阅读说明：本技术 Arr分层诊断新切点在制备用于原发性醛固酮增多症筛查试剂盒中的应用 (Application of ARR (auto regressive and Redox) hierarchical diagnosis new cut point in preparation of screening kit for primary aldosteronism ) 是由 李晓牧 徐晶 于 2020-05-08 设计创作，主要内容包括：本发明公开了醛固酮/肾素比值分层诊断新切点在制备用于原发性醛固酮增多症筛查试剂盒中的应用,其特征在于,对原醛症高危人群按eGFR进行分层,1)针对eGFR≥90ml/min/1.73m<Sup>2</Sup>部分人群,ARR切点为52ng/dl per ng/ml.h；2))针对eGFR＜90ml/min/1.73m<Sup>2</Sup>部分人群,ARR切点为18ng/dl per ng/ml.h。本发明取肾小球滤过率预估值(eGFR)作为反映肾功能的主要指标,通过研究eGFR与ARR的相关性从而制定适合不同类型高危人群的最适筛查切点,提高原醛症筛查试验的敏感性和特异性,提高对该病的诊治水平。本发明易于标准化并有望进一步推广,对于原醛症的早期筛查诊断具有良好的应用价值。(The invention discloses application of a new cutting point for aldosterone/renin ratio layered diagnosis in preparation of a primary aldosteronism screening kit, which is characterized in that the high risk group of the protoaldosteronism is layered according to eGFR, and 1) aiming at the eGFR of more than or equal to 90ml/min/1.73m 2 The ARR tangent point of part of population is 52ng/dl per ng/ml.h; 2) for eGFR < 90ml/min/1.73m 2 In some groups, the ARR cut point is 18ng/dl per ng/ml. The invention takes an estimated glomerular filtration rate (eGFR) value as a main index for reflecting the renal function, establishes an optimal screening cut point suitable for different types of high risk groups by researching the correlation between eGFR and ARR, improves the sensitivity and specificity of the propaldehyde disease screening test and improves the diagnosis and treatment level of the disease. The invention is easy to standardize and hopeful to be further popularized, and has good application value for early screening and diagnosis of the aldonolemia.)

1. The application of the new cutting point for the hierarchical diagnosis of the ratio of aldosterone to renin in the preparation of the screening kit for primary aldosteronism is characterized in that the high risk group of the orthoaldosteronism is layered according to eGFR,

1) aiming at the eGFR being more than or equal to 90ml/min/1.73m²The ARR cut point of part of the population is 52 ng/dler ng/ml.h;

2) aiming at eGFR < 90ml/min/1.73m²The ARR cut point of part of the population is 18 ng/dler ng/ml.h.

Technical Field

The invention belongs to the field of disease screening and treatment, and particularly relates to application of a new cutting point of aldosterone/renin ratio layered diagnosis in primary aldosteronism screening.

Background

Researches report that the protoaldoses account for 5% -10% of hypertensive population, and are up to 20% of intractable hypertension patients, which are common endocrine hypertension. Because of the characteristics of higher morbidity, low discovery rate, high cardiovascular risk and the like of the aldonolactoses, the new guidelines clearly suggest that the diagnosis and treatment of the aldonolactoses should be regarded as a public health problem, not just the diagnosis and treatment problem of a certain patient. Similar to the foreign situation, the current domestic original aldoses have low discovery rate and high misdiagnosis rate, and the reasons include: the understanding and the attention to the protoaldosis are not enough; the diagnosis process is complex; plasma aldosterone/renin assays are not widely performed; plasma aldosterone/renin assay standards are not uniform, etc. The importance of screening is apparent as the initial link in the overall diagnostic procedure. The current guidelines and consensus emphasize that the improvement of the screening consciousness of the high risk group of the aldehyde disease is urgent.

The diagnosis and research level of the protoaldoses in China is relatively lagged. Many have been screening for "primary levels" of proaldolase based on "hypertension with hypokalemia" cues. Studies report that hypokalemia is present in only a small proportion of patients with proaldosteronism, with about 50% of patients with aldosterone adenoma exhibiting hypokalemia and only 17% of patients with idiopathic hyperaldosteronism exhibiting hypokalemia. Hypokalemia is therefore of limited diagnostic value for the case of proaldosteronism and is very insensitive.

