量之推算腎絲球濾過率之算出式，又，可記憶受驗者之年齡、性別。又，亦記憶分析測定部13所測得之結果、或資料處理部14所進行之處理之結果。The memory section 11 has RAM (Random Access Memory), ROM (Read Only Memory), flash memory and other memory devices, hard disk drives and other fixed disk devices, or soft Portable memory devices such as discs, optical discs, etc. The memory unit stores the data measured by the analysis and measurement unit, the data and instructions input from the input unit, the results of calculation processing by the data processing unit, etc., and also stores the computer used for various processing of the information processing device Programs, databases, etc. Computer programs can also be accessed through computer-readable recording media such as CD-ROM (Compact Disc-Read Only Memory), DVD-ROM (Digital Versatile Disc-Read Only Memory), etc. Or the Internet for installation. The computer program is installed in the memory using a well-known setup program. The memory unit can memorize the threshold value of D-serine content inputted from the input unit 12 in advance, and the renal function test result based on the cystin C content in the blood. Furthermore, the threshold value of cystin C content in blood used for renal function test can be memorized. In addition, when the estimated glomerular filtration rate is used to replace the cystatin C content in the blood, the threshold for the estimated glomerular filtration rate can also be memorized, and then the estimated glomerulus based on the cystatin C content in the blood can be memorized The calculation formula of the filtration rate can also memorize the age and gender of the subject. In addition, the result measured by the analysis measurement unit 13 or the result of the processing performed by the data processing unit 14 is also memorized.

輸入部12為介面等，亦包含鍵盤、滑鼠等操作部。藉此，輸入部可輸入藉由分析測定部13所測得之資料、藉由資料處理部14進行之運算處理之指示等。又，於例如分析測定部13位於外部之情形時，輸入部12亦可與操作部分開地包含可經由網路或記憶媒體輸入所測得之資料等之介面部。The input part 12 is an interface, etc., and also includes operation parts such as a keyboard and a mouse. Thereby, the input unit can input the data measured by the analysis measurement unit 13 and the instruction of the calculation processing by the data processing unit 14 and the like. In addition, for example, when the analysis and measurement unit 13 is located outside, the input unit 12 may also include an interface that can input measured data via a network or a storage medium separately from the operation part.

分析測定部13進行血液試樣中之D-絲胺酸之測定步驟。因此，分析測定部13具有可進行胺基酸之D體及L體之分離及測定之構成。胺基酸可逐個進行分析，亦可對一部分或全部種類之胺基酸一起分析。雖不意欲限定於以下者，但分析測定部13例如可為具備試樣導入部、光學分割管柱、檢測部之手性層析系統、較佳為高效液相層析系統。就僅檢測出特定之胺基酸含量之觀點而言，亦可藉由酵素法或免疫學方法實施。分析測定部13亦可與試樣分析系統分開地構成，亦可使用網路或記憶媒體經由輸入部12輸入所測得之資料等。進而，於另一態樣中，分析測定部13亦可測定血液中之胱蛋白C含量。The analysis measurement unit 13 performs a measurement step of D-serine in the blood sample. Therefore, the analysis and measurement unit 13 has a configuration capable of separating and measuring the D-body and the L-body of the amino acid. Amino acids can be analyzed one by one, or part or all of the amino acids can be analyzed together. Although not intended to be limited to the following, the analysis measurement unit 13 may be, for example, a chiral chromatography system equipped with a sample introduction unit, an optical segmentation column, and a detection unit, preferably a high performance liquid chromatography system. From the viewpoint of detecting only a specific amino acid content, it can also be implemented by an enzyme method or an immunological method. The analysis measurement unit 13 may also be configured separately from the sample analysis system, or the measured data and the like may be input through the input unit 12 using a network or a storage medium. Furthermore, in another aspect, the analysis and measurement unit 13 may also measure the cystatin C content in the blood.

資料處理部14依照記憶部中所記憶之程式對藉由分析測定部13所測得並記憶於記憶部11之資料執行各種運算處理。運算處理係藉由資料處理部中所包含之處理器或CPU(Central Processing Unit，中央處理單元)進行。該處理器或CPU包含控制分析測定部13、輸入部12、記憶部11、及輸出部15之功能模組，可進行各種控制。該等各部亦可分別由獨立之積體電路、微處理器、韌體等構成。資料處理部14將D-絲胺酸含量與記憶部中所記憶之D-絲胺酸含量之閾值進行比較而對記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果的妥當性進行判定。於另一態樣中，資料處理部14可根據血液中之胱蛋白C含量、記憶部中所記憶之受驗者之年齡、性別、及推算腎絲球濾過率之算出式而算出推算腎絲球濾過率。於該情形時，資料處理部14進而可將記憶部中所記憶之推算腎絲球濾過率之閾值與所算出之推算腎絲球濾過率進行比較並進行根據血液中之胱蛋白C含量之腎功能檢查結果之判定。The data processing unit 14 performs various arithmetic processing on the data measured by the analysis measurement unit 13 and stored in the memory unit 11 in accordance with the program stored in the memory unit. The arithmetic processing is performed by a processor or a CPU (Central Processing Unit) included in the data processing unit. The processor or CPU includes functional modules that control the analysis measurement unit 13, the input unit 12, the storage unit 11, and the output unit 15, and can perform various controls. These parts can also be composed of independent integrated circuits, microprocessors, firmware, etc. The data processing unit 14 compares the D-serine content with the threshold value of the D-serine content memorized in the memory unit, and compares the renal function test results stored in the memory unit based on the blood cystin C content Appropriateness is judged. In another aspect, the data processing unit 14 can calculate the estimated renal filaments based on the cystatin C content in the blood, the age and sex of the subject memorized in the memory unit, and the calculation formula for the estimated glomerular filtration rate. Ball filtration rate. In this case, the data processing unit 14 can further compare the threshold value of the estimated glomerular filtration rate memorized in the memory unit with the calculated estimated glomerular filtration rate, and perform a kidney analysis based on the cystin C content in the blood. Judgment of the result of functional inspection.

