Original Article
Decreased plasma prorenin levels in primary aldosteronism: potential diagnostic implications Constance Berge a,, Pierre-Yves Courand a,b,c,, Brahim Harbaoui a, Vinciane Paget d, Fouad Khettab a, Giampiero Bricca b,c, Jean-Pierre Fauvel b,c,e, and Pierre Lantelme a,b,c,d
Aim: Primary aldosteronism could exert a negative feedback on prorenin secretion, of possibly different magnitude, whether it is related to an aldosteroneproducing adenoma (APA) or an idiopathic hyperaldosteronism (IHA). The objectives of this study were to evaluate the level of prorenin in three subgroups: APA, IHA, and essential hypertension; and the performance of the aldosterone-to-prorenin ratio (APR) for the diagnosis of an APA. Methods: Seven hundred and forty-six hypertensive patients with a standardized work-up, including a prorenin measurement, were considered. Ninety-six patients without neutral treatment and 38 patients with other forms of secondary hypertension were excluded. APA and IHA were categorized according to computed tomography scan, adrenal venous sampling, pathological analysis and improvement of hypertension after surgery. Results: Thirty-five patients had a diagnosis of APA, 57 of IHA and 504 of essential hypertension. Prorenin was lower in APA and IHA than in essential hypertension (32.9, 40.4 and 50.3 pg/ml, respectively; P < 0.001). APR was higher in patients with APA and IHA than in those with essential hypertension (24.0, 11.8, and 4.0 pmol/l per pg/ml, respectively; P < 0.001). The APR was more discriminant than the aldosterone-to-renin ratio to identify APA compared to IHA (area under the receiver operating curve at 0.750 and 0.639, respectively; P ¼ 0.04). The optimal cut-off values were 22 pmol/l per pg/ml for APR (sensitivity 57.0%, specificity 93.0%) and 440 pmol/l per pg/ml for aldosterone-to-renin ratio (sensitivity 54.3%, specificity 82.5%). Conclusion: Primary aldosteronism and particularly its most caricatural form, that is APA, seems associated with a lower level of prorenin than essential hypertension. The APR could be included in the diagnostic strategy of APA. Keywords: aldosterone, aldosterone-producing adenoma, primary aldosteronism, prorenin Abbreviations: APA, aldosterone-producing adenoma; APR, aldosterone-to-prorenin ratio; ARR, aldosterone-torenin ratio; AUC, area under receiver-operating characteristic curve; AVS, adrenal vein sampling; CAD, coronary artery disease; CT, computed tomography; GRA, glucocorticoid remediable aldosteronism; IHA, idiopathic hyperaldosteronism; PAD, peripheral artery disease; PRA,
plasma renin activity; PWV, pulse wave velocity; RAS, renal artery stenosis; RaVL, R amplitude of R wave in aVL lead; ROC, receiver-operating characteristic
INTRODUCTION
P
rimary aldosteronism is one of the most frequent causes of secondary hypertension. In tertiary hypertension center, the prevalence of primary aldosteronism currently ranges from 10 to 20% [1]. Therapeutic options to control patients with primary aldosteronism include spironolactone and surgery depending on the subtype of primary aldosteronism, that is, aldosteroneproducing adenoma (APA) or idiopathic hyperaldosteronism (IHA). In the clinical setting, identifying these two subtypes is often difficult and selecting patients for surgery usually requires a set of criteria [2]. Primary aldosteronism is defined as a primary excess of aldosterone leading to a down-regulation of renin. Thus, the diagnosis is based on an increased plasma aldosterone associated with low renin levels. A major limitation of renin measurement is its variability [3], making the diagnosis often difficult and unreliable. Interestingly, renin is derived from an inactive precursor, prorenin, which is constitutively released from the kidney. Prorenin is activated by two classical processes: irreversible proteolytic activation to mature renin, characterized by the removal of the prosegment; and reversible nonproteolytic activation to gain ‘renin activity’ as a result of prosegment unfolding resulting from
Journal of Hypertension 2015, 33:118–125 a
Cardiology Department, European Society of Hypertension Excellence Center, Hoˆpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, bGe´nomique Fonctionnelle de l’Hypertension arte´rielle, EA 4173, Universite´ Claude Bernard Lyon1, Villeurbanne, c Hoˆpital Nord-Ouest, Villefranche sur saoˆne, dCardiology Department, Hoˆpital NordOuest, Villefranche sur saoˆne and eNephrology and Hypertension Department, Hoˆpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France Correspondence to Pierre-Yves Courand, Cardiology Department, Hoˆpital de la CroixRousse, 103 Grande Rue de la Croix-Rousse, F-69004 Lyon, France. Tel: +33 472 071 667; fax: +33 472 071 674; e-mail: [email protected]
Constance Berge and Pierre-Yves Courand contributed equally to the writing of this article. Received 11 May 2014 Revised 30 July 2014 Accepted 30 July 2014 J Hypertens 33:118–125 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000367
118
www.jhypertension.com
Volume 33 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Prorenin and aldosterone-producing adenoma
a conformational change [4]. Elevated levels of prorenin relative to renin have been reported in diabetic patients with microvascular diseases [5–7]. In primary aldosteronism, the chronic excess of aldosterone may exert a negative feedback on prorenin as it does on renin; in addition, since aldosterone levels are usually higher in APA than in IHA, prorenin levels may be more intensely suppressed in APA. Thus, the aim of the present study was to evaluate the level of prorenin according to the cause of hypertension (APA, IHA, and essential) and to test its diagnostic significance for categorizing different forms of primary aldosteronism.