Current guidelines and consensus recommend ARR as the first screening indicator for the case of proaldolase. It is noted that age, sex, blood sampling time, diet, body position, blood sampling method, blood potassium level, creatinine level, etc. are important factors affecting ARR. Studies have shown that changes in Plasma Renin Activity (PRA) and plasma aldosterone/renin activity ratio (ARR) levels in patients with chronic kidney damage associated with proaldolase may be independent confounds in the screening for proaldolase. On one hand, for high risk population, if screening criteria of patients with normal renal function are adopted, the change of the ARR value related to the eGFR can cause the misdiagnosis risk of hypertension patients to be increased; on the other hand, a lower screening threshold will result in an increased false positive rate in those with normal renal function.

As ARR is influenced by a plurality of factors such as age, sex, body position, blood potassium level, creatinine level and the like, and the ARR is reported differently by various centers at home and abroad, the current situation that the discovery rate is low and the misdiagnosis rate is high still exists in the domestic original aldoses at present. Therefore, the screening of the proaldolase for the hypertension, particularly for the people with the refractory hypertension, has practical guiding significance for clinical work.

Notably, studies have shown that changes in Plasma Renin Activity (PRA) and plasma aldosterone/renin activity ratio (ARR) levels in patients with chronic kidney damage associated with proaldolase may be independent confounds in the screening for proaldolase, and this finding led our thinking. In the case that full-automatic biochemical analysis is becoming mature, the determination of the ratio of aldosterone/renin activity in plasma (ARR) is becoming widespread, and the cost of required medical treatment is low, can the original screening model be further optimized? According to the glomerular filtration rate estimation value (eGFR), the high-risk population of the protoaldosis is preferentially stratified, the corresponding plasma aldosterone/renin (ARR) cut point is taken as the thinking of screening and diagnosis, the strategy of preferential renal function examination is adopted, the method is applied to the screening of the protoaldosis, and the new thinking of the screening and diagnosis of the protoaldosis is explored.

Disclosure of Invention

The invention aims to establish the optimum screening cut point suitable for different populations by layering the high risk population of the primary aldoses according to eGFR, improve the sensitivity and specificity of the screening test, enable patients to be diagnosed and treated early and improve the diagnosis and treatment level of the primary aldoses.

In order to achieve the aim, the invention provides the application of a new cutting point for the aldosterone/renin ratio layered diagnosis in the preparation of a screening kit for primary aldosteronism, which is characterized in that the high risk group of the aldosteronism is layered according to eGFR,

1) aiming at the eGFR being more than or equal to 90ml/min/1.73m²The ARR tangent point of part of population is 52ng/dl per ng/ml.h;

2) aiming at eGFR < 90ml/min/1.73m²In some groups, the ARR cut point is 18ng/dl per ng/ml.

Compared with the traditional tangent points, the advantages of screening the tangent points by adopting the invention are explained as follows:

the sensitivity and specificity of the screening test can be improved.

The optimal ARR screening cut point obtained according to the John index was 40ng/dl per ng/ml.h. Aiming at eGFR < 90ml/min/1.73m²In some groups, the invention recommends using 18ng/dl per ng/ml.h, and if 40 or 52ng/dlper ng/ml.h is used, the ROC shows that the sensitivity of the screening test is reduced from 100% to 85.2%; similarly, for eGFR ≥ 90ml/min/1.73m²In some populations, 52ng/dl per ng/ml.h is recommended, and if 18 or 40ng/dlper ng/ml.h is used, ROC shows that the specificity of the screening test will be reduced from 95.4% to 90.7%. Based on the above analysis, adopt the pair-pressing eThe optimum screening cut point obtained after the GFR level is layered can obviously improve the sensitivity and specificity of the aldonolactosis screening test.

And the early detection rate of the primary aldehyde disease of the CKD patient can be effectively improved.

For eGFR < 90ml/min/1.73m²If the traditional screening cut point is selected, which is not recommended by the invention, the high risk group with renal insufficiency will result in a high missed diagnosis rate of 16.3%. The screening cut point recommended by the invention is particularly critical to screening and diagnosing CKD patients with renal insufficiency, and even if the application of the method can effectively reduce the missed diagnosis rate of screening and ensure that high-risk patients are diagnosed and treated early.

The needed medical cost is low, and the standardization and the popularization are easy.