輸出部15係以將藉由資料處理部所判定之根據血液中之胱蛋白C含量之腎功能檢查結果的妥當性，即真陰性、真陽性、偽陰性、或偽陽性輸出之方式構成。進而，輸出部15亦可將藉由分析測定部13所測得之D-絲胺酸含量、血液中之胱蛋白C含量、或藉由資料處理部14所算出之推算腎絲球濾過率與上述妥當性一併輸出。輸出部15可為直接顯示運算處理結果之液晶顯示器等顯示裝置、印表機等輸出機構，亦可為用以經由向外部記憶裝置之輸出或網路進行輸出之介面部。The output unit 15 is configured to output the validity of the renal function test result determined by the data processing unit based on the cystatin C content in the blood, that is, true negative, true positive, false negative, or false positive. Furthermore, the output unit 15 may also compare the D-serine content measured by the analysis and measurement unit 13, the cystin C content in the blood, or the estimated glomerular filtration rate calculated by the data processing unit 14 and The above-mentioned validity is output together. The output unit 15 may be an output mechanism such as a display device such as a liquid crystal display or a printer that directly displays the results of the calculation processing, or may be an interface for output through an output to an external memory device or a network.

圖5係表示利用本發明之程式之用以確定腎絲球濾過率之動作之例的流程圖。具體而言，本發明之程式係使包含輸入部、輸出部、資料處理部、記憶部之資訊處理裝置確定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性的程式。本發明之程式包含用以使上述資訊處理裝置執行以下內容之指令： 使記憶部記憶自輸入部所輸入之D-絲胺酸含量之閾值， 使記憶部記憶自輸入部所輸入之根據血液中之胱蛋白C含量之腎功能檢查結果， 使記憶自輸入部所輸入之血液試樣中之D-絲胺酸含量， 讀出記憶部中所記憶之D-絲胺酸含量及D-絲胺酸含量之閾值，利用資料處理部進行比較，並使記憶部記憶關於高於閾值還是低於閾值之比較結果， 讀出記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果及比較之結果，判定腎功能檢查之結果之妥當性並使記憶部記憶， 使輸出部輸出所記憶之妥當性。 本發明之程式可儲存於記憶媒體中，亦可經由網際網路或LAN(Local Area Network，區域網路)等電氣通信線路提供。FIG. 5 is a flowchart showing an example of the action used to determine the glomerular filtration rate using the program of the present invention. Specifically, the program of the present invention is a program for an information processing device including an input unit, an output unit, a data processing unit, and a memory unit to determine the validity of the renal function test result based on the cystin C content in the blood. The program of the present invention includes commands for causing the information processing device to execute the following: Make the memory part memorize the threshold value of D-serine content input from the input part, Make the memory part memorize the renal function test results based on the content of cystin C in the blood input from the input part, To memorize the D-serine content in the blood sample input from the input unit, Read out the D-serine content and the threshold value of D-serine content memorized in the memory unit, compare them with the data processing unit, and make the memory unit memorize the comparison result of whether it is above the threshold or below the threshold, Read the renal function test results based on the content of cystin C in the blood and the results of the comparison stored in the memory unit to determine the validity of the renal function test results and make the memory unit memorize it. Make the output unit output the validity of the memory. The program of the present invention can be stored in a memory medium, and can also be provided via electrical communication lines such as the Internet or LAN (Local Area Network).

腎功能檢查之結果之妥當性係基於腎功能檢查之結果及比較之結果所確定。具體而言，於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，但D-絲胺酸含量低於上述閾值之情形時，可確定為偽陽性，於D-絲胺酸含量高於上述閾值之情形時，可確定為真陽性。另一方面，於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為正常，但D-絲胺酸含量高於上述閾值之情形時，可確定為偽陰性，於D-絲胺酸含量低於上述閾值之情形時，可確定為真陰性。The validity of the results of the renal function test is determined based on the results of the renal function test and the results of comparison. Specifically, when the renal function is determined to be decreased by the renal function test based on the blood cystatin C content, but the D-serine content is lower than the above threshold, it can be determined as a false positive. When the amino acid content is higher than the above threshold, it can be determined as a true positive. On the other hand, when the renal function test based on the cystin C content in the blood is judged to be normal, but the D-serine content is higher than the above threshold, it can be determined as a false negative. When the content is lower than the above threshold, it can be determined as true negative.

