AbstractApparent resistant hypertension (aTRH) is a significant public health issue. Once low adherence to antihypertensive treatment has been ruled out and true resistant hypertension is diagnosed, aldosterone-direct-renin-ratio (ADRR) aids in the screening of an aldosterone-producing adenoma (APA) and primary aldosteronism (PA).

摘要表观耐药性高血压（aTRH）是一个重要的公共卫生问题。。

Once PA and other secondary causes have been ruled out, the values of aldosterone and renin allow patients to be classified into phenotypes such as low renin hypertension (LRH), Liddle’s-like (LLph), and primary hyperaldosteronism (PAph). These classifications could aid in the treatment decision-making process.

一旦排除了PA和其他继发原因，醛固酮和肾素的值就可以将患者分为低肾素高血压（LRH），利德尔样（LLph）和原发性醛固酮增多症（PAph）等表型。这些分类可以帮助治疗决策过程。

However, optimal cut-off points for these classifications remain uncertain. This study aims to assess the prevalence of these phenotypes and the behavior of different cut-offs of the ADRR in an Afro-Colombian population with apparent resistant hypertension, as well to describe their sodium consumption.

然而，这些分类的最佳截止点仍然不确定。这项研究旨在评估这些表型的患病率以及具有明显耐药性高血压的非洲裔哥伦比亚人群中ADRR的不同临界值的行为，并描述他们的钠消耗量。

Afro-descendant individuals 18 years of age or older, diagnosed with resistant hypertension and attending to a primary care center in Colombia were recruited as volunteers. As part of the study, their plasma renin concentration (PRC) and plasma aldosterone concentration (PAC) were measured. The phenotypes were categorized into three groups based on multiple cut-off points from different authors: low renin and low aldosterone phenotype (LLph), low renin and high aldosterone phenotype (PAph), and high renin and high aldosterone phenotype, referred to as the renal phenotype (Rph).

招募了18岁或以上被诊断患有顽固性高血压并在哥伦比亚初级保健中心就诊的非洲裔个体作为志愿者。作为研究的一部分，测量了他们的血浆肾素浓度（PRC）和血浆醛固酮浓度（PAC）。根据不同作者的多个临界点，将表型分为三组：低肾素和低醛固酮表型（LLph），低肾素和高醛固酮表型（PAph），以及高肾素和高醛固酮表型，称为肾表型（Rph）。

The prevalence of ADRR values exceeding the cut-off and phenotypes were calculated. A linear regression model was derived to assess the effect of sodium consumption with PAC, PRC and ADRR. A total of 88 patients with aTRH were included. Adherence to at least 3 anti.

计算了ADRR值超过临界值和表型的患病率。建立了一个线性回归模型来评估PAC，PRC和ADRR对钠消耗的影响。共纳入88例aTRH患者。坚持至少3个反。

IntroductionHypertension (HTN) is a global public health concern1. Resistant arterial hypertension (RAH) has been observed in up to 10 to 20% of hypertensive individuals. It is important to discriminate apparent treatment-resistant hypertension (aTRH), defined as uncontrolled blood pressure (BP) in patients taking three or more antihypertensive medications, from pseudoresistant hypertension (PSH), mainly due to poor adherence.

引言高血压（HTN）是一个全球公共卫生问题1。在多达10%至20%的高血压患者中观察到耐药性动脉高血压（RAH）。重要的是要区分明显的治疗抵抗性高血压（aTRH），即服用三种或三种以上抗高血压药物的患者的不受控制的血压（BP）与假性抵抗性高血压（PSH），主要是由于依从性差。

The prevalence of PSH among individuals with apparent resistant hypertension (aTRH) is estimated to be as high as 50%2,3. Primary aldosteronism (PA) is a recognized etiology of secondary hypertension, characterized by excessive aldosterone production, reduced plasma renin levels and diverse pathological lesions.