The screening standard of the invention is established to carry out glomerular filtration rate estimation (eGFR) and plasma aldosterone/renin (ARR) determination. The glomerular filtration rate estimation value (eGFR) of the invention selects a simplified kidney disease diet improvement formula, namely an MDRD equation [ eGFR (ml/min/1.73 m)²)＝186×Scr(mg/d1)^-1.154×age^-0.203×0.742(if female)×1.210(if black)]And estimating, wherein the renal function index Serum Creatinine (SCR) is from a full-automatic biochemical analyzer and a matched reagent, and the method is convenient and easy to obtain and has lower medical cost. Plasma aldosterone/renin (ARR) levels are administered by radioimmunoassay currently employed in most centers. The principle is to reflect plasma aldosterone activity (PRA) by measuring the rate of angiotensin i production. At present, the plasma aldosterone/renin determination technology is widely developed in clinic in various large and medium hospitals. With the growth of third-party testing facilities, more and more small or primary hospitals are also in force to routinely provide plasma aldosterone/renin assay services. Therefore, the related renal function indexes are convenient to measure and have strong operability; the method has low medical cost, is easy to standardize and further popularize, and has good application value for clinical work of screening the primary aldoses of hypertension, particularly of people suffering from refractory hypertension.

In conclusion, the invention preferentially classifies the high risk group of the protoaldehyde disease according to the glomerular filtration rate estimation value (eGFR) in a layering way, and the corresponding plasma aldosterone/renin (ARR) cut point is adopted as a screening method to screen the disease condition of the protoaldehyde disease in the outpatient hypertension patients. The applicant evaluates the clinical significance of the method in early screening diagnosis of hypertensive population through retrospective analysis, and researches show that compared with a traditional method without layering, the proposed screening method can obviously improve the sensitivity and specificity of screening tests, and particularly can effectively improve the early detection rate of the original aldoses of CKD patients.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.

The applicants have evaluated the clinical significance of the ARR hierarchical diagnostic new cutting point of the present invention in early screening diagnosis of hypertensive patients with Aldosterone-high risk factors by retrospective analysis (Xu J, Yang Y, Ling Y, et al. the association between eGFR and the Aldosterone-to-Renin Ratio and Its effective screening for Primary aldosteronism. int J Endocrinol.2020; 2020:2639813.Published 2020Feb 7.doi: 10.1155/2020/2639813). Researches show that compared with the traditional method without layering, the proposed recommendation method can obviously improve the sensitivity and specificity of a screening test, and particularly can effectively improve the early detection rate of the primary aldoses of CKD patients.

The procedure for the screening of the proaldosteronism is briefly summarized as follows:

firstly, primarily recovering and treating: hypertension patients with high risk factors for primary aldoses were treated at the outpatient clinic according to the standards set by the world health organization/hypertension expert committee (WHO/ISH) in 1999 (systolic blood pressure up to or above 140mmHg and diastolic blood pressure up to or above 90mmHg, 3 examinations and verifications are required). Further, known secondary hypertension (including diagnosed endocrine and renal hypertension) and known endocrine system diseases (pituitary tumor, hyperthyroidism, etc.) are excluded by using techniques such as color Doppler ultrasound.

② classifying according to the kidney function evaluation index eGFR ≥ 90 or < 90ml/min/1.73m²Levels classify the high risk population for the case of the primary aldoses. Specifically, the method comprises the following steps: for eGFR more than or equal to 90ml/min/1.73m²Screening the tangent point of a hypertensive patient by adopting ARR with 52ng/dl per ng/ml.h; for eGFR < 90ml/min/1.73m²Patients with hypertension with renal dysfunction were screened at a lower screening threshold of 18ng/dl per ng/ml.

(iii) final confirmation: the plasma aldosterone/renin activity ratio (ARR) is indirectly obtained by measuring the Plasma Aldosterone Concentration (PAC) and the plasma aldosterone activity (PRA) by the currently generally adopted radioimmunoassay. The invention selects the normal saline infusion test which is commonly used at home at present as the definitive diagnosis test of the primary aldoses. The test method comprises the following steps: before the test, the patient must rest in bed for 1 hour, 2L of 0.9% normal saline is statically dripped for 4 hours, the test is started at 8: 00-9: 00 in the morning, the blood pressure and heart rate change need to be monitored in the whole process, and blood is respectively collected before and after the infusion to measure the activity of plasma renin, aldosterone, cortisol and potassium hemokalium. However, the blood volume is rapidly increased to induce hypertension crisis and cardiac failure, and thus patients with difficult blood pressure control, cardiac insufficiency and hypokalemia must be excluded. After the physiological saline infusion test, the diagnosis of the aldosteronism with the blood aldosterone (PAC) being more than 10ng/dl is clear, and the aldosteronism is excluded when the concentration is less than 5ng/dl, and if the concentration is between 5ng/dl and 10ng/dl, the comprehensive evaluation must be carried out according to the clinical performance, laboratory examination and imaging performance of a patient.