本發明之程式亦可包含如下指令代替自輸入部12輸入根據血液中之胱蛋白C含量之腎功能檢查結果：藉由自輸入部12輸入血液中之胱蛋白C含量，而資料處理部14將其與記憶部11中所記憶之血液中之胱蛋白C含量之閾值進行比較而判定腎功能檢查之結果。The program of the present invention may also include the following command instead of inputting the renal function test result based on the cystatin C content in the blood from the input part 12: by inputting the cystatin C content in the blood from the input part 12, the data processing part 14 will It is compared with the threshold value of the cystin C content in the blood stored in the memory unit 11 to determine the result of the renal function test.

更具體而言，本發明之程式亦可為包含以下指令代替使記憶部11記憶自輸入部12所輸入之根據血液中之胱蛋白C含量之腎功能檢查結果之指令的程式： 使記憶部11記憶自輸入部12所輸入之血液中之胱蛋白C含量之閾值， 使記憶部11記憶自輸入部12所輸入之血液中之胱蛋白C含量， 讀出記憶部11中所記憶之血液中之胱蛋白C含量及血液中之胱蛋白C含量之閾值，利用資料處理部14進行比較，根據高於閾值還是低於閾值判定腎功能檢查之結果並使記憶部11記憶腎功能檢查之結果。More specifically, the program of the present invention can also be a program that includes the following commands instead of the commands for the memory unit 11 to memorize the renal function test results based on the blood cystatin C content inputted from the input unit 12: Make the memory unit 11 memorize the threshold value of the cystatin C content in the blood input from the input unit 12, To make the memory part 11 memorize the content of cystin C in the blood input from the input part 12, Read the cystatin C content in the blood and the threshold value of the cystatin C content in the blood stored in the memory unit 11, compare it with the data processing unit 14, and determine the result of the renal function test based on whether it is higher or lower than the threshold. Make the memory unit 11 memorize the results of the renal function test.

於資訊處理裝置具備分析測定部13之情形時，亦可包含如下指令代替自輸入部12輸入根據血液中之胱蛋白C含量之腎功能檢查結果：使分析測定部13對血液試樣中之D-絲胺酸含量進行分離定量，資料處理部14將其與記憶部11中所記憶之血液中之胱蛋白C含量之閾值進行比較，藉此判定腎功能檢查之結果。When the information processing device is equipped with the analysis and measurement unit 13, the following command may be included instead of inputting the renal function test result based on the cystin C content in the blood from the input unit 12: the analysis and measurement unit 13 is required to determine the D in the blood sample. -The serine content is separated and quantified, and the data processing unit 14 compares it with the threshold value of the cystin C content in the blood stored in the memory unit 11 to determine the result of the renal function test.

更具體而言，本發明之程式亦可為包含以下指令代替使記憶部11記憶自輸入部12所輸入之根據血液中之胱蛋白C含量之腎功能檢查結果之指令的程式： 使記憶部11記憶自輸入部12所輸入之血液中之胱蛋白C含量之閾值， 使分析測定部13作動而測定血液中之胱蛋白C含量，並使記憶部11記憶， 讀出記憶部11中所記憶之血液中之胱蛋白C含量及血液中之胱蛋白C含量之閾值，利用資料處理部14進行比較而判定腎功能檢查之結果，並使記憶部11記憶腎功能檢查之結果。More specifically, the program of the present invention can also be a program that includes the following commands instead of the commands for the memory unit 11 to memorize the renal function test results based on the blood cystatin C content inputted from the input unit 12: Make the memory unit 11 memorize the threshold value of the cystatin C content in the blood input from the input unit 12, The analysis and measurement unit 13 is activated to measure the cystatin C content in the blood, and the memory unit 11 is memorized, Read the blood cystatin C content and the blood cystatin C content threshold value memorized in the memory unit 11, compare with the data processing unit 14 to determine the result of the renal function test, and make the memory unit 11 remember the renal function The result of the inspection.

亦可利用使用根據血液中之胱蛋白C含量算出之推算腎絲球濾過率代替血液中之胱蛋白C含量之程式。於該情形時，亦可進而包含如下指令代替使記憶部記憶自輸入部所輸入之推算腎絲球濾過率之指令： 使記憶部11記憶自輸入部12所輸入之受驗者之年齡、性別， 使記憶部11記憶自輸入部12所輸入之基於血液中之胱蛋白C含量之推算腎絲球濾過率之算出式， 使分析測定部13測定血液試樣中之胱蛋白C含量並使記憶部11記憶， 使資料處理部將記憶部中所記憶之年齡、性別、及血液中之胱蛋白C含量代入算出式而算出推算腎絲球濾過率，並使記憶部11記憶。It is also possible to use a program that uses the estimated glomerular filtration rate calculated based on the cystatin C content in the blood to replace the cystatin C content in the blood. In this case, the following command may be included instead of the command to make the memory unit memorize the estimated glomerular filtration rate input from the input unit: Make the memory unit 11 memorize the age and sex of the subject input from the input unit 12, Make the memory unit 11 memorize the calculation formula of the estimated glomerular filtration rate based on the cystin C content in the blood input from the input unit 12, Make the analysis measurement unit 13 measure the content of cystin C in the blood sample and make the memory unit 11 memorize it, The data processing unit substitutes the age, gender, and cystatin C content in the blood stored in the memory unit into the calculation formula to calculate the estimated glomerular filtration rate, and the memory unit 11 memorizes it.