据估计，表观耐药性高血压（aTRH）患者的PSH患病率高达50%2,3。原发性醛固酮增多症（PA）是继发性高血压的公认病因，其特征是醛固酮产生过多，血浆肾素水平降低和多种病理病变。

Clinicians can suspect this pathology when a patient's aldosterone-direct-renin-ratio (ADRR) exceeds the cut-off reference value4. The estimated prevalence of PA is around 20% among those with true resistant hypertension (TRH)5.Once TRH is diagnosed, the aldosterone and renin measurements can classify the patient in different phenotypes.

当患者的醛固酮直接肾素比率（ADRR）超过临界参考值4时，临床医生可能会怀疑这种病理。在真正的耐药性高血压（TRH）患者中，PA的估计患病率约为20%。一旦诊断出TRH，醛固酮和肾素的测量可以将患者分为不同的表型。

The physiological low renin phenotype in normotensive population is associated with increased risk of incident hypertension, while the low renin hypertension (LRH) phenotype is associated with a salt-retaining state, a low response to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) and better response to mineralocorticoid receptor antagonists (MRA)6,7,8,9,10.

血压正常人群的生理性低肾素表型与高血压发病风险增加有关，而低肾素高血压（LRH）表型与盐保留状态，对血管紧张素转换酶抑制剂/血管紧张素受体阻滞剂（ACEi/ARB）的低反应以及对盐皮质激素受体拮抗剂（MRA）6,7,8,9,10的更好反应有关。

Primary Hyperaldosteronism phenotype (PAph) is also suggested as a spectrum of conditions that exhibit favorable responses to MRA11. Liddle'-like phenotype (LLph) is characterized by elevated blood pressure, low plasma aldosterone, low plasma renin, hypokalemia, and metabolic alkalosis. This differentiates it from Lid.

原发性醛固酮增多症表型（PAph）也被认为是对MRA11表现出良好反应的一系列疾病。Liddle'样表型（LLph）的特征是血压升高，血浆醛固酮低，血浆肾素低，低钾血症和代谢性碱中毒。这与Lid有所不同。

PRC < 10 mU/L, as reported by Byrd JB et al. and Macchiavello et al. or < 15 mU/L, as reported by Monticone et al.

Byrd JB等人和Macchiavello等人报告的Prc<10 mU/L，或Monticone等人报告的<15 mU/L。

PAC < 6 pg/mL, as reported by Macchiavello et al. or < 10 pg/mL, as reported by Byrd JB et al. and Monticone et al.

Macchiavello等人报道的PAC<6 pg/mL或Byrd-JB等人和Monticone等人报道的PAC<10 pg/mL。

Based on these criteria, three hypertension phenotypes were defined:

根据这些标准，定义了三种高血压表型：

Low renin and low aldosterone (LLph): PRC < 10 mU/L or < 15 mU/L, and PAC < 6 pg/mL or < 10 pg/mL.

低肾素和低醛固酮（LLph）：PRC<10 mU/L或<15 mU/L，PAC<6 pg/mL或<10 pg/mL。

Low renin and high aldosterne phenotype (PAph): PRC < 10 mU/L or < 15 mU/L, and PAC > 10 pg/mL.

低肾素和高醛固酮表型（PAph）：PRC<10 mU/L或<15 mU/L，PAC>10 pg/mL。

High renin and high aldosterone phenotype, referred to as the renal phenotype (Rph): PRC > 10 mU/L or > 15 mU/L, and PAC > 10 pg/mL

高肾素和高醛固酮表型，称为肾表型（Rph）：PRC>10 mU/L或>15 mU/L，PAC>10 pg/mL

Additionally, we reported the definitions of low-renin hypertension (LRH) by PRC quartiles distribution.Laboratory methodsFollowing an overnight fasting period, venous blood samples were drawn and subjected to biochemical analysis through clinically standardized methods at laboratories. A calibrated Roche Cobas 6000 modular analyzer, consisting of the e501 module, was used to measure plasma potassium, serum and spontaneous urine creatinine, urine sodium, and spontaneous urine proteinuria using the manufacturer's reagents and calibrators (Roche, Mannheim, Germany).

