JP2006280320A - Renal function measuring agent - Google Patents
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本発明は、新規腎機能測定剤、より具体的には、ヒトレニンを含む、ヒト尿中アンジオテンシノーゲン測定剤に関するものである。 The present invention relates to a novel renal function measuring agent, more specifically to a human urinary angiotensinogen measuring agent containing human renin.
わが国の慢性透析患者数は、増加の一途をたどっており、腎臓病の治療における重要な問題点の一つは、血液透析が必要となるような腎不全の進行に関与する腎硬化性病変の進行の抑制にある。近年、腎硬化性病変の進行には腎内のレニン・アンジオテンシン系(RAS)が重要な役割を果たしていることが明らかとなり、RASの最も重要な作用因子であるアンジオテンシンII(AII)を抑制するAII受容体拮抗薬やアンジオテンシン変換酵素(ACE)阻害薬が使用され、一定の腎保護効果を上げている。しかし、これらAII阻害薬による腎保護効果の発現には必要十分な量を投与する必要があるが、AII阻害薬は、腎保護効果を有すると同時に高カリウム血症、糸球体濾過低下、アシドーシスといった腎機能障害患者に投与するにあたっては多くの注意すべき作用を有しており、その至適投与量を知るための適切な臨床的指標は知られていなかった。 The number of chronic dialysis patients in Japan continues to increase, and one of the important problems in the treatment of kidney disease is that of renal sclerotic lesions involved in the progression of renal failure that requires hemodialysis. In the suppression of progress. In recent years, it has become clear that the renin-angiotensin system (RAS) in the kidney plays an important role in the progression of nephrosclerotic lesions and suppresses angiotensin II (AII), the most important agent of RAS. Receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors are used to achieve a certain level of renal protection. However, it is necessary to administer a necessary and sufficient amount for the manifestation of nephroprotective effects by these AII inhibitors, but AII inhibitors have nephroprotective effects and at the same time hyperkalemia, decreased glomerular filtration, acidosis When administered to patients with renal dysfunction, it has many cautionary effects, and no appropriate clinical index for knowing the optimal dose has been known.
AII活性抑制薬の効果の指標としては、腎臓内AII濃度を測定するのが直接的であるが、臨床において患者の腎臓内AII濃度測定方法は確立していない。 As an index of the effect of an AII activity inhibitor, it is straightforward to measure the AII concentration in the kidney, but no method for measuring the AII concentration in the patient's kidney has been established clinically.
また、AIIは、血中にも存在するが、血中AII濃度は、腎臓内AII濃度とは相関しないことから、腎機能障害患者に対するAII阻害薬の投与への臨床的指標としては、適切とはいえない。 AII is also present in the blood, but the blood AII concentration does not correlate with the renal AII concentration. Therefore, it is appropriate as a clinical indicator for the administration of AII inhibitors to patients with renal impairment. I can't say that.
RASには、循環血中に由来するRASに加えて、腎などでは組織内で発現する組織特有RASがある。腎内RASにおいては、アンジオテンシノーゲン(Ao)は、主に近位尿細管の上皮細胞によって尿細管に分泌されるが、一部は糸球体内皮細胞や直血管にも発現がみられる(非特許文献1)。また、レニンは傍糸球体装置に加え、糸球体上皮、尿細管上皮にも正常腎で発現している。さらに高血圧や腎疾患患者の腎では、メサンギウム細胞や上皮細胞にもAoやレニンが発現してくる(非特許文献2)。したがって、尿中には腎局所由来のAo、AIIが存在する(特許文献1)。 In addition to RAS derived from circulating blood, RAS includes tissue-specific RAS expressed in tissues such as kidney. In intrarenal RAS, angiotensinogen (Ao) is secreted into the tubules mainly by epithelial cells of the proximal tubules, but some are also expressed in glomerular endothelial cells and straight blood vessels (non-) Patent Document 1). In addition to the paraglomerular apparatus, renin is expressed in the glomerular epithelium and tubular epithelium in normal kidneys. Furthermore, Ao and renin are also expressed in mesangial cells and epithelial cells in the kidneys of patients with hypertension and renal diseases (Non-patent Document 2). Therefore, Ao and AII derived from the local kidney are present in urine (Patent Document 1).