本說明書中所提及之全部文獻均藉由引用而整體併入至本說明書中。All documents mentioned in this specification are incorporated into this specification as a whole by reference.

以下所說明之本發明之實施例之目的僅在於例示，不對本發明之技術範圍進行限定。本發明之技術範圍僅由申請專利範圍之記載進行限定。在不脫離本發明之主旨之條件下可進行本發明之變更，例如本發明之構成要件之追加、刪除及置換。 [實施例]The purpose of the embodiments of the present invention described below is only to illustrate, and does not limit the technical scope of the present invention. The technical scope of the present invention is limited only by the description of the scope of patent application. Modifications of the present invention, such as addition, deletion, and replacement of constituent elements of the present invention, can be made without departing from the spirit of the present invention. [Example]

受驗者集合 自由以診斷及/或治療為目的於2016年～2017年間在大阪大學醫學部附屬醫院腎臟內科(Department of Nephrology，Osaka University Hospital)住院之慢性腎臟病(CKD)患者所組成之群組中選擇11名患者用於回溯性研究。此外，在國立醫藥基礎、健康、營養研究所採用15名20歲以上之健康志願者。試驗協議得到了各機構之倫理委員會之承認，且自所有受驗者處取得了書面形式之知情同意。Subject Set Free to choose from a group of patients with chronic kidney disease (CKD) hospitalized in the Department of Nephrology, Osaka University Hospital between 2016 and 2017 for the purpose of diagnosis and/or treatment11 One patient was used for retrospective study. In addition, 15 healthy volunteers over the age of 20 are employed in the National Institute of Medicine, Health, and Nutrition. The trial protocol was recognized by the ethics committees of various institutions, and written informed consent was obtained from all subjects.

健康者及慢性腎臟病患者之資訊如下所述。 [表2] 表2 受驗者之基線特徵    健康受驗者 n＝15 CKD患者 (n＝11) P值 年齡 44(39-50) 50(40-65) 0.232 男性比例(%) 80(12) 45.5(5). 0.103 身高(m) 1.70(1.68-1.75) 1.63(1.59-1.66) 0.043 體重(kg) 68.9(61.0-73.5) 59.8(51.5-66.7) 0.194 BSA(m2 ) 1.80(1.72-1.90) 1.61(1.54-1.75) 0.102 BMI(kg/m2 ) 22.6(21.1-25.7) 22.5(19.3-24.2) 0.452 血清肌酸酐(mg/dL) 0.75(0.68-0.83) 1.14(0.75-2.59) 0.069 血清胱蛋白C(mg/L) 0.78(0.69-0.84) 1.14(0.87-2.11) 0.005 菊糖清除率 (mL/min/1.73m2 ) 97.0(94.1-107.3) 46.0(19.8-66.9) ＜0.001 值係以中央值(IQR)或%(計數)表示 Information for healthy people and chronic kidney disease patients is as follows. [Table 2] Table 2 Baseline characteristics of subjects Healthy subjects n=15 CKD patients (n=11) P value age 44(39-50) 50(40-65) 0.232 Male ratio (%) 80(12) 45.5(5). 0.103 Height (m) 1.70(1.68-1.75) 1.63(1.59-1.66) 0.043 Weight (kg) 68.9(61.0-73.5) 59.8(51.5-66.7) 0.194 BSA(m 2 ) 1.80 (1.72-1.90) 1.61(1.54-1.75) 0.102 BMI(kg/m 2 ) 22.6 (21.1-25.7) 22.5(19.3-24.2) 0.452 Serum creatinine (mg/dL) 0.75(0.68-0.83) 1.14(0.75-2.59) 0.069 Serum Cystatin C (mg/L) 0.78 (0.69-0.84) 1.14(0.87-2.11) 0.005 Inulin clearance rate (mL/min/1.73m 2 ) 97.0 (94.1-107.3) 46.0(19.8-66.9) ＜0.001 The value is expressed as the median value (IQR) or% (count)