此外，我们报道了PRC四分位数分布对低肾素高血压（LRH）的定义。实验室方法在禁食过夜后，抽取静脉血样本，并通过实验室的临床标准化方法进行生化分析。使用制造商的试剂和校准品（Roche，曼海姆，德国），使用由e501模块组成的校准罗氏Cobas 6000模块化分析仪测量血浆钾，血清和自发性尿肌酐，尿钠和自发性尿蛋白尿。

Direct renin and aldosterone concentrations were assayed at a clinical laboratory in Cali, Colombia, using a fully automated LIAISON XL platform (DiaSorin, Dietzenbach, Germany), which uses chemiluminescent immunoassay technology.Statistical methodsCategorical variables were represented as relative frequencies, and their association was assessed for significance using Fisher's Exact tests.

使用全自动联络XL平台（DiaSorin，Dietzenbach，Germany），使用化学发光免疫测定技术，在哥伦比亚卡利的临床实验室测定了直接肾素和醛固酮的浓度。统计方法数字变量表示为相对频率，并使用Fisher精确检验评估其关联的显着性。

For continuous variables that did not follow a normal distribution, we presented them as medians along with their interquartile ranges (IQRs). Associations were tested for significance using the Mann–Whitney U test. The study conducted linear regression analyses to explore relationships involving PAC, PRC, and the ADRR.

对于不遵循正态分布的连续变量，我们将其作为中位数及其四分位间距（IQR）表示。使用Mann-Whitney U检验对关联进行了显着性检验。该研究进行了线性回归分析，以探索涉及PAC，PRC和ADRR的关系。

The linear regression model used. Logarithmic normalization was applied to address skewed distributions, and multicollinearity among independent variables was rigorously examined. A normal distribution of residuals was confirmed through histogram inspection. Statistical analyses were performed using R software version 4.4.1 (https://cran.r-project.org/bin/), with a significance threshold of < 0.05 for one-sided p-values.Ethical statementAccording to Resolution 8430 of 1993 (Article 11), this study poses minim.

使用的线性回归模型。应用对数归一化来解决偏态分布，并严格检查自变量之间的多重共线性。通过直方图检查确认残差的正态分布。使用R软件版本4.4.1进行统计分析(https://cran.r-project.org/bin/)，单侧p值的显着性阈值为0.05。道德声明根据1993年第8430号决议（第11条），这项研究提出了最小的要求。

ResultsThe baseline characteristics of the participants are presented in Table 1. The study included a total of 88 individuals. The median BMI of 28.7 (IQR: 26.2 to 32.3) indicates that the population is far from the recommended goals, which is reflected by the high prevalence of diabetes mellitus (20%) and obesity (43%).

。这项研究共包括88个人。BMI中位数为28.7（IQR:26.2至32.3），表明该人群远未达到推荐的目标，这反映在糖尿病（20%）和肥胖（43%）的高患病率上。

Hypokalemia, a diagnostic clue for primary aldosteronism (PA), was observed in 3.4% (N = 3) of the participants. The daily sodium intake average exceeded the recommended 2000 mg/day. The spot urine protein to creatinine ratio had a median of 0.06 mg/mg (IQR: 0.05 to 0.09 mg/mg), which is well below the most used cutoff value of 0.2 mg/mg for diagnostic work up.

在3.4%（N=3）的参与者中观察到低钾血症，这是原发性醛固酮增多症（PA）的诊断线索。每日钠摄入量平均超过建议的2000毫克/天。尿蛋白与肌酐的中位数为0.06 mg/mg（IQR:0.05至0.09 mg/mg），远低于诊断检查中最常用的临界值0.2 mg/mg。

The reported use of antihypertensive medications in the study population revealed that ACEi were the least commonly used, while ARBs, CCBs, and diuretics were used by over three-quarters of the cohort. Most participants reported taking multiple antihypertensive medications, with most using either two or three different drugs.