しかし、尿中Ao及びAIIの臨床的意義は、AIIに関連した高血圧症との関連が示唆されている(特許文献1、非特許文献3、4)のみで、腎機能との関連は、知られていない。
本発明は、ヒト尿中アンジオテンシノーゲン(Ao)測定剤を提供する。 The present invention provides a human urinary angiotensinogen (Ao) measuring agent.
本発明は、予想外にも、尿中AII量と腎機能(糸球体濾過率:GFR)とは十分な相関がみられないこと、尿中Ao量は、GFRと負の相関があること、そして、アンジオテンシンII(AII)受容体拮抗薬であるロサルタン服用によって尿中Ao量が減少することを見出し完成された。 Unexpectedly, the present invention, urinary AII amount and renal function (glomerular filtration rate: GFR) is not sufficiently correlated, urinary Ao amount is negatively correlated with GFR, The inventors have found that urinary Ao levels can be reduced by taking losartan, an angiotensin II (AII) receptor antagonist.
また、より簡易かつ迅速な測定のために、尿中Aoを、ヒトレニンを用いてアンジオテンシノーゲンI(AI)を生成させ、生成されたAIをラジオイムノアッセイを用いて測定することによって、尿中Aoを測定する方法を開発した。 For simpler and quicker measurement, urinary Ao is produced by using human renin to produce angiotensinogen I (AI), and the produced AI is measured using a radioimmunoassay. A method of measuring was developed.
したがって、本発明は、ヒトレニンを含む、ヒト尿中アンジオテンシノーゲン(Ao)測定剤に関する。 Therefore, the present invention relates to a human urinary angiotensinogen (Ao) measuring agent containing human renin.
尿中Ao量は、慢性腎疾患の治療におけるAII阻害薬の投与についての臨床的指標として有用である。
さらに、尿中Ao量は、腎不全をきたす腎硬化性病変の進行に関与する腎内RAS活性を知る臨床的指標としても有用である。
Urinary Ao levels are useful as a clinical indicator for the administration of AII inhibitors in the treatment of chronic kidney disease.
Furthermore, the amount of urinary Ao is also useful as a clinical index to know intrarenal RAS activity involved in the progression of renal sclerotic lesions that cause renal failure.
本発明のヒトレニンは、鈴木らの方法に従い以下の方法で得られたものを用いた。すなわち、ヒトプロレニンcDNAを含むpSVD発現ベクターをリン酸カルシウム法にてCHO/dhfr−細胞に導入してヒトプロレニンを産生させた。得られたプロレニンのレニンへの活性化は、プロレニンを5μg/mlのトリプシンで25℃、10分間インキュベーションし、1mMフェニルメチルスルホニルフルオリドで反応を停止したものを用いた(Suzuki et al. Biochem Biophys Res Commun 2000, 267: 577-580)。 The human renin of the present invention was obtained by the following method according to the method of Suzuki et al. That is, a pSVD expression vector containing human prorenin cDNA was introduced into CHO / dhfr-cells by the calcium phosphate method to produce human prorenin. Activation of the obtained prorenin to renin was performed by incubating prorenin with 5 μg / ml trypsin at 25 ° C. for 10 minutes and stopping the reaction with 1 mM phenylmethylsulfonyl fluoride (Suzuki et al. Biochem Biophys Res Commun 2000, 267: 577-580).
Aoの定量は、サンプル中のAoを過量のヒトレニンによってアンジオテンシンI(AI)に変え、そのAIをラジオイムノアッセイ(SRL, Tokyo, Japan)によって定量し、尿サンプルについては尿中クレアチニン(Cre)1g当たりのAI当量として算出した。 The amount of Ao is determined by changing Ao in the sample to angiotensin I (AI) with an excessive amount of human renin, quantifying the AI by radioimmunoassay (SRL, Tokyo, Japan), and for urine samples per urine creatinine (Cre) Calculated as the AI equivalent of.
すなわち、血漿サンプルを0.2M PBS、125M EDTA、1mMカプトプリル及び50mMフェニルメチルスルホニルフルオリドを含む溶液を用いて200倍に希釈し、また、尿サンプルを同様の溶液を用いて10倍に希釈した。次いで、35fMヒトレニンを加え37℃で18時間インキュベーションした。 That is, the plasma sample was diluted 200 times with a solution containing 0.2 M PBS, 125 M EDTA, 1 mM captopril and 50 mM phenylmethylsulfonyl fluoride, and the urine sample was diluted 10 times with the same solution. . Subsequently, 35 fM human renin was added and incubated at 37 ° C. for 18 hours.