METHODS Participants A prospective cohort of 746 consecutive patients was completed from April 1999 to December 2012. Patients were referred to our center for evaluation and treatment of hypertension; they also had a plasma prorenin measurement (same venous sampling used for plasma renin). Among these patients, 650 had an antihypertensive treatment compatible with hormonal measurements, that is, a neutral treatment including only alpha-blockers, centrally acting drugs, or calcium antagonists according to current guidelines [8]. If needed prior to this work-up, spironolactone was withdrawn for at least 6 weeks, and diuretics, beta-blockers, or renin–angiotensin system inhibitors for 2 weeks. The study was approved by the local review board. In accordance with the current French legislation, an observational study that does not change routine management of patient does not need to be submitted to the opinion of a research ethics board.
Protocol Over a 2-day hospital stay, all the participants filled out a questionnaire (morphometric characteristics, cardiovascular risk factors, symptoms, etc.), underwent a physical examination, and had various biological tests as well as a 24-h blood pressure (BP) recording, a 12-lead ECG and a pulse wave velocity assessment. Plasma renin activity (PRA) was assessed after one night in supine position (around 8 h) using a commercial immunoradiometric kit (Renin III generation; Cisbio, France). Values below the detection limit of the assay (
Decreased plasma prorenin levels in primary aldosteronism: potential diagnostic implications Constance Berge a,, Pierre-Yves Courand a,b,c,, Brahim Harbaoui a, Vinciane Paget d, Fouad Khettab a, Giampiero Bricca b,c, Jean-Pierre Fauvel b,c,e, and Pierre Lantelme a,b,c,d
Aim: Primary aldosteronism could exert a negative feedback on prorenin secretion, of possibly different magnitude, whether it is related to an aldosteroneproducing adenoma (APA) or an idiopathic hyperaldosteronism (IHA). The objectives of this study were to evaluate the level of prorenin in three subgroups: APA, IHA, and essential hypertension; and the performance of the aldosterone-to-prorenin ratio (APR) for the diagnosis of an APA. Methods: Seven hundred and forty-six hypertensive patients with a standardized work-up, including a prorenin measurement, were considered. Ninety-six patients without neutral treatment and 38 patients with other forms of secondary hypertension were excluded. APA and IHA were categorized according to computed tomography scan, adrenal venous sampling, pathological analysis and improvement of hypertension after surgery. Results: Thirty-five patients had a diagnosis of APA, 57 of IHA and 504 of essential hypertension. Prorenin was lower in APA and IHA than in essential hypertension (32.9, 40.4 and 50.3 pg/ml, respectively; P < 0.001). APR was higher in patients with APA and IHA than in those with essential hypertension (24.0, 11.8, and 4.0 pmol/l per pg/ml, respectively; P < 0.001). The APR was more discriminant than the aldosterone-to-renin ratio to identify APA compared to IHA (area under the receiver operating curve at 0.750 and 0.639, respectively; P ¼ 0.04). The optimal cut-off values were 22 pmol/l per pg/ml for APR (sensitivity 57.0%, specificity 93.0%) and 440 pmol/l per pg/ml for aldosterone-to-renin ratio (sensitivity 54.3%, specificity 82.5%). Conclusion: Primary aldosteronism and particularly its most caricatural form, that is APA, seems associated with a lower level of prorenin than essential hypertension. The APR could be included in the diagnostic strategy of APA. Keywords: aldosterone, aldosterone-producing adenoma, primary aldosteronism, prorenin Abbreviations: APA, aldosterone-producing adenoma; APR, aldosterone-to-prorenin ratio; ARR, aldosterone-torenin ratio; AUC, area under receiver-operating characteristic curve; AVS, adrenal vein sampling; CAD, coronary artery disease; CT, computed tomography; GRA, glucocorticoid remediable aldosteronism; IHA, idiopathic hyperaldosteronism; PAD, peripheral artery disease; PRA,
plasma renin activity; PWV, pulse wave velocity; RAS, renal artery stenosis; RaVL, R amplitude of R wave in aVL lead; ROC, receiver-operating characteristic
INTRODUCTION
P