菊糖腎臟清除率之計測方法 依照Clin Exp Nephrol 13, 50-54(2009)中所記載之標準方法，根據血漿及尿之菊糖濃度、以及尿體積計算出受驗者之菊糖清除率(Cin)。簡而言之，於禁食、延期服藥、及水負荷環境下在2小時之1%之菊糖(INULEAD INJ.：富士藥品股份有限公司)之持續靜脈內點滴期間於3個不同之時間點採集血液及尿樣。受驗者於點滴開始30分鐘前經口喝下500 mL水。為了維持水負荷，菊糖點滴開始後於40分鐘、60分鐘、90分鐘喝下60 mL水。點滴之初始速度於最初30分鐘為300 mL/h，於之後的90分鐘設為100 mL/h。菊糖點滴開始後，於45分鐘、75分鐘、及105分鐘採集血液試樣。受驗者於點滴開始後30分鐘以將膀胱完全排空之方式進行排尿。繼而，於30分鐘～60分鐘之間、60分鐘～90分鐘之間、及90分鐘～120分鐘之間採集尿樣。菊糖係使用酵素法進行計測。使用3個Cin值之平均值作為利用標準方法之Cin(Cin-ST)。Measurement method of renal clearance rate of inulin According to the standard method described in Clin Exp Nephrol 13, 50-54 (2009), the inulin clearance rate (Cin) of the subject was calculated based on the plasma and urine inulin concentration and urine volume. In short, the continuous intravenous drip of 1% inulin (INULEAD INJ.: Fuji Pharmaceutical Co., Ltd.) at 3 different time points under fasting, delayed medication, and water load environments for 2 hours Collect blood and urine samples. The subject drank 500 mL of water 30 minutes before the start of the instillation. In order to maintain the water load, 60 mL of water was drunk 40 minutes, 60 minutes, and 90 minutes after the inulin infusion started. The initial rate of instillation is 300 mL/h for the first 30 minutes and 100 mL/h for the next 90 minutes. After the inulin infusion started, blood samples were collected at 45 minutes, 75 minutes, and 105 minutes. The subject urinates by completely emptying the bladder 30 minutes after the start of the instillation. Then, urine samples are collected between 30 minutes and 60 minutes, between 60 minutes and 90 minutes, and between 90 minutes and 120 minutes. The inulin system is measured using the enzyme method. Use the average of 3 Cin values as Cin (Cin-ST) using the standard method.

血液中D-胺基酸之測定 樣品調整 以如下方式進行來自人類血漿之樣品調整。 向血漿中添加20倍體積之甲醇並完全地混合。離心後，將自甲醇勻漿所獲得之上清液之10 μL移至褐色管中，並於減壓下進行乾燥。對殘渣添加20 μL之200 mM硼酸鈉緩衝液(pH值8.0)及5 μL之螢光標記試劑(向無水MeCN中添加40 mM之4-氟-7-硝基-2,1,3-苯并㗁二唑(NBD-F))，繼而於60℃下加熱2分鐘。添加75 μl之0.1%TFA(trifluoroacetic acid，三氟乙酸)水溶液(v/v)使反應終止，繼而將2 μL之反應混合液供於二維HPLC。Determination of D-amino acid in blood Sample adjustment The adjustment of samples from human plasma is performed in the following manner. Add 20 times the volume of methanol to the plasma and mix thoroughly. After centrifugation, 10 μL of the supernatant obtained from the methanol homogenization was transferred to a brown tube and dried under reduced pressure. Add 20 μL of 200 mM sodium borate buffer (pH 8.0) and 5 μL of fluorescent labeling reagent to the residue (add 40 mM 4-fluoro-7-nitro-2,1,3-benzene to anhydrous MeCN And diazole (NBD-F)), and then heated at 60°C for 2 minutes. Add 75 μl of 0.1% TFA (trifluoroacetic acid, trifluoroacetic acid) aqueous solution (v/v) to terminate the reaction, and then supply 2 μL of the reaction mixture to two-dimensional HPLC.

藉由二維HPLC進行之胺基酸光學異構物之定量 使用以下之二維HPLC系統對胺基酸光學異構物進行定量。使用逆相管柱(KSAA RP，1.0 mmi.d. ×400 mm；資生堂股份有限公司)利用流動相(5～35%MeCN、0～20%THF、及0.05%TFA)將胺基酸之NBD(nitrobenzoxadiazole，硝基苯并㗁二唑)衍生物分離、溶出。管柱溫度設定為45℃，流動相之流速設定為25 μL/分鐘。使用多環閥分取所分離之胺基酸之組分，利用手性管柱(KSAACSP-001S，1.5 mmi.d.×250 mm；資生堂)連續地進行光學分割。作為流動相，視胺基酸之滯留情況使用包含檸檬酸(0～10 mM)或甲酸(0～4%)之MeOH-MeCN之混合用液。NBD-胺基酸係使用470 nm之激發光以530 nm進行螢光檢測。NBD-胺基酸之滯留時間係利用胺基酸光學異構物之標準品進行鑑定，並利用校準曲線進行定量。Quantification of amino acid optical isomers by two-dimensional HPLC The following two-dimensional HPLC system was used to quantify the optical isomers of amino acids. Use reverse phase column (KSAA RP, 1.0 mmi.d. ×400 mm; Shiseido Co., Ltd.) to use mobile phase (5～35% MeCN, 0～20% THF, and 0.05% TFA) to reduce the NBD of amino acid (Nitrobenzoxadiazole, nitrobenzoxadiazole) derivative separation and dissolution. The column temperature is set to 45°C, and the flow rate of the mobile phase is set to 25 μL/min. Use a multi-ring valve to separate the separated amino acid components, and use a chiral column (KSAACSP-001S, 1.5 mmi.d.×250 mm; Shiseido) for continuous optical separation. As the mobile phase, a MeOH-MeCN mixture containing citric acid (0-10 mM) or formic acid (0-4%) is used depending on the retention of amino acid. NBD-amino acid uses 470 nm excitation light and 530 nm for fluorescence detection. The retention time of NBD-amino acid is identified by the standard product of the optical isomer of amino acid and quantified by the calibration curve.