生成されたAIをフロリジル30mgに吸着させ、これを純水で洗浄後、0.5N HClを含むアセトンで抽出し、ラジオイムノアッセイにて定量した。このヒトレニンとの反応で生成されたAI量から元来サンプル中にあるAI量を差し引くことでサンプル中のAo量をAI当量として算出した。なお、尿サンプル内のAoから生成されるAIは、35fMヒトレニンとの37℃、18時間以上のインキュベーションにて上限量での平衡に達することが確認されている。 The produced AI was adsorbed on 30 mg of Florisil, washed with pure water, extracted with acetone containing 0.5N HCl, and quantified by radioimmunoassay. The amount of Ao in the sample was calculated as an AI equivalent by subtracting the amount of AI originally in the sample from the amount of AI generated by the reaction with human renin. It has been confirmed that AI produced from Ao in the urine sample reaches equilibrium at the upper limit amount by incubation with 35 fM human renin at 37 ° C. for 18 hours or longer.
結果1:尿中Ao量は、各種の慢性腎疾患における腎機能(糸球体濾過率:GFR)と負の相関を呈する。
AII抑制性の薬剤を服用していない慢性腎疾患患者54例(GFR;4〜110ml/分)において、GFRと、血漿中と尿中のAo、アンジオテンシンII(AII)、アルドステロン(Ald)、血漿レニン活性、尿蛋白、尿中IV型コラーゲン(Col IV)、平均血圧との関連を調べたところ、GFRとの単相関は尿中Ao、尿中AII、尿中Col IV、尿蛋白、平均血圧でみられたが、尿中Aoが最もGFRと負の相関(r=-0.768)が強く、かつ、尿中Aoは、腎内の細胞外基質の発現との関連が報告されている尿中Col IV(非特許文献5)と強い正の相関(r=0.839)を認めた。GFRと相関する上記の変数の中で、尿中Aoと多重共線性が高い尿中Col IVを除いた尿中Ao、尿中AII、尿蛋白、平均血圧のうち、重回帰分析によりGRFと有意な関連性を呈するのは尿中Aoのみであった。(図1、表1、2)
一方、尿中Aoは血漿レニン活性、血漿Ao、血漿AII、血漿Aldとは相関は見られなかった。
In 54 patients with chronic kidney disease who did not take AII inhibitory drugs (GFR; 4-110 ml / min), GFR, plasma and urine Ao, angiotensin II (AII), aldosterone (Ald), plasma The relationship between renin activity, urinary protein, urinary type IV collagen (Col IV), and mean blood pressure was examined. The simple correlation with GFR was urinary Ao, urinary AII, urinary Col IV, urinary protein, mean blood pressure. Urinary Ao had the strongest negative correlation with GFR (r = -0.768), and urinary Ao was reported to be associated with the expression of extracellular matrix in the kidney. A strong positive correlation (r = 0.839) was observed with Col IV (Non-patent Document 5). Among the variables correlated with GFR, urinary Ao, urinary AII, urinary protein, and mean blood pressure excluding urinary Col IV, which is highly collinear with urinary Ao, are significantly different from GRF by multiple regression analysis. Only the urinary Ao showed a significant relationship. (Figure 1, Tables 1 and 2)
On the other hand, urinary Ao was not correlated with plasma renin activity, plasma Ao, plasma AII, and plasma Ald.
AII抑制性の薬剤を服用していない慢性腎疾患患者54例におけるGFRとの相関検定の結果を示す。
(表1)
変数 相関係数r p値
log(尿中Ao) -0.768 <0.0001
log(尿中AII) -0.437 0.0008
log(尿中Ald) 0.165 0.2336
log(尿蛋白) -0.364 0.0077
log(尿中Col IV) -0.743 <0.0001
log(血漿レニン活性) 0.147 0.2948
log(血漿Ao) 0.l99 0.1494
log(血漿AII) -0.093 0.5041
log(血漿Ald) -0.137 0.3245
尿中Ao -0.519 <0.0001
尿中AII -0.371 0.0054
尿中Ald 0.166 0.2303
尿蛋白 -0.308 0.0232
尿中Col IV -0.437 0.0009
血漿レニン活性 0.098 0.4840
血漿Ao 0.201 0.1465
血漿AII -0.038 0.7840
血漿Ald -0.180 0.1927
平均血圧 -0.418 0.0016
The result of the correlation test with GFR in 54 chronic kidney disease patients who are not taking the AII inhibitory drug is shown.