rimary aldosteronism is one of the most frequent causes of secondary hypertension. In tertiary hypertension center, the prevalence of primary aldosteronism currently ranges from 10 to 20% [1]. Therapeutic options to control patients with primary aldosteronism include spironolactone and surgery depending on the subtype of primary aldosteronism, that is, aldosteroneproducing adenoma (APA) or idiopathic hyperaldosteronism (IHA). In the clinical setting, identifying these two subtypes is often difficult and selecting patients for surgery usually requires a set of criteria [2]. Primary aldosteronism is defined as a primary excess of aldosterone leading to a down-regulation of renin. Thus, the diagnosis is based on an increased plasma aldosterone associated with low renin levels. A major limitation of renin measurement is its variability [3], making the diagnosis often difficult and unreliable. Interestingly, renin is derived from an inactive precursor, prorenin, which is constitutively released from the kidney. Prorenin is activated by two classical processes: irreversible proteolytic activation to mature renin, characterized by the removal of the prosegment; and reversible nonproteolytic activation to gain ‘renin activity’ as a result of prosegment unfolding resulting from
Journal of Hypertension 2015, 33:118–125 a
Cardiology Department, European Society of Hypertension Excellence Center, Hoˆpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, bGe´nomique Fonctionnelle de l’Hypertension arte´rielle, EA 4173, Universite´ Claude Bernard Lyon1, Villeurbanne, c Hoˆpital Nord-Ouest, Villefranche sur saoˆne, dCardiology Department, Hoˆpital NordOuest, Villefranche sur saoˆne and eNephrology and Hypertension Department, Hoˆpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France Correspondence to Pierre-Yves Courand, Cardiology Department, Hoˆpital de la CroixRousse, 103 Grande Rue de la Croix-Rousse, F-69004 Lyon, France. Tel: +33 472 071 667; fax: +33 472 071 674; e-mail: [email protected]
Constance Berge and Pierre-Yves Courand contributed equally to the writing of this article. Received 11 May 2014 Revised 30 July 2014 Accepted 30 July 2014 J Hypertens 33:118–125 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000367
118
www.jhypertension.com
Volume 33 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Prorenin and aldosterone-producing adenoma
a conformational change [4]. Elevated levels of prorenin relative to renin have been reported in diabetic patients with microvascular diseases [5–7]. In primary aldosteronism, the chronic excess of aldosterone may exert a negative feedback on prorenin as it does on renin; in addition, since aldosterone levels are usually higher in APA than in IHA, prorenin levels may be more intensely suppressed in APA. Thus, the aim of the present study was to evaluate the level of prorenin according to the cause of hypertension (APA, IHA, and essential) and to test its diagnostic significance for categorizing different forms of primary aldosteronism.
METHODS Participants A prospective cohort of 746 consecutive patients was completed from April 1999 to December 2012. Patients were referred to our center for evaluation and treatment of hypertension; they also had a plasma prorenin measurement (same venous sampling used for plasma renin). Among these patients, 650 had an antihypertensive treatment compatible with hormonal measurements, that is, a neutral treatment including only alpha-blockers, centrally acting drugs, or calcium antagonists according to current guidelines [8]. If needed prior to this work-up, spironolactone was withdrawn for at least 6 weeks, and diuretics, beta-blockers, or renin–angiotensin system inhibitors for 2 weeks. The study was approved by the local review board. In accordance with the current French legislation, an observational study that does not change routine management of patient does not need to be submitted to the opinion of a research ethics board.
Protocol Over a 2-day hospital stay, all the participants filled out a questionnaire (morphometric characteristics, cardiovascular risk factors, symptoms, etc.), underwent a physical examination, and had various biological tests as well as a 24-h blood pressure (BP) recording, a 12-lead ECG and a pulse wave velocity assessment. Plasma renin activity (PRA) was assessed after one night in supine position (around 8 h) using a commercial immunoradiometric kit (Renin III generation; Cisbio, France). Values below the detection limit of the assay (