與GFR(菊糖清除率)之關聯分析 (1)經體表面積修正 對於26名受驗者，將進行了體表面積修正之GFR(菊糖清除率)與血液中之D-絲胺酸含量(A)、胱蛋白C含量(B)繪製成散佈圖並算出關聯係數r與p值。將結果示於圖1。顯示出對於GFR(菊糖清除率)而言，血液中之D-絲胺酸含量與血液中之胱蛋白C含量同等。又，於GFR(菊糖清除率) 為100以下(n＝21)之資料分析中，對血液中之D-絲胺酸含量與進行了體表面積修正之GFR(菊糖清除率)之關聯性、及血液中之胱蛋白C含量與進行了體表面積修正之GFR(菊糖清除率)之關聯性進行了分析。於GFR為100以下時，血液中之D-絲胺酸含量與GFR(菊糖清除率)之關聯係數r值及p值分別為-0.713及0.00042，血液中之胱蛋白C含量與GFR(菊糖清除率)之關聯係數r值及p值分別為-0.656及0.0013。顯示出於GFR為100以下時，血液中之D-絲胺酸含量與GFR(菊糖清除率)之關聯性高於血液中之胱蛋白C含量與GFR(菊糖清除率)之關聯性。Correlation analysis with GFR (inulin clearance rate) (1) Corrected by body surface area For 26 subjects, the GFR (inulin clearance rate) with body surface area correction and the blood D-serine content (A) and cystatin C content (B) were plotted as a scatter diagram and the correlation coefficient was calculated r and p values. The results are shown in Figure 1. It is shown that for GFR (inulin clearance rate), the content of D-serine in the blood is equivalent to the content of cystin C in the blood. In addition, in the analysis of data with GFR (inulin clearance) below 100 (n=21), the correlation between the content of D-serine in blood and GFR (inulin clearance) corrected for body surface area , And the correlation between cystatin C content in blood and GFR (inulin clearance rate) corrected for body surface area was analyzed. When the GFR is below 100, the correlation coefficient r and p values of the blood D-serine content and GFR (inulin clearance) are -0.713 and 0.00042, respectively, and the blood cystatin C content and GFR (chrysanthemum) The r value and p value of the correlation coefficient of sugar clearance rate are -0.656 and 0.0013, respectively. It shows that when GFR is below 100, the correlation between blood D-serine content and GFR (inulin clearance rate) is higher than the correlation between blood cystatin C content and GFR (inulin clearance rate).

(2)未經體表面積修正 對於26名受驗者，將未進行體表面積修正之GFR(菊糖清除率)與血液中之D-絲胺酸含量(A)、胱蛋白C含量(B)繪製成散佈圖並算出關聯係數r與p值。將結果示於圖2。顯示出與血液中之胱蛋白C含量相比而言，血液中之D-絲胺酸含量對未經體表面積修正之GFR(菊糖清除率)之關聯性高。(2) Without body surface area correction For 26 subjects, plot the GFR (inulin clearance rate) without body surface area correction and the blood D-serine content (A) and cystin C content (B) into a scatter diagram and calculate the correlation coefficient r and p values. The results are shown in Figure 2. It shows that compared with the content of cystin C in the blood, the content of D-serine in the blood has a high correlation with the GFR (inulin clearance rate) without body surface area correction.

與體表面積(BSA)之關聯 關於健康者(GFR＞70)之資料，將體表面積(BSA)與所測得之血液中之D-絲胺酸含量及胱蛋白C含量表示成散佈圖並算出關聯係數r值及p值。將結果示於圖3。胱蛋白C含量與體表面積相關聯，相對於此，血液中之D-絲胺酸含量與體表面積不相關。Correlation with body surface area (BSA) Regarding the data of healthy people (GFR>70), the body surface area (BSA) and the measured blood D-serine content and cystatin C content are expressed as a scatter diagram and the correlation coefficient r and p values are calculated. The results are shown in Figure 3. The content of cystin C is correlated with the body surface area. In contrast, the content of D-serine in the blood is not correlated with the body surface area.