(Table 1)
Variable Correlation coefficient rp value
log (urinary Ao) -0.768 <0.0001
log (urinary AII) -0.437 0.0008
log (urinary Ald) 0.165 0.2336
log (urine protein) -0.364 0.0077
log (Urine Col IV) -0.743 <0.0001
log (plasma renin activity) 0.147 0.2948
log (plasma Ao) 0.199 0.1494
log (plasma AII) -0.093 0.5041
log (plasma Ald) -0.137 0.3245
Urinary Ao -0.519 <0.0001
Urinary AII -0.371 0.0054
Urinary Ald 0.166 0.2303
Urine protein -0.308 0.0232
Urinary Col IV -0.437 0.0009
Plasma renin activity 0.098 0.4840
Plasma Ao 0.201 0.1465
Plasma AII -0.038 0.7840
Plasma Ald -0.180 0.1927
Average blood pressure -0.418 0.0016
表1においてGFRと相関する変数の中で、尿中Aoと多重共線性が高い尿中Col IVを省いた尿中Ao、尿中AII、尿蛋白、平均血圧のうち、重回帰分析によりGRFと有意な関連性を呈するのは尿中Aoのみであることが明らかとなった。
(表2)
│R│=0.798、R2 = 0.636
回帰係数 標準誤差 標準回帰係数 t値 p値
log(尿中Ao) -53.573 8.486 -0.885 -6.311 <0.0001
log(尿中AII) -7.216 10.600 -0.070 -0.681 0.4994
log(尿蛋白) 18.252 9.244 0.244 1.975 0.0542
平均血圧 -0.073 0.249 -0.031 -0.295 0.7691
│R│=0.604、R2 = 0.365
回帰係数 標準誤差 標準回帰係数 t値 p値
尿中Ao -0.727 0.277 -0.436 -2.628 0.0114
尿中AII -0.273 0.150 -0.221 -1.814 0.0758
尿蛋白 0.002 0.004 0.069 0.434 0.6659
平均血圧 -0.447 0.308 -0.189 -1.450 0.1534
Among the variables correlated with GFR in Table 1, among urinary Ao, urinary AII, urinary protein, and mean blood pressure excluding urinary Col IV that is highly collinear with urinary Ao, Only urinary Ao was found to have a significant association.
(Table 2)
│R│ = 0.798, R 2 = 0.636
Regression coefficient Standard error Standard regression coefficient t value p value
log (Ao in urine) -53.573 8.486 -0.885 -6.311 <0.0001
log (urinary AII) -7.216 10.600 -0.070 -0.681 0.4994
log (urine protein) 18.252 9.244 0.244 1.975 0.0542
Average blood pressure -0.073 0.249 -0.031 -0.295 0.7691
│R│ = 0.604, R 2 = 0.365
Regression coefficient Standard error Standard regression coefficient t value p value Urinary Ao -0.727 0.277 -0.436 -2.628 0.0114
Urinary AII -0.273 0.150 -0.221 -1.814 0.0758
Urine protein 0.002 0.004 0.069 0.434 0.6659
Average blood pressure -0.447 0.308 -0.189 -1.450 0.1534
結果2:尿中AoはAII阻害薬ロサルタン服用後、有意に減少する。
AII抑制性の薬剤を服用していない慢性腎疾患患者23例(GFR;6〜110ml/分)においてロサルタン25mg服用開始前と服用2週間後での変化を調べたところ、血漿Ald、尿中AII、尿中Ald、尿中Col IVに有意な変化はなく、血漿レニン活性、血漿AIIは増加したにもかかわらず、尿中Aoは有意に減少した(表3)。
Result 2: Urinary Ao decreases significantly after taking the AII inhibitor losartan.
In 23 patients with chronic kidney disease who did not take AII inhibitory drugs (GFR; 6-110 ml / min), changes in the dose of losartan 25 mg before and after 2 weeks were examined. Plasma Ald and urinary AII There was no significant change in urinary Ald and urinary Col IV, and plasma renin activity and plasma AII increased, but urinary Ao decreased significantly (Table 3).