据报道，研究人群中使用抗高血压药物的情况显示，ACEi是最不常用的药物，而超过四分之三的人群使用ARB，CCB和利尿剂。大多数参与者报告服用多种抗高血压药物，大多数使用两种或三种不同的药物。

A smaller proportion of participants reported the use of a single antihypertensive. Notably, 37.5% (n = 33) of the participants did not comply with the use of at least 3 antihypertensive medications. The distribution of variables was similar among patients adhering to less than three or three or more antihypertensives..

较小比例的参与者报告使用单一抗高血压药。值得注意的是，37.5%（n=33）的参与者不遵守至少3种抗高血压药物的使用。。。

Table 1 Baseline clinical characteristics.Full size tableThe prevalence of suspected PA was evaluated using different ADRR cut-off values and did not differ between individuals taking less than three antihypertensive drugs and those taking more than three antihypertensive drugs across the multiple authors' cut-offs (Table 2).

表1基线临床特征。全尺寸表使用不同的ADRR临界值评估疑似PA的患病率，服用少于三种抗高血压药物的个体与服用三种以上抗高血压药物的个体在多个作者的临界值之间没有差异（表2）。

Similarly, the prevalence of LRH did not vary significantly based on antihypertensive drug regimens nor authors. The prevalence of PAph ranged from 23 to 51%, while the prevalence of LLph varied from 15 to 41%. Interestingly, the prevalence of renal conditions remained consistent at around 30% across the different author's cut-off values (Tables 3, 4).

同样，根据抗高血压药物治疗方案和作者，LRH的患病率也没有显着差异。PAph的患病率为23%至51%，而LLph的患病率为15%至41%。有趣的是，在不同作者的临界值中，肾脏疾病的患病率保持在30%左右（表3,4）。

The linear multivariate regression analysis showed that sodium consumption had a statistically significant effect in the PRC, the Model but not with the ADRR (Table 5, Fig. 1) (Supplementary material: Figures 1–3)..

线性多元回归分析表明，钠的消耗量在中华人民共和国具有统计学意义上的显着影响，该模型但与ADRR无关（表5，图1）（补充材料：图1-3）。。

Table 2 Distribution of suspected patients by reported ADRR cutoff ratio for screening in the diagnosis of primary hyperaldosteronism.Full size tableTable 3 Distribution of suspected patients by reported plasma renin concentration cutoff ratio for screening in the diagnosis of low renin hypertension.Full size tableTable 4 Distribution of hypertension phenotypes, according to Akintunde et al.12.Full size tableTable 5 Linear regression aldosterone-renin ratio, renin, and aldosterone levels and sodium consumption calculated by Kawasaki formula BMI and age.Full size tableFigure 1Correlation between renin and aldosterone secretion and sodium consumption measured by the Kawasaki formula.Full size imageDiscussionIn this study, we investigated physiologically induced phenotypes associated with apparent treatment-resistant arterial hypertension in 88 Afro-descendant patients hailing from a community in the northern region of the Cauca department within the Pacific region of Colombia.

表2根据报告的ADRR截止比对疑似患者的分布进行筛查，以诊断原发性醛固酮增多症。全尺寸表表3通过报告的血浆肾素浓度截止比对疑似患者的分布进行筛查，以诊断低肾素高血压。全尺寸表4根据Akintunde等人的研究，高血压表型的分布。全尺寸表5线性回归醛固酮-肾素比率，肾素和醛固酮水平以及通过川崎公式BMI和年龄计算的钠消耗量。全尺寸表图1川崎公式测得的肾素和醛固酮分泌与钠消耗之间的相关性。全尺寸图像讨论在这项研究中，我们调查了来自哥伦比亚太平洋地区高加索地区北部社区的88名非洲裔患者的生理诱导表型与明显的难治性动脉高血压相关。

Observed low treatment adherence (38%) may reflect PSH or white coat hypertension (WCH)3. This observation aligns with documented challenges in enhancing adherence in TRH management, debates over its prevalence, and the emerging value of therapeutic drug monitoring in adherence assessment21. Furthermore, our findings indicate non-adherence to non-pharmacological interventions, particularly high sodium intake, which may attenuate the nephroprotective effects of ACEi14,22.