10:試樣分析系統 11:記憶部 12:輸入部 13:分析測定部 14:資料處理部 15:輸出部 10: Sample analysis system 11: Memory Department 12: Input section 13: Analysis and Measurement Department 14: Data Processing Department 15: Output section

圖1係表示血液中之D-絲胺酸含量(A)及胱蛋白C含量(B)與GFR(菊糖清除率)(經體表面積修正)之散佈圖之圖表。 圖2係表示血液中之D-絲胺酸含量(A)及胱蛋白C含量(B)與GFR(菊糖清除率)(未經體表面積修正)之散佈圖之圖表。 圖3係表示血液中之D-絲胺酸含量(A)及胱蛋白C含量(B)與體表面積(BSA)之散佈圖之圖表。 圖4表示本發明之試樣分析系統之構成圖。 圖5係表示利用本發明之程式之用以檢定腎功能檢查結果之妥當性之動作之例的流程圖。Figure 1 is a graph showing the scatter diagram of blood D-serine content (A) and cystatin C content (B) and GFR (inulin clearance rate) (corrected by body surface area). Figure 2 is a graph showing the scatter diagram of blood D-serine content (A) and cystatin C content (B) and GFR (inulin clearance rate) (without body surface area correction). Figure 3 is a graph showing the scatter diagram of D-serine content (A) and cystatin C content (B) and body surface area (BSA) in blood. Fig. 4 shows the configuration diagram of the sample analysis system of the present invention. Fig. 5 is a flow chart showing an example of an operation for verifying the validity of a renal function test result using the program of the present invention.

Claims (13)