AII抑制性の薬剤を服用していない慢性腎疾患患者23例におけるロサルタン25mgを服用開始前と服用2週間後での血漿中・尿中RAS関連因子の変化を示す。ロサルタン25mgの2週間投与により尿中AII、尿中Ald、尿中Col IV、血漿Ald、平均血圧に有意な変化はなく、血漿レニン活性、血漿AIIは増加したにもかかわらず、尿中Ao、尿蛋白、血漿Aoは有意に減少した。
(表3)
投与前 投与2週間後 p値
尿中Ao(μg AI当量/g Cre) 7.2±2.6 4.8±1.6 0.0350
尿中AII(ng/g Cre) 31.5±6.0 42.0±10.3 0.1547
尿中Ald(μg/g Cre) 3.3±0.7 3.2±0.7 0.7420
尿蛋白(mg/day) 1597±326 830±182 0.0011
尿中Col IV(μg/g Cre) 10.3±3.0 7.3±2.3 0.1787
血漿レニン活性(ng/ml/hr) 1.6±0.4 3.9±0.9 0.0019
血漿Ao(ng/ml AI当量) 428.4±36.6 369.0±30.4 0.0170
血漿AII(pg/ml) 6.7±1.1 14.3±3.3 0.0141
血漿Ald(pg/ml) 66.0±12.3 69.9±16.0 0.7398
平均血圧(mmHg) 92±4 85±3 0.0677
値は平均値±標準誤差を示す
2 shows changes in RAS-related factors in plasma and urine before and 2 weeks after taking 25 mg of losartan in 23 patients with chronic kidney disease who are not taking an AII inhibitory drug. Although urinary AII, urinary Ald, urinary Col IV, plasma Ald, and mean blood pressure were not significantly changed by administration of 25 mg of losartan for 2 weeks, plasma renin activity and plasma AII increased, urinary Ao, Urinary protein and plasma Ao were significantly decreased.
(Table 3)
Before administration 2 weeks after administration p-value urinary Ao (μg AI equivalent / g Cre) 7.2 ± 2.6 4.8 ± 1.6 0.0350
Urinary AII (ng / g Cre) 31.5 ± 6.0 42.0 ± 10.3 0.1547
Urinary Ald (μg / g Cre) 3.3 ± 0.7 3.2 ± 0.7 0.7420
Urine protein (mg / day) 1597 ± 326 830 ± 182 0.0011
Urinary Col IV (μg / g Cre) 10.3 ± 3.0 7.3 ± 2.3 0.1787
Plasma renin activity (ng / ml / hr) 1.6 ± 0.4 3.9 ± 0.9 0.0019
Plasma Ao (ng / ml AI equivalent) 428.4 ± 36.6 369.0 ± 30.4 0.0170
Plasma AII (pg / ml) 6.7 ± 1.1 14.3 ± 3.3 0.0141
Plasma Ald (pg / ml) 66.0 ± 12.3 69.9 ± 16.0 0.7398
Mean blood pressure (mmHg) 92 ± 4 85 ± 3 0.0677
Values indicate mean ± standard error
結論:各種の慢性腎疾患において、尿中Ao量は、血中RAS活性とは関連がなく、腎内RAS活性が亢進して腎硬化性病変が強くGFRが低下している患者ほど高値であり、ロサルタン服用にて減少することから、腎内RAS活性の指標となると考えられた。 Conclusion: In various chronic kidney diseases, urinary Ao levels are not related to blood RAS activity, and are higher in patients with increased intrarenal RAS activity, strong nephrosclerotic lesions, and decreased GFR. It was considered to be an index of intrarenal RAS activity because it decreased with the administration of losartan.
尿中Ao量は、腎疾患患者において腎硬化性病変の進行に関与する腎内RAS活性を知るための臨床的指標として、さらには、同疾患患者にAII阻害薬を投与する際にその至適投与量を知る臨床的指標として有用である。 The urinary Ao level is a clinical indicator to know the intra-renal RAS activity involved in the progression of nephrosclerotic lesions in patients with renal disease, and is also optimal when an AII inhibitor is administered to patients with the disease. It is useful as a clinical index to know the dosage.
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JP2002524723A (en) * | 1998-09-04 | 2002-08-06 | ユニバーシティ・オブ・ユタ・リサーチ・ファウンデーション | Drug screening and diagnosis based on the tubular renin-angiotensin system of paracrine |
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RU2446745C2 (en) * | 2010-05-26 | 2012-04-10 | Государственное образовательное учреждение высшего профессионального образования "Уральская государственная медицинская академия Федерального агентства по здравоохранению и социальному развитию" (ГОУ ВПО УГМА Росздрава) | Method of estimating dopplerographic indices of renal blood flow in children and teenagers |
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