观察到的低治疗依从性（38%）可能反映了PSH或白大衣高血压（WCH）3。这一观察结果与提高TRH管理依从性方面的记录挑战，关于其流行率的辩论以及治疗药物监测在依从性评估中的新兴价值相一致21。此外，我们的研究结果表明不坚持非药物干预，特别是高钠摄入，这可能会减弱ACEi14,22的肾保护作用。

The diverse prevalence of altered ADRR among multiple authors cut-off is problematic for early diagnosis and medical or surgical therapy of PA4. The priority must be to detect and diagnose first specific causes of secondary hypertension and then think about the phenotype in specific populations where these causes can be ruled out4,1.

多个作者之间ADRR改变的不同患病率对于PA4的早期诊断和医学或外科治疗是有问题的。首先必须检测和诊断继发性高血压的第一个特定原因，然后考虑可以排除这些原因的特定人群的表型4,1。

Data availability

数据可用性

The datasets generated and/or analyzed during the current study are not publicly available due to their sensitive nature, containing confidential information but are available from the corresponding author on reasonable request.

在当前研究期间生成和/或分析的数据集由于其敏感性质而不公开，其中包含机密信息，但可根据合理要求从通讯作者处获得。

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Download referencesFundingThis project is/was funded through a general research grant from Tecnoquimicas S.A to Centro de Investigaciones Clínicas at Fundación Valle del Lili. The results and conclusions are those by the authors and do not necessarily represent the view of either institution.Author informationAuthors and AffiliationsServicio de Nefrología, Fundación Valle del Lili, Carrera 98 No.18-49, 760032, Cali, ColombiaC.

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E. Durán, J. Schweineberg, L. Mesa & J. G. PosadaCentro de Investigaciones Clínicas (CIC), Fundación Valle del Lili, Carrera 98 No.18-49, Valle del Cauca, 760032, Cali, ColombiaM. Barbosa, E. M. Useche, J. Triviño, L. Sandoval, P. A. Moncayo & A. M. RivasFacultad de Ciencias de la Salud, Universidad Icesi, Calle 18 # 122-135, Cali, ColombiaC.

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Reprints and permissionsAbout this articleCite this articleDurán, C.E., Bustamante, M., Barbosa, M. et al. Evaluation of aldosterone to direct renin ratio, low renin and related Phenotypes in Afro-Colombian patients with apparent treatment resistant hypertension.

转载和许可本文引用本文Durán，C.E.，Bustamante，M.，Barbosa，M。等人对患有明显难治性高血压的非洲裔哥伦比亚患者的醛固酮与直接肾素比率，低肾素和相关表型的评估。

Sci Rep 14, 18091 (2024). https://doi.org/10.1038/s41598-024-67261-wDownload citationReceived: 14 December 2023Accepted: 09 July 2024Published: 05 August 2024DOI: https://doi.org/10.1038/s41598-024-67261-wShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 1418091（2024）。https://doi.org/10.1038/s41598-024-67261-wDownload引文接收日期：2023年12月14日接收日期：2024年7月9日发布日期：2024年8月5日OI：https://doi.org/10.1038/s41598-024-67261-wShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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KeywordsENaCAfro-AmericanResistant hypertensionLow renin hypertensionAmiloride

关键词非裔美国人难治性高血压低肾素性高血压阿米洛利

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