一種檢定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性之方法，其包括如下步驟： 對接受了根據血液中之胱蛋白C含量之腎功能檢查之對象的血液中之D-絲胺酸含量進行測定之步驟、 將D-絲胺酸含量與特定之閾值進行比較之步驟、及 確定根據血液中之胱蛋白C含量之腎功能檢查之結果之妥當性之步驟。A method for determining the validity of the renal function test results based on the content of cystin C in the blood, which includes the following steps: Steps for measuring the D-serine content in the blood of subjects who have undergone a renal function test based on the content of cystin C in the blood, Steps to compare the content of D-serine with a specific threshold, and Steps to determine the validity of the results of renal function tests based on the content of cystin C in the blood. 如請求項1之方法，其中檢定腎功能檢查結果之妥當性之方法係對根據血液中之胱蛋白C含量之腎功能檢查結果之偽陽性及/或偽陰性進行判定。Such as the method of claim 1, wherein the method for determining the validity of the renal function test results is to determine the false positive and/or false negative results of the renal function test based on the content of cystin C in the blood. 如請求項2之方法，其中上述確定步驟係於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，但D-絲胺酸含量低於上述閾值之情形時，確定為偽陽性。The method of claim 2, wherein the above-mentioned determining step is determined to be a case where the renal function is determined to be decreased by a renal function test based on the blood cystatin C content, but the D-serine content is lower than the above-mentioned threshold False positive. 如請求項2之方法，其中上述確定步驟係於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為正常，但D-絲胺酸含量高於上述閾值之情形時，確定為偽陰性。The method of claim 2, wherein the above determination step is determined as a false negative when the renal function test based on the content of cystin C in the blood is determined to be normal, but the D-serine content is higher than the above threshold . 如請求項1至4中任一項之方法，其中於同一樣品中測定D-絲胺酸含量及血液中之胱蛋白C含量。The method according to any one of claims 1 to 4, wherein the content of D-serine and the content of cystin C in blood are measured in the same sample. 如請求項1至5中任一項之方法，其中上述對象係被投予了作用於免疫系統之藥劑之對象。The method according to any one of claims 1 to 5, wherein the above-mentioned subject is a subject to which a drug that acts on the immune system is administered. 一種試樣分析系統，其係包含記憶部、輸入部、分析測定部、資料處理部、及輸出部，對根據胱蛋白C含量之腎功能檢查結果之妥當性進行檢定者，且包含： 記憶部記憶自輸入部所輸入之D-絲胺酸含量之閾值， 記憶部記憶自輸入部所輸入之根據血液中之胱蛋白C含量之腎功能檢查結果， 分析測定部對血液試樣中之D-絲胺酸進行分離定量， 資料處理部將D-絲胺酸含量與記憶部中所記憶之D-絲胺酸含量之閾值進行比較而對記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性進行判定， 輸出部輸出根據血液中之胱蛋白C含量之腎功能檢查之結果之妥當性。A sample analysis system, which includes a memory unit, an input unit, an analysis and measurement unit, a data processing unit, and an output unit, which verifies the validity of the renal function test results based on the content of cystin C, and includes: The memory part memorizes the threshold value of D-serine content input from the input part, The memory part remembers the renal function test results based on the cystatin C content in the blood input from the input part, The analysis and measurement department separates and quantifies D-serine in the blood sample, The data processing unit compares the D-serine content with the threshold value of the D-serine content memorized in the memory unit to determine the appropriateness of the renal function test results stored in the memory unit based on the blood cystin C content Judgement, The output unit outputs the validity of the results of the renal function test based on the content of cystin C in the blood. 如請求項7之試樣分析系統，其中腎功能檢查結果之妥當性之判定係對根據血液中之胱蛋白C含量之腎功能檢查結果之偽陽性及/或偽陰性進行判定。For example, in the sample analysis system of claim 7, the adequacy of the renal function test result is determined based on the false positive and/or false negative of the renal function test result based on the content of cystin C in the blood. 如請求項8之試樣分析系統，其中上述判定係於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為腎功能降低，但D-絲胺酸含量低於上述閾值之情形時，判定為偽陽性。Such as the sample analysis system of claim 8, wherein the above determination is when the renal function is determined to be decreased by the renal function test based on the cystin C content in the blood, but the D-serine content is lower than the above threshold, Determined as false positive. 如請求項8之試樣分析系統，其中上述判定係於藉由根據血液中之胱蛋白C含量之腎功能檢查判定為正常，但D-絲胺酸含量高於上述閾值之情形時，確定為偽陰性。Such as the sample analysis system of claim 8, wherein the above determination is determined to be normal by renal function tests based on the content of cystin C in the blood, but the D-serine content is higher than the above threshold False negative. 如請求項7至10中任一項之試樣分析系統，其中於同一樣品中測定D-絲胺酸含量及血液中之胱蛋白C含量。The sample analysis system of any one of claims 7 to 10, wherein the content of D-serine and the content of cystin C in blood are measured in the same sample. 一種程式，其係使包含輸入部、輸出部、資料處理部、及記憶部之資訊處理裝置確定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性者，且包含用以使上述資訊處理裝置執行以下內容之指令： 使記憶部記憶自輸入部所輸入之D-絲胺酸含量之閾值， 使記憶部記憶自輸入部所輸入之根據血液中之胱蛋白C含量之腎功能檢查之結果， 使記憶自輸入部所輸入之血液試樣中之D-絲胺酸含量， 讀出記憶部中所記憶之D-絲胺酸含量及D-絲胺酸含量之閾值，利用資料處理部進行比較並使記憶部記憶關於高於閾值還是低於閾值之比較結果， 讀出記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果及比較之結果，判定腎功能檢查之結果之妥當性並使記憶部記憶， 使輸出部輸出所記憶之妥當性。A program that enables an information processing device including an input unit, an output unit, a data processing unit, and a memory unit to determine the validity of a renal function test result based on the content of cystin C in the blood, and includes a program for making the above information The processing device executes the following instructions: Make the memory part memorize the threshold value of D-serine content input from the input part, Make the memory part memorize the results of the renal function test based on the cystin C content in the blood input from the input part, To memorize the D-serine content in the blood sample input from the input unit, Read out the D-serine content and the threshold value of D-serine content memorized in the memory unit, use the data processing unit to compare and make the memory unit memorize the comparison result of whether it is above the threshold or below the threshold, Read the renal function test results based on the content of cystin C in the blood and the results of the comparison stored in the memory unit to determine the validity of the renal function test results and make the memory unit memorize it. Make the output unit output the validity of the memory. 一種程式，其係使包含輸入部、輸出部、資料處理部、及記憶部之資訊處理裝置確定根據血液中之胱蛋白C含量之腎功能檢查結果之妥當性者，且包含用以使上述資訊處理裝置執行以下內容之指令： 使記憶部記憶自輸入部所輸入之血液中之胱蛋白C含量之閾值， 使記憶自輸入部所輸入之血液試樣中之胱蛋白C含量， 使記憶部記憶自輸入部所輸入之D-絲胺酸含量之閾值， 使記憶自輸入部所輸入之血液試樣中之D-絲胺酸含量， 讀出記憶部中所記憶之血液中之胱蛋白C含量及血液中之胱蛋白C含量之閾值，利用資料處理部進行比較並使記憶部記憶根據胱蛋白C含量之腎功能檢查結果， 讀出記憶部中所記憶之D-絲胺酸含量及D-絲胺酸含量之閾值，利用資料處理部進行比較並使記憶部記憶比較之結果， 讀出記憶部中所記憶之根據血液中之胱蛋白C含量之腎功能檢查結果及比較之結果，判定腎功能檢查之結果之妥當性並使記憶部記憶， 使輸出部輸出所記憶之妥當性。A program that enables an information processing device including an input unit, an output unit, a data processing unit, and a memory unit to determine the validity of a renal function test result based on the content of cystin C in the blood, and includes a program for making the above information The processing device executes the following instructions: Make the memory part remember the threshold value of the cystin C content in the blood input from the input part, To memorize the cystatin C content in the blood sample input from the input unit, Make the memory part memorize the threshold value of D-serine content input from the input part, To memorize the D-serine content in the blood sample input from the input unit, Read the blood cystatin C content and the blood cystatin C content threshold value memorized in the memory part, use the data processing part to compare and make the memory part remember the renal function test results based on the cystin C content, Read the D-serine content and the threshold value of D-serine content memorized in the memory unit, compare the results with the data processing unit and make the memory unit memorize the comparison result. Read the renal function test results based on the content of cystin C in the blood and the results of the comparison stored in the memory unit to determine the validity of the renal function test results and make the memory unit memorize it. Make the output unit output the validity of the memory